FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Singh, H Nikiforow, S Li, SL Ballen, KK Spitzer, TR Soiffer, R Antin, JH Cutler, C Chen, YB AF Singh, Harshabad Nikiforow, Sarah Li, Shuli Ballen, Karen K. Spitzer, Thomas R. Soiffer, Robert Antin, Joseph H. Cutler, Corey Chen, Yi-Bin TI Outcomes and management strategies for graft failure after umbilical cord blood transplantation SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; PERIPHERAL-BLOOD; SALVAGE THERAPY AB Graft failure is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). Graft failure is more prevalent after umbilical cord blood transplantation (UCBT) compared with conventional adult stem cell sources. We identified 21 consecutive patients who experienced graft failure after UCBT at our center between 2004 and 2013 and describe their treatment strategies and outcomes. Two patients experienced early death. Seven patients had return of autologous hematopoiesis including 1 patient who was given previously collected autologous stem cells. Twelve patients received a second early HSCT, six from separate UCB units and six from a haploidentical donor. With a median follow-up of 33.2 months for surviving patients, 3-year PFS is 23% and 3-year OS is 37%. Of the six long-term survivors without relapse, four received a second HSCT from a haploidentical donor with post-HSCT high-dose cyclophosphamide based GVHD prophylaxis. This strategy appears safe and merits further investigation in this setting. Am. J. Hematol. 89:1097-1101, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Singh, Harshabad] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Nikiforow, Sarah; Soiffer, Robert; Antin, Joseph H.; Cutler, Corey] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Li, Shuli] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Ballen, Karen K.; Spitzer, Thomas R.; Chen, Yi-Bin] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. RP Chen, YB (reprint author), Massachusetts Gen Hosp, Bone Marrow Transplant Unit, Cox 108,55 Fruit St, Boston, MA 02114 USA. EM ychen6@partners.org NR 16 TC 0 Z9 0 U1 1 U2 5 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 DEC PY 2014 VL 89 IS 12 BP 1097 EP 1101 DI 10.1002/ajh.23845 PG 5 WC Hematology SC Hematology GA AU1CK UT WOS:000345358600008 PM 25195500 ER PT J AU Archer, NM Shmukler, BE Andolfo, I Vandorpe, DH Gnanasambandam, R Higgins, JM Rivera, A Fleming, MD Sachs, F Gottlieb, PA Iolascon, A Brugnara, C Alper, SL Nathan, DG AF Archer, Natasha M. Shmukler, Boris E. Andolfo, Immacolata Vandorpe, David H. Gnanasambandam, Radhakrishnan Higgins, John M. Rivera, Alicia Fleming, Mark D. Sachs, Frederick Gottlieb, Philip A. Iolascon, Achille Brugnara, Carlo Alper, Seth L. Nathan, David G. TI Hereditary xerocytosis revisited SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID RED-BLOOD-CELL; CHANNEL PIEZO1; HEMOLYTIC-ANEMIA; IRON OVERLOAD; HEMOCHROMATOSIS; ASSOCIATION; MUTATIONS; ERYTHROPOIESIS; STOMATOCYTOSIS; SPHEROCYTOSIS C1 [Archer, Natasha M.; Nathan, David G.] Boston Childrens Hosp, Div Hematol & Oncol, Boston, MA USA. [Archer, Natasha M.; Nathan, David G.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Shmukler, Boris E.; Vandorpe, David H.; Alper, Seth L.] Beth Israel Deaconess Med Ctr, Renal Div, Boston, MA 02215 USA. [Shmukler, Boris E.; Vandorpe, David H.; Alper, Seth L.] Beth Israel Deaconess Med Ctr, Mol & Vasc Med Div, Boston, MA 02215 USA. [Andolfo, Immacolata; Iolascon, Achille] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy. [Andolfo, Immacolata; Iolascon, Achille] CEINGE, Naples, Italy. [Gnanasambandam, Radhakrishnan; Sachs, Frederick; Gottlieb, Philip A.] SUNY Buffalo, Dept Physiol & Biophys, Buffalo, NY 14260 USA. [Higgins, John M.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Higgins, John M.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Higgins, John M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Rivera, Alicia; Brugnara, Carlo] Boston Childrens Hosp, Dept Lab Med, Boston, MA USA. [Rivera, Alicia; Fleming, Mark D.; Brugnara, Carlo] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Alper, Seth L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Nathan, David G.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Nathan, DG (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM salper@bidmc.harvard.edu; david_nathan@dfci.harvard.edu RI Andolfo, Immacolata/K-7381-2016 OI Gottlieb, Philip/0000-0003-3764-9885; Andolfo, Immacolata/0000-0003-0493-812X FU NIH [T32HL007574, R01HL054887, R34HL108757]; MIUR and Telethon (Italy) [GGP09044]; Doris Duke Charitable Foundation [2013010, 2011094] FX Contract grant sponsor: NIH; Contract grant numbers: T32HL007574; R01HL054887; R34HL108757.; Contract grant sponsor: MIUR and Telethon (Italy); Contract grant number: GGP09044.; Contract grant sponsor: Doris Duke Charitable Foundation; Contract grant numbers: 2013010; 2011094. NR 26 TC 6 Z9 6 U1 0 U2 8 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 DEC PY 2014 VL 89 IS 12 BP 1142 EP 1146 DI 10.1002/ajh.23799 PG 5 WC Hematology SC Hematology GA AU1CK UT WOS:000345358600016 PM 25044010 ER PT J AU Kadauke, S Khor, B Van Cott, EM AF Kadauke, Stephan Khor, Bernard Van Cott, Elizabeth M. TI Activated protein C resistance testing for factor V Leiden SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID VIPER VENOM TIME; APC-RESISTANCE; COAGULATION ASSAYS; DEFICIENT PLASMA; MYOCARDIAL-INFARCTION; LABORATORY EVALUATION; LUPUS ANTICOAGULANTS; THROMBOSIS; MUTATION; RISK AB Activated protein C resistance assays can detect factor V Leiden with high accuracy, depending on the method used. Factor Xa inhibitors such as rivaroxaban and direct thrombin inhibitors including dabigatran, argatroban, and bivalirudin can cause falsely normal results. Lupus anticoagulants can cause incorrect results in most current assays. Assays that include dilution into factor V-deficient plasma are needed to avoid interference from factor deficiencies or elevations, which can arise from a wide variety of conditions such as warfarin, liver dysfunction, or pregnancy. The pros and cons of the currently available assays are discussed. Am. J. Hematol. 89:1147-1150, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Kadauke, Stephan; Khor, Bernard; Van Cott, Elizabeth M.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Van Cott, EM (reprint author), GRJ235,55 Fruit St, Boston, MA 02114 USA. OI Khor, Bernard/0000-0003-4689-5092 NR 39 TC 7 Z9 7 U1 2 U2 3 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 DEC PY 2014 VL 89 IS 12 BP 1147 EP 1150 DI 10.1002/ajh.23867 PG 4 WC Hematology SC Hematology GA AU1CK UT WOS:000345358600017 PM 25293789 ER PT J AU Kuter, DJ Meibohm, A Lopez, A AF Kuter, David J. Meibohm, Anne Lopez, Angela TI TPO concentrations and response to romiplostim SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter C1 [Kuter, David J.] Massachusetts Gen Hosp, Dept Hematol, Boston, MA 02114 USA. [Meibohm, Anne; Lopez, Angela] Amgen Inc, Dept Biostat, Thousand Oaks, CA 91320 USA. RP Kuter, DJ (reprint author), Massachusetts Gen Hosp, Dept Hematol, Yawkey 7940, Boston, MA 02114 USA. EM DKUTER@PARTNERS.ORG NR 2 TC 0 Z9 0 U1 1 U2 3 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 DEC PY 2014 VL 89 IS 12 BP 1155 EP 1156 DI 10.1002/ajh.23818 PG 2 WC Hematology SC Hematology GA AU1CK UT WOS:000345358600022 PM 25132329 ER PT J AU Beltran, BE Maza, I Moises-Alfaro, CB Vasquez, L Quinones, P Morales, D Sanchez, G Paredes, G Oscanoa, M Geronimo, J Miranda, RN Castillo, JJ AF Beltran, Brady E. Maza, Ivan Moises-Alfaro, Celia B. Vasquez, Liliana Quinones, Pilar Morales, Domingo Sanchez, Gadwin Paredes, Gloria Oscanoa, Monica Geronimo, Jenny Miranda, Roberto N. Castillo, Jorge J. TI Thalidomide for the treatment of hydroa vacciniforme-like lymphoma: Report of four pediatric cases from Peru SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter ID T-CELL LYMPHOMA; CHILDHOOD C1 [Beltran, Brady E.; Maza, Ivan; Vasquez, Liliana; Paredes, Gloria; Oscanoa, Monica; Geronimo, Jenny] Hosp Nacl Edgardo Rebagliati Martins, Dept Radiotherapy & Oncol, Lima, Peru. [Moises-Alfaro, Celia B.; Sanchez, Gadwin] Hosp Nacl Edgardo Rebagliati Martins, Dermatol Serv, Lima, Peru. [Quinones, Pilar; Morales, Domingo] Hosp Nacl Edgardo Rebagliati Martins, Dept Pathol, Lima, Peru. [Miranda, Roberto N.] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 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 Maza, Ivan/0000-0001-7281-9259; Beltran, Brady/0000-0003-4469-3817; Castillo, Jorge/0000-0001-9490-7532 NR 8 TC 2 Z9 2 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 DEC PY 2014 VL 89 IS 12 BP 1160 EP 1161 DI 10.1002/ajh.23843 PG 2 WC Hematology SC Hematology GA AU1CK UT WOS:000345358600027 PM 25196949 ER PT J AU Branch-Elliman, W Strymish, J Itani, KMF Gupta, K AF Branch-Elliman, Westyn Strymish, Judith Itani, Kamal M. F. Gupta, Kalpana TI Using clinical variables to guide surgical site infection detection: A novel surveillance strategy SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article DE Post-operative care; Quality improvement; Electronic tool ID CARE-ASSOCIATED INFECTIONS; HOSPITAL DISCHARGE; HEALTH; IMPROVEMENT; RATIONALE; IMPACT; COSTS AB Background: Surgical site infections (SSIs) are a common and expensive health care-associated infection, and are used as a health care quality benchmark. As such, SSI detection is a major focus of infection prevention programs. In an effort to improve on conventional surveillance methods, a simple algorithm for SSI detection was developed using clinical variables not traditionally included in National Healthcare Safety Network definitions. Methods: A case-control study was conducted among surgeries performed at the Veterans Affairs Boston Healthcare System between January 2008 and December 2009. SSI cases were matched to controls without SSI. Clinical variables (administrative, microbiological, pharmacy, radiology) were compared between the groups to determine those that best identified SSI. Results: A total of 70 SSIs were matched to 70 controls. On multivariable analysis, variables significantly associated with SSI identification were wound culture order, computed tomography scan/magnetic resonance imaging order, antibiotic order within 30 days after surgery, and application of a relevant International Classification of Disease, Ninth Revision code. Among patients with no SSI identifiers, 98% were correctly classified as having no SSI. Among patients with multiple SSI identifiers, 97.1% were correctly identified as having SSI. The area under the curve for this model was 0.87. Conclusion: We have derived a novel surveillance algorithm for SSI detection with excellent operating characteristics. This algorithm could be automated to streamline infection control efforts. Published by Elsevier Inc. on behalf of the Association for Professionals in Infection Control and Epidemiology, Inc. C1 [Branch-Elliman, Westyn; Strymish, Judith; Gupta, Kalpana] Boston VA Healthcare Syst, Dept Med, Boston, MA USA. [Branch-Elliman, Westyn] Beth Israel Deaconess Med Ctr, Dept Healthcare Qual, Div Infect Control, Boston, MA 02215 USA. [Branch-Elliman, Westyn; Strymish, Judith; Itani, Kamal M. F.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Itani, Kamal M. F.] Boston VA Healthcare Syst, Dept Surg, Boston, MA USA. [Itani, Kamal M. F.] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. [Gupta, Kalpana] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP Branch-Elliman, W (reprint author), 1055 Clermont St,Mailstop 111L, Denver, CO 80220 USA. EM westyn.branch-elliman@ucdenver.edu NR 25 TC 1 Z9 1 U1 0 U2 8 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 DEC PY 2014 VL 42 IS 12 BP 1291 EP 1295 DI 10.1016/j.ajic.2014.08.013 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AU4JY UT WOS:000345578200009 PM 25465259 ER PT J AU Caroff, DA Norris, AH Keller, S Vinnard, C Zeitler, KE Lukaszewicz, J Zborowski, KA Linkin, DR AF Caroff, Daniel A. Norris, Anne H. Keller, Sara Vinnard, Christopher Zeitler, Kristen E. Lukaszewicz, Jennifer Zborowski, Kristine A. Linkin, Darren R. CA CDC Prevent Epictr Program TI Catheter salvage in home infusion patients with central line-associated bloodstream infection SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article DE Central line-associated bloodstream infection; Home infusion; Central line; Catheter salvage ID GUIDELINES; SOCIETY AB In a retrospective study of home infusion patients with central line-associated bloodstream infection, use of a central venous port, cancer diagnosis, and absence of systemic inflammatory response syndrome were associated with use of catheter salvage. Relapse of infection was uncommon. Copyright (C) 2014 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. C1 [Caroff, Daniel A.] Harvard Univ, Brigham & Womens Hosp, Massachusetts Gen Hosp, Sch Med,Dept Med,Div Infect Dis, Boston, MA 02115 USA. [Norris, Anne H.; Linkin, Darren R.] Univ Penn, Perelman Sch Med, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Keller, Sara] Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. [Vinnard, Christopher] Drexel Univ, Coll Med, Dept Med, Philadelphia, PA 19104 USA. [Zeitler, Kristen E.] Tampa Gen Hosp, Dept Pharm, Tampa, FL 33606 USA. [Lukaszewicz, Jennifer] Univ Penn, Dept Pharm, Philadelphia, PA 19104 USA. [Zborowski, Kristine A.] Penn Home Infus Therapy, Penn Home Care & Hospice Serv, King Of Prussia, PA USA. [Linkin, Darren R.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Caroff, DA (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St,GRJ 504, Boston, MA 02114 USA. EM dcaroff@mgh.harvard.edu OI Caroff, Daniel/0000-0002-9598-2232 FU National Institutes of Health [K23AI102639]; Agency for Healthcare Research and Quality [GIM 400-4239-4-555854-XXXX-2446-2192]; Centers for Disease Control and Prevention Epicenters Program [U54 CK000163] FX This work was supported by the National Institutes of Health (grant no. K23AI102639 to C. V.), Agency for Healthcare Research and Quality (grant no. GIM 400-4239-4-555854-XXXX-2446-2192 to S. K.), and in part by the Centers for Disease Control and Prevention Epicenters Program (grant no. U54 CK000163 to Ebbing Lautenbach). NR 8 TC 0 Z9 0 U1 0 U2 1 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 DEC PY 2014 VL 42 IS 12 BP 1331 EP 1333 DI 10.1016/j.ajic.2014.08.015 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AU4JY UT WOS:000345578200019 PM 25465266 ER PT J AU Byrne-Dugan, CJ Collins, AB Lam, AQ Batal, I AF Byrne-Dugan, Cathryn J. Collins, A. Bernard Lam, Albert Q. Batal, Ibrahim TI Membranous Nephropathy as a Manifestation of Graft-Versus-Host Disease: Association With HLA Antigen Typing, Phospholipase A(2) Receptor, and C4d SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Membranous nephropathy; glomerulonephritis; membranous; hematopoietic stem cell transplantation; receptor; phospholipase A(2) (PLA(2)R); graft-vs-host disease; complement C4d; HLA serological subtypes ID STEM-CELL TRANSPLANTATION; DE-NOVO; NEPHROTIC SYNDROME; T-CELLS; KIDNEY; GLOMERULONEPHRITIS; GLOMERULOPATHY; PATHOGENESIS; PREDNISONE; SURVIVORS AB Glomerulopathy is an uncommon but increasingly recognized complication of hematopoietic cell transplantation. It typically manifests as membranous nephropathy, less commonly as minimal change disease, and rarely as proliferative glomerulonephritis. There is evidence to suggest that these glomerulopathies might represent manifestations of chronic graft-versus-host disease. In this report, we focus on membranous nephropathy as the most common form of glomerulopathy after hematopoietic cell transplantation. We present a case of membranous nephropathy that developed 483 days post-allogeneic hematopoietic stem cell transplantation in a patient with a history of acute graft-versus-host disease. We also share our experience with 4 other cases of membranous nephropathy occurring after allogeneic hematopoietic stem cell transplantation. Clinicopathologic correlates, including the association with graft-versus-host-disease, HLA antigen typing, glomerular deposition of immunoglobulin G (IgG) subclasses, subepithelial colocalization of IgG deposits with phospholipase A(2) receptor staining, C4d deposition along the peritubular capillaries, and treatment, are discussed with references to the literature. (C) 2014 by the National Kidney Foundation, Inc. C1 [Byrne-Dugan, Cathryn J.; Batal, Ibrahim] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Byrne-Dugan, Cathryn J.; Collins, A. Bernard; Lam, Albert Q.; Batal, Ibrahim] Harvard Univ, Sch Med, Boston, MA USA. [Collins, A. Bernard] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Lam, Albert Q.] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. RP Batal, I (reprint author), Columbia Univ, Dept Pathol & Cellular Biol, 630 W 168th St, New York, NY 10032 USA. EM ib2349@cumc.columbia.edu NR 31 TC 4 Z9 4 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 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD DEC PY 2014 VL 64 IS 6 BP 987 EP 993 DI 10.1053/j.ajkd.2014.09.001 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AU1TZ UT WOS:000345404200020 PM 25304985 ER PT J AU Plotkin, SR Albers, AC Babovic-Vuksanovic, D Blakeley, JO Breakefield, XO Dunn, CM Evans, DG Fisher, MJ Friedman, JM Giovannini, M Gutmann, DH Kalamarides, M McClatchey, AI Messiaen, L Morrison, H Parkinson, DB Stemmer-Rachamimov, AO Van Raamsdonk, CD Riccardi, VM Rosser, T Schindeler, A Smith, MJ Stevenson, DA Ullrich, NJ van der Vaart, T Weiss, B Widemann, BC Zhu, Y Bakker, AC Lloyd, AC AF Plotkin, Scott R. Albers, Anne C. Babovic-Vuksanovic, Dusica Blakeley, Jaishri O. Breakefield, Xandra O. Dunn, Courtney M. Evans, D. Gareth Fisher, Michael J. Friedman, Jan M. Giovannini, Marco Gutmann, David H. Kalamarides, Michel McClatchey, Andrea I. Messiaen, Ludwine Morrison, Helen Parkinson, David B. Stemmer-Rachamimov, Anat O. Van Raamsdonk, Catherine D. Riccardi, Vincent M. Rosser, Tena Schindeler, Aaron Smith, Miriam J. Stevenson, David A. Ullrich, Nicole J. van der Vaart, Thijs Weiss, Brian Widemann, Brigitte C. Zhu, Yuan Bakker, Annette C. Lloyd, Alison C. TI Update from the 2013 International Neurofibromatosis Conference SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE NF1; NF2; SMARCB1; neurofibromatosis 1; neurofibromatosis 2; schwannomatosis; tumor suppressor; merlin; neurofibromin; preclinical models ID VESTIBULAR-SCHWANNOMA; MUSCLE DEVELOPMENT; CONTROLLED-TRIAL; SKELETAL-MUSCLE; NORTH-WEST; TYPE-1; NF1; MENINGIOMAS; POPULATION; CHILDREN C1 [Plotkin, Scott R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Albers, Anne C.; Dunn, Courtney M.; Gutmann, David H.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Babovic-Vuksanovic, Dusica] Mayo Clin, Dept Med Genet, Rochester, MN USA. [Blakeley, Jaishri O.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Breakefield, Xandra O.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosci Ctr,Ctr Mol Imaging, Boston, MA USA. [Evans, D. Gareth; Smith, Miriam J.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Ctr Genom Med, St Marys Hosp, Manchester, Lancs, England. [Fisher, Michael J.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Friedman, Jan M.; Van Raamsdonk, Catherine D.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Giovannini, Marco] House Res Inst, Ctr Neural Tumor Res, Los Angeles, CA USA. [Kalamarides, Michel] Hop La Pitie Salpetriere, Dept Neurosurg, Paris, France. [McClatchey, Andrea I.; Stemmer-Rachamimov, Anat O.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Messiaen, Ludwine] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [Morrison, Helen] Leibniz Inst Age Res, Jena, Germany. [Parkinson, David B.] Univ Plymouth, Peninsula Coll Med & Dent, Ctr Biomed Res, Plymouth PL4 8AA, Devon, England. [Riccardi, Vincent M.] Neurofibromatosis Inst, La Crescenta, CA USA. [Rosser, Tena] Univ So Calif, Childrens Hosp, Dept Neurol, Los Angeles, CA 90027 USA. [Schindeler, Aaron] Univ Sydney, Childrens Hosp Westmead, Kids Res Inst, Westmead, NSW 2145, Australia. [Stevenson, David A.] Univ Utah, Dept Pediat, Div Med Genet, Salt Lake City, UT USA. [Ullrich, Nicole J.] Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Neurol, Boston, MA USA. [van der Vaart, Thijs] Erasmus MC, ENCORE Ctr NF1, Rotterdam, Netherlands. [Weiss, Brian] Cincinnati Childrens Hosp Med Ctr, Div Hematol Oncol, Cincinnati, OH 45229 USA. [Widemann, Brigitte C.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Zhu, Yuan] Childrens Natl Med Ctr, Gilbert Neurofibromatosis Inst, Washington, DC 20010 USA. [Bakker, Annette C.] Childrens Tumor Fdn, New York, NY USA. [Lloyd, Alison C.] UCL, MRC Lab Mol Cell Biol, London, England. [Plotkin, Scott R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA. [Breakefield, Xandra O.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Ullrich, Nicole J.] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Pediat Oncol, Boston, MA USA. RP Plotkin, SR (reprint author), Massachusetts Gen Hosp, Yawkey 9E,55 Fruit St, Boston, MA 02114 USA. EM splotkin@partners.org; alison.lloyd@ucl.ac.uk RI Smith, Miriam/J-4001-2015; Van Raamsdonk, Catherine/B-6207-2017; Morrison, Helen/B-3984-2017; OI Evans, Gareth/0000-0002-8482-5784; Smith, Miriam/0000-0002-3184-0817; Van Raamsdonk, Catherine/0000-0002-4309-3513; Morrison, Helen/0000-0003-4938-1409; Friedman, Jan/0000-0002-7482-9570 FU National Institutes of Health [1R13NS084619-01] FX Grant sponsor: National Institutes of Health Grant Award; Grant number: 1R13NS084619-01. NR 40 TC 6 Z9 6 U1 5 U2 8 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 DEC PY 2014 VL 164 IS 12 BP 2969 EP 2978 DI 10.1002/ajmg.a.36754 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AU0DJ UT WOS:000345293300003 PM 25255738 ER PT J AU Nussmeier, N Saidman, LJ Shafer, S AF Nussmeier, Nancy Saidman, Lawrence J. Shafer, Steven TI A&A Case Reports: A Progress Report and an Update on Requirements for Patient Consent SO ANESTHESIA AND ANALGESIA LA English DT Editorial Material C1 [Nussmeier, Nancy; Saidman, Lawrence J.; Shafer, Steven] Int Anesthesia Res Soc, Stanford, CA USA. [Nussmeier, Nancy] Harvard Univ, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02115 USA. [Shafer, Steven] Stanford Univ, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA 94305 USA. RP Shafer, S (reprint author), Stanford Univ, Sch Med, Dept Anesthesia Perioperat & Pain Med, 300 Pasteur Dr,MC-5640, Stanford, CA 94305 USA. EM steven.shafer@stanford.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 EI 1526-7598 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2014 VL 119 IS 6 BP 1251 EP 1251 DI 10.1213/ANE.0000000000000489 PG 1 WC Anesthesiology SC Anesthesiology GA AT9SO UT WOS:000345266600010 PM 25405687 ER PT J AU Bateman, BT Tsen, LC Liu, J Butwick, AJ Huybrechts, KF AF Bateman, Brian T. Tsen, Lawrence C. Liu, Jun Butwick, Alexander J. Huybrechts, Krista F. TI Patterns of Second-Line Uterotonic Use in a Large Sample of Hospitalizations for Childbirth in the United States: 2007-2011 SO ANESTHESIA AND ANALGESIA LA English DT Article ID MAJOR NONCARDIAC SURGERY; POSTPARTUM HEMORRHAGE; DELIVERIES; MORTALITY; THERAPY; EPIDEMIOLOGY; DEATH; RISK AB BACKGROUND: The incidence of postpartum hemorrhage due to uterine atony has increased significantly in the United States during the past decade. For patients with refractory uterine atony after oxytocin administration, second-line uterotonics including methylergonovine maleate, carboprost, and misoprostol are recommended. In this study, we describe hospital-level patterns of second-line uterotonic use in a large, nationwide sample of admissions for childbirth in the United States. METHODS: The Premier Research Database was used to define a cohort of 2,180,916 patients hospitalized for delivery at 1 of 367 hospitals from 2007 to 2011. Mixed-effects logistic regression models were used to estimate the hospital-specific frequency of second-line uterotonic use adjusting for measured patient-level and hospital-level characteristics that might be risk factors for uterine atony. RESULTS: The median hospital-level frequency of second-line uterotonic use was 7.1% (inter-quartile range 5.2-% to 10.8%). In the fully adjusted model, the mean (SE) predicted probability of second-line uterotonic use was 7.02% (0.26%), with 95% of the hospitals having a predicted (SE) probability between 1.69% (0.12%) and 24.96% (1.28%). CONCLUSIONS: We observed wide interhospital variation in the use of second-line uterotonics that was not explained by patient-level or hospital-level characteristics. Studies aimed at defining the optimal pharmacologic strategies for the management of uterine atony are needed, particularly in light of the increasing incidence of atonic postpartum hemorrhage in the United States and other developed countries. C1 [Bateman, Brian T.; Liu, Jun; Huybrechts, Krista F.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02120 USA. [Bateman, Brian T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesiol Crit Care & Pain Med, Boston, MA USA. [Tsen, Lawrence C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Butwick, Alexander J.] Stanford Univ, Sch Med, Dept Anesthesia, Stanford, CA 94305 USA. RP Bateman, BT (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. EM bbateman@partners.org OI Tsen, Lawrence/0000-0002-1964-723X; Butwick, Alexander/0000-0002-2048-0879 FU Eunice Kennedy Shriver National Institute of Child Health & Human Development of the NIH (Bethesda, Maryland) [K08HD075831, K23HD070972] FX B.T.B. and A.J.B. are supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the NIH (Bethesda, Maryland) under Award Numbers K08HD075831 (B.T.B.) and K23HD070972 (A.J.B.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 24 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 EI 1526-7598 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2014 VL 119 IS 6 BP 1344 EP 1349 DI 10.1213/ANE.0000000000000398 PG 6 WC Anesthesiology SC Anesthesiology GA AT9SO UT WOS:000345266600021 PM 25166464 ER PT J AU Sun, YX Zhang, YY Cheng, BQ Dong, YL Pan, CX Li, TZ Xie, ZC AF Sun, Yongxing Zhang, Yiying Cheng, Baiqi Dong, Yuanlin Pan, Chuxiong Li, Tianzuo Xie, Zhongcong TI Glucose May Attenuate Isoflurane-Induced Caspase-3 Activation in H4 Human Neuroglioma Cells SO ANESTHESIA AND ANALGESIA LA English DT Article ID BETA-PROTEIN-LEVELS; NONCARDIAC SURGERY; COGNITIVE DECLINE; INDUCED APOPTOSIS; ANESTHESIA; DEMENTIA; POPULATION; RISK; TERM; HYPERGLYCEMIA AB BACKGROUND: The commonly used inhaled anesthetic isoflurane has been shown to induce caspase-3 activation. However, the underlying mechanism(s) and targeted intervention(s) remain largely to be determined. Isoflurane may induce caspase-3 activation via causing accumulation of reactive oxygen species (ROS), mitochondrial dysfunction, and reduction in adenosine triphosphate (ATP) levels. Therefore, we performed a hypothesis-generation study to determine whether glucose could attenuate isoflurane-induced caspase-3 activation, ROS accumulation, mitochondrial dysfunction, and ATP reduction in cultured cells. METHODS: H4 human neuroglioma cells (H4 cells) were treated with 2% isoflurane or the control condition plus saline or 50 mM glucose for 6 or 3 hours. Caspase-3 activation, cell viability, levels of ROS and AIR and mitochondrial membrane potential were determined at the end of the experiments by Western blot analysis and fluorescence assay. RESULTS: We found that the glucose treatment might attenuate isoflurane-induced caspase-3 activation and reduction of cell viability in H4 cells. Moreover, the glucose treatment mitigated the isoflurane-induced increase in ROS levels and reduction in ATP levels in H4 cells. Unexpectedly, we observed that the glucose treatment might not inhibit the isoflurane-induced decrease in mitochondrial membrane potential in H4 cells. CONCLUSIONS: Pending further studies, these results suggested that glucose might attenuate isoflurane-induced caspase-3 activation through a mitochondria-independent reduction in ROS levels and enhancement in ATP levels. These findings have established a system and suggest that it is worth performing more research to further investigate whether glucose can attenuate anesthesia neurotoxicity. C1 [Sun, Yongxing; Zhang, Yiying; Cheng, Baiqi; Dong, Yuanlin; Xie, Zhongcong] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Geriatr Anesthesia Res Unit, Charlestown, MA USA. [Sun, Yongxing; Zhang, Yiying; Cheng, Baiqi; Dong, Yuanlin; Xie, Zhongcong] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Sun, Yongxing; Pan, Chuxiong; Li, Tianzuo] Capital Med Univ, Beijing Tongren Hosp, Dept Anesthesia, Beijing, Peoples R China. RP Xie, ZC (reprint author), Harvard Univ, Sch Med, Dept Anesthesia Crit Care & Pain Med, Geriatr Anesthesia Res Unit,Massachusetts Gen Hos, 13th St,Room 4310, Charlestown, MA 02129 USA. EM zxie@mgh.harvard.edu FU National Institutes of Health, Bethesda, Maryland [R21AG038994, R01GM088801, R01AG041274]; Alzheimer's Association, Chicago, Illinois; Cure Alzheimer Fund, Wellesley, Massachusetts FX This study was supported by R21AG038994, R01GM088801, and R01AG041274 from the National Institutes of Health, Bethesda, Maryland; Investigator-initiated Research grant from Alzheimer's Association, Chicago, Illinois, and Cure Alzheimer Fund, Wellesley, Massachusetts, to Zhongcong Xie. The Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital and Harvard Medical School generously provided the cost of inhalation anesthetic isoflurane. NR 29 TC 5 Z9 8 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2014 VL 119 IS 6 BP 1373 EP 1380 DI 10.1213/ANE.0000000000000383 PG 8 WC Anesthesiology SC Anesthesiology GA AT9SO UT WOS:000345266600025 PM 25068691 ER PT J AU Bateman, BT Sandberg, WS AF Bateman, Brian T. Sandberg, Warren S. TI Incidence of Laminectomy and Imaging After Neuraxial Anesthesia Response SO ANESTHESIA AND ANALGESIA LA English DT Letter C1 [Bateman, Brian T.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Bateman, Brian T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pharmacoepidemiol & Pharmacoecon,Dept Med, Boston, MA 02115 USA. [Sandberg, Warren S.] Vanderbilt Univ, Sch Med, Dept Anesthesiol, Nashville, TN 37212 USA. [Sandberg, Warren S.] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37212 USA. [Sandberg, Warren S.] Vanderbilt Univ, Sch Med, Dept Surg, Nashville, TN 37212 USA. RP Bateman, BT (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM BBateman@partners.org NR 2 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 EI 1526-7598 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2014 VL 119 IS 6 BP 1452 EP 1452 DI 10.1213/ANE.0000000000000432 PG 1 WC Anesthesiology SC Anesthesiology GA AT9SO UT WOS:000345266600033 PM 25405696 ER PT J AU Forman, SA Miller, KW Talmor, D Hickey, P Strichartz, G Wiener-Kronish, J AF Forman, Stuart A. Miller, Keith W. Talmor, Daniel Hickey, Paul Strichartz, Gary Wiener-Kronish, Jeanine TI Research at the Harvard Anesthesia Departments SO ANESTHESIOLOGY LA English DT Editorial Material C1 [Forman, Stuart A.; Miller, Keith W.; Wiener-Kronish, Jeanine] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Talmor, Daniel] Beth Israel Deaconess Med Ctr, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02215 USA. [Hickey, Paul] Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. [Strichartz, Gary] Brigham & Womens Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02115 USA. RP Forman, SA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM saforman@partners.org FU NIGMS NIH HHS [P01 GM058448] NR 5 TC 0 Z9 0 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 DEC PY 2014 VL 121 IS 6 BP 1141 EP 1143 DI 10.1097/ALN.0000000000000483 PG 3 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700003 PM 25299744 ER PT J AU Maeda, A Bateman, BT Clancy, CR Creanga, AA Leffert, LR AF Maeda, Ayumi Bateman, Brian T. Clancy, Caitlin R. Creanga, Andreea A. Leffert, Lisa R. TI Opioid Abuse and Dependence during Pregnancy Temporal Trends and Obstetrical Outcomes SO ANESTHESIOLOGY LA English DT Article ID VITAL SIGNS OVERDOSES; UNITED-STATES; MATERNAL MORBIDITY; CESAREAN DELIVERY; PAIN MANAGEMENT; SMOKING; PREECLAMPSIA; ADDICTION; WOMEN; HEALTH AB Background: The authors investigated nationwide trends in opioid abuse or dependence during pregnancy and assessed the impact on maternal and obstetrical outcomes in the United States. Methods: Hospitalizations for delivery were extracted from the Nationwide Inpatient Sample from 1998 to 2011. Temporal trends were assessed and logistic regression was used to examine the associations between maternal opioid abuse or dependence and obstetrical outcomes adjusting for relevant confounders. Results: The prevalence of opioid abuse or dependence during pregnancy increased from 0.17% (1998) to 0.39% (2011) for an increase of 127%. Deliveries associated with maternal opioid abuse or dependence compared with those without opioid abuse or dependence were associated with an increased odds of maternal death during hospitalization (adjusted odds ratio [aOR], 4.6; 95% CI, 1.8 to 12.1, crude incidence 0.03 vs. 0.006%), cardiac arrest (aOR, 3.6; 95% CI, 1.4 to 9.1; 0.04 vs. 0.01%), intrauterine growth restriction (aOR, 2.7; 95% CI, 2.4 to 2.9; 6.8 vs. 2.1%), placental abruption (aOR, 2.4; 95% CI, 2.1 to 2.6; 3.8 vs. 1.1%), length of stay more than 7 days (aOR, 2.2; 95% CI, 2.0 to 2.5; 3.0 vs. 1.2%), preterm labor (aOR, 2.1; 95% CI, 2.0 to 2.3; 17.3 vs. 7.4%), oligohydramnios (aOR, 1.7; 95% CI, 1.6 to 1.9; 4.5 vs. 2.8%), transfusion (aOR, 1.7; 95% CI, 1.5 to 1.9; 2.0 vs. 1.0%), stillbirth (aOR, 1.5; 95% CI, 1.3 to 1.8; 1.2 vs. 0.6%), premature rupture of membranes (aOR, 1.4; 95% CI, 1.3 to 1.6; 5.7 vs. 3.8%), and cesarean delivery (aOR, 1.2; 95% CI, 1.1 to 1.3; 36.3 vs. 33.1%). Conclusions: Opioid abuse or dependence during pregnancy is associated with considerable obstetrical morbidity and mortality, and its prevalence is dramatically increasing in the United States. Identifying preventive strategies and therapeutic interventions in pregnant women who abuse drugs are important priorities for clinicians and scientists. C1 [Maeda, Ayumi; Bateman, Brian T.; Clancy, Caitlin R.; Leffert, Lisa R.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Bateman, Brian T.] Harvard Univ, Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Sch Med,Dept Med, Boston, MA 02115 USA. [Creanga, Andreea A.] Ctr Dis Control & Prevent, Div Reprod Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. RP Leffert, LR (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Div Obstet Anesthesia, 55 Fruit St, Boston, MA 02114 USA. EM lleffert@partners.org NR 44 TC 16 Z9 16 U1 2 U2 14 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 DEC PY 2014 VL 121 IS 6 BP 1158 EP 1165 DI 10.1097/ALN.0000000000000472 PG 8 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700007 PM 25405293 ER PT J AU McCarty, LK Saddawi-Konefka, D Gargan, LM Driscoll, WD Walsh, JL Peterfreund, RA AF McCarty, L. Kelsey Saddawi-Konefka, Daniel Gargan, Lauren M. Driscoll, William D. Walsh, John L. Peterfreund, Robert A. TI Application of Process Improvement Principles to Increase the Frequency of Complete Airway Management Documentation SO ANESTHESIOLOGY LA English DT Article ID DIFFICULT TRACHEAL INTUBATION; DIRECT LARYNGOSCOPY; MASK VENTILATION; ANESTHESIA; DEVICES; DEFINITION; EVOLUTION; SYSTEM; VIDEO; SCORE AB Background: Process improvement in healthcare delivery settings can be difficult, even when there is consensus among clinicians about a clinical practice or desired outcome. Airway management is a medical intervention fundamental to the delivery of anesthesia care. Like other medical interventions, a detailed description of the management methods should be documented. Despite this expectation, airway documentation is often insufficient. The authors hypothesized that formal adoption of process improvement methods could be used to increase the rate of "complete" airway management documentation. Methods: The authors defined a set of criteria as a local practice standard of "complete" airway management documentation. The authors then employed selected process improvement methodologies over 13 months in three iterative and escalating phases to increase the percentage of records with complete documentation. The criteria were applied retrospectively to determine the baseline frequency of complete records, and prospectively to measure the impact of process improvements efforts over the three phases of implementation. Results: Immediately before the initial intervention, a retrospective review of 23,011 general anesthesia cases over 6 months showed that 13.2% of patient records included complete documentation. At the conclusion of the 13-month improvement effort, documentation improved to a completion rate of 91.6% (P<0.0001). During the subsequent 21 months, the completion rate was sustained at an average of 90.7% (SD, 0.9%) across 82,571 general anesthetic records. Conclusion: Systematic application of process improvement methodologies can improve airway documentation and may be similarly effective in improving other areas of anesthesia clinical practice. C1 [McCarty, L. Kelsey; Saddawi-Konefka, Daniel; Gargan, Lauren M.; Driscoll, William D.; Walsh, John L.; Peterfreund, Robert A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP McCarty, LK (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRJ 447, Boston, MA 02114 USA. EM Lkmccarty@mgh.harvard.edu NR 40 TC 2 Z9 2 U1 1 U2 7 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 DEC PY 2014 VL 121 IS 6 BP 1166 EP 1174 DI 10.1097/ALN.0000000000000480 PG 9 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700008 PM 25299742 ER PT J AU D'Angelo, OM Diaz-Gil, D Nunn, D Simons, JCP Gianatasio, C Mueller, N Meyer, MJ Pierce, E Rosow, C Eikermann, M AF D'Angelo, Olivia M. Diaz-Gil, Daniel Nunn, Danuza Simons, Jeroen C. P. Gianatasio, Chloe Mueller, Noomi Meyer, Matthew J. Pierce, Eric Rosow, Carl Eikermann, Matthias TI Anesthesia and Increased Hypercarbic Drive Impair the Coordination between Breathing and Swallowing SO ANESTHESIOLOGY LA English DT Article ID PHARYNGEAL FUNCTION; PARKINSONS-DISEASE; PREDICT IMMOBILITY; AIRWAY-PROTECTION; PAINFUL STIMULI; F-WAVES; PATTERN; HUMANS; COLLAPSIBILITY; INDIVIDUALS AB Background: Coordination between breathing and swallowing helps prevent aspiration of foreign material into the respiratory tract. The authors examined the effects of anesthesia and hypercapnia on swallowing-breathing coordination. Methods: In a randomized controlled crossover study, general anesthesia with propofol or sevoflurane was titrated using an up-down method to identify the threshold for suppression of the motor response to electrical stimulation of the forearm. Additional measurements included bispectral index, genioglossus electromyogram, ventilation (pneumotachometer), and hypopharyngeal pressure. During wakefulness and at each level of anesthesia, carbon dioxide was added to increase the end-tidal pressure by 4 and 8 mmHg. A swallow was defined as increased genioglossus activity with deglutition apnea and an increase in hypopharyngeal pressure. Spontaneous swallows were categorized as physiological (during expiration or followed by expiration) or pathological (during inspiration or followed by an inspiration). Results: A total of 224 swallows were analyzed. Anesthesia increased the proportion of pathological swallows (25.9% vs. 4.9%) and decreased the number of swallows per hour (1.7 +/- 3.3 vs. 28.0 +/- 22.3) compared to wakefulness. During anesthesia, hypercapnia decreased hypopharyngeal pressure during inspiration (-14.1 +/- 3.7 vs. -8.7 +/- 2 mmHg) and increased minute ventilation, the proportion of pathological swallows (19.1% vs. 12.3%), and the number of swallows per hour (5.5 +/- 17.0. vs. 1.3 +/- 5.5). Conclusions: Anesthesia impaired the coordination between swallowing and respiration. Mild hypercapnia increased the frequency of swallowing during anesthesia and the likelihood of pathological swallowing. During anesthesia, the risk for aspiration may be further increased when ventilatory drive is stimulated. C1 [D'Angelo, Olivia M.; Diaz-Gil, Daniel; Simons, Jeroen C. P.; Gianatasio, Chloe; Mueller, Noomi; Meyer, Matthew J.; Pierce, Eric; Rosow, Carl; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Carl Rosow Clin Res Ctr, Boston, MA 02114 USA. [Nunn, Danuza] Massachusetts Gen Hosp, Dept Speech Language & Swallowing Disorders, Boston, MA 02114 USA. [Eikermann, Matthias] Univ Klinikum Essen, Klin Anasthesie & Intens Med, Essen, Germany. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM meikermann@partners.org FU Buzen Fund; Harvard Clinical and Translational Science Center, from the National Center for Advancing Translational Science, Bethesda, Maryland [8 UL1 TR000170-05] FX The Carl Rosow Clinical Research Center and this project were supported by an unrestricted research grant from the Buzen Fund, established by Jeffrey Buzen, Ph.D., and Judith Buzen, as well as an unrestricted gift from Carl Rosow, M. D., Ph.D. This project was also supported by grant number 8 UL1 TR000170-05, Harvard Clinical and Translational Science Center, from the National Center for Advancing Translational Science, Bethesda, Maryland. NR 27 TC 1 Z9 1 U1 1 U2 4 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 DEC PY 2014 VL 121 IS 6 BP 1175 EP 1183 DI 10.1097/ALN.0000000000000462 PG 9 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700009 PM 25275368 ER PT J AU Campagna, JA Pojasek, K Grayzel, D Randle, J Raines, DE AF Campagna, Jason A. Pojasek, Kevin Grayzel, David Randle, John Raines, Douglas E. TI Advancing Novel Anesthetics Pharmacodynamic and Pharmacokinetic Studies of Cyclopropyl-methoxycarbonyl Metomidate in Dogs SO ANESTHESIOLOGY LA English DT Article ID RAPID-SEQUENCE INTUBATION; MULTIPLE TRAUMA PATIENTS; CRITICALLY-ILL PATIENTS; ADRENOCORTICAL SUPPRESSION; ADRENAL STEROIDOGENESIS; ETOMIDATE ANALOG; SEPTIC SHOCK; IN-VITRO; INDUCTION; MORTALITY AB Background: Cyclopropyl-methoxycarbonyl metomidate (CPMM, also known as ABP-700) is a second-generation "soft" (i.e., metabolically labile) etomidate analogue. The purpose of this study was to characterize CPMM's pharmacology in beagle dogs in preparation for potential first in human phase 1 clinical trials. Methods: CPMM's and etomidate's hypnotic activity and duration of action were assessed using loss of righting reflex and anesthesia score assays in three or four dogs. Their pharmacokinetics were defined after single bolus administration and single bolus followed by 2-h infusion. Adrenocortical recovery times after single bolus followed by 2-h infusion of CPMM, propofol, etomidate, and vehicle were measured using an adrenocorticotropic hormone stimulation test. Results: Compared with etomidate, CPMM was half as potent as a hypnotic (ED50 approximately 0.8 mg/kg), was more rapidly metabolized, and had a shorter duration of sedative-hypnotic action. Recovery times after CPMM administration were also independent of infusion duration. After hypnotic infusion, adrenocorticotropic hormone-stimulated plasma cortisol concentrations were 4- to 27-fold higher in dogs that received CPMM versus etomidate. Adrenocortical recovery was faster in dogs after CPMM infusion versus etomidate infusion (half-time: 215 vs. 1,623 min, respectively). Adrenocortical responsiveness assessed 90 min after CPMM infusion was not significantly different from that after propofol infusion. Conclusion: The studies in dogs confirm that CPMM has hypnotic and adrenocortical recovery profiles that are superior than those of etomidate, supporting the continued development of CPMM as a clinical sedative-hypnotic to be used as a single bolus and by continuous infusion to induce and maintain general anesthesia or procedural sedation. C1 [Campagna, Jason A.] Medicines Co Inc, Parsippany, NJ USA. [Pojasek, Kevin; Grayzel, David; Randle, John] Annovat BioPharma Inc, Cambridge, MA USA. [Raines, Douglas E.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Raines, DE (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRB444, Boston, MA 02114 USA. EM draines@partners.org FU Annovation BioPharma, Inc., Cambridge, Massachusetts; National Institutes of Health, Bethesda, Maryland [R01-GM087316]; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts FX Supported by Annovation BioPharma, Inc., Cambridge, Massachusetts, and 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 6 Z9 6 U1 0 U2 10 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 DEC PY 2014 VL 121 IS 6 BP 1203 EP 1216 DI 10.1097/ALN.0000000000000416 PG 14 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700012 PM 25170571 ER PT J AU Mietto, C Pinciroli, R Piriyapatsom, A Thomas, JG Bry, L Delaney, ML Du Bois, A Truelove, J Ackman, JB Wojtkiewicz, GR Nahrendorf, M Kacmarek, RM Berra, L AF Mietto, Cristina Pinciroli, Riccardo Piriyapatsom, Annop Thomas, John G. Bry, Lynn Delaney, Mary L. Du Bois, Andrea Truelove, Jessica Ackman, Jeanne B. Wojtkiewicz, Gregory R. Nahrendorf, Matthias Kacmarek, Robert M. Berra, Lorenzo TI Tracheal Tube Obstruction in Mechanically Ventilated Patients Assessed by High-resolution Computed Tomography SO ANESTHESIOLOGY LA English DT Article ID ENDOTRACHEAL-TUBE; MUCUS SHAVER; BACTERIAL-COLONIZATION; DIAMETER; DEVICE; INTUBATION; SECRETIONS; RESISTANCE; REDUCTION; PNEUMONIA AB Background: Tracheal intubation compromises mucus clearance and secretions accumulate inside the tracheal tube (TT). The aim of this study was to evaluate with a novel methodology TT luminal obstruction in critically ill patients. Methods: This was a three-phase study: (1) the authors collected 20 TTs at extubation. High-resolution computed tomography (CT) was performed to determine cross-sectional area (CSA) and mucus distribution within the TT; (2) five TTs partially filled with silicone were used to correlate high-resolution CT results and increased airflow resistance; and (3) 20 chest CT scans of intubated patients were reviewed for detection of secretions in ventilated patients' TT. Results: Postextubation TTs showed a maximum CSA reduction of (mean +/- SD) 24.9 +/- 3.9% (range 3.3 to 71.2%) after a median intubation of 4.5 (interquartile range 2.5 to 6.5) days. CSA progressively decreased from oral to lung end of used TTs. The luminal volume of air was different between used and new TTs for all internal diameters (P < 0.01 for new vs. used TTs for all studied internal diameters). The relationship between pressure drop and increasing airflow rates was nonlinear and depended on minimum CSA available to ventilation. Weak correlation was found between TT occlusion and days of intubation (R-2 = 0.352, P = 0.006). With standard clinical chest CT scans, 6 of 20 TTs showed measurable secretions with a CSA reduction of 24.0 +/- 3.9%. Conclusions: TT luminal narrowing is a common finding and correlates with increased airflow resistance. The authors propose high-resolution CT as a novel technique to visualize and quantify secretions collected within the TT lumen. C1 [Mietto, Cristina; Pinciroli, Riccardo; Piriyapatsom, Annop; Kacmarek, Robert M.; Berra, Lorenzo] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Thomas, John G.] W Virginia Univ, Sch Dent, Morgantown, WV 26506 USA. [Bry, Lynn; Delaney, Mary L.; Du Bois, Andrea] Brigham & Womens Hosp, Dept Pathol, Ctr Clin & Translat Metagen, Boston, MA 02115 USA. [Truelove, Jessica; Wojtkiewicz, Gregory R.; Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Ackman, Jeanne B.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. RP Berra, L (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, White 434-B,55 Fruit St, Boston, MA 02114 USA. EM lberra@mgh.harvard.edu FU Department of Anesthesia, Critical Care, and Pain Medicine and the Department of Respiratory Care, Massachusetts General Hospital, Boston, Massachusetts; Harvard Digestive Diseases Center, Brigham [NIH P30DK034854]; Women's Hospital, Boston, Massachusetts FX This study was supported by the Department of Anesthesia, Critical Care, and Pain Medicine and the Department of Respiratory Care, Massachusetts General Hospital, Boston, Massachusetts. endOclear LLC (Petoskey, Michigan) supported microbiological testing and high-resolution computed tomography analysis. Infrastructure at the Center for Clinical and Translational Metagenomics was supported by the Harvard Digestive Diseases Center (NIH P30DK034854), Brigham and Women's Hospital, Boston, Massachusetts. NR 28 TC 6 Z9 6 U1 1 U2 3 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 DEC PY 2014 VL 121 IS 6 BP 1226 EP 1235 DI 10.1097/ALN.0000000000000455 PG 10 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700014 PM 25254903 ER PT J AU Gong, Y Zou, L Feng, Y Li, D Cai, JY Chen, DJ Chao, W AF Gong, Yu Zou, Lin Feng, Yan Li, Dan Cai, Jiayan Chen, Dunjin Chao, Wei TI Importance of Toll-like Receptor 2 in Mitochondrial Dysfunction during Polymicrobial Sepsis SO ANESTHESIOLOGY LA English DT Article ID INDUCED CARDIAC DYSFUNCTION; REACTIVE OXYGEN; OXIDATIVE STRESS; ORGAN FAILURE; SEPTIC SHOCK; UNITED-STATES; MOUSE MODEL; DNA DAMAGE; SUPEROXIDE; NEUTROPHIL AB Background: Toll-like receptor 2 (TLR2) contributes to sepsis pathogenesis such as deleterious systemic inflammation, cardiac dysfunction, and high mortality in animal studies. Mitochondrial dysfunction is a key molecular event that is associated with organ injury in sepsis. The role of TLR2 in sepsis-induced mitochondrial dysfunction remains unclear. Methods: Intracellular hydrogen peroxide (H2O2), mitochondrial superoxide (O-2(-)), mitochondrial membrane potential (Delta Psi m), and intracellular adenosine triphosphate (ATP) were measured in peritoneal leukocytes. A mouse model of polymicrobial sepsis was generated by cecum ligation and puncture (CLP). Wild-type and TLR2-deficient (TLR2(-/-)) mice were subjected to sham or CLP. Mitochondrial functions including reactive oxygen species (ROS), Delta Psi m, intracellular ATP, and complex III activity were measured. Results: TLR2/1 activation by Pam3Cys enhanced intracellular H2O2 and mitochondrial O-2(-) production in leukocytes, but had no effect on mitochondrial Delta Psi m and ATP production. The effect was specific for TLR2/1 as TLR3 or TLR9 ligands did not induce ROS production. Polymicrobial sepsis induced mitochondrial dysfunction in leukocytes, as demonstrated by increased H2O2 and mitochondrial O-2(-) production (CLP vs. sham; H2O2 : 3,173 +/- 498, n = 5 vs. 557 +/- 38, n = 4; O-2(-): 707 +/- 66, n = 35 vs. 485 +/- 35, n = 17, mean fluorescence intensity, mean +/- SEM), attenuated complex III activity (13 +/- 2, n = 16 vs. 30 +/- 3, n = 7, millioptical densities/min), loss of mitochondrial Delta Psi m, and depletion of intracellular ATP (33 +/- 6, n = 11 vs. 296 +/- 29, n = 4, nmol/mg protein). In comparison, there was significant improvement in mitochondrial function in septic TLR2(-/-) mice as evidenced by attenuated mitochondrial ROS production, better-maintained mitochondrial Delta Psi m, and higher cellular ATP production. Conclusions: TLR2 signaling plays a critical role in mediating mitochondrial dysfunction in peritoneal leukocytes during polymicrobial sepsis. C1 [Gong, Yu; Zou, Lin; Feng, Yan; Li, Dan; Cai, Jiayan; Chao, Wei] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02129 USA. [Gong, Yu; Chen, Dunjin] Guangzhou Med Univ, Affiliated Hosp 3, Inst Gynecol & Obstet, Key Lab Major Obstetr Dis, Guangzhou, Guangdong, Peoples R China. RP Chao, W (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Room 4-212,149 13th St, Boston, MA 02129 USA. EM wchao@mgh.harvard.edu FU National Institutes of Health, Bethesda, Maryland [R01-GM080906, R01-GM097259]; International Anesthesia Research Society, San Francisco, California FX This work was supported in part by the National Institutes of Health (grant nos. R01-GM080906 and R01-GM097259), Bethesda, Maryland (to Dr. Chao), and a mentored research award from the International Anesthesia Research Society, San Francisco, California (to Dr. Zou). NR 64 TC 5 Z9 6 U1 0 U2 4 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 DEC PY 2014 VL 121 IS 6 BP 1236 EP 1247 DI 10.1097/ALN.0000000000000470 PG 12 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700015 PM 25272245 ER PT J AU Sakaguchi, M Marutani, E Shin, HS Chen, W Hanaoka, K Xian, M Ichinose, F AF Sakaguchi, Masahiro Marutani, Eizo Shin, Hae-sook Chen, Wei Hanaoka, Kenjiro Xian, Ming Ichinose, Fumito TI Sodium Thiosulfate Attenuates Acute Lung Injury in Mice SO ANESTHESIOLOGY LA English DT Article ID HYDROGEN-SULFIDE; PROTECTS; INFLAMMATION; ACTIVATION; CISPLATIN; FAILURE; SEPSIS AB Background: Acute lung injury is characterized by neutrophilic inflammation and increased lung permeability. Thiosulfate is a stable metabolite of hydrogen sulfide, a gaseous mediator that exerts antiinflammatory effects. Although sodium thiosulfate (STS) has been used as an antidote, the effect of STS on acute lung injury is unknown. The authors assessed the effects of STS on mice lung and vascular endothelial cells subjected to acute inflammation. Methods: Lung injury was assessed in mice challenged with intratracheal lipopolysaccharide or subjected to cecal ligation and puncture with or without STS. Effects of STS on endothelial permeability and the production of inflammatory cytokines and reactive oxygen species were examined in cultured endothelial cells incubated with lipopolysaccharide or tumor necrosis factor-a. Levels of sulfide and sulfane sulfur were measured using novel fluorescence probes. Results: STS inhibited lipopolysaccharide-induced production of cytokines (interleukin-6 [pg/ml]; 313 +/- 164, lipopolysaccharide; 79 +/- 27, lipopolysaccharide + STS [n = 10]), lung permeability, histologic lung injury, and nuclear factor-kappa B activation in the lung. STS also prevented up-regulation of interleukin-6 in the mouse lung subjected to cecal ligation and puncture. In endothelial cells, STS increased intracellular levels of sulfide and sulfane sulfur and inhibited lipopolysaccharide or tumor necrosis factor-alpha-induced production of cytokines and reactive oxygen species. The beneficial effects of STS were associated with attenuation of the lipopolysaccharide-induced nuclear factor-kappa B activation through the inhibition of tumor necrosis factor receptor-associated factor 6 ubiquitination. Conclusions: STS exerts robust antiinflammatory effects in mice lung and vascular endothelium. The results suggest a therapeutic potential of STS in acute lung injury. C1 [Sakaguchi, Masahiro; Marutani, Eizo; Shin, Hae-sook; Ichinose, Fumito] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Sakaguchi, Masahiro; Marutani, Eizo; Shin, Hae-sook; Ichinose, Fumito] Harvard Univ, Sch Med, Boston, MA USA. [Chen, Wei; Xian, Ming] Washington State Univ, Dept Chem, Pullman, WA 99164 USA. [Hanaoka, Kenjiro] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo, Japan. RP Ichinose, F (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM fichinose@mgh.harvard.edu FU National Institutes of Health (Bethesda, Maryland) [R01HL101930] FX This study was supported by a National Institutes of Health (Bethesda, Maryland) grant R01HL101930 (to Dr. Ichinose). NR 37 TC 13 Z9 15 U1 0 U2 10 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 DEC PY 2014 VL 121 IS 6 BP 1248 EP 1257 DI 10.1097/ALN.0000000000000456 PG 10 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700016 PM 25260144 ER PT J AU Feng, Y Zou, L Chen, C Li, D Chao, W AF Feng, Yan Zou, Lin Chen, Chan Li, Dan Chao, Wei TI Role of Cardiac- and Myeloid-MyD88 Signaling in Endotoxin Shock A Study with Tissue-specific Deletion Models SO ANESTHESIOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; TOLL-LIKE-RECEPTORS; SEPTIC SHOCK; IN-VIVO; NITRIC-OXIDE; FACTOR-ALPHA; POLYMICROBIAL SEPSIS; MOLECULAR-MECHANISMS; MYOCYTE IMPAIRMENT; MYOCARDIAL INJURY AB Background: Myeloid differentiation factor 88 (MyD88) is an adaptor molecule critical for host innate immunity. Studies have shown that signaling via MyD88 contributes to cytokine storm, cardiac dysfunction, and high mortality during endotoxin shock. However, the specific contribution of MyD88 signaling of immune and cardiac origins to endotoxin shock remains unknown. Methods: Tissue-specific MyD88 deletion models: Cre-recombinase transgenic mice with alpha-myosin heavy chain (alpha-MHC) or lysozyme M promoters were cross-bred with MyD88-loxP (MyD88(fl/fl)) mice, respectively, to generate cardiomyocyte-(alpha-MHC-MyD88(-/-)) or myeloid-specific (Lyz-MyD88(-/-)) MyD88 deletion models and their respective MyD88(fl/fl) littermates. Endotoxin shock model: Mice were subjected to 15 mg/kg lipopolysaccharide (intraperitoneal injection). Cardiac function was measured by echocardiography and cytokines by multiplex assay and quantitative reverse transcription-polymerase chain reaction. Results: alpha-MHC-MyD88(-/-) mice had 61 and 87% reduction in MyD88 gene and protein expression in cardiomyocytes, respectively, whereas Lyz-MyD88(-/-) had 73 and 67% decrease, respectively, in macrophages (n = 3 per group). After lipopolysaccharide treatment, the two groups of MyD88fl/fl littermates had 46% (n = 10) and 60% (n = 15) of mortality, respectively. Both alpha-MHC-MyD88(-/-) and Lyz-MyD88(-/-) mice had markedly improved survival. Compared with the MyD88fl/fl littermates, Lyz-MyD88(-/-) mice had warmer body temperature, attenuated systemic and cardiac inflammatory cytokine production, and significantly improved cardiac function, whereas alpha-MHC-MyD88(-/-) mice had decreased myocardial inducible nitric oxide synthase induction and modestly preserved cardiac function. Conclusions: Both cardiomyocyte- and myeloid-MyD88 signaling play a role in cardiac dysfunction and mortality during endotoxin shock. Myeloid-MyD88 signaling plays a predominant role in systemic and cardiac inflammation after endotoxin challenge. C1 [Feng, Yan; Zou, Lin; Chen, Chan; Li, Dan; Chao, Wei] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. RP Feng, Y (reprint author), Massachusetts Gen Hosp, 149 13th St,Room 4423, Charlestown, MA 02129 USA. EM yfeng@partners.org FU National Institutes of Health, Bethesda, Maryland [R01-GM080906, R01-GM097259] FX This work was supported in part by the grants R01-GM080906 and R01-GM097259 (to Dr. Chao) from the National Institutes of Health, Bethesda, Maryland. NR 56 TC 3 Z9 3 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 DEC PY 2014 VL 121 IS 6 BP 1258 EP 1269 DI 10.1097/ALN.0000000000000398 PG 12 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700017 PM 25089642 ER PT J AU Zhang, M Zou, L Feng, Y Chen, YJ Zhou, QC Ichinose, F Chao, W AF Zhang, Ming Zou, Lin Feng, Yan Chen, Yu-Jung Zhou, Qichang Ichinose, Fumito Chao, Wei TI Toll-like Receptor 4 Is Essential to Preserving Cardiac Function and Survival in Low-grade Polymicrobial Sepsis SO ANESTHESIOLOGY LA English DT Article ID SEPTIC SHOCK; CONTRACTILE DYSFUNCTION; MYOCARDIAL DYSFUNCTION; NEUTROPHIL MIGRATION; INNATE IMMUNITY; UNITED-STATES; MYD88; IMPAIRMENT; PROTECTION; ISCHEMIA AB Background: Toll-like receptor 4 (TLR4), the receptor for endotoxin, mediates hyperinflammatory response and contributes to high mortality during both endotoxin shock and severe sepsis. However, little is known about the role of TLR4 in the pathogenesis of low-grade polymicrobial sepsis, which is often associated with immunosuppression. Methods: Low-grade polymicrobial sepsis was generated by cecum ligation and puncture. Mortality was monitored in wildtype (C57BL/10ScSn) and TLR4(def) (C57BL/10ScCr) mice. Ex vivo heart and individual cardiomyocyte function were assessed in Langendorff (Hugo Sachs Elektronik; Harvard Apparatus, Holliston, MA) and IonOptix systems (IonOptix, Milton, MA), respectively. Serum chemistry was tested for liver and kidney injury. Cytokines were examined using a multiplex immunoassay. Neutrophil migratory and phagocytic functions were assessed using flow cytometry. Reactive oxygen species were measured using redox-sensitive dichlorodihydrofluorescein dye. Results: Following cecum ligation and puncture, wild-type mice developed bacterial peritonitis with mild cardiac dysfunction (n = 3 in sham and n = 8 in cecum ligation and puncture) and a mortality of 23% within 14 days (n = 22). In comparison, septic TLR4(def) mice had deleterious cardiac dysfunction (n = 6 in sham and n = 10 in cecum ligation and puncture), kidney and liver injury (n = 7), and much higher mortality at 81% (n = 21). The deleterious effects observed in septic TLR4(def) mice were associated with increased local and systemic cytokine response, reduced neutrophil migratory and phagocytic function, increased reactive oxygen species generation in leukocytes, and impaired bacterial clearance. Conclusion: TLR4 plays an essential role in host defense against low-grade polymicrobial sepsis by mediating neutrophil migratory/phagocytic functions, attenuating inflammation, reducing reactive oxygen species generation, and enhanced-bacterial clearance. C1 [Zhang, Ming; Zou, Lin; Feng, Yan; Chen, Yu-Jung; Ichinose, Fumito; Chao, Wei] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Zhang, Ming; Zhou, Qichang] Xiangya Sch Med, Xiangya Hosp 2, Dept Ultrasound Med, Changsha, Hunan, Peoples R China. RP Zou, L (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 149 13th St,Room 4423, Charlestown, MA 02129 USA. EM lzou3@mgh.harvard.edu FU National Institutes of Health (Bethesda, Maryland) [R01-GM080906, R01-GM097259]; International Anesthesia Research Society (San Francisco, California) FX This work was supported in part by the National Institutes of Health (Bethesda, Maryland; grant nos. R01-GM080906 and R01-GM097259 to Dr. Chao) and a mentored research award from International Anesthesia Research Society (San Francisco, California; to Dr. Zou). NR 49 TC 1 Z9 1 U1 1 U2 3 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 DEC PY 2014 VL 121 IS 6 BP 1270 EP 1280 DI 10.1097/ALN.0000000000000337 PG 11 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700018 PM 24937074 ER PT J AU Ueda, M Iwasaki, H Wang, SX Murata, E Poon, KYT Mao, JR Martyn, JAJ AF Ueda, Masashi Iwasaki, Hajime Wang, Shuxing Murata, Eri Poon, K. Y. Trudy Mao, Jianren Martyn, J. A. Jeevendra TI Cannabinoid Receptor Type 1 Antagonist, AM251, Attenuates Mechanical Allodynia and Thermal Hyperalgesia after Burn Injury SO ANESTHESIOLOGY LA English DT Article ID PERIPHERAL MONONEUROPATHY; INSULIN-RESISTANCE; SPINAL-CORD; YOUNG-RATS; PAIN; MORPHINE; ENDOCANNABINOIDS; BEHAVIOR; PROTEIN; SENSITIZATION AB Background: Burn injury causes nociceptive behaviors, and inflammation-related pathologic pain can lead to glial cell activation. This study tested the hypothesis that burn injury activates glial cells, and cannabinoid receptor 1 (CB1R) antagonist, AM251, will decrease burn pain. Methods: Anesthetized rats received 0.75-cm(2) third-degree burn on dorsal hind paw. Vehicle or AM251 30 mu g intrathecally (older rats, n = 6 per group) or, either vehicle, 0.1 or 1.0 mg/kg intraperitoneally (younger rats, n = 6 per group), started immediate postburn, was administered for 7 days. Mechanical allodynia and thermal hyperalgesia were tested on ventral paw for 14 days. Microglial and astroglial activity was assessed by immunocytochemistry. Results: Allodynia, observed on burn side from day 1 to 14, was significantly (P < 0.05) attenuated by intrathecal and intraperitoneal AM251 (1 mg/kg) starting from 3 to 14 days. Hyperalgesia, observed from day 3 to 12, was completely (P < 0.05) reversed by intrathecal and intraperitoneal AM251 (1 mg/kg). AM251 0.1 mg/kg had no effect. Microglial activity (n = 3 per time point) increased (P < 0.05) 18.5 +/- 7.5 and 12.3 +/- 1.6 (mean +/- SD) fold at 7 and 14 days, respectively. Astroglial activity (n = 4 per time point) increased 2.9 +/- 0.3 fold at day 7 only. Glial activities were unaltered by AM251. Conclusions: AM251 inhibited nociceptive behaviors after burn even beyond 7-day period of administration. Although many studies have documented the utility of CB1R agonists, this study indicates that endogenous cannabinoids may have an unexpected pronociceptive effect during development of burn pain, explaining why CB1R antagonist, AM251, improves nociceptive behaviors. The decreased nociception with AM251 without altering glial activity indicates that AM251 acts further downstream of activated glial cells. C1 Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, Boston, MA 02114 USA. Shriners Hosp Children, Boston, MA USA. [Ueda, Masashi; Iwasaki, Hajime; Wang, Shuxing; Murata, Eri; Poon, K. Y. Trudy; Mao, Jianren; Martyn, J. A. Jeevendra] Harvard Univ, Sch Med, Boston, MA USA. [Murata, Eri] Univ Fukui, Dept Anesthesiol, Fukui 910, Japan. RP Martyn, JAJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesiol, 51 Blossom St,Room 206, Boston, MA 02114 USA. EM jmartyn@mgh.harvard.edu FU National Institutes of Health (Bethesda, Maryland) [GM P50-2500] FX Supported in part by a grant from the National Institutes of Health (Bethesda, Maryland) GM P50-2500 Project I (to Dr. Martyn). NR 42 TC 8 Z9 9 U1 0 U2 5 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 DEC PY 2014 VL 121 IS 6 BP 1311 EP 1319 DI 10.1097/ALN.0000000000000422 PG 9 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700022 PM 25188001 ER PT J AU Stahl, DL North, CM Lewis, A Kimberly, WT Hess, DR AF Stahl, David L. North, Crystal M. Lewis, Ariane Kimberly, W. Taylor Hess, Dean R. TI Case Scenario: Power of Positive End-expiratory Pressure Use of Esophageal Manometry to Illustrate Pulmonary Physiology in an Obese Patient SO ANESTHESIOLOGY LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; ACUTE LUNG INJURY; CEREBRAL PERFUSION-PRESSURE; RANDOMIZED CONTROLLED-TRIAL; TRAUMATIC BRAIN INJURY; LOWER TIDAL VOLUMES; MECHANICAL VENTILATION; TRANSPULMONARY PRESSURE; STRESS; METAANALYSIS C1 [Stahl, David L.; Hess, Dean R.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [North, Crystal M.] Massachusetts Gen Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02114 USA. [Lewis, Ariane; Kimberly, W. Taylor] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care, Boston, MA 02114 USA. RP Stahl, DL (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,Gray Bigelow 444, Boston, MA 02114 USA. EM dstahl@partners.org RI Stahl, David/E-8015-2015; OI Lewis, Ariane/0000-0002-0756-7320 NR 37 TC 0 Z9 0 U1 0 U2 5 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 DEC PY 2014 VL 121 IS 6 BP 1320 EP 1326 DI 10.1097/ALN.0000000000000377 PG 7 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700023 PM 25057842 ER PT J AU Williams, EC Buchbinder, BR Ahmed, S Alston, TA Rathmell, JP Wang, JP AF Williams, Elizabeth Cox Buchbinder, Bradley R. Ahmed, Shihab Alston, Theodore A. Rathmell, James P. Wang, Jingping TI Spontaneous Intracranial Hypotension Presentation, Diagnosis, and Treatment SO ANESTHESIOLOGY LA English DT Article ID EPIDURAL BLOOD PATCH; CEREBROSPINAL-FLUID LEAKS; SPINAL CSF LEAKS; POSTLUMBAR-PUNCTURE HEADACHE; AUTOLOGOUS BLOOD; FIBRIN SEALANT; MR-MYELOGRAPHY; DURAL PUNCTURE; PRESSURE; PATHOPHYSIOLOGY C1 [Williams, Elizabeth Cox; Ahmed, Shihab; Alston, Theodore A.; Rathmell, James P.; Wang, Jingping] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Buchbinder, Bradley R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Div Neuroradiol, Boston, MA USA. RP Wang, JP (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Jackson Bldg,Room 420,55 Fruit St, Boston, MA 02114 USA. EM jwang23@partners.org NR 63 TC 3 Z9 3 U1 0 U2 6 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 DEC PY 2014 VL 121 IS 6 BP 1327 EP 1333 DI 10.1097/ALN.0000000000000410 PG 7 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700024 PM 25118954 ER PT J AU Sharifpour, M Bittner, EA AF Sharifpour, Milad Bittner, Edward A. TI Postpneumonectomy Syndrome A Case of Shifting Priorities SO ANESTHESIOLOGY LA English DT Editorial Material ID MANAGEMENT C1 [Sharifpour, Milad] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Sharifpour, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM msharifpour@partners.org NR 4 TC 0 Z9 2 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 DEC PY 2014 VL 121 IS 6 BP 1334 EP 1334 DI 10.1097/01.anes.0000435638.00429.ac PG 1 WC Anesthesiology SC Anesthesiology GA AU2FB UT WOS:000345430700025 PM 24047857 ER PT J AU Zeitels, SM Burns, JA AF Zeitels, Steven M. Burns, James A. TI Oncologic Efficacy of Angiolytic KTP Laser Treatment of Early Glottic Cancer SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE glottic cancer; vocal cord cancer; vocal fold cancer; KTP laser; voice surgery; voice preservation; phonomicrosurgery ID VOCAL FOLD; CLINICAL EXPERIENCE; LARYNGEAL-CANCER; IN-SITU; SURGERY; CARCINOMA; VOICE; RADIOTHERAPY; CO2-LASER AB Objective: Angiolytic laser removal of early glottic cancer with ultra-narrow margins was reported in a pilot study 5 years ago as an innovative surgical treatment strategy to better preserve vocal function. Subsequently, in a cohort of > 90 patients, enhanced voice outcomes were achieved and there was diminished need for post-treatment phonosurgical reconstruction. However, the initial pilot study examining oncologic efficacy had a limited number of patients and most did not have 3-year follow-up. Consequently, further analysis of the oncologic efficacy is valuable. Method: Retrospective review. Results: One hundred seventeen patients (T1a-71, T1b-11, T2a-10, T2b-25) underwent potassium-titanyl-phosphate (KTP) laser treatment of early glottic cancer with a minimum 3-year follow-up (average = 53 months). The "b" designation delineated bilateral disease. Disease control for T1 and T2 lesions was 96% (79/82) and 80% (28/35), respectively. All 10 recurrences were treated with radiotherapy. Fifty percent (5/10) were controlled with radiotherapy, and the other 5 died of disease. Larynx preservation and survival were achieved in 99% (81/82) with T1 disease and 89% (31/35) with T2 disease. Conclusion: This investigation provides further evidence that angiolytic KTP laser removal of early glottic cancer with ultra-narrow margins is an effective oncologic treatment strategy. Radiotherapy was preserved for future use in more than 90% of patients. Since a majority of patients are referred by an otolaryngologist to undergo treatment of early glottic cancer with radiotherapy, this investigation provides compelling information to reappraise this paradigm. C1 [Zeitels, Steven M.; Burns, James A.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Zeitels, Steven M.; Burns, James A.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. RP Zeitels, SM (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, One Bowdoin Sq,11th Floor, Boston, MA 02114 USA. EM zeitels.steven@mgh.harvard.edu FU National Philanthropic Trust; 'V' Foundation; Eugene B. Casey Foundation; Voice Health Institute FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by the following nonprofit foundations: National Philanthropic Trust, 'V' Foundation, Eugene B. Casey Foundation, and the Voice Health Institute. NR 42 TC 4 Z9 4 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-4894 EI 1943-572X J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD DEC PY 2014 VL 123 IS 12 BP 840 EP 846 DI 10.1177/0003489414538936 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA AU0KC UT WOS:000345310700005 PM 24970297 ER PT J AU Ainsworth, TA Kobler, JB Loan, GJ Burns, JA AF Ainsworth, Tiffiny A. Kobler, James B. Loan, Gregory J. Burns, James A. TI Simulation Model for Transcervical Laryngeal Injection Providing Real-time Feedback SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE larynx; laryngology; otolaryngology; voice disorders; neurological disorders; motor speech disorders; vocal fold ID VALIDATION; EDUCATION; SURGERY AB Objective: This study aimed to develop and evaluate a model for teaching transcervical laryngeal injections. Methods: A 3-dimensional printer was used to create a laryngotracheal framework based on de-identified computed tomography images of a human larynx. The arytenoid cartilages and intrinsic laryngeal musculature were created in silicone from clay casts and thermoplastic molds. The thyroarytenoid (TA) muscle was created with electrically conductive silicone using metallic filaments embedded in silicone. Wires connected TA muscles to an electrical circuit incorporating a cell phone and speaker. A needle electrode completed the circuit when inserted in the TA during simulated injection, providing real-time feedback of successful needle placement by producing an audible sound. Face validation by the senior author confirmed appropriate tactile feedback and anatomical realism. Otolaryngologists pilot tested the model and completed presimulation and postsimulation questionnaires. Results: The high-fidelity simulation model provided tactile and audio feedback during needle placement, simulating transcervical vocal fold injections. Otolaryngology residents demonstrated higher comfort levels with transcervical thyroarytenoid injection on postsimulation questionnaires. Conclusion: This is the first study to describe a simulator for developing transcervical vocal fold injection skills. The model provides real-time tactile and auditory feedback that aids in skill acquisition. Otolaryngologists reported increased confidence with transcervical injection after using the simulator. C1 [Ainsworth, Tiffiny A.; Kobler, James B.; Burns, James A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil,Dept Surg, Boston, MA 02114 USA. [Loan, Gregory J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Simulat Grp, Cambridge, MA 02138 USA. RP Burns, JA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil,Dept Surg, One Bowdoin Sq,11th Floor, Boston, MA 02114 USA. EM burns.james@mgh.harvard.edu FU Institute of Laryngology and Voice Restoration; "V" Foundation; Eugene B. Casey Foundation FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by the Institute of Laryngology and Voice Restoration, the "V" Foundation, and the Eugene B. Casey Foundation. NR 10 TC 2 Z9 2 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-4894 EI 1943-572X J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD DEC PY 2014 VL 123 IS 12 BP 881 EP 886 DI 10.1177/0003489414539922 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA AU0KC UT WOS:000345310700011 PM 24963092 ER PT J AU Zhu, XS Lu, WD AF Zhu, Xiaoshu Lu, Weidong TI ACUPUNCTURE FOR CANCER PATIENTS SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract ID ALTERNATIVE MEDICINE; BREAST-CANCER; COMPLEMENTARY C1 [Zhu, Xiaoshu] NICM, Sydney, NSW, Australia. [Lu, Weidong] Dana Farber Canc Inst, Boston, MA 02115 USA. RI Lu, Weidong/C-3844-2008 OI Lu, Weidong/0000-0003-2838-6307 NR 7 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-7555 EI 1743-7563 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD DEC PY 2014 VL 10 SU 8 SI SI MA 40 BP 87 EP 88 PG 2 WC Oncology SC Oncology GA AU0ZN UT WOS:000345350900040 ER PT J AU Brahmer, JR Horn, L Gandhi, L Spigel, DR Antonia, SJ Rizvi, NA Powderly, JD Heist, RS Carvajal, RD Jackman, DM Sequist, LV Smith, DC Leming, PD Topalian, SL Hodi, S Snzol, M Harbison, CT Kollia, GD Gupta, A Gettinger, SN AF Brahmer, Julie R. Horn, Leora Gandhi, Leena Spigel, David R. Antonia, Scott J. Rizvi, Naiyer A. Powderly, John D. Heist, Rebecca S. Carvajal, Richard D. Jackman, David M. Sequist, Lecia V. Smith, David C. Leming, Philip D. Topalian, Suzanne L. Hodi, Stephen Snzol, Mario Harbison, Christopher T. Kollia, Gerogia D. Gupta, Ashok Gettinger, Scott N. TI NIVOLUMAB IN PATIENTS WITH ADVANCED NON-SMALL-CELL LUNG CANCER (NSCLC): SURVIVAL AND CLINICAL ACTIVITY BY SUBGROUP ANALYSIS SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Brahmer, Julie R.; Topalian, Suzanne L.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Horn, Leora] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Gandhi, Leena; Jackman, David M.; Hodi, Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Spigel, David R.] Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN USA. [Antonia, Scott J.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Rizvi, Naiyer A.; Carvajal, Richard D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Powderly, John D.] Carolina BioOncol Inst, Huntersville, NC USA. [Heist, Rebecca S.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Sequist, Lecia V.; Smith, David C.] Univ Michigan, Ann Arbor, MI 48109 USA. [Leming, Philip D.] Christ Hosp Canc Ctr, Cincinnati, OH USA. [Snzol, Mario; Gettinger, Scott N.] Yale Canc Ctr, New Haven, CT USA. [Harbison, Christopher T.; Kollia, Gerogia D.; Gupta, Ashok] Bristol Myers Squibb Co, Princeton, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-7555 EI 1743-7563 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD DEC PY 2014 VL 10 SU 8 SI SI MA 299 BP 157 EP 157 PG 1 WC Oncology SC Oncology GA AU0ZN UT WOS:000345350900247 ER PT J AU Hodi, S Sznol, M Kluger, HM McDermott, DF Carvajal, RD Lawrence, DP Topalian, SL Atkins, MB Powderly, JD Sharfman, WH Puzanov, I Smith, DC Leming, PD Lipson, EJ Taube, JM Anders, RA Horak, CE Kollia, G Gupta, A Sosman, JA AF Hodi, Stephen Sznol, Mario Kluger, Harriet M. McDermott, David F. Carvajal, Richard D. Lawrence, Donald P. Topalian, Suzanne L. Atkins, Michael B. Powderly, John D. Sharfman, William H. Puzanov, Igor Smith, David C. Leming, Philip D. Lipson, Evan J. Taube, Janis M. Anders, Robert A. Horak, Christine E. Kollia, Georgia Gupta, Ashok Sosman, Jeffrey A. TI LONG-TERM SURVIVAL OF IPILIMUMAB-NAIVE PATIENTS WITH ADVANCED MELANOMA (MEL) TREATED WITH NIVOLUMAB (ANTI-PROGRAMMED DEATH-1; ANTI-PD-1; BMS-936558; ONO-4538) IN A PHASE I TRIAL SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Hodi, Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sznol, Mario; Kluger, Harriet M.] Yale Univ, Sch Med, New Haven, CT USA. [Sznol, Mario; Kluger, Harriet M.] Yale New Haven Med Ctr, Smilow Canc Ctr, New Haven, CT 06504 USA. [McDermott, David F.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Carvajal, Richard D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Lawrence, Donald P.; Sharfman, William H.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Topalian, Suzanne L.; Lipson, Evan J.; Taube, Janis M.; Anders, Robert A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Atkins, Michael B.] Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. [Powderly, John D.] Carolina BioOncol Inst, Huntersville, NC USA. [Puzanov, Igor; Sosman, Jeffrey A.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Smith, David C.] Univ Michigan, Ann Arbor, MI 48109 USA. [Leming, Philip D.] Christ Hosp, Ctr Canc, Cincinnati, OH 45219 USA. [Horak, Christine E.; Kollia, Georgia; Gupta, Ashok] Bristol Myers Squibb Co, Princeton, NJ USA. NR 0 TC 1 Z9 1 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-7555 EI 1743-7563 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD DEC PY 2014 VL 10 SU 8 SI SI MA 378 BP 177 EP 177 PG 1 WC Oncology SC Oncology GA AU0ZN UT WOS:000345350900306 ER PT J AU Al-Malki, MM Castillo, JJ Sloan, JM Re, A AF Al-Malki, Monzr M. Castillo, Jorge J. Sloan, J. Mark Re, Alessandro TI Hematopoietic Cell Transplantation for Plasmablastic Lymphoma: A Review SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Review DE Plasmablastic lymphoma; Autologous hematopoietic cell; transplantation; MYC rearrangement; HIV-related lymphoma; Non-Hodgkin lymphoma; Epstein-Barr virus; CD20-negative lymphoma ID HUMAN-IMMUNODEFICIENCY-VIRUS; NON-HODGKINS-LYMPHOMA; BONE-MARROW-TRANSPLANTATION; HIGH-DOSE THERAPY; HIV-ASSOCIATED LYMPHOMA; INTERNATIONAL PROGNOSTIC INDEX; ACTIVE ANTIRETROVIRAL THERAPY; INFUSIONAL CYCLOPHOSPHAMIDE; AUTOLOGOUS TRANSPLANTATION; 2ND-LINE CHEMOTHERAPY AB Plasmablastic lymphoma (PBL) is recognized by the World Health Organization as a very aggressive subtype of non-Hodgkin lymphoma. It was initially described in the setting of human immunodeficiency virus (HIV) infection, but it has since been identified in immunocompetent patients, as well. PBL is characterized by CD20 negativity and is associated with Epstein-Barr virus infection. The outcome with available therapy is poor, with median survival of less than 1 year. Multiple adverse prognostic factors have been identified, including HIV-negativity, MYC gene rearrangement, high-risk international prognostic index, and not achieving complete remission after induction therapy. The role of intensification of induction chemotherapy is controversial. Novel agent's have shown some activity in relapsed setting and may have a role in upfront line of treatment. The outcome for relapsed PBL is dismal. Autologous hematopoietic cell transplantation (AHCT) appears to be feasible and may produce better results than chemotherapy, but definitive data are sparse. Chemosensitivity before transplantation might be required to benefit from such therapy. Some data suggest a better outcome of PBL if consolidation with AHCf is used in first-line setting, particularly for those with high-risk disease. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Al-Malki, Monzr M.] Roger Williams Med Ctr, Div Hematol & Med Oncol, Providence, RI USA. [Al-Malki, Monzr M.; Sloan, J. Mark] Boston Univ, Sch Med, Providence, RI 02906 USA. [Castillo, Jorge J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Sloan, J. Mark] Boston Med Ctr, Div Hematol & Med Oncol, Boston, MA USA. [Re, Alessandro] Spedali Civil Brescia, Div Hematol, I-25125 Brescia, Italy. RP Al-Malki, MM (reprint author), Boston Univ, Sch Med, Roger Williams Med Ctr, Div Hematol & Med Oncol, Providence, RI 02906 USA. EM monzr.almalki@chartercare.org OI AL-MALKI, MONZR M./0000-0001-8226-471X; Castillo, Jorge/0000-0001-9490-7532 NR 73 TC 9 Z9 10 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2014 VL 20 IS 12 BP 1877 EP 1884 DI 10.1016/j.bbmt.2014.06.009 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AU4UJ UT WOS:000345606500003 PM 24946718 ER PT J AU Freytes, CO Toro, JJ Yeh, RF Stadtmauer, EA Ratanatharathorn, V Akpek, G Sahovic, E Tricot, GJ Shaughnessy, PJ White, DJ Rodriguez, TE Solomon, SR Yu, LH Zhao, C Patil, S Armstrong, E Smith, A Elekes, A Kato, K Reece, DE AF Freytes, Cesar O. Toro, Juan J. Yeh, Rosa F. Stadtmauer, Edward A. Ratanatharathorn, Voravit Akpek, Goerguen Sahovic, Entezam Tricot, Guido J. Shaughnessy, Paul J. White, Darrell J. Rodriguez, Tulio E. Solomon, Scott R. Yu, Louie H. Zhao, Cathy Patil, Shiva Armstrong, Elizabeth Smith, Angela Elekes, Agnes Kato, Kazunobu Reece, Donna E. TI Safety and Efficacy of Targeted-Dose Busulfan and Bortezomib as a Conditioning Regimen for Patients with Relapsed Multiple Myeloma Undergoing a Second Autologous Blood Progenitor Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Multiple myeloma; Autologous transplantation; Busulfan; Bortezomib ID BONE-MARROW-TRANSPLANTATION; HEPATIC VENOOCCLUSIVE DISEASE; DAILY INTRAVENOUS BUSULFAN; ORAL BUSULFAN; PREPARATIVE REGIMEN; DECREASED INCIDENCE; SYSTEMIC EXPOSURE; MELPHALAN; CYCLOPHOSPHAMIDE; SCHEDULE AB Patients with multiple myeloma (MM) who relapse after autologous transplantation have limited therapeutic options. We conducted a prospective, multicenter, phase ha study to investigate the safety and efficacy of i.v. busulfan (Bu) in combination with bortezomib as a conditioning regimen for a second autotransplantation. Because a safe Bu exposure was unknown in patients receiving this combination, Bu was initially targeted to a total area under the concentration time curve (AUC) of 20,000 mu M x minute. As no concentration-limiting toxicity was observed in 6 patients, this Bu exposure was utilized in the following treatment cohort (n = 24). Individualized Bu dose, based on test dose.8 mg/kg pharmacokinetics (PR), was administered daily for 4 consecutive days starting 5 days before transplantation, followed by a single dose of bortezomib (1.3 mg/m(2)) 1 day before transplantation. The total mean dose of i.v. Bu (including the test dose and 4-day administration) was 142 mg/kg (standard deviation = 2.48; range, 8.7 to 19.2). Confirmatory PR demonstrated that only 2 of 30 patients who underwent transplantation were dosed outside the Bu AUC target and dose adjustments were made for the last 2 doses of i.v. Bu. The median age was 59 years (range, 48 to 73). Median time from first to second transplantation was 28.0 months (range, 12 to 119). Of 26 evaluable patients, 10 patients attained a partial response (PR) or better at 3 months after transplantation, with 2 patients attaining a complete response. At 6 months after transplantation, 5 of 12 evaluable patients had maintained or improved their disease status. Median progression-free survival was 191 days, whereas median overall survival was not reached during the study period. The most common grade 3 and 4 toxicities were febrile neutropenia (50.0%) and stomatitis (43.3%). One transplantation-related death was observed. A combination of dose-targeted i.v. Bu and bortezomib induced PR or better in one third of patients with MM who underwent a second autotransplantation, with acceptable toxicity. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation. C1 [Freytes, Cesar O.; Toro, Juan J.] Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Yeh, Rosa F.; Yu, Louie H.] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, Seattle, WA 98104 USA. [Stadtmauer, Edward A.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Ratanatharathorn, Voravit] Karmanos Canc Inst, Detroit, MI USA. [Akpek, Goerguen] Univ Maryland, Dept Med Oncol, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Sahovic, Entezam] Western Penn Hosp, Pittsburgh, PA 15224 USA. [Tricot, Guido J.] Univ Utah, Sch Med, Div Hematol BMT, Dept Internal Med Hematol, Salt Lake City, UT USA. [Tricot, Guido J.] Univ Utah, Sch Med, Myeloma Program, Dept Internal Med Hematol, Salt Lake City, UT USA. [Shaughnessy, Paul J.] Texas Transplant Inst, San Antonio, TX USA. [White, Darrell J.] Queen Elizabeth 2 Hlth Sci Ctr, Div Hematol, Halifax, NS, Canada. [Rodriguez, Tulio E.] Loyola Univ, Chicago Med Ctr, Cardinal Bernardin Canc Ctr, Maywood, IL 60153 USA. [Solomon, Scott R.] Northside Hosp, Blood & Marrow Transplant Program, Atlanta, GA USA. [Zhao, Cathy; Patil, Shiva; Armstrong, Elizabeth; Smith, Angela; Elekes, Agnes; Kato, Kazunobu] Otsuka Pharmaceut Dev & Commercializat Inc, Princeton, NJ USA. [Reece, Donna E.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. RP Freytes, CO (reprint author), BMT 111,7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM cesar.freytes@va.gov FU Otsuka; Sanofi; Celgene and Janssen; Millennium; Merck; Novartis; BMS; Johnson and Johnson FX grant/research support from Otsuka and Merck; consultant for Otsuka; speakers bureau for Sanofi; advisory board for Spectrum Pharmaceuticals; and other for Cardiovascular Clinical Science Foundation. R.F.Y. reports consultancy for Otsuka. E.S. reports activity with the Millennium speakers bureau and advisory boards with honoraria. P.J.S. reports honoraria from Sanofi and Millenium and research funding from Sanofi. D.J.W. reports honoraria from Otsuka. T.E.R. reports grant/research support from Millennium and Otsuka; consultancy for Celgene, Millennium, and Otsuka; speakers bureau participation for Celgene, Millennium, and Onyx; and advisory board position for Celgene and Millennium. D.E.R. reports research funding, consultant/advisory role, and honoraria from Celgene and Janssen; research funding from Millennium, Merck, Novartis, and BMS; consultancy and advisory role for Onyx; honoraria from Amgen; research funding and honoraria from Otsuka; and research funding from and consultant/advisory role for Johnson and Johnson. C.Z., S.P. E.A., A.S., A.E., and K.K. report Otsuka employment. J.J.T., E.A.S, V.R., G.A., G.J.T., S.R.S., and L.H.Y. report no financial disclosures. NR 33 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2014 VL 20 IS 12 BP 1949 EP 1957 DI 10.1016/j.bbmt.2014.08.007 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AU4UJ UT WOS:000345606500013 PM 25139216 ER PT J AU Chen, YB Li, SL Lane, AA Connolly, C Del Rio, C Valles, B Curtis, M Ballen, K Cutler, C Dey, BR El-Jawahri, A Fathi, AT Ho, VT Joyce, A McAfee, S Rudek, M Rajkhowa, T Verselis, S Antin, JH Spitzer, TR Levis, M Soiffer, R AF Chen, Yi-Bin Li, Shuli Lane, Andrew A. Connolly, Christine Del Rio, Candice Valles, Betsy Curtis, Morgan Ballen, Karen Cutler, Corey Dey, Bimalangshu R. El-Jawahri, Areej Fathi, Amir T. Ho, Vincent T. Joyce, Amy McAfee, Steven Rudek, Michelle Rajkhowa, Trivikram Verselis, Sigitas Antin, Joseph H. Spitzer, Thomas R. Levis, Mark Soiffer, Robert TI Phase I Trial of Maintenance Sorafenib after Allogeneic Hematopoietic Stem Cell Transplantation for Fms-like Tyrosine Kinase 3 Internal Tandem Duplication Acute Myeloid Leukemia SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD); Sorafenib; Maintenance; Acute myeloid leukemia; Allogeneic stem cell transplantation ID CHRONIC MYELOGENOUS LEUKEMIA; WILD-TYPE; ELDERLY-PATIENTS; ALLELIC BURDEN; OPEN-LABEL; ALLO-SCT; FLT3; AML; INHIBITOR; MUTATION AB The fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is associated with a high relapse rate for patients with acute myeloid leukemia (AML) even after allogeneic hematopoietic stem cell transplantation (HSCT). Sorafenib is a tyrosine kinase inhibitor, which inhibits the FLT3 tyrosine kinase and has shown encouraging activity in FLT3-ITD AML. We conducted a phase I trial of maintenance sorafenib after HSCT in patients with FLT3-ITD AML (ClinicalTrials.gov NCT01398501). Patients received a variety of conditioning regimens and graft sources. A dose escalation 3 + 3 cohort design was used to define the maximum tolerated dose (MTD), with an additional 10 patients treated at the MTD. Sorafenib was initiated between days 45 and 120 after HSCT and continued for 12 28-day cycles. Twenty-two patients were enrolled (status at HSCT: first complete remission [CR1], n = 16; second complete remission [CR2], n = 3; refractory, n = 3). The MTD was established at 400 mg twice daily with 1 dose-limiting toxicity (DLT) observed (pericardial effusion). Two patients died of transplantation-related causes, both unrelated to sorafenib. Two patients stopped sorafenib after relapse and 5 stopped because of attributable toxicities after the DLT period. Median follow-up for surviving patients is 16.7 months after HSCT (range, 8.1 to 35.0). There was 1 case of grade II acute graft-versus-host disease (GVHD) after starting sorafenib and the 12-month cumulative incidence of chronic GVHD was 38% (90% confidence interval [CI], 21% to 56%). For all patients, 1-year progression-free survival (PFS) was 85% (90% CI, 66% to 94%) and 1-year overall survival (OS) was 95% (90% CI, 79% to 99%) after HSCT. For patients in CR1/CR2 before HSCT (n = 19), 1-year PFS was 95% (90% CI, 76% to 99%) and 1-year OS was 100%, with only 1 patient who relapsed. Sorafenib is safe after HSCT for FLT3-ITD AML and merits further investigation for the prevention of relapse. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Chen, Yi-Bin; Connolly, Christine; Del Rio, Candice; Valles, Betsy; Curtis, Morgan; Ballen, Karen; Dey, Bimalangshu R.; El-Jawahri, Areej; Fathi, Amir T.; McAfee, Steven; Spitzer, Thomas R.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Li, Shuli] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Lane, Andrew A.; Cutler, Corey; Ho, Vincent T.; Joyce, Amy; Rudek, Michelle; Rajkhowa, Trivikram; Verselis, Sigitas; Antin, Joseph H.; Soiffer, Robert] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Levis, Mark] Johns Hopkins Univ, Sidney Kimmel Canc Ctr, Baltimore, MD USA. RP Chen, YB (reprint author), Massachusetts Gen Hosp, Cox 106,55 Fruit St, Boston, MA 02114 USA. EM ychen6@partners.org FU Bayer Pharmaceuticals, Inc; National Institutes of Health (NIH) [CA 006516]; National Cancer Institute Leukemia SPORE [P50 CA100632-11]; Jock and Bunny Adams Research and Education Endowment; Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH) [P30 CA006973, UL1 RR025005, 1S10RR026824-01]; National Center for Research Resources, NIH [UL1 RR025005] FX Financial disclosure: Funding for this clinical trial was provided in part by a grant from Bayer Pharmaceuticals, Inc.; S.L. is partially supported by National Institutes of Health (NIH) grant CA 006516. This work was supported in part by the National Cancer Institute Leukemia SPORE P50 CA100632-11, the Jock and Bunny Adams Research and Education Endowment, and the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (M.R.; NIH grants P30 CA006973 and UL1 RR025005; Shared Instrument Grant (1S10RR026824-01). This publication was made possible in part by Grant Number UL1 RR025005 from the National Center for Research Resources, a component of the NIH, and NIH Roadrnap for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The authors thank Dr. Timothy Graubert for his thoughtful review of the manuscript. NR 41 TC 44 Z9 47 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2014 VL 20 IS 12 BP 2042 EP 2048 DI 10.1016/j.bbmt.2014.09.007 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AU4UJ UT WOS:000345606500026 PM 25239228 ER PT J AU Dalamaga, M Polyzos, SA Karmaniolas, K Chamberland, J Lekka, A Migdalis, I Papadavid, E Dionyssiou-Asteriou, A Mantzoros, CS AF Dalamaga, Maria Polyzos, Stergios A. Karmaniolas, Konstantinos Chamberland, John Lekka, Antigoni Migdalis, Ilias Papadavid, Evangelia Dionyssiou-Asteriou, Amalia Mantzoros, Christos S. TI Circulating fetuin-A in patients with pancreatic cancer: a hospital-based case-control study SO BIOMARKERS LA English DT Article DE Alpha-2-HS-glycoprotein; insulin; insulin resistance; leptin; malignancy; pancreas ID MYELODYSPLASTIC-SYNDROME; INSULIN-RESISTANCE; ADIPONECTIN; GLYCOPROTEIN; LEPTIN; BREAST; RISK; ATHEROSCLEROSIS; PATHOGENESIS; PROTEINS AB Context: A proteomic analysis has proposed fetuin-A (alpha-2-HS-glycoprotein) as a new potential marker for pancreatic cancer (PC). Objective: Circulating fetuin-A levels in patients with PC. Methods: Serum fetuin-A was measured in 81 cases with PC and 81 matched controls before the initiation of any treatment. Results: Serum fetuin-A was not independently associated with the presence of PC. Although there was a trend with higher fetuin-A levels across PC stages, comparisons of fetuin-A in patients within different PC prognostic stages revealed no differences. Conclusions: Circulating fetuin-A was similar between patients and controls and was not associated with the disease severity. C1 [Dalamaga, Maria; Dionyssiou-Asteriou, Amalia] Univ Athens, Sch Med, Attikon Gen Univ Hosp, Dept Clin Biochem, GR-11527 Athens, Greece. [Polyzos, Stergios A.; Chamberland, John] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02130 USA. [Karmaniolas, Konstantinos; Migdalis, Ilias] 417 Army Share Fund Gen Hosp, Dept Internal Med, Athens, Greece. [Lekka, Antigoni; Mantzoros, Christos S.] 417 Army Share Fund Gen Hosp, Hematol Lab, Athens, Greece. [Papadavid, Evangelia] Univ Athens, Attikon Gen Univ Hosp, Sch Med, Dermatol Clin,Dept Internal Med, Athens, Greece. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA 02130 USA. RP Mantzoros, CS (reprint author), Harvard Univ, Sch Med, 150 S Huntington Ave, Boston, MA 02130 USA. EM cmantzor@bidmc.harvard.edu OI Dalamaga, Maria/0000-0002-7008-388X FU Beth Israel Deaconess Medical Center FX The authors report no declarations of interest. This study was supported by a discretionary grant from Beth Israel Deaconess Medical Center. NR 34 TC 3 Z9 3 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-750X EI 1366-5804 J9 BIOMARKERS JI Biomarkers PD DEC PY 2014 VL 19 IS 8 BP 660 EP 666 DI 10.3109/1354750X.2014.974071 PG 7 WC Biotechnology & Applied Microbiology; Toxicology SC Biotechnology & Applied Microbiology; Toxicology GA AU3FO UT WOS:000345498100006 PM 25347061 ER PT J AU Neilan, TG Bakker, JP Sharma, B Owens, RL Farhad, H Shah, RV Abbasi, SA Kohli, P Wilson, J DeMaria, A Jerosch-Herold, M Kwong, RY Malhotra, A AF Neilan, Tomas G. Bakker, Jessie P. Sharma, Bhavneesh Owens, Robert L. Farhad, Hoshang Shah, Ravi V. Abbasi, Siddique A. Kohli, Puja Wilson, Joel DeMaria, Anthony Jerosch-Herold, Michael Kwong, Raymond Y. Malhotra, Atul TI T1 Measurements for Detection of Expansion of the Myocardial Extracellular Volume in Chronic Obstructive Pulmonary Disease SO CANADIAN JOURNAL OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR MASS; CARDIOVASCULAR MAGNETIC-RESONANCE; SLEEP-APNEA SYNDROME; ARTERIAL-HYPERTENSION; DIASTOLIC DYSFUNCTION; SYSTOLIC FUNCTION; WALK DISTANCE; HEART-DISEASE; FIBROSIS; COPD AB Background: We aimed to assess whether chronic obstructive pulmonary disease (COPD) is associated with expansion of the myocardial extracellular volume (ECV) using T1 measurements. Methods: Adult COPD patients Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2 or higher and free of known cardiovascular disease were recruited. All study patients underwent measures of pulmonary function, 6-minute walk test, serum measures of inflammation, overnight polysomnography, and a contrast cardiac magnetic resonance study. Results: Eight patients with COPD were compared with 8 healthy control subjects. The mean predicted forced expiratory volume at 1 second of COPD subjects was 68%. Compared with control subjects, patients had normal left ventricular (LV) and right ventricular size, mass, and function. However, compared with control subjects, the LV remodelling index (median, 0.87; interquartile range [IQR], 0.71-1.14; vs median, 0.62; IQR, 0.60-0.77; P 1/4 0.03) and active left atrial emptying fraction was increased (median, 46; IQR, 41-49; vs median, 38; IQR, 33-43; P 1/4 0.005), and passive left atrial emptying fraction was reduced (median, 24; IQR, 20-30; vs median, 44; IQR, 31-51; P 1/4 0.007). The ECV was increased in patients with COPD (median, 0.32; IQR, 0.05; vs median, 0.27; IQR, 0.05; P = 0.001). The ECV showed a strong positive association with LV remodelling (r = 0.72; P = 0.04) and an inverse association with the 6-minute walk duration (r = -0.79; P = 0.02) and passive left atrial emptying fraction (r = -0.68; P = 0.003). Conclusions: Expansion of the ECV, suggestive of diffuse myocardial fibrosis, is present in COPD and is associated with LV remodelling, and reduced left atrial function and exercise capacity. C1 [Neilan, Tomas G.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Neilan, Tomas G.] Massachusetts Gen Hosp, Div Radiol, Cardiac MR PET CT Program, Boston, MA USA. [Neilan, Tomas G.; Bakker, Jessie P.; Sharma, Bhavneesh; Owens, Robert L.; Farhad, Hoshang; Shah, Ravi V.; Abbasi, Siddique A.; Kohli, Puja; Jerosch-Herold, Michael; Kwong, Raymond Y.] Harvard Univ, Sch Med, Boston, MA USA. [Bakker, Jessie P.; Sharma, Bhavneesh; Owens, Robert L.; Kohli, Puja] Brigham & Womens Hosp, Dept Med, Div Sleep & Circadian Disorders, Boston, MA 02115 USA. [Farhad, Hoshang; Shah, Ravi V.; Abbasi, Siddique A.; Jerosch-Herold, Michael; Kwong, Raymond Y.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Wilson, Joel; DeMaria, Anthony] Univ Calif San Diego, Div Cardiovasc Med, San Diego, CA 92103 USA. [Jerosch-Herold, Michael] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Malhotra, Atul] Univ Calif San Diego, Pulm & Crit Care Div, San Diego, CA 92103 USA. RP Bakker, JP (reprint author), Dept Med, Div Sleep & Circadian Disorders, 221 Longwood Ave Off BL230, Boston, MA 02115 USA. EM jpbakker@partners.org OI Abbasi, Siddique/0000-0002-9601-7565 FU American Heart Association [12FTF12060588]; [AHA 0840159N]; [NIH R01 HL090897]; [NIH K24 HL 093218]; [NIH 1 P01 HL 095491]; [NIH R01HL110350]; [NIH UM1HL108724]; [NIH R01-AG035117]; [NIH R01 HL085188]; [UL1 RR 025758-01]; [R01HL090634-01A1]; [R01HL091157] FX This work was supported in part by an American Heart Association Fellow to Faculty Grant (12FTF12060588, TGN), and project grants (R01HL090634-01A1, MJH; R01HL091157, RYK). Dr Malhotra is Principal Investigator (PI) on the following grants: AHA 0840159N, NIH R01 HL090897, NIH K24 HL 093218, NIH 1 P01 HL 095491 (Overall PI: Saper, Brigham PI: Malhotra), NIH R01HL110350, NIH UM1HL108724 (Overall PIs: Talmor/Loring, Brigham PI: Malhotra), NIH R01-AG035117, NIH R01 HL085188. The Harvard Catalyst is funded by UL1 RR 025758-01. NR 47 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 0828-282X EI 1916-7075 J9 CAN J CARDIOL JI Can. J. Cardiol. PD DEC PY 2014 VL 30 IS 12 BP 1668 EP 1675 DI 10.1016/j.cjca.2014.08.006 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AU4ME UT WOS:000345584400037 PM 25442461 ER PT J AU Parikh, SA Drachman, DE AF Parikh, Sahil A. Drachman, Douglas E. TI Will Drug Coated Balloons Score Another Victory? SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material DE drug coated balloon; paclitaxel; scoring balloon ID PACLITAXEL; ANGIOPLASTY; RESTENOSIS; DELIVERY C1 [Parikh, Sahil A.] Univ Hosp Case Med Ctr, Div Cardiovasc Med, Cleveland, OH 44106 USA. [Parikh, Sahil A.] Harrington Heart & Vasc Inst, Cleveland, OH USA. [Parikh, Sahil A.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Drachman, Douglas E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Drachman, Douglas E.] Harvard Univ, Sch Med, Boston, MA USA. RP Parikh, SA (reprint author), Univ Hosp Case Med Ctr, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM sahil.parikh@uhhospitals.org 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 1522-1946 EI 1522-726X J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD DEC 1 PY 2014 VL 84 IS 7 SI 1029 BP 1099 EP 1100 DI 10.1002/ccd.25701 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AU3LJ UT WOS:000345514400015 PM 25418004 ER PT J AU Parikh, SA Shishehbor, MH Gray, BH White, CJ Jaff, MR AF Parikh, Sahil A. Shishehbor, Mehdi H. Gray, Bruce H. White, Christopher J. Jaff, Michael R. TI SCAI Expert Consensus Statement for Renal Artery Stenting Appropriate Use SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE renovascular hypertension; renal artery stenosis; stent ID TRANSLESIONAL PRESSURE-GRADIENTS; CONGESTIVE-HEART-FAILURE; FRACTIONAL FLOW RESERVE; RENOVASCULAR HYPERTENSION; ISCHEMIC NEPHROPATHY; EMBOLIC PROTECTION; PULMONARY-EDEMA; MEDICAL THERAPY; STENOSIS; ANGIOPLASTY AB The pathophysiology of atherosclerotic renal artery stenosis (RAS) includes activation of the renin-angiotensin-aldosterone axis with resultant renovascular hypertension. Renal artery stenting has emerged as the primary revascularization strategy in most patients with hemodynamically significant atherosclerotic RAS. Despite the frequency with which hemodynamically significant RAS is observed and high rates of technical success of renal artery stenting, there remains considerable debate among experts regarding the role of medical therapy versus revascularization for renovascular hypertension. Modern, prospective, multicenter registries continue to demonstrate improvement in systolic and diastolic blood pressure with excellent safety profiles in patients with RAS. Modern randomized, controlled clinical trials of optimal medical therapy versus renal stenting particularly designed to demonstrate preservation in renal function after renal artery stenting have demonstrated limited benefit. However, these trials frequently excluded patients that may benefit from renal artery stenting. This document was developed to guide physicians in the modern practical application of renal stenting, to highlight the current limitations in the peer-reviewed literature, to suggest best-practices in the performance of renal stenting and to identify opportunities to advance the field. (c) 2014 Wiley Periodicals, Inc. C1 [Parikh, Sahil A.] Univ Hosp Case Med Ctr, Harrington Heart & Vasc Inst, Cleveland, OH 44106 USA. [Parikh, Sahil A.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Shishehbor, Mehdi H.] Cleveland Clin, Cleveland, OH 44106 USA. [Gray, Bruce H.] Univ S Carolina, Sch Med Greenville, Greenville, SC USA. [White, Christopher J.] Univ Queensland, New Orleans, LA USA. [White, Christopher J.] Ochsner Med Ctr, John Ochsner Heart & Vasc Inst, New Orleans, LA USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Parikh, SA (reprint author), Univ Hosp Case Med Ctr, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM sahil.parikh@uhhospitals.org RI White, Christopher/J-6686-2012 OI White, Christopher/0000-0001-8618-7539 NR 43 TC 15 Z9 20 U1 1 U2 2 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 DEC 1 PY 2014 VL 84 IS 7 SI 1029 BP 1163 EP 1172 DI 10.1002/ccd.25559 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AU3LJ UT WOS:000345514400026 PM 25138644 ER PT J AU Gaensbauer, JT Rakhola, JT Onyango-Makumbi, C Mubiru, M Westcott, JE Krebs, NF Asturias, EJ Fowler, MG McFarland, E Janoff, EN AF Gaensbauer, James T. Rakhola, Jeremy T. Onyango-Makumbi, Carolyne Mubiru, Michael Westcott, Jamie E. Krebs, Nancy F. Asturias, Edwin J. Fowler, Mary Glenn McFarland, Elizabeth Janoff, Edward N. TI Impaired Haemophilus influenzae Type b Transplacental Antibody Transmission and Declining Antibody Avidity through the First Year of Life Represent Potential Vulnerabilities for HIV-Exposed but - Uninfected Infants SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CONJUGATE VACCINE; MATERNAL IMMUNIZATION; POLYSACCHARIDE VACCINE; ROUTINE IMMUNIZATION; PLACENTAL-TRANSFER; IGG ANTIBODIES; CHILDREN; INFECTION; RESPONSES AB To determine whether immune function is impaired among HIV-exposed but - uninfected (HEU) infants born to HIV-infected mothers and to identify potential vulnerabilities to vaccine-preventable infection, we characterized the mother-to-infant placental transfer of Haemophilus influenzae type b-specific IgG (Hib-IgG) and its levels and avidity after vaccination in Ugandan HEU infants and in HIV-unexposed U. S. infants. Hib-IgG was measured by enzyme-linked immunosorbent assay in 57 Ugandan HIV-infected mothers prenatally and in their vaccinated HEU infants and 14 HIV-unexposed U. S. infants at birth and 12, 24, and 48 weeks of age. Antibody avidity at birth and 48 weeks of age was determined with 1 M ammonium thiocyanate. A median of 43% of maternal Hib-IgG was transferred to HEU infants. Although its level was lower in HEU infants than in U. S. infants at birth (P < 0.001), Hib-IgG was present at protective levels (> 1.0 mu g/ml) at birth in 90% of HEU infants and all U. S. infants. HEU infants had robust Hib-IgG responses to a primary vaccination. Although Hib-IgG levels declined from 24 to 48 weeks of age in HEU infants, they were higher than those in U. S. infants (P = 0.002). Antibody avidity, comparable at birth, declined by 48 weeks of age in both populations. Early vaccination of HEU infants may limit an initial vulnerability to Hib disease resulting from impaired transplacental antibody transfer. While initial Hib vaccine responses appeared adequate, the confluence of lower antibody avidity and declining Hib-IgG levels in HEU infants by 12 months support Hib booster vaccination at 1 year. Potential immunologic impairments of HEU infants should be considered in the development of vaccine platforms for populations with high maternal HIV prevalence. C1 [Gaensbauer, James T.; Westcott, Jamie E.; Krebs, Nancy F.; Asturias, Edwin J.; McFarland, Elizabeth] Univ Colorado Denver, Dept Pediat, Aurora, CO 80045 USA. [Rakhola, Jeremy T.; Janoff, Edward N.] Univ Colorado Denver, Dept Med, Aurora, CO USA. [Onyango-Makumbi, Carolyne; Mubiru, Michael; Fowler, Mary Glenn] Johns Hopkins Univ, Res Collaborat, Makerere Univ, Kampala, Uganda. [Gaensbauer, James T.; Asturias, Edwin J.] Colorado Sch Publ Hlth, Ctr Global Hlth, Aurora, CO USA. [Rakhola, Jeremy T.; McFarland, Elizabeth; Janoff, Edward N.] Mucosal & Vaccine Res Colorado MAVRC, Aurora, CO USA. [Janoff, Edward N.] Denver Vet Affairs Med Ctr, Denver, CO USA. RP Gaensbauer, JT (reprint author), Univ Colorado Denver, Dept Pediat, Aurora, CO 80045 USA. EM james.gaensbauer@childrenscolorado.org FU National Institutes of Health [R01 HD059527, R21AI083615, NIH K24 DK083772]; Elisabeth Glaser Pediatric AIDS Foundation [MV-00-9-900-01432-0-00]; National Institutes of Health/National Center for Advancing Translational Sciences, Colorado Clinical and Translational Sciences Institute [UL1 TR000154, UL1 RR025780]; Mucosal and Vaccine Research Colorado program; Veterans Affairs Research Service FX This work was supported by the National Institutes of Health (R01 HD059527 and R21AI083615 to E.J., NIH K24 DK083772 to N.F.K.), the Elisabeth Glaser Pediatric AIDS Foundation (MV-00-9-900-01432-0-00 to E.J.), the National Institutes of Health/National Center for Advancing Translational Sciences, Colorado Clinical and Translational Sciences Institute (UL1 TR000154 to J.T.G. and UL1 RR025780 to E.J.), the Mucosal and Vaccine Research Colorado program, and the Veterans Affairs Research Service. The contents of this report are solely our responsibility and do not necessarily represent the official views of the National Institutes of Health or the Department of Veterans Affairs. NR 49 TC 9 Z9 9 U1 1 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 EI 1556-679X J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD DEC PY 2014 VL 21 IS 12 BP 1661 EP 1667 DI 10.1128/CVI.00356-14 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AU3RX UT WOS:000345532300008 PM 25298109 ER PT J AU Wason, S Mount, D Faulkner, R AF Wason, Suman Mount, David Faulkner, Robert TI Single-Dose, Open-Label Study of the Differences in Pharmacokinetics of Colchicine in Subjects with Renal Impairment, Including End-Stage Renal Disease SO CLINICAL DRUG INVESTIGATION LA English DT Article ID US GENERAL-POPULATION; SERUM CREATININE; ACUTE GOUT; HYPERURICEMIA; GUIDELINES; TOXICITY AB Background and Objective The effect of renal impairment on colchicine pharmacokinetics in patients with chronic kidney disease (CKD) has not been studied previously. We evaluated the effect of renal impairment on colchicine pharmacokinetics in patients with CKD. Methods The pharmacokinetics and safety of a single, oral 0.6-mg dose of colchicine was evaluated in an open-label study in eight healthy subjects with normal renal function; eight subjects each with mild, moderate, or severe renal impairment; and eight subjects with end-stage renal disease (ESRD) who received a single dose prior to receiving, and again following, hemodialysis. Results Colchicine exposure was similar for subjects with normal renal function, mild impairment, or ESRD prior to and during hemodialysis (24.7-31.7 ng.h/mL), but was up to twofold higher in subjects with moderate or severe renal impairment (48.9 and 48.0 ng.h/mL, respectively). A very small amount of the colchicine dose (mean of 5.2 %) was recovered in dialysate. Conclusions It appears that patients with mild or moderate renal impairment or those actively receiving hemodialysis do not show accumulation of colchicine, whereas those with severe renal impairment show a doubling of exposure. All patients with renal impairment taking colchicine should be closely monitored, especially as many patients taking colchicine often have other comorbidities and may be taking other medications. C1 [Wason, Suman; Faulkner, Robert] Mutual Pharmaceut Co Inc, Philadelphia, PA 19124 USA. [Mount, David] Brigham & Womens Hosp, Div Renal, Harvard Inst Med, Boston, MA 02115 USA. [Mount, David] VA Boston Healthcare Syst, Div Renal, Boston, MA USA. RP Faulkner, R (reprint author), URL Pharma Inc, 1100 Orthodox St, Philadelphia, PA 19124 USA. EM Robert.Faulkner@sunpharma.com FU URL Pharma, Inc., (Philadelphia, PA, USA); Takeda Pharmaceuticals International, Inc., Deerfield, IL, USA FX Initial editorial assistance in the preparation of this manuscript was provided by Peter Todd, PhD, and James A. Shiffer, RPh, of Write On Time Medical Communications, LLC, who received original financial support from URL Pharma, Inc., (Philadelphia, PA, USA). Additional writing and editorial assistance was provided by Courtney Mezzacappa Zeni, PhD, and Meryl Gersh, PhD, of AlphaBioCom, LLC (King of Prussia, PA, USA) and was supported by Takeda Pharmaceuticals International, Inc., Deerfield, IL, USA. NR 23 TC 5 Z9 5 U1 0 U2 2 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 1173-2563 EI 1179-1918 J9 CLIN DRUG INVEST JI Clin. Drug Invest. PD DEC PY 2014 VL 34 IS 12 BP 845 EP 855 DI 10.1007/s40261-014-0238-6 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AU1NR UT WOS:000345388000002 PM 25385362 ER PT J AU Sonpavde, G Bellmunt, J Rosenberg, JE Regazzi, AM Bajorin, DF Choueiri, TK Qu, AQ Niegisch, G Albers, P Necchi, A Di Lorenzo, G Fougeray, R Wong, YN Sridhar, SS Ko, YJ Milowsky, MI Galsky, MD Pond, GR AF Sonpavde, Guru Bellmunt, Joaquim Rosenberg, Jonathon E. Regazzi, Ashley M. Bajorin, Dean F. Choueiri, Toni K. Qu, Angela Q. Niegisch, Guenter Albers, Peter Necchi, Andrea Di Lorenzo, Giuseppe Fougeray, Ronan Wong, Yu-Ning Sridhar, Srikala S. Ko, Yoo-Joung Milowsky, Matthew I. Galsky, Matthew D. Pond, Gregory R. TI Patient Eligibility and Trial Design for the Salvage Therapy of Advanced Urothelial Carcinoma SO CLINICAL GENITOURINARY CANCER LA English DT Editorial Material ID CISPLATIN-BASED CHEMOTHERAPY; TRANSITIONAL-CELL CARCINOMA; PHASE-III; 2ND-LINE THERAPY; SINGLE GROUP; CANCER; SURVIVAL; TRACT; MULTICENTER; PACLITAXEL C1 [Sonpavde, Guru] UAB Comprehens Canc Ctr, Birmingham, AL 35233 USA. [Bellmunt, Joaquim] Univ Hosp del Mar IMIM, Barcelona, Spain. [Rosenberg, Jonathon E.; Regazzi, Ashley M.; Bajorin, Dean F.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Choueiri, Toni K.; Qu, Angela Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Choueiri, Toni K.; Qu, Angela Q.] Harvard Univ, Sch Med, Boston, MA USA. [Niegisch, Guenter; Albers, Peter] Univ Dusseldorf, Dusseldorf, Germany. [Necchi, Andrea] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Di Lorenzo, Giuseppe] Univ Naples Federico II, Naples, Italy. [Fougeray, Ronan] Inst Rech Pierre Fabre, Boulogne, France. [Wong, Yu-Ning] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Sridhar, Srikala S.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Ko, Yoo-Joung] Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Milowsky, Matthew I.] Univ N Carolina, Chapel Hill, NC USA. [Galsky, Matthew D.] Mt Sinai Sch Med, Tisch Canc Ctr Inst, New York, NY USA. [Pond, Gregory R.] McMaster Univ, Hamilton, ON, Canada. RP Sonpavde, G (reprint author), UAB Comprehens Canc Ctr, Birmingham, AL 35233 USA. OI Niegisch, Gunter/0000-0001-6929-8691; Regazzi, Ashley/0000-0002-6019-1852; Rosenberg, Jonathan/0000-0003-2637-4249; Necchi, Andrea/0000-0002-3007-2756 NR 18 TC 7 Z9 7 U1 0 U2 0 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD DEC PY 2014 VL 12 IS 6 BP 395 EP 398 DI 10.1016/j.clgc.2014.03.016 PG 4 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AU3YZ UT WOS:000345547700001 PM 25035282 ER PT J AU Pond, GR Milowsky, MI Kolinsky, MP Eigl, BJ Necchi, A Harshman, LC Di Lorenzo, G Dorff, TB Lee, RJ Sonpavde, G AF Pond, Gregory R. Milowsky, Matthew I. Kolinsky, Michael P. Eigl, Bernhard J. Necchi, Andrea Harshman, Lauren C. Di Lorenzo, Giuseppe Dorff, Tanya B. Lee, Richard J. Sonpavde, Guru TI Concurrent Chemoradiotherapy for Men With Locally Advanced Penile Squamous Cell Carcinoma SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Chemoradiation; Locally advanced; Outcomes; Penile squamous cell carcinoma; Prognosis ID TO-LYMPHOCYTE RATIO; PHASE-II; NEOADJUVANT CHEMOTHERAPY; PRETREATMENT NEUTROPHIL; PREOPERATIVE NEUTROPHIL; CANCER; CISPLATIN; THERAPY; METHOTREXATE; COMBINATION AB Chemoradiotherapy is often administered for locally advanced penile squamous cell carcinoma (PSCC), an orphan malignancy, but outcomes with this approach are unclear. This retrospective analysis of 26 patients reports outcomes with concurrent chemoradiotherapy for locally advanced and advanced PSCC. The study highlights dismal outcomes with chemoradiotherapy and suggests the need for better understanding of tumor biology and evaluation of novel systemic agents. Background: Outcomes with concurrent chemoradiotherapy for penile squamous cell carcinoma (PSCC) are unclear, and only anecdotal reports have been published. This study was a retrospective analysis of patients who received concurrent chemotherapy and radiotherapy for PSCC. Patients and Methods: Individual patient-level data were obtained from 5 institutions for outcomes with concurrent chemoradiotherapy for PSCC. Descriptive statistics were calculated, and univariable Cox proportional hazards regression analysis was conducted to examine the prognostic effect of candidate factors on progression-free survival (PFS) and overall survival (OS). Results: A total of 26 men were evaluable. The mean age was 60.3 years. The clinical stage was <= III in 9 patients (36%) and stage IV in the rest. Soft tissue and visceral metastasis were present in 35% and 20% of patients, respectively. The chemotherapy was cisplatin-based in 92.3% of patients, and the median (range) of external beam radiotherapy administered was 4900 cGy (range, 1800-7000 cGy). The median OS was 6.9 months (95% CI, 5-14), and the median PFS was 5.1 months (95% CI, 2.5-7.0). When excluding patients with M1 disease, the remaining patients (n = 21) had a median OS and PFS of 10.0 months (95% CI, 5-14) and 6.0 months (95% CI, 2.0-7.0), respectively. Baseline neutrophil to lymphocyte ratio (NLR) was significantly associated with survival, and visceral metastasis showed a trend for association with OS. Conclusions: Concurrent chemoradiotherapy demonstrated poor outcomes for locally advanced PSCC. Better understanding of tumor biology and study of novel combinations of biologic agents with radiation are warranted. (C) 2014 Elsevier Inc. All rights reserved. C1 [Pond, Gregory R.] McMaster Univ, Hamilton, ON, Canada. [Milowsky, Matthew I.] Univ N Carolina, Chapel Hill, NC USA. [Kolinsky, Michael P.] Univ Alberta, Edmonton, AB, Canada. [Eigl, Bernhard J.] BC Canc Agcy, Vancouver, BC, Canada. [Necchi, Andrea] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Harshman, Lauren C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Di Lorenzo, Giuseppe] Univ Naples Federico II, Naples, Italy. [Dorff, Tanya B.] Univ So Calif, Los Angeles, CA 90089 USA. [Lee, Richard J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Sonpavde, Guru] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. RP Sonpavde, G (reprint author), UAB Comprehens Canc Ctr, Div Hematol Oncol, 1802 6th Ave S,NP2540, Birmingham, AL 35294 USA. EM gsonpavde@uabmc.edu OI Necchi, Andrea/0000-0002-3007-2756 NR 32 TC 3 Z9 3 U1 1 U2 3 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 DEC PY 2014 VL 12 IS 6 BP 440 EP 446 DI 10.1016/j.clgc.2014.03.009 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AU3YZ UT WOS:000345547700008 PM 24787971 ER PT J AU Khalilzadeh, O Sabel, B Sung, Y Parikh, A Phan, CM Dinkel, J Yoo, AJ Romero, J Gupta, R AF Khalilzadeh, O. Sabel, B. Sung, Y. Parikh, A. Phan, C. M. Dinkel, J. Yoo, A. J. Romero, J. Gupta, R. TI Temporal Evolution of Intraparenchymal Hyperdensity After Intra-arterial Therapy in Patients with Ischemic Stroke: Optimal Discrimination Between Hemorrhage and Iodinated Contrast SO CLINICAL NEURORADIOLOGY LA English DT Article DE Computed tomography; Conventional CT; Ischemic stroke; Intra-arterial thrombolysis; Thrombectomy; Intraparenchymal hemorrhage ID CEREBRAL-ARTERY OCCLUSION; DUAL-ENERGY CT; REVASCULARIZATION THERAPIES; INTRACEREBRAL HEMORRHAGE; INTRACRANIAL HEMORRHAGE; REPERFUSION THERAPY; COMPUTED-TOMOGRAPHY; BRAIN; TRANSFORMATION; EXTRAVASATION AB CT hyperattenuation arising from iodinated contrast has a different temporal evolution than that arising due to hemorrhage. This paper presents a method for optimal discrimination between hemorrhage and iodinated contrast in a postintervention CT in stroke patients. We analyzed the brain computed tomography (CT) scans of consecutive patients with intraparenchymal hyperattenuation due to hemorrhage (n= 41), those due to iodinated contrast alone (n= 24), and those due to contrast mixed with hemorrhage after reperfusion therapy (n= 14) in stroke patients. The difference between the maximum enhancement in hyperattenuation in the affected area and the corresponding contralateral area, dubbed Relative Maximum Enhancement (RME), was tracked over time. We fitted regression models to the RME changes due to hemorrhage and contrast to describe their temporal decay, and then derived the optimal discriminant curve that distinguishes the two. A computer algorithm coregistered the baseline and follow-up CT scans and performed pixel-by-pixel comparison to determine hemorrhage and iodinated contrast based on the RME changes with respect to the discriminant curve. For both hemorrhage (k= -aEuro parts per thousand 0.004, R (2) = 0.7) and iodinated contrast (k= -aEuro parts per thousand 0.064, R (2) = 0.9), the temporal evolution of RMEs were best fitted by exponential decay curves, with respective half-lives of 192.3 and 10.7 h. An exponential decay model (k= -aEuro parts per thousand 0.026) for optimal discrimination of hemorrhage vs. contrast was fitted. The computer algorithm implementing this model was successful in predicting the presence of hemorrhage in a hyperdense lesion with sensitivity = 93 % and specificity = 91 %. Intraparenchymal hemorrhage and contrast have markedly different decay half-lives that can be used to assess hemorrhage in a hyperdense lesion on a CT scan after intra-arterial therapy. C1 [Gupta, R.] Massachusetts Gen Hosp, Dept Radiol B75 240, Boston, MA 02114 USA. [Khalilzadeh, O.; Sabel, B.; Sung, Y.; Parikh, A.; Phan, C. M.; Dinkel, J.; Yoo, A. J.; Romero, J.; Gupta, R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Khalilzadeh, O.; Sabel, B.; Sung, Y.; Parikh, A.; Phan, C. M.; Dinkel, J.; Yoo, A. J.; Romero, J.; Gupta, R.] Harvard Univ, Sch Med, Boston, MA USA. RP Gupta, R (reprint author), Massachusetts Gen Hosp, Dept Radiol B75 240, Boston, MA 02114 USA. EM rgupta1@partners.org FU Siemens Medical Solutions FX This study is supported by a research grant from Siemens Medical Solutions. NR 25 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1869-1439 EI 1869-1447 J9 CLIN NEURORADIOL JI Clin. Neuroradiol. PD DEC PY 2014 VL 24 IS 4 BP 365 EP 371 DI 10.1007/s00062-013-0268-0 PG 7 WC Clinical Neurology; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU1SJ UT WOS:000345400200008 PM 24477664 ER PT J AU Stuyckens, K Saad, F Xu, XS Ryan, CJ Smith, MR Griffin, TW Yu, MK Vermeulen, A Nandy, P Poggesi, I AF Stuyckens, Kim Saad, Fred Xu, Xu Steven Ryan, Charles J. Smith, Matthew R. Griffin, Thomas W. Yu, Margaret K. Vermeulen, An Nandy, Partha Poggesi, Italo TI Population Pharmacokinetic Analysis of Abiraterone in Chemotherapy-Na < ve and Docetaxel-Treated Patients with Metastatic Castration-Resistant Prostate Cancer SO CLINICAL PHARMACOKINETICS LA English DT Article ID ACETATE PLUS PREDNISONE; I CLINICAL-TRIAL; PHASE-I; INTRAPATIENT VARIABILITY; OPEN-LABEL; CYP17; INHIBITOR; MODEL; MEN; QUANTIFICATION AB Abiraterone acetate, an androgen biosynthesis inhibitor, prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) in the pre- and post-chemotherapy setting as demonstrated by the pivotal phase III studies COU-AA-301 and COU-AA-302. We performed population pharmacokinetic analyses to estimate pharmacokinetic parameters after oral administration of 1,000 mg/day of abiraterone acetate in patients with mCRPC, with or without prior chemotherapy, and after a single 1,000 mg dose in healthy volunteers. The study objectives were to determine consistency between patient populations and to characterize factors that may influence abiraterone pharmacokinetics. Studies in this analysis included COU-AA-302 (chemotherapy na < ve); COU-AA-301 and COU-AA-006 (chemotherapy pretreated); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 359 subjects (62 healthy volunteers, 297 patients) were analyzed using non-linear mixed-effects modeling. An Erlang-type absorption model with first-order elimination and three-transit compartments following sequential zero- and first-order processes was used to characterize abiraterone pharmacokinetics. Absorption-related parameters were affected by food intake. Abiraterone pharmacokinetics were characterized by an extensive apparent clearance, which was lower in patients with mCRPC (1,550 L/h) versus healthy subjects (2,240 L/h), and by large apparent central (5,620 L) and peripheral (17,400 L) volumes of distribution. Abiraterone pharmacokinetics were similar in chemotherapy-pretreated and -na < ve patients and were characterized by a high between- and within-subject variability [e.g., between-subject coefficient of variation (CV%) for relative bioavailability for the modified fasting state was 61.1 % and the CV% for within-subject variability was 71.3 %]. The fat content of food taken with abiraterone acetate affected the bioavailability of abiraterone. No factors beyond food intake and health status (healthy vs. mCRPC) impacted abiraterone pharmacokinetics. Based on the pharmacokinetics model, the recommended 1,000 mg/day of abiraterone acetate resulted in similar abiraterone exposure for patients with mCRPC regardless of prior chemotherapy. The fat content of food affected relative bioavailability of abiraterone, though the extent of this effect is dependent on health status. C1 [Stuyckens, Kim; Vermeulen, An; Poggesi, Italo] Janssen Res & Dev, B-2340 Beerse, Belgium. [Saad, Fred] Univ Montreal, Montreal, PQ, Canada. [Xu, Xu Steven; Nandy, Partha] Janssen Res & Dev, Raritan, NJ USA. [Ryan, Charles J.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Smith, Matthew R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Griffin, Thomas W.; Yu, Margaret K.] Janssen Res & Dev, Los Angeles, CA USA. RP Stuyckens, K (reprint author), Janssen Res & Dev, Turnhoutseweg 30, B-2340 Beerse, Belgium. EM kstuyck1@its.jnj.com FU Janssen Research & Development, Raritan, NJ, USA; Janssen Global Services, LLC.; Janssen Research Development FX This study was sponsored by Janssen Research & Development, Raritan, NJ, USA. Writing assistance was provided by Shala Thomas, PhD, of PAREXEL, and was funded by Janssen Global Services, LLC. The authors wish to also thank Sandra Boom (Pharma-Plus) for her assistance in the preparation of this manuscript, funded by Janssen Research & Development. NR 38 TC 7 Z9 7 U1 2 U2 15 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0312-5963 EI 1179-1926 J9 CLIN PHARMACOKINET JI Clin. Pharmacokinet. PD DEC PY 2014 VL 53 IS 12 BP 1149 EP 1160 DI 10.1007/s40262-014-0178-6 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AU1OF UT WOS:000345389300005 PM 25204404 ER PT J AU Bellmunt, J Puente, J de Muro, JG Lainez, N Rodriguez, C Duran, I AF Bellmunt, J. Puente, J. Garcia de Muro, J. Lainez, N. Rodriguez, C. Duran, I. TI SEOM clinical guidelines for the treatment of renal cell carcinoma SO CLINICAL & TRANSLATIONAL ONCOLOGY LA English DT Article DE Renal cell carcinoma; SEOM; Guidelines ID PHASE-III TRIAL; RADICAL NEPHRECTOMY; INTERFERON-ALPHA; TARGETED THERAPY; DOUBLE-BLIND; CANCER; SORAFENIB; TUMORS; SUNITINIB; PAZOPANIB AB The purpose of this article was to provide updated recommendations for the diagnosis and treatment of renal cell carcinoma. Pathological confirmation is mandatory before treatment with ablative or focal therapies before any type of systemic therapy. Renal cell cancer should be staged according to the TNM classification system. A laparoscopic nephron-sparing surgery should be the approach for tumors < 4 cm if technically feasible. Otherwise, radical (or partial in selected cases) nephrectomy is the treatment of choice, with lymph node dissection only performed in patients with clinically detected lymph node involvement. Some retrospective evidence for a cytoreductive nephrectomy in the postimmunotherapy era suggests a benefit in patients with good or intermediate risk or for patients with a symptomatic primary lesion. Adjuvant treatment with chemotherapy or with targeted agents is not recommended and studies are ongoing today. Patients with metastatic disease should be staged by computed tomography scans of the chest, abdomen and pelvis. The efficacy of sunitinib, bevacizumab plus interferon-alpha, and pazopanib is well established in patients with good and intermediate risk as well for temsirolimus in poor-risk patients. These four agents are considered standard of care in first-line treatment. Sorafenib, axitinib and everolimus are standard of care in second line in different settings based on their benefit in PFS. Besides some benefit described for IL-2 in highly selected patients in first line, there is a promising and emerging role for the new immunotherapeutic approaches in metastatic renal cell carcinoma. C1 [Bellmunt, J.] Harvard Univ, Sch Med, Dana Farber Canc Ctr, Boston, MA 02163 USA. [Bellmunt, J.] Hosp del Mar IMIM, Barcelona, Spain. [Puente, J.] Hosp Clin San Carlos, Dept Med Oncol, Madrid, Spain. [Garcia de Muro, J.] Inst Catala Oncol, Dept Med Oncol, Barcelona, Spain. [Lainez, N.] Complejo Hosp Navarra, Dept Med Oncol, Pamplona, Spain. [Rodriguez, C.] Hosp Univ Salamanca, Dept Med Oncol, Salamanca, Spain. [Duran, I.] Hosp Univ Virgen del Rocio, Dept Med Oncol, Seville, Spain. RP Bellmunt, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Ctr, Boston, MA 02163 USA. EM joaquim_bellmunt@dfci.harvard.edu RI IBIS, NUEVAS TERAPIA/P-3415-2015 NR 48 TC 8 Z9 8 U1 0 U2 3 PU SPRINGER-VERLAG ITALIA SRL PI MILAN PA VIA DECEMBRIO, 28, MILAN, 20137, ITALY SN 1699-048X EI 1699-3055 J9 CLIN TRANSL ONCOL JI Clin. Transl. Oncol. PD DEC PY 2014 VL 16 IS 12 BP 1043 EP 1050 DI 10.1007/s12094-014-1219-1 PG 8 WC Oncology SC Oncology GA AU1RG UT WOS:000345397300004 PM 25274276 ER PT J AU Pedrelli, P Blais, MA Alpert, JE Shelton, RC Walker, RSW Fava, M AF Pedrelli, Paola Blais, Mark A. Alpert, Jonathan E. Shelton, Richard C. Walker, Rosemary S. W. Fava, Maurizio TI Reliability and validity of the Symptoms of Depression Questionnaire (SDQ) SO CNS SPECTRUMS LA English DT Article DE anxious depression; assessment; depression ID STAR-ASTERISK-D; PSYCHOMETRIC PROPERTIES; ANXIOUS DEPRESSION; PRIMARY-CARE; ANXIETY; INVENTORY; DISORDERS; OUTPATIENTS AB Current measures for major depressive disorder focus primarily on the assessment of depressive symptoms, while often omitting other common features. However, the presence of comorbid features in the anxiety spectrum influences outcome and may effect treatment. More comprehensive measures of depression are needed that include the assessment of symptoms in the anxiety-depression spectrum. This study examines the reliability and validity of the Symptoms of Depression Questionnaire (SDQ), which assesses irritability, anger attacks, and anxiety symptoms together with the commonly considered symptoms of depression. Analysis of the factor structure of the SDQ identified 5 subscales, including one in the anxiety-depression spectrum, with adequate internal consistency and concurrent validity. The SDQ may be a valuable new tool to better characterize depression and identify and administer more targeted interventions. C1 [Pedrelli, Paola; Blais, Mark A.] Massachusetts Gen Hosp, Dept Psychol, Boston, MA 02114 USA. [Alpert, Jonathan E.; Walker, Rosemary S. W.] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Shelton, Richard C.] Vanderbilt Univ, Sch Med, Dept Psychiat, Nashville, TN 37212 USA. [Fava, Maurizio] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02114 USA. RP Pedrelli, P (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Bowdoin Sq,6th Fl, Boston, MA 02114 USA. EM ppedrelli@partners.org OI Alpert, Jonathan/0000-0002-4332-908X FU Bristol- Myers Squibb, Co.; Cerecor, Inc.; Janssen Pharmaceutica; Naurex, Inc.; Pamlab, Inc.; Ridge Diagnostics; Shire Pic; Takada Pharmaceuticals; Novartis Pharmaceuticals; Otsuka America; Abbott Laboratories, Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells Inc.; Bristol- Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen RD, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; MedAvante; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC; Pfizer Inc.; Pharmacia-Upjohn, Pharmaceutical Research Associates, Inc.; Pharmavite(R) LLC; PharmoRx Therapeutics; Photothera; Roche Pharmaceuticals; RCT Logic, Inc.; Clinical Trials Solutions, LLC; Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc., Synthelabo; Wyeth-Ayerst Laboratories FX Paola Pedrelli, Mark A. Blais, Jonathan E. Alpert, and Rosemary S. W. Walker do not have anything to disclose. Richard C. Shelton has the following disclosures: Bristol- Myers Squibb, Co., consultant, consulting fees; Cerecor, Inc., consultant, research support; Janssen Pharmaceutica, consultant, research support; Naurex, Inc., consultant, research support; Pamlab, Inc., consultant, consulting fees; Ridge Diagnostics, consultant, consulting fees; Shire Pic, consultant, consulting fees; Takada Pharmaceuticals, consultant, research support; Cerecor, Inc., consultant, research support; Novartis Pharmaceuticals, research, grant; Otsuka America, research, grant. Maurizio S. Fava has the following disclosures: Research support: Abbott Laboratories, Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells Inc.; Bristol- Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; MedAvante; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC; Pfizer Inc.; Pharmacia-Upjohn, Pharmaceutical Research Associates, Inc.; Pharmavite (R) LLC; PharmoRx Therapeutics; Photothera; Roche Pharmaceuticals; RCT Logic, Inc.; (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc., Synthelabo; Wyeth-Ayerst Laboratories. Advisory/consulting: Abbott Laboratories; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Bayer AG; Best Practice Project Management, Inc.; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells Inc.; Bristol- Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dianippon Sumitomo Pharma Co. Inc.; Dove Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc; Eisai Inc.; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; ePharma-Solutions; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; i3 Innovus/Ingenis; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research and Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Neuralstem, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG; Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Otsuka Pharmaceuticals; Pamlab, LLC.; Pfizer Inc.; PharmaStar; Pharmavite (R) LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; Puretech Ventures; PsychGenics; Psylin Neurosciences, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi-Aventis US LLC.; Sepracor Inc.; Servier Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; ; Synthelabo; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenenx Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc. Speaking/publishing: Adamed, Co.; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Bevoir Media Group; Boehringer Ingelheim GmbH; BristolMyers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc., Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier, Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar, United BioSource, Corp.; Wyeth-Ayerst Laboratories. Equity holdings: Compellis; PsyBrain, Inc. Royalty/patent, other income: Patent for Sequential Parallel Comparison Design (SPCD), which is licensed by MGH to RCT Logic, LLC; and patent application for a combination of ketamine plus scopolamine in major depressive disorder (MDD). Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte. Ltd. NR 27 TC 1 Z9 1 U1 0 U2 2 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 DEC PY 2014 VL 19 IS 6 BP 535 EP 546 DI 10.1017/S1092852914000406 PG 12 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AU4CU UT WOS:000345557400010 PM 25275853 ER PT J AU Luke, JJ Ott, PA Shapiro, GI AF Luke, Jason J. Ott, Patrick A. Shapiro, Geoffrey I. TI The Biology and Clinical Development of MEK Inhibitors for Cancer SO DRUGS LA English DT Article ID PAPILLARY THYROID-CARCINOMA; SIGNAL-REGULATED KINASE; OVARIAN SEROUS CARCINOMA; TUMOR-GROWTH INHIBITION; DOSE-ESCALATION TRIAL; CELL LUNG-CANCER; PHASE-II TRIAL; WILD-TYPE BRAF; OPEN-LABEL; AZD6244 ARRY-142886 AB The mitogen-activated protein kinase kinases (MAPKK) MEK1 and MEK2 are integral members of the MAPK/ERK signaling pathway and are of interest in the development of anti-cancer therapeutics. The MAPK/ERK pathway is dysregulated in more than 30 % of cancers, predominately by mutations in RAS and BRAF proteins, and MEK serves as a potential downstream target for both of these. The biology of MEK inhibition is complex, as the molecule is differentially regulated by upstream RAS or RAF. This has impacted on the past development of MEK inhibitors as treatments for cancer and may be exploited in more rational, molecularly selected drug development plans in the future. The role of MEK in cancer and the mechanism of action of MEK inhibitors is reviewed. Furthermore, MEK inhibitors that are available in standard practice, as well as those most advanced in clinical development, are discussed. Finally, next steps in the development of MEK inhibitors are considered. C1 [Ott, Patrick A.; Shapiro, Geoffrey I.] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Ott, Patrick A.; Shapiro, Geoffrey I.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Ott, Patrick A.] Dana Farber Canc Inst, Ctr Melanoma Oncol, Dept Med Oncol, Boston, MA 02215 USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Early Drug Dev Ctr, Dept Med Oncol, Boston, MA 02215 USA. RP Luke, JJ (reprint author), Univ Chicago, Ctr Canc, Melanoma & Dev Therapeut Clin, 5841 S Maryland Ave,MC2115, Chicago, IL 60637 USA. EM jluke@medicine.bsd.uchicago.edu; geoffrey_shapiro@dfci.harvard.edu NR 118 TC 6 Z9 6 U1 2 U2 20 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 0012-6667 EI 1179-1950 J9 DRUGS JI Drugs PD DEC PY 2014 VL 74 IS 18 BP 2111 EP 2128 DI 10.1007/s40265-014-0315-4 PG 18 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA AU4MU UT WOS:000345586200001 PM 25414119 ER PT J AU Graff, JN Beer, TM AF Graff, Julie N. Beer, Tomasz M. TI Pharmacotherapeutic Management of Metastatic, Castration-Resistant Prostate Cancer in the Elderly: Focus on Non-Chemotherapy Agents SO DRUGS & AGING LA English DT Review ID PHASE-III TRIAL; I CLINICAL-TRIAL; ABIRATERONE ACETATE; DOUBLE-BLIND; OPEN-LABEL; DENDRITIC CELLS; PLUS PREDNISONE; DOCETAXEL; PLACEBO; ENZALUTAMIDE AB In the past 4 years, five new agents have been approved for metastatic, castration-resistant prostate cancer. Four of them are non-chemotherapeutic and generally well tolerated. However, each has toxicities that can negatively impact patients, particularly the elderly. This review covers the epidemiology of prostate cancer in elderly men. It discusses the efficacy data for sipuleucel-T, abiraterone in chemotherapy-naive patients, enzalutamide in chemotherapy-naive patients and radium-223 and presents any additional studies done for those over 75 years of age. Disease burden, such as the presence or absence of visceral disease, and comorbid conditions weigh into the selection of therapy and are discussed here. Drug-drug interactions between these agents and other drugs commonly used in the elderly population are also considered. The emerging therapies tasquinimod and ipilimumab are reviewed. With the arrival of so many agents for prostate cancer, selection of the most appropriate agent can be perplexing, particularly because these agents were tested against placebo, not one another. Furthermore, the study population differs significantly from those seen in clinical practice. This review addresses these issues. C1 [Graff, Julie N.; Beer, Tomasz M.] Portland VA Med Ctr, Portland, OR USA. [Graff, Julie N.; Beer, Tomasz M.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. RP Graff, JN (reprint author), Oregon Hlth & Sci Univ, Knight Canc Inst, 3710 SW US Vet Hosp Rd,P3CHEMO, Portland, OR 97239 USA. EM graffj@ohsu.edu FU Medivation; Sanofi; Janssen; Astellas; Dendreon; Bayer; Astellas/Medivation FX J.N. Graff (JNG) and T.M. Beer (TMB) have received research funding from Medivation. JNG also received research funding from Sanofi. TMB also received research funding from Janssen, Astellas and Dendreon. TMB received consulting fees from Bayer, Dendreon, Janssen. TMB participated in a certified nursing program that received support from Astellas/Medivation, Bayer and Dendreon. JNG and TMB received an honorarium from Bayer for writing an educational piece. JNG and TMB received money from Bayer to travel to a research-related meeting. No funding was used in the preparation of this manuscript. NR 52 TC 3 Z9 3 U1 0 U2 4 PU ADIS INT LTD PI NORTHCOTE PA 5 THE WAREHOUSE WAY, NORTHCOTE 0627, AUCKLAND, NEW ZEALAND SN 1170-229X EI 1179-1969 J9 DRUG AGING JI Drugs Aging PD DEC PY 2014 VL 31 IS 12 BP 873 EP 882 DI 10.1007/s40266-014-0224-y PG 10 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA AU1PH UT WOS:000345392100003 PM 25387443 ER PT J AU Milowsky, MI Dittrich, C Duran, I Jagdev, S Millard, FE Sweeney, CJ Bajorin, D Cerbone, L Quinn, DI Stadler, WM Rosenberg, JE Lochheed, M Sen, P Squires, M Shi, M Sternberg, CN AF Milowsky, Matthew I. Dittrich, Christian Duran, Ignacio Jagdev, Satinder Millard, Frederick E. Sweeney, Christopher J. Bajorin, Dean Cerbone, Linda Quinn, David I. Stadler, Walter M. Rosenberg, Jonathan E. Lochheed, Melissa Sen, Paramita Squires, Matthew Shi, Michael Sternberg, Cora N. TI Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Urothelial carcinoma; Dovitinib; Receptor tyrosine kinase; Fibroblast growth factor; FGFR3; VEGFR ID TRANSITIONAL-CELL CARCINOMA; BLADDER-CANCER; TUMORS; CHEMOTHERAPY; MUTATIONS; SUNITINIB; FAILURE; TRACT AB Background: Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non-mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib-a broad-targeted inhibitor of tyrosine kinases, including FGFR3-were evaluated in patients with previously treated advanced UC with and without FGFR3 mutations. Methods: Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant (FGFR3(MUT); n = 12), wild-type (FGFR3(WT); n = 31), or unknown (n = 1) FGFR3 status. Patients received 500 mg dovitinib once daily on a 5-days-on/2-days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR). Results: Most of the patients were men (75%) and over half of the patients were aged >= 65 years (61%). All patients had received >= 1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3(MUT) (0%; 95% confidence interval [CI], 0.0-26.5) and FGFR3(WT) (3.2%; 95% CI, 0.1-16.7) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%). Conclusion: Although generally well tolerated, dovitinib has very limited single-agent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Milowsky, Matthew I.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Med, Div Hematol Oncol, Chapel Hill, NC 27599 USA. [Dittrich, Christian] Kaiser Franz Josef Spital, Ctr Oncol & Haematol, LBI ACR VIEnna, Vienna, Austria. [Dittrich, Christian] Kaiser Franz Josef Spital, Ctr Oncol & Haematol, ACR ITR VIEnna, Vienna, Austria. [Duran, Ignacio] Univ CEU San Pablo, Ctr Integral Oncol Clara Campal, Madrid, Spain. [Jagdev, Satinder] St Jamess Inst Oncol, Leeds, W Yorkshire, England. [Millard, Frederick E.] Univ Calif San Diego, Dept Med, Div Hematol Oncol, San Diego, CA 92103 USA. [Sweeney, Christopher J.] Dana Farber Canc Inst, Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Bajorin, Dean; Rosenberg, Jonathan E.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Cerbone, Linda] San Camillo Hosp, Dept Med Oncol, Rome, Italy. [Cerbone, Linda] Forlanini Hosp, Dept Med Oncol, Rome, Italy. [Quinn, David I.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Div Med Oncol, Los Angeles, CA 90033 USA. [Stadler, Walter M.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Lochheed, Melissa; Sen, Paramita; Shi, Michael] Novartis Pharmaceut, E Hanover, NJ USA. [Squires, Matthew] Novartis Pharma AG, Basel, Switzerland. RP Milowsky, MI (reprint author), Univ N Carolina, 170 Manning Dr,3rd Floor,Phys Off Bldg, Chapel Hill, NC 27599 USA. EM matt_milowsky@med.unc.edu RI Quinn, David/F-4343-2015; OI Quinn, David/0000-0002-1411-0417; Rosenberg, Jonathan/0000-0003-2637-4249 FU Novartis Pharmaceuticals FX This work was supported by Novartis Pharmaceuticals. NR 22 TC 28 Z9 28 U1 1 U2 3 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 DEC PY 2014 VL 50 IS 18 BP 3145 EP 3152 DI 10.1016/j.ejca.2014.10.013 PG 8 WC Oncology SC Oncology GA AU2FH UT WOS:000345431300008 PM 25457633 ER PT J AU Eyal, O Oren, A Juppner, H Somech, R De Bellis, A Mannstadt, M Szalat, A Bleiberg, M Weisman, Y Weintrob, N AF Eyal, Ori Oren, Asaf Jueppner, Harald Somech, Raz De Bellis, Annamaria Mannstadt, Michael Szalat, Auryan Bleiberg, Margalit Weisman, Yosef Weintrob, Naomi TI Hypoparathyroidism and central diabetes insipidus: in search of the link SO EUROPEAN JOURNAL OF PEDIATRICS LA English DT Article DE Hypoparathyroidism; Central diabetes insipidus; Autoimmune polyendocrine syndrome type 1 (APS1) ID POLYENDOCRINE SYNDROME TYPE-1; CANDIDIASIS-ECTODERMAL DYSTROPHY; AUTOSOMAL-DOMINANT; RECESSIVE HYPOPARATHYROIDISM; AUTOIMMUNE; MUTATIONS; GENE; AUTOANTIBODIES; DIAGNOSIS; RECEPTOR AB Two siblings (a 15-year-old boy and an 11-year-old girl) who presented with hypocalcemic seizure at the age of 2 years and 2 months (boy) and 2 years and 4 months (girl) were diagnosed with hypoparathyroidism. At the age of 3 years, the girl developed central diabetes insipidus with good response to desmopressin acetate treatment. The family history was unremarkable, and there was no consanguinity between the parents. The father is of Iraqi/Egyptian Jewish origin and the mother is of Iranian/Romanian Jewish origin. Sequence analysis of the candidate genes for isolated hypoparathyroidism encoding calcium-sensing receptor, parathyroid hormone, and glial cells missing homolog B did not reveal any mutations. Whole-exome sequencing identified a homozygous mutation in the autoimmune regulatory gene (AIRE), c.374A > G;p.Y85C, characteristic for Jewish Iranians with autoimmune polyendocrine syndrome type 1 (APS1), which was confirmed by the Sanger sequencing. Antibodies against the adrenal, pancreatic islet cell, ovary, thyroid, pituitary, celiac, and parietal cell were negative in both siblings, while anti-diuretic hormone antibodies were positive only in the girl. No other symptoms or signs of APS1 developed during all the years of follow-up. Conclusion: APS1 should be part of the differential diagnosis in children presenting with isolated hypoparathyroidism or hypoparathyroidism with central diabetes insipidus (CDI). These cases show that the AIRE mutation characteristic of Iranian Jews can also be found in non-Iranian Jews. C1 [Eyal, Ori; Oren, Asaf; Weisman, Yosef; Weintrob, Naomi] Dana Dwek Children Hosp, Pediat Endocrinol & Diabet Unit, Tel Aviv Sourasky Med Ctr, IL-6423906 Tel Aviv, Israel. [Eyal, Ori; Oren, Asaf; Somech, Raz; Weisman, Yosef; Weintrob, Naomi] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Jueppner, Harald; Mannstadt, Michael] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Jueppner, Harald; Mannstadt, Michael] Harvard Univ, Sch Med, Boston, MA USA. [Somech, Raz] Edmond & Lily Safra Childrens Hosp, Canc Res Ctr, Chaim Sheba Med Ctr, Pediat Dept,Pediat Immunol Serv,Jeffery Modell Fd, Ramat Gan, Israel. [De Bellis, Annamaria] Univ Naples 2, Dept Cardiothorac & Resp Sci, Endocrinol Sect, Fac Med & Surg, Naples, Italy. [Szalat, Auryan] Hadassah Hebrew Univ, Dept Internal Med, Endocrinol & Metab Serv, Med Ctr, Jerusalem, Israel. [Bleiberg, Margalit] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Clin Immunol Lab, IL-69978 Tel Aviv, Israel. RP Eyal, O (reprint author), Dana Dwek Children Hosp, Pediat Endocrinol & Diabet Unit, Tel Aviv Sourasky Med Ctr, 6 Weizmann St, IL-6423906 Tel Aviv, Israel. EM ori.eyal27@gmail.com; orenasaf@hotmail.com; hjueppner@mgh.harvard.edu; raz.somech@sheba.health.gov.il; annamaria.debellis@unina2.it; mmannstadt@partners.org; auryans@hadassah.org.il; margalitb@tlvmc.gov.il; yosef.weisman@gmail.com; naomiw@tlvmc.gov.il FU National Institutes of Health [1R01DK100584, R01DK46718-20] FX We gratefully acknowledge Esther Eshkol for editing the manuscript and providing helpful comments. We thank Sophie Bensing and Tomas Hokfelt for their valuable advice. This work was supported in part by grants from the National Institutes of Health (1R01DK100584to MM and R01DK46718-20 to HJ). NR 29 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6199 EI 1432-1076 J9 EUR J PEDIATR JI Eur. J. Pediatr. PD DEC PY 2014 VL 173 IS 12 BP 1731 EP 1734 DI 10.1007/s00431-014-2448-6 PG 4 WC Pediatrics SC Pediatrics GA AU4ND UT WOS:000345587200048 PM 25367057 ER PT J AU Tsai, TH Ahsen, OO Lee, HC Liang, KC Figueiredo, M Tao, YK Giacomelli, MG Potsaid, BM Jayaraman, V Huang, Q Cable, AE Fujimoto, JG Mashimo, H AF Tsai, Tsung-Han Ahsen, Osman O. Lee, Hsiang-Chieh Liang, Kaicheng Figueiredo, Marisa Tao, Yuankai K. Giacomelli, Michael G. Potsaid, Benjamin M. Jayaraman, Vijaysekhar Huang, Qin Cable, Alex E. Fujimoto, James G. Mashimo, Hiroshi TI Endoscopic Optical Coherence Angiography Enables 3-Dimensional Visualization of Subsurface Microvasculature SO GASTROENTEROLOGY LA English DT Editorial Material ID TOMOGRAPHY; ENDOMICROSCOPY; MICROSCOPY C1 [Tsai, Tsung-Han; Ahsen, Osman O.; Lee, Hsiang-Chieh; Liang, Kaicheng; Tao, Yuankai K.; Giacomelli, Michael G.; Potsaid, Benjamin M.; Fujimoto, James G.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Tsai, Tsung-Han; Ahsen, Osman O.; Lee, Hsiang-Chieh; Liang, Kaicheng; Tao, Yuankai K.; Giacomelli, Michael G.; Potsaid, Benjamin M.; Fujimoto, James G.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Figueiredo, Marisa; Huang, Qin; Mashimo, Hiroshi] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Figueiredo, Marisa; Huang, Qin; Mashimo, Hiroshi] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Potsaid, Benjamin M.; Cable, Alex E.] Thorlabs Inc, Adv Imaging Grp, Newton, NJ USA. [Jayaraman, Vijaysekhar] Praevium Res Inc, Santa Barbara, CA USA. RP Mashimo, H (reprint author), Harvard Univ, Sch Med, Gastroenterol Sect, VA Boston Healthcare Syst, Boston, MA 02114 USA. EM hmashimo@hms.harvard.edu RI Ahsen, Osman/K-4524-2015 OI Ahsen, Osman/0000-0003-4811-3429 FU NCI NIH HHS [R01 CA075289, R01 CA178636, R01-CA178636-01, R01-CA75289-16, R44 CA101067, R44-CA101067-06]; NEI NIH HHS [R01 EY011289, R01-EY011289-27, R44 EY022864, R44EY022864-01]; NHLBI NIH HHS [R01 HL095717, R01-HL095717-04] NR 8 TC 9 Z9 9 U1 2 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 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2014 VL 147 IS 6 BP 1219 EP 1221 DI 10.1053/j.gastro.2014.08.034 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3PC UT WOS:000345524800016 PM 25172015 ER PT J AU Dawes, AJ Louie, R Nguyen, DK Maggard-Gibbons, M Parikh, P Ettner, SL Ko, CY Zingmond, DS AF Dawes, Aaron J. Louie, Rachel Nguyen, David K. Maggard-Gibbons, Melinda Parikh, Punam Ettner, Susan L. Ko, Clifford Y. Zingmond, David S. TI The Impact of Continuous Medicaid Enrollment on Diagnosis, Treatment, and Survival in Six Surgical Cancers SO HEALTH SERVICES RESEARCH LA English DT Article DE Medicaid; cancer; surgery; access to care; survival ID HEALTH-INSURANCE COVERAGE; SERVICES TASK-FORCE; COLORECTAL-CANCER; RACIAL DISPARITIES; BREAST-CANCER; SOCIOECONOMIC-STATUS; AMERICAN-COLLEGE; LUNG-CANCER; CARE; QUALITY AB ObjectiveTo examine the effect of Medicaid enrollment on the diagnosis, treatment, and survival of six surgically relevant cancers among poor and underserved Californians. Data SourcesCalifornia Cancer Registry (CCR), California's Patient Discharge Database (PDD), and state Medicaid enrollment files between 2002 and 2008. Study DesignWe linked clinical and administrative records to differentiate patients continuously enrolled in Medicaid from those receiving coverage at the time of their cancer diagnosis. We developed multivariate logistic regression models to predict death within 1year for each cancer after controlling for sociodemographic and clinical variables. Data Collection/Extraction MethodsAll incident cases of six cancers (colon, esophageal, lung, pancreas, stomach, and ovarian) were identified from CCR. CCR records were linked to hospitalizations (PDD) and monthly Medicaid enrollment. Principal FindingsContinuous enrollment in Medicaid for at least 6months prior to diagnosis improves survival in three surgically relevant cancers. Discontinuous Medicaid patients have higher stage tumors, undergo fewer definitive operations, and are more likely to die even after risk adjustment. ConclusionsExpansion of continuous insurance coverage under the Affordable Care Act is likely to improve both access and clinical outcomes for cancer patients in California. C1 [Dawes, Aaron J.; Nguyen, David K.; Maggard-Gibbons, Melinda; Ko, Clifford Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Dawes, Aaron J.] Univ Calif Los Angeles, Robert Wood Johnson Clin Scholars Program, Los Angeles, CA 90095 USA. [Dawes, Aaron J.; Maggard-Gibbons, Melinda; Ko, Clifford Y.] VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. [Louie, Rachel; Parikh, Punam; Ettner, Susan L.; Zingmond, David S.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, Dept Med, Los Angeles, CA 90095 USA. [Ettner, Susan L.] Univ Calif Los Angeles, Jonathan & Karin Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA 90095 USA. RP Dawes, AJ (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, 757 Westwood Plaza,B711, Los Angeles, CA 90095 USA. EM adawes@mednet.ucla.edu OI Dawes, Aaron/0000-0003-4574-6765 FU VA Office of Academic Affiliations through VA/Robert Wood Johnson Clinical Scholars Program; American Cancer Society [RSGI-11-005-01-CPHPS] FX This manuscript reflects work that was a presented at the 2014 AcademyHealth Annual Research Meeting. Dr. Dawes was supported by the VA Office of Academic Affiliations through the VA/Robert Wood Johnson Clinical Scholars Program. Dr. Zingmond was supported by a grant from the American Cancer Society (RSGI-11-005-01-CPHPS). NR 50 TC 5 Z9 5 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD DEC PY 2014 VL 49 IS 6 BP 1787 EP 1811 DI 10.1111/1475-6773.12237 PG 25 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AU0XT UT WOS:000345346300006 PM 25256223 ER PT J AU Fortney, JC Pyne, JM Burgess, JF AF Fortney, John C. Pyne, Jeffrey M. Burgess, James F., Jr. TI Population-Level Cost-Effectiveness of Implementing Evidence-Based Practices into Routine Care SO HEALTH SERVICES RESEARCH LA English DT Article DE Cost-effectiveness; implementation; depression ID BUDGET IMPACT ANALYSIS; QUALITY IMPROVEMENT; COLLABORATIVE CARE; PREVENTIVE INTERVENTIONS; RANDOMIZED-TRIAL; HEALTH-CARE; DEPRESSION; OUTCOMES; CLINICS; SYSTEM AB ObjectiveThe objective of this research was to apply a new methodology (population-level cost-effectiveness analysis) to determine the value of implementing an evidence-based practice in routine care. Data Sources/Study SettingData are from sequentially conducted studies: a randomized controlled trial and an implementation trial of collaborative care for depression. Both trials were conducted in the same practice setting and population (primary care patients prescribed antidepressants). Study DesignThe study combined results from a randomized controlled trial and a pre-post-quasi-experimental implementation trial. Data Collection/Extraction MethodsThe randomized controlled trial collected quality-adjusted life years (QALYs) from survey and medication possession ratios (MPRs) from administrative data. The implementation trial collected MPRs and intervention costs from administrative data and implementation costs from survey. Principal FindingsIn the randomized controlled trial, MPRs were significantly correlated with QALYs (p=.03). In the implementation trial, patients at implementation sites had significantly higher MPRs (p=.01) than patients at control sites, and by extrapolation higher QALYs (0.00188). Total costs (implementation, intervention) were nonsignificantly higher ($63.76) at implementation sites. The incremental population-level cost-effectiveness ratio was $33,905.92/QALY (bootstrap interquartile range -$45,343.10/QALY to $99,260.90/QALY). ConclusionsThe methodology was feasible to operationalize and gave reasonable estimates of implementation value. C1 [Fortney, John C.; Pyne, Jeffrey M.] Cent Arkansas Vet Healthcare Syst, Hlth Serv Res & Dev, North Little Rock, AR 72114 USA. [Fortney, John C.; Pyne, Jeffrey M.] Cent Arkansas Vet Healthcare Syst, South Cent Mental Illness Res Educ & Clin Ctr, Little Rock, AR USA. [Fortney, John C.; Pyne, Jeffrey M.] Univ Arkansas Med Sci, Dept Psychiat, North Little Rock, AR USA. [Burgess, James F., Jr.] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Burgess, James F., Jr.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. RP Fortney, JC (reprint author), Cent Arkansas Vet Healthcare Syst, Hlth Serv Res & Dev, 152 NLR, North Little Rock, AR 72114 USA. EM fortneyj@uw.edu FU VA Quality Enhancement Research Initiative (QUERI) [IMV 04-360, VA IIR 00-078-3, VA NPI-01-006-1]; VA HSR&D Center for Mental Healthcare and Outcomes Research; VA South Central Mental Illness Research Education and Clinical Center FX This research was supported by VA Quality Enhancement Research Initiative (QUERI) IMV 04-360 grant to Dr. Fortney, VA IIR 00-078-3 grant to Dr. Fortney, VA NPI-01-006-1 grant to Dr. Pyne, the VA HSR&D Center for Mental Healthcare and Outcomes Research, and the VA South Central Mental Illness Research Education and Clinical Center. The clinical trials numbers are NCT00105690 and NCT00317018. NR 29 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD DEC PY 2014 VL 49 IS 6 BP 1832 EP 1851 DI 10.1111/1475-6773.12247 PG 20 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AU0XT UT WOS:000345346300008 PM 25328029 ER PT J AU Stryjewski, TP Zhang, F Eliott, D Wharam, JF AF Stryjewski, Tomasz P. Zhang, Fang Eliott, Dean Wharam, J. Frank TI Effect of Massachusetts Health Reform on Chronic Disease Outcomes SO HEALTH SERVICES RESEARCH LA English DT Article DE Health reform; observational data; time series analysis ID BLOOD-PRESSURE; INSURANCE COVERAGE; CLINICAL-OUTCOMES; SERUM-CHOLESTEROL; PROPENSITY SCORE; MORTALITY; CARE; DISPARITIES; MEDICAID; ACCESS AB ObjectiveTo determine whether Massachusetts Health Reform improved health outcomes in uninsured patients with hyperlipidemia, diabetes, or hypertension. Data SourcePartners HealthCare Research Patient Data Registry (RPDR). Study DesignWe examined 1,463 patients with hyperlipidemia, diabetes, or hypertension who were uninsured in the 3years before the 2006 Massachusetts Health Reform implementation. We assessed mean quarterly total cholesterol, glycosylated hemoglobin, and systolic blood pressure in the respective cohorts for five follow-up years compared with 3,448 propensity score-matched controls who remained insured for the full 8-year study period. We used person-level interrupted time series analysis to estimate changes in outcomes adjusting for sex, age, race, estimated household income, and comorbidity. We also analyzed the subgroups of uninsured patients with poorly controlled disease at baseline, no evidence of established primary care in the baseline period, and those who received insurance in the first follow-up year. Principal FindingsIn 5years after Massachusetts Health Reform, patients who were uninsured at baseline did not experience detectable trend changes in total cholesterol (-0.39mg/dl per quarter, 95 percent confidence interval [-1.11 to 0.33]), glycosylated hemoglobin (-0.02 percent per quarter [-0.06 to 0.03]), or systolic blood pressure (-0.06mmHg per quarter [-0.29 to 0.18]). Analyses of uninsured patients with poorly controlled disease, no evidence of established primary care in the baseline period, and those who received insurance in the first follow-up year yielded similar findings. ConclusionsMassachusetts Health Reform was not associated with improvements in hyperlipidemia, diabetes, or hypertension control after 5years. Interventions beyond insurance coverage might be needed to improve the health of chronically ill uninsured persons. C1 [Stryjewski, Tomasz P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Zhang, Fang; Wharam, J. Frank] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Zhang, Fang; Wharam, J. Frank] Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Eliott, Dean] Massachusetts Gen Hosp, Dept Ophthalmol, Boston, MA 02114 USA. [Eliott, Dean] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Wharam, J. Frank] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Stryjewski, TP (reprint author), Massachusetts Gen Hosp, Dept Med, 55 Fruit St,GRB 740, Boston, MA 02114 USA. EM tstryjewski@partners.org NR 38 TC 4 Z9 4 U1 3 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 EI 1475-6773 J9 HEALTH SERV RES JI Health Serv. Res. PD DEC PY 2014 VL 49 SU 2 BP 2086 EP 2103 DI 10.1111/1475-6773.12196 PG 18 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AU3IM UT WOS:000345506000004 PM 25039480 ER PT J AU Truong, QA Januzzi, JL Szymonifka, J Thai, WE Wai, B Lavender, Z Sharma, U Sandoval, RM Grunau, ZS Basnet, S Babatunde, A Ajijola, OA Min, JK Singh, JP AF Truong, Quynh A. Januzzi, James L. Szymonifka, Jackie Thai, Wai-ee Wai, Bryan Lavender, Zachary Sharma, Umesh Sandoval, Ryan M. Grunau, Zachary S. Basnet, Sandeep Babatunde, Adefolakemi Ajijola, Olujimi A. Min, James K. Singh, Jagmeet P. TI Coronary sinus biomarker sampling compared to peripheral venous blood for predicting outcomes in patients with severe heart failure undergoing cardiac resynchronization therapy: The BIOCRT study SO HEART RHYTHM LA English DT Article DE Biomarker; Coronary sinus; Galectin-3; Soluble 512; Cardiac resynchronization therapy ID BRAIN NATRIURETIC PEPTIDE; VENTRICULAR SYSTOLIC DYSFUNCTION; RECEPTOR FAMILY-MEMBER; OF-CARE ASSAY; SOLUBLE ST2; MYOCARDIAL-INFARCTION; GALECTIN-3; POINT; MORTALITY; MARKERS AB BACKGROUND A significant minority of patients receiving cardiac resynchronization therapy (CRT) remain nonresponsive to this intervention. OBJECTIVE This study aimed to determine whether coronary sinus (CS) or baseline peripheral venous (PV) levels of established and emerging heart failure (H F) biomarkers are predictive of CRT outcomes. METHODS In 73 patients (aged 68 +/- 12 years; 83% men; ejection fraction 27% +/- 7%) with CS and PV blood samples drawn simultaneously at the time of CRT device implantation, we measured aminoterminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3 (gal-3), and soluble 512 (sST2) Levels. NT-proBNP concentrations >2000 pg/mL, gal-3 concentrations >25.9 ng/mL, and sST2 concentrations >35 ng/mL were considered positive on the basis of established PV cut points for identifying "high-risk" individuals with HF. CRT response was adjudicated by the HF Clinical Composite Score. A major adverse cardiovascular event (MACE) was defined as the composite end point of death, cardiac transplant, Left ventricular assist device, and HF hospitalization at 2 years. RESULTS NT-proBNP concentrations were 20% higher in the CS than in the periphery, white gal-3 and s512 concentrations were 10% higher in the periphery than in the CS (all P < .001). There were 45% CRT nonresponders at 6 months and 16 (22%) patients with MACE. Triple-positive CS values yielded the highest specificity of 95% for predicting CRT nonresponse. Consistently, CS strategies identified patients at higher risk of developing MACE, with > 11-fold adjusted increase for triple-positive CS patients compared to triple-negative patients (all P <= .04). PV strategies were not predictive of MACE. CONCLUSION Our findings suggest that CS sampling of HF biomarkers may be better than PV sampling for predicting CRT outcomes. Larger studies are needed to confirm our findings. C1 [Truong, Quynh A.; Min, James K.] New York Presbyterian Hosp, Weill Cornell Med Coll, Dalio Inst Cardiovasc Imaging, New York, NY 10021 USA. [Truong, Quynh A.; Januzzi, James L.; Thai, Wai-ee; Wai, Bryan; Lavender, Zachary; Sharma, Umesh; Sandoval, Ryan M.; Grunau, Zachary S.; Basnet, Sandeep; Babatunde, Adefolakemi; Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Div Cardiol, Sch Med, Boston, MA 02114 USA. [Szymonifka, Jackie] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Biostat Ctr, Boston, MA USA. [Ajijola, Olujimi A.] Calif State Univ Los Angeles, Cardiac Arrhythmia Ctr, Ronald Reagan Med Ctr, Los Angeles, CA 90032 USA. [Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv, Boston, MA 02115 USA. RP Truong, QA (reprint author), New York Presbyterian Hosp, Weill Cornell Med Coll, Dalio Inst Cardiovasc Imaging, 413 69th St,Suite 108, New York, NY 10021 USA. EM qat9001@med.cornell.edu FU NIH/NHLBI [K23HL098370]; NIH [L30HL093896]; A.P. Giannini Foundation; St Jude Medical; American College of Radiology Imaging Network; Duke Clinical Research Institute; Roman W. Desanctis Distinguished Clinical Scholar Endowment; Roche Diagnostics; Siemens; BG Medicine; Critical Diagnostics; Singulex; Thermo Fisher Scientific; GE Healthcare; Vital Images; Phillips Healthcare; Medtronic; Boston Scientific; Sorin Group; Biotronik FX This study was supported by NIH/NHLBI K23HL098370. Dr Truong also received support from the NIH L30HL093896. Dr Ajijola was supported by an A.P. Giannini Foundation award. The reagents were provided and assays were performed by Siemens Healthcare Diagnostics, BG Medicine, and Critical Diagnostics. Dr Truong has received grant support from St Jude Medical, the American College of Radiology Imaging Network, and Duke Clinical Research Institute, Dr Januzzi is supported in part by the Roman W. Desanctis Distinguished Clinical Scholar Endowment and has received grant support from Roche Diagnostics, Siemens, BG Medicine, Critical Diagnostics, Singulex, and Thermo Fisher Scientific. Dr Min has served on the medical advisory boards of GE Healthcare, Arineta, Astra Zeneca, and Bristol-Myers Squibb; is on speakers bureau of GE Healthcare; and has received research support from GE Healthcare, Vital Images, and Phillips Healthcare, Dr Singh has received grant support from St Jude Medical, Medtronic, Boston Scientific, Sorin Group, Biotronik, BG Medicine, and Siemens. NR 33 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD DEC PY 2014 VL 11 IS 12 BP 2167 EP 2175 DI 10.1016/j.hrthm.2014.07.007 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AU1SM UT WOS:000345400500008 PM 25014756 ER PT J AU Poordad, F Sievert, W Mollison, L Brau, N Levin, JM Sepe, TE Lee, SS Boyer, N Bronowicki, JP Jacobson, IM Boparai, N Hughes, EA Swenson, ES Yin, PD AF Poordad, Fred Sievert, William Mollison, Lindsay Brau, Norbert Levin, James M. Sepe, Thomas E. Lee, Samuel S. Boyer, Nathalie Bronowicki, Jean-Pierre Jacobson, Ira M. Boparai, Navdeep Hughes, Eric A. Swenson, Eugene S. Yin, Philip D. TI All-oral, fixed-dose combination therapy with daclatasvir/asunaprevir/BMS-791325 for non-cirrhotic patients with chronic HCV genotype 1 infection: UNITY-1 Phase 3 SVR12 results SO HEPATOLOGY LA English DT Meeting Abstract C1 [Poordad, Fred] Univ Texas Hlth Sci Ctr San Antonio, Texas Liver Inst, San Antonio, TX 78229 USA. [Sievert, William] Monash Hlth, Melbourne, Vic, Australia. [Sievert, William] Monash Univ, Melbourne, Vic 3004, Australia. [Mollison, Lindsay] Fremantle Hosp, Fremantle Hepatitis Serv, Fremantle, WA, Australia. [Brau, Norbert] Bronx Vet Affairs Med Ctr, New York, NY USA. [Levin, James M.] Dean Fdn, Madison, WI USA. [Sepe, Thomas E.] Univ Gastroenterol, Providence, RI USA. [Lee, Samuel S.] Univ Calgary, Calgary, AB, Canada. [Boyer, Nathalie] Hop Beaujon, Serv Hepatol, Clichy, France. [Bronowicki, Jean-Pierre] Univ Lorraine, Ctr Hosp Univ Nancy, Vandoeuvre Les Nancy, France. [Jacobson, Ira M.] Weill Cornell Med Coll, New York, NY USA. [Boparai, Navdeep; Hughes, Eric A.] Bristol Myers Squibb Co, Princeton, NJ USA. [Swenson, Eugene S.; Yin, Philip D.] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. NR 0 TC 5 Z9 5 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2014 VL 60 IS 6 MA LB-7 BP 1271A EP 1272A PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3MI UT WOS:000345517000008 ER PT J AU Weeder, PD op den Dries, S Martins, PN Bruinsma, BG Markmann, JF Yeh, H Porte, RJ Uygun, K AF Weeder, Pepijn D. op den Dries, Sanna Martins, Paulo N. Bruinsma, Bote G. Markmann, James F. Yeh, Heidi Porte, Robert J. Uygun, Korkut TI Active oxygenation of University of Wisconsin solution for cold storage restores cellular energy levels of human bile ducts from donors after brain-dead donation but not after circulatory death SO HEPATOLOGY LA English DT Meeting Abstract C1 [Weeder, Pepijn D.; Bruinsma, Bote G.; Uygun, Korkut] Harvard Univ, Sch Med, Ctr Engn Med, Boston, MA USA. [Weeder, Pepijn D.; Markmann, James F.; Yeh, Heidi] Massachusetts Gen Hosp, Transplant Div, Boston, MA 02114 USA. [op den Dries, Sanna; Porte, Robert J.] Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Martins, Paulo N.] Umass Mem Med Ctr, Worcester, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2014 VL 60 IS 6 MA LB-14 BP 1276A EP 1276A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3MI UT WOS:000345517000015 ER PT J AU Harrison, SA Castiblanco, JE Park, S Handler, TE Barstow, K He, WJ Harper, N Ahuja, SK AF Harrison, Stephen A. Castiblanco, John E. Park, Stephen Handler, Tristan E. Barstow, Karol He, Weijing Harper, Nathan Ahuja, Sunil K. TI Whole Genome RNA Sequencing (RNA-seq) Identifies CHI3L1 Gene Expression as a Stronger Discriminator of Isolated Steatosis vs. NASH Compared with Established Biomarker Scoring Systems SO HEPATOLOGY LA English DT Meeting Abstract C1 [Harrison, Stephen A.; Park, Stephen; Handler, Tristan E.; Barstow, Karol] Brooke Army Med Ctr, Ft Sam Houston, TX 78234 USA. [Castiblanco, John E.; He, Weijing; Harper, Nathan] South Texas Vet Hlth Care Syst, Vet Adm Ctr Personalized Med, San Antonio, TX USA. [Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD DEC PY 2014 VL 60 IS 6 MA LB-41 BP 1290A EP 1290A PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3MI UT WOS:000345517000041 ER PT J AU Bandyopadhyay, S Mercier, PP Lysaght, AC Stankovic, KM Chandrakasan, AP AF Bandyopadhyay, Saurav Mercier, Patrick P. Lysaght, Andrew C. Stankovic, Konstantina M. Chandrakasan, Anantha P. TI A 1.1 nW Energy-Harvesting System with 544 pW Quiescent Power for Next-Generation Implants SO IEEE JOURNAL OF SOLID-STATE CIRCUITS LA English DT Article; Proceedings Paper CT 1st IEEE International Solid-State Circuits Conference (ISSCC) CY FEB 09-13, 2014 CL San Francisco, CA SP IEEE DE Boost converter; charge pump; endo-cochlear potential (EP); energy harvesting; low-power design ID BOOST CONVERTER; BATTERY; VOLTAGE; MPPT AB This paper presents a nW power management unit (PMU) for an autonomous wireless sensor that sustains itself by harvesting energy from the endocochlear potential (EP), the 70-100 mV electrochemical bio-potential inside the mammalian ear. Due to the anatomical constraints inside the inner ear, the total extractable power from the EP is limited close to 1.1-6.25 nW. A nW boost converter is used to increase the input voltage (30-55 mV) to a higher voltage (0.8-1.1 V) usable by CMOS circuits in the sensor. A pW charge pump circuit is used to minimize the leakage in the boost converter. Furthermore, ultralow-power control circuits consisting of digital implementations of input impedance adjustment circuits and zero current switching circuits along with Timer and Reference circuits keep the quiescent power of the PMU down to 544 pW. The designed boost converter achieves a peak power conversion efficiency of 56%. The PMU can sustain itself, and a duty-cyled ultralow-power load while extracting power from the EP of a live guinea pig. The PMU circuits have been implemented on a 0.18-mu m CMOS process. C1 [Bandyopadhyay, Saurav; Chandrakasan, Anantha P.] MIT, Cambridge, MA 02139 USA. [Mercier, Patrick P.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Lysaght, Andrew C.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Stankovic, Konstantina M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MEEI, Boston, MA 02114 USA. RP Bandyopadhyay, S (reprint author), Texas Instruments Inc, Dallas, TX 75243 USA. EM s-bandyopadhyay@ti.com FU National Institutes of Health [K08 DC010419, T32 DC00038]; Bertarelli Foundation; C2S2 Focus Center and the Interconnect Focus Center, two of six research centers - Focus Center Research Program (FCRP), a Semiconductor Research Corporation entity FX This work was supported in part by the C2S2 Focus Center and the Interconnect Focus Center, two of six research centers funded under the Focus Center Research Program (FCRP), a Semiconductor Research Corporation entity, by the National Institutes of Health under Grants K08 DC010419 and T32 DC00038, and by the Bertarelli Foundation. NR 28 TC 15 Z9 15 U1 0 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9200 EI 1558-173X J9 IEEE J SOLID-ST CIRC JI IEEE J. Solid-State Circuit PD DEC PY 2014 VL 49 IS 12 SI SI BP 2812 EP 2824 DI 10.1109/JSSC.2014.2350260 PG 13 WC Engineering, Electrical & Electronic SC Engineering GA AU5AS UT WOS:000345620100007 PM 25983340 ER PT J AU Sauk, J Nguyen, D Yajnik, V Khalili, H Konijeti, G Hodin, R Bordeianou, L Shellito, P Sylla, P Korzenik, J Friedman, S Ananthakrishnan, AN AF Sauk, Jenny Deanna Nguyen Yajnik, Vijay Khalili, Hamed Konijeti, Gauree Hodin, Richard Bordeianou, Liliana Shellito, Paul Sylla, Patricia Korzenik, Joshua Friedman, Sonia Ananthakrishnan, Ashwin N. TI Natural History of Perianal Crohn's Disease After Fecal Diversion SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE Crohn's disease; ileostomy; surgery; perianal disease; diversion ID MANAGEMENT; INFLIXIMAB; FISTULAS AB Background:Temporary fecal diversion has been used to allow severe perianal Crohn's disease (CD) to heal. Most data on intestinal reconnection rates precede the biological era with limited patient follow-up after reconnection. We, therefore, sought to evaluate the natural history of perianal CD after fecal diversion.Methods:We identified 49 patients with CD and perianal involvement who underwent fecal diversion between 1991 and 2011 at a tertiary referral care center. Demographics, medication use, onset and extent of disease, and surgical interventions were abstracted. We determined the percentage of patients who were able to restore intestinal continuity and assessed the sustainability of this reversal. Time to intestinal reconnection and subsequent procedures were determined. We also examined temporal trends in the proportion of patients with perianal CD undergoing diversion or management with seton/EUA/fistulotomy between 2000 and 2011.Results:Fifteen of 49 patients (31%) reestablished intestinal continuity during the study follow-up period. Ten of 15 patients (67%) who had reestablished intestinal continuity required an additional procedure to divert the fecal stream. Of the 5 patients who remained reconnected, 3 patients required further procedures to control sepsis. The proportion of patients with CD requiring perianal surgical interventions declined between 2000 and 2011.Conclusions:Severe perianal CD remains a challenging problem. In patients with CD with perianal disease requiring fecal diversion, the likelihood of sustained intestinal continuity remains low, despite greater biological use. However, there has been a temporal decline in the rate of surgical interventions required for perianal CD from 2000 to 2011. C1 [Sauk, Jenny; Deanna Nguyen; Yajnik, Vijay; Khalili, Hamed; Konijeti, Gauree] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Hodin, Richard; Bordeianou, Liliana; Shellito, Paul; Sylla, Patricia; Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Korzenik, Joshua; 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]; National Institutes of Health [K23 DK097142]; National Institutes of Health (NIH NIDDK) [1DK083430]; American Gastroenterological Association (AGA); National Institute of Diabetes and Digestive and Kidney Diseases [K23 DK099681] 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 National Institutes of Health (K23 DK097142). D. Nguyen is supported by a grant from the National Institutes of Health (NIH NIDDK #1DK083430). H. Khalili is supported by a career development award from the American Gastroenterological Association (AGA) and by National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK099681). NR 18 TC 5 Z9 5 U1 0 U2 2 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 DEC PY 2014 VL 20 IS 12 BP 2260 EP 2265 DI 10.1097/MIB.0000000000000216 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3ND UT WOS:000345519400011 PM 25230164 ER PT J AU Deberry, JJ Bielefeldt, K Davis, BM Szigethy, EM Hartman, DJ Coates, MD AF Deberry, Jennifer J. Bielefeldt, Klaus Davis, Brian M. Szigethy, Eva M. Hartman, Douglas J. Coates, Matthew D. TI Abdominal Pain and the Neurotrophic System in Ulcerative Colitis SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE inflammatory bowel disease; ulcerative colitis; abdominal pain; cytokines; nerve-gut interactions ID IRRITABLE-BOWEL-SYNDROME; QUALITY-OF-LIFE; FUNCTIONAL GASTROINTESTINAL DISORDERS; NERVE GROWTH-FACTOR; MAJOR DEPRESSION; COLON AFFERENTS; MOOD DISORDERS; SENSORY FIBERS; DISEASE; INFLAMMATION AB Background:We undertook a study to test the hypothesis that inflammation alters peripheral sensory mechanisms, thereby contributing to chronic abdominal pain in ulcerative colitis (UC).Methods:Patients with UC and healthy individuals rated abdominal pain using a visual analog scale and completed surveys describing anxiety or depression (Hospital Anxiety and Depression Score) and gastrointestinal symptoms (Rome III questionnaire). Patient age, sex, and severity of inflammation were determined. Rectal biopsies were processed using immunohistochemical techniques to assess nerve fiber density and real-time PCR to determine transcript expression of neurotrophins (nerve growth factor, glial cell-derived neurotrophic factor, artemin, neurturin), ion channels (transient receptor potential vanilloid type 1, transient receptor potential ankyrin 1) and inflammatory mediators (tumor necrosis factor-, interleukin [IL]-1, IL-6, IL-10, IL-17).Results:A total of 77 patients with UC (27 female, 50 male) and 21 controls (10 female, 11 male) were enrolled. Patients with UC with pain had significantly higher depression scores than controls and patients with UC without pain (P < 0.05). There was no correlation between any of the inflammatory markers and pain scores. Visual analog scale pain scores significantly correlated with younger age, higher depression scores, increased expression of neurturin and decreased expression of transient receptor potential ankyrin 1 in the mucosa. Mucosal nerve fiber density did not correlate with any measures of inflammation or pain. Only higher depression scores independently predicted pain in UC (r > 0.5).Conclusions:We did not observe changes in mucosal innervation and did not see a significant relationship between nerve fiber density, inflammatory mediators, neurotrophic factors, or mucosal ion channel expression and pain. In contrast, the importance of depression as the only independent predictor of pain ratings mirrors functional disorders, where central processes significantly contribute to symptom development and/or perpetuation. C1 [Deberry, Jennifer J.] Univ Alabama Birmingham, Dept Psychol, Birmingham, AL 35294 USA. [Bielefeldt, Klaus; Szigethy, Eva M.] Univ Pittsburgh, Med Ctr, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. [Davis, Brian M.] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA USA. [Hartman, Douglas J.] Univ Pittsburgh, Dept Pathol, Med Ctr, Pittsburgh, PA USA. [Coates, Matthew D.] VA Pittsburgh Healthcare Syst, Div Gastroenterol, Dept Med, Pittsburgh, PA USA. RP Coates, MD (reprint author), VA Pittsburgh Healthcare Syst, Div Gastroenterol, Univ Dr, Pittsburgh, PA 15240 USA. EM Matthew.Coates@va.gov OI Davis, Brian/0000-0002-4646-0569 FU NIH [DK063922]; BaCCoR grant from the University of Pittsburgh; Inflammatory Bowel Disease Working Group GI Fellows Research Award grant FX Supported by NIH grant DK063922, a BaCCoR grant from the University of Pittsburgh and an Inflammatory Bowel Disease Working Group GI Fellows Research Award grant. NR 57 TC 0 Z9 0 U1 0 U2 4 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 DEC PY 2014 VL 20 IS 12 BP 2330 EP 2339 DI 10.1097/MIB.0000000000000207 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU3ND UT WOS:000345519400020 PM 25358061 ER PT J AU Yao, M Hasturk, H Kantarci, A Gu, GS Garcia-Lavin, S Fabbi, M Park, N Hayashi, H Attala, K French, MA Driver, VR AF Yao, Min Hasturk, Hatice Kantarci, Alpdogan Gu, Guosheng Garcia-Lavin, Silvia Fabbi, Matteo Park, Nanjin Hayashi, Hisae Attala, Khaled French, Michael A. Driver, Vickie R. TI A pilot study evaluating non-contact low-frequency ultrasound and underlying molecular mechanism on diabetic foot ulcers SO INTERNATIONAL WOUND JOURNAL LA English DT Article DE Non-contact low frequency ultrasound; Chronic wound; Inflammatory cytokines; Matrix metalloproteinase; Vascular endothelial growth factor; Diabetic foot ulcers ID COLONY-STIMULATING FACTOR; THERAPEUTIC ULTRASOUND; WOUND AREA; PROLIFERATION; FIBROBLASTS AB Non-contact low-frequency ultrasound (NCLF-US) devices have been increasingly used for the treatment of chronic non-healing wounds. The appropriate dose for NCLF-US is still in debate. The aims of this pilot study were to evaluate the relationship between dose and duration of treatment for subjects with non-healing diabetic foot ulcers (DFUs) and to explore the correlation between wound healing and change of cytokine/proteinase/growth factor profile. This was a prospective randomised clinical study designed to evaluate subjects with non-healing DFUs for 5 weeks receiving standard of care and/or NCLF-US treatment. Subjects were randomly assigned to one of the three groups: application of NCLF-US thrice per week (Group 1), NCLF-US once per week (Group 2) and the control (Group 3) that received no NCLF-US. All subjects received standard wound care plus offloading for a total of 4 weeks. Percent area reduction (PAR) of each wound compared with baseline was evaluated weekly. Profiles of cytokines/proteinase/growth factors in wound fluid and biopsied tissue were quantified to explore the correlation between wound healing and cytokines/growth factor expression. Twelve DFU patients, 2 (167%) type 1 and 10 (833%) type 2 diabetics, with an average age of 58 +/- 10 years and a total of 12 foot ulcers were enrolled. Average ulcer duration was 3644 +/- 2478 weeks and the average ABI was 091 +/- 006. Group 1 showed significant wound area reduction at weeks 3, 4 and 5 compared with baseline, with the greatest PAR, 86% (P < 005); Groups 2 and 3 showed 25% PAR and 39% PAR, respectively, but there were no statistically significant differences between Groups 2 and 3 over time. Biochemical and histological analyses indicated a trend towards reduction of pro-inflammatory cytokines (IL-6, IL-8, IL-1, TNF- and GM-CSF), matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and macrophages in response to NCLF-US consistent with wound reduction, when compared with control group subjects. This proof-of-concept pilot study demonstrates that NCLF-US is effective in treating neuropathic diabetic foot ulcers through, at least in part, inhibiting pro-inflammatory cytokines in chronic wound and improving tissue regeneration. Therapeutic application of NFLU, thrice (3) per week, renders the best wound area reduction. C1 [Yao, Min; Driver, Vickie R.] VA New England Hlth Care Div, Dept Surg, Ctr Restorat & Regenerat Med, Providence, RI 02908 USA. [Yao, Min; Gu, Guosheng; Garcia-Lavin, Silvia; Fabbi, Matteo; Park, Nanjin; Hayashi, Hisae; Attala, Khaled; French, Michael A.; Driver, Vickie R.] Boston Univ, Med Ctr, Sch Med, Dept Surg, Boston, MA 02118 USA. [Hasturk, Hatice; Kantarci, Alpdogan] Forsyth Inst, Dept Periodontol, Cambridge, MA USA. RP Driver, VR (reprint author), VA New England Hlth Care Div, BLDG 32 Res Ctr,830 Chalkstone Ave, Providence, RI 02908 USA. EM Vickie.Driver@va.gov NR 35 TC 4 Z9 4 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-4801 EI 1742-481X J9 INT WOUND J JI Int. Wound J. PD DEC PY 2014 VL 11 IS 6 BP 586 EP 593 DI 10.1111/iwj.12005 PG 8 WC Dermatology; Surgery SC Dermatology; Surgery GA AU3JS UT WOS:000345509700005 PM 23163982 ER PT J AU Schumm, JA O'Farrell, TJ Kahler, CW Murphy, MM Muchowski, P AF Schumm, Jeremiah A. O'Farrell, Timothy J. Kahler, Christopher W. Murphy, Marie M. Muchowski, Patrice TI A Randomized Clinical Trial of Behavioral Couples Therapy Versus Individually Based Treatment for Women With Alcohol Dependence SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE female alcoholism; couples therapy; treatment outcomes ID MARITAL VIOLENCE; PARTNER VIOLENCE; METAANALYSIS; INVOLVEMENT; ABUSE AB Objective: Multiple studies show that behavioral couples therapy (BCT) is more efficacious than individually based therapy (IBT) for substance use and relationship outcomes among men with alcohol use disorder (AUD). The present study compared BCT with IBT for women with AUD. Method: Participants were women with AUD (N = 105) and their male partners without substance use disorder. Participants were mostly White and in their 40s. Women were randomized to equally intensive treatments consisting of either BCT plus 12-step-oriented IBT or IBT only. Primary outcomes included time line follow-back interview percentage days abstinent (PDA) and Inventory of Drug Use Consequences measure of substance-related problems. Secondary outcomes included the Dyadic Adjustment Scale (DAS), Relationship Happiness Scale (RHS), and Revised Conflict Tactics Scales measure of intimate partner violence (IPV). Outcome data were collected at baseline, posttreatment, and quarterly for 1-year follow-up. Results: Compared with IBT only, BCT plus IBT had significantly better primary outcomes of higher PDA and fewer substance-related problems during the 1-year follow-up period. Compared with IBT only, BCT had significantly higher male RHS during the 1-year follow-up. Women with lower pretreatment DAS had significantly higher DAS following BCT versus IBT, and there was an increasing advantage for BCT on female DAS over the follow-up. IPV was significantly reduced from pretreatment to follow-up, with no differences between treatment conditions. Conclusion: Results showed that BCT for women with AUD was more efficacious than IBT in reducing substance use and substance-related problems and improving partner relationships. C1 [Schumm, Jeremiah A.] Cincinnati VA Med Ctr, Cincinnati, OH USA. [Schumm, Jeremiah A.] Univ Cincinnati, Dept Psychiat & Behav Neurosci, Cincinnati, OH 45221 USA. [O'Farrell, Timothy J.; Murphy, Marie M.] VA Boston Healthcare Syst, Families & Addict Program, Brockton, MA USA. [O'Farrell, Timothy J.; Murphy, Marie M.] Harvard Univ, Sch Med, Dept Psychiat, Brockton, MA 02301 USA. [Kahler, Christopher W.] Brown Univ, Ctr Alcohol & Addict Studies, Dept Behav & Social Sci, Sch Publ Hlth, Providence, RI 02912 USA. [Muchowski, Patrice] AdCare Hosp Worcester Inc, Worcester, MA USA. RP O'Farrell, TJ (reprint author), Harvard Univ, Sch Med, Dept Psychiat, VA Boston Healthcare Syst, VAMC 116B1,940 Belmont St, Brockton, MA 02301 USA. EM timothy_ofarrell@hms.harvard.edu FU NIAAA NIH HHS [R01AA14700, R01 AA014700] NR 41 TC 9 Z9 9 U1 3 U2 14 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 DEC PY 2014 VL 82 IS 6 BP 993 EP 1004 DI 10.1037/a0037497 PG 12 WC Psychology, Clinical SC Psychology GA AU2MQ UT WOS:000345452900007 PM 25045910 ER PT J AU Stewart, MO Raffa, SD Steele, JL Miller, SA Clougherty, KF Hinrichsen, GA Karlin, BE AF Stewart, Michael O. Raffa, Susan D. Steele, Jennifer L. Miller, Sarah A. Clougherty, Kathleen F. Hinrichsen, Gregory A. Karlin, Bradley E. TI National Dissemination of Interpersonal Psychotherapy for Depression in Veterans: Therapist and Patient-Level Outcomes SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE interpersonal psychotherapy; depression; dissemination; training; veterans ID WORKING ALLIANCE INVENTORY; HEALTH-CARE-SYSTEM; PSYCHOMETRIC PROPERTIES; IMPLEMENTATION AB Objective: To evaluate the effects of training in and delivery of interpersonal psychotherapy (IPT) for depression throughout the U. S. Department of Veterans Affairs health care system on therapists' competency and patients' clinical outcomes. Method: Participants included 124 therapists and 241 veteran patients. Therapists participated in a 3-day workshop followed by 6 months of weekly group consultation. Therapy session tapes were rated by expert IPT training consultants using a standardized competency rating form. Patient outcomes were assessed with the Beck Depression Inventory-II and the World Health Organization Quality of Life-BREF. Therapeutic alliance was assessed with the Working Alliance Inventory-Short Revised. Results: Of the 124 therapists receiving IPT training, 115 (93%) completed all training requirements. Therapist competence in IPT increased from their 1st patient to their 2nd for both initial (d = 0.36) and intermediate (d = 0.24) treatment phases. Of the 241 veteran patients treated with IPT, 167 (69%) completed = 12 sessions. Intent-to-treat analyses indicated large overall reductions in depression (d = 1.26) and significant improvements in quality of life (d = 0.57 to 0.86) and the therapeutic alliance (d = 0.50 to 0.83). Conclusions: National IPT training in the VA health care system was associated with significant increases in therapist competencies to deliver IPT, as well as large overall reductions in depression and improvements in quality of life among veterans, many of whom presented with high levels of depression. Results support the feasibility and effectiveness of broad dissemination of IPT in routine clinical settings. C1 [Stewart, Michael O.; Raffa, Susan D.; Steele, Jennifer L.; Miller, Sarah A.; Karlin, Bradley E.] US Dept Vet Affairs, Cent Off, Washington, DC USA. [Raffa, Susan D.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Clougherty, Kathleen F.] Columbia Univ, Sch Social Work, New York, NY 10027 USA. [Hinrichsen, Gregory A.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Karlin, Bradley E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. RP Karlin, BE (reprint author), Educ Dev Ctr Inc, 96 Morton St,7th Floor, New York, NY 10014 USA. EM bkarlin@edc.org NR 18 TC 3 Z9 3 U1 0 U2 7 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 DEC PY 2014 VL 82 IS 6 BP 1201 EP 1206 DI 10.1037/a0037410 PG 6 WC Psychology, Clinical SC Psychology GA AU2MQ UT WOS:000345452900024 PM 25045906 ER PT J AU Hove, MJ Balasubramaniam, R Keller, PE AF Hove, Michael J. Balasubramaniam, Ramesh Keller, Peter E. TI The Time Course of Phase Correction: A Kinematic Investigation of Motor Adjustment to Timing Perturbations During Sensorimotor Synchronization SO JOURNAL OF EXPERIMENTAL PSYCHOLOGY-HUMAN PERCEPTION AND PERFORMANCE LA English DT Article DE sensorimotor synchronization; phase correction; motion capture; timing; movement kinematics ID RHYTHMIC AUDITORY-STIMULI; MOVEMENT TRAJECTORIES; ERROR-CORRECTION; RESPONSES; CONTINUATION; BEAT; ADAPTATION; METRONOME; PRIMATES; POSITION AB Synchronizing movements with a beat requires rapid compensation for timing errors. The phase-correction response (PCR) has been studied extensively in finger tapping by shifting a metronome onset and measuring the adjustment of the following tap time. How the response unfolds during the subsequent tap cycle remains unknown. Using motion capture, we examined finger kinematics during the PCR. Participants tapped with a metronome containing phase perturbations. They tapped in "legato" and "staccato" style at various tempi, which altered the timing of the constituent movement stages (dwell at the surface, extension, and flexion). After a phase perturbation, tapping kinematics changed compared with baseline, and the PCR was distributed differently across movement stages. In staccato tapping, the PCR trajectory changed primarily during finger extension across tempi. In legato tapping, at fast tempi the PCR occurred primarily during extension, whereas at slow tempi most phase correction was already completed during dwell. Across conditions, timing adjustments occurred primarily 100-250 ms into the following tap cycle. The change in movement around 100 ms represents the time to integrate information into an already planned movement and the rapidity suggests a subcortical route. C1 [Hove, Michael J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. [Hove, Michael J.; Keller, Peter E.] Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany. [Balasubramaniam, Ramesh] Univ Calif Merced, Merced, CA USA. [Keller, Peter E.] Univ Western Sydney, MARCS Inst, Sydney, NSW, Australia. RP Hove, MJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Room 2651,149 13th St, Charlestown, MA 02129 USA. EM michaeljhove@gmail.com OI Keller, Peter/0000-0001-7579-6515 FU Max Planck Society; Erasmus Mundus Auditory Cognitive Neuroscience program; National Institute of Mental Health [T32-MH16259] FX This work was partially supported by the Max Planck Society, and by funding to Michael J. Hove from The Erasmus Mundus Auditory Cognitive Neuroscience program, and National Institute of Mental Health Grant T32-MH16259. We thank Bruno Repp for feedback in the early stages of this project. NR 52 TC 5 Z9 5 U1 2 U2 7 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0096-1523 EI 1939-1277 J9 J EXP PSYCHOL HUMAN JI J. Exp. Psychol.-Hum. Percept. Perform. PD DEC PY 2014 VL 40 IS 6 BP 2243 EP 2251 DI 10.1037/a0037826 PG 9 WC Psychology; Psychology, Experimental SC Psychology GA AU2MT UT WOS:000345453300013 PM 25151103 ER PT J AU Nau, P Rattner, D AF Nau, Peter Rattner, David TI Laparoscopic Heller Myotomy as the Gold Standard for Treatment of Achalasia SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Achalasia; Heller myotomy; Dysphagia ID PNEUMATIC DILATATION; TOUPET FUNDOPLICATION; ESOPHAGEAL ACHALASIA; CARDIOMYOTOMY; EXPERIENCE; DILATION; EFFICACY; TRIAL; POEM AB The recent introductions of novel methods for the treatment of achalasia as well as ongoing controversies about the merits of surgical and endoscopic treatment options have created controversy in identifying the optimal treatment for this condition. This lack of clarity prompted this review of 206 consecutive patients treated with a laparoscopic Heller (LH) myotomy over a 16-year period. A retrospective review of a prospectively collected database was performed of 206 consecutive LH performed by a single surgeon. In this cohort, 58 % of patients had undergone a prior therapeutic intervention. Over 90 % of patients had relief of dysphagia post-operatively. There was one intraoperative esophageal perforation. There were no mortalities. Only 4/206 patients sustained complications that required either post-op therapeutic intervention or delayed hospital discharge. This paper outlines an operative technique that has yielded outstanding results and may be used as a benchmark against which other therapies can be judged. C1 [Nau, Peter; Rattner, David] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Rattner, D (reprint author), Massachusetts Gen Hosp, Dept Surg, WACC 460 15 Parkman St, Boston, MA 02114 USA. EM peter-nau@uiowa.edu; drattner@mgh.harvard.edu NR 24 TC 6 Z9 6 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD DEC PY 2014 VL 18 IS 12 BP 2201 EP 2207 DI 10.1007/s11605-014-2655-5 PG 7 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AT9YX UT WOS:000345281100018 PM 25205539 ER PT J AU Jackevicius, CA Glassman, P AF Jackevicius, Cynthia A. Glassman, Peter TI Laboratory Monitoring for Pharmaceuticals: Familiarity Does Not Breed Contempt SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material ID THERAPY C1 [Jackevicius, Cynthia A.] Western Univ Hlth Sci, Pomona, CA USA. [Jackevicius, Cynthia A.; Glassman, Peter] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Jackevicius, Cynthia A.] Univ Toronto, Inst Clin Evaluat Sci, Toronto, ON, Canada. [Jackevicius, Cynthia A.] Univ Toronto, Fac Med, Inst Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Jackevicius, Cynthia A.] Univ Hlth Network, Toronto, ON, Canada. [Glassman, Peter] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Glassman, P (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Med 111G, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Peter.Glassman@va.gov NR 9 TC 0 Z9 0 U1 1 U2 3 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 DEC PY 2014 VL 29 IS 12 BP 1574 EP 1576 DI 10.1007/s11606-014-3048-x PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1PY UT WOS:000345393700002 PM 25287479 ER PT J AU Dhaliwal, G AF Dhaliwal, Gurpreet TI Capsule Commentary on Guerrasio and Aagaard, Methods and Outcomes for the Remediation of Clinical Reasoning SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 [Dhaliwal, Gurpreet] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Dhaliwal, Gurpreet] San Francisco VA Med Ctr, Med Serv, San Francisco, CA USA. RP Dhaliwal, G (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM gurpreet.dhaliwal@ucsf.edu NR 4 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2014 VL 29 IS 12 BP 1687 EP 1687 DI 10.1007/s11606-014-2971-1 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1PY UT WOS:000345393700020 PM 25183473 ER PT J AU Giridhar, KV Dhaliwal, G Tierney, L AF Giridhar, Karthik V. Dhaliwal, Gurpreet Tierney, Lawrence TI Split Decision SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material DE shared decision making; flank pain; radiation safety ID RENAL-ARTERY DISSECTION; INFARCTION; CANCER C1 [Giridhar, Karthik V.; Dhaliwal, Gurpreet; Tierney, Lawrence] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Dhaliwal, Gurpreet; Tierney, Lawrence] San Francisco VA Med Ctr, Med Serv, San Francisco, CA USA. RP Giridhar, KV (reprint author), Univ Calif San Francisco, Dept Med, 505 Parnassus Ave, San Francisco, CA 94143 USA. EM Karthik.giridhar@ucsf.edu OI Giridhar, Karthik/0000-0003-4640-9197 NR 12 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2014 VL 29 IS 12 BP 1707 EP 1710 DI 10.1007/s11606-014-2874-1 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1PY UT WOS:000345393700027 PM 24913002 ER PT J AU Charns, MP Egede, LE Rumsfeld, JS McGlynn, GC Yano, EM AF Charns, Martin P. Egede, Leonard E. Rumsfeld, John S. McGlynn, Geraldine C. Yano, Elizabeth M. TI Advancing Partnered Research in the VA Healthcare System: The Pursuit of Increased Research Engagement, Responsiveness, and Impact SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 [Charns, Martin P.] VA Boston Healthcare Syst, CHOIR, Boston, MA 02130 USA. [Charns, Martin P.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Egede, Leonard E.] Charleston VA HSR&D Ctr Innovat, HEROIC, Charleston, SC USA. [Egede, Leonard E.] Med Univ S Carolina, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Rumsfeld, John S.] Vet Hlth Adm, Washington, DC USA. [Rumsfeld, John S.] Univ Colorado, Sch Med, Div Cardiol, Denver, CO USA. [McGlynn, Geraldine C.] VA Boston Healthcare Syst, HSR&D Ctr Informat Disseminat & Educ Resources CI, Boston, MA USA. [Yano, Elizabeth M.] VA Greater Los Angeles Healthcare Syst, VA HSR&D Ctr Study Healthcare Innovat Implementat, Sepulveda, CA USA. [Yano, Elizabeth M.] UCLA Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. RP Charns, MP (reprint author), VA Boston Healthcare Syst, CHOIR, 150 S Huntington Ave, Boston, MA 02130 USA. EM martin.charns@va.gov FU NIDDK NIH HHS [K24 DK093699] NR 6 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2014 VL 29 SU 4 BP S811 EP S813 DI 10.1007/s11606-014-3060-1 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1XG UT WOS:000345410200001 PM 25355095 ER PT J AU Dobscha, SK Denneson, LM Kovas, AE Teo, A Forsberg, CW Kaplan, MS Bossarte, R McFarland, BH AF Dobscha, Steven K. Denneson, Lauren M. Kovas, Anne E. Teo, Alan Forsberg, Christopher W. Kaplan, Mark S. Bossarte, Robert McFarland, Bentson H. TI Correlates of Suicide Among Veterans Treated in Primary Care: Case-Control Study of a Nationally Representative Sample SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE mental health; veterans; primary care health services research ID POSTTRAUMATIC-STRESS-DISORDER; RISK-ASSESSMENT; HEALTH SYSTEM; MENTAL-HEALTH; DEPRESSION; IDEATION; MORTALITY; DEATH; PATTERNS; CONTACT AB BACKGROUND: Veterans receiving Veterans Affairs (VA) healthcare have increased suicide risk compared to the general population. Many patients see primary care clinicians prior to suicide. Yet little is known about the correlates of suicide among patients who receive primary care treatment prior to death. OBJECTIVE: Our aim was to describe characteristics of veterans who received VA primary care in the 6 months prior to suicide: and to compare these to characteristics of control patients who also received VA primary care. DESIGN: This was a retrospective case-control study. SUBJECTS: The investigators partnered with VA operations leaders to obtain death certificate data from 11 states for veterans who died by suicide in 2009. Cases were matched 1:2 to controls based on age, sex, and clinician. MAIN MEASURES: Demographic, diagnosis, and utilization data were obtained from VA's Corporate Data Warehouse. Additional clinical and psychosocial context data were collected using manual medical record review. Multivariate conditional logistic, regression was used to examine associations between potential predictor variables and suicide. KEY RESULTS: Two hundred and sixty-nine veteran cases were matched to 538 controls. Average subject age was 63 years; 97 % were male. Rates of mental health conditions, functional decline, sleep disturbance, suicidal ideation, and psychosocial stressors were all significantly greater in cases compared to controls. In the final model describing men in the sample, non-white race (OR=0.51; 95 % CI=0.27-0.98) and VA service-connected disability (OR= 0.54: 95 % CI=0.36-0.80) were associated with decreased odds of suicide, while anxiety disorder (OR= 3.52: 95 % Cl= 1.79-6.92), functional decline (OR=2.52; 95 % CI = 1.55-4.10), depression (OR=1.82; 95 % CI= 1.073.10). and endorsement of suicidal ideation (OR= 2.27: 95 % CI= 1.07-4.83) were associated with greater odds of suicide. CONCLUSIONS: Assessment for anxiety disorders and functional decline in addition to suicidal ideation and depression may be especially important for determining suicide risk in this population. Continued development of interventions that support identifying and addressing these conditions in primary care is indicated. C1 [Dobscha, Steven K.; Denneson, Lauren M.; Kovas, Anne E.; Teo, Alan; Forsberg, Christopher W.] Portland VA Med Ctr, Ctr Improve Vet Involvement Care, Portland, OR 97207 USA. [Dobscha, Steven K.; Denneson, Lauren M.; Teo, Alan; McFarland, Bentson H.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Kaplan, Mark S.] UCLA Luskin Sch Publ Affairs, Dept Social Welf, Los Angeles, CA USA. [Bossarte, Robert] VISN, Ctr Excellence Suicide Prevent 2, Canandaigua, NY USA. RP Dobscha, SK (reprint author), Portland VA Med Ctr, Ctr Improve Vet Involvement Care, POB 1034 R&D 66, Portland, OR 97207 USA. EM steven.dobscha@va.gov FU Department of Veterans Affairs; Veterans Health Administration; Health Services Research and Development Service Project [IIR 10-331]; VA Mental Health Services-Suicide Prevention Program; VISN 2 Center of Excellence for Suicide Prevention FX This material is based upon work supported by the Department of Veterans Affairs, the Veterans Health Administration, and Health Services Research and Development Service Project IIR 10-331, VA Mental Health Services-Suicide Prevention Program, and VISN 2 Center of Excellence for Suicide Prevention. Dr Dobscha is the Director of the Center to Improve Veteran Involvement in Care (CIVIC) at the Portland VA Medical Center. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Affairs or the United States government. NR 45 TC 9 Z9 9 U1 4 U2 10 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 DEC PY 2014 VL 29 SU 4 BP S853 EP S860 DI 10.1007/s11606-014-3028-1 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1XG UT WOS:000345410200009 PM 25355088 ER PT J AU Elwy, AR Bokhour, BG Maguire, EM Wagner, TH Asch, SM Gifford, AL Gallagher, TH Durfee, JM Martinello, RA Schiffner, S Jesse, RL AF Elwy, A. Rani Bokhour, Barbara G. Maguire, Elizabeth M. Wagner, Todd H. Asch, Steven M. Gifford, Allen L. Gallagher, Thomas H. Durfee, Janet M. Martinello, Richard A. Schiffner, Susan Jesse, Robert L. TI Improving Healthcare Systems' Disclosures of Large-Scale Adverse Events: A Department of Veterans Affairs Leadership, Policymaker, Research and Stakeholder Partnership SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE adverse events Veterans; qualitative; communication: partnered-based research AB BACKGROUND: The Department of Veterans Affairs (VA) mandates disclosure of large-scale adverse events to patients, even if risk of harm is not clearly present. Concerns about past disclosures warranted further examination of the impact of this policy. OBJECTIVE: Through a collaborative partnership between VA leaders, policymakers, researchers and stakeholders, the objective was to empirically identify critical aspects of disclosure processes as a first step towards improving future disclosures. DESIGN: Semi-structured interviews were conducted with participants at nine VA facilities where recent disclosures took place. PARTICIPANTS: Ninety-seven stakeholders participated in the interviews: 38 employees, 28 leaders (from facilities, regions and national offices), 27 Veteran patients and family members, and four congressional staff members. APPROACH: Facility and regional leaders were interviewed by telephone, followed by a two-day site visit where employees, patients and family members were interviewed face-to-face. National leaders and congressional staff also completed telephone interviews. Interviews were analyzed using rapid qualitative assessment processes. Themes were mapped to the stages of the Crisis and Emergency Risk Communication model: pre-crisis, initial event, maintenance, resolution and evaluation. KEY RESULTS: Many areas for improvement during disclosure were identified, such as preparing facilities better (pre-crisis), creating rapid communications, modifying disclosure language, addressing perceptions of harm, reducing complexity, and seeking assistance from others (initial event), managing communication with other stakeholders (maintenance), minimizing effects on staff and improving trust (resolution), and addressing facilities' needs (evaluation). CONCLUSIONS: Through the partnership, five recommendations to improve disclosures during each stage of communication have been widely disseminated throughout the VA using non-academic strategies. Some improvements have been made; other recommendations will be addressed through implementation of a large-scale adverse event disclosure toolkit. These toolkit strategies will enable leaders to provide timely and transparent information to patients and families, while reducing the burden on employees and the healthcare system during these events. C1 [Elwy, A. Rani; Bokhour, Barbara G.; Maguire, Elizabeth M.; Gifford, Allen L.] Edith Nourse Rogers Mem Vet Adm Hosp, Ctr Healthcare Org & Implementat Res, Bedford, MA 01730 USA. [Elwy, A. Rani; Bokhour, Barbara G.; Gifford, Allen L.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Elwy, A. Rani; Bokhour, Barbara G.; Asch, Steven M.; Gifford, Allen L.] Vet Hlth Adm, HIV Hepatitis Qual Enhancement Res Initiat, Washington, DC USA. [Wagner, Todd H.] VA Palo Alto Healthcare Syst, Hlth Econ Resource Ctr, Menlo Pk, CA USA. [Wagner, Todd H.; Asch, Steven M.] VA Palo Alto Healthcare Syst, Ctr Innovat Implementat, Menlo Pk, CA USA. [Wagner, Todd H.; Asch, Steven M.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Gallagher, Thomas H.] Univ Washington, Sch Med, Seattle, WA USA. [Durfee, Janet M.; Martinello, Richard A.] US Dept Vet Affairs, Clin Publ Hlth Program, Off Publ Hlth, Vet Hlth Adm, Washington, DC USA. [Martinello, Richard A.] Yale Univ, Sch Med, New Haven, CT USA. [Schiffner, Susan; Jesse, Robert L.] US Dept Vet Affairs, Off Principal Deputy Secretary Hlth, Vet Hlth Adm, Washington, DC USA. RP Elwy, AR (reprint author), Edith Nourse Rogers Mem Vet Adm Hosp, Ctr Healthcare Org & Implementat Res, 200 Springs Rd,Mailstop152, Bedford, MA 01730 USA. EM Rani.Elwy@va.gov FU Department of Veterans Affairs, Health Services Research and Development Service [SDR 11-440]; HIV/Hepatitis Quality Enhancement Research Initiative, Veterans Health Administration; National Institute of Mental Health [R25 MH080916-01A2]; Department of Veterans Affairs, Health Services Research & Development Service, Quality Enhancement Research Initiative FX This study was supported by the Department of Veterans Affairs, Health Services Research and Development Service, SDR 11-440. The views, opinions, and content of this publication are those of the authors and do not necessarily reflect the views, opinions, or policies of the Department of Veterans Affairs or the United States Government.; Drs. Elwy, Bokhow, Maguire, Asch and Gifford are supported by the HIV/Hepatitis Quality Enhancement Research Initiative, Veterans Health Administration.; Dr. Elwy is also an investigator with the Implementation Research Institute, 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. NR 15 TC 3 Z9 3 U1 2 U2 7 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 DEC PY 2014 VL 29 SU 4 BP S895 EP S903 DI 10.1007/s11606-014-3034-3 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1XG UT WOS:000345410200014 PM 25355090 ER PT J AU Kertesz, SG Austin, EL Holmes, SK Pollio, DE Schumacher, JE White, B Lukas, AV AF Kertesz, Stefan G. Austin, Erika Laine Holmes, Sally K. Pollio, David E. Schumacher, Joseph E. White, Bert Lukas, Andcarol VanDeusen TI Making Housing First Happen: Organizational Leadership in VA's Expansion of Permanent Supportive Housing SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE homeless persons; organizational behavior; implementation; community health; veterans; housing policy ID HEALTH-CARE; CONSOLIDATED FRAMEWORK; HOMELESS; IMPLEMENTATION; OUTCOMES; FIDELITY; SERVICES; PROGRAM; IMPACT; CHALLENGES AB BACKGROUND: While most organizational literature has focused on initiatives that transpire inside the hospital walls, the redesign of American health care increasingly asks that health care institutions address matters outside their walls, targeting the health of populations. The US Department of Veterans Affairs (VA)'s national effort to end Veteran homelessness represents an externally focused organizational endeavor. OBJECTIVE: Our aim was to evaluate the role of organizational practices in the implementation of Housing First (MI, an evidence-based homeless intervention for chronically homeless individuals. DESIGN: This was an interview-based comparative case study conducted across eight VA Medical Centers (VAMCs). PARTICIPANTS: Front line staff, mid-level managers, and senior leaders at VA Medical Centers were interviewed between February and December 2012. APPROACH: Using a structured narrative and numeric scoring, we assessed the correlation between successful HF implementation and organizational practices devised according to the organizational transformation model (OTM). KEY RESULTS: Scoring results suggested a strong association between HF implementation and OTM practice. Strong impetus to house Veterans came from national leadership, reinforced by Medical Center directors closely tracking results. More effective Medical Center leaders differentiated themselves by joining front-line staff in the work (at public events and in process improvement exercises), by elevating homeless-knowledgeable persons into senior leadership, and by exerting themselves to resolve logistic challenges. Vertical alignment and horizontal integration advanced at sites that fostered work groups cutting across service lines and hierarchical levels. By contrast, weak alignment from top to bottom typically also hindered cooperation across departments. Staff commitment to ending homelessness was high, though sustainability planning was limited in this baseline year of observation. CONCLUSION: Key organizational practices correlated with more successful implementation of HF for homeless Veterans. Medical Center directors substantively influenced the success of this endeavor through their actions to foster impetus, demonstrate commitment and support alignment and integration. C1 [Kertesz, Stefan G.; Austin, Erika Laine] Birmingham VA Med Ctr, Birmingham, AL 35233 USA. [Kertesz, Stefan G.; Austin, Erika Laine; Pollio, David E.; Schumacher, Joseph E.] Univ Alabama Birmingham, Birmingham, AL USA. [Holmes, Sally K.; White, Bert] Boston VA Med Ctr, CHOIR, Jamaica Plain, MA USA. [Holmes, Sally K.; Lukas, Andcarol VanDeusen] Boston Univ, Boston, MA 02215 USA. RP Kertesz, SG (reprint author), Birmingham VA Med Ctr, 700 19th St S,REAP Mailstop 151, Birmingham, AL 35233 USA. EM skertesz@uabmc.edu OI Kertesz, Stefan/0000-0001-6101-8421 FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development branch [SDR-11233] FX This study was funded by grant SDR-11233 from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development branch. The authors thank the many VA staff who graciously shared their observations and experiences with this research team. The authors also thank Vincent Kane, MSW, National Center on Homelessness Among Veterans, Department of Veterans Affairs, and Keith Harris, PhD, National Director of Clinical Operations, Mental Health Homeless and Residential Rehabilitation Treatment Programs, Department of Veterans Affairs, for their partnership in this study. They also thank N. Kay Johnson, BSN, MPH and Carolyn Ray, JD for their assistance with the study. NR 33 TC 3 Z9 3 U1 12 U2 30 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 DEC PY 2014 VL 29 SU 4 BP S835 EP S844 DI 10.1007/s11606-014-3025-4 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1XG UT WOS:000345410200007 PM 25355085 ER PT J AU Kilbourne, AM Atkins, D AF Kilbourne, Amy M. Atkins, David TI Partner or Perish: VA Health Services and the Emerging Bi-Directional Paradigm SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material ID MEDICAL HOME; VETERANS; CARE C1 [Kilbourne, Amy M.; Atkins, David] US Dept Vet Affairs, VA Hlth Serv Res & Dev Serv, Washington, DC 20420 USA. [Kilbourne, Amy M.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. RP Kilbourne, AM (reprint author), US Dept Vet Affairs, Hlth Serv Res & Dev Serv, 810 Vermont Ave NW, Washington, DC 20420 USA. NR 15 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD DEC PY 2014 VL 29 SU 4 BP S817 EP S819 DI 10.1007/s11606-014-3050-3 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1XG UT WOS:000345410200003 PM 25355094 ER PT J AU Midboe, AM Elwy, AR Durfee, JM Gifford, AL Yakovchenko, V Martinello, RA Ross, D Czarnogorski, M Goetz, MB Asch, SM AF Midboe, Amanda M. Elwy, A. Rani Durfee, Janet M. Gifford, Allen L. Yakovchenko, Vera Martinello, Richard A. Ross, David Czarnogorski, Maggie Goetz, Matthew B. Asch, Steven M. TI Building Strong Research Partnerships Between Public Health and Researchers: A VA Case Study SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE Partner-based research; Public health; Infectious disease ID HIV; QUERI AB We are in a new era of partner-based implementation research, and we need clear strategies for how to navigate this new era. Drawing on principles from community-based participatory research, the Clinical Public Health group of the Department of Veterans Affairs and the HIV/Hepatitis Quality Enhancement Research Initiative (HHQUERI) forged a longstanding partnership that has improved the care of Veterans with Human immunodeficiency Virus (HIV) and Hepatitis C Virus. An exemplar HIV testing project epitomizes this partnership and is discussed in terms of the lessons learned as a result of our high level of collaboration around design, analysis, implementation, and dissemination across projects over the past several years. Lessons learned through this partnered testing program involve respecting different time horizons among the partners, identifying relevant research questions for both parties, designing flexible studies, engaging all partners throughout the research, and placing an emphasis on relationship building at all times. These lessons and strategies can benefit others conducting partner-based research both within the Veterans Health Administration (VA) and in other integrated healthcare systems. C1 [Midboe, Amanda M.; Asch, Steven M.] VA Palo Alto Hlth Care Syst, Ctr Innovat Implementat Ci2i, Menlo Pk, CA 94025 USA. [Elwy, A. Rani; Gifford, Allen L.; Yakovchenko, Vera] Edith Nourse Rogers Mem Vet Hosp, Ctr Hlth Care Org & Implementat Res, Bedford, MA USA. [Elwy, A. Rani; Gifford, Allen L.; Yakovchenko, Vera] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Durfee, Janet M.; Martinello, Richard A.; Ross, David; Czarnogorski, Maggie] VA Cent Off Publ Hlth Clin Publ Hlth Grp, Charlottesville, VA USA. [Martinello, Richard A.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Martinello, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Goetz, Matthew B.] VA Greater Los Angeles Healthcare Syst, Infect Dis Sect, Los Angeles, CA USA. [Goetz, Matthew B.] VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Goetz, Matthew B.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Asch, Steven M.] Stanford Univ, Div Gen Med Disciplines, Stanford, CA 94305 USA. RP Midboe, AM (reprint author), VA Palo Alto Hlth Care Syst, Ctr Innovat Implementat Ci2i, 795 Willow Rd,152, Menlo Pk, CA 94025 USA. EM amanda.midboe@va.gov OI Goetz, Matthew/0000-0003-4542-992X FU Department of Veterans Affairs, Veterans Health Administration's Quality Enhancement Research Initiative (QUERI) Program FX This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration's Quality Enhancement Research Initiative (QUERI) Program, which has supported the HIV/Hepatitis is QUERI. NR 13 TC 0 Z9 0 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 DEC PY 2014 VL 29 SU 4 BP S831 EP S834 DI 10.1007/s11606-014-3017-4 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1XG UT WOS:000345410200006 PM 25355082 ER PT J AU Nieuwsma, JA Jackson, GL DeKraai, MB Bulling, DJ Cantrell, WC Rhodes, JE Bates, MJ Ethridge, K Lane, ME Tenhula, WN Batten, SV Meador, KG AF Nieuwsma, Jason A. Jackson, George L. DeKraai, Mark B. Bulling, Denise J. Cantrell, William C. Rhodes, Jeffrey E. Bates, Mark J. Ethridge, Keith Lane, Marian E. Tenhula, Wendy N. Batten, Sonja V. Meador, Keith G. TI Collaborating Across the Departments of Veterans Affairs and Defense to Integrate Mental Health and Chaplaincy Services SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE mental health; spirituality; patient centered care. veterans; implementation research ID POSTTRAUMATIC-STRESS-DISORDER; CARE-SYSTEM; UNITED-STATES; BARRIERS; STIGMA; FORGIVENESS; SOLDIERS; COMBAT; PTSD; PERCEPTIONS AB BACKGROUND: Recognizing that clergy and spiritual care providers are a key part of mental health care systems, the Department of Veterans Affairs (VA) and Department of Defense (DoD) jointly examined chaplains' current and potential roles in caring for veterans and service members with mental health needs. OBJECTIVE: Our aim was to evaluate the intersection of chaplain and mental health care practices in VA and DoD in order to determine if improvement is needed, and if so, to develop actionable recommendations as indicated by evaluation findings. DESIGN: A 38-member multidisciplinary task group partnered with researchers in designing, implementing, and interpreting a mixed methods study that included: 1) a quantitative survey of VA and DoD chaplains; and 2) qualitative interviews with mental health providers and chaplains. PARTICIPANTS: Quantitative: the survey included all full-time VA chaplains and all active duty military chaplains (n=2,163 completed of 3,464 invited; 62 % response rate). Qualitative: a total of 291 interviews were conducted with mental health providers and chaplains during site visits to 33 VA and DoD facilities. MAIN MEASURES: Quantitative: the online survey assessed intersections between chaplaincy and mental health care and took an average of 37 mm to complete. Qualitative: the interviews assessed current integration of mental health and chaplain services and took an average of 1 h to complete. KEY RESULTS:When included on interdisciplinary mental health care teams, chaplains feel understood and valued (82.8-100 % of chaplains indicated this, depending on the team). However, findings from the survey and site visits suggest that integration of services is often lacking and can be improved. CONCLUSIONS: Closely coordinating with a multidisciplinary task group in conducting a mixed method evaluation of chaplain-mental health integration in VA and DoD helped to ensure that researchers assessed relevant domains and that findings could be rapidly translated into actionable recommendations. C1 [Nieuwsma, Jason A.; Cantrell, William C.; Meador, Keith G.] Mid Atlantic Mental Illness Res Educ & Clin Ctr, Dept Vet Affairs, Durham, NC USA. [Nieuwsma, Jason A.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Jackson, George L.] Durham Vet Affairs Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Jackson, George L.] Duke Univ, Med Ctr, Div Gen Internal Med, Durham, NC USA. [DeKraai, Mark B.; Bulling, Denise J.] Univ Nebraska, Publ Policy Ctr, Lincoln, NE USA. [Cantrell, William C.] US Navy, Chaplain Corps, Marine Forces Reserve, New Orleans, LA USA. [Rhodes, Jeffrey E.; Bates, Mark J.] Def Ctr Excellence Psychol Hlth & Traumat Brain I, Deployment Hlth Clin Ctr, Silver Spring, MD USA. [Ethridge, Keith] Natl Chaplain Ctr, Dept Vet Affairs, Hampton, VA USA. [Lane, Marian E.] RTI Int, Durham, NC USA. [Tenhula, Wendy N.] US Dept Vet Affairs, Mental Hlth Serv, Washington, DC USA. [Batten, Sonja V.] Booz Allen Hamilton, Washington, DC USA. [Meador, Keith G.] Vanderbilt Univ, Ctr Biomed Eth & Soc, Dept Psychiat, Nashville, TN 37235 USA. [Meador, Keith G.] Vanderbilt Univ, Ctr Biomed Eth & Soc, Dept Hlth Policy, Nashville, TN 37235 USA. [Meador, Keith G.] Vanderbilt Univ, Grad Dept Relig, Nashville, TN 37235 USA. RP Nieuwsma, JA (reprint author), VA Mid Atlantic MIRECC, Legacy Towers 800B,411 West Chapel Hill St, Durham, NC 27701 USA. EM jason.nieuwsma@duke.edu FU Department of Veterans Affairs and Department of Defense Integrated Mental Health Strategy (VA/DoD IMHS); VA/DoD Joint Incentive Fund FX Funding support provided by Department of Veterans Affairs and Department of Defense Integrated Mental Health Strategy (VA/DoD IMHS) and the VA/DoD Joint Incentive Fund. NR 46 TC 3 Z9 3 U1 2 U2 4 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 DEC PY 2014 VL 29 SU 4 BP S885 EP S894 DI 10.1007/s11606-014-3032-5 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1XG UT WOS:000345410200013 PM 25355089 ER PT J AU Kozanek, M Bartonicek, J Chase, SM Jupiter, JB AF Kozanek, Michal Bartonicek, Jan Chase, Samantha M. Jupiter, Jesse B. TI Treatment of Distal Humerus Fractures in Adults: A Historical Perspective SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Distal humerus fractures; elbow trauma; history ID PROSPECTIVE RANDOMIZED-TRIAL; TOTAL ELBOW ARTHROPLASTY; INTERNAL-FIXATION; OPEN REDUCTION; INTERCONDYLAR FRACTURES; PLATE; SYSTEM AB Nonsurgical treatment was the mainstay of management of distal humerus fractures for centuries and nonunions and malunions were common. The 19th century featured the recognition of distinct injury patterns. With advances in radiology, anesthesia, antisepsis, and hardware technology, surgical treatment is now generally preferred, yet loss of elbow joint mobility can still be a vexing problem. Copyright (C) 2014 by the American Society for Surgery of the Hand. All rights reserved.) C1 Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. Harvard Combined Orthopaed Residency Program, Boston, MA USA. Charles Univ Prague, Fac Med 1, Dept Orthopaed Trauma, Prague, Czech Republic. Cent Mil Hosp, Prague, Czech Republic. Comenius Univ, Fac Med, Bratislava, Slovakia. RP Jupiter, JB (reprint author), Massachusetts Gen Hosp, YAW 2,55 Fruit St, Boston, MA 02114 USA. EM jjupiter1@partners.org RI Bartonicek, Jan/E-8217-2017 OI Bartonicek, Jan/0000-0002-2228-1443 FU Orthopaedic Research and Education Foundation FX This work was aided by a grant from the Orthopaedic Research and Education Foundation. NR 38 TC 3 Z9 3 U1 0 U2 7 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 DEC PY 2014 VL 39 IS 12 BP 2481 EP 2485 DI 10.1016/j.jhsa.2014.08.003 PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AU4CX UT WOS:000345557600021 PM 25442772 ER PT J AU Tallaj, JA Pamboukian, SV George, JF Kirklin, JK Brown, RN McGiffin, DC Acharya, D Loyaga-Rendon, R Melby, SJ Bourge, RC Naftel, DC AF Tallaj, Jose A. Pamboukian, Salpy V. George, James F. Kirklin, James K. Brown, Robert N. McGiffin, David C. Acharya, Deepak Loyaga-Rendon, Renzo Melby, Spencer J. Bourge, Robert C. Naftel, David C. TI Have risk factors for mortality after heart transplantation changed over time? Insights from 19 years of Cardiac Transplant Research Database study SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article DE Heart Transplantation; Survival post-transplantation; Left ventricular assist device; Pulmonary hypertension; Heart failure; Immunosuppression; Allograft rejection; Racial disparities ID LUNG TRANSPLANTATION; DEATH; RECIPIENTS; REJECTION; HYPERTENSION; TRIAL AB BACKGROUND: The Cardiac Transplant Research Database (CTRD) collected data from 26 U.S. institutions from January 1, 1990 to December 31, 2008 providing the opportunity for construction of a comprehensive multivariable model of risk for death after transplantation. We analyzed risk factors for death over 19 years of experience to determine how risk profiles have changed over time and how they interact with age. METHODS: A multivariable parametric hazard model for death was created for 7,015 patients entered into the CTRD. Variables collected over 19 years of experience were examined as potential risk factors and tested for interaction with date of transplantation to determine if their relative risk (RR) changed over time. RESULTS: The hazard for death post-transplant occurred in 2 phases: an early phase of acute risk lasting <1 year, and a late phase of relatively low, gradually increasing risk (<0.1 event/year). In the early phase, predictive models showed that ventricular assist device (VAD) at the time of transplant did not increase the RR of death for recipient transplant at 30 years of age, but the RR of death was increased by 60% (p = 0.04) at 60 years of age. Of the late-phase variables found to be risk factors, the RR of age, date of transplant and pulmonary vascular resistance changed with respect to transplant year. The overall risk of death dropped importantly over the study period, but the RR of all other variables remained unchanged. RR was 2.6 (p < 0.0001) for 25-year-old African-American (AA) versus non-AA recipients and 1.6 for 60-year-old AA recipients (p = 0.02). CONCLUSION: Over 19 years, the baseline risk of death has decreased, but the specific risk factors and the magnitudes of their RR have remained unchanged. Therefore, despite advances in clinical management and improvement in overall survival, the risk profile for death after cardiac transplantation is similar to that in 1990. (C) 2014 International Society for Heart and Lung Transplantation. All rights reserved. C1 [Tallaj, Jose A.; Pamboukian, Salpy V.; Acharya, Deepak; Loyaga-Rendon, Renzo; Bourge, Robert C.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Tallaj, Jose A.] Birmingham VA Med Ctr, Dept Med, Birmingham, AL USA. [George, James F.; Kirklin, James K.; Brown, Robert N.; McGiffin, David C.; Melby, Spencer J.; Naftel, David C.] Univ Alabama Birmingham, Dept Surg, Div Cardiothorac Surg, Birmingham, AL 35294 USA. RP Tallaj, JA (reprint author), Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, THT 338,1900 Univ Blvd, Birmingham, AL 35294 USA. EM jtallaj@uab.edu NR 23 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD DEC PY 2014 VL 33 IS 12 BP 1304 EP 1311 DI 10.1016/j.healun.2014.08.014 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA AU3XS UT WOS:000345544600014 PM 25443871 ER PT J AU Hatfield, SM Kjaergaard, J Lukashev, D Belikoff, B Schreiber, TH Sethumadhavan, S Abbott, R Philbrook, P Thayer, M Shujia, D Rodig, S Kutok, JL Ren, J Ohta, A Podack, ER Karger, B Jackson, EK Sitkovsky, M AF Hatfield, Stephen M. Kjaergaard, Jorgen Lukashev, Dmitriy Belikoff, Bryan Schreiber, Taylor H. Sethumadhavan, Shalini Abbott, Robert Philbrook, Phaethon Thayer, Molly Shujia, Dai Rodig, Scott Kutok, Jeffrey L. Ren, Jin Ohta, Akio Podack, Eckhard R. Karger, Barry Jackson, Edwin K. Sitkovsky, Michail TI Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1 alpha-dependent and extracellular adenosine-mediated tumor protection SO JOURNAL OF MOLECULAR MEDICINE-JMM LA English DT Article DE Hypoxia; HIF-1 alpha; Adenosine; CD73; Cancer; Immunology ID LUNG INJURY; CANCER-IMMUNOTHERAPY; T-CELLS; GROWTH; CD73; INFLAMMATION; EXPRESSION; PATHWAYS; DISEASE; HIF-1 AB Intratumoral hypoxia and hypoxia inducible factor-1 alpha (HIF-1-alpha)-dependent CD39/CD73 ectoenzymes may govern the accumulation of tumor-protecting extracellular adenosine and signaling through A2A adenosine receptors (A2AR) in tumor microenvironments (TME). Here, we explored the conceptually novel motivation to use supplemental oxygen as a treatment to inhibit the hypoxia/HIF-1 alpha-CD39/CD73-driven accumulation of extracellular adenosine in the TME in order to weaken the tumor protection. We report that hyperoxic breathing (60 % O-2) decreased the TME hypoxia, as well as levels of HIF-1 alpha and downstream target proteins of HIF-1 alpha in the TME according to proteomic studies in mice. Importantly, oxygenation also downregulated the expression of adenosine-generating ectoenzymes and significantly lowered levels of tumor-protecting extracellular adenosine in the TME. Using supplemental oxygen as a tool in studies of the TME, we also identified FHL-1 as a potentially useful marker for the conversion of hypoxic into normoxic TME. Hyperoxic breathing resulted in the upregulation of antigen-presenting MHC class I molecules on tumor cells and in the better recognition and increased susceptibility to killing by tumor-reactive cytotoxic T cells. Therapeutic breathing of 60 % oxygen resulted in the significant inhibition of growth of established B16.F10 melanoma tumors and prolonged survival of mice. Taken together, the data presented here provide proof-of principle for the therapeutic potential of systemic oxygenation to convert the hypoxic, adenosine-rich and tumor-protecting TME into a normoxic and extracellular adenosine-poor TME that, in turn, may facilitate tumor regression. We propose to explore the combination of supplemental oxygen with existing immunotherapies of cancer. C1 [Hatfield, Stephen M.; Kjaergaard, Jorgen; Lukashev, Dmitriy; Belikoff, Bryan; Sethumadhavan, Shalini; Abbott, Robert; Philbrook, Phaethon; Thayer, Molly; Ohta, Akio; Sitkovsky, Michail] Northeastern Univ, New England Inflammat & Tissue Protect Inst, Boston, MA 02115 USA. [Sitkovsky, Michail] Harvard Inst Med, Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Schreiber, Taylor H.; Podack, Eckhard R.] Univ Miami, Miller Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 USA. [Rodig, Scott; Kutok, Jeffrey L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Shujia, Dai; Karger, Barry] Northeastern Univ, Barnett Inst, Boston, MA 02115 USA. [Shujia, Dai; Karger, Barry] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Ren, Jin; Jackson, Edwin K.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15219 USA. RP Hatfield, SM (reprint author), Northeastern Univ, New England Inflammat & Tissue Protect Inst, 360 Huntington Ave, Boston, MA 02115 USA. EM s.hatfield@neu.edu; m.sitkovsky@neu.edu FU Northeastern University; NIH [R01 CA-111985, R01GM-097320, R01 CA-112561, R21AT 002788] FX This work was supported by the funding from Northeastern University and NIH grants (PI: M.S.) R01 CA-111985; R01GM-097320; R01 CA-112561; R21AT 002788. We thank Dr. Richard Marsh, an expert in the field of energetics, kinematics, and kinetics for assistance with monitoring gas compositions in hyperoxia units. NR 35 TC 14 Z9 15 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0946-2716 EI 1432-1440 J9 J MOL MED JI J. Mol. Med. PD DEC PY 2014 VL 92 IS 12 BP 1283 EP 1292 DI 10.1007/s00109-014-1189-3 PG 10 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA AU5KF UT WOS:000345644900007 PM 25120128 ER PT J AU Vranceanu, AM Ring, D AF Vranceanu, Ana-Maria Ring, David TI Cognitive Coping Predicts Pain Intensity and Disability in Patients with Upper Extremity Musculoskeletal Pain SO JOURNAL OF MUSCULOSKELETAL PAIN LA English DT Article DE Disability; pain; pain intensity; self-efficacy ID LOW-BACK-PAIN; SELF-EFFICACY; ARM PAIN; STRATEGIES AB Objective: The Negative Pain Thoughts Questionnaire [NPTQ], Pain Catastrophizing Scale [PCS], and Pain Self-Efficacy Questionnaire [PSEQ] are validated measures of cognitive coping with pain. The objective of this study was to assess their individual and combined interrelation with pain intensity and disability, and determine the amount of overlap variance among these coping measures. Methods: One hundred and nineteen patients presenting to a hand practice completed validated questionnaires assessing pain intensity [an 11-point ordinal scale], and disability [the Disabilities of the Arm, Shoulder and Hand Questionnaire; DASH] along with the three cognitive coping questionnaires. Results: Regression models with NPTQ controlling for covariates explained 24% of variance in pain intensity, of which NPTQ alone explained 10%, and 32% in DASH, of which NPTQ alone explained 16%. Regression models with PCS controlling for covariates explained 24% of variance in pain intensity, of which PCS alone explained 10% and 46% in DASH, of which PCS alone explained 29%. Regression models with PSEQ controlling for covariates explained 29% of variance in pain intensity, of which PSEQ alone explained 16% and 56% in DASH, of which PSEQ alone explained 39%. Models including all variables explained 31% of the variance in pain intensity and 61% of the variance in DASH. Pain self-efficacy alone accounted for five percent of the variance in pain intensity and 14% of the variance in DASH scores. The three cognitive coping measures shared a large amount of overlapping variance. Conclusion: Pain self-efficacy may be most useful for understanding variations in arm pain and disability. C1 [Vranceanu, Ana-Maria] Massachusetts Gen Hosp, Behav Med Serv, Benson Henry Inst Mind Body Med, Boston, MA USA. [Vranceanu, Ana-Maria] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA USA. [Ring, David] Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Boston, MA USA. [Ring, David] Harvard Univ, Sch Med, Boston, MA USA. RP Vranceanu, AM (reprint author), Harvard Univ, Sch Med, One Bowdoin Sq,7th Floor, Boston, MA 02138 USA. EM avranceanu@partners.org NR 13 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1058-2452 J9 J MUSCULOSKELET PAIN JI J. Musculoskelet. Pain PD DEC PY 2014 VL 22 IS 4 BP 373 EP 377 DI 10.3109/10582452.2014.976326 PG 5 WC Rehabilitation; Rheumatology SC Rehabilitation; Rheumatology GA AU3GG UT WOS:000345499800005 ER PT J AU Echlin, PS Johnson, AM Holmes, JD Tichenoff, A Gray, S Gatavackas, H Walsh, J Middlebro, T Blignaut, A MacIntyre, M Anderson, C Fredman, E Mayinger, M Skopelja, EN Sasaki, T Bouix, S Pasternak, O Helmer, KG Koerte, IK Shenton, ME Forwell, LA AF Echlin, Paul S. Johnson, Andrew M. Holmes, Jeffrey D. Tichenoff, Annalise Gray, Sarah Gatavackas, Heather Walsh, Joanne Middlebro, Tim Blignaut, Angelique MacIntyre, Martin Anderson, Chris Fredman, Eli Mayinger, Michael Skopelja, Elaine N. Sasaki, Takeshi Bouix, Sylvain Pasternak, Ofer Helmer, Karl G. Koerte, Inga K. Shenton, Martha E. Forwell, Lorie A. TI The Sport Concussion Education Project. A brief report on an educational initiative: from concept to curriculum SO JOURNAL OF NEUROSURGERY LA English DT Article DE concussion; mild traumatic brain injury; education; student; youth athlete ID PROFESSIONAL FOOTBALL PLAYERS; TRAUMATIC BRAIN-INJURY; HIGH-SCHOOL SPORTS; RECURRENT CONCUSSION; KNOWLEDGE TRANSFER; HEAD-INJURY; HOCKEY; INTERVENTION; EPIDEMIOLOGY; TRENDS AB Current research on concussion is primarily focused on injury identification and treatment. Prevention initiatives are, however, important for reducing the incidence of brain injury. This report examines the development and implementation of an interactive electronic teaching program (an e-module) that is designed specifically for concussion education within an adolescent population. This learning tool and the accompanying consolidation rubric demonstrate that significant engagement occurs in addition to the knowledge gained among participants when it is used in a school curriculum setting. C1 [Echlin, Paul S.] Elliott Sports Med Clin, Burlington, ON L7N 2G3, Canada. [Gray, Sarah; Gatavackas, Heather; Walsh, Joanne; Middlebro, Tim; Blignaut, Angelique; MacIntyre, Martin; Anderson, Chris] Halton Dist Board Educ, Burlington, ON, Canada. [Johnson, Andrew M.; Tichenoff, Annalise] Univ Western Ontario, Sch Hlth Studies, London, ON, Canada. [Holmes, Jeffrey D.] Univ Western Ontario, Sch Occupat Therapy, London, ON, Canada. [Forwell, Lorie A.] Univ Western Ontario, Sch Phys Therapy, London, ON, Canada. [Forwell, Lorie A.] Univ Western Ontario, Fowler Kennedy Sports Med Clin, London, ON, Canada. [Fredman, Eli; Mayinger, Michael; Sasaki, Takeshi; Bouix, Sylvain; Pasternak, Ofer; Koerte, Inga K.; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Koerte, Inga K.; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Helmer, Karl G.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Shenton, Martha E.] VA Boston Healthcare Syst, Brockton, MA USA. [Skopelja, Elaine N.] Indiana Univ, Sch Med Lib, Indianapolis, IN 46204 USA. [Mayinger, Michael; Koerte, Inga K.] Univ Munich, Inst Clin Radiol, Munich, Germany. RP Echlin, PS (reprint author), Elliott Sports Med Clin, 1100 Walkers Line,Ste 102, Burlington, ON L7N 2G3, Canada. EM psechlin@gmail.com RI Holmes, Jeffrey/M-6484-2015; OI Holmes, Jeffrey/0000-0002-5744-8338; Skopelja, Elaine/0000-0002-2847-8909; Johnson, Andrew/0000-0002-7269-3016 FU Ontario Trillium Foundation; Dave Irwin Foundation for Brain Injury Recovery; Ontario Neurotrauma Foundation, Air Canada; Ontario Ministry of Health and Long-Term Care; Ontario Ministry of Tourism, Culture and Sport; Ontario Ministry of Education; National Institutes of Health (NIH) [P41RR013218, P41EB015902, R01MH074794]; Department of Defense [X81XWH-07-CC-CSDoD]; VA merit grant; Brain & Behavior Research Foundation; Japan Society for the Promotion of Science; Petraeic Legate Foundation; NIEI grant; Henry Jackson Foundation FX This work is funded by the Ontario Trillium Foundation, the Dave Irwin Foundation for Brain Injury Recovery, the Ontario Neurotrauma Foundation, Air Canada, the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Tourism, Culture and Sport, and the Ontario Ministry of Education. This work was partially funded by grants from the National Institutes of Health (NIH) (P41RR013218, P41EB015902, R01MH074794), the Department of Defense (X81XWH-07-CC-CSDoD), and a VA merit grant. Dr. Ofer Pasternak was partially supported by a NARSAD Young Investigator grant from the Brain & Behavior Research Foundation. Dr. Inga Koerte is supported by the Else Kroner-Fresenius Stiftung, Germany. Dr. Takeshi Sasaki is supported by the Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation from the Japan Society for the Promotion of Science. Mr. Michael Mayinger is supported by the Petraeic Legate Foundation. Dr. Shenton is a consultant on an NIEI grant to SUNY on velocardiofascial syndrome and on a grant supported by the Henry Jackson Foundation. NR 38 TC 7 Z9 7 U1 7 U2 47 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD DEC PY 2014 VL 121 IS 6 BP 1331 EP 1336 DI 10.3171/2014.8.JNS132804 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AU3CP UT WOS:000345490700005 PM 25280091 ER PT J AU Martini, RP Ward, J Siler, DA Eastman, JM Nelson, JW Borkar, RN Alkayed, NJ Dogan, A Cetas, JS AF Martini, Ross P. Ward, Jonathan Siler, Dominic A. Eastman, Jamie M. Nelson, Jonathan W. Borkar, Rohan N. Alkayed, Nabil J. Dogan, Aclan Cetas, Justin S. TI Genetic variation in soluble epoxide hydrolase: association with outcome after aneurysmal subarachnoid hemorrhage SO JOURNAL OF NEUROSURGERY LA English DT Article DE soluble epoxide hydrolase; epoxyeicosatrienoic acids; subarachnoid hemorrhage; vascular disorders ID DELAYED CEREBRAL-ISCHEMIA; EPOXYEICOSATRIENOIC ACIDS; STROKE; EPHX2; RISK; POLYMORPHISMS; PREDICTORS; VASOSPASM; PLATELET AB Object. Patients with aneurysmal subarachnoid hemorrhage (SAH) are at high risk for delayed cerebral ischemia (DCI) and stroke. Epoxyeicosatrienoic acids (EETs) play an important role in cerebral blood flow regulation and neuroprotection after brain injury. Polymorphisms in the gene for the enzyme soluble epoxide hydrolase (sEH), which inactivates EETs, are associated with ischemic stroke risk and neuronal survival after ischemia. This prospective observational study of patients with SAH compares vital and neurologic outcomes based on functional polymorphisms of sEH. Methods. Allelic discrimination based on quantitative real-time polymerase chain reaction was used to differentiate wild-type sEH from K55R heterozygotes (predictive of increased sEH activity and reduced EETs) and R287Q heterozygotes (predictive of decreased sEH activity and increased EETs). The primary outcome was new stroke after SAH. Secondary outcomes were death, Glasgow Outcome Scale score, and neurological deterioration attributable to DCI. Results. Multivariable logistic regression models adjusted for age at admission and Glasgow Coma Scale scores revealed an increase in the odds of new stroke (OR 5.48 [95% CI 1.51-19.91]) and death (OR 7.52 [95% CI 1.27- 44.46]) in the K55R group, but no change in the odds of new stroke (OR 0.56 [95% CI 0.16-1.96]) or death (OR 3.09 [95% CI 0.51-18.52]) in patients with R287Q genotype, compared with wild-type sEH. The R287Q genotype was associated with reduced odds of having a Glasgow Outcome Scale score of <= 3 (OR 0.23 [95% CI 0.06-0.82]). There were no significant differences in the odds of neurological deterioration due to DCI. Conclusions. Genetic polymorphisms of sEH are associated with neurological and vital outcomes after aneurysmal SAH. C1 [Martini, Ross P.; Ward, Jonathan; Siler, Dominic A.; Eastman, Jamie M.; Nelson, Jonathan W.; Borkar, Rohan N.; Alkayed, Nabil J.] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. [Dogan, Aclan; Cetas, Justin S.] Oregon Hlth & Sci Univ, Dept Neurol Surg, Portland, OR 97239 USA. [Cetas, Justin S.] Portland VA Med Ctr, Portland, OR USA. RP Cetas, JS (reprint author), Oregon Hlth & Sci Univ, Dept Neurol Surg, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM cetasj@ohsu.edu OI Robertson, Jamie/0000-0001-8252-6644 FU Brain Aneurysm Foundation FX This study was supported by a grant from the Brain Aneurysm Foundation (Dr. Cetas). NR 33 TC 2 Z9 2 U1 0 U2 2 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD DEC PY 2014 VL 121 IS 6 BP 1359 EP 1366 DI 10.3171/2014.7.JNS131990 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AU3CP UT WOS:000345490700011 PM 25216066 ER PT J AU Agarwalla, PK Stapleton, CJ Phillips, MT Walcott, BP Venteicher, AS Ogilvy, CS AF Agarwalla, Pankaj K. Stapleton, Christopher J. Phillips, Michael T. Walcott, Brian P. Venteicher, Andrew S. Ogilvy, Christopher S. TI Surgical outcomes following encephaloduroarteriosynangiosis in North American adults with moyamoya SO JOURNAL OF NEUROSURGERY LA English DT Article DE bypass; EDAS; hemorrhage; moyamoya; stroke; vascular disorders ID INDIRECT REVASCULARIZATION; DISEASE; FEATURES; CHILDREN; SURGERY AB Object. Moyamoya disease/syndrome (MMD/S) is a progressive, occlusive vasculopathy of the intracranial vasculature that leads to ischemic and hemorrhagic strokes. Significant debate exists regarding the role of indirect cerebrovascular bypass surgery in its management. The authors review their institution's experience with indirect bypass in the surgical management of patients with MMD/S. Methods. The authors conducted a retrospective review of patients with MMD/S who underwent encephaloduroarteriosynangiosis (EDAS), a form of indirect bypass, from 1996 to 2013. Results. A total of 37 patients (52 hemispheres) underwent an EDAS procedure for MMD/S; 21 patients received revascularization of both hemispheres. Patients presented with the following: 49% with stroke, 35% with transient ischemic attack, 13% with hemorrhage, and 3% with seizure. The mean Suzuki grade was 3.46. The number of patients with a modified Rankin Scale score of 0-1 improved from 21 to 29 (p = 0.002) from the time of surgery to the time of last follow-up. The number of neurological events (i.e., transient ischemic attacks, strokes, and hemorrhages) decreased from a mean of 1.7 events per patient to 0.14 (p < 0.001). The mean length of follow-up was 32.8 months. Conclusions. This series demonstrates that EDAS is an effective procedure for MMD/S in a North American cohort of patients. C1 [Agarwalla, Pankaj K.; Stapleton, Christopher J.; Phillips, Michael T.; Walcott, Brian P.; Venteicher, Andrew S.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Agarwalla, Pankaj K.; Stapleton, Christopher J.; Phillips, Michael T.; Walcott, Brian P.; Venteicher, Andrew S.; Ogilvy, Christopher S.] Harvard Univ, Sch Med, Boston, MA USA. [Walcott, Brian P.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Walcott, Brian P.] Harvard Univ, Sch Med, Charlestown, MA USA. [Ogilvy, Christopher S.] Beth Israel Deaconess Med Ctr, Dept Surg, Div Neurosurg, Boston, MA 02215 USA. RP Stapleton, CJ (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,ACC 745, Boston, MA 02114 USA. EM cstapleton@partners.org NR 24 TC 7 Z9 7 U1 0 U2 4 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 EI 1933-0693 J9 J NEUROSURG JI J. Neurosurg. PD DEC PY 2014 VL 121 IS 6 BP 1394 EP 1400 DI 10.3171/2014.8.JNS132176 PG 7 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AU3CP UT WOS:000345490700016 PM 25280094 ER PT J AU Thanos, A Mantagos, IS AF Thanos, Aristomenis Mantagos, Iason S. TI A 13-Year-Old Boy with Asthma, Itchy Eyes, and Decreased Vision SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID VERNAL KERATOCONJUNCTIVITIS C1 [Thanos, Aristomenis] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Cambridge, MA 02138 USA. [Mantagos, Iason S.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston Childrens Hosp, Boston, MA USA. RP Thanos, A (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Cambridge, MA 02138 USA. OI Mantagos, Iason/0000-0002-3510-5465 NR 2 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD DEC PY 2014 VL 165 IS 6 BP 1267 EP 1267 DI 10.1016/j.jpeds.2014.07.044 PG 1 WC Pediatrics SC Pediatrics GA AU3PS UT WOS:000345526500041 PM 25219875 ER PT J AU Ollila, HM Kettunen, J Pietilainen, O Aho, V Silander, K Kronholm, E Perola, M Lahti, J Raikkonen, K Widen, E Palotie, A Eriksson, JG Partonen, T Kaprio, J Salomaa, V Raitakari, O Lehtimaki, T Sallinen, M Harma, M Porkka-Heiskanen, T Paunio, T AF Ollila, Hanna M. Kettunen, Johannes Pietilainen, Olli Aho, Vilma Silander, Kaisa Kronholm, Erkki Perola, Markus Lahti, Jari Raikkonen, Katri Widen, Elisabeth Palotie, Aarno Eriksson, Johan G. Partonen, Timo Kaprio, Jaakko Salomaa, Veikko Raitakari, Olli Lehtimaki, Terho Sallinen, Mikael Harma, Mikko Porkka-Heiskanen, Tarja Paunio, Tiina TI Genome-wide association study of sleep duration in the Finnish population SO JOURNAL OF SLEEP RESEARCH LA English DT Article DE genome-wide association; single nucleotide polymorphism; sleep duration; sleep restriction; RNA expression ID COMPLEX TRAITS; GROWTH; CHILDREN; RISK; TWIN AB Sleep duration is genetically regulated, but the genetic variants are largely unknown. We aimed to identify such genes using a genome-wide association study (GWAS) combined with RNA expression at the population level, and with experimental verification. A GWAS was performed in a Finnish sample (n=1941), and variants with suggestive association (P<5x10(-5)) were tested in a follow-up sample from the same population with sleep duration (n=6834) and time in bed (n=1720). Variants with pointwise association of P<0.05 in the follow-up sample were analysed further. First, we correlated genotypes with transcript expression levels with sleep duration (n=207). The expression levels of significant transcripts were further studied in experimental sleep restriction. Of the 31 variants with P<5x10(-5) in the discovery sample, three variants showed nominal allelic association (P<0.05) in the follow-up sample: rs10914351, near PTPRU (P= 0.049), rs1037079 in PCDH7-CENTD1 (P=0.011) and rs2031573 near KLF6 (P=0.044). The risk alleles for shorter sleep (rs2031573 and rs1037079) were also associated with higher KLF6 and PCDH7 expression levels (P<0.05). Experimental sleep restriction increased the expression of KLF6 (P<0.01). These data suggest that rs2031573 near KLF6 or related loci and rs1037079 between PCDH7-CENTD1 or related loci may contribute to the regulation of sleep duration via gene expression. These results illustrate the utility of combining different analytical approaches to identify genetic determinants for traits related to sleep physiology. However, additional studies are needed in order to understand the roles of KLF6 and PCDH7 in sleep regulation. C1 [Ollila, Hanna M.; Kettunen, Johannes; Pietilainen, Olli; Silander, Kaisa; Perola, Markus; Paunio, Tiina] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki 00251, Finland. [Ollila, Hanna M.; Kettunen, Johannes; Pietilainen, Olli; Silander, Kaisa; Perola, Markus; Paunio, Tiina] Natl Inst Hlth & Welf, Inst Mol Med FIMM, Helsinki 00251, Finland. [Ollila, Hanna M.; Aho, Vilma; Porkka-Heiskanen, Tarja] Univ Helsinki, Inst Biomed, Helsinki, Finland. [Ollila, Hanna M.; Paunio, Tiina] Univ Helsinki, Dept Psychiat, SF-00180 Helsinki, Finland. [Pietilainen, Olli] Wellcome Trust Sanger Inst, Cambridge, England. [Kronholm, Erkki] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Populat Studies Unit, Turku, Finland. [Lahti, Jari; Raikkonen, Katri] Univ Helsinki, Inst Behav Sci, Helsinki, Finland. [Lahti, Jari; Raikkonen, Katri; Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Widen, Elisabeth; Palotie, Aarno] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Palotie, Aarno] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Palotie, Aarno] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Palotie, Aarno] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa, Finland. [Partonen, Timo; Kaprio, Jaakko] Natl Inst Hlth & Welf, Dept Mental Hlth, Helsinki 00251, Finland. [Partonen, Timo; Kaprio, Jaakko] Natl Inst Hlth & Welf, Subst Abuse Serv, Helsinki 00251, Finland. [Kaprio, Jaakko] Univ Helsinki, Hjelt Inst, Dept Publ Hlth, Helsinki, Finland. [Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki 00251, Finland. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, Olli] Univ Turku, Dept Clin Physiol & Nucl Med, Turku, Finland. [Raitakari, Olli] Turku Univ Hosp, FIN-20520 Turku, Finland. [Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere, Finland. [Lehtimaki, Terho] Tampere Univ, Sch Med, FIN-33101 Tampere, Finland. [Sallinen, Mikael; Harma, Mikko] Finnish Inst Occupat Hlth, Working Hours Alertness & Profess Traff Team, Helsinki, Finland. RP Paunio, T (reprint author), Natl Inst Hlth & Welf, Publ Hlth Genom Unit, POB 104, Helsinki 00251, Finland. EM Tiina.Paunio@thl.fi OI Partonen, Timo/0000-0003-1951-2455; Eriksson, Johan/0000-0002-2516-2060; Kaprio, Jaakko/0000-0002-3716-2455; Stenberg, Tarja/0000-0003-1843-7625; Lahti, Jari/0000-0002-4310-5297; Raikkonen, Katri/0000-0003-3124-3470 FU Academy of Finland [124404, 265240, 263278, 139635, 126925, 121584, 124282, 129378, 117787, 41071]; Sigrid Juselius Foundation; University of Helsinki [TYH2010306]; Emil Aaltonen Foundation; Instrumentarium Science Foundation; Jalmari and Rauha Ahokas Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Biomedicum Helsinki Foundation; NIH [DA12854]; Global Research Awards for Nicotine Dependence (GRAND); Wellcome Trust Sanger Institute; Social Insurance Institution of Finland, Kuopio, Tampere; Turku University Hospital Medical Funds [9N035]; Juho Vainio Foundation; Finnish Foundation of Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation FX We thank Auli Toivola, Irina Lisinen, Ville Aalto and Finnish Genome Center for technical assistance and study participants. This study was supported by the Academy of Finland (no. 124404), Sigrid Juselius Foundation and University of Helsinki (TYH2010306) to TP, Emil Aaltonen Foundation, Instrumentarium Science Foundation, Jalmari and Rauha Ahokas Foundation, Paavo Nurmi Foundation, Finnish Foundation for Cardiovascular Research and Biomedicum Helsinki Foundation to HMO. Blood sample collection and genotyping in the Finnish Twin Cohort was supported by NIH DA12854 to Pamela A. F. Madden, Global Research Awards for Nicotine Dependence (GRAND) to JK, and the Wellcome Trust Sanger Institute, and the Academy of Finland (no. 265240, no. 263278). VS was supported by the Academy of Finland (no. 139635) and the Finnish Foundation for Cardiovascular Research. YF was supported by the Academy of Finland: grant numbers 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi) and 41071 (Skidi), the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (grant 9N035 for TL), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation (TL). NR 31 TC 9 Z9 10 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1105 EI 1365-2869 J9 J SLEEP RES JI J. Sleep Res. PD DEC PY 2014 VL 23 IS 6 BP 609 EP 618 DI 10.1111/jsr.12175 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AU4OK UT WOS:000345590700002 PM 25109461 ER PT J AU Mavros, MN Velmahos, GC Lee, J Larentzakis, A Kaafarani, HMA AF Mavros, Michael N. Velmahos, George C. Lee, Jarone Larentzakis, Andreas Kaafarani, Haytham M. A. TI Morbidity related to concomitant adhesions in abdominal surgery SO JOURNAL OF SURGICAL RESEARCH LA English DT Article; Proceedings Paper CT 9th Annual Academic Surgical Congress of the Association-for-Academic-Surgery and the Society-of-University-Surgeons CY FEB 04-07, 2014 CL San Diego, CA SP Assoc Acad Surg, Soc Univ Surg DE Adhesions; Adhesiolysis; General surgery; Postoperative complications ID QUALITY IMPROVEMENT PROGRAM; POSTOPERATIVE PERITONEAL ADHESIONS; PATIENT SAFETY; MULTIVARIABLE PREDICTORS; VASCULAR-SURGERY; RISK; OPERATIONS; ENTEROTOMY; MORTALITY; DESIGN AB Background: We sought to assess the independent effect of concomitant adhesions (CAs) on patient outcome in abdominal surgery. Materials and methods: Using the American College of Surgeons National Surgical Quality Improvement Program data, we created a uniform data set of all gastrectomies, enterectomies, hepatectomies, and pancreatectomies performed between 2007 and 2012 at our tertiary academic center. American College of Surgeons National Surgical Quality Improvement Program data were supplemented with additional variables (e. g., procedure complexity-relative value unit). The presence of CAs was detected using the Current Procedural Terminology codes for adhesiolysis (44005, 44180, 50715, 58660, and 58740). Cases where adhesiolysis was the primary procedure (e. g., bowel obstruction) were excluded. Multivariable logistic regression analyses were performed to assess the independent effect of CAs on 30-d morbidity and mortality, while controlling for age, comorbidities and the type/complexity/approach/emergency nature of surgery. Results: Adhesiolysis was performed in 875 of 5940 operations (14.7%). Operations with CAs were longer (median duration 3.2 versus 2.7 h, P < 0.001), more complex (median relative value unit 37.5 versus 33.4, P < 0.001), performed in sicker patients (American Society for Anesthesiologists class >= 3 in 49.9% versus 41.2%, P < 0.001), and harbored higher risk for inadvertent enterotomies (3.0% versus 0.9%, P < 0.001). In multivariable analyses, CAs independently predicted higher morbidity (adjusted odds ratio [OR], 1.35; 95% confidence interval, 1.13-1.61, P = 0.001). Specifically, CAs independently correlated with superficial and deep or organ-space surgical site infections (OR = 1.42 (1.02-1.86), P = 0.036; OR = 1.47 (1.09-1.99), P = 0.013, respectively), and prolonged postoperative hospital stay (>= 7 d, OR = 1.34 [1.11-1.61], P = 0.002). No difference in 30-d mortality was detected. Conclusions: CAs significantly increase morbidity in abdominal surgery. Risk adjusting for the presence of adhesions is crucial in any efforts aimed at quality assessment and/or benchmarking of abdominal surgery. (C) 2014 Elsevier Inc. All rights reserved. C1 [Mavros, Michael N.; Velmahos, George C.; Lee, Jarone; Larentzakis, Andreas; Kaafarani, Haytham M. A.] Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Mavros, Michael N.; Velmahos, George C.; Lee, Jarone; Larentzakis, Andreas; Kaafarani, Haytham M. A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mavros, Michael N.] MedStar Washington Hosp Ctr, Dept Surg, Washington, DC USA. RP Kaafarani, HMA (reprint author), Massachusetts Gen Hosp, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM hkaafarani@mgh.harvard.edu NR 24 TC 8 Z9 8 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD DEC PY 2014 VL 192 IS 2 BP 286 EP 292 DI 10.1016/j.jss.2014.07.044 PG 7 WC Surgery SC Surgery GA AU2BA UT WOS:000345419900010 PM 25151471 ER PT J AU Berger, RL Li, LDT Hicks, SC Liang, MK AF Berger, Rachel L. Li, Linda T. Hicks, Stephanie C. Liang, Mike K. TI Suture versus preperitoneal polypropylene mesh for elective umbilical hernia repairs SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE Umbilical hernia; Ventral hernia; Recurrence; Surgical site infection; Seroma; Mesh; Polypropylene; Suture ID EXPERIENCE; RECURRENCE AB Background: Repair of primary ventral hernias (PVH) such as umbilical hernias is a common surgical procedure. There is a paucity of risk-adjusted data comparing suture versus mesh repair of these hernias. We compared preperitoneal polypropylene (PP) repair versus suture repair for elective umbilical hernia repair. Methods: A retrospective review of all elective open PVH repairs at a single institution from 2000 2010 was performed. Only patients with suture or PP repair of umbilical hernias were included. Univariate analysis was conducted and propensity for treatment-adjusted multivariate logistic regression. Results: There were 442 elective open PVH repairs performed; 392 met our inclusion criteria. Of these patients, 126 (32.1%) had a PP repair and 266 (67.9%) underwent suture repair. Median (range) follow-up was 60 mo (1-143). Patients who underwent PP repair had more surgical site infections (SSIs; 19.8% versus 7.9%, P < 0.01) and seromas (14.3% versus 4.1%, P < 0.01). There was no difference in recurrence (5.6% versus 7.5%, P = 0.53). On propensity score-adjusted multivariate analysis, we found that body mass index (odds ratio [OR], 1.10) and smoking status (OR, 2.3) were associated with recurrence. Mesh (OR, 2.34) and American Society of Anesthesiologists (OR, 1.95) were associated with SSI. Only mesh (OR, 3.41) was associated with seroma formation. Conclusions: Although there was a trend toward more recurrence with suture repair in our study, this was not statistically significant. Mesh repair was associated with more SSI and seromas. Further prospective randomized controlled trial is needed to clarify the role of suture and mesh repair in PVH. (C) 2014 Elsevier Inc. All rights reserved. C1 [Berger, Rachel L.; Li, Linda T.] Baylor Coll Med, Dept Surg, Houston, TX 77030 USA. [Hicks, Stephanie C.] Dana Farber Canc Inst, Dept Stat, Boston, MA 02115 USA. [Liang, Mike K.] Univ Texas Houston, Hlth Sci Ctr, Dept Surg, Houston, TX 77023 USA. RP Liang, MK (reprint author), Univ Texas Houston, Hlth Sci Ctr, Dept Surg, 5656 Kelley St, Houston, TX 77023 USA. EM mike.liang@uth.tmc.edu RI Liang, Mike/L-8493-2015 OI Hicks, Stephanie/0000-0002-7858-0231; Liang, Mike/0000-0001-7063-7291 FU Center for Clinical and Translational Sciences - National Institutes of Health Clinical and Translational Award from the National Center for Advancing Translational Sciences [UL1 TR000371, KL2 TR000370] FX Liang reports the following disclosures: This work was supported by the Center for Clinical and Translational Sciences, which is funded by National Institutes of Health Clinical and Translational Award UL1 TR000371 and KL2 TR000370 from the National Center for Advancing Translational Sciences. 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.-Recipient of investigator initiated research support and consulting work with Lifecell in the past 12 months. NR 26 TC 4 Z9 4 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 EI 1095-8673 J9 J SURG RES JI J. Surg. Res. PD DEC PY 2014 VL 192 IS 2 BP 426 EP 431 DI 10.1016/j.jss.2014.05.080 PG 6 WC Surgery SC Surgery GA AU2BA UT WOS:000345419900029 PM 24980854 ER PT J AU Strazzula, L Vedak, P Hoang, MP Sober, A Tsao, HS Kroshinsky, D AF Strazzula, Lauren Vedak, Priyanka Hoang, Mai P. Sober, Arthur Tsao, Hensin Kroshinsky, Daniela TI The utility of re-excising mildly and moderately dysplastic nevi: A retrospective analysis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE dermatopathology; dysplastic nevus; melanoma; nevus; pigmented lesions; surgical management ID MELANOCYTIC NEVI; CUTANEOUS MELANOMA; OUTCOMES; INTEROBSERVER; ASSOCIATION; MANAGEMENT; DIAGNOSIS; LESIONS AB Background: The management of dysplastic nevi (DN) is a highly debated and controversial topic within the dermatology community. Clinicians agree that margin-positive severely DN should be removed with a surgical margin, however, there is disagreement surrounding the appropriate management of margin-positive mildly and moderately DN. Objective: We sought to evaluate the utility of re-excising margin-positive mildly and moderately DN. Methods: A retrospective chart review was conducted on all adult patients given the diagnosis of a biopsy-proven DN from 2010 through 2011. The primary outcomes were defined as the presence of melanocytic residuum in re-excisional specimens and a clinically significant change in diagnosis. Results: A total of 1809 mildly and moderately DN were diagnosed from 2010 through 2011. In all, 765 (42.3%) of these lesions were found to have positive surgical margins during biopsy, and 495 (64.7) of the 765 lesions were subsequently re-excised. Melanocytic residuum was present in 18.2% of re-excisional specimens. Re-excision resulted in a clinically significant alteration of the diagnosis in only 1 case (0.2%). Limitations: Limitations include retrospective design and inability to assess for malignant transformation given limited follow-up. Conclusions: Re-excising mildly and moderately DN results in a low histopathological yield and rarely results in a clinically significant change in diagnosis. As such, clinical monitoring of margin-positive lesions may be warranted. C1 [Strazzula, Lauren; Vedak, Priyanka; Sober, Arthur; Tsao, Hensin; Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Hoang, Mai P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Kroshinsky, D (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,200, Boston, MA 02114 USA. EM dkroshinsky@mgh.harvard.edu NR 24 TC 10 Z9 10 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD DEC PY 2014 VL 71 IS 6 BP 1071 EP 1076 DI 10.1016/j.jaad.2014.08.025 PG 6 WC Dermatology SC Dermatology GA AT9FD UT WOS:000345232400015 PM 25262175 ER PT J AU Boyers, LN Karimkhani, C Naghavi, M Sherwood, D Margolis, DJ Hay, RJ Williams, HC Naldi, L Coffeng, LE Weinstock, MA Dunnick, CA Pederson, H Vos, T Dellavalle, RP AF Boyers, Lindsay N. Karimkhani, Chante Naghavi, Mohsen Sherwood, David Margolis, David J. Hay, Roderick J. Williams, Hywel C. Naldi, Luigi Coffeng, Luc E. Weinstock, Martin A. Dunnick, Cory A. Pederson, Hannah Vos, Theo Dellavalle, Robert P. TI Global mortality from conditions with skin manifestations SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE basal cell carcinoma; burden of disease; dermatology; developed countries; developing countries; epidemiology; Global Burden of Disease Study 2010; measles; melanoma; mortality; non-melanoma; skin cancer; rate of death; squamous cell carcinoma; syphilis ID SYSTEMATIC ANALYSIS; 187 COUNTRIES; RISK-FACTORS; CUTANEOUS MELANOMA; UNITED-STATES; GBD 2010; BURDEN; DISEASE; PREVALENCE; CHALLENGES AB Background: Global Burden of Disease Study is a research database containing systematically compiled information from vital statistics and epidemiologic literature to inform research, public policy, and resource allocation. Objective: We sought to compare mortality among conditions with skin manifestations in 50 developed and 137 developing countries from 1990 to 2010. Methods: This was a cross-sectional study to calculate mean age-standardized mortality (per 100,000 persons) across countries for 10 disease categories with skin manifestations. We compared differences in mortality from these disorders by time period (year 1990 vs year 2010) and by developing versus developed country status. Results: Melanoma death rates were 5.6 and 4.7 times greater in developed compared with developing countries in 1990 and 2010, respectively. Measles death rates in 1990 and 2010 were 345 and 197 times greater in developing countries, and corresponding syphilis death rates were 33 and 45 times greater. Limitations: Inability to adjust for patient-, provider-, and geographic-level confounders may limit the accuracy and generalizability of these results. Conclusion: The mortality burden from skin-related conditions differs between developing and developed countries, with the greatest differences observed for melanoma, measles, and syphilis. These results may help prioritize and optimize efforts to prevent and treat these disorders. C1 [Boyers, Lindsay N.] Georgetown Univ, Sch Med, Washington, DC USA. [Karimkhani, Chante] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Naghavi, Mohsen; Coffeng, Luc E.; Vos, Theo] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Sherwood, David] Univ Colorado, Dept Integrat Physiol, Boulder, CO 80309 USA. [Margolis, David J.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol & Dermatol, Philadelphia, PA 19104 USA. [Hay, Roderick J.] Kings Coll Hosp Natl Hlth Serv Trust, Dept Dermatol, London, England. [Williams, Hywel C.] Univ Nottingham, Ctr Evidence Based Dermatol, Nottingham NG7 2RD, England. [Naldi, Luigi] Azienda Osped Papa Giovanni XXIII, Dept Dermatol, Bergamo, Italy. [Weinstock, Martin A.] US Dept Vet Affairs, Med Ctr Providence, Dermatoepidemiol Unit, Washington, DC USA. [Weinstock, Martin A.] Rhode Isl Hosp, Dept Dermatol, Providence, RI 02903 USA. [Weinstock, Martin A.] Brown Univ, Dept Dermatol, Providence, RI 02912 USA. [Weinstock, Martin A.] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Dunnick, Cory A.; Dellavalle, Robert P.] Univ Colorado, Dept Dermatol, Aurora, CO USA. [Dunnick, Cory A.; Dellavalle, Robert P.] Eastern Colorado Hlth Care Syst, US Dept Vet Affairs, Dermatol Serv, Denver, CO USA. [Pederson, Hannah] Univ Colorado, Sch Med, Aurora, CO USA. [Dellavalle, Robert P.] Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. RP Dellavalle, RP (reprint author), US Dept Vet Affairs, Med Ctr, Dermatol Serv, 1055 Clermont St,Box 165, Denver, CO 80220 USA. EM robert.dellavalle@ucdenver.edu RI Naldi, Luigi/K-6343-2016 OI Naldi, Luigi/0000-0002-3160-2835 FU Bill and Melinda Gates Foundation [OPP43650_01] FX The Global Burden of Disease Study 2010 was supported in part by the Bill and Melinda Gates Foundation (grant number: OPP43650_01). NR 45 TC 7 Z9 9 U1 3 U2 10 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD DEC PY 2014 VL 71 IS 6 BP 1137 EP U168 DI 10.1016/j.jaad.2014.08.022 PG 24 WC Dermatology SC Dermatology GA AT9FD UT WOS:000345232400023 PM 25282129 ER PT J AU Shlyankevich, J Chen, AJ Kim, GE Kimball, AB AF Shlyankevich, Julia Chen, Allison J. Kim, Grace E. Kimball, Alexandra B. TI Hidradenitis suppurativa is a systemic disease with substantial comorbidity burden: A chart-verified case-control analysis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE acne inversa; cardiovascular disease; comorbidities; hidradenitis; hidradenitis suppurativa; lymphoma; metabolic syndrome; obesity; prevalence ID NECROSIS-FACTOR-ALPHA; SQUAMOUS-CELL CARCINOMA; ACNE INVERSA; METABOLIC SYNDROME; PSORIASIS; PREVALENCE; LYMPHOMA; MODERATE; THERAPY; LESIONS AB Background: Hidradenitis suppurativa (HS) is a chronic inflammatory disease involving intertriginous skin. Previous epidemiologic studies have been limited by small sample size. Objective: We sought to describe the prevalence and comorbidities of HS in a large patient care database. Methods: In this retrospective case-control study, we chart-validated all patients within a hospital database who received at least 1 billing code for HS between 1980 and 2013. Verified cases were matched with controls based on age, gender, and race. Prevalences of a priori selected comorbidities were compared between HS and control groups. Results: A total of 2292 patients at Massachusetts General Hospital received at least 1 code for HS. A total of 1776 cases had a validated diagnosis of HS, yielding a prevalence of 0.08%. In unadjusted analysis, all comorbidities were diagnosed significantly more in HS compared with control including (in rank order of likelihood): smoking, arthropathies, dyslipidemia, polycystic ovarian syndrome, psychiatric disorders, obesity, drug dependence, hypertension, diabetes, thyroid disease, alcohol dependence, and lymphoma (all P < .01). Limitations: Control subjects were not validated for absence of HS and comorbidity validation was not performed for either group. Conclusions: Our results highlights the high comorbidity burden of patients with HS compared with matched control subjects. C1 [Shlyankevich, Julia; Kim, Grace E.; Kimball, Alexandra B.] Massachusetts Gen Hosp, Clin Unit Res Trials & Outcomes Skin, Boston, MA 02114 USA. [Shlyankevich, Julia; Kim, Grace E.; Kimball, Alexandra B.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Shlyankevich, Julia; Chen, Allison J.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Kim, Grace E.; Kimball, Alexandra B.] Harvard Univ, Sch Med, Boston, MA USA. RP Kimball, AB (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,Suite 240, Boston, MA 02114 USA. EM harvardskinstudies@partners.org FU Janssen FX Dr Shlyankevich has partial fellowship funding from Janssen. NR 47 TC 28 Z9 28 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD DEC PY 2014 VL 71 IS 6 BP 1144 EP 1150 DI 10.1016/j.jaad.2014.09.012 PG 7 WC Dermatology SC Dermatology GA AT9FD UT WOS:000345232400024 PM 25440440 ER PT J AU Xiong, MY Rabkin, MS Piepkorn, MW Barnhill, RL Argenyi, Z Erickson, L Guitart, J Lowe, L Shea, CR Trotter, MJ Lew, RA Weinstock, MA AF Xiong, Michael Y. Rabkin, Michael S. Piepkorn, Michael W. Barnhill, Raymond L. Argenyi, Zsolt Erickson, Lori Guitart, Joan Lowe, Lori Shea, Christopher R. Trotter, Martin J. Lew, Robert A. Weinstock, Martin A. TI Diameter of dysplastic nevi is a more robust biomarker of increased melanoma risk than degree of histologic dysplasia: A case-control study SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter ID MELANOCYTIC NEVI C1 [Xiong, Michael Y.; Weinstock, Martin A.] VA Med Ctr, Dermatoepidemiol Unit, Providence, RI USA. [Xiong, Michael Y.; Shea, Christopher R.; Weinstock, Martin A.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Rabkin, Michael S.] Rabkin Dermatopathol Lab PC, Tarentum, PA USA. [Piepkorn, Michael W.; Argenyi, Zsolt] Univ Washington, Med Ctr, Dept Med Dermatol, Seattle, WA 98195 USA. [Barnhill, Raymond L.] Univ Calif, Dept Pathol & Lab Med, Berkeley, CA USA. [Barnhill, Raymond L.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Erickson, Lori] Mayo Clin, Dept Pathol & Lab Med, Rochester, MN USA. [Guitart, Joan] Northwestern Univ, Dept Dermatol, Chicago, IL 60611 USA. [Shea, Christopher R.] Univ Chicago Med, Sand Sect Dermatol, Chicago, IL USA. [Lowe, Lori] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Lowe, Lori] Univ Michigan, Dept Dermatol, Ann Arbor, MI 48109 USA. [Trotter, Martin J.] Univ Calgary, Dept Pathol & Lab Med, Calgary Lab Serv, Calgary, AB T2N 1N4, Canada. [Lew, Robert A.] VA Boston Hlth Care Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Weinstock, Martin A.] Brown Univ, Rhode Isl Hosp, Dept Dermatol, Providence, RI 02903 USA. [Weinstock, Martin A.] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. RP Rabkin, MS (reprint author), 419 East Second Ave, Tarentum, PA 15084 USA. EM msrabkin@gmail.com NR 5 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD DEC PY 2014 VL 71 IS 6 BP 1257 EP 1258 DI 10.1016/j.jaad.2014.07.030 PG 2 WC Dermatology SC Dermatology GA AT9FD UT WOS:000345232400039 PM 25454033 ER PT J AU Rudolph, JL Archambault, E Kelly, B AF Rudolph, James L. Archambault, Elizabeth Kelly, Brittany CA VA Boston Delirium Task Force TI A Delirium Risk Modification Program Is Associated With Hospital Outcomes SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Article DE Delirium; risk stratification; prevention; rehabilitation; aged; health care cost ID CONFUSION ASSESSMENT METHOD; INTENSIVE-CARE-UNIT; OLDER PATIENTS; PREVENT DELIRIUM; NURSING-HOMES; HIP FRACTURE; HEALTH-CARE; INTERVENTION; PERFORMANCE; IMPROVEMENT AB Background: Delirium has been associated with negative health consequences, which can potentially be improved by delirium risk modification. This study sought to determine if a quality improvement project to identify and modify delirium risk and discharge to rehabilitation is associated with improved outcomes for patients and health care systems. Methods: In older veterans admitted to a tertiary VA hospital, delirium risk was assessed using cognitive impairment, vision impairment, and dehydration. Delirium risk was communicated to providers via electronic medical record. To modify delirium risk, interventions were provided in cognitive stimulation, sensory improvement, and sleep promotion. Primary outcomes included length of stay, restraint use, discharge to rehabilitation, and hospital variable direct costs. Outcomes were compared using a propensity-matched cohort of patients without intervention. Number of intervention categories was compared with primary outcomes. Results: Patients (n = 1527) were older (78.2 +/- 8.3 years) and male (98%). Propensity-matched patients (n = 566) werewell matched for age, gender, cognitive deficits, vision impairment, and dehydration. Patients with interventions were discharged to rehabilitation similarly (mean difference [MD] 2.2%, 95% CI -2.5 -6.9) and had lower lengths of stay (MD -0.7 day, 95% CI -1.3 to -0.1), lower restraint use (MD -4.0%, 95% CI -6.7 to -1.2) and trended toward lower variable direct costs(MD $ 1390,95% CI 3586 807). Increasing number of interventions was associated with shorter length of stay, lower rate of restraint use, and lower variable direct costs. Conclusions: This delirium risk modification project was associated with patient outcomes and reduced costs. Serious consideration should be given to delirium risk identification and modification programs. Published by Elsevier Inc. on behalf of AMDA - The Society for Post-Acute and Long-Term Care Medicine. C1 [Rudolph, James L.; Archambault, Elizabeth; Kelly, Brittany] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA 02130 USA. [Rudolph, James L.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Rudolph, James L.] Harvard Univ, Sch Med, Boston, MA USA. [Kelly, Brittany] Regis Coll, Sch Nursing Sci & Hlth Profess, Boston, MA USA. RP Rudolph, JL (reprint author), VA Boston Healthcare Syst, GRECC, 150 S Huntington Ave, Boston, MA 02130 USA. EM jrudolph@partners.org FU Department of Veterans Affairs; VA Career Development Award; VA Patient Safety Center of Inquiry FX This study was funded by a Department of Veterans Affairs-funded T21 Alternative to Non-institutional Long Term Care award. JLR, EA, and BK are employees of the US government. JLR also received support from a VA Career Development Award and a VA Patient Safety Center of Inquiry. The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The opinions expressed are those of the authors and not necessarily those of the Department of Veterans Affairs or the US government. NR 38 TC 0 Z9 0 U1 1 U2 20 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 DEC PY 2014 VL 15 IS 12 DI 10.1016/j.jamda.2014.08.009 PG 5 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA AU3GD UT WOS:000345499500021 ER PT J AU Chen, AB Li, L Cronin, A Schrag, D AF Chen, Aileen B. Li, Ling Cronin, Angel Schrag, Deborah TI Comparative Effectiveness of Intensity-Modulated Versus 3D Conformal Radiation Therapy Among Medicare Patients with Stage III Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Radiation therapy; Lung cancer; Comparative effectiveness ID COMORBIDITY INDEX; PROPENSITY SCORE; UNITED-STATES; RADIOTHERAPY; POPULATION; VALIDATION; OUTCOMES AB Introduction: The clinical benefit of intensity-modulated radiation therapy (IMRT) compared to 3D conformal radiation (3D-RT) has not been well established for locally advanced non-small-cell lung cancer (NSCLC). Methods: Using SEER-Medicare, we identified Medicare beneficiaries diagnosed with stage III NSCLC who received potentially curative (>= 25 fractions) thoracic IMRT or 3D-RT from 2002-2009. Overall survival and number of hospital days within 90 days of radiation were analyzed using Cox proportional hazard and negative binomial regression models, respectively. Propensity score adjustment was used to control for clinical and demographic variables associated with outcomes. Results: IMRT comprised an increasing proportion of conformal thoracic radiation for NSCLC, rising from 3.0% in 2002 to 26.8% in 2009. Use of IMRT varied significantly by year of diagnosis, facility type, and geographic region and was more likely to be used among patients receiving chemotherapy or with higher comorbidity scores. Among patients receiving potentially curative treatment, there was no difference in overall survival (propensity adj HR .99, p = 0.83) or number of hospital days in the 90 days following radiation start (propensity adj HR 1.15, p = 0.23). Conclusions: When radiation is used to treat locally advanced NSCLC, IMRT is increasingly preferred to 3D-RT. However, among patients receiving potentially curative radiation there was no significant difference in overall survival or time spent hospitalized following treatment. C1 [Chen, Aileen B.; Li, Ling; Cronin, Angel; Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02215 USA. [Chen, Aileen B.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Chen, AB (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 1111, Boston, MA 02215 USA. EM achen@lroc.harvard.edu NR 32 TC 8 Z9 10 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD DEC PY 2014 VL 9 IS 12 BP 1788 EP 1795 DI 10.1097/JTO.0000000000000331 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AU4DR UT WOS:000345559900008 PM 25226428 ER PT J AU Mayer, VL Hillier, A Bachhuber, MA Long, JA AF Mayer, Victoria L. Hillier, Amy Bachhuber, Marcus A. Long, Judith A. TI Food Insecurity, Neighborhood Food Access, and Food Assistance in Philadelphia SO JOURNAL OF URBAN HEALTH-BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE LA English DT Article DE Environment and public health; Nutrition policy; Hunger; Food assistance ID PHYSICAL-ACTIVITY; GLYCEMIC CONTROL; HEALTHY FOODS; STAMPS; US AB An estimated 17.6 million American households were food insecure in 2012, meaning they were unable to obtain enough food for an active and healthy life. Programs to augment local access to healthy foods are increasingly widespread, with unclear effects on food security. At the same time, the US government has recently enacted major cuts to federal food assistance programs. In this study, we examined the association between food insecurity (skipping or reducing meal size because of budget), neighborhood food access (self-reported access to fruits and vegetables and quality of grocery stores), and receipt of food assistance using the 2008, 2010, and 2012 waves of the Southeastern Pennsylvania Household Health Survey. Of 11,599 respondents, 16.7 % reported food insecurity; 79.4 % of the food insecure found it easy or very easy to find fruits and vegetables, and 60.6 % reported excellent or good quality neighborhood grocery stores. In our regression models adjusting for individual- and neighborhood-level covariates, compared to those who reported very difficult access to fruits and vegetables, those who reported difficult, easy or very easy access were less likely to report food insecurity (OR 0.62: 95 % CI 0.43-0.90, 0.33: 95 % CI 0.23-0.47, and 0.28: 95 % CI 0.20-0.40). Compared to those who reported poor stores, those who reported fair, good, and excellent quality stores were also less likely to report food insecurity (OR 0.81: 95 % CI 0.60-1.08, 0.58: 95 % CI 0.43-0.78, and 0.43: 95 % CI 0.31-0.59). Compared to individuals not receiving food assistance, those receiving Supplemental Nutrition Assistance Program (SNAP) benefits were significantly more likely to be food insecure (OR 1.36: 95 % CI 1.11-1.67), while those receiving benefits from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) (OR 1.17: 95 % CI 0.77-1.78) and those receiving both SNAP and WIC (OR 0.84: 95 % CI 0.61-1.17) did not have significantly different odds of food insecurity. In conclusion, better neighborhood food access is associated with lower risk of food insecurity. However, most food insecure individuals reported good access. Improving diet in communities with high rates of food insecurity likely requires not only improved access but also greater affordability. C1 [Mayer, Victoria L.; Long, Judith A.] Univ Penn, Div Gen Internal Med, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Mayer, Victoria L.; Bachhuber, Marcus A.; Long, Judith A.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Hillier, Amy] Univ Penn, Dept City & Reg Planning, Sch Design, Philadelphia, PA 19104 USA. [Bachhuber, Marcus A.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Bachhuber, Marcus A.] Univ Penn, Robert Wood Johnson Fdn, Clin Scholars Program, Philadelphia, PA 19104 USA. RP Mayer, VL (reprint author), Univ Penn, Div Gen Internal Med, Dept Med, Perelman Sch Med, 1205 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM vmayer@mail.med.upenn.edu OI Bachhuber, Marcus/0000-0002-5610-8382 FU Division of General Internal Medicine Matt Slap Award from the Perelman School of Medicine at the University of Pennsylvania; National Institutes of Health Institutional Training Grant [5-T32-HP-100296-20-00] FX The authors would like to thank Christopher Wirtalla for assistance with developing Stata programming. V.L.M. was supported with funding from the Division of General Internal Medicine Matt Slap Award from the Perelman School of Medicine at the University of Pennsylvania and the National Institutes of Health Institutional Training Grant 5-T32-HP-100296-20-00. NR 28 TC 7 Z9 7 U1 3 U2 28 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 DEC PY 2014 VL 91 IS 6 BP 1087 EP 1097 DI 10.1007/s11524-014-9887-2 PG 11 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AU1RA UT WOS:000345396700005 PM 25047157 ER PT J AU Gowda, C Compher, C Amorosa, VK Lo Re, V AF Gowda, C. Compher, C. Amorosa, V. K. Lo Re, V., III TI Association between chronic hepatitis C virus infection and low muscle mass in US adults SO JOURNAL OF VIRAL HEPATITIS LA English DT Article DE chronic hepatitis C; low muscle mass; malnutrition; NHANES ID HUMAN-IMMUNODEFICIENCY-VIRUS; NUTRITIONAL-STATUS; HIV-INFECTION; LIVER-CIRRHOSIS; BODY-COMPOSITION; PRIMARY-CARE; WEIGHT-LOSS; MALNUTRITION; DISEASE; TUBERCULOSIS AB Given that low muscle mass can lead to worse health outcomes in patients with chronic infections, we assessed whether chronic hepatitis C virus (HCV) infection was associated with low muscle mass among US adults. We performed a cross-sectional study of the National Health Examination and Nutrition Study (1999-2010). Chronic HCV-infected patients had detectable HCV RNA. Low muscle mass was defined as <10th percentile for mid-upper arm circumference (MUAC). Multivariable logistic regression was used to determine adjusted odds ratios (aORs) with 95% confidence intervals (CIs) of low muscle mass associated with chronic HCV. Among 18513 adults, chronic HCV-infected patients (n=303) had a higher prevalence of low muscle mass than uninfected persons (13.8% vs 6.7%; aOR, 2.22; 95% CI, 1.39-3.56), and this association remained when analyses were repeated among persons without significant liver fibrosis (aOR, 2.12; 95% CI, 1.30-3.47). This study demonstrates that chronic HCV infection is associated with low muscle mass, as assessed by MUAC measurements, even in the absence of advanced liver disease. C1 [Gowda, C.; Amorosa, V. K.; Lo Re, V., III] Univ Penn, Perelman Sch Med, Div Infect Dis, Dept Med, Philadelphia, PA 19104 USA. [Gowda, C.; Lo Re, V., III] Univ Penn, Perelman Sch Med, Dept Biostatist & Epidemiol, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Compher, C.] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Amorosa, V. K.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Gowda, C (reprint author), Univ Penn, Div Infect Dis, 3400 Spruce St,Ste D, Philadelphia, PA 19104 USA. EM gowdac@uphs.upenn.edu RI Lo Re, Vincent/N-7817-2015 FU National Institutes of Health [T32-AI-055435, K01-AI070001] FX This work was supported by the National Institutes of Health research Grants T32-AI-055435 (to C.G.) and K01-AI070001 (to V.L.R.). NR 38 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1352-0504 EI 1365-2893 J9 J VIRAL HEPATITIS JI J. Viral Hepatitis PD DEC PY 2014 VL 21 IS 12 BP 938 EP 943 DI 10.1111/jvh.12273 PG 6 WC Gastroenterology & Hepatology; Infectious Diseases; Virology SC Gastroenterology & Hepatology; Infectious Diseases; Virology GA AU1YP UT WOS:000345413700018 PM 24989435 ER PT J AU Lanske, B Razzaque, MS AF Lanske, Beate Razzaque, Mohammed S. TI Molecular interactions of FGF23 and PTH in phosphate regulation SO KIDNEY INTERNATIONAL LA English DT Editorial Material ID FIBROBLAST GROWTH FACTOR-23; PARATHYROID-HORMONE; HYPOPHOSPHATEMIA; KLOTHO; MICE AB Bone-derived fibroblast growth factor-23 (FGF23) plays an important role in systemic phosphate turnover. Increased FGF23 activity results in hypophosphatemic disorders, while reduced activity is linked to hyperphosphatemic disorders. FGF23, together with klotho as cofactor, can activate FGF receptors in its target tissues to exert its functions. However, the molecular regulation of FGF23 synthesis is not clearly defined, and recent studies have found that parathyroid hormone (PTH) can activate the nuclear receptor-associated protein-1 (Nurr1) to induce FGF23 transcription in bone cells. C1 [Lanske, Beate] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Razzaque, Mohammed S.] Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA USA. RP Lanske, B (reprint author), Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, 188 Longwood Ave, Boston, MA 02115 USA. EM beate_lanske@hsdm.harvard.edu FU NIDDK NIH HHS [R01 DK097105, DK097105] NR 12 TC 13 Z9 16 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD DEC PY 2014 VL 86 IS 6 BP 1071 EP 1074 DI 10.1038/ki.2014.316 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA AU4ZN UT WOS:000345616900002 PM 25427080 ER PT J AU Bhama, PK Park, JG Shanley, K Hadlock, TA AF Bhama, Prabhat K. Park, Jong G. Shanley, Kerry Hadlock, Tessa A. TI Refinements in Nasolabial Fold Reconstruction for Facial Paralysis SO LARYNGOSCOPE LA English DT Article DE Facial paralysis; facial nerve; nasolabial fold; reanimation ID NERVE PARALYSIS; MANAGEMENT AB Objectives/HypothesisThe objective of this study was to describe a methodology for creation of a nasolabial fold in patients with facial paralysis and to report patient-reported outcome measures following this procedure. Study DesignRetrospective case series. MethodsAll patients who underwent nasolabial fold modification at our institution since July 2010 were included in our analysis. Patient demographics and characteristics of their facial paralysis were noted. Preoperative Facial Clinimetric Evaluation scores were compared with postoperative scores to quantify outcomes. Pre- and postoperative photos were then presented to an observer for ratings of overall midfacial appearance. ResultsThirty-one patients were included in the review. Most of the patients were male. The average onset of paralysis was 50 years, and the average age at time of surgery was 61 years. The majority of patients had flaccid paralysis, with 10% of patients having synkinesis. Most patients presented with complaints of oral incompetence or drooling and generalized facial asymmetry. Facial Clinimetric Evaluation scores (P<.004) and overall midfacial appearance (P<.05) improved significantly following surgery. ConclusionsThe nasolabial fold is an important aesthetic component of the face commonly affected in patients with facial paralysis. We demonstrate quantitative improvement in quality of life scores and aesthetic appearance following nasolabial fold refinement and describe the procedure in depth. Level of Evidence4. Laryngoscope, 124:2687-2692, 2014 C1 [Bhama, Prabhat K.; Shanley, Kerry; Hadlock, Tessa A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Div Facial Plast & Reconstruct Surg,Dept Otol & L, Boston, MA USA. [Park, Jong G.] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. RP Bhama, PK (reprint author), Alaska Native Med Ctr, 4315 Diplomacy Dr, Anchorage, AK 99508 USA. EM pbhama@gmail.com NR 14 TC 8 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD DEC PY 2014 VL 124 IS 12 BP 2687 EP 2692 DI 10.1002/lary.24843 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA AU0WZ UT WOS:000345344200013 PM 25043990 ER PT J AU Sedaghat, AR Gray, ST Kieff, DA AF Sedaghat, Ahmad R. Gray, Stacey T. Kieff, David A. TI In Response to Preapproval of Sinus Computed Tomography for Otolaryngologic Evaluation of Chronic Rhinosinusitis Does Not Save Health Care Costs SO LARYNGOSCOPE LA English DT Letter ID PRIOR-AUTHORIZATION PROGRAMS; ADULT; COSTS C1 [Sedaghat, Ahmad R.; Gray, Stacey T.; Kieff, David A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol Head & Neck Surg,Dept Otol & Lar, Boston, MA 02163 USA. RP Sedaghat, AR (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol Head & Neck Surg,Dept Otol & Lar, Boston, MA 02163 USA. NR 10 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD DEC PY 2014 VL 124 IS 12 BP E471 EP E472 DI 10.1002/lary.24725 PG 2 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA AU0WZ UT WOS:000345344200005 PM 24752641 ER PT J AU Uno, H Cronin, AM Wadleigh, M Schrag, D Abel, GA AF Uno, Hajime Cronin, Angel M. Wadleigh, Martha Schrag, Deborah Abel, Gregory A. TI Derivation and validation of the SEER-Medicare myelodysplastic syndromes risk score (SMMRS) SO LEUKEMIA RESEARCH LA English DT Article DE MDS; SEER; SEER-Medicare; Prognosis; Comparative effectiveness ID UNITED-STATES; PHASE-III; SYSTEM; SURVIVAL; AZACITIDINE; DECITABINE; EFFICACY; CANCER; MODEL AB Accruing data since 2001, the SEER-Medicare dataset is an outstanding resource for MDS-related comparative effectiveness research; however, although several MDS prognostic models exist, complete data required to calculate them are not available therein. Using SEER-Medicare as a training and internal validation set (n = 9820) and clinical data at our institution as an external validation set (n = 307), we created a new MDS risk score (the SMMRS) for use with SEER-Medicare. Risk stratification by the SMMRS was comparable to the IPSS (net reclassification improvement index was 0.0), demonstrating that it is a useful research tool to stratify MDS patients in studies using SEER-Medicare. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Uno, Hajime; Cronin, Angel M.; Schrag, Deborah; Abel, Gregory A.] Dana Farber Canc Inst, Dept Med Oncol, Div Populat Sci, Boston, MA 02115 USA. [Wadleigh, Martha; Abel, Gregory A.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Leukaemia, Boston, MA 02115 USA. RP Abel, GA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 1106, Boston, MA 02115 USA. EM gregory_abel@dfci.harvard.edu FU R21 (NIH); Leukemia; Lymphoma Society FX Internal, R21 (NIH), Leukemia and Lymphoma Society. NR 17 TC 4 Z9 4 U1 1 U2 2 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 DEC PY 2014 VL 38 IS 12 BP 1420 EP 1424 DI 10.1016/j.leukres.2014.09.011 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA AU4YN UT WOS:000345614400007 PM 25443886 ER PT J AU Sylling, PW Wong, ES Liu, CF Hernandez, SE Batten, AJ Helfrich, CD Nelson, K Fihn, SD Hebert, PL AF Sylling, Philip W. Wong, Edwin S. Liu, Chuan-Fen Hernandez, Susan E. Batten, Adam J. Helfrich, Christian D. Nelson, Karin Fihn, Stephan D. Hebert, Paul L. TI Patient-Centered Medical Home Implementation and Primary Care Provider Turnover SO MEDICAL CARE LA English DT Article DE primary care provider; turnover; patient-centered medical home; Veterans Health Administration ID PHYSICIAN TURNOVER; EMPLOYEE TURNOVER; JOB-SATISFACTION; PREDICTORS; COMMITMENT; BEHAVIOR; LESSONS; BURNOUT; MODELS; COSTS AB Background: The Veterans Health Administration (VHA) began implementing a patient-centered medical home (PCMH) model of care delivery in April 2010 through its Patient Aligned Care Team (PACT) initiative. PACT represents a substantial system reengineering of VHA primary care and its potential effect on primary care provider (PCP) turnover is an important but unexplored relationship. This study examined the association between a system-wide PCMH implementation and PCP turnover. Methods: This was a retrospective, longitudinal study of VHA-employed PCPs spanning 29 calendar quarters before PACT and eight quarters of PACT implementation. PCP employment periods were identified from administrative data and turnover was defined by an indicator on the last quarter of each uncensored period. An interrupted time series model was used to estimate the association between PACT and turnover, adjusting for secular trend and seasonality, provider and job characteristics, and local unemployment. We calculated average marginal effects (AME), which reflected the change in turnover probability associated with PACT implementation. Results: The quarterly rate of PCP turnover was 3.06% before PACT and 3.38% after initiation of PACT. In adjusted analysis, PACT was associated with a modest increase in turnover (AME = 4.0 additional PCPs per 1000 PCPs per quarter, P = 0.004). Models with interaction terms suggested that the PACT-related change in turnover was increasing in provider age and experience. Conclusions: PACT was associated with a modest increase in PCP turnover, concentrated among older and more experienced providers, during initial implementation. Our findings suggest that policymakers should evaluate potential workforce effects when implementing PCMH. C1 [Sylling, Philip W.; Wong, Edwin S.; Liu, Chuan-Fen; Hernandez, Susan E.; Batten, Adam J.; Helfrich, Christian D.; Nelson, Karin; Hebert, Paul L.] VA Puget Sound Healthcare Syst, Northwest HSR&D Ctr Innovat, Seattle, WA 98101 USA. [Wong, Edwin S.; Liu, Chuan-Fen; Hernandez, Susan E.; Helfrich, Christian D.; Fihn, Stephan D.; Hebert, Paul L.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Nelson, Karin; Fihn, Stephan D.] VA Puget Sound Healthcare Syst, Gen Internal Med Serv, Seattle, WA 98101 USA. [Nelson, Karin; Fihn, Stephan D.] Univ Washington, Dept Med, Sch Med, Seattle, WA 98195 USA. [Fihn, Stephan D.] VA Puget Sound Healthcare Syst, VHA Off Analyt & Business Intelligence, Seattle, WA 98101 USA. RP Sylling, PW (reprint author), VA Puget Sound Healthcare Syst, Northwest HSR&D Ctr Innovat, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM philip.sylling@va.gov FU Veterans Health Administration Patient Centered Medical Home Demonstration Laboratory Coordination Center [XVA-61-041] FX Supported by the Veterans Health Administration Patient Centered Medical Home Demonstration Laboratory Coordination Center (XVA-61-041). NR 30 TC 4 Z9 4 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD DEC PY 2014 VL 52 IS 12 BP 1017 EP 1022 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AU0DP UT WOS:000345294100003 PM 25271536 ER PT J AU Graetz, I Reed, M Shortell, SM Rundall, TG Bellows, J Hsu, J AF Graetz, Ilana Reed, Mary Shortell, Stephen M. Rundall, Thomas G. Bellows, Jim Hsu, John TI The Next Step Towards Making Use Meaningful Electronic Information Exchange and Care Coordination Across Clinicians and Delivery Sites SO MEDICAL CARE LA English DT Article DE clinical information systems; continuity of care; coordinated care; health care technology; informatics; survey research ID IMPROVING PRIMARY-CARE; HEALTH INFORMATION; TRANSITIONAL CARE; CHRONIC ILLNESS; UNITED-STATES; OPPORTUNITIES; CHALLENGES; QUALITY; SYSTEM; NEEDS AB Background: Care for patients with chronic conditions often requires coordination between multiple physicians and delivery sites. Electronic Health Record (EHR) use could improve care quality and efficiency in part by facilitating care coordination. Objective: We examined the association between EHR use and clinician perceptions of care coordination for patients transferred across clinicians and delivery sites. Research Design: Repeated surveys of primary care clinicians during the staggered implementation of an outpatient EHR (2005-2008), followed by an integrated inpatient EHR (2006-2010). We measured the association between EHR use stages (no use, outpatient EHR only, and integrated inpatient-outpatient EHR) and care coordination using logistic regression, adjusting for clinician characteristics, study year, and medical center. Subjects: Adult primary care clinicians in a large Integrated Delivery System. Measures: Three measures of clinician-reported care coordination for patient care transferred across clinicians (eg, from specialist to primary care team) and across delivery sites (eg, from the hospital to outpatient care). Results: Outpatient EHR use was associated with higher reports of access to complete and timely clinical information and higher agreement on clinician roles and responsibilities for patients transferred across clinicians, but not for patients transferred across delivery sites. Use of the integrated outpatient-inpatient EHR was associated with higher reports of access to timely and complete clinical information, clinician agreement on the patient's treatment plan for patients transferred across delivery sites, and with all coordination measures for patients transferred across clinicians. Conclusion: Use of an integrated EHR with health information exchange across delivery settings improved patient care coordination. C1 [Graetz, Ilana; Reed, Mary] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Graetz, Ilana] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN 38163 USA. [Shortell, Stephen M.; Rundall, Thomas G.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Bellows, Jim] Kaiser Permanente, Care Management Inst, Oakland, CA USA. [Hsu, John] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Hsu, John] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Graetz, I (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, 66 N Pauline St,Suite 633, Memphis, TN 38163 USA. EM igraetz@uthsc.edu RI Graetz, Ilana/N-1189-2016 OI Graetz, Ilana/0000-0003-3664-5815 FU Agency for Healthcare Research and Quality [1R36HS021082, R01HS015280] FX Supported by Grants from the Agency for Healthcare Research and Quality (1R36HS021082 and R01HS015280). NR 20 TC 5 Z9 5 U1 6 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD DEC PY 2014 VL 52 IS 12 BP 1037 EP 1041 PG 5 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AU0DP UT WOS:000345294100006 PM 25304020 ER PT J AU Stevens, J Johansson, A Lennes, I Hsu, D Tess, A Howell, M AF Stevens, Jennifer Johansson, Anna Lennes, Inga Hsu, Douglas Tess, Anjala Howell, Michael TI Long-term culture change related to rapid response system implementation SO MEDICAL EDUCATION LA English DT Article ID SUPERVISION; RESIDENTS; TRAINEES; SKILL; TEAM AB ObjectivesIncreasing attention to patient safety in training hospitals may come at the expense of trainee autonomy and professional growth. This study sought to examine changes in medical trainees' self-reported behaviour after the institution-wide implementation of a rapid response system. MethodsWe conducted a two-point cross-sectional survey of medical trainees in 2006, during the implementation of a rapid response system, and in 2010, in a single academic medical centre. A novel instrument was used to measure trainee likelihood of calling for supervisory assistance, perception of autonomy, and comfort in managing decompensating patients. Non-parametric tests to assess for change were used and year of training was evaluated as an effect modifier. ResultsResponse rates were 38% in 2006 and 70% in 2010. After 5years of the full implementation of the rapid response system, residents were significantly more likely to report calling their attending physicians for assistance (rising from 40% to 65% of relevant situations; p<0.0001). Year of training was a significant effect modifier. Interns felt significantly more comfortable in managing acutely ill patients; juniors and seniors felt significantly less concerned about their autonomy at 5years after the implementation of the rapid response system. These changes were mirrored in the actual use of the rapid response system, which increased by 41% during the 5-year period after adjustment for patient volume (p<0.0001). ConclusionsA primary team-focused implementation of a rapid response system was associated with durable changes in resident physicians' reported behaviour, including increased comfort with involving more experienced physicians and managing unstable patients. C1 [Stevens, Jennifer; Johansson, Anna; Hsu, Douglas; Tess, Anjala] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Stevens, Jennifer] Beth Israel Deaconess Med Ctr, Ctr Healthcare Delivery Sci, Boston, MA 02215 USA. [Lennes, Inga] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Howell, Michael] Univ Chicago, Dept Med, Chicago, IL 60637 USA. RP Stevens, J (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, 330 Brookline Ave, Boston, MA 02215 USA. EM jpsteven@bidmc.harvard.edu RI Howell, Michael/B-8065-2009 OI Howell, Michael/0000-0001-7003-6971 FU Physician Faculty Scholars Programme of the Robert Wood Johnson Foundation [66350] FX this work was partly supported by the Physician Faculty Scholars Programme of the Robert Wood Johnson Foundation (grant 66350, to MDH). NR 18 TC 1 Z9 1 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0308-0110 EI 1365-2923 J9 MED EDUC JI Med. Educ. PD DEC PY 2014 VL 48 IS 12 BP 1211 EP 1219 DI 10.1111/medu.12538 PG 9 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA AU3HH UT WOS:000345502500011 PM 25413914 ER PT J AU Giannakis, M Hodis, E Mu, XJ Yamauchi, M Rosenbluh, J Cibulskis, K Saksena, G Lawrence, MS Qian, ZR Nishihara, R Van Allen, EM Hahn, WC Gabriel, SB Lander, ES Getz, G Ogino, S Fuchs, CS Garraway, LA AF Giannakis, Marios Hodis, Eran Mu, Xinmeng Jasmine Yamauchi, Mai Rosenbluh, Joseph Cibulskis, Kristian Saksena, Gordon Lawrence, Michael S. Qian, Zhi Rong Nishihara, Reiko Van Allen, Eliezer M. Hahn, William C. Gabriel, Stacey B. Lander, Eric S. Getz, Gad Ogino, Shuji Fuchs, Charles S. Garraway, Levi A. TI RNF43 is frequently mutated in colorectal and endometrial cancers SO NATURE GENETICS LA English DT Article ID COMPREHENSIVE MOLECULAR CHARACTERIZATION; GASTRIC ADENOCARCINOMA; DRIVER MUTATIONS; CARCINOMA; LANDSCAPE; COLON AB We report somatic mutations of RNF43 in over 18% of colorectal adenocarcinomas and endometrial carcinomas. RNF43 encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling. Truncating mutations of RNF43 are more prevalent in microsatellite-unstable tumors and show mutual exclusivity with inactivating APC mutations in colorectal adenocarcinomas. These results indicate that RNF43 is one of the most commonly mutated genes in colorectal and endometrial cancers. C1 [Giannakis, Marios; Hodis, Eran; Mu, Xinmeng Jasmine; Yamauchi, Mai; Rosenbluh, Joseph; Qian, Zhi Rong; Nishihara, Reiko; Van Allen, Eliezer M.; Hahn, William C.; Ogino, Shuji; Fuchs, Charles S.; Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Van Allen, Eliezer M.; Hahn, William C.; Garraway, Levi A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Giannakis, Marios; Hodis, Eran; Mu, Xinmeng Jasmine; Rosenbluh, Joseph; Cibulskis, Kristian; Saksena, Gordon; Lawrence, Michael S.; Van Allen, Eliezer M.; Hahn, William C.; Gabriel, Stacey B.; Lander, Eric S.; Getz, Gad; Ogino, Shuji; Garraway, Levi A.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Hodis, Eran] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Hodis, Eran] Harvard Univ, Biophys Program, Cambridge, MA 02138 USA. [Nishihara, Reiko; Ogino, Shuji] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Nishihara, Reiko] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Nishihara, Reiko] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Lander, Eric S.] MIT, Dept Biol, Cambridge, MA USA. [Lander, Eric S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Getz, Gad] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Ogino, Shuji] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Fuchs, Charles S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Charming Div Network Med,Dept Med, Boston, MA 02115 USA. RP Garraway, LA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM levi_garraway@dfci.harvard.edu RI Mu, Xinmeng/P-2562-2016 OI Mu, Xinmeng/0000-0002-8079-0828 FU Dana-Farber Cancer Institute Leadership Council; Colon Cancer Alliance-American Association for Cancer Research Fellowship for Biomarker Research [14-40-40-GIAN]; Perry S. Levy Endowed Fellowship; National Institute of General Medical Sciences [T32GM007753]; Herchel Smith Fellowship; Agrusa Fund for Colorectal Cancer Research; National Human Genome Research Institute [U54HG003067]; National Cancer Institute [K07CA190673, P01CA87969, UM1CA167552, R01CA151993, R01CA118553, R01CA168141, P50CA127003] FX We thank S. Bahl, E. Nickerson and S. Chauvin for project management and A. Regev for help with computing resources, as well as A. Sivachenko, F. Huang and P. Tamayo for helpful discussions. This work was supported by the Dana-Farber Cancer Institute Leadership Council, the 2014 Colon Cancer Alliance-American Association for Cancer Research Fellowship for Biomarker Research, grant 14-40-40-GIAN, the Perry S. Levy Endowed Fellowship (M.G.), award T32GM007753 from the National Institute of General Medical Sciences, the Herchel Smith Fellowship (E.H.) and the Agrusa Fund for Colorectal Cancer Research (C.S.F.), as well as National Human Genome Research Institute grant U54HG003067 (E.S.L. and S.B.G.) and National Cancer Institute grants, K07CA190673 (R.N.), P01CA87969, UM1CA167552 and R01CA151993 (S.O.), R01CA118553 and R01CA168141 (C.S.F.) and P50CA127003 (M.G., W.C.H., L.A.G. and C.S.F.). NR 16 TC 58 Z9 60 U1 3 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD DEC PY 2014 VL 46 IS 12 BP 1264 EP 1266 DI 10.1038/ng.3127 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA AU3YU UT WOS:000345547300006 PM 25344691 ER PT J AU Zheng, ZL Liebers, M Zhelyazkova, B Cao, Y Panditi, D Lynch, KD Chen, JX Robinson, HE Shim, HS Chmielecki, J Pao, W Engelman, JA Iafrate, AJ Le, LP AF Zheng, Zongli Liebers, Matthew Zhelyazkova, Boryana Cao, Yi Panditi, Divya Lynch, Kerry D. Chen, Juxiang Robinson, Hayley E. Shim, Hyo Sup Chmielecki, Juliann Pao, William Engelman, Jeffrey A. Iafrate, A. John Le, Long Phi TI Anchored multiplex FOR for targeted next-generation sequencing SO NATURE MEDICINE LA English DT Article ID CELL LUNG-CANCER; PCR; GENOMES; DNA; ENRICHMENT; DISCOVERY; VARIANTS; FUSIONS; TUMORS; ROS1 AB We describe a rapid target enrichment method for next-generation sequencing, termed anchored multiplex PCR (AMP), that is compatible with low nucleic acid input from formalin-fixed paraffin-embedded (FFPE) specimens. AMP is effective in detecting gene rearrangements (without prior knowledge of the fusion partners), single nucleotide variants, insertions, deletions and copy number changes. Validation of a gene rearrangement panel using 319 FFPE samples showed 100% sensitivity (95% confidence limit: 96.5-100%) and 100% specificity (95% confidence limit: 99.3-100%) compared with reference assays. On the basis of our experience with performing AMP on 986 clinical FFPE samples, we show its potential as both a robust clinical assay and a powerful discovery tool, which we used to identify new therapeutically important gene fusions: ARHGEF2-NTRK1 and CHTOP-NTRK1 in glioblastoma, MSN-ROS1, TRIM4-BRAF, VAMP2-NRG1, TPM3-NTRK1 and RUFY2-RET in lung cancer, FGFR2-CREB5 in cholangiocarcinoma and PPL-NTRK1 in thyroid carcinoma. AMP is a scalable and efficient next-generation sequencing target enrichment method for research and clinical applications. C1 [Zheng, Zongli; Liebers, Matthew; Zhelyazkova, Boryana; Cao, Yi; Panditi, Divya; Lynch, Kerry D.; Chen, Juxiang; Robinson, Hayley E.; Shim, Hyo Sup; Iafrate, A. John; Le, Long Phi] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Zheng, Zongli] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Chen, Juxiang] Shanghai Changzheng Hosp, Dept Neurosurg, Shanghai, Peoples R China. [Shim, Hyo Sup] Yonsei Univ, Coll Med, Dept Pathol, Seoul, South Korea. [Chmielecki, Juliann; Pao, William] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Engelman, Jeffrey A.; Iafrate, A. John; Le, Long Phi] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Iafrate, AJ (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM aiafrate@partners.org; lple@partners.org RI zheng, zongli/B-2917-2011 OI zheng, zongli/0000-0003-4849-4903 FU US National Institutes of Health [R21CA161590]; Swedish Research Council [350-2012-368] FX This study was supported by a US National Institutes of Health grant (R21CA161590) to A.J.I. and a postdoctoral fellowship from the Swedish Research Council (350-2012-368) to Z.Z. NR 26 TC 75 Z9 75 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD DEC PY 2014 VL 20 IS 12 BP 1479 EP 1484 DI 10.1038/nm.3729 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AU7ZZ UT WOS:000345817900025 PM 25384085 ER PT J AU Vidal, M Fields, S AF Vidal, Marc Fields, Stanley TI The yeast two-hybrid assay: still finding connections after 25 years SO NATURE METHODS LA English DT Article ID PROTEIN INTERACTION NETWORK; INTERACTIONS IN-VIVO; SACCHAROMYCES-CEREVISIAE; C-ELEGANS; 3-HYBRID SYSTEM; HYBRID SYSTEMS; MAP; INTERACTOME; COMPLEXES; SCREENS AB The idea of using hybrid proteins containing transcription factor domains to analyze protein-protein interactions was described in 1989. Over the past 25 years, this method has begun to reveal the complex protein networks that underlie cellular behavior. C1 [Vidal, Marc] Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02138 USA. [Vidal, Marc] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Fields, Stanley] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Fields, Stanley] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Fields, Stanley] Univ Washington, Dept Med, Seattle, WA USA. RP Vidal, M (reprint author), Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02138 USA. EM marc_vidal@dfci.harvard.edu; fields@uw.edu FU Howard Hughes Medical Institute NR 34 TC 12 Z9 13 U1 5 U2 36 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD DEC PY 2014 VL 11 IS 12 BP 1203 EP 1206 DI 10.1038/nmeth.3182 PG 4 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AU4FF UT WOS:000345564600012 PM 25584376 ER PT J AU Mujica-Parodi, LR Carlson, JM Cha, J Rubin, D AF Mujica-Parodi, L. R. Carlson, Joshua M. Cha, Jiook Rubin, Denis TI The fine line between 'brave' and 'reckless': Amygdala reactivity and regulation predict recognition of risk SO NEUROIMAGE LA English DT Article DE Sensation-seeking; Stress; Resilience; Fear; Limbic; Amygdala; Prefrontal cortex; Cortisol; Complexity, chaos, fractal, power spectrum scale invariance ID IMPULSIVE-SENSATION SEEKING; SPECTRUM SCALE-INVARIANCE; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; DRUG-USE; LIMBIC DYSREGULATION; PREFRONTAL CORTEX; GRAY-MATTER; BRAIN; BEHAVIOR AB Background: High sensation-seekers (HSS) pursue novelty even at the cost of self-harm. When challenged, HSS are less anxious, showblunted physiological (cortisol, startle) and neurobiological (prefrontal-limbic) responses, and devalue aversive outcomes. Here, we investigate how these features interact under conditions of physical danger, in distinguishing between adaptive and maladaptive approaches to risk. Methods: We recruited a cohort of individuals who voluntarily sought out recreational exposure to physical risk, and obtained serial cortisol values over two time-locked days. On the 'baseline' day, we scanned subjects' brains with functional and structural MRI; on the 'skydiving day,' subjects completed a first-time tandem skydive. During neuroimaging, subjects viewed cues that predicted aversive noise; neural data were analyzed for prefrontallimbic reactivity (activation) and regulation (non-linear complexity), as well as cortical thickness. To probe threat perception, subjects identified aggression for ambiguous faces morphed between neutral and angry poles. Results: Individuals with prefrontal-limbic meso-circuits with less balanced regulation between excitatory and inhibitory components showed both diminished cortisol/anxiety responses to their skydives, as well as less accurate perceptual recognition of threat. This impaired control was localized to the inferior frontal gyrus, with associated cortical thinning. Structural equation modeling suggests that sensation-seeking is primarily mediated via threat-perception, which itself is primarily mediated via neural reactivity and regulation. Conclusions: Our results refine the sensation-seeking construct to provide important distinctions (brain-based, but with endocrine and cognitive consequences) between the brave, who feel fear but nonetheless overcome it, and the reckless, who fail to recognize danger. This distinction has important real-world implications, as those who fail to recognize risk are less likely to mitigate it. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). C1 [Mujica-Parodi, L. R.; Rubin, Denis] SUNY Stony Brook, Dept Biomed Engn, Sch Med, Stony Brook, NY 11794 USA. [Mujica-Parodi, L. R.] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Carlson, Joshua M.] No Michigan Univ, Dept Psychol, Marquette, MI 49855 USA. [Cha, Jiook] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY 10032 USA. [Rubin, Denis] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. RP Mujica-Parodi, LR (reprint author), SUNY Stony Brook, Dept Biomed Engn, Lab Computat Neurodiagnost, Stony Brook, NY 11794 USA. EM Lilianne.Strey@stonybrook.edu OI Mujica-Parodi, Lilianne/0000-0002-3752-5519; Rubin, Denis/0000-0002-0483-9458; Cha, Jiook/0000-0002-5314-7992 FU Office of Naval Research [N0014-04-1-005]; National Science Foundation [0954643] FX We would like to thank Dr. Tsafrir Greenberg for his valuable assistance with the data collection. This research was supported by the Office of Naval Research (N0014-04-1-005; LRMP) and the National Science Foundation (0954643; LRMP). NR 69 TC 10 Z9 10 U1 2 U2 15 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 DEC PY 2014 VL 103 BP 1 EP 9 DI 10.1016/j.neuroimage.2014.08.038 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU1PR UT WOS:000345393100001 PM 25175540 ER PT J AU Sitnikova, T Rosen, BR Lord, LD West, WC AF Sitnikova, Tatiana Rosen, Bruce R. Lord, Louis-David West, W. Caroline TI Understanding human original actions directed at real-world goals: The role of the lateral prefrontal cortex SO NEUROIMAGE LA English DT Article DE Goal inference; Real-world comprehension; fMRI; Lateral prefrontal cortex ID INTRINSIC FUNCTIONAL CONNECTIVITY; INFERIOR FRONTAL GYRUS; MIRROR-NEURON SYSTEM; HUMAN BRAIN; VISUAL CATEGORIZATION; SEMANTIC INTEGRATION; COGNITIVE CONTROL; PARIETAL CORTEX; REPRESENTATION; MEMORY AB Adaptive, original actions, which can succeed in multiple contextual situations, require understanding of what is relevant to a goal. Recognizing what is relevant may also help in predicting kinematics of observed, original actions. During action observation, comparisons between sensory input and expected action kinematics have been argued critical to accurate goal inference. Experimental studies with laboratory tasks, both in humans and nonhuman primates, demonstrated that the lateral prefrontal cortex (LPFC) can learn, hierarchically organize, and use goal-relevant information. To determine whether this LPFC capacity is generalizable to real-world cognition, we recorded functional magnetic resonance imaging (fMRI) data in the human brain during comprehension of original and usual object-directed actions embedded in video-depictions of real-life behaviors. We hypothesized that LPFC will contribute to forming goal-relevant representations necessary for kinematic predictions of original actions. Additionally, resting-state fMRI was employed to examine functional connectivity between the brain regions delineated in the video fMRI experiment. According to behavioral data, original videos could be understood by identifying elements relevant to real-life goals at different levels of abstraction. Patterns of enhanced activity in four regions in the left LPFC, evoked by original, relative to usual, video scenes, were consistent with previous neuroimaging findings on representing abstract and concrete stimuli dimensions relevant to laboratory goals. In the anterior left LPFC, the activity increased selectively when representations of broad classes of objects and actions, which could achieve the perceived overall behavioral goal, were likely to bias kinematic predictions of original actions. In contrast, in the more posterior regions, the activity increased even when concrete properties of the target object were more likely to bias the kinematic prediction. Functional connectivity was observed between contiguous regions along the rostro-caudal LPFC axis, but not between the regions that were not immediately adjacent. These findings generalize the representational hierarchy account of LPFC function to diverse core principles that can govern both production and comprehension of flexible real-life behavior. (C) 2014 Elsevier Inc. All rights reserved. C1 [Sitnikova, Tatiana; Rosen, Bruce R.; Lord, Louis-David] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Sitnikova, Tatiana; Rosen, Bruce R.] Harvard Univ, Sch Med, Boston, MA USA. [West, W. Caroline] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. RP Sitnikova, T (reprint author), Harvard Univ, Dept Psychiat, Athinoula A Martinos Ctr Biomed Imaging, Sch Med, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM tatiana@nmr.mgh.harvard.edu; bruce@nmr.mgh.harvard.edu; ld.lord13@googlemail.com; wcwest@fas.harvard.edu FU NIMH [MH085062, MH065356]; NARSAD; Sidney R. Baer, Jr. Foundation; MGH Fund for Medical Discovery; MGH Claflin Distinguished Scholars Award; National Center for Research Resources (NCRR) [P41RR14075] FX We thank Christopher M. Perrone, Jeremy W. Hughes, Natalie C. Hughes, Robert W. Boyle, David R. Hughes, Daphne Robakis, and Alexis Coty for their assistance in preparing the materials and collecting the data. This research was supported by NIMH (grants MH085062 to TS and MH065356 to WCW), grants to TS from NARSAD (with the Sidney R. Baer, Jr. Foundation), MGH Fund for Medical Discovery, and MGH Claflin Distinguished Scholars Award, as well as by the National Center for Research Resources (NCRR; grant P41RR14075). NR 79 TC 0 Z9 0 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD DEC PY 2014 VL 103 BP 91 EP 105 DI 10.1016/j.neuroimage.2014.09.012 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU1PR UT WOS:000345393100010 PM 25224997 ER PT J AU Trief, PM Cibula, D Delahanty, LM Weinstock, RS AF Trief, Paula M. Cibula, Donald Delahanty, Linda M. Weinstock, Ruth S. TI Depression, Stress, and Weight Loss in Individuals with Metabolic Syndrome in SHINE, a DPP Translation Study SO OBESITY LA English DT Article ID DIABETES-PREVENTION-PROGRAM; LIFE-STYLE INTERVENTION; ANTIDEPRESSANT MEDICINE USE; PARTICIPANTS; PREDICTORS; OUTCOMES; ADULTS; SYMPTOMS; IMPACT; RACE AB ObjectiveTo examine the relationships between elevated depression symptoms (EDS) or stress and weight loss in SHINE, a telephonic, primary-care based, translation of the Diabetes Prevention Program. MethodsN=257 adults with metabolic syndrome were randomized to individual (IC) or group (CC) phone participation. Weight, depression, anti-depressant use (ADMs), and stress (baseline, 6 months, 1 and 2 years) were assessed. Univariate analyses used linear and logistic regression, t tests for continuous variables and exact tests for categorical variables. Stratified analyses assessed modifiers of effects of depression/stress on weight loss. ResultsApproximately 35% reported EDS, with no change over time. Approximately 28% of all participants used ADMs. Participants with EDS had lower mean % weight loss and a smaller % who achieved 5% weight loss. Participants with EDS were less likely to be completers (40.1% vs. 61.5%, P=0.002), coached (48.0% vs. 60.7%, P=0.049), or log diet/activity (19.4% vs. 42.7%, P<0.001), behaviors related to weight loss. Results were similar for high stress. ADM use had no independent effect on weight loss. ConclusionsIndividuals with metabolic syndrome and EDS and/or high stress were less likely to lose significant weight. Pre-intervention depression and stress screening to intervene may improve weight loss. C1 [Trief, Paula M.] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, New York, NY 13210 USA. [Trief, Paula M.; Weinstock, Ruth S.] SUNY Upstate Med Univ, Dept Med, New York, NY USA. [Cibula, Donald] SUNY Upstate Med Univ, Dept Publ Hlth & Prevent Med, New York, NY USA. [Delahanty, Linda M.] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. [Delahanty, Linda M.] Harvard Univ, Dept Med, Cambridge, MA 02138 USA. RP Trief, PM (reprint author), SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, New York, NY 13210 USA. EM triefp@upstate.edu FU National Institutes of Health [R18-DK078553] FX Funding agencies: Study supported by grant R18-DK078553, National Institutes of Health. NR 25 TC 5 Z9 5 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD DEC PY 2014 VL 22 IS 12 BP 2532 EP 2538 DI 10.1002/oby.20916 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AU1XA UT WOS:000345409500012 PM 25251749 ER PT J AU Perng, W Gillman, MW Fleisch, AF Michalek, RD Watkins, SM Isganaitis, E Patti, ME Oken, E AF Perng, Wei Gillman, Matthew W. Fleisch, Abby F. Michalek, Ryan D. Watkins, Steven M. Isganaitis, Elvira Patti, Mary-Elizabeth Oken, Emily TI Metabolomic Profiles and Childhood Obesity SO OBESITY LA English DT Article DE branched-chain amino acids; androgen; steroid hormones; DHEA-S; metabolomics; obesity; insulin resistance; untargeted ID AMINO-ACID-METABOLISM; INSULIN-RESISTANCE; PREMATURE ADRENARCHE; SENSITIVITY; HUMANS; MARKERS; SYSTEM; MODEL; YOUTH; RISK AB ObjectiveTo identify metabolite patterns associated with childhood obesity, to examine relations of these patterns with measures of adiposity and cardiometabolic risk, and to evaluate associations with maternal peripartum characteristics. MethodsUntargeted metabolomic profiling was used to quantify metabolites in plasma of 262 children (6-10 years). Principal components analysis was used to consolidate 345 metabolites into 18 factors and identified two that differed between obese (BMI95; n=84) and lean children (BMI<85; n=150). The relations of these factors with adiposity (fat mass, BMI, skinfold thicknesses) and cardiometabolic biomarkers (HOMA-IR, triglycerides, leptin, adiponectin, hsCRP, IL-6) using multivariable linear regression was then investigated. Finally, the associations of maternal prepregnancy obesity, gestational weight gain, and gestational glucose tolerance with the offspring metabolite patterns was examined. ResultsA branched-chain amino acid (BCAA)-related pattern and an androgen hormone pattern were higher in obese vs. lean children. Both patterns were associated with adiposity and worse cardiometabolic profiles. For example, each increment in the BCAA and androgen pattern scores corresponded with 6% (95% CI: 1, 13%) higher HOMA-IR. Children of obese mothers had 0.61 (0.13, 1.08) higher BCAA score than their counterparts. ConclusionsBCAA and androgen metabolites were associated with adiposity and cardiometabolic risk during mid-childhood. Maternal obesity may contribute to altered offspring BCAA metabolism. C1 [Perng, Wei; Gillman, Matthew W.; Oken, Emily] Harvard Univ, Sch Med, Dept Populat Med, Obes Prevent Program, Boston, MA 02138 USA. [Perng, Wei; Gillman, Matthew W.; Oken, Emily] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Gillman, Matthew W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Fleisch, Abby F.] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA. [Michalek, Ryan D.] Metabolon Inc, Durham, NC USA. [Watkins, Steven M.] Div Metabolon Inc, Lipomics, West Sacramento, CA USA. [Isganaitis, Elvira; Patti, Mary-Elizabeth] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. RP Perng, W (reprint author), Harvard Univ, Sch Med, Dept Populat Med, Obes Prevent Program, Boston, MA 02138 USA. EM wei.perng@gmail.com FU US National Institutes of Health [K24 HD069408, R37 HD 034568, P30 DK092924]; Thomas O' Pyle Fellowship FX Funding agencies: This study was funded by the US National Institutes of Health (K24 HD069408, R37 HD 034568, P30 DK092924). Dr. Perng is supported by the Thomas O' Pyle Fellowship. The funder was not involved in the design and conduct of the study; collection, management, analysis, or interpretation of the data; and preparation, review, or approval of the manuscript. NR 38 TC 18 Z9 18 U1 0 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1930-7381 EI 1930-739X J9 OBESITY JI Obesity PD DEC PY 2014 VL 22 IS 12 BP 2570 EP 2578 DI 10.1002/oby.20901 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA AU1XA UT WOS:000345409500017 PM 25251340 ER PT J AU Hwang, U Belland, LK Handel, DA Yadav, K Heard, K Rivera-Reyes, L Eisenberg, A Noble, MJ Mekala, S Valley, M Winkel, G Todd, KH Morrison, RS AF Hwang, Ula Belland, Laura K. Handel, Daniel A. Yadav, Kabir Heard, Kennon Rivera-Reyes, Laura Eisenberg, Amanda Noble, Matthew J. Mekala, Sudha Valley, Morgan Winkel, Gary Todd, Knox H. Morrison, R. Sean TI Is all pain is treated equally? A multicenter evaluation of acute pain care by age SO PAIN LA English DT Article DE Acute pain care; Emergency department; Geriatrics ID EMERGENCY-DEPARTMENT ANALGESIA; DISPARITIES; ETHNICITY; MEDICINE; QUALITY AB Pain is highly prevalent in health care settings; however, disparities continue to exist in pain care treatment. Few studies have investigated if differences exist based on patient-related characteristics associated with aging. The objective of this study was to determine if there are differences in acute pain care for older vs younger patients. This was a multicenter, retrospective, cross-sectional observation study of 5 emergency departments across the United States evaluating the 2 most commonly presenting pain conditions for older adults, abdominal and fracture pain. Multivariable adjusted hierarchical modeling was completed. A total of 6,948 visits were reviewed. Older (>= 65 years) and oldest (>= 85 years) were less likely to receive analgesics compared to younger patients (<65 years), yet older patients had greater reductions in final pain scores. When evaluating pain treatment and final pain scores, differences appeared to be based on type of pain. Older patients with abdominal pain were less likely to receive pain medications, while older patients with fracture were more likely to receive analgesics and opioids compared to younger patients. Differences in pain care for older patients appear to be driven by the type of presenting pain. Published by Elsevier B.V. on behalf of International Association for the Study of Pain. C1 [Hwang, Ula; Belland, Laura K.; Rivera-Reyes, Laura] Icahn Sch Med Mt Sinai, Dept Emergency Med, New York, NY 10029 USA. [Hwang, Ula; Morrison, R. Sean] Icahn Sch Med Mt Sinai, Brookdale Dept Geriatr & Palliat Med, New York, NY 10029 USA. [Hwang, Ula; Morrison, R. Sean] James J Peters VAMC, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. [Handel, Daniel A.] Med Univ S Carolina, Charleston, SC 29425 USA. [Handel, Daniel A.; Noble, Matthew J.; Mekala, Sudha] Oregon Hlth & Sci Univ, Dept Emergency Med, Portland, SC USA. [Yadav, Kabir; Eisenberg, Amanda] George Washington Univ, Med Ctr, Dept Emergency Med, Washington, DC 20037 USA. [Heard, Kennon; Valley, Morgan] Univ Colorado, Dept Emergency Med, Aurora, CO USA. [Winkel, Gary] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Todd, Knox H.] Univ Texas MD Anderson Canc Ctr, Dept Emergency Med, Houston, TX 77030 USA. RP Hwang, U (reprint author), Dept Emergency Med, One Gustave L Levy Pl,Box 1062, New York, NY 10029 USA. EM ula.hwang@mountsinai.org OI Yadav, Kabir/0000-0002-1092-9935 FU National Institute on Aging [K23 AG031218, K24 AG022345] FX UH was supported by a K23 award from the National Institute on Aging (K23 AG031218), and RSM by a K24 from the National Institute on Aging (K24 AG022345). NR 26 TC 7 Z9 7 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 EI 1872-6623 J9 PAIN JI Pain PD DEC PY 2014 VL 155 IS 12 BP 2568 EP 2574 DI 10.1016/j.pain.2014.09.017 PG 7 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA AU1YZ UT WOS:000345414700019 PM 25244947 ER PT J AU Quinn, BL Sheldon, LK Cooley, ME AF Quinn, Brenna L. Sheldon, Lisa Kennedy Cooley, Mary E. TI Pediatric Pain Assessment by Drawn Faces Scales: A Review SO PAIN MANAGEMENT NURSING LA English DT Review ID INTENSITY; CHILDRENS; VALIDITY; RATINGS; IMPACT; MOOD AB Pediatric pain assessment is a significant issue yet the topic is under-studied. Unique challenges, namely reporting biases, are present when assessing pain in children. The aim of this review of the literature is to increase awareness of biases when assessing pain in children, suggest changes in practice, and state priorities for future research. Five computerized databases were searched to identify original research pertaining to the use of drawnfaces scales for pediatric pain assessment. Twelve studies met inclusion criteria. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines provided a framework for this review. Relevant articles were identified and data were extracted from the studies. Content analyses were then used to synthesize the findings. The age of a child being assessed contributed to biases in pain assessment. Drawn faces scales may provide inaccurate pain assessment results if a child has difficulty separating the feelings of pain and mood. Smiling faces on pain assessment scales may lead to overestimation of pain intensity. Nurses should consider biases when selecting and implementing a drawn faces pain assessment tool and when planning pain management interventions. An increase in the use of technology in pediatric pain assessment practices may provide opportunities to implement individualized pain assessment in practice. Further research is needed to determine the most reliable methods for pediatric pain assessment including the use of technology. Evidence would assist nurses in determining the best tool to assess each child based on cognitive abilities and developmental level. (C) 2014 by the American Society for Pain Management Nursing C1 [Quinn, Brenna L.; Sheldon, Lisa Kennedy; Cooley, Mary E.] Univ Massachusetts, Boston, MA 02125 USA. [Cooley, Mary E.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Quinn, BL (reprint author), Univ Massachusetts, 100 Morrissey Blvd, Boston, MA 02125 USA. EM brenna.quinn001@umb.edu OI Quinn, Brenna/0000-0001-9876-4700; Sheldon, Lisa Kennedy/0000-0002-5958-8529 NR 20 TC 2 Z9 2 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1524-9042 EI 1532-8635 J9 PAIN MANAG NURS JI Pain Manag. Nurs. PD DEC PY 2014 VL 15 IS 4 BP 909 EP 918 DI 10.1016/j.pmn.2014.03.004 PG 10 WC Nursing SC Nursing GA AU2ES UT WOS:000345429800023 PM 24973799 ER PT J AU Geyer, MB Radhakrishnan, K Van de Ven, C Suri, MS Ayello, J Cairo, MS AF Geyer, Mark B. Radhakrishnan, Kavita Van de Ven, Carmella Suri, Mandhir S. Ayello, Janet Cairo, Mitchell S. TI Enhanced Survival During Experimental Listeria monocytogenes Sepsis in Neonatal Mice Prophylactically Treated With Th1 and Macrophage Immunoregulatory Cytokines and Mediators SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE Listeria monocytogenes; neonatal; cytokine; interleukins; host defense ID COLONY-STIMULATING FACTOR; INTERFERON-GAMMA PRODUCTION; PLACEBO-CONTROLLED TRIAL; BLOOD MONONUCLEAR-CELLS; B STREPTOCOCCAL SEPSIS; T-CELLS; IFN-GAMMA; GENE-EXPRESSION; ACTIVATED CORD; NATURAL-KILLER AB Background: Impairments in T-cell and macrophage-mediated host defense lead to increased infection-related morbidity and mortality in neonates, partly because of immaturity in T helper (Th)1 function. Listeria monocytogenes (Lm) is an intracellular pathogen disproportionately causing severe disease among neonates and the immunocompromised. Intact macrophage and Th1-mediated immune responses are critical for Lm clearance. We and others have previously demonstrated downregulation of Th1 and macrophage immunoregulatory cytokines in cord blood versus adult peripheral blood. We sought to determine whether therapeutic or prophylactic single agent or combination recombinant murine interleukin (rmIL)12, rmIL-18, recombinant murine macrophage-colony stimulating factor (rmM-CSF), recombinant murine granulocyte macrophage-colony stimulating factor (rmGM-CSF) and recombinant murine interferon (rmIFN)-gamma would enhance survival during experimental neonatal Lm sepsis. Methods: A 90% lethal dose (LD90) of Lm was established in C57/BL/6 neonatal mice. rmIL-12, rmIL-18, rmM-CSF, rmGM-CSF and rmIFN-gamma were administered singly or sequentially, before or after LD90 Lm inoculation; ampicillin was administered 24 hours after inoculation. Results: Therapeutic doses of rmIL-12, rmIL-18, rmM-CSF, rmGM-CSF and rmIFN-gamma as single agents and sequential therapy with rmM-CSF + (rmIL-12 and/or rmIL-18) + rmIFN-gamma in addition to ampicillin were not associated with increased survival. However, prophylactic single doses of rmIL-12, rmIL-18, rmM-CSF and rmIFN-gamma and prophylactic sequential doses of rmM-CSF + (rmIL-12 and/or rmIL-18) + rmIFN-gamma in addition to ampicillin were associated with significantly enhanced survival compared with ampicillin alone. Conclusions: These data suggest prophylactic administration of macrophage and Th1 immunoregulatory cytokines can potentially overcome deficits in neonatal immunity to protect against Lm. C1 [Geyer, Mark B.; Cairo, Mitchell S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Radhakrishnan, Kavita] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. [Radhakrishnan, Kavita; Van de Ven, Carmella; Ayello, Janet; Cairo, Mitchell S.] New York Med Coll, Dept Pediat, Valhalla, NY 10595 USA. [Suri, Mandhir S.] Childrens Hosp & Hlth Ctr, Dept Pediat, San Diego, CA USA. [Cairo, Mitchell S.] New York Med Coll, Dept Med, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Pathol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. RP Cairo, MS (reprint author), New York Med Coll, Dept Pediat, 19 Skyline Dr,Room IN D12, Valhalla, NY 10595 USA. EM mitchell_cairo@nymc.edu OI Geyer, Mark/0000-0001-5248-9117 FU Pediatric Cancer Research Foundation (Irvine, CA) FX New York Medical College (PI: M. S. C.) received a grant from the Pediatric Cancer Research Foundation (Irvine, CA) in part to support this work. The authors have no other funding or conflict of interest to disclose. NR 39 TC 0 Z9 1 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD DEC PY 2014 VL 33 IS 12 BP E330 EP E337 DI 10.1097/INF.0000000000000442 PG 8 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA AU2ND UT WOS:000345454300003 PM 24911893 ER PT J AU Mayo-Smith, WW Hara, AK Mahesh, M Sahani, DV Pavlicek, W AF Mayo-Smith, William W. Hara, Amy K. Mahesh, Mahadevappa Sahani, Dushyant V. Pavlicek, William TI How I Do It: Managing Radiation Dose in CT SO RADIOLOGY LA English DT Article ID ITERATIVE RECONSTRUCTION TECHNIQUE; X-RAY CT; COMPUTED-TOMOGRAPHY; BODY CT; MULTIDETECTOR CT; CANCER INCIDENCE; LENGTH PRODUCT; IMAGE QUALITY; ABDOMINAL CT; TUBE VOLTAGE AB Computed tomography (CT) is an imaging test that is widely used worldwide to establish medical diagnoses and perform image-guided interventions. More recently, concern has been raised about the risk of carcinogenesis from medical radiation, with a focus on CT. The purpose of this article is to (a) describe the importance of educating radiology personnel, patients, and referring clinicians about the concerns over CT radiation, (b) describe commonly used CT parameters and radiation units, (c) discuss the importance of establishing a dedicated radiology team to manage CT radiation, and (d) describe specific CT techniques to minimize radiation while providing diagnostic examinations. (C) RSNA, 2014 C1 [Mayo-Smith, William W.] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Dept Radiol, Providence, RI 02903 USA. [Hara, Amy K.; Pavlicek, William] Mayo Clin Arizona, Dept Radiol, Scottsdale, AZ USA. [Mahesh, Mahadevappa] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Sch Med, Baltimore, MD USA. [Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Abdominal Imaging Intervent, Boston, MA 02114 USA. RP Mayo-Smith, WW (reprint author), Brigham & Womens Hosp, Dept Radiol, One Brigham Circle BC-3-010C 11,1620 Tremont St, Boston, MA 02115 USA. EM wmayo-smith@partners.org NR 80 TC 18 Z9 18 U1 2 U2 6 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD DEC PY 2014 VL 273 IS 3 BP 657 EP 672 DI 10.1148/radiol.14132328 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AU3LQ UT WOS:000345515100005 PM 25420167 ER PT J AU Pang, Y Yao, Y Grottkau, B AF Pang, Y. Yao, Y. Grottkau, B. TI Rapid 3D Printing Anatomically Shaped Bone Scaffolds Using Novel Molding and Perfusion Techniques SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Pang, Y.; Yao, Y.; Grottkau, B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 8 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA O-149 BP S13 EP S13 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300042 ER PT J AU Tseng, A Pomerantseva, I Cronce, MJ Kimura, AM Neville, CM Randolph, MA Vacanti, JP Sundback, CA AF Tseng, A. Pomerantseva, I. Cronce, M. J. Kimura, A. M. Neville, C. M. Randolph, M. A. Vacanti, J. P. Sundback, C. A. TI Extensively Expanded Auricular Chondrocytes Form Neocartilage In Vivo SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Tseng, A.; Pomerantseva, I.; Cronce, M. J.; Kimura, A. M.; Neville, C. M.; Randolph, M. A.; Vacanti, J. P.; Sundback, C. A.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA O-589 BP S47 EP S47 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300179 ER PT J AU Zeng, L Leahy, A Esfahani, SA Foote, A Hui, C Rainbow, R Nakamura, D Tracey, B Mahmood, U AF Zeng, L. Leahy, A. Esfahani, S. A. Foote, A. Hui, C. Rainbow, R. Nakamura, D. Tracey, B. Mahmood, U. TI Near Infrared Fluorescence Imaging for Visualizing Cartilage Destructive Activities in 3D Cultured Chondrocytes and in Osteoarthritis SO TISSUE ENGINEERING PART A LA English DT Meeting Abstract CT TERMIS-AM Conference CY DEC 13-16, 2014 CL Washington, DC SP TERMIS AM C1 [Zeng, L.; Leahy, A.; Foote, A.; Hui, C.; Rainbow, R.; Nakamura, D.; Tracey, B.] Tufts Univ, Boston, MA 02111 USA. [Esfahani, S. A.; Mahmood, U.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 EI 1937-335X J9 TISSUE ENG PT A JI Tissue Eng. Part A PD DEC 1 PY 2014 VL 20 SU 1 MA O-570 BP S46 EP S46 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AU6AK UT WOS:000345684300174 ER PT J AU Baker, ME Nelson, RC Rosen, MP Blake, MA Cash, BD Hindman, NM Kamel, IR Kaur, H Piorkowski, RJ Qayyum, A Yarmish, GM AF Baker, Mark E. Nelson, Rendon C. Rosen, Max P. Blake, Michael A. Cash, Brooks D. Hindman, Nicole M. Kamel, Ihab R. Kaur, Harmeet Piorkowski, Robert J. Qayyum, Aliya Yarmish, Gail M. TI ACR Appropriateness Criteria (R) Acute Pancreatitis SO ULTRASOUND QUARTERLY LA English DT Article DE appropriateness criteria; imaging of acute pancreatitis ID TOMOGRAPHY SEVERITY INDEX; REVISED ATLANTA CLASSIFICATION; ACUTE NECROTIZING PANCREATITIS; INTRAVENOUS CONTRAST-MEDIUM; COMPUTED-TOMOGRAPHY; SCORING SYSTEMS; CT; PROGNOSIS; MR; CHOLEDOCHOLITHIASIS AB The American College of Radiology Appropriateness Criteria (R) are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The Atlanta Classification by the Acute Pancreatitis Classification Working Group recently modified the terminology for the clinical course and the morphologic changes identified on imaging, primarily contrast-enhanced multidetector computed tomography (MDCT). The two distinct clinical courses of the disease are classified as (1) early phase, which lasts approximately 1 week, and (2) late phase, which starts after the first week and can last for months after the initial episode. The two, primary, morphologic changes are acute, interstitial edematous and necrotizing pancreatitis. Timing of imaging, primarily MDCT, is based on the clinical phases and is, therefore, important for these imaging guidelines. Ultrasound's role is to detect gallstones after the first episode. MDCT plays a primary role in the management of acutely ill patients, only after a minimum of 48-72 hours and generally after one week. MR plays a supplementary role to MDCT. Follow-up MDCT guides management and therapy: percutaneous aspiration of fluid collections and/or placement of large caliber catheters in infected necrosis. C1 [Baker, Mark E.] Cleveland Clin, Cleveland, OH 44195 USA. [Nelson, Rendon C.] Duke Univ, Med Ctr, Durham, NC USA. [Rosen, Max P.] Univ Massachusetts, Mem Med Ctr, Worcester, MA 01605 USA. [Blake, Michael A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cash, Brooks D.] Univ S Alabama, Mobile, AL 36688 USA. [Cash, Brooks D.] Amer Gastroenterol Assoc, Bethesda, MD USA. [Hindman, Nicole M.] NYU, Med Ctr, New York, NY 10016 USA. [Kamel, Ihab R.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Kaur, Harmeet; Qayyum, Aliya] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Piorkowski, Robert J.] Hartford Hosp, Hartford, CT 06115 USA. [Yarmish, Gail M.] Staten Isl Univ Hosp, Staten Isl, NY USA. RP Baker, ME (reprint author), Cleveland Clin, CWRU, Lerner Coll Med, 9500 Euclid Ave,Desk L10, Cleveland, OH 44195 USA. EM bakerm@ccf.org FU Bracco; Wemoto International; Becton-Dickinson FX Rendon C. Nelson, MD reported "Consultant with GE Healthcare. Research support with Bracco, Wemoto International and Becton-Dickinson." NR 46 TC 6 Z9 6 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-8771 EI 1536-0253 J9 ULTRASOUND Q JI Ultrasound Q. PD DEC PY 2014 VL 30 IS 4 BP 267 EP 273 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AU3RE UT WOS:000345530500004 PM 25364960 ER PT J AU McQuaid, JW Gorman, EF Johnson, EK Cilento, BG AF McQuaid, Joseph W. Gorman, Emily F. Johnson, Emilie K. Cilento, Bartley G. TI Granulomatous Inflammation Masquerading as an Infected Urachal Cyst SO UROLOGY LA English DT Article ID DIAGNOSIS; ANOMALIES; DISEASE AB Errors in urachal obliteration may result in 4 clinical anomalies: patent urachus, urachal cyst, urachal sinus, or vesicourachal diverticulum. Despite the fact that urachal cysts are one of the more common of these anomalies, most go undetected, presenting in the setting of infection. There are reports in the literature of cysts misdiagnosed as other inflammatory processes; however, the converse is reported with less frequency. We present the case of a 3-year-old girl who was admitted to our institution with a suspected urachal cyst. This was subsequently diagnosed as a granulomatous mass caused by the gram negative bacterium Bartonella. (C) 2014 Elsevier Inc. C1 Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Cilento, Bartley G.] Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Urol, Boston, MA 02468 USA. RP Cilento, BG (reprint author), Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Urol, 300 Longwood Ave, Boston, MA 02468 USA. EM bartley.cilento@childrens.harvard.edu NR 14 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD DEC PY 2014 VL 84 IS 6 BP 1496 EP 1498 DI 10.1016/j.urology.2014.08.003 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA AU4KT UT WOS:000345580500075 PM 25432845 ER PT J AU Montironi, R Hammond, EH Lin, DW Gore, JL Srigley, JR Samaratunga, H Egevad, L Rubin, MA Nacey, J Klotz, L Sandler, H Zietman, AL Holden, S Humphrey, PA Evans, AJ Delahunt, B McKenney, JK Berney, D Wheeler, TM Chinnaiyan, A True, L Knudsen, B Epstein, JI Amin, MB AF Montironi, Rodolfo Hammond, Elizabeth H. Lin, Daniel W. Gore, John L. Srigley, John R. Samaratunga, Hema Egevad, Lars Rubin, Mark A. Nacey, John Klotz, Laurence Sandler, Howard Zietman, Anthony L. Holden, Stuart Humphrey, Peter A. Evans, Andrew J. Delahunt, Brett McKenney, Jesse K. Berney, Daniel Wheeler, Thomas M. Chinnaiyan, Arul True, Lawrence Knudsen, Beatrice Epstein, Jonathan I. Amin, Mahul B. TI Consensus statement with recommendations on active surveillance inclusion criteria and definition of progression in men with localized prostate cancer: the critical role of the pathologist SO VIRCHOWS ARCHIV LA English DT Article DE Localized prostate cancer; Low-risk prostate cancer; Active surveillance; Overtreatment; Accurate pathology reporting ID RADICAL PROSTATECTOMY; CONSERVATIVE MANAGEMENT; DISCONTINUOUS FOCI; TUMOR-EXTENT; UPDATE; CORE; MORTALITY; OUTCOMES; LESSONS; TRENDS AB Active surveillance (AS) is an important management option for men with low-risk, clinically localized prostate cancer. The clinical parameters for patient selection and definition of progression for AS protocols are evolving as data from several large cohorts matures. Vital to this process is the critical role pathologic parameters play in identifying appropriate candidates for AS. These findings need to be reproducible and consistently reported by surgical pathologists. This report highlights the importance of accurate pathology reporting as a critical component of these protocols. C1 [Montironi, Rodolfo] Polytechn Univ Marche Reg, Sch Med, United Hosp, Sect Pathol Anat, I-60126 Ancona, Italy. [Hammond, Elizabeth H.] Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT USA. [Lin, Daniel W.; Gore, John L.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Srigley, John R.] Mississauga & McMaster Univ, Trillium Hlth Partners, Hamilton, ON, Canada. [Samaratunga, Hema] Aquesta Pathol & Univ Queensland, Brisbane, Qld, Australia. [Egevad, Lars] Karolinska Univ Hosp, Dept Pathol, Stockholm, Sweden. [Rubin, Mark A.] Cornell Univ, Weill Med Coll, Inst Precis Med, New York, NY 10021 USA. [Rubin, Mark A.] Cornell Univ, Weill Med Coll, Dept Pathol & Lab Med, New York, NY 10021 USA. [Rubin, Mark A.] New York Presbyterian Hosp, New York, NY USA. [Nacey, John] Univ Otago, Wellington Sch Med & Hlth, Dept Surg, Wellington, New Zealand. [Klotz, Laurence] Univ Toronto, Sunnybrook Hlth Sci Ctr, Div Urol, Toronto, ON, Canada. [Sandler, Howard] Cedars Sinai Med Ctr, Dept Radiat Oncol, Los Angeles, CA 90048 USA. [Zietman, Anthony L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Holden, Stuart] Univ Calif Los Angeles, Sch Med, Dept Urol, Los Angeles, CA USA. [Humphrey, Peter A.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Evans, Andrew J.] Univ Toronto, Univ Hlth Network, Toronto, ON, Canada. [Delahunt, Brett] Univ Otago, Wellington Sch Med & Hlth Sci, Dept Pathol & Mol Med, Wellington, New Zealand. [McKenney, Jesse K.] Cleveland Clin Fdn, Pathol & Lab Med Inst, Cleveland, OH 44195 USA. [Berney, Daniel] Royal London Hosp, Dept Cellular Pathol, London E1 1BB, England. [Wheeler, Thomas M.] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Chinnaiyan, Arul] Michigan Ctr Translat Pathol, Ann Arbor, MI USA. [True, Lawrence] Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA. [Knudsen, Beatrice] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Knudsen, Beatrice] Cedars Sinai Med Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90048 USA. [Epstein, Jonathan I.] Johns Hopkins Univ, Sch Med, Dept Pathol Urol & Oncol, Baltimore, MD USA. [Amin, Mahul B.] Cedars Sinai Med Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90048 USA. RP Montironi, R (reprint author), Polytechn Univ Marche Reg, Sch Med, United Hosp, Sect Pathol Anat, Via Conca 71, I-60126 Ancona, Italy. EM r.montironi@univpm.it RI Samaratunga, Hemamali/D-1559-2013; OI Samaratunga, Hemamali/0000-0001-5796-1791; Rubin, Mark/0000-0002-8321-9950; Berney, Daniel/0000-0001-5474-8696 FU College of American Pathologists; International Society of Urologic Pathology; Association of Directors of Anatomic and Surgical Pathology; New Zealand Society of Pathologists; Prostate Cancer Foundation FX This study is supported by The College of American Pathologists, International Society of Urologic Pathology, Association of Directors of Anatomic and Surgical Pathology, The New Zealand Society of Pathologists, and The Prostate Cancer Foundation. NR 25 TC 10 Z9 10 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0945-6317 EI 1432-2307 J9 VIRCHOWS ARCH JI Virchows Arch. PD DEC PY 2014 VL 465 IS 6 BP 623 EP 628 DI 10.1007/s00428-014-1668-5 PG 6 WC Pathology SC Pathology GA AU4RC UT WOS:000345598300001 PM 25316188 ER PT J AU Becker, A Bianchi, M Hansen, J Tian, Z Shariat, SF Popa, I Perrotte, P Trinh, QD Karakiewicz, PI Sun, M AF Becker, Andreas Bianchi, Marco Hansen, Jens Tian, Zhe Shariat, Shahrokh F. Popa, Ioana Perrotte, Paul Quoc-Dien Trinh Karakiewicz, Pierre I. Sun, Maxine TI Benefit in regionalization of care for patients treated with nephrectomy: a Nationwide Inpatient Sample SO WORLD JOURNAL OF UROLOGY LA English DT Article DE Hospital volume; Nephrectomy; Academic; Morbidity; Renal cell carcinoma ID LENGTH-OF-STAY; HOSPITAL VOLUME; RADICAL PROSTATECTOMY; OPERATIVE MORTALITY; CANCER-SURGERY; MEDICAL-CENTERS; HEALTH-CARE; OUTCOMES; COMPLICATIONS; CYSTECTOMY AB To provide in absolute terms a quantification of regionalization of care from low- to high-volume hospitals in patients treated with nephrectomy for non-metastatic renal cell carcinoma. Relying on the Nationwide Inpatient Sample, 48,172 patients with non-metastatic renal cell carcinoma undergoing nephrectomy were identified. All analyses focused on five specific endpoints: intraoperative complications, postoperative complications, blood transfusions, prolonged hospitalization, and in-hospital mortality. First, multivariable logistic regression models for prediction of the aforementioned endpoints were fitted among high-volume hospitals treated patients. Second, obtained coefficients from such models were applied onto low-volume hospitals treated individuals. Potentially avoidable events were computed through differences between observed and predicted adverse events. The number needed to treat was generated. Low-volume hospitals treated individuals were between 11 and 28 % more likely to succumb to an adverse outcome (all P < 0.001). Differences between observed and predicted adverse outcome rates were all in favor of high-volume hospitals, except for in-hospital mortality. Potentially avoidable intraoperative complications, postoperative complications, blood transfusions, prolonged hospitalization, and in-hospital mortality rates were 1.4, 5.6, 7.6, 24.0, and 0.7 %, respectively. Thus, for every 71, 18, 13, 4, and 143 nephrectomies that are redirected to high-volume hospitals, 1 intraoperative complication, postoperative complication, blood transfusion, prolonged hospitalization, and in-hospital mortality could be potentially avoided. Regionalization from low- to high-volume hospitals for patients undergoing a nephrectomy is associated with important benefits, for both the payer and patient's perspectives. C1 [Becker, Andreas; Bianchi, Marco; Hansen, Jens; Tian, Zhe; Popa, Ioana; Perrotte, Paul; Karakiewicz, Pierre I.; Sun, Maxine] Univ Montreal, Canc Prognost & Hlth Outcomes Unit, Ctr Hlth, Montreal, PQ H2X 3J4, Canada. [Becker, Andreas; Hansen, Jens] Prostate Canc Ctr Hamburg Eppendorf, Martini Clin, Hamburg, Germany. [Bianchi, Marco] Univ Vita Salute San Raffaele, Dept Urol, Milan, Italy. [Shariat, Shahrokh F.] Med Univ Vienna, Dept Urol, Vienna, Austria. [Perrotte, Paul; Karakiewicz, Pierre I.] Univ Montreal, Dept Urol, Ctr Hlth, Montreal, PQ H2X 3J4, Canada. [Quoc-Dien Trinh] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Urol Surg,Dana Farber Canc Inst, Boston, MA 02115 USA. RP Becker, A (reprint author), Univ Montreal, Canc Prognost & Hlth Outcomes Unit, Ctr Hlth, 1058 Rue St Denis, Montreal, PQ H2X 3J4, Canada. EM a.becker@uke.de; mcw.sun@umontreal.ca FU University of Montreal Health Center Urology Specialists; Fonds de la Recherche en Sante du Quebec; University of Montreal Department of Surgery; University of Montreal Health Center (CHUM) Foundation FX Pierre I Karakiewicz is partially supported by the University of Montreal Health Center Urology Specialists, Fonds de la Recherche en Sante du Quebec, the University of Montreal Department of Surgery and the University of Montreal Health Center (CHUM) Foundation. NR 30 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-4983 EI 1433-8726 J9 WORLD J UROL JI World J. Urol. PD DEC PY 2014 VL 32 IS 6 BP 1511 EP 1521 DI 10.1007/s00345-014-1256-y PG 11 WC Urology & Nephrology SC Urology & Nephrology GA AU0TD UT WOS:000345336500019 PM 24515596 ER PT J AU Baheti, AD Tirumani, SH Shinagare, AB Rosenthal, MH Hornick, JL Ramaiya, NH Wolpin, BM AF Baheti, Akshay D. Tirumani, Sree Harsha Shinagare, Atul B. Rosenthal, Michael H. Hornick, Jason L. Ramaiya, Nikhil H. Wolpin, Brian M. TI Correlation of CT patterns of primary intrahepatic cholangiocarcinoma at the time of presentation with the metastatic spread and clinical outcomes: retrospective study of 92 patients SO ABDOMINAL IMAGING LA English DT Article DE Intrahepatic cholangiocarcinoma; TNM staging; MDCT; Metastatic spread; Prognosis; Pattern ID PERIPHERAL CHOLANGIOCARCINOMA; ENHANCEMENT PATTERNS; PROGNOSTIC-FACTORS; SURGICAL-TREATMENT; STAGING SYSTEM; CLASSIFICATION; CARCINOMA; MANAGEMENT; DIAGNOSIS; PATHOLOGY AB To study the CT appearance and histopathology of mass-forming intrahepatic cholangiocarcinoma (IHCC) at presentation and correlate these features with metastatic disease and patient survival. In this IRB-approved, HIPAA compliant retrospective study, we reviewed pathology database of 459 patients with cholangiocarcinoma seen from 2004 through 2013 to identify 92 patients with IHCC (48 women, 44 men, mean age 61 years) who had CT scans of primary tumor available for review. All baseline and follow-up CT's were reviewed by two radiologists in consensus to record imaging characteristics and metastatic patterns. Clinical and histopathology data were obtained from electronic medical records. Imaging patterns and histopathology were analyzed for associations with metastatic spread and survival. Three distinct CT patterns of IHCC at presentation were identified: solitary dominant mass (type I IHCC, n = 34), dominant mass with satellite nodules in same segment (type II IHCC, n = 19), and multiple scattered hepatic lesions (type III IHCC, n = 39). Distant metastases developed in 49/92 patients (53%); 39 (42%) of which were present at diagnosis. Lungs (22/92; 24%), peritoneum (17/92; 18%), and bones (13/92; 14%) were most common metastatic sites. Type I IHCC had smaller size, lowest incidence of metastases at presentation, and best overall survival, while type III IHCC had shortest survival (p < 0.017). Poorly differentiated IHCC had higher proportion of osseous metastases (p = 0.042) and worse survival (p = 0.027). IHCC has three distinct CT patterns at presentation with different prognoses. Knowledge of these patterns can help radiologists to detect the extrahepatic disease and predict prognosis. C1 [Baheti, Akshay D.; Tirumani, Sree Harsha; Shinagare, Atul B.; Rosenthal, Michael H.; Ramaiya, Nikhil H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, Boston, MA 02215 USA. [Baheti, Akshay D.; Tirumani, Sree Harsha; Shinagare, Atul B.; Rosenthal, Michael H.; Ramaiya, Nikhil H.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02215 USA. [Hornick, Jason L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. [Wolpin, Brian M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Tirumani, SH (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA. EM stirumani@partners.org RI Rosenthal, Michael/D-4080-2015 NR 35 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 EI 1432-0509 J9 ABDOM IMAGING JI Abdom. Imaging PD DEC PY 2014 VL 39 IS 6 BP 1193 EP 1201 DI 10.1007/s00261-014-0167-0 PG 9 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA AT5SW UT WOS:000345003100008 PM 24869789 ER PT J AU Rosenthal, MH Kim, KW Fuchs, CS Meyerhardt, JA Ramaiya, NH AF Rosenthal, Michael H. Kim, Kyung Won Fuchs, Charles S. Meyerhardt, Jeffrey A. Ramaiya, Nikhil H. TI Relationships between KRAS mutation status and baseline radiographic distribution of disease in patients with stage IV colorectal cancer SO ABDOMINAL IMAGING LA English DT Article DE Colorectal cancer; Diagnostic imaging; KRAS oncogenes ID K-RAS MUTATIONS; MOLECULAR-FEATURES; LIVER METASTASES; CARCINOMA; CETUXIMAB; BRAF; ASSOCIATION; IRINOTECAN AB KRAS oncogene testing is recommended in all patients with metastatic colorectal cancer due to its impact on treatment selection, but we do not know if KRAS genotype affects extent or pattern of metastases. We investigated whether the initial radiographic distribution of disease varies by KRAS genotype in stage IV colorectal cancer. This retrospective study of 65 patients with stage IV colorectal cancer was derived from an institutional clinical trials database. Inclusion criteria required KRAS testing and pretreatment CT studies to be available. Disease burden was characterized by two radiologists. Univariate analysis showed that there was no significant difference in the initial distribution of disease between KRAS mutant and wild type tumors (P > 0.05). Exploratory analyses showed that patients with poorly differentiated histology had a statistically significant increase in hepatic metastases in the presence of KRAS mutations vs. KRAS wild type genotype (median 5.0 vs. 0.5, P = 0.02). No overall difference was found in the initial radiographic distribution of disease between KRAS mutant and wild type colorectal cancers. Patients with both poorly differentiated histology and KRAS mutations had more liver metastases in subgroup analyses. C1 [Rosenthal, Michael H.; Kim, Kyung Won; Ramaiya, Nikhil H.] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02215 USA. [Rosenthal, Michael H.; Kim, Kyung Won; Ramaiya, Nikhil H.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Kim, Kyung Won] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Radiol, Ulsan 680749, South Korea. [Fuchs, Charles S.; Meyerhardt, Jeffrey A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Rosenthal, Michael H.; Kim, Kyung Won; Fuchs, Charles S.; Meyerhardt, Jeffrey A.; Ramaiya, Nikhil H.] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Rosenthal, MH (reprint author), Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA. EM Michael_Rosenthal@dfci.harvard.edu RI Rosenthal, Michael/D-4080-2015 FU National Institutes of Health [5P50CA127003, R01CA149222, R01CA118 553]; National Cancer Institute Cancer Center [5P30CA06516] FX This work was supported in part by National Institutes of Health Grants 5P50CA127003, R01CA149222, R01CA118 553, and National Cancer Institute Cancer Center Support Grant 5P30CA06516. We thank Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Pathology Specimen Locator Core, which provided data on KRAS mutation testing. NR 26 TC 0 Z9 0 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 EI 1432-0509 J9 ABDOM IMAGING JI Abdom. Imaging PD DEC PY 2014 VL 39 IS 6 BP 1261 EP 1266 DI 10.1007/s00261-014-0165-2 PG 6 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA AT5SW UT WOS:000345003100016 PM 24906690 ER PT J AU Crary, JF Trojanowski, JQ Schneider, JA Abisambra, JF Abner, EL Alafuzoff, I Arnold, SE Attems, J Beach, TG Bigio, EH Cairns, NJ Dickson, DW Gearing, M Grinberg, LT Hof, PR Hyman, BT Jellinger, K Jicha, GA Kovacs, GG Knopman, DS Kofler, J Kukull, WA Mackenzie, IR Masliah, E McKee, A Montine, TJ Murray, ME Neltner, JH Santa-Maria, I Seeley, WW Serrano-Pozo, A Shelanski, ML Stein, T Takao, M Thal, DR Toledo, JB Troncoso, JC Vonsattel, JP White, CL Wisniewski, T Woltjer, RL Yamada, M Nelson, PT AF Crary, John F. Trojanowski, John Q. Schneider, Julie A. Abisambra, Jose F. Abner, Erin L. Alafuzoff, Irina Arnold, Steven E. Attems, Johannes Beach, Thomas G. Bigio, Eileen H. Cairns, Nigel J. Dickson, Dennis W. Gearing, Marla Grinberg, Lea T. Hof, Patrick R. Hyman, Bradley T. Jellinger, Kurt Jicha, Gregory A. Kovacs, Gabor G. Knopman, David S. Kofler, Julia Kukull, Walter A. Mackenzie, Ian R. Masliah, Eliezer McKee, Ann Montine, Thomas J. Murray, Melissa E. Neltner, Janna H. Santa-Maria, Ismael Seeley, William W. Serrano-Pozo, Alberto Shelanski, Michael L. Stein, Thor Takao, Masaki Thal, Dietmar R. Toledo, Jonathan B. Troncoso, Juan C. Vonsattel, Jean Paul White, Charles L., III Wisniewski, Thomas Woltjer, Randall L. Yamada, Masahito Nelson, Peter T. TI Primary age-related tauopathy (PART): a common pathology associated with human aging SO ACTA NEUROPATHOLOGICA LA English DT Article DE TPSD; TOD; Braak; Neuropathology; Consensus ID MILD COGNITIVE IMPAIRMENT; NEUROFIBRILLARY TANGLE TYPE; ARGYROPHILIC GRAIN DISEASE; FRONTOTEMPORAL LOBAR DEGENERATION; PAIRED HELICAL FILAMENTS; ONSET ALZHEIMERS-DISEASE; NEUROPATHOLOGICALLY DEFINED SUBTYPES; PARKINSONISM-DEMENTIA COMPLEX; POSTERIOR CORTICAL ATROPHY; APOLIPOPROTEIN-E GENOTYPE AB We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (A beta) plaques. For these "NFT+/A beta-aEuroe brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of A beta accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed. C1 [Crary, John F.; Santa-Maria, Ismael; Shelanski, Michael L.; Vonsattel, Jean Paul] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Crary, John F.; Santa-Maria, Ismael; Shelanski, Michael L.; Vonsattel, Jean Paul] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY 10032 USA. [Trojanowski, John Q.; Toledo, Jonathan B.] Univ Penn, Dept Pathol, Div Neuropathol, Philadelphia, PA 19104 USA. [Schneider, Julie A.] Rush Univ, Med Ctr, Dept Pathol Neuropathol, Chicago, IL 60612 USA. [Schneider, Julie A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Abisambra, Jose F.] Univ Kentucky, Dept Physiol, Lexington, KY 40536 USA. [Abisambra, Jose F.; Abner, Erin L.] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. [Abner, Erin L.] Univ Kentucky, Dept Publ Hlth, Lexington, KY 40536 USA. [Alafuzoff, Irina] Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden. [Arnold, Steven E.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Arnold, Steven E.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Attems, Johannes] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England. [Beach, Thomas G.] Banner Sun Hlth Res Inst, Civin Lab Neuropathol, Sun City, AZ 85351 USA. [Bigio, Eileen H.] Northwestern Univ, Feinberg Sch Med, Northwestern Cognit Neurol & Alzheimer Dis Ctr, Dept Pathol Neuropathol, Chicago, IL 60611 USA. [Cairns, Nigel J.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Dickson, Dennis W.; Murray, Melissa E.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Gearing, Marla] Emory Univ, Sch Med, Dept Pathol & Lab Med Neuropathol, Atlanta, GA 30322 USA. [Grinberg, Lea T.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94110 USA. [Grinberg, Lea T.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94110 USA. [Grinberg, Lea T.] Univ Sao Paulo, Dept Pathol, Sao Paulo, Brazil. [Hof, Patrick R.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY 10029 USA. [Hof, Patrick R.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Hyman, Bradley T.] Harvard Univ, Sch Med, Dept Neurol, Charlestown, MA 02129 USA. [Hyman, Bradley T.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Jellinger, Kurt] Inst Clin Neurobiol, A-1070 Vienna, Austria. [Jicha, Gregory A.] Univ Kentucky, Dept Neurol, Lexington, KY 40536 USA. [Jicha, Gregory A.] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. [Kovacs, Gabor G.] Med Univ Vienna, Inst Neurol, A-1090 Vienna, Austria. [Knopman, David S.] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Kofler, Julia] Univ Pittsburgh, Med Ctr, Dept Pathol Neuropathol, Pittsburgh, PA 15213 USA. [Kukull, Walter A.] Univ Washington, Dept Epidemiol, Seattle, WA 98104 USA. [Mackenzie, Ian R.] Univ British Columbia, Dept Pathol, Vancouver, BC V5Z 1M9, Canada. [Masliah, Eliezer] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Masliah, Eliezer] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [McKee, Ann] Boston Univ, Dept Pathol Neuropathol, Boston, MA 02118 USA. [Montine, Thomas J.] Univ Washington, Dept Pathol, Seattle, WA 98104 USA. [Neltner, Janna H.] Univ Kentucky, Dept Pathol, Lexington, KY 40536 USA. [Seeley, William W.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Seeley, William W.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Serrano-Pozo, Alberto] Univ Iowa Hosp & Clin, Dept Neurol, Iowa City, IA 52242 USA. [Stein, Thor] VA Med Ctr, Dept Pathol Neuropathol, Boston, MA 02118 USA. [Stein, Thor] Boston Univ, Sch Med, Boston, MA 02118 USA. [Takao, Masaki] Tokyo Metropolitan Geriatr Hosp, Dept Neuropathol, Tokyo 1730015, Japan. [Thal, Dietmar R.] Univ Ulm, Neuropathol Lab, D-89081 Ulm, Germany. [Troncoso, Juan C.] Univ Penn, Perelman Sch Med, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med,Inst Aging, Philadelphia, PA 19104 USA. [White, Charles L., III] Univ Texas Southwestern Med Sch, Dept Pathol Neuropathol, Dallas, TX 75390 USA. [Wisniewski, Thomas] NYU, Sch Med, Dept Neurol, New York, NY 10016 USA. [Wisniewski, Thomas] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Wisniewski, Thomas] NYU, Sch Med, Dept Psychiat, New York, NY 10016 USA. [Woltjer, Randall L.] Oregon Hlth & Sci Univ, Dept Pathol L113, Portland, OR 97239 USA. [Yamada, Masahito] Kanazawa Univ, Grad Sch Med Sci, Dept Neurol, Kanazawa, Ishikawa 9208640, Japan. [Yamada, Masahito] Kanazawa Univ, Grad Sch Med Sci, Dept Neurobiol Aging, Kanazawa, Ishikawa 9208640, Japan. [Nelson, Peter T.] Univ Kentucky, Dept Pathol Neuropathol, Lexington, KY 40536 USA. [Nelson, Peter T.] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. RP Crary, JF (reprint author), Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY 10032 USA. EM john.crary@mountsinai.org; pnels2@email.uky.edu RI Attems, Johannes/B-8368-2015; Murray, Melissa/C-2763-2015; Kovacs, Gabor/A-7468-2013; OI Murray, Melissa/0000-0001-7379-2545; Kovacs, Gabor/0000-0003-3841-5511; grinberg, lea/0000-0002-6809-0618; Kukull, Walter/0000-0001-8761-9014; Toledo, Jon/0000-0003-4366-9268; SERRANO-POZO, ALBERTO/0000-0003-0899-7530; Wisniewski, Thomas/0000-0002-3379-8966 FU Society for Supporting Research in Experimental Neurology, Vienna, Austria, National Institutes of Health [P50AG08702, R01 AG037212, P01AG07232, P30 AG028383, P50 AG005138, P50 AG016574, U01 AG006786, R01 AG041851, R01 AG011378]; Medical Research Council (MRC) [G0400074]; National Institute for Health Research (NIHR) [R:CH/ML/0712]; Dunhill Medical Trust [R173/1110]; Alzheimer's Research UK (ARUK); Alzheimer's Society [AS-PG-2013-011]; Louis V. Gerstner, Jr., Foundation; Alzheimer's Association [NIRG-11-204450, NIRGD-12-242642]; FP7 EU Project Develage [278486]; Comprehensive brain research network [26430060]; Daiwa Health Science Foundation; BrightFocus Foundation; Alzheimer Forschung Initiative (AFI) [13803]; German Ministry for Research and Education (BMBF) FTLD-Net; Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation; Society for Supporting Research in Experimental Neurology, Vienna, Austria, National Institutes of Health. [P01 AG003949, P30 AG012300, P50 AG005146, P50 AG005136, P50 AG025688, P01 AG002219, P50 AG005133, P50 AG005681, P01 AG003991, R01 AG038651, P30 AG019610, P30 AG013854, P30 AG036453, P30 AG010124, AG005131, AG184440, AG008051] FX We are extremely grateful to the patients, clinicians, and fellow researchers that made this effort possible. We also acknowledge the following funding sources: the Society for Supporting Research in Experimental Neurology, Vienna, Austria, National Institutes of Health Grants P50AG08702, R01 AG037212, P01AG07232, P30 AG028383, P50 AG005138, P50 AG016574, U01 AG006786, R01 AG041851, R01 AG011378, P30 AG028383, P50 AG016574, P01 AG003949, P30 AG012300, P50 AG005146, P50 AG005136, P50 AG025688, P50 AG005138, P01 AG002219, P50 AG005133, P50 AG005681, P01 AG003991, R01 AG038651, P30 AG019610, P30 AG013854, P30 AG036453, P30 AG010124, AG005131, AG184440, AG008051, Medical Research Council (MRC, G0400074), National Institute for Health Research (NIHR, R:CH/ML/0712), the Dunhill Medical Trust (R173/1110), Alzheimer's Research UK (ARUK), and the Alzheimer's Society (AS-PG-2013-011), Louis V. Gerstner, Jr., Foundation, Alzheimer's Association (NIRG-11-204450), FP7 EU Project Develage (No. 278486), Comprehensive brain research network, Grant-in-Aid for Scientific Research (C; 26430060), and Daiwa Health Science Foundation, BrightFocus Foundation, Alzheimer's Association NIRGD-12-242642, Alzheimer Forschung Initiative (AFI # 13803) (DRT); German Ministry for Research and Education (BMBF) FTLD-Net, Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation. NR 153 TC 164 Z9 165 U1 8 U2 40 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD DEC PY 2014 VL 128 IS 6 BP 755 EP 766 DI 10.1007/s00401-014-1349-0 PG 12 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA AT7TC UT WOS:000345139100001 PM 25348064 ER PT J AU Berghoff, AS Bartsch, R Wohrer, A Streubel, B Birner, P Kros, JM Brastianos, PK von Deimling, A Preusser, M AF Berghoff, Anna Sophie Bartsch, Rupert Woehrer, Adelheid Streubel, Berthold Birner, Peter Kros, Johan M. Brastianos, Priscilla K. von Deimling, Andreas Preusser, Matthias TI Predictive molecular markers in metastases to the central nervous system: recent advances and future avenues SO ACTA NEUROPATHOLOGICA LA English DT Review DE Brain metastases; Cancer; Biomarkers; Prediction; Review ID CELL LUNG-CANCER; HER2-POSITIVE BREAST-CANCER; CLINICAL-PRACTICE GUIDELINES; MUTATION-POSITIVE MELANOMA; BRAIN METASTASES; OPEN-LABEL; FOLLOW-UP; ADJUVANT CHEMOTHERAPY; TARGETED THERAPIES; EGFR MUTATIONS AB Metastases to the central nervous system (CNS) are common in several cancer types. For most primary tumors that commonly metastasize to the CNS, molecular biomarker analyses are recommended in the clinical setting for selection of appropriate targeted therapies. Therapeutic efficacy of some of these agents has been documented in patients with brain metastases, and molecular testing of CNS metastases should be considered in the clinical setting. Here, we summarize the clinically relevant biomarker tests that should be considered in neurosurgical specimens based on the current recommendations of the European Society of Medical Oncology (ESMO) or the National Comprehensive Cancer Network (NCCN) for the most relevant primary tumor types: lung cancer (EGFR mutations, ALK rearrangement, BRAF mutations), breast cancer (HER2 amplification, steroid receptor overexpression), melanoma (BRAF mutations), and colorectal cancer (RAS mutations). Furthermore, we discuss emerging therapeutic targets including novel oncogenic alterations (ROS1 rearrangements, FGFR1 amplifications, CMET amplifications, and others) and molecular features of the tumor microenvironment (including immune-checkpoint molecules such as CTLA4 and PD-1/PD-L1). We also discuss the potential role of advanced biomarker tests such as next-generation sequencing and "liquid biopsies" for patients with CNS metastases. C1 [Berghoff, Anna Sophie; Bartsch, Rupert; Preusser, Matthias] Med Univ Vienna, Dept Med 1, A-1090 Vienna, Austria. [Berghoff, Anna Sophie; Bartsch, Rupert; Woehrer, Adelheid; Streubel, Berthold; Birner, Peter; Preusser, Matthias] Med Univ Vienna, Comprehens Canc Ctr Vienna, A-1090 Vienna, Austria. [Woehrer, Adelheid] Med Univ Vienna, Inst Neurol, Vienna, Austria. [Streubel, Berthold] Med Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria. [Birner, Peter] Med Univ Vienna, Clin Inst Pathol, Vienna, Austria. [Kros, Johan M.] Erasmus MC, Dept Pathol, Rotterdam, Netherlands. [von Deimling, Andreas] Heidelberg Univ, Dept Neuropathol, Heidelberg, Germany. [von Deimling, Andreas] DKFZ, Clin Cooperat Unit Neuropathol, Heidelberg, Germany. [von Deimling, Andreas] DKTK, Heidelberg, Germany. [Brastianos, Priscilla K.] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Boston, MA 02114 USA. [Brastianos, Priscilla K.] Harvard Univ, Sch Med, Boston, MA USA. RP Preusser, M (reprint author), Med Univ Vienna, Dept Med 1, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. EM matthias.preusser@meduniwien.ac.at RI von Deimling, Andreas/F-7774-2013; OI von Deimling, Andreas/0000-0002-5863-540X; Brastianos, Priscilla/0000-0003-4470-8425; Preusser, Matthias/0000-0003-3541-2315 NR 99 TC 10 Z9 10 U1 0 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD DEC PY 2014 VL 128 IS 6 BP 879 EP 891 DI 10.1007/s00401-014-1350-7 PG 13 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA AT7TC UT WOS:000345139100011 PM 25287912 ER PT J AU Ostergaard, SD Fava, M Rothschild, AJ Deligiannidis, KM AF Ostergaard, S. D. Fava, M. Rothschild, A. J. Deligiannidis, K. M. TI The implications of the National Institute of Mental Health Research Domain Criteria for researchers and clinicians SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Editorial Material ID PERSONALIZED MEDICINE; UNCOMPLICATED DEPRESSION; PRECISION MEDICINE; RDOC FRAMEWORK; PSYCHIATRY; PSYCHOPATHOLOGY; VALIDITY C1 [Ostergaard, S. D.] Aarhus Univ Hosp, Res Dept P, Risskov, Denmark. [Ostergaard, S. D.] Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Aarhus, Denmark. [Fava, M.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Rothschild, A. J.; Deligiannidis, K. M.] Univ Massachusetts, Sch Med, Dept Psychiat, Ctr Psychopharmacol Res & Treatment, Worcester, MA 01655 USA. [Rothschild, A. J.; Deligiannidis, K. M.] UMassMem Hlth Care, Worcester, MA USA. RP Ostergaard, SD (reprint author), Aarhus Univ Hosp, Res Dept P, Risskov, Denmark. EM soeoes@rm.dk RI Deligiannidis, Kristina/C-3654-2014; OI Deligiannidis, Kristina/0000-0001-7439-2236; Ostergaard, Soren Dinesen/0000-0002-8032-6208 FU NIMH NIH HHS [K23 MH097794, L30 MH104713] NR 27 TC 3 Z9 3 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-690X EI 1600-0447 J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD DEC PY 2014 VL 130 IS 6 BP 409 EP 414 DI 10.1111/acps.12331 PG 6 WC Psychiatry SC Psychiatry GA AT8TJ UT WOS:000345204500001 PM 25201294 ER PT J AU Flash, CA Stone, VE Mitty, JA Mimiaga, MJ Hall, KT Krakower, D Mayer, KH AF Flash, Charlene A. Stone, Valerie E. Mitty, Jennifer A. Mimiaga, Matthew J. Hall, Kathryn T. Krakower, Douglas Mayer, Kenneth H. TI Perspectives on HIV Prevention Among Urban Black Women: A Potential Role for HIV Pre-Exposure Prophylaxis SO AIDS PATIENT CARE AND STDS LA English DT Article ID AFRICAN-AMERICAN WOMEN; INTIMATE PARTNER VIOLENCE; CONSISTENT CONDOM USE; VAGINAL MICROBICIDE; DOMESTIC VIOLENCE; FOCUS GROUPS; HIGH-RISK; ACCEPTABILITY; TRIAL; YOUNG AB Limited data exist regarding attitudes and acceptability of topical and oral HIV pre-exposure prophylaxis (PrEP) among US black women. This investigation explored interest in HIV chemoprophylaxis and modes of use. Five focus groups enrolled 26 black women recruited from an inner-city community health center and affiliated HIV testing sites. Thematic analysis utilized Atlas.ti. Most women expressed interest in PrEP, as many reported condom failure concerns. Most women preferred a pill formulation to intravaginal gel because of greater perceived privacy and concerns about vaginal side effects and gel leakage. Women who had taken pills previously advocated daily dosing and indicated adherence concerns about episodic or post-coital PrEP. Many women desired prophylactic strategies that included partner testing. Urban black women are interested in utilizing PrEP; however, misgivings exist about gel inconvenience and potential side effects for themselves and their partners. Most women preferred oral PrEP, dosed daily. C1 [Flash, Charlene A.] Baylor Coll Med, Dept Med, Div Infect Dis, Houston, TX 77030 USA. [Stone, Valerie E.] Harvard Univ, Sch Med, Dept Med, Div Gen Med,Mt Auburn Hosp, Boston, MA USA. [Stone, Valerie E.] Harvard Univ, Sch Med, Dept Med, Div Infect Dis,Mt Auburn Hosp, Boston, MA USA. [Mitty, Jennifer A.; Krakower, Douglas; Mayer, Kenneth H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Infect Dis, Boston, MA 02215 USA. [Hall, Kathryn T.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Mitty, Jennifer A.; Mimiaga, Matthew J.; Mayer, Kenneth H.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Mimiaga, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Hall, Kathryn T.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Flash, CA (reprint author), Baylor Coll Med, Dept Med, 1 Baylor Plaza,BCM 286,Room N1317, Houston, TX 77030 USA. EM Charlene.Flash@bcm.edu FU AMA Foundation FX We would like to acknowledge the AMA Foundation for providing grant support for this research, the Dimock Community Health Center, Marguerite Gunning for transcription, and Rose Closson for help coordinating this study. NR 50 TC 5 Z9 5 U1 2 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 EI 1557-7449 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD DEC 1 PY 2014 VL 28 IS 12 BP 635 EP 642 DI 10.1089/apc.2014.0003 PG 8 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AU4FI UT WOS:000345564900004 PM 25295393 ER PT J AU Nishihara, R Wang, ML Qian, ZR Baba, Y Yamauchi, M Mima, K Sukawa, Y Kim, SA Inamura, K Zhang, XH Wu, KN Giovannucci, EL Chan, AT Fuchs, CS Ogino, S Schernhammer, ES AF Nishihara, Reiko Wang, Molin Qian, Zhi Rong Baba, Yoshifumi Yamauchi, Mai Mima, Kosuke Sukawa, Yasutaka Kim, Sun A. Inamura, Kentaro Zhang, Xuehong Wu, Kana Giovannucci, Edward L. Chan, Andrew T. Fuchs, Charles S. Ogino, Shuji Schernhammer, Eva S. TI Alcohol, one-carbon nutrient intake, and risk of colorectal cancer according to tumor methylation level of IGF2 differentially methylated region SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE molecular pathological epidemiology; biomarker; epigenetics; imprinting; one carbon metabolism ID MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; FACTOR-II GENE; DNA METHYLATION; COLON-CANCER; FOLATE; HYPOMETHYLATION; EXPRESSION; METABOLISM; METHIONINE; VITAMIN-B-6 AB Background: Although a higher consumption of alcohol, which is a methyl-group antagonist, was previously associated with colorectal cancer risk, mechanisms remain poorly understood. Objective: We hypothesized that excess alcohol consumption might increase risk of colorectal carcinoma with hypomethylation of insulin-like growth factor 2 (IGF2) differentially methylated region-0 (DMR0), which was previously associated with a worse prognosis. Design: With the use of a molecular pathologic epidemiology database in 2 prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association between alcohol intake and incident colorectal cancer according to the tumor methylation level of IGF2 DMR0. Duplication-method Cox proportional cause-specific hazards regression for competing risk data were used to compute HRs and 95% CIs. In addition, we investigated intakes of vitamin B-6, vitamin B-12, methionine, and folate as exposures. Results: During 3,206,985 person-years of follow-up, we identified 993 rectal and colon cancer cases with an available tumor DNA methylation status. Compared with no alcohol consumption, the consumption of >= 15 g alcohol/d was associated with elevated risk of colorectal cancer with lower levels of IGF2 DMR0 methylation [within the first and second quartiles: HRs of 1.55 (95% CI: 1.08, 2.24) and 2.11(95% CI: 1.44, 3.07), respectively]. By contrast, alcohol consumption was not associated with cancer with higher levels of IGF2 DMR0 methylation. The association between alcohol and cancer risk differed significantly by IGF2 DMR0 methylation level (P-heterogeneity = 0.006). The association of vitamin B-6, vitamin B-12, and folate intakes with cancer risk did not significantly differ according to IGF2 DMR0 methylation level (P-heterogeneity > 0.2). Conclusions: Higher alcohol consumption was associated with risk of colorectal cancer with IGF2 DMR0 hypomethylation but not risk of cancer with high-level IGF2 DMR0 methylation. The association between alcohol intake and colorectal cancer risk may differ by tumor epigenetic features. C1 [Nishihara, Reiko; Qian, Zhi Rong; Yamauchi, Mai; Mima, Kosuke; Sukawa, Yasutaka; Kim, Sun A.; Inamura, Kentaro; Fuchs, Charles S.; Ogino, Shuji] Harvard Univ, Sch Publ Hlth, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Nishihara, Reiko; Wang, Molin; Qian, Zhi Rong; Yamauchi, Mai; Mima, Kosuke; Sukawa, Yasutaka; Kim, Sun A.; Inamura, Kentaro; Zhang, Xuehong; Wu, Kana; Giovannucci, Edward L.; Chan, Andrew T.; Fuchs, Charles S.; Ogino, Shuji; Schernhammer, Eva S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Nishihara, Reiko; Wu, Kana; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Wang, Molin; Giovannucci, Edward L.; Ogino, Shuji; Schernhammer, Eva S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wang, Molin] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Wang, Molin; Zhang, Xuehong; Wu, Kana; Giovannucci, Edward L.; Chan, Andrew T.; Fuchs, Charles S.; Schernhammer, Eva S.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Baba, Yoshifumi] Kumamoto Univ, Grad Sch Med Sci, Dept Surg Gastroenterol, Kumamoto, Japan. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Schernhammer, Eva S.] Appl Canc Res Inst Translat Res Vienna, Vienna, Austria. RP Nishihara, R (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Dept Med Oncol,Dana Farber Canc Inst, 665 Huntington Ave,Bldg 2,Room 304, Boston, MA 02115 USA. EM rnishiha@hsph.harvard.edu; shuji_ogino@dfci.harvard.edu FU NIH [P01 CA87969, P01 CA55075, UM1 CA167552, K07CA190673, P50 CA127003, R01 CA137178, R01 CA151993]; Bennett Family Fund; Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance; Asan Medical Center; Japan Society for Promotion of Sciences; Takashi Tsuruo Memorial Fund; Uehara Memorial Foundation FX Supported by NIH grants (P01 CA87969 to SEH; P01 CA55075 and UM1 CA167552 to WCW; K07CA190673 to RN; P50 CA127003 to CSF; R01 CA137178 to ATC; and R01 CA151993 to SO), a grant from the Bennett Family Fund and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance, and postdoctoral fellowships from the Asan Medical Center (to SAK), the Japan Society for Promotion of Sciences (to KI), the Takashi Tsuruo Memorial Fund (to KI), and the Uehara Memorial Foundation (to KM). ATC is a Damon Runyon Clinical Investigator. NR 55 TC 4 Z9 7 U1 0 U2 16 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2014 VL 100 IS 6 BP 1479 EP 1488 DI 10.3945/ajcn.114.095539 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AT9SZ UT WOS:000345267600011 PM 25411283 ER PT J AU Rao, LKF Gilbertson, JR AF Rao, Luigi K. F. Gilbertson, John R. TI Longitudinal Engagement of Pathology Residents A Proposed Approach for Informatics Training SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Informatics; Pathology residency; Training; Education; Laboratory management ID UTILIZATION MANAGEMENT; PROGRAMS; ERA AB Objectives: The intersecting of pathology training and practice and the utilization of information technology has become an increasingly common occurrence, and the most effective means of teaching residents informatics during these invaluable years has yet to be firmly established. Methods: In offering the idea of longitudinal engagement that stresses early and extended trainee involvement, we attempt to provide a different manner of helping address some of the leading time-limited issues surrounding education in informatics. Results: The proposed model is intended to allow building off a base of fundamentals reached through introductory didactics, exposure to and active participation in departmental and hospital-wide administrative bodies, refining of initial skills gained through frequent mentoring and coaching, and combining these cumulative knowledge and experiential underpinnings with graduated responsibility in a particular area of expertise. Conclusions: In transforming the ways in which pathology residencies teach their trainees informatics, the prospects of realizing its potential utility are heightened. C1 [Rao, Luigi K. F.; Gilbertson, John R.] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. RP Rao, LKF (reprint author), Walter Reed Natl Mil Med Ctr, Dept Pathol, Arrowhead Bldg Rm 810,8901 Rockville Pike, Bethesda, MD 20889 USA. EM LuigiRao@alumni.nd.edu NR 27 TC 3 Z9 3 U1 0 U2 1 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD DEC PY 2014 VL 142 IS 6 BP 748 EP 754 DI 10.1309/AJCPWJ61RERWEDIK PG 7 WC Pathology SC Pathology GA AT6MZ UT WOS:000345053900005 PM 25389327 ER PT J AU Courville, EL Sohani, AR Hasserjian, RP Zukerberg, LR Harris, NL Ferry, JA AF Courville, Elizabeth L. Sohani, Aliyah R. Hasserjian, Robert P. Zukerberg, Lawrence R. Harris, Nancy L. Ferry, Judith A. TI Diverse Clinicopathologic Features in Human Herpesvirus 8-Associated Lymphomas Lead to Diagnostic Problems SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE HHV8 lymphoma; Human herpesvirus 8; Extracavitary primary effusion lymphoma; Plasmablastic microlymphoma; Germinotropic lymphoproliferative disorder; Primary effusion lymphoma; Multicentric Castleman disease ID PRIMARY-EFFUSION-LYMPHOMA; SARCOMA-ASSOCIATED HERPESVIRUS; GERMINOTROPIC LYMPHOPROLIFERATIVE DISORDER; MULTICENTRIC CASTLEMANS-DISEASE; B-CELL LYMPHOMA; KAPOSIS-SARCOMA; DNA-SEQUENCES; PLASMABLASTIC MICROLYMPHOMA; VIRUS; HIV AB Objectives: Human herpesvirus 8 (HHV8)-associated lymphomas are uncommon, mainly affect men infected with the human immunodeficiency virus (HIV), and usually have a poor prognosis. We sought to characterize the HHV8+ lymphomas seen at our institution since the mid-1990s. Methods: We identified 15 patients with HHV8-associated lymphomas and evaluated their clinical and pathologic features. Results: Diagnoses included primary effusion lymphoma (PEL) (n = 2), extracavitaiy PEL (n = 8), intravascular large B-cell lymphoma (n = 1), HHV8+ plasmablastic microlymphoma (n = 3), and germinotropic lymphoproliferative disorder (GLD) (n = I). The case of GLD progressed to a high-grade HHV8+ Epstein-Barr virus positive lymphoma, an evolution that has not been previously reported. Four patients were HIV-(three from an HHV8-endemic area). Potentially misleading pathologic features in our series of extracavitary PEL included classic Hodgkin lymphoma like features, lymph node sinus involvement, and T-cell antigen expression. Conclusions: HHV8-associated lymphomas can be clinically and pathologically heterogeneous, with features that may lead to misdiagnosis as other types of lymphoma. C1 [Courville, Elizabeth L.; Sohani, Aliyah R.; Hasserjian, Robert P.; Zukerberg, Lawrence R.; Harris, Nancy L.; Ferry, Judith A.] Harvard Univ, Sch Med, James Homer Wright Pathol Labs, Massachusetts Gen Hosp,Dept Pathol, Boston, MA 02115 USA. RP Courville, EL (reprint author), Univ Minnesota, Dept Lab Med & Pathol, 420 Delaware St SE MMC 609, Minneapolis, MN 55455 USA. EM ecourvil@umn.edu NR 42 TC 7 Z9 7 U1 0 U2 2 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD DEC PY 2014 VL 142 IS 6 BP 816 EP 829 DI 10.1309/AJCPULI3W6WUGGPY PG 14 WC Pathology SC Pathology GA AT6MZ UT WOS:000345053900014 PM 25389336 ER PT J AU Starkstein, SE Dragovic, M Dujardin, K Marsh, L Martinez-Martin, P Pontone, GM Richard, IH Weintraub, D Leentjens, AFG AF Starkstein, Sergio E. Dragovic, Milan Dujardin, Kathy Marsh, Laura Martinez-Martin, Pablo Pontone, Gregory M. Richard, Irene H. Weintraub, Daniel Leentjens, Albert F. G. TI Anxiety Has Specific Syndromal Profiles in Parkinson Disease: A Data-Driven Approach SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Parkinson disease; anxiety; depression; diagnosis; phenomenology ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; PSYCHOMETRIC PROPERTIES; RATING-SCALES; DSM-IV; DISORDERS; DEPRESSION; MINI; COMORBIDITY; PREVALENCE; VALIDATION AB Background: Anxiety symptoms are common in Parkinson disease (PD). Recent evidence suggests that anxiety syndromes as encountered in clinical practice may not correspond to the DSM-IV classification of anxiety disorders. Objective: To examine the syndromal pattern of the anxiety spectrum in a large series of patients with PD, as determined with a data-driven approach using latent class analysis (LCA). Methods: 342 patients with PD were recruited from referrals to movement disorders or psychiatry clinics at six tertiary centers. Participants were assessed with a structured psychiatric interview and specific scales rating the severity of anxiety, depression, cognition and parkinsonism. The main outcome measure was classes of patients with a specific syndromal profile of anxiety symptoms based on LCA. Results: LCA identified four classes that were interpreted as "no anxiety or depression", "episodic anxiety without depression", "persistent anxiety with depression", and "both persistent and episodic anxiety with depression". Symptoms of persistent anxiety were almost invariably associated with symptoms of depression. There were significant differences between classes in terms of history of depression and anxiety, use of psychoactive medication, and on the Mentation and Complications sections of the Unified Parkinson Disease Rating Scale. Conclusions: Patients with PD show different syndromic profiles of anxiety that do not align with the symptom profiles represented by DSM-IV anxiety disorders and major depression. Accordingly, DSM-IV criteria for anxiety disorders may not be clinically useful in PD. The different classes identified here provide empirically validated phenotypes for future research. C1 [Starkstein, Sergio E.; Dragovic, Milan] Univ Western Australia, Sch Psychiat & Clin Neurosci, Fremantle, WA, Australia. [Starkstein, Sergio E.; Dragovic, Milan] Fremantle Hosp, Fremantle, WA 6959, Australia. [Dujardin, Kathy] Univ Lille 2, Lab Neurosci Fonct & Pathol, Lille, France. [Marsh, Laura] Mental Hlth Care Line, Michael E DeBakey Vet Adm Med Ctr, Houston, TX USA. [Marsh, Laura] Baylor Coll Med, Menninger Dept Psychiat, Houston, TX 77030 USA. [Martinez-Martin, Pablo] Alzheimer Ctr Reina Sofia Fdn, Madrid, Spain. [Martinez-Martin, Pablo] Carlos III Inst Hlth, Consortium Biomed Res Neurodegenerat Dis CIBERNED, Madrid, Spain. [Pontone, Gregory M.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Richard, Irene H.] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. [Richard, Irene H.] Univ Rochester, Sch Med & Dent, Dept Psychiat, Rochester, NY 14642 USA. [Weintraub, Daniel] Univ Penn, Pereleman Sch Med, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia VA Med Ctr, Parkinson Dis & Mental Illness Clin Res & Educ Ct, Philadelphia, PA USA. [Leentjens, Albert F. G.] Maastricht Univ, Med Ctr, Dept Psychiat, Maastricht, Netherlands. RP Starkstein, SE (reprint author), Fremantle Hosp, Educ Bldg T-7, Fremantle, WA 6959, Australia. EM sergio.starkstein@uwa.edu.au NR 25 TC 9 Z9 9 U1 4 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD DEC PY 2014 VL 22 IS 12 BP 1410 EP 1417 DI 10.1016/j.jagp.2013.09.006 PG 8 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AT7LO UT WOS:000345118500005 PM 24200594 ER PT J AU Lin, F Roiland, R Polesskaya, O Chapman, B Johnson, M Brasch, J Chen, DG Mapstone, M AF Lin, Feng Roiland, Rachel Polesskaya, Oksana Chapman, Benjamin Johnson, Melissa Brasch, Judith Chen, Ding-Geng Mapstone, Mark TI Fatigability Disrupts Cognitive Processes' Regulation of Inflammatory Reactivity in Old Age SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Fatigability; aging; attention; speed of processing; executive function; interleukin-6 reactivity ID ACUTE PSYCHOLOGICAL STRESS; SOCIOECONOMIC-STATUS; ASSESS FATIGUE; INTERLEUKIN-6; ADULTS; RESPONSES; BRAIN; METAANALYSIS; CYTOKINES; MARKERS AB Objective: High fatigability, a dysfunctional adaption to fatigue, may lead to difficulties performing otherwise regularly encountered cognitive activities and may be related to pro-inflammatory reactivity. The purpose of the study was to investigate the effect of fatigability on cognitive processes and inflammatory response after an acute cognitive stress task in older adults. Methods: In an observational stress reactivity study conducted in a light-and temperature-controlled laboratory, we measured IL-6, self-reported acute fatigue, and frontally oriented cognitive processes in 55 community-dwelling individuals aged 75 years or older as part of a demanding set of cognitive tasks intended to induce stress. Results: Subjects were classified into groups of low and high fatigability based on cluster analysis of their self-report acute fatigue before and after the cognitive tasks. The two clusters were comparable on levels of baseline IL-6 and cognitive processes; however, the high fatigability cluster had significantly higher levels of IL-6 response than the low fatigability cluster. After controlling for multiple covariates, fatigability moderated the relationship between speed of processing and IL-6 reactivity. Further exploratory analyses indicated significant adverse associations between speed of processing and attention and IL-6 reactivity in the group with low but not high fatigability. Conclusion: Although observational, these data are consistent with the notion that pro-inflammatory states in older adults might be reduced by improvements in cognitive processes. Because fatigability was associated with increased acute inflammatory response and disrupted the normal stress regulation provided by the cognitive processes, future randomized studies might examine whether fatigability alleviation reduces IL-6. C1 [Lin, Feng; Polesskaya, Oksana; Johnson, Melissa; Brasch, Judith; Chen, Ding-Geng] Univ Rochester, Sch Nursing, Rochester, NY 14414 USA. [Lin, Feng; Chapman, Benjamin] Univ Rochester, Sch Med & Dent, Dept Psychiat, Rochester, NY 14414 USA. [Polesskaya, Oksana] Univ Rochester, Sch Med & Dent, Dept Microbiol & Immunol, Rochester, NY 14414 USA. [Chen, Ding-Geng] Univ Rochester, Sch Med & Dent, Dept Biostat & Computat Biol, Rochester, NY 14414 USA. [Mapstone, Mark] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14414 USA. [Roiland, Rachel] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Lin, F (reprint author), Univ Rochester, Med Ctr, HWH 2w128,601 Elmwood Ave, Rochester, NY 14414 USA. EM vankee_lin@urmc.rochester.edu FU University of Rochester CTSA award from the National Center for Advancing Translational Sciences of the National Institutes of Health [KL2 TR000095]; [K08AG031328]; [R01AG044588] FX Data collection of the present project was supported by Sigma Theta Tau International Small Grants (to FL). The manuscript preparation of the project was supported by the University of Rochester CTSA award number KL2 TR000095 from the National Center for Advancing Translational Sciences of the National Institutes of Health (to FL) and K08AG031328 and R01AG044588 (to BC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. government, or the Department of Veterans Affairs. NR 52 TC 0 Z9 0 U1 2 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD DEC PY 2014 VL 22 IS 12 BP 1544 EP 1554 DI 10.1016/j.jagp.2013.12.003 PG 11 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AT7LO UT WOS:000345118500020 PM 24388221 ER PT J AU Donovan, NJ Amariglio, RE Zoller, AS Rudel, RK Gomez-Isla, T Blacker, D Hyman, BT Locascio, JJ Johnson, KA Sperling, RA Marshall, GA Rentz, DM AF Donovan, Nancy J. Amariglio, Rebecca E. Zoller, Amy S. Rudel, Rebecca K. Gomez-Isla, Teresa Blacker, Deborah Hyman, Bradley T. Locascio, Joseph J. Johnson, Keith A. Sperling, Reisa A. Marshall, Gad A. Rentz, Dorene M. TI Subjective Cognitive Concerns and Neuropsychiatric Predictors of Progression to the Early Clinical Stages of Alzheimer Disease SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Neuropsychiatric and neuropsychological factors; subjective cognitive concerns; mild cognitive impairment; Alzheimer disease ID LATE-LIFE DEPRESSION; PRIMARY-CARE PATIENTS; MEMORY COMPLAINTS; INCIDENT DEMENTIA; OLDER-ADULTS; RISK-FACTORS; PRE-MCI; IMPAIRMENT; SYMPTOMS; DECLINE AB Objective: To examine neuropsychiatric and neuropsychological predictors of progression from normal to early clinical stages of Alzheimer disease (AD). Methods: From a total sample of 559 older adults from the Massachusetts Alzheimer's Disease Research Center longitudinal cohort, 454 were included in the primary analysis: 283 with clinically normal cognition (CN), 115 with mild cognitive impairment (MCI), and 56 with subjective cognitive concerns (SCC) but no objective impairment, a proposed transitional group between CN and MCI. Two latent cognitive factors (memory-semantic, attention-executive) and two neuropsychiatric factors (affective, psychotic) were derived from the Alzheimer's Disease Centers' Uniform Data Set neuropsychological battery and Neuropsychiatric Inventory brief questionnaire. Factors were analyzed as predictors of time to progression to a worse diagnosis using a Cox proportional hazards regression model with backward elimination. Covariates included baseline diagnosis, gender, age, education, prior depression, antidepressant medication, symptom duration, and interaction terms. Results: Higher/better memory-semantic factor score predicted lower hazard of progression (hazard ratio [HR] = 0.4 for 1 standard deviation [SD] increase, p < 0.0001), and higher/worse affective factor score predicted higher hazard (HR = 1.3 for one SD increase, p = 0.01). No other predictors were significant in adjusted analyses. Using diagnosis as a sole predictor of transition to MCI, the SCC diagnosis carried a fourfold risk of progression compared with CN (HR = 4.1, p < 0.0001). Conclusion: These results identify affective and memory-semantic factors as significant predictors of more rapid progression from normal to early stages of cognitive decline and highlight the subgroup of cognitively normal elderly with SCC as those with elevated risk of progression to MCI. C1 [Donovan, Nancy J.; Amariglio, Rebecca E.; Johnson, Keith A.; Sperling, Reisa A.; Marshall, Gad A.; Rentz, Dorene M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Alzheimer Res & Treatment, Boston, MA 02115 USA. [Donovan, Nancy J.; Amariglio, Rebecca E.; Johnson, Keith A.; Sperling, Reisa A.; Marshall, Gad A.; Rentz, Dorene M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Donovan, Nancy J.; Amariglio, Rebecca E.; Rentz, Dorene M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Amariglio, Rebecca E.; Gomez-Isla, Teresa; Hyman, Bradley T.; Locascio, Joseph J.; Sperling, Reisa A.; Marshall, Gad A.; Rentz, Dorene M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Zoller, Amy S.; Rudel, Rebecca K.; Blacker, Deborah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Johnson, Keith A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Donovan, Nancy J.; Rudel, Rebecca K.; Gomez-Isla, Teresa; Blacker, Deborah; Hyman, Bradley T.; Locascio, Joseph J.; Johnson, Keith A.; Sperling, Reisa A.; Marshall, Gad A.; Rentz, Dorene M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Massachusetts Alzheimers Dis Res Ctr, Boston, MA USA. RP Donovan, NJ (reprint author), Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, 221 Longwood Ave,BL 104H, Boston, MA 02115 USA. EM njdonovan@partners.org FU National Institute of Aging (NIA) grants [R03 AG045080, R01 AG027435, K23 AG033634, K24 AG035007]; Dupont-Warren/Livingston Fellowships; Harvard Medical School; Massachusetts Alzheimer's Disease Research Center [P50 AG005134]; Harvard Aging Brain Study [NIA P01 AGO36694]; National Institute of Aging grant [U01 AG016976] FX This study was supported by National Institute of Aging (NIA) grants R03 AG045080, R01 AG027435, K23 AG033634, and K24 AG035007; the Dupont-Warren/Livingston Fellowships; Harvard Medical School; the Massachusetts Alzheimer's Disease Research Center (P50 AG005134); and the Harvard Aging Brain Study (NIA P01 AGO36694). The National Alzheimer's Coordinating Center database is funded by National Institute of Aging grant U01 AG016976. NR 48 TC 21 Z9 21 U1 4 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD DEC PY 2014 VL 22 IS 12 BP 1642 EP 1651 DI 10.1016/j.jagp.2014.02.007 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AT7LO UT WOS:000345118500030 PM 24698445 ER PT J AU Hoang, TD Byers, AL Barnes, DE Yaffe, K AF Hoang, Tina D. Byers, Amy L. Barnes, Deborah E. Yaffe, Kristine TI Alcohol Consumption Patterns and Cognitive Impairment in Older Women SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Cognitive impairment; dementia; alcohol ID DRINKING PATTERNS; LATE-LIFE; ADULTS; RISK; DEMENTIA AB Objective: Few studies have investigated changes in alcohol consumption and risk of cognitive impairment among oldest old adults. Methods: In a prospective study of 1309 women >= 65 years old, alcohol use was assessed at repeated visits and used to estimate average change in alcohol consumption over 16 years. Clinically significant cognitive impairment (mild cognitive impairment and dementia) was assessed at year 20. Results: Compared with the reference group (slight decrease in alcohol consumption by 0-0.5 drinks/week, 60.4%), increasing consumption over time (>0 drinks/week) was not associated with risk of cognitive impairment (5.0%, odds ratio [OR]: 1.00, 95% confidence interval [CI]: 0.54-1.85). Decreasing consumption by >0.5 drinks/week was associated with increased risk (34.5%, OR: 1.34, 95% CI: 1.05-1.70). Adjustment for age, education, diabetes, smoking, BMI, and physical activity attenuated the magnitude of the effect slightly and resulted in borderline statistical significance. Conclusion: Women in their ninth and tenth decade of life who decrease alcohol use may be at risk of cognitive impairment. C1 [Hoang, Tina D.] Northern Calif Inst Res & Educ, San Francisco, CA USA. [Byers, Amy L.; Barnes, Deborah E.; Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. RP Hoang, TD (reprint author), 4150 Clement St,VAMC 116-H, San Francisco, CA 94121 USA. EM tina.hoang@va.gov FU National Institutes of Health funding; National Institute on Aging (NIA) [R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576, R01 AG026720]; NIA [AG026720, K24 AG031155]; Independent Investigator Award from the Alzheimer's Association; National Institute on Aging [R01 AG026720]; National Institute of Mental Health [R01 MH086498]; National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK069406]; Department of Defense; Department of Veterans Affairs; BrightFocus Foundation; National Institutes of Health; Department of Defense grant [W81XWH-11-2-0189]; National Institute on Minority Health and Health Disparities grant [R01 MD007019]; Department of Veterans Affairs Mental Illness Research, Educational, and Clinical Center; National Institutes of Health [R01 AG045043]; Department of Defense [W81XWH-11-2-0189]; Brain and Behavior Research Foundation; Department of Veterans Affairs [REA 01-097, 1IO1HX000694]; UCB Pharma; S.D. Bechtel, Jr., Foundation; philanthropic fund of the Osher Center for Integrative Medicine FX The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576, and R01 AG026720. In addition, this study was supported by NIA AG026720.; Dr. Kristine Yaffe is supported in part by NIA grant K24 AG031155 and an Independent Investigator Award from the Alzheimer's Association. She has also received grants from National Institute on Aging R01 AG026720, the National Institute of Mental Health R01 MH086498, National Institute of Diabetes and Digestive and Kidney Diseases R01 DK069406, Department of Defense, Department of Veterans Affairs, and the BrightFocus Foundation. She serves on data safety monitoring boards for Takeda, Inc., and a study sponsored by the National Institutes of Health and has served as a consultant for Novartis, Inc., and Pfizer.; Dr. Byers is supported by a Department of Defense grant (W81XWH-11-2-0189) and a National Institute on Minority Health and Health Disparities grant (R01 MD007019), which are administered by the Northern California Institute for Research and Education and with resources of the San Francisco Veterans Affairs Medical Center. In addition, she is supported in part by the Department of Veterans Affairs Mental Illness Research, Educational, and Clinical Center.; Dr. Barnes is supported in part by research grants from the National Institutes of Health R01 AG045043 Department of Defense (W81XWH-11-2-0189), Brain and Behavior Research Foundation (formerly NARSAD), Department of Veterans Affairs (REA 01-097, 1IO1HX000694), UCB Pharma, the S.D. Bechtel, Jr., Foundation, and the philanthropic fund of the Osher Center for Integrative Medicine. NR 18 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD DEC PY 2014 VL 22 IS 12 BP 1663 EP 1667 DI 10.1016/j.jagp.2014.04.006 PG 5 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AT7LO UT WOS:000345118500032 PM 24862680 ER PT J AU Mascarinas, AL Newman, JS Warner, JJP Jain, NB AF Mascarinas, Angelie L. Newman, Joel S. Warner, Jon J. P. Jain, Nitin B. TI Ultrasound of the Pectoralis Major Muscle After Reverse Shoulder Arthroplasty A Case Report SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Pectoralis Major Muscle Atrophy; Ultrasound; Reverse Shoulder Arthroplasty ID INJURIES; TEARS AB Only a few reports exist in the literature for sonographic assessment of the pectoralis major muscle. Presented is a case of pectoralis major muscle atrophy as a cause of persistent internal rotation weakness diagnosed via ultrasound in a patient with multiple previous surgeries and contraindication to magnetic resonance imaging because of a shoulder implant. This patient's physical examination suggested an abnormal contour of the pectoralis major muscle on contraction, so he was referred for diagnostic ultrasound. The ultrasound was key to guiding the management of this patient because surgical repair of a torn pectoralis major muscle was planned if this was found. No pectoralis major tear or rupture was seen on ultrasound, but there was evidence of pectoralis major muscle atrophy. Accordingly, surgery was avoided and the patient was able to continue with his physical therapy program. C1 [Mascarinas, Angelie L.] Harvard Univ, Med Sch, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Charlestown, MA USA. [Newman, Joel S.] New England Baptist Hosp, Dept Radiol, Boston, MA USA. [Warner, Jon J. P.] Massachusetts Gen Hosp, Dept Orthopaed, Boston, MA 02114 USA. [Jain, Nitin B.] Vanderbilt Univ, Med Ctr, Dept Phys Med & Rehabil, Nashville, TN USA. RP Mascarinas, AL (reprint author), Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, 300 First Ave, Charlestown, MA 02129 USA. FU NIH; Foundation for PMR; Biomedical Research Institute [K23AR059199] FX Supported by NIH, Foundation for PM&R, Biomedical Research Institute (grant K23AR059199). This outside source of funds was not involved in data collection, data analysis, or the preparation or editing of the manuscript. NR 12 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 EI 1537-7385 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD DEC PY 2014 VL 93 IS 12 BP E9 EP E14 DI 10.1097/PHM.0000000000000197 PG 6 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA AU0TS UT WOS:000345338100001 PM 25251253 ER PT J AU Eisen, SV Schultz, MR Glickman, ME Vogt, D Martin, JA Osei-Bonsu, PE Drainoni, ML Elwy, R AF Eisen, Susan V. Schultz, Mark R. Glickman, Mark E. Vogt, Dawne Martin, James A. Osei-Bonsu, Princess E. Drainoni, Mari-Lynn Elwy, Rani TI Postdeployment Resilience as a Predictor of Mental Health in Operation Enduring Freedom/Operation Iraqi Freedom Returnees SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; NATIONAL COMORBIDITY SURVEY; GULF-WAR VETERANS; SOCIAL SUPPORT; PSYCHOLOGICAL-RESILIENCE; SCREENING-TEST; ZONE STRESS; HARDINESS; AFGHANISTAN; SYMPTOMS AB Background: Much of the research on the impact of trauma exposure among veterans has focused on factors that increase risk for mental health problems. Fewer studies have investigated factors that may prevent mental health problems following trauma exposure. This study examines resilience variables as factors that may prevent subsequent mental health problems. Purpose: To determine whether military service members returning from Afghanistan and Iraq who exhibit higher levels of resilience, including hardiness (encompassing control, commitment, and challenge), self-efficacy, and social support after returning from deployment are less vulnerable to subsequent mental health problems, alcohol, and drug use. Methods: A national sample of 512 service members was surveyed between 3 and 12 months of return from deployment and 6-12 months later. Data were collected in 2008-2009 and analyzed in 2013. Regression analyses ascertained whether resilience 3-12 months after return predicted later mental health and substance problems, controlling for demographic characteristics, mental health, and risk factors, including predeployment stressful events, combat exposure, and others. Results: Greater hardiness predicted several indicators of better mental health and lower levels of alcohol use 6-12 months later, but did not predict subsequent posttraumatic stress symptom severity. Postdeployment social support predicted better overall mental health and less posttraumatic stress symptom severity, alcohol, and drug use. Conclusions: Some aspects of resilience after deployment appear to protect returning service members from the negative effects of traumatic exposure, suggesting that interventions to promote and sustain resilience after deployment have the potential to enhance the mental health of veterans. (C) 2014 American Journal of Preventive Medicine. All rights reserved. C1 [Eisen, Susan V.; Schultz, Mark R.; Glickman, Mark E.; Drainoni, Mari-Lynn; Elwy, Rani] Edith Nourse Rogers Mem Vet Adm Hosp, Ctr Healthcare Org & Implementat Res, Bedford, MA 01730 USA. [Eisen, Susan V.; Glickman, Mark E.; Drainoni, Mari-Lynn; Elwy, Rani] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Vogt, Dawne] Boston Univ, Sch Med, Div Psychiat, Boston, MA 02118 USA. [Vogt, Dawne] Vet Affairs Boston Healthcare Syst, Natl Ctr Posttraumat Stress Disorder, Womens Hlth Sci Div, Boston, MA USA. [Martin, James A.] Bryn Mawr Coll, Bryn Mawr, PA 19010 USA. [Osei-Bonsu, Princess E.] Minneapolis Vet Adm Hlth Care Syst, Ctr Chron Dis Outcomes Res & Polytrauma & Blast R, Minneapolis, MN USA. RP Eisen, SV (reprint author), Edith Nourse Rogers Mem Vet Adm Hosp, Ctr Healthcare Org & Implementat Res, 200 Springs Rd 152, Bedford, MA 01730 USA. EM susan.eisen@va.gov FU Veterans Administration Health Services Research and Development (HSRD) [JAG 06-259-2]; Center for Healthcare Organization and Implementation Research; National Center for Post-traumatic Stress Disorder Women's Health Sciences Division FX This research was funded by the Veterans Administration Health Services Research and Development (HSR&D) Grant No. JAG 06-259-2, the Center for Healthcare Organization and Implementation Research, and the National Center for Post-traumatic Stress Disorder Women's Health Sciences Division. NR 58 TC 2 Z9 2 U1 3 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2014 VL 47 IS 6 BP 754 EP 761 DI 10.1016/j.amepre.2014.07.049 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AT9RP UT WOS:000345264200007 PM 25455117 ER PT J AU Hagen, CE Kamionek, M McKinsey, DS Misdraji, J AF Hagen, Catherine E. Kamionek, Michal McKinsey, David S. Misdraji, Joseph TI Syphilis Presenting as Inflammatory Tumors of the Liver in HIV-positive Homosexual Men SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE syphilis; T. pallidum; inflammatory pseudotumor; HIV; liver; immunohistochemistry ID SECONDARY SYPHILIS; INFECTED PATIENTS; TERTIARY SYPHILIS; HEPATIC SYPHILIS; INVOLVEMENT; LESIONS; SEX; DISEASE; STATES AB Syphilis, a sexually transmitted infection caused by the spirochete Treponema pallidum, has seen a resurgence since 2001, particularly in men who have sex with men. Syphilis can affect the liver during the secondary stage as syphilitic hepatitis and during the tertiary stage as gummas. We describe 3 cases of syphilis in human immunodeficiency virus-positive homosexual men that presented as hepatic mass lesions clinically suspected of being malignant tumors. Histologically, 2 of the 3 cases showed a plump spindle cell proliferation, mixed inflammatory infiltrate with numerous neutrophils, and abscesses, whereas the third case showed granulomas and pericholangitis/cholangitis. Immunohistochemical staining for T. pallidum showed innumerable organisms in 2 of the cases. Pathologists must be aware of the possibility of syphilis causing hepatic inflammatory masses in human immunodeficiency virus-positive men who have sex with men in order to avoid misdiagnosis or delayed treatment. C1 [Hagen, Catherine E.; Misdraji, Joseph] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hagen, Catherine E.; Misdraji, Joseph] Harvard Univ, Sch Med, Boston, MA USA. [Kamionek, Michal] Carolinas Med Ctr, Carolinas Pathol Grp, Charlotte, NC 28203 USA. [McKinsey, David S.] Infect Dis Associates Kansas City, Kansas City, MO USA. RP Misdraji, J (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 105, Boston, MA 02114 USA. EM jmisdraji@partners.org NR 36 TC 3 Z9 3 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD DEC PY 2014 VL 38 IS 12 BP 1636 EP 1643 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA AT7QD UT WOS:000345131700007 PM 24921640 ER PT J AU Shi, M Roemer, MGM Chapuy, B Liao, XY Sun, H Pinkus, GS Shipp, MA Freeman, GJ Rodig, SJ AF Shi, Min Roemer, Margaretha G. M. Chapuy, Bjoern Liao, Xiaoyun Sun, Heather Pinkus, Geraldine S. Shipp, Margaret A. Freeman, Gordon J. Rodig, Scott J. TI Expression of Programmed Cell Death 1 Ligand 2 (PD-L2) Is a Distinguishing Feature of Primary Mediastinal (Thymic) Large B-cell Lymphoma and Associated With PDCD1LG2 Copy Gain SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE PD-1; PD-L2; primary mediastinal large B-cell lymphoma; diffuse large B-cell lymphoma; PDCD1LG2 ID INTEGRATIVE ANALYSIS REVEALS; HODGKIN LYMPHOMA; MARKER; ACTIVATION; INDUCTION; CANCER; AMPLIFICATION; DIAGNOSIS; RECURRENT; ANTIBODY AB Primary mediastinal (thymic) large B-cell lymphoma (PMBL) and diffuse large B-cell lymphoma (DLBCL) are tumors with distinct clinical and molecular characteristics that are difficult to distinguish by histopathologic and phenotypic analyses alone. Programmed cell death 1 ligand 2 (PD-L2) is a cell surface protein expressed by activated macrophages and dendritic cells that binds PD-1 on T cells to inhibit immune responses. Amplification and/or translocations involving chromosome 9p24.1, a region that includes PDCD1LG2-encoding PD-L2, is a common event in PMBL but not DLBCL and suggests that PD-L2 expression might be a distinguishing feature of PMBL. We developed an assay for the immunohistochemical detection of PD-L2 protein in fixed biopsy specimens (PD-L2 IHC), which we applied to a cohort of PMBLs and DLBCLs. For a subset of cases, we correlated the results of PD-L2 IHC with PDCD1LG2 copy number (CN) as determined by quantitative polymerase chain reaction. Twenty-three of 32 (72%) PMBLs but only 1 of 37 (3%) DLBCLs were positive by PD-L2 IHC. Among PMBLs with PDCD1LG2 CN gain, all were positive by PD-L2 IHC. One PMBL without CN gain was positive by PD-L2 IHC. When expressed in PMBL, PD-L2 was restricted to tumor cells and not detected on intra-tumoral macrophages. We conclude that PD-L2 protein is robustly expressed by the majority of PMBLs but only rare DLBCLs and often associated with PDCD1LG2 copy gain. PD-L2 IHC may serve as a useful ancillary test for distinguishing PMBL from DLBCL and for the rational selection of patients for therapeutic antibodies that inhibit PD-1 signaling. C1 [Shi, Min; Liao, Xiaoyun; Sun, Heather; Pinkus, Geraldine S.; Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Roemer, Margaretha G. M.; Chapuy, Bjoern; Shipp, Margaret A.; Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Rodig, SJ (reprint author), Brigham & Womens Hosp, Dept Pathol, Amory 3rd Floor,75 Francis St, Boston, MA 02115 USA. EM srodig@partners.org FU DFCI Center for Immune Oncology; Specialized Center of Research (SCOR) grant from the Leukemia and Lymphoma Society; NIH [AI56299, U19AI082630, HHSN27220110001, U54CA163125]; [R01 CA161026] FX Financially supported, in part, by the following: DFCI Center for Immune Oncology (S.J.R.), R01 CA161026 (M.A.S.), a Specialized Center of Research (SCOR) grant from the Leukemia and Lymphoma Society (M. A. S.; S.J.R.), and NIH grants AI56299, U19AI082630, HHSN27220110001, and U54CA163125 (G.J.F.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. NR 37 TC 29 Z9 29 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD DEC PY 2014 VL 38 IS 12 BP 1715 EP 1723 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA AT7QD UT WOS:000345131700017 PM 25025450 ER PT J AU Yamada, Y Ochiai, T Boskovic, S Nadazdin, O Oura, T Schoenfeld, D Cappetta, K Smith, RN Colvin, RB Madsen, JC Sachs, DH Benichou, G Cosimi, AB Kawai, T AF Yamada, Y. Ochiai, T. Boskovic, S. Nadazdin, O. Oura, T. Schoenfeld, D. Cappetta, K. Smith, R. -N. Colvin, R. B. Madsen, J. C. Sachs, D. H. Benichou, G. Cosimi, A. B. Kawai, T. TI Use of CTLA4Ig for Induction of Mixed Chimerism and Renal Allograft Tolerance in Nonhuman Primates SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Basic (laboratory) research; science; bone marrow; hematopoietic stem cell transplantation; kidney transplantation; nephrology; tolerance: chimerism; tolerance: costimulation blockade; tolerance: experimental ID BONE-MARROW-TRANSPLANTATION; ANTI-CD154 MONOCLONAL-ANTIBODY; CYNOMOLGUS MONKEYS; MAINTENANCE IMMUNOSUPPRESSION; HEMATOPOIETIC CHIMERISM; COSTIMULATORY BLOCKADE; CONDITIONING REGIMEN; CLONAL DELETION; RHESUS MACAQUE; PHASE-III AB We have previously reported successful induction of renal allograft tolerance via a mixed chimerism approach in nonhuman primates. In those studies, we found that costimulatory blockade with anti-CD154 mAb was an effective adjunctive therapy for induction of renal allograft tolerance. However, since anti-CD154 mAb is not clinically available, we have evaluated CTLA4Ig as an alternative agent for effecting costimulation blockade in this treatment protocol. Two CTLA4Igs, abatacept and belatacept, were substituted for anti-CD154 mAb in the conditioning regimen (low dose total body irradiation, thymic irradiation, anti-thymocyte globulin and a 1-month posttransplant course of cyclosporine [CyA]). Three recipients treated with the abatacept regimen failed to develop comparable lymphoid chimerism to that achieved with anti-CD154 mAb treatment and these recipients rejected their kidney allografts early. With the belatacept regimen, four of five recipients developed chimerism and three of these achieved long-term renal allograft survival (>861, >796 and >378 days) without maintenance immunosuppression. Neither chimerism nor long-term allograft survival were achieved in two recipients treated with the belatacept regimen but with a lower, subtherapeutic dose of CyA. This study indicates that CD28/B7 blockade with belatacept can provide a clinically applicable alternative to anti-CD154 mAb for promoting chimerism and renal allograft tolerance. This study shows that belatacept promotes induction of mixed chimerism and renal allograft tolerance in nonhuman primates. C1 [Yamada, Y.; Ochiai, T.; Boskovic, S.; Nadazdin, O.; Oura, T.; Cappetta, K.; Madsen, J. C.; Benichou, G.; Cosimi, A. B.; Kawai, T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplant Ctr,Dept Surg, Boston, MA 02163 USA. [Schoenfeld, D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Biostat, Boston, MA USA. [Smith, R. -N.; Colvin, R. B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [Sachs, D. H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplant Biol Res Ctr, Boston, MA USA. RP Kawai, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplant Ctr,Dept Surg, Boston, MA 02163 USA. EM tkawai@partners.org FU NIH [AI102405-01, PO-1 HL 18646-25]; Bristol Myers Squib FX This study was supported in part by NIH AI102405-01, PO-1 HL 18646-25 and a research fund provided by Bristol Myers Squib. We thank Ms. Susan Shea for technical assistance. Part of this study was conducted by research fund provided by Bristol Myers Squib. NR 44 TC 14 Z9 15 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2014 VL 14 IS 12 BP 2704 EP 2712 DI 10.1111/ajt.12936 PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA AU0DR UT WOS:000345294300008 PM 25394378 ER PT J AU Tena, A Kurtz, J Leonard, DA Dobrinsky, JR Terlouw, SL Mtango, N Verstegen, J Germana, S Mallard, C Arn, JS Sachs, DH Hawley, RJ AF Tena, A. Kurtz, J. Leonard, D. A. Dobrinsky, J. R. Terlouw, S. L. Mtango, N. Verstegen, J. Germana, S. Mallard, C. Arn, J. S. Sachs, D. H. Hawley, R. J. TI Transgenic Expression of Human CD47 Markedly Increases Engraftment in a Murine Model of Pig-to-Human Hematopoietic Cell Transplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Animal models: nonhuman primate; animal models: porcine; basic (laboratory) research; science; immunosuppression; immune modulation; tolerance: chimerism; xenotransplantation ID NONLETHAL PREPARATIVE REGIMEN; BONE-MARROW-TRANSPLANTATION; RENAL-ALLOGRAFT TOLERANCE; LARGE-ANIMAL-MODEL; MIXED CHIMERISM; XENOGRAFT REJECTION; XENOGENEIC BARRIER; CYNOMOLGUS MONKEYS; NUCLEAR TRANSFER; GENE-EXPRESSION AB Mixed chimerism approaches for induction of tolerance of solid organ transplants have been applied successfully in animal models and in the clinic. However, in xenogeneic models (pig-to-primate), host macrophages participate in the rapid clearance of porcine hematopoietic progenitor cells, hindering the ability to achieve mixed chimerism. CD47 is a cell-surface molecule that interacts in a species-specific manner with SIRP receptors on macrophages to inhibit phagocytosis and expression of human CD47 (hCD47) on porcine cells has been shown to inhibit phagocytosis by primate macrophages. We report here the generation of hCD47 transgenic GalT-KO miniature swine that express hCD47 in all blood cell lineages. The effect of hCD47 expression on xenogeneic hematopoietic engraftment was tested in an in vivo mouse model of human hematopoietic cell engraftment. High-level porcine chimerism was observed in the bone marrow of hCD47 progenitor cell recipients and smaller but readily measurable chimerism levels were observed in the peripheral blood of these recipients. In contrast, transplantation of WT progenitor cells resulted in little or no bone marrow engraftment and no detectable peripheral chimerism. These results demonstrate a substantial protective effect of hCD47 expression on engraftment and persistence of porcine cells in this model, presumably by modulation of macrophage phagocytosis. The authors demonstrate that hematopoietic stem and progenitor cells from transgenic swine expressing human CD47 show increased engraftment in a mouse model of pig-to-human hematopoietic cell transplantation, suggesting that this genetic modification may provide a helpful addition to protocols designed toward inducing tolerance of pig-to-primate xenotransplants through mixed chimerism. C1 [Tena, A.; Kurtz, J.; Leonard, D. A.; Germana, S.; Mallard, C.; Arn, J. S.; Sachs, D. H.; Hawley, R. J.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. [Kurtz, J.] Emmanuel Coll, Dept Biol, Boston, MA USA. [Dobrinsky, J. R.; Terlouw, S. L.; Mtango, N.; Verstegen, J.] Minitube Amer, Mt Horeb, WI USA. RP Hawley, RJ (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. EM rhawley1@partners.org FU NIH/NIAID [5R42AI082853, 2P01AI45897]; NIH [C06 RR020135-01] FX We wish to acknowledge Richard Koppang, Angelo Leto Barone, Harrison Powell and Nicole Turcotte for expert cloning, surgical and technical assistance. We are grateful to Lucia Maria Madariaga and Christene Huang for comments on the manuscript and Rebecca Brophy for editorial assistance. This research was supported by grants NIH/NIAID 5R42AI082853, NIH/NIAID 2P01AI45897 and NIH C06 RR020135-01 (MGH Swine Facility). NR 49 TC 8 Z9 9 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2014 VL 14 IS 12 BP 2713 EP 2722 DI 10.1111/ajt.12918 PG 10 WC Surgery; Transplantation SC Surgery; Transplantation GA AU0DR UT WOS:000345294300009 PM 25278264 ER PT J AU Winston, DJ Limaye, AP Pelletier, S Safdar, N Morris, MI Meneses, K Busuttil, RW Singh, N AF Winston, D. J. Limaye, A. P. Pelletier, S. Safdar, N. Morris, M. I. Meneses, K. Busuttil, R. W. Singh, N. TI Randomized, Double-Blind Trial of Anidulafungin Versus Fluconazole for Prophylaxis of Invasive Fungal Infections in High-Risk Liver Transplant Recipients SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Clinical research; practice; fungal; infection and infectious agents; infectious disease ID AMPHOTERICIN-B; ANTIFUNGAL PROPHYLAXIS; CELL TRANSPLANTATION; OPEN-LABEL; MICAFUNGIN; CANDIDA; ASPERGILLOSIS; PREVENTION; ECHINOCANDIN; ITRACONAZOLE AB Invasive fungal infections (IFIs) are a common complication in liver transplant recipients. There are no previous randomized trials of an echinocandin for the prevention of IFIs in solid organ transplant recipients. In a randomized, double-blind trial conducted at University-affiliated transplant centers, 200 high-risk liver transplant recipients (100 patients per group) received either anidulafungin or fluconazole for antifungal prophylaxis. Randomization was stratified by Model for End-Stage Liver Disease score 30 and receipt of a pretransplant antifungal agent. The primary end point was IFI in a modified intent-to-treat analysis. The overall incidence of IFI was similar for the anidulafungin (5.1%) and the fluconazole groups (8.0%) (OR 0.61, 95% CI 0.19-1.94, p=0.40). However, anidulafungin prophylaxis was associated with less Aspergillus colonization or infection (3% vs. 9%, p=0.08), lower breakthrough IFIs among patients who had received pretransplant fluconazole (0% vs. 27%, p=0.07), and fewer cases of antifungal resistance (no cases vs. 5 cases). Both drugs were well-tolerated. Graft rejection, fungal-free survival, and mortality were similar for both groups. Thus, anidulafungin and fluconazole have similar efficacy for antifungal prophylaxis in most liver transplant recipients. Anidulafungin may be beneficial if the patient has an increased risk for Aspergillus infection or received fluconazole before transplantation. This randomized, double-blind trial shows that anidulafungin and fluconazole have similar efficacy for antifungal prophylaxis in most liver transplant recipients at high risk for invasive fungal infections, although anidulafungin may be beneficial for patients who have an increased risk for Aspergillus infection or received fluconazole before transplantation. See editorial by Huprikar on page . C1 [Winston, D. J.; Meneses, K.; Busuttil, R. W.] Univ Calif Los Angeles, Med Ctr, Dept Surg, Los Angeles, CA 90024 USA. [Limaye, A. P.] Univ Washington, Dept Med, Seattle, WA USA. [Pelletier, S.] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. [Safdar, N.] Univ Wisconsin, Dept Med, Madison, WI USA. [Morris, M. I.] Univ Miami, Dept Med, Miami, FL USA. [Singh, N.] VA Pittsburgh Healthcare Syst, Dept Med, Pittsburgh, PA 15261 USA. [Singh, N.] Univ Pittsburgh, Pittsburgh, PA USA. RP Singh, N (reprint author), VA Pittsburgh Healthcare Syst, Dept Med, Pittsburgh, PA 15261 USA. EM nis5@pitt.edu FU Pfizer, Inc. [GA8851MQ] FX We thank Marilyn Wagener, MPH, for statistical analyses. We are also grateful to the transplant physicians and nurses for their assistance and care of the patients during the study. The study was supported by an Investigator-Initiated Research Grant from Pfizer, Inc. (GA8851MQ). The sponsor had no role in the design and conduct of the study, data collection, analysis and interpretation of the data orpreparation of the manuscript. The study was registered at ClinicalTrials.gov #NCT00841971. NR 33 TC 13 Z9 13 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2014 VL 14 IS 12 BP 2758 EP 2764 DI 10.1111/ajt.12963 PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA AU0DR UT WOS:000345294300013 PM 25376267 ER PT J AU Clavien, PA Lillemoe, KD AF Clavien, Pierre-Alain Lillemoe, Keith D. TI A New Policy to Implement CONSORT Guidelines for Surgical Randomized Controlled Trials SO ANNALS OF SURGERY LA English DT Editorial Material ID STATEMENT; QUALITY C1 [Clavien, Pierre-Alain] Univ Zurich Hosp, Dept Surg & Transplantat, CH-8091 Zurich, Switzerland. [Lillemoe, Keith D.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Clavien, PA (reprint author), Univ Zurich Hosp, Dept Surg & Transplantat, Ramistr 100, CH-8091 Zurich, Switzerland. EM clavien@access.uzh.ch NR 11 TC 7 Z9 7 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD DEC PY 2014 VL 260 IS 6 BP 947 EP 948 DI 10.1097/SLA.0000000000001057 PG 2 WC Surgery SC Surgery GA AT8ZJ UT WOS:000345217200001 PM 25386861 ER PT J AU Cooper, Z Courtwright, A Karlage, A Gawande, A Block, S AF Cooper, Zara Courtwright, Andrew Karlage, Ami Gawande, Atul Block, Susan TI Pitfalls in Communication That Lead to Nonbeneficial Emergency Surgery in Elderly Patients With Serious Illness Description of the Problem and Elements of a Solution SO ANNALS OF SURGERY LA English DT Article DE critical care; end-of-life care; shared decision making; structured communication; surgical emergencies ID INTENSIVE-CARE-UNIT; LIFE-SUSTAINING CARE; HIGH-RISK OPERATIONS; DECISION-MAKING; ADVANCE-DIRECTIVES; PALLIATIVE CARE; CANCER-PATIENTS; TREATMENT PREFERENCES; INFORMED-CONSENT; CONTROLLED-TRIAL AB Objective: To provide a description of communication breakdowns and to identify interventions to improve surgical decision making for elderly patients with serious illness and acute, life-threatening surgical conditions. Background: Communication between surgeons, patients, and surrogates about goals of treatment plays an important and understudied role in determining the surgical interventions elderly patients with serious illness receive. Communication breakdowns may lead to nonbeneficial procedures in acute events near the end of life. Methods: We review the available literature on factors that lead to communication challenges and nonbeneficial surgery at the end of life. We use this review to identify solutions for navigating surgical decision making for seriously ill elderly patients with acute surgical conditions. Results: Surgeon, patient, surrogate, and systemic factors-including time constraints, inadequate provider communication skills and training, uncertainty about prognosis, patient and surrogate anxiety and fear of inaction, and limitations in advance care planning-contribute to communication challenges and nonbeneficial surgery at the end of life. Surgeons could accomplish more effective communication with seriously ill elderly patients if they had a structured, standardized approach to exploring patients' preferences and to integrating those preferences into surgical decisions in the acute setting. Conclusions: Improved communication among surgeons, patients, and surrogates is necessary to ensure that patients receive the care that they want and to avoid nonbeneficial treatment. Further research is needed to learn how to best structure these conversations in the emergency surgical setting. C1 [Cooper, Zara; Gawande, Atul] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Cooper, Zara; Karlage, Ami; Gawande, Atul; Block, Susan] Brigham & Womens Hosp, Ariadne Labs, Boston, MA 02115 USA. [Courtwright, Andrew] Brigham & Womens Hosp, Dept Pulm & Crit Care Med, Boston, MA 02115 USA. [Courtwright, Andrew] Massachusetts Gen Hosp, Inst Patient Care, Boston, MA 02114 USA. [Karlage, Ami; Gawande, Atul] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Block, Susan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Block, Susan] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Block, Susan] Harvard Univ, Sch Med, Ctr Palliat Care, Boston, MA 02115 USA. RP Cooper, Z (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg,Div Trauma Burn & Surg Crit Care, 75 Francis St, Boston, MA 02115 USA. EM zcooper@partners.org NR 110 TC 12 Z9 12 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD DEC PY 2014 VL 260 IS 6 BP 949 EP 957 DI 10.1097/SLA.0000000000000721 PG 9 WC Surgery SC Surgery GA AT8ZJ UT WOS:000345217200002 PM 24866541 ER PT J AU Gates, JD Arabian, S Biddinger, P Blansfield, J Burke, P Chung, S Fischer, J Friedman, F Gervasini, A Goralnick, E Gupta, A Larentzakis, A McMahon, M Mella, J Michaud, Y Mooney, D Rabinovici, R Sweet, D Ulrich, A Velmahos, G Weber, C Yaffe, MB AF Gates, Jonathan D. Arabian, Sandra Biddinger, Paul Blansfield, Joe Burke, Peter Chung, Sarita Fischer, Jonathan Friedman, Franklin Gervasini, Alice Goralnick, Eric Gupta, Alok Larentzakis, Andreas McMahon, Maria Mella, Juan Michaud, Yvonne Mooney, David Rabinovici, Reuven Sweet, Darlene Ulrich, Andrew Velmahos, George Weber, Cheryl Yaffe, Michael B. TI The Initial Response to the Boston Marathon Bombing Lessons Learned to Prepare for the Next Disaster SO ANNALS OF SURGERY LA English DT Article ID IMPROVISED EXPLOSIVE DEVICES; MULTIPLE CASUALTY INCIDENTS; BLAST INJURIES; TERRORIST BOMBINGS; MANAGEMENT; CARE; PATTERNS; TRAUMA; ATTACK; OPERATIONS AB Objective: We discuss the strengths of the medical response to the Boston Marathon bombings that led to the excellent outcomes. Potential shortcomings were recognized, and lessons learned will provide a foundation for further improvements applicable to all institutions. Background: Multiple casualty incidents from natural or man-made incidents remain a constant global threat. Adequate preparation and the appropriate alignment of resources with immediate needs remain the key to optimal outcomes. Methods: A collaborative effort among Boston's trauma centers (2 level I adult, 3 combined level I adult/pediatric, 1 freestanding level I pediatric) examined the details and outcomes of the initial response. Each center entered its respective data into a central database (REDCap), and the data were analyzed to determine various prehospital and early in-hospital clinical and logistical parameters that collectively define the citywide medical response to the terrorist attack. Results: A total of 281 people were injured, and 127 patients received care at the participating trauma centers on that day. There were 3 (1%) immediate fatalities at the scene and no in-hospital mortality. A majority of the patients admitted (66.6%) suffered lower extremity soft tissue and bony injuries, and 31 had evidence for exsanguinating hemorrhage, with field tourniquets in place in 26 patients. Of the 75 patients admitted, 54 underwent urgent surgical intervention and 12 (22%) underwent amputation of a lower extremity. Conclusions: Adequate preparation, rapid logistical response, short transport times, immediate access to operating rooms, methodical multidisciplinary care delivery, and good fortune contributed to excellent outcomes. C1 [Gates, Jonathan D.; Goralnick, Eric; Michaud, Yvonne] Brigham & Womens Hosp, Boston, MA 02215 USA. [Arabian, Sandra; Friedman, Franklin; Rabinovici, Reuven; Weber, Cheryl] Tufts Med Ctr, Boston, MA USA. [Biddinger, Paul; Gervasini, Alice; Larentzakis, Andreas; Velmahos, George] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Blansfield, Joe; Burke, Peter; Mella, Juan; Ulrich, Andrew] Boston Med Ctr, Boston, MA USA. [Chung, Sarita; McMahon, Maria; Mooney, David] Bostons Childrens Hosp, Boston, MA USA. [Fischer, Jonathan; Gupta, Alok; Sweet, Darlene; Yaffe, Michael B.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Gates, JD (reprint author), Brigham & Womens Hosp, Dept Surg, Div Trauma Burns & Crit Care, 75 Francis St, Boston, MA 02215 USA. EM jgates@partners.org FU NIEHS NIH HHS [P30 ES002109] NR 49 TC 20 Z9 21 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD DEC PY 2014 VL 260 IS 6 BP 960 EP 966 DI 10.1097/SLA.0000000000000914 PG 7 WC Surgery SC Surgery GA AT8ZJ UT WOS:000345217200004 PM 25386862 ER PT J AU Singh, JA Lu, X Rosenthal, GE Ibrahim, S Cram, P AF Singh, Jasvinder A. Lu, Xin Rosenthal, Gary E. Ibrahim, Said Cram, Peter TI Racial disparities in knee and hip total joint arthroplasty: an 18-year analysis of national medicare data SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID CARDIAC RISK-ASSESSMENT; SURGEON PROCEDURE VOLUME; ETHNIC DISPARITIES; AFRICAN-AMERICANS; UNITED-STATES; OSTEOARTHRITIS PHENOTYPES; REPLACEMENT SURGERY; ADMINISTRATIVE DATA; NONCARDIAC SURGERY; EUROPEAN-SOCIETY AB Objective To examine whether racial disparities in usage and outcomes of total knee and total hip arthroplasty (TKA and THA) have declined over time. Methods We used data from the US Medicare Program (MedPAR data) for years 1991-2008 to identify four separate cohorts of patients (primary TKA, revision TKA, primary THA, revision THA). For each cohort, we calculated standardised arthroplasty usage rates for Caucasian and African-American Medicare beneficiaries for each calendar year, and examined changes in disparities over time. We examined unadjusted and adjusted outcomes (30-day readmission rate, discharge disposition etc.) for Caucasians and African-Americans, and whether disparities decreased over time. Results In 1991, the use of primary TKA was 36% lower for African-Americans compared with Caucasians (20.6 per 10 000 for African-Americans; 32.1 per 10 000 for Caucasians; p<0.0001); in 2008, usage of primary TKA was 40% lower for African-Americans (41.5 per 10 000 for African-Americans; 68.8 per 10 000 for Caucasians; p<0.0001) with similar findings for the other cohorts. Black-White disparities in 30-day hospital readmission increased significantly from 19912008 among three patient cohorts. For example in 1991 30-day readmission rates for African-Americans receiving primary TKA were 6% higher than for Caucasians; by 2008 readmission rates for African-Americans were 24% higher (p<0.05 for change in disparity). Similarly, black-white disparities in the proportion of patients discharged to home after surgery increased across the study period for all cohorts (p<0.05). Conclusions In an 18-year analysis of US Medicare data, we found little evidence of declines in racial disparities for joint arthroplasty usage or outcomes. C1 [Singh, Jasvinder A.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Med Serv, Birmingham, AL USA. [Singh, Jasvinder A.] Mayo Clin, Coll Med, Dept Orthoped Surg, Rochester, MN USA. [Lu, Xin; Rosenthal, Gary E.; Cram, Peter] Univ Iowa, Dept Internal Med, Carver Coll Med, Div Gen Internal Med, Iowa City, IA 52242 USA. [Lu, Xin; Rosenthal, Gary E.; Cram, Peter] Iowa City Vet Adm Med Ctr, CADRE, Iowa City, IA USA. [Ibrahim, Said] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Ibrahim, Said] Perelman Univ Penn, Sch Med, Philadelphia, PA USA. RP Singh, JA (reprint author), Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. OI singh, jasvinder/0000-0003-3485-0006 FU National Institute of Aging; National Cancer Institute; Agency for Health Quality and Research Center for Education and Research on Therapeutics (CERTs); Department of Veterans Affairs; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Heart, Lung and Blood Institute FX National Institute of Aging, National Cancer Institute, Agency for Health Quality and Research Center for Education and Research on Therapeutics (CERTs), Department of Veterans Affairs, National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Heart, Lung and Blood Institute. NR 75 TC 30 Z9 30 U1 2 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD DEC PY 2014 VL 73 IS 12 BP 2107 EP 2115 DI 10.1136/annrheumdis-2013-203494 PG 9 WC Rheumatology SC Rheumatology GA AT2RY UT WOS:000344783900013 PM 24047869 ER PT J AU Bremmer, DN Clancy, CJ Press, EG Almaghrabi, R Chen, L Doi, YH Nguyen, H Shields, RK AF Bremmer, Derek N. Clancy, Cornelius J. Press, Ellen G. Almaghrabi, Reem Chen, Liang Doi, Yohei Hong Nguyen Shields, Ryan K. TI KPC-Producing Klebsiella pneumoniae Strains That Harbor AAC(6 ')-Ib Exhibit Intermediate Resistance to Amikacin SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID CRITICALLY-ILL PATIENTS; COLISTIN; GENE; AMINOGLYCOSIDES; COMBINATIONS; DORIPENEM; RMTB AB The aminoglycoside-modifying enzyme AAC(6')-Ib is common among carbapenem-resistant Klebsiella pneumoniae (CR-Kp) strains. We investigated amikacin (AMK) activity against 20 AAC(6')-Ib-producing CR-Kp strains. MICs clustered at 16 to 32 mu g/ml. By the time-kill study, AMK (1x and 4x the MIC) was bactericidal against 30% and 85% of the strains, respectively. At achievable human serum concentrations, however, the majority of strains showed regrowth, suggesting that AAC(6')-Ib confers intermediate AMK resistance. AMK and trimethoprim-sulfamethoxazole (TMP-SMX) were synergistic against 90% of the strains, indicating that the combination may overcome resistance. C1 [Bremmer, Derek N.] Univ Pittsburgh, Dept Pharm & Therapeut, Pittsburgh, PA USA. [Clancy, Cornelius J.; Press, Ellen G.; Almaghrabi, Reem; Doi, Yohei; Hong Nguyen; Shields, Ryan K.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Hong Nguyen; Shields, Ryan K.] Univ Pittsburgh, Med Ctr, XDR Pathogen Lab, Pittsburgh, PA USA. [Clancy, Cornelius J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Chen, Liang] Rutgers State Univ, New Jersey Med Sch, Publ Hlth Res Inst, Newark, NJ 07102 USA. RP Shields, RK (reprint author), Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. EM shieldsrk@upmc.edu FU National Institutes of Health [KL2TR000146]; University of Pittsburgh Medical Center XDR Pathogen Laboratory FX This project was supported by the National Institutes of Health through grant no. KL2TR000146 awarded to R. K. S. and by the University of Pittsburgh Medical Center XDR Pathogen Laboratory. NR 20 TC 4 Z9 4 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD DEC PY 2014 VL 58 IS 12 BP 7597 EP 7600 DI 10.1128/AAC.03831-14 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AT9AW UT WOS:000345221000076 PM 25288089 ER PT J AU Shields, RK Nguyen, MH Press, EG Clancy, CJ AF Shields, Ryan K. Hong Nguyen, M. Press, Ellen G. Clancy, Cornelius J. TI Abdominal Candidiasis Is a Hidden Reservoir of Echinocandin Resistance SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID INVASIVE CANDIDIASIS; CASPOFUNGIN MICS; GLABRATA; OUTCOMES; THERAPY; SUSCEPTIBILITY; PERSISTENCE; CANDIDEMIA; MICAFUNGIN; FAILURE AB FKS mutant Candida isolates were recovered from 24% (6/25) of abdominal candidiasis patients exposed to echinocandin. Candida glabrata (29%) and Candida albicans (14%) mutants were identified. Multidrug-resistant bacteria were recovered from 83% of FKS mutant infections. Mutations were associated with prolonged echinocandin exposure (P = 0.01), breakthrough infections (P = 0.03), and therapeutic failures despite source control interventions (100%). Abdominal candidiasis is a hidden reservoir for the emergence of echinocandin-resistant Candida. C1 [Shields, Ryan K.; Hong Nguyen, M.; Press, Ellen G.; Clancy, Cornelius J.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Shields, Ryan K.; Hong Nguyen, M.] Univ Pittsburgh, Med Ctr, XDR Pathogen Lab, Pittsburgh, PA USA. [Clancy, Cornelius J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Nguyen, MH (reprint author), Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. EM mhn5@pitt.edu FU Astellas; Merck; National Institutes of Health [KL2TR000146] FX This work was supported by investigator-initiated grants from Astellas and Merck and by the National Institutes of Health through grant KL2TR000146, awarded to R.K.S. NR 19 TC 18 Z9 19 U1 2 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD DEC PY 2014 VL 58 IS 12 BP 7601 EP 7605 DI 10.1128/AAC.04134-14 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AT9AW UT WOS:000345221000077 PM 25288081 ER PT J AU Lapenta, OM Di Sierve, K de Macedo, EC Fregni, F Boggio, PS AF Lapenta, Olivia Morgan Di Sierve, Karina de Macedo, Elizeu Coutinho Fregni, Felipe Boggio, Paulo Sergio TI Transcranial direct current stimulation modulates ERP-indexed inhibitory control and reduces food consumption SO APPETITE LA English DT Article DE Food craving; Dorsolateral prefrontal cortex; EEG; Response inhibition; Eye-tracking; tDCS ID PREFRONTAL CORTEX; CORTICAL STIMULATION; MAGNETIC STIMULATION; COMPONENTS; DISORDERS; GO/NOGO; ADULTS; TASKS AB Food craving can be defined as the "urge to eat a specific food". Previous findings suggest impairment of inhibitory control, specifically a regulatory deficit in the lateral prefrontal circuitry that is associated with a compulsion for food. As demonstrated by three previous studies, bilateral transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) (anode right/cathode left) reduces food craving and caloric intake. We designed the present study to evaluate the neural mechanisms that underlie these effects. We replicated the design of one of these previous studies but included electroencephalographic assessments to register evoked potentials in a Go/No-go task that contained pictures of food and furniture (a control visual stimulus). We collected data from nine women (mean age = 23.4 +/- 2 years) in a crossover experiment. We observed that active DLPFC tDCS (anode right/cathode left), compared with sham stimulation, reduced the frontal N2 component and enhanced the P3a component of responses to No-go stimuli, regardless of the stimulus condition (food or furniture). Active tDCS was also associated with a reduction in caloric intake. We discuss our findings in the context of cortico-subcortical processing of craving and tDCS effects on inhibitory control neural circuitry. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Lapenta, Olivia Morgan; Di Sierve, Karina; de Macedo, Elizeu Coutinho; Boggio, Paulo Sergio] Univ Prebiteriana Mackenzie, Ctr Hlth & Biol Sci, Social & Cognit Neurosci Lab & Dev Disorders Prog, Sao Paulo, Brazil. [Fregni, Felipe] Harvard Univ, Sch Med, Spaulding Neuromodulat Ctr, Spaulding Rehabil Hosp, Boston, MA USA. [Fregni, Felipe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Boggio, PS (reprint author), Univ Prebiteriana Mackenzie, Ctr Hlth & Biol Sci, Social & Cognit Neurosci Lab & Dev Disorders Prog, Sao Paulo, Brazil. EM boggio@mackenzie.br RI Boggio, Paulo/K-6272-2012; Macedo, Elizeu/N-4387-2015 OI Boggio, Paulo/0000-0002-6109-0447; FU FAPESP [2012/24696-1] FX OML is supported by a PhD grant (FAPESP - 2012/24696-1). PSB and ECM are CNPq research fellows. NR 32 TC 18 Z9 18 U1 5 U2 20 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 EI 1095-8304 J9 APPETITE JI Appetite PD DEC 1 PY 2014 VL 83 BP 42 EP 48 DI 10.1016/j.appet.2014.08.005 PG 7 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA AT3GP UT WOS:000344824200006 PM 25128836 ER PT J AU Hsiao, JJ Fisher, DE AF Hsiao, Jennifer J. Fisher, David E. TI The roles of microphthalmia-associated transcription factor and pigmentation in melanoma SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Review DE MITF; Melanoma; Melanocyte; Pigmentation ID CELL-CYCLE ARREST; BRAF MUTATIONS; METASTATIC MELANOMA; MALIGNANT-MELANOMA; LINEAGE SURVIVAL; FACTOR MITF; B-RAF; MELANOCYTES; TARGET; EXPRESSION AB MITF and pigmentation play important roles in both normal melanocyte and transformed melanoma cell biology. MITF is regulated by many pathways and it also regulates many targets, some of which are still being discovered and functionally validated. MITF is involved in a wide range of processes in melanocytes, including pigment synthesis and lineage survival. Pigmentation itself plays an important role as the interface between genetic and environmental factors that contribute to melanoma. (C) 2014 Elsevier Inc. All rights reserved. C1 Harvard Univ, Sch Med, Boston, MA 02115 USA. [Fisher, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cutaneous Biol Res Ctr,Dept Dermatol, Charlestown, MA 02129 USA. RP Fisher, DE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cutaneous Biol Res Ctr,Dept Dermatol, Bldg 149,13th St, Charlestown, MA 02129 USA. EM dfisher3@partners.org FU NIH [P01 CA163222, R01 AR043369, R01CA150226]; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation FX We thank Marcelo Pereira da Silva for his generous help with rendering the figures. We also thank Dr. Roydon Price and Dr. Katey Robinson for insightful comments on the manuscript. This work was supported by grants to DEF from NIH (P01 CA163222; R01 AR043369; R01CA150226) and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. NR 74 TC 20 Z9 20 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 EI 1096-0384 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD DEC 1 PY 2014 VL 563 SI SI BP 28 EP 34 DI 10.1016/j.abb.2014.07.019 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AT8QT UT WOS:000345198000005 PM 25111671 ER PT J AU Wilking, MJ Singh, C Nihal, M Zhong, WX Ahmad, N AF Wilking, Melissa J. Singh, Chandra Nihal, Minakshi Zhong, Weixiong Ahmad, Nihal TI SIRT1 deacetylase is overexpressed in human melanoma and its small molecule inhibition imparts anti-proliferative response via p53 activation SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE SIRT1; Melanoma; p53; p21; Tenovin-1 ID PROSTATE-CANCER CELLS; MALIGNANT-MELANOMA; IN-VITRO; APOPTOSIS; EXPRESSION; ACETYLATION; SENESCENCE; SIRTUINS; INSIGHTS; ROLES AB Melanoma causes more deaths than any other skin cancer, and its incidence in the US continues to rise. Current medical therapies are insufficient to control this deadly neoplasm, necessitating the development of new target-based approaches. The objective of this study was to determine the role and functional significance of the class III histone deacetylase SIRT1 in melanoma. We have found that SIRT1 is overexpressed in clinical human melanoma tissues and human melanoma cell lines (Sk-Mel-2, WM35, G361, A375, and Hs294T) compared to normal skin and normal melanocytes, respectively. In addition, treatment of melanoma cell lines A375, Hs294T, and G361 with Tenovin-1, a small molecule SIRT1 inhibitor, resulted in a significant decrease in cell growth and cell viability. Further, Tenovin-1 treatment also resulted in a marked decrease in the clonogenic survival of melanoma cells. Further experiments showed that the anti-proliferative response of Tenovin-1 was accompanied by an increase in the protein as well as activity of the tumor suppressor p53. This increase in p53 activity was substantiated by an increase in the protein level of its downstream target p21. Overall, these data suggest that small molecule inhibition of SIRT1 causes anti-proliferative effects in melanoma cells. SIRT1 appears to be acting through the activity of the tumor suppressor p53, which is not mutated in the majority of melanomas. However, future detailed studies are needed to further explore the role and mechanism of SIRT1 in melanoma development and progression and its usefulness in melanoma treatment. (C) 2014 Elsevier Inc. All rights reserved. C1 [Wilking, Melissa J.; Singh, Chandra; Nihal, Minakshi; Ahmad, Nihal] Univ Wisconsin, Dept Dermatol, Madison, WI 53706 USA. [Zhong, Weixiong] Univ Wisconsin, Dept Pathol, Madison, WI 53706 USA. [Ahmad, Nihal] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. RP Ahmad, N (reprint author), Univ Wisconsin, Med Sci Ctr, Dept Dermatol, 1300 Univ Ave,Room 423, Madison, WI 53706 USA. EM nahmad@wisc.edu FU NIH [R01AR059130, R01CA176748]; Department of Veterans Affairs [1I01BX001008] FX This work was partially supported by funding from the NIH (R01AR059130 and R01CA176748 and the Department of Veterans Affairs (VA Merit Review Award 1I01BX001008). NR 37 TC 11 Z9 14 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 EI 1096-0384 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD DEC 1 PY 2014 VL 563 SI SI BP 94 EP 100 DI 10.1016/j.abb.2014.04.001 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AT8QT UT WOS:000345198000013 PM 24751483 ER PT J AU Opoliner, A Carwile, JL Blacker, D Fitzmaurice, GM Austin, SB AF Opoliner, April Carwile, Jenny L. Blacker, Deborah Fitzmaurice, Garrett M. Austin, S. Bryn TI Early and late menarche and risk of depressive symptoms in young adulthood SO ARCHIVES OF WOMENS MENTAL HEALTH LA English DT Article DE Depression; Growing Up Today Study; Menarche; Puberty ID GENDER DIFFERENCES; ADOLESCENT GIRLS; CHILDHOOD ABUSE; AGE; PUBERTY; POPULATION; WOMEN; LIFE AB We investigated whether girls experiencing early menarche have an increased risk of depression during young adulthood. This study used data collected in the Growing Up Today Study (N = 9,039), an ongoing prospective cohort of the daughters of women enrolled in the Nurses' Health Study II. After excluding girls who were postmenarcheal at baseline in 1996, < 20 or a parts per thousand yen26 years old in 2007, or missing data on key covariates, the final sample size was 3,711. Self-reported age at menarche was collected annually. Depressive symptomatology was measured in 2007 using the 10-item Center for Epidemiologic Studies Depression (CES-D-10) score. Sixteen percent of girls (N = 596) reported high levels of depressive symptoms (CES-D-10 a parts per thousand yenaEuro parts per thousand 14) in 2007. Neither early nor late menarche was associated with high depressive symptoms (for early vs. normative menarche, odds ratio (OR) = 1.08, 95 % confidence interval (CI) = 0.85-1.38; for late vs. normative menarche, OR = 0.91, 95 % CI = 0.70-1.18) or with differences in continuous CES-D-10 score in young adulthood. Although previous studies suggest that girls with early menarche suffer from an increased risk of adolescent depression, this does not appear to persist into young adulthood. C1 [Opoliner, April; Carwile, Jenny L.; Blacker, Deborah] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Carwile, Jenny L.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Fitzmaurice, Garrett M.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Austin, S. Bryn] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Blacker, Deborah] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fitzmaurice, Garrett M.] McLean Hosp, Belmont, MA 02178 USA. [Austin, S. Bryn] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Austin, S. Bryn] Childrens Hosp, Div Adolescent & Young Adult Med, Boston, MA 02115 USA. RP Opoliner, A (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM apo870@mail.harvard.edu FU Breast Cancer Research Foundation; National Institute of Environmental Health Sciences, National Institutes of Health [T32ES007069]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [T32HD060454]; [R03 CA 106238] FX The Growing Up Today Study is supported by grant R03 CA 106238. JC was supported by the Breast Cancer Research Foundation; training grant T32ES007069 in Environmental Epidemiology from the National Institute of Environmental Health Sciences, National Institutes of Health; and training grant T32HD060454 in Reproductive, Perinatal and Pediatric Epidemiology from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. We thank the participants of the Growing Up Today Study. NR 30 TC 3 Z9 3 U1 2 U2 7 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 1434-1816 EI 1435-1102 J9 ARCH WOMEN MENT HLTH JI Arch. Womens Ment. Health PD DEC PY 2014 VL 17 IS 6 BP 511 EP 518 DI 10.1007/s00737-014-0435-6 PG 8 WC Psychiatry SC Psychiatry GA AU0RP UT WOS:000345332100005 PM 25048175 ER PT J AU Shivakumar, G Brandon, AR Johnson, NL Freeman, MP AF Shivakumar, Geetha Brandon, Anna R. Johnson, Neysa L. Freeman, Marlene P. TI Screening to Treatment: Obstacles and Predictors in Perinatal Depression (STOP-PPD) in the Dallas Healthy Start program SO ARCHIVES OF WOMENS MENTAL HEALTH LA English DT Article DE Perinatal; Postpartum depression; Screening; Healthy Start; Community ID POSTPARTUM DEPRESSION; BARRIERS; WOMEN AB Healthy Start programs have made tremendous contributions toward improving the health of mothers and infants through the screening and early detection of perinatal depression. In a collaborative partnership with the Dallas Healthy Start (DHS) program, this pilot study investigated rates of follow-up to systematic referrals for the treatment of perinatal depression in the DHS, as well as identified specific barriers and predictors or treatment follow-up. Results of this study support strengthening existing community-based treatment programs for perinatal depression. C1 [Shivakumar, Geetha] Dallas VA Med Ctr, Mental Hlth Trauma Serv, Dallas, TX 75216 USA. [Shivakumar, Geetha; Johnson, Neysa L.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Brandon, Anna R.] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC USA. [Johnson, Neysa L.] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Freeman, Marlene P.] Massachusetts Gen Hosp, Perinatal & Reprod Psychiat Program, Ctr Womens Mental Hlth, Boston, MA 02114 USA. RP Shivakumar, G (reprint author), Dallas VA Med Ctr, Mental Hlth Trauma Serv, 4500 S Lancaster Rd,Mail Code 116A, Dallas, TX 75216 USA. EM geetha.shivakumar@utsouthwestern.edu FU Program for the Development and Evaluation of Model Community Health Initiatives in Dallas (PDEMCHID); UT Southwestern Medical Center; Institute of Mental Health Research (IMHR) FX The STOP-PPD project was funded by the Program for the Development and Evaluation of Model Community Health Initiatives in Dallas (PDEMCHID), UT Southwestern Medical Center (Co PIs Dr. Shivakumar and Dr. Freeman) as a community-based collaborative initiative between the Women's Mental Health Center, UT Southwestern, and the Dallas Healthy Start (DHS) program. Dr. Freeman received funding from Institute of Mental Health Research (IMHR), which helped with conceptualization and development of the provider utilization survey in the STOP-PPD study. Results of STOP- PPD study were presented at the Marc, 2010, Perinatal Mental Health Research, October 2730, 2010, Pittsburgh, PA. NR 7 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 1434-1816 EI 1435-1102 J9 ARCH WOMEN MENT HLTH JI Arch. Womens Ment. Health PD DEC PY 2014 VL 17 IS 6 BP 575 EP 578 DI 10.1007/s00737-014-0438-3 PG 4 WC Psychiatry SC Psychiatry GA AU0RP UT WOS:000345332100012 PM 25012198 ER PT J AU Camsari, U Viguera, AC Ralston, L Baldessarini, RJ Cohen, LS AF Camsari, Ulas Viguera, Adele C. Ralston, Laurel Baldessarini, Ross J. Cohen, Lee S. TI Prevalence of atypical antipsychotic use in psychiatric outpatients: comparison of women of childbearing age with men SO ARCHIVES OF WOMENS MENTAL HEALTH LA English DT Article DE Atypical antipsychotics; Second generation antipsychotics; Childbearing age women; Sex differences; Mood disorders; Anxiety disorders ID PREGNANCY REGISTRIES; EXPOSURE; DRUGS AB To characterize current treatment practices, we compared the use of atypical antipsychotic drugs among women of childbearing age to men based on electronic medical records of 1073 hospital-based psychiatric outpatients given at least one second-generation antipsychotic drug. One quarter of psychiatric outpatients sampled were prescribed at least one atypical antipsychotic, in more than half of cases for off-label indications. Women were significantly more likely than men to be diagnosed with mood or anxiety disorders than psychotic disorders and to be prescribed quetiapine (60.7 vs. 48.0 %) or aripiprazole (31.2 vs. 23.9 %), but less likely risperidone (15.8 vs. 26.1 %) or ziprasidone (10 vs. 14 %). C1 [Camsari, Ulas] Mayo Clin, Coll Med, Dept Psychiat, Rochester, MN USA. [Viguera, Adele C.; Baldessarini, Ross J.; Cohen, Lee S.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Viguera, Adele C.; Cohen, Lee S.] Massachusetts Gen Hosp, Ctr Womens Mental Hlth, Perinatal & Reprod Psychiat Clin Res Program, Boston, MA 02114 USA. [Viguera, Adele C.; Ralston, Laurel] Cleveland Clin, Dept Psychiat, Neurol Inst, Cleveland, OH 44106 USA. [Baldessarini, Ross J.] McLean Hosp, Int Consortium Bipolar & Psychot Disorders Res, Belmont, MA 02478 USA. RP Viguera, AC (reprint author), Cleveland Clin, Dept Psychiat, Neurol Inst, Cleveland, OH 44106 USA. EM VIGUERA@ccf.org FU NIH [MH-1609, MH-071762]; Bruce J Anderson Foundation; McLean Private Donors Research Fund FX This research was supported in part by NIH grants MH-1609 and MH-071762 to Dr. Viguera and a grant from the Bruce J Anderson Foundation and the McLean Private Donors Research Fund to Dr. Baldessarini. NR 18 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 1434-1816 EI 1435-1102 J9 ARCH WOMEN MENT HLTH JI Arch. Womens Ment. Health PD DEC PY 2014 VL 17 IS 6 BP 583 EP 586 DI 10.1007/s00737-014-0465-0 PG 4 WC Psychiatry SC Psychiatry GA AU0RP UT WOS:000345332100014 PM 25253022 ER PT J AU Singh, RP Hasan, S Sharma, S Nagra, S Yamaguchi, DT Wong, DTW Hahn, BH Hossain, A AF Singh, Ram Pyare Hasan, Sascha Sharma, Sherven Nagra, Saranpreet Yamaguchi, Dean T. Wong, David T. W. Hahn, Bevra H. Hossain, Awlad TI Th17 cells in inflammation and autoimmunity SO AUTOIMMUNITY REVIEWS LA English DT Review DE Th17; Sex hormones; Autoimmunity; Systemic lupus erythematosus; Cancer; Mesenchymal stem cells ID MESENCHYMAL STEM-CELLS; REGULATORY T-CELLS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; CENTRAL-NERVOUS-SYSTEM; TUMOR-INFILTRATING LYMPHOCYTES; HELPER 17 CELLS; SJOGRENS-SYNDROME; RHEUMATOID-ARTHRITIS; MULTIPLE-SCLEROSIS; HEPATOCELLULAR-CARCINOMA AB T helper 17 (Th17), a distinct subset of CD4(+) T cells with IL-17 as their major cytokine, orchestrate the pathogenesis of inflammatory and autoimmune diseases. Dysregulated Th17 cells contribute to inflammatory and autoimmune diseases. Candidate biologics are in development for targeting IL-17, IL-17 receptors or IL-17 pathways. Several drugs that impact the IL-17 pathway are already in clinical trials for the treatment of autoimmune diseases. In this review we provide evidence for the role of Th17 cells in immune-mediated diseases. An understanding of the role of Th17 in these conditions will provide important insights and unravel novel targets for therapeutic intervention. (C) 2014 Elsevier B.V. All rights reserved. C1 [Singh, Ram Pyare; Nagra, Saranpreet; Hahn, Bevra H.; Hossain, Awlad] Univ Calif Los Angeles, David Geffen Sch Med, Div Rheumatol, Los Angeles, CA 90095 USA. [Hasan, Sascha] Univ Calif Los Angeles, David Geffen Sch Med, Sanguine Biosci Inc, Los Angeles, CA 90095 USA. [Sharma, Sherven; Yamaguchi, Dean T.] Univ Calif Los Angeles, David Geffen Sch Med, Vet Affairs Greater Los Angeles Hlth Care Syst, Res Serv, Los Angeles, CA 90095 USA. [Wong, David T. W.] Univ Calif Los Angeles, David Geffen Sch Med, Sch Dent, Los Angeles, CA 90095 USA. RP Singh, RP (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Rheumatol, Los Angeles, CA 90095 USA. EM rsingh@ucla.edu FU NIH [AR54034, AI 083894, AI65645]; UCLA Senate Core Grant; UCLA Oppenheimer Clinical Seed Grant; American Autoimmune Related Disease Association; Lupus Foundation of America; VA Merit Review Award [2101 BX000170-05] FX Supported by NIH grants AR54034, AI 083894, AI65645 to RPS, UCLA Senate Core Grant to BHH and RPS, UCLA Oppenheimer Clinical Seed Grant and American Autoimmune Related Disease Association and the Lupus Foundation of America Awards to RPS, and VA Merit Review Award 2101 BX000170-05 to DTY. NR 117 TC 47 Z9 56 U1 7 U2 37 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9972 EI 1873-0183 J9 AUTOIMMUN REV JI Autoimmun. Rev. PD DEC PY 2014 VL 13 IS 12 BP 1174 EP 1181 DI 10.1016/j.autrev.2014.08.019 PG 8 WC Immunology SC Immunology GA AT8TC UT WOS:000345203800002 PM 25151974 ER PT J AU Brito-Zeron, P Ramos-Casals, M Bosch, X Stone, JH AF Brito-Zeron, Pilar Ramos-Casals, Manuel Bosch, Xavier Stone, John H. TI The clinical spectrum of IgG4-related disease SO AUTOIMMUNITY REVIEWS LA English DT Review DE IgG4-related disease; Autoimmune pancreatitis; Sclerosing cholangitis; Retroperitoneal fibrosis; Aortitis; Mikulicz disease ID PRIMARY SCLEROSING CHOLANGITIS; IMMUNOGLOBULIN G4-RELATED DISEASE; AUTOIMMUNE PANCREATITIS; TUBULOINTERSTITIAL NEPHRITIS; PATHOLOGICAL CHARACTERISTICS; MIKULICZS-DISEASE; PLASMA-CELLS; CT FINDINGS; DIAGNOSIS; FEATURES AB IgG4-related disease (IgG4-RD) is an emerging immune-mediated disease with the capability of involving essentially any organ. The epidemiology of this disease has not been explored in detail. A majority of patients reported in the literature to date are from Japan, but the condition has been described all across the world and there is no strong evidence to suggest a predilection for Asian populations. The mean age at diagnosis is approximately 60 years and there is a decided male predominance for many clinical features, with an overall male:female ratio of 8:3. A cardinal feature of IgG4-RD is single or multiple organ swelling that often raises concern for malignancy. IgG4-RD should be suspected in patients presenting with unexplained enlargement or swelling of one or more organs. Presenting features vary substantially according to the specialty to which patients present first; in addition, the disease can be diagnosed unexpectedly in pathological specimens or identified incidentally on radiology studies. Involvement of major organs is common and IgG4-RD may lead to organ failure, particularly in the pancreas, liver and biliary tree, kidneys, thyroid gland, lungs, and aorta. The diagnosis of IgG4-RD relies on the coexistence of various clinical, laboratory and histopathological findings, although none is pathognomonic by itself. (C) 2014 Elsevier B.V. All rights reserved. C1 [Brito-Zeron, Pilar; Ramos-Casals, Manuel] CELLEX Inst Invest Biomed August & Sunyer IDIBAPS, Josep Font Lab Autoimmune Dis, Barcelona, Spain. [Brito-Zeron, Pilar; Ramos-Casals, Manuel] Hosp Clin Barcelona, Dept Autoimmune Dis, Barcelona, Spain. [Bosch, Xavier] Hosp Clin Barcelona, Dept Internal Med ICMiD, Barcelona, Spain. [Stone, John H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Stone, John H.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Rheumatol Unit, 55 Fruit St Yawkey 2, Boston, MA 02114 USA. EM jhstone@partners.org RI brito zeron, pilar/L-6551-2014 OI brito zeron, pilar/0000-0003-1016-5055 FU Josep Font Research Fellow Award, Hospital Clinic, Barcelona, Spain FX Supported by the Josep Font Research Fellow Award, Hospital Clinic, Barcelona, Spain. NR 69 TC 45 Z9 51 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9972 EI 1873-0183 J9 AUTOIMMUN REV JI Autoimmun. Rev. PD DEC PY 2014 VL 13 IS 12 BP 1203 EP 1210 DI 10.1016/j.autrev.2014.08.013 PG 8 WC Immunology SC Immunology GA AT8TC UT WOS:000345203800006 PM 25151972 ER PT J AU Tuyishime, M Danish, M Princiotto, A Mankowski, MK Lawrence, R Lombart, HG Esikov, K Berniac, J Kuang, L Ji, JJ Ptak, RG Madani, N Cocklin, S AF Tuyishime, Marina Danish, Matt Princiotto, Amy Mankowski, Marie K. Lawrence, Rae Lombart, Henry-Georges Esikov, Kirill Berniac, Joel Kuang Liang Ji Jingjing Ptak, Roger G. Madani, Navid Cocklin, Simon TI Discovery and optimization of novel small-molecule HIV-1 entry inhibitors using field-based virtual screening and bioisosteric replacement SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Field-based virtual screening; Three-dimensional virtual screening; HIV-1 Env; Antiviral; Bioisostere; Entry inhibitor; Field-based scaffold hopping ID GP120 ENVELOPE GLYCOPROTEIN; ATTACHMENT INHIBITOR; RECEPTOR-BINDING; PRODRUG BMS-663068; ACTIVE COMPONENT; MATRIX PROTEIN; CD4 RECEPTOR; IDENTIFICATION; BMS-626529; ANTIBODY AB With the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication. The inhibition of HIV-1 entry is an attractive, yet underexploited therapeutic approach with implications for salvage and preexposure prophylactic regimens, as well as topical microbicides. Using the combination of a field-derived bioactive conformation template to perform virtual screening and iterative bioisosteric replacements, coupled with in silico predictions of absorption, distribution, metabolism, and excretion, we have identified new leads for HIV-1 entry inhibitors. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Tuyishime, Marina; Danish, Matt; Cocklin, Simon] Drexel Univ, Coll Med, Dept Biochem & Mol Biol, Philadelphia, PA 19104 USA. [Princiotto, Amy; Madani, Navid] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Mankowski, Marie K.; Ptak, Roger G.] So Res Inst, Dept Infect Dis Res, Frederick, MD 21701 USA. [Lawrence, Rae] Cresset, Litlington, Cambs, England. [Lombart, Henry-Georges; Esikov, Kirill; Berniac, Joel] AsisChem Inc, Watertown, MA 02472 USA. [Kuang Liang; Ji Jingjing] HD Biosci Co Ltd, Shanghai 201201, Peoples R China. RP Cocklin, S (reprint author), Drexel Univ, Coll Med, Dept Biochem & Mol Biol, Rooms 10302-10306,245 North 15th St, Philadelphia, PA 19104 USA. EM scocklin@drexelmed.edu FU NIH/NIAID [1R21AI104354-01A1]; Smith Charitable Trust (Four Falls Corporate Center, Gladwyne,USA) [A1301] FX This work was supported in part by NIH/NIAID grant 1R21AI104354-01A1 (Cocklin, PI) and W.W. Smith Charitable Trust (Four Falls Corporate Center, Gladwyne, PA 19035, USA) grant # A1301 (Cocklin, PI). We thank Diana Winters (Academic Publishing Services, Drexel University College of Medicine) for proofreading the manuscript. NR 41 TC 4 Z9 4 U1 0 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X EI 1464-3405 J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD DEC 1 PY 2014 VL 24 IS 23 BP 5439 EP 5445 DI 10.1016/j.bmcl.2014.10.027 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA AT7NW UT WOS:000345125500020 PM 25454268 ER PT J AU Hegarty, PK Eardley, I Heidenreich, A McDougal, WS Minhas, S Spiess, PE Watkin, N Horenblas, S AF Hegarty, Paul K. Eardley, Ian Heidenreich, Axel McDougal, W. Scott Minhas, Suks Spiess, Philippe E. Watkin, Nick Horenblas, Simon TI Penile cancer: organ-sparing techniques SO BJU INTERNATIONAL LA English DT Review DE penile cancer; surgery; treatment; organ preservation; review ID SQUAMOUS-CELL CARCINOMA; FOLLOW-UP; ONCOLOGICAL CONTROL; PRESERVING SURGERY; RESECTION MARGINS; INCIDENCE TRENDS; LASER THERAPY; IN-SITU; RECOMMENDATIONS; MANAGEMENT AB To compare the oncological safety of treating patients with penile cancer with conservative techniques developed to preserve function, cosmesis and psychological well-being with more radical ablative strategies. We conducted an extensive review of the literature of penile-preserving and ablative techniques and report on the oncological as well as functional outcomes. There were no randomised studies comparing penile-preserving and ablative techniques. Most studies consisted of retrospective cohorts. The quality of evidence was level 3 at best. Cancer-specific survival is similar in penile-preserving and ablative approaches for low-stage disease. Penile preservation is better for functional and cosmetic outcomes and should be offered as a primary treatment method in men with low-stage penile cancer. C1 [Hegarty, Paul K.] Mater Misericordiae Univ Hosp, Dept Urol, Dublin 7, Ireland. [Hegarty, Paul K.] Mater Private, Dublin, Ireland. [Eardley, Ian] St James Univ Hosp, Dept Urol, Leeds, W Yorkshire, England. [Minhas, Suks] UCLH Inst Urol London, London, England. [Watkin, Nick] St Helier Hosp, Dept Urol, Carshalton SM5 1AA, Surrey, England. [Heidenreich, Axel] Rhein Westfal TH Aachen, Dept Urol, Aachen, Germany. [McDougal, W. Scott] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Spiess, Philippe E.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Urol, Tampa, FL 33682 USA. [Horenblas, Simon] Netherlands Canc Inst, Dept Urol, Amsterdam, Netherlands. RP Hegarty, PK (reprint author), Mater Misericordiae Univ Hosp, Dept Urol, Eccles St, Dublin 7, Ireland. EM paul.hegarty@materprivate.ie NR 50 TC 6 Z9 7 U1 0 U2 1 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 DEC PY 2014 VL 114 IS 6 BP 799 EP 805 DI 10.1111/bju.12338 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AU0UX UT WOS:000345341300008 PM 24053403 ER PT J AU Mullen, JT Hornicek, FJ Harmon, DC Raskin, KA Chen, YL Szymonifka, J Yeap, BY Choy, E DeLaney, TF Nielsen, GP AF Mullen, John T. Hornicek, Francis J. Harmon, David C. Raskin, Kevin A. Chen, Yen-Lin Szymonifka, Jackie Yeap, Beow Y. Choy, Edwin DeLaney, Thomas F. Nielsen, G. Petur TI Prognostic Significance of Treatment-Induced Pathologic Necrosis in Extremity and Truncal Soft Tissue Sarcoma After Neoadjuvant Chemoradiotherapy SO CANCER LA English DT Article DE pathologic necrosis; soft tissue sarcoma; neoadjuvant therapy; outcome; prognosis ID CHEMOTHERAPY-INDUCED NECROSIS; TUMOR NECROSIS; SINGLE INSTITUTION; LOCAL RECURRENCE; EWINGS-SARCOMA; GRADE; OSTEOSARCOMA; PREDICTOR; SURVIVAL; RADIOTHERAPY AB BACKGROUNDHistologic response to chemotherapy has been shown to be an independent prognostic factor in patients with osteosarcoma and Ewing sarcoma. However, in patients with soft tissue sarcoma (STS), the prognostic impact of histologic response to chemotherapy is less clear. In the current study, the authors sought to determine the prognostic significance of treatment-induced pathologic necrosis in patients receiving neoadjuvant chemoradiotherapy for STS. METHODSBetween 1989 and 2011, a total of 113 patients with grade 2 or 3 (graded according to the National Cancer Institute grading system using 3 tiers) extremity or truncal STS were identified who received neoadjuvant interdigitated chemoradiotherapy according to protocol followed by surgery. The extent of tumor necrosis in the resected specimens was quantified and correlated with outcome. RESULTSThe median tumor necrosis rate was 90%, and 103 patients (91%) received all 3 cycles of planned neoadjuvant chemotherapy. The likelihood of achieving 95% necrosis was not related to the number of preoperative cycles of chemotherapy received but was found to be related to tumor histology (62% for malignant fibrous histiocytoma vs 0% for synovial sarcoma [P<.001]; 56% for myxoid liposarcoma vs 0% for synovial sarcoma [P=.002]). At a median follow-up of 6 years, there were no statistically significant differences noted in the 5-year local control, disease-specific survival, and overall survival rates for patients with 95% necrosis (50 patients; 44%) and <95% necrosis (63 patients; 56%), even when stratifying by histology. CONCLUSIONSIn a homogeneous population of patients with high-grade extremity and truncal STS who were treated with neoadjuvant chemoradiotherapy, the extent of pathologic tumor necrosis did not correlate with outcome. Cancer 2014;120:3676-3682. (c) 2014 American Cancer Society. Although histologic response to chemotherapy has been shown to be an independent prognostic factor in patients with osteosarcoma and Ewing sarcoma, its prognostic impact among patients with soft tissue sarcoma is less clear. In a homogeneous population of patients with high-grade extremity and truncal soft tissue sarcoma who were treated with neoadjuvant chemoradiotherapy, the extent of pathologic tumor necrosis did not appear to correlate with outcome. C1 [Mullen, John T.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Hornicek, Francis J.; Raskin, Kevin A.] Massachusetts Gen Hosp, Dept Orthoped Oncol, Boston, MA 02114 USA. [Harmon, David C.; Yeap, Beow Y.; Choy, Edwin] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Chen, Yen-Lin; DeLaney, Thomas F.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Szymonifka, Jackie; Yeap, Beow Y.] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Nielsen, G. Petur] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Mullen, JT (reprint author), Massachusetts Gen Hosp, Dept Surg, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. EM jmullen@partners.org FU National Cancer Institute Cancer Center [NIH 5 P30 CA06516] FX The Dana-Farber/Harvard Cancer Center Biostatistics Core facility is supported in part by the National Cancer Institute Cancer Center Support Grant NIH 5 P30 CA06516. NR 23 TC 13 Z9 14 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 DEC 1 PY 2014 VL 120 IS 23 BP 3676 EP 3682 DI 10.1002/cncr.28945 PG 7 WC Oncology SC Oncology GA AU0QU UT WOS:000345329600015 PM 25081640 ER PT J AU Papaioannou, G Mirzamohammadi, F Kobayashi, T AF Papaioannou, Garyfallia Mirzamohammadi, Fatemeh Kobayashi, Tatsuya TI MicroRNAs involved in bone formation SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Bone development; Cartilage; Mesenchymal stem cells; Osteoporosis; Dicer ID MESENCHYMAL STEM-CELLS; HUMAN ADIPOSE-TISSUE; REGULATES CHONDROGENIC DIFFERENTIATION; SUPPRESSES OSTEOGENIC DIFFERENTIATION; PRE-OSTEOBLAST DIFFERENTIATION; TRANSCRIPTION FACTOR; TARGETING OSTERIX; CHONDROCYTE DIFFERENTIATION; OSTEOCLAST DIFFERENTIATION; SKELETAL DEVELOPMENT AB During skeletal development, mesenchymal progenitor cells undergo a multistage differentiation process in which they proliferate and become bone- and cartilage-forming cells. This process is tightly regulated by multiple levels of regulatory systems. The small non-coding RNAs, microRNAs (miRNAs), post-transcriptionally regulate gene expression. Recent studies have demonstrated that miRNAs play significant roles in all stages of bone formation, suggesting the possibility that miRNAs can be novel therapeutic targets for skeletal diseases. Here, we review the role and mechanism of action of miRNAs in bone formation. We discuss roles of specific miRNAs in major types of bone cells, osteoblasts, chondrocytes, osteoclasts, and their progenitors. Except a few, the current knowledge about miRNAs in bone formation has been obtained mainly by in vitro studies; further validation of these findings in vivo is awaited. We also discuss about several miRNAs of particular interest in the light of future therapies of bone diseases. C1 [Papaioannou, Garyfallia; Mirzamohammadi, Fatemeh; Kobayashi, Tatsuya] Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. [Papaioannou, Garyfallia; Mirzamohammadi, Fatemeh; Kobayashi, Tatsuya] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Kobayashi, T (reprint author), Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Thier 1101,50 Blossom St, Boston, MA 02114 USA. EM gpapaioannou@mgh.harvard.edu; fmirzamohammadi@mgh.harvard.edu; kobayash@helix.mgh.harvard.edu FU NIH [AR056645] FX This work is supported by the NIH grant, AR056645, to T.K. NR 129 TC 17 Z9 17 U1 1 U2 9 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X EI 1420-9071 J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD DEC PY 2014 VL 71 IS 24 BP 4747 EP 4761 DI 10.1007/s00018-014-1700-6 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AT6ZM UT WOS:000345085600004 PM 25108446 ER PT J AU Chen, JS Roberts, JD AF Chen, Jingsi Roberts, Jesse D., Jr. TI cGMP-dependent protein kinase I gamma encodes a nuclear localization signal that regulates nuclear compartmentation and function SO CELLULAR SIGNALLING LA English DT Article DE cGMP-dependent protein kinase; cGMP signal transduction; Nuclear translocation; Smooth muscle cell ID SMOOTH-MUSCLE-CELLS; CYCLIC-GMP; NITRIC-OXIDE; BINDING PROTEIN; GENE-EXPRESSION; IMPORTIN-ALPHA; FOS PROMOTER; BETA; TRANSLOCATION; ACTIVATION AB cGMP-dependent protein kinase I (PKGI) plays an important role in regulating how cGMP specifies vascular smooth muscle cell (SMC) phenotype. Although studies indicate that PKGI nuclear localization controls how cGMP regulates gene expression in SMC, information about the mechanisms that regulate PKGI nuclear compartmentation and its role in directly regulating cell phenotype is limited. Here we characterize a nuclear localization signal sequence (NLS) in PKGI gamma, a proteolytically cleaved PKGI kinase fragment that translocates to the nucleus of SMC Immuno-localization studies using cells expressing native and NLS-mutant PKGl gamma, and treated with a small molecule nuclear transport inhibitor, indicated that PKGl gamma encodes a constitutively active NLS that requires importin alpha and beta for regulation of its compartmentation. Moreover, studies utilizing a genetically encoded nuclear phospho-CREB biosensor probe and fluorescence lifetime imaging microscopy demonstrated that this NLS controls PKGl gamma nuclear function. In addition, although cytosolic PKGl gamma-activity was observed to stimulate MAPK/ERK-mediated nuclear CREB signaling in SMC, NLS-mediated PKGI gamma nuclear activity alone was determined to increase the expression of differentiation marker proteins in these cells. These results indicate that NLS-mediated nuclear PKGl gamma localization plays an important role in how PKGI regulates vascular SMC phenotype. (C) 2014 Elsevier Inc. All rights reserved. C1 [Chen, Jingsi; Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Chen, Jingsi; Roberts, Jesse D., Jr.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Dept Anesthesia, Boston, MA 02114 USA. [Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Roberts, JD (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, East 149 13th St, Charlestown, MA 02129 USA. EM roberts@cvrc.mgh.harvard.edu FU US National Institutes of Health [R01HL096779]; MGH Department of Anesthesia, Critical Care, and Pain Medicine FX The US National Institutes of Health (R01HL096779) and the MGH Department of Anesthesia, Critical Care, and Pain Medicine supported this work. We are grateful to Drs. Michael Friedrich (Max Plank Institute of Neurobiology, Martinsried Germany) and Michael Uhler (Univ. of Michigan, Michigan USA) for providing plasmid reagents, to Dr. Gorin Martic for technical help in constructing the FLAG-PKGI gamma construct, and to Drs. Angela Schmider, Roy Soberman, and the MGH Molecular Imaging Core Facility for providing technical support with the FLIM instrument. NR 60 TC 1 Z9 1 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD DEC PY 2014 VL 26 IS 12 BP 2633 EP 2644 DI 10.1016/j.cellsig.2014.08.004 PG 12 WC Cell Biology SC Cell Biology GA AT7HQ UT WOS:000345107700006 PM 25172423 ER PT J AU De Melo, J Lin, XZ He, LZ Wei, FX Major, P Tang, DM AF De Melo, Jason Lin, Xiaozeng He, Lizhi Wei, Fengxiang Major, Pierre Tang, Damu TI SIPL1-facilitated PTEN ubiquitination contributes to its association with PTEN SO CELLULAR SIGNALLING LA English DT Article DE SIPL1/sharpin; PTEN; Ubiquitination; Protein-protein interaction ID MEDIATED UBIQUITINATION; NUCLEAR PTEN; E3 LIGASE; PROTEIN; PHOSPHATASE; SHARPIN; PATHWAY; COMPLEX; NEDD4-1; TUMORIGENESIS AB PTEN is post-translationally modified by ubiquitin via association with multiple E3 ubiquitin ligases, including NEDD4-1, XIAP, and WWP2. Despite the rapid progress made in researching the impact of ubiquitination on PTEN function, our understanding remains fragmented. Building on the previously observed interaction between SIPL1 and PTEN, we report here that SIPL1 promotes PTEN polyubiquitination via lysine 48 (K48)-independent polyubiquitin chains. Substitution of the K48 residue of ubiquitin with arginine (R) enhanced SIPL1-mediated PTEN polyubiquitination. In contrast, the K63R substitution significantly reduced it. The ubiquitin-like (UBL) domain is required for SIPL1-induced PTEN polyubiquitination. This post-translational modification promoted the association of SIPL1 with PTEN. Elevated amounts of the SIPL1/PTEN complex were precipitated in 293T cells co-transfected with PTEN, SIPL1, and ubiquitin compared to cells co-transfected with SIPL1 and PTEN only. Additionally, formation of the SIPL1/PTEN complex was inhibited when either lysine-less (KO) ubiquitin or K63R ubiquitin was co-transfected together with SIPL1 + PTEN. The PTEN component in the SIPL1/PTEN complex contained polyubiquitin chains. The ubiquitination reaction may play a structural role, stabilizing the SIPL1/PTEN complex, as a ubiquitin binding-defective SIPL1 mutant (TFLV) is proficient in PTEN association. Collectively, we demonstrate that SIPL1 binds PTEN and enhances PTEN polyubiquitination which in turn promotes the interaction between SIPL1 and PTEN. (C) 2014 Elsevier Inc. All rights reserved. C1 [De Melo, Jason; Lin, Xiaozeng; He, Lizhi; Wei, Fengxiang; Tang, Damu] McMaster Univ, Dept Med, Div Nephrol, Hamilton, ON L8S 4L8, Canada. [De Melo, Jason; Lin, Xiaozeng; He, Lizhi; Wei, Fengxiang; Tang, Damu] St Josephs Hosp, Father Sean OSullivan Res Inst, Hamilton, ON L8N 4A6, Canada. [He, Lizhi] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wei, Fengxiang] Inst Women & Childrens Hlth, Genet Lab, Shenzhen, Guangdong, Peoples R China. [Major, Pierre] McMaster Univ, Dept Oncol, Hamilton, ON, Canada. RP Tang, DM (reprint author), St Josephs Hosp, T3310,50 Charlton Ave East, Hamilton, ON L8N 4A6, Canada. EM damut@mcmaster.ca OI De Melo, Jason/0000-0001-6519-4879 FU Canadian Institutes of Health Research (CIHR) grant [COP - 107971] FX This work was supported by a Canadian Institutes of Health Research (CIHR) grant (COP - 107971) to D. Tang. NR 40 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD DEC PY 2014 VL 26 IS 12 BP 2749 EP 2756 DI 10.1016/j.cellsig.2014.08.013 PG 8 WC Cell Biology SC Cell Biology GA AT7HQ UT WOS:000345107700018 PM 25152374 ER PT J AU Emami, H Tawakol, A AF Emami, Hamed Tawakol, Ahmed TI Noninvasive imaging of arterial inflammation using FDG-PET/CT SO CURRENT OPINION IN LIPIDOLOGY LA English DT Review DE atherosclerosis; imaging; inflammation; PET ID POSITRON-EMISSION-TOMOGRAPHY; ATHEROSCLEROTIC PLAQUE INFLAMMATION; IMPAIRED GLUCOSE-TOLERANCE; ACUTE CORONARY SYNDROME; RHEUMATOID-ARTHRITIS; F-18-FDG PET/CT; CLINICAL-TRIAL; PIOGLITAZONE; FLUORODEOXYGLUCOSE; EVENTS AB Purpose of review Noninvasive imaging of atherosclerotic plaques has substantially advanced over the past decade such that currently available imaging techniques allow for characterization of high-risk morphological features of the plaques and quantification of the biological activity within the atherosclerotic milieu. Vascular PET/CT imaging provides insights into the biological activity of atherosclerotic plaques and, in particular, plaque inflammation. Fluoro-deoxyglucose-PET/CT imaging is currently used to improve the understanding of atherosclerotic pathophysiology, facilitate the discovery of new treatments and improve clinical prognostication in humans. Recent findings Several studies have evaluated the feasibility, validity and reproducibility of fluoro-deoxyglucose-PET/CT for imaging of atherosclerotic plaque inflammation. Fluoro-deoxyglucose-PET/CT imaging is demonstrated to have the potential to predict the efficacy of novel antiatherosclerotic therapeutics by using a relatively small sample size and within a relatively short time period in several multicenter trials. Summary The currently feasible assessment of inflammation within the atherosclerotic plaques has been demonstrated to enhance assessment of clinical risk, provide a better understanding of therapeutic efficacy of novel drugs, and it may provide a window into inflammation within the coronary tree. Further technological advances in PET technology have the potential to catalyze further progress in imaging of atherosclerotic plaque biology. C1 [Emami, Hamed; Tawakol, Ahmed] Massachusetts Gen Hosp, Dept Imaging, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Emami, Hamed; Tawakol, Ahmed] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Emami, Hamed; Tawakol, Ahmed] Harvard Univ, Sch Med, Boston, MA USA. [Tawakol, Ahmed] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Tawakol, A (reprint author), Massachusetts Gen Hosp, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM atawakol@partners.org NR 37 TC 3 Z9 3 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0957-9672 EI 1473-6535 J9 CURR OPIN LIPIDOL JI Curr. Opin. Lipidology PD DEC PY 2014 VL 25 IS 6 BP 431 EP 437 DI 10.1097/MOL.0000000000000135 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Cardiovascular System & Cardiology GA AT5XD UT WOS:000345012300004 PM 25340479 ER PT J AU Zephyrin, LC Katon, JG Yano, EM AF Zephyrin, Laurie C. Katon, Jodie G. Yano, Elizabeth M. TI Strategies for transforming reproductive healthcare delivery in an integrated healthcare system: a national model with system-wide implications SO CURRENT OPINION IN OBSTETRICS & GYNECOLOGY LA English DT Review DE health policy; health system; programmatic development; reproductive health; women Veterans ID LIFE-COURSE APPROACH; WOMEN VETERANS; FEMALE VETERANS; RESEARCH AGENDA; MILITARY; TRAUMA AB Purpose of review As the number of women serving in the US military has grown, so too has the number of women using the US Department of Veterans Affairs Healthcare System (VA). This poses tremendous opportunity to integrate reproductive health services across a national healthcare system. This review summarizes the approaches used to assess, rapidly design, and integrate VA's first National Reproductive Health Program. Recent findings Compared with the civilian population, women Veterans have poorer health status including increased likelihood of medical comorbidities and mental health conditions. Given these complex health needs, a health systems approach that integrates reproductive health with other needs is essential in this vulnerable population. Summary Delivery of high-quality reproductive healthcare must incorporate a systems perspective. Promoting major organizational and cultural change in a national system has required use of an evidence-based strategic framework, which has relied on several key tenets including the following: understanding the population of women Veterans served, developing research clinical partnerships, building interdisciplinary initiatives for system-wide integration of reproductive healthcare, and developing innovative tools for enhancing care delivery. This approach can serve as a model for other healthcare systems committed to developing an integrated system of reproductive healthcare and addressing reproductive health conditions in women with complex needs. C1 [Zephyrin, Laurie C.; Katon, Jodie G.] Womens Hlth Serv, Off Patient Care Serv, US Dept Vet Affairs, Washington, DC 20420 USA. [Zephyrin, Laurie C.] NYU, Dept Obstet & Gynecol, Langone Sch Med, New York, NY 10016 USA. [Katon, Jodie G.] VA Puget Sound Healthcare Syst, Seattle, WA USA. [Katon, Jodie G.] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Yano, Elizabeth M.] VA Greater Los Angeles Healthcare Syst, VA HSR Ctr Study Healthcare Innovat Implementat &, Los Angeles, CA USA. [Yano, Elizabeth M.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Los Angeles, CA USA. RP Zephyrin, LC (reprint author), Womens Hlth Serv, Off Patient Care Serv, US Dept Vet Affairs, 810 Vermont Ave, Washington, DC 20420 USA. EM Laurie.Zephyrin@va.gov FU US Department of Veteran Affairs, Office of Research and Development, Health Services Research and Development Senior Career Scientist Award [RCS 05-195] FX E.M.Y.'s time was supported by the US Department of Veteran Affairs, Office of Research and Development, Health Services Research and Development Senior Career Scientist Award to E.M.Y. (grant RCS 05-195). NR 27 TC 3 Z9 3 U1 3 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-872X EI 1473-656X J9 CURR OPIN OBSTET GYN JI Curr. Opin. Obstet. Gynecol. PD DEC PY 2014 VL 26 IS 6 BP 503 EP 510 DI 10.1097/GCO.0000000000000124 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AT5KL UT WOS:000344982000012 PM 25333678 ER PT J AU Terashima, AV Mudumana, SP Drummond, IA AF Terashima, Alexandra V. Mudumana, Sudha P. Drummond, Iain A. TI odd skipped related 1 Is a Negative Feedback Regulator of Nodal-Induced Endoderm Development SO DEVELOPMENTAL DYNAMICS LA English DT Article DE odd skipped related 1; osr1; nodal; endoderm development ID ONE-EYED-PINHEAD; ZEBRAFISH ENDODERM; FEEDFORWARD LOOP; GENE-EXPRESSION; GERM RING; PROTEIN; GASTRULATION; CASANOVA; SIGNALS; MESODERM AB Background: Early embryo patterning is orchestrated by tightly regulated morphogen gradients. The Nodal morphogen patterns the mesendoderm, giving rise to all endoderm and head and trunk mesoderm. High Nodal concentrations favor endoderm differentiation while lower promote mesoderm differentiation. Nodal signaling is controlled by both positive and negative feedback regulation to ensure robust developmental patterning. Results: Here we identify odd skipped related 1 (osr1), a zinc finger transcription factor, as a new element in Nodal feedback regulation affecting endoderm development. We show that osr1 expression in zebrafish germ ring mesendoderm requires Nodal signaling; osr1 expression was lost in embryos lacking Nodal signaling. Conversely, osr1 expression was ectopically induced by the activation of Nodal signaling. Furthermore we demonstrate that osr1 responds directly to Nodal signaling. Additionally, osr1 knockdown generated excess endoderm cells marked by sox32 expression while expression of osr1 mRNA was not affected in sox32-deficient embryos. Conclusions: Our findings identify osr1 as a Nodal-induced, negative feedback regulator of Nodal signaling that acts at the earliest stages of endoderm differentiation to limit the number of endoderm progenitors. As such, we propose that osr1 represents a novel network motif controlling the output of Nodal signaling to regulate mesendoderm patterning. Developmental Dynamics 243:1571-1580, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Terashima, Alexandra V.; Drummond, Iain A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Mudumana, Sudha P.; Drummond, Iain A.] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA. RP Drummond, IA (reprint author), Massachusetts Gen Hosp, Div Nephrol, 149 13th St,Rm 149-8000, Charlestown, MA 02129 USA. EM idrummond@mgh.harvard.edu FU NIH [R01 DK071041] FX Grant sponsor: NIH; Grant number: R01 DK071041. NR 49 TC 2 Z9 2 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1058-8388 EI 1097-0177 J9 DEV DYNAM JI Dev. Dyn. PD DEC PY 2014 VL 243 IS 12 BP 1571 EP 1580 DI 10.1002/dvdy.24191 PG 10 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA AU0JD UT WOS:000345308300007 PM 25233796 ER PT J AU Buchan, JG Gray, RS Gansner, JM Alvarado, DM Burgert, L Gitlin, JD Gurnett, CA Goldsmith, MI AF Buchan, Jillian G. Gray, Ryan S. Gansner, John M. Alvarado, David M. Burgert, Lydia Gitlin, Jonathan D. Gurnett, Christina A. Goldsmith, Matthew I. TI Kinesin Family Member 6 (kif6) Is Necessary for Spine Development in Zebrafish SO DEVELOPMENTAL DYNAMICS LA English DT Article DE kinesin; scoliosis; Danio rerio ID ADOLESCENT IDIOPATHIC SCOLIOSIS; CORONARY-HEART-DISEASE; TRP719ARG POLYMORPHISM; MYOCARDIAL-INFARCTION; GENE VARIANTS; GENOME; SUPERFAMILY; CILIA; IDENTIFICATION; ASSOCIATION AB Background: Idiopathic scoliosis is a form of spinal deformity that affects 2-3% of children and results in curvature of the spine without structural defects of the vertebral units. The pathogenesis of idiopathic scoliosis remains poorly understood, in part due to the lack of a relevant animal model. Results: We performed a forward mutagenesis screen in zebrafish to identify new models for idiopathic scoliosis. We isolated a recessive zebrafish mutant, called skolios, which develops isolated spinal curvature that arises independent of vertebral malformations. Using meiotic mapping and whole genome sequencing, we identified a nonsense mutation in kinesin family member 6 (kif6(gw326)) unique to skolios mutants. Three additional kif6 frameshift alleles (gw327, gw328, gw329) were generated with transcription activator-like effector nucleases (TALENs). Zebrafish homozygous or compound heterozygous for kif6 frameshift mutations developed a scoliosis phenotype indistinguishable from skolios mutants, confirming that skolios is caused by the loss of kif6. Although kif6 may play a role in cilia, no evidence for cilia dysfunction was seen in kif6(gw326) mutants. Conclusions: Overall, these findings demonstrate a novel role for kif6 in spinal development and identify a new candidate gene for human idiopathic scoliosis. Developmental Dynamics 243:1646-1657, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Buchan, Jillian G.; Goldsmith, Matthew I.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Gray, Ryan S.] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA. [Gansner, John M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Alvarado, David M.; Gurnett, Christina A.] Washington Univ, Sch Med, Dept Orthopaed Surg, St Louis, MO 63110 USA. [Burgert, Lydia; Gurnett, Christina A.; Goldsmith, Matthew I.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Gitlin, Jonathan D.] Marine Biol Lab, Eugene Bell Ctr Regenerat Biol, Woods Hole, MA 02543 USA. [Gurnett, Christina A.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. RP Goldsmith, MI (reprint author), Washington Univ, Sch Med, Dept Pediat, 660 S Euclid Ave,Campus Box 8208, St Louis, MO 63110 USA. EM goldsmith_m@kids.wustl.edu RI Gray, Ryan/G-2187-2010 OI Gray, Ryan/0000-0001-9668-6497 NR 51 TC 9 Z9 9 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1058-8388 EI 1097-0177 J9 DEV DYNAM JI Dev. Dyn. PD DEC PY 2014 VL 243 IS 12 BP 1646 EP 1657 DI 10.1002/dvdy.24208 PG 12 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA AU0JD UT WOS:000345308300014 PM 25283277 ER PT J AU Kulkarni, RN Stewart, AF AF Kulkarni, Rohit N. Stewart, Andrew F. TI Summary of the Keystone Islet Workshop (April 2014): The Increasing Demand for Human Islet Availability in Diabetes Research SO DIABETES LA English DT Article ID BETA-CELL PROLIFERATION; HUMAN PANCREATIC-ISLETS; ROAD MAP; DARK C1 [Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Med, Boston, MA 02115 USA. [Stewart, Andrew F.] Mt Sinai Sch Med, Diabet Obes & Metab Inst, New York, NY USA. RP Kulkarni, RN (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Med, Boston, MA 02115 USA. EM rohit.kulkarni@joslin.harvard.edu; andrew.stewart@mssm.edu FU Sanofi US; ALPCO Diagnostics; NIH from NIDDK; National Institute on Aging [5-R13-DK-084688-05] FX The authors also acknowledge the support of Keystone Symposia on Molecular and Cellular Biology (Keystone, CO) for holding this meeting, which was generously sponsored by Sanofi US with additional support from ALPCO Diagnostics and an NIH grant from NIDDK and the National Institute on Aging (grant no. 5-R13-DK-084688-05). NR 13 TC 9 Z9 9 U1 1 U2 6 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 DEC PY 2014 VL 63 IS 12 BP 3979 EP 3981 DI 10.2337/db14-1303 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU0ST UT WOS:000345335500003 PM 25414011 ER PT J AU Iovino, S Burkart, AM Kriauciunas, K Warren, L Hughes, KJ Molla, M Lee, YK Patti, ME Kahn, CR AF Iovino, Salvatore Burkart, Alison M. Kriauciunas, Kristina Warren, Laura Hughes, Katelyn J. Molla, Michael Lee, Youn-Kyoung Patti, Mary-Elizabeth Kahn, C. Ronald TI Genetic Insulin Resistance Is a Potent Regulator of Gene Expression and Proliferation in Human iPS Cells SO DIABETES LA English DT Article ID PLURIPOTENT STEM-CELLS; RECEPTOR GENE; GLUCOSE-METABOLISM; NONSENSE MUTATION; DONOHUE SYNDROME; SKELETAL-MUSCLE; MESSENGER-RNA; BINDING; TRANSPORT; FIBROBLASTS AB Insulin resistance is central to diabetes and metabolic syndrome. To define the consequences of genetic insulin resistance distinct from those secondary to cellular differentiation or in vivo regulation, we generated induced pluripotent stem cells (iPSCs) from individuals with insulin receptor mutations and age-appropriate control subjects and studied insulin signaling and gene expression compared with the fibroblasts from which they were derived. iPSCs from patients with genetic insulin resistance exhibited altered insulin signaling, paralleling that seen in the original fibroblasts. Insulin-stimulated expression of immediate early genes and proliferation were also potently reduced in insulin resistant iPSCs. Global gene expression analysis revealed marked differences in both insulin-resistant iPSCs and corresponding fibroblasts compared with control iPSCs and fibroblasts. Patterns of gene expression in patients with genetic insulin resistance were particularly distinct in the two cell types, indicating dependence on not only receptor activity but also the cellular context of the mutant insulin receptor. Thus, iPSCs provide a novel approach to define effects of genetically determined insulin resistance. This study demonstrates that effects of insulin resistance on gene expression are modified by cellular context and differentiation state. Moreover, altered insulin receptor signaling and insulin resistance can modify proliferation and function of pluripotent stem cell populations. C1 [Iovino, Salvatore; Burkart, Alison M.; Kriauciunas, Kristina; Warren, Laura; Hughes, Katelyn J.; Molla, Michael; Patti, Mary-Elizabeth; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Integrat Physiol & Metab Res Div, Boston, MA 02115 USA. [Lee, Youn-Kyoung] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Integrat Physiol & Metab Res Div, Boston, MA 02115 USA. EM mary.elizabeth.patti@joslin.harvard.edu; c.ronald.kahn@joslin.harvard.edu FU American Diabetes Association; Joslin Diabetes Center Diabetes and Research Center - Novo Nordisk Foundation [P30-DK-036836]; National Institutes of Health [R01-DK-31036]; Harvard Stem Cell Institute; [T32-DK-007260] FX A.M.B. was supported by grant T32-DK-007260 and the American Diabetes Association mentor-based fellowship (to M.-E. P.). This work was supported by a Joslin Diabetes Center Diabetes and Research Center grant (P30-DK-036836), funding from the Novo Nordisk Foundation (to M.-E. P. and C. R. K.), National Institutes of Health grant R01-DK-31036 (to C. R. K.), and pilot funding from the Harvard Stem Cell Institute. NR 48 TC 7 Z9 7 U1 0 U2 5 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 DEC PY 2014 VL 63 IS 12 BP 4130 EP 4142 DI 10.2337/db14-0109 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU0ST UT WOS:000345335500024 PM 25059784 ER PT J AU Yaghootkar, H Scott, RA White, CC Zhang, WH Speliotes, E Munroe, PB Ehret, GB Bis, JC Fox, CS Walker, M Borecki, IB Knowles, JW Yerges-Armstrong, L Ohlsson, C Perry, JRB Chambers, JC Kooner, JS Franceschini, N Langenberg, C Hivert, MF Dastani, Z Richards, JB Semple, RK Frayling, TM AF Yaghootkar, Hanieh Scott, Robert A. White, Charles C. Zhang, Weihua Speliotes, Elizabeth Munroe, Patricia B. Ehret, Georg B. Bis, Joshua C. Fox, Caroline S. Walker, Mark Borecki, Ingrid B. Knowles, Joshua W. Yerges-Armstrong, Laura Ohlsson, Claes Perry, John R. B. Chambers, John C. Kooner, Jaspal S. Franceschini, Nora Langenberg, Claudia Hivert, Marie-France Dastani, Zari Richards, J. Brent Semple, Robert K. Frayling, Timothy M. TI Genetic Evidence for a Normal-Weight "Metabolically Obese" Phenotype Linking Insulin Resistance, Hypertension, Coronary Artery Disease, and Type 2 Diabetes SO DIABETES LA English DT Article ID ADIPOSE-TISSUE EXPANDABILITY; GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; PPAR-GAMMA; PLASMA ADIPONECTIN; GLYCEMIC TRAITS; LOCI; VARIANTS; LIPOTOXICITY; PATHWAYS AB The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy-a reduction in subcutaneous adipose tissue-it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin-based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (beta = 0.018; P = 4 x 10(-29)), lower HDL cholesterol (beta = -0.020; P = 7 x 10(-37)), greater hepatic steatosis (beta = 0.021; P = 3 x 10(-4)), higher alanine transaminase (beta = 0.002; P = 3 x 10(-5)), lower sex-hormone-binding globulin (beta = -0.010; P = 9 x 10(-13)), and lower adiponectin (beta = -0.015; P = 2 x 10(-26)). The same risk alleles were associated with lower BMI (per-allele beta = -0.008; P = 7 x 10(-8)) and increased visceral-to-subcutaneous adipose tissue ratio (beta = -0.015; P = 6 x 10(-7)). Individuals carrying >= 17 fasting insulin-raising alleles (5.5% population) were slimmer (0.30 kg/m(2)) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 x 10(-13)), CAD (OR 1.12; per-allele P = 1 x 10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 x 10(-5)] and 0.67 mmHg [per-allele P = 2 x 10(-4)], respectively) compared with individuals carrying <= 9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism. C1 [Yaghootkar, Hanieh] Univ Exeter, Sch Med, Exeter, Devon, England. [Scott, Robert A.; Perry, John R. B.; Langenberg, Claudia] Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [White, Charles C.; Fox, Caroline S.] NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. [White, Charles C.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Zhang, Weihua; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Speliotes, Elizabeth] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Barts & London Genome Ctr, London, England. [Ehret, Georg B.] Univ Hosp Geneva, Ctr Cardiol, Geneva, Switzerland. [Ehret, Georg B.] Johns Hopkins Univ, Inst Med Genet, Baltimore, MD USA. [Bis, Joshua C.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Bis, Joshua C.] Univ Washington, Dept Med, Seattle, WA USA. [Fox, Caroline S.] NHLBI, Ctr Populat Studies, NIH, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Knowles, Joshua W.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Knowles, Joshua W.] Stanford Univ, Sch Med, Cardiovasc Inst, Stanford, CA 94305 USA. [Yerges-Armstrong, Laura] Univ Maryland, Sch Med, Div Endocrinol, Baltimore, MD 21201 USA. [Ohlsson, Claes] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden. [Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Langenberg, Claudia] UCL, Dept Epidemiol & Publ Hlth, London, England. [Hivert, Marie-France] Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA USA. [Hivert, Marie-France] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Dastani, Zari] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Dastani, Zari] McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ, Canada. [Richards, J. Brent] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Richards, J. Brent] McGill Univ, Dept Med Human Genet Epidemiol & Biostat, Montreal, PQ, Canada. [Semple, Robert K.] Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England. [Semple, Robert K.] Univ Cambridge, Metab Res Labs, Inst Metab Sci, Cambridge, England. RP Frayling, TM (reprint author), Univ Exeter, Sch Med, Exeter, Devon, England. EM t.m.frayling@ex.ac.uk OI Semple, Robert/0000-0001-6539-3069 FU European Research Council [ERS: 323195]; Wellcome Trust; University of Exeter Medical School; National Institute for Health Research Barts Cardiovascular Biomedical Research Unit FX The authors thank the European Research Council (ERS: 323195), Wellcome Trust, and University of Exeter Medical School. P. B. M. acknowledges the National Institute for Health Research Barts Cardiovascular Biomedical Research Unit for supporting this work. NR 37 TC 32 Z9 32 U1 0 U2 16 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 DEC PY 2014 VL 63 IS 12 BP 4369 EP 4377 DI 10.2337/db14-0318 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU0ST UT WOS:000345335500045 PM 25048195 ER PT J AU Brooks-Worrell, BM Boyko, EJ Palmer, JP AF Brooks-Worrell, Barbara M. Boyko, Edward J. Palmer, Jerry P. TI Impact of Islet Autoimmunity on the Progressive beta-Cell Functional Decline in Type 2 Diabetes SO DIABETES CARE LA English DT Article ID GLUTAMIC-ACID DECARBOXYLASE; INSULIN REQUIREMENT; ADULTS LADA; AUTOANTIBODIES; ANTIBODIES; MELLITUS; RESPONSES; PREVALENCE; DIAGNOSIS; PROTEINS AB OBJECTIVE Cross-sectional studies have suggested that islet autoimmunity may be more prevalent in type 2 diabetes (T2D) than previously appreciated and may contribute to the progressive decline in beta-cell function. In this study, we longitudinally evaluated the effect of islet autoimmune development on the progressive beta-cell dysfunction in T2D patients. RESEARCH DESIGN AND METHODS Twenty-three T2D patients negative for islet autoantibodies (GAD antibody and insulinoma-associated protein 2) and islet-specific T cells were evaluated prospectively for up to 36 months. We investigated the percentage of patients who developed islet autoantibodies (Ab+) and/or islet-reactive T cells (T+) and the effect of the islet autoimmunity on fasting and glucagon-stimulated C-peptide responses. We defined positive islet autoimmunity as Ab+ and/or T+ for at least two study visits. RESULTS Of the 23 patients, 6(26%) remained negative for islet autoimmunity (Ab T), 14 (61%) developed Ab+ and/or T+, and 3 (13%) were unclassifiable because they developed islet autoimmunity at only one study visit. Islet Ab+ was observed to be less stable than islet-specific T-cell responses. Development of islet autoimmunity was significantly associated with a more rapid decline in fasting (P < 0.0001) and glucagon-stimulated (P < 0.05) C-peptide responses. CONCLUSIONS These pilot data suggest that the development of islet autoimmunity in T2D is associated with a significantly more rapid beta-cell functional decline. C1 [Brooks-Worrell, Barbara M.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, Dept Med, Seattle, WA USA. RP Brooks-Worrell, BM (reprint author), VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. EM bbrooks@u.washington.edu FU National Institutes of Health [P01-DK-053004, P30-DK-017047] FX This work was supported by resources from the VA Puget Sound Health Care System, Seattle, WA. In addition, partial support was provided by National Institutes of Health grants P01-DK-053004 and P30-DK-017047. NR 38 TC 10 Z9 10 U1 1 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 DEC PY 2014 VL 37 IS 12 BP 3286 EP 3293 DI 10.2337/dc14-0961 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU0SQ UT WOS:000345335200038 PM 25239783 ER PT J AU Garvey, WT Ryan, DH Bohannon, NJV Kushner, RF Rueger, M Dvorak, RV Troupin, B AF Garvey, W. Timothy Ryan, Donna H. Bohannon, Nancy J. V. Kushner, Robert F. Rueger, Miriam Dvorak, Roman V. Troupin, Barbara TI Weight-Loss Therapy in Type 2 Diabetes: Effects of Phentermine and Topiramate Extended Release SO DIABETES CARE LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; LIFE-STYLE INTERVENTION; EUROPEAN-ASSOCIATION; CONSENSUS STATEMENT; METABOLIC SYNDROME; OBESE ADULTS; OVERWEIGHT; MANAGEMENT; ALGORITHM; MELLITUS AB Treatment algorithms for type 2 diabetes recommend weight loss for disease management. The safety and efficacy of treatment with phentermine (PHEN)/topiramate (TPM) extended release (ER) plus lifestyle modification for weight loss and glycemic benefits were assessed in two randomized, double-blind, placebo-controlled 56-week studies of obese/overweight adults with type 2 diabetes. RESEARCH DESIGN AND METHODS The OB-202/DM-230 Study was a 56-week phase 2 trial that randomized subjects to receive once-daily placebo or PHEN/TPMER 15 mg/92 mg (15/92). The primary end point was change in HbA(1c) level. A post hoc analysis of a subpopulation with type 2 diabetes from a second study, CONQUER, is also presented. All subjects made lifestyle modifications, and comorbidities were managed to the standard of care. RESULTS The study groups comprised 130 subjects with type 2 diabetes enrolled in the OB-202/DM-230 Study (mean baseline HbA(1c) 8.7% [72 mmol/mol]) and 388 subjects with type 2 diabetes in the CONQUER Study (mean baseline HbA1c 6.8% [51 mmol/mol]). At week 56 in the OB-202/DM-230, change in weight (from intent-to-treat sample with last observation carried forward [ITT-LOCF]) was - 22.7% for placebo and -9.4% for PHEN/TPM ER 15/92 (P < 0.0001 vs. placebo). Change in HbA(1c) level (from ITT-LOCF) was 21.2% (-13.1 mmol/mol) for placebo and -1.6% (-17.5 mmol/mol) for PHEN/TPM ER 15/92 (P = 0.0381). In both the OB-202/DM-230 and CONQUER, greater numbers of patients randomized to receive PHEN/TPM ER treatment achieved HbA(1c) targets with reduced need for diabetic medications when compared with the placebo group. Common adverse events included paraesthesia, constipation, and insomnia. CONCLUSIONS PHEN/TPM ER plus lifestyle modification can effectively promote weight loss and improve glycemic control as a treatment approach in obese/overweight patients with type 2 diabetes. C1 [Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Garvey, W. Timothy] Birmingham VA Med Ctr, Birmingham, AL USA. [Ryan, Donna H.] Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Bohannon, Nancy J. V.] Monteagle Med Ctr, San Francisco, CA USA. [Kushner, Robert F.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Rueger, Miriam] Univ Alabama Birmingham, Birmingham, AL USA. [Dvorak, Roman V.; Troupin, Barbara] VIVUS Inc, Mountain View, CA USA. RP Garvey, WT (reprint author), Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. EM garveyt@uab.edu FU VIVUS, Inc. FX Funding for the study and for editorial assistance was provided by VIVUS, Inc. NR 28 TC 18 Z9 18 U1 3 U2 12 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 DEC PY 2014 VL 37 IS 12 BP 3309 EP 3316 DI 10.2337/dc14-0930 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU0SQ UT WOS:000345335200041 PM 25249652 ER PT J AU Gabbay, RA McGinley, EL AF Gabbay, Robert A. McGinley, Erin L. TI The Affordable Care Act, Technology, and Type 1 Diabetes Mellitus SO DIABETES TECHNOLOGY & THERAPEUTICS LA English DT Editorial Material C1 [Gabbay, Robert A.; McGinley, Erin L.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Gabbay, Robert A.] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Gabbay, RA (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM Robert.Gabbay@joslin.harvard.edu NR 11 TC 1 Z9 1 U1 2 U2 3 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 DEC 1 PY 2014 VL 16 IS 12 BP 819 EP 821 DI 10.1089/dia.2014.0258 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU3GH UT WOS:000345499900001 PM 25437015 ER PT J AU Jaacks, LM Ma, Y Davis, N Delahanty, LM Mayer-Davis, EJ Franks, PW Brown-Friday, J Isonaga, M Kriska, AM Venditti, EM Wylie-Rosett, J AF Jaacks, L. M. Ma, Y. Davis, N. Delahanty, L. M. Mayer-Davis, E. J. Franks, P. W. Brown-Friday, J. Isonaga, M. Kriska, A. M. Venditti, E. M. Wylie-Rosett, J. CA Diabet Prevention Program Res Grp TI Long-term changes in dietary and food intake behaviour in the Diabetes Prevention Program Outcomes Study SO DIABETIC MEDICINE LA English DT Article ID LIFE-STYLE INTERVENTION; IMPAIRED GLUCOSE-TOLERANCE; FOLLOW-UP; SUSTAINED REDUCTION; MEDITERRANEAN DIET; MODIFICATION TRIAL; WEIGHT-LOSS; BASE-LINE; COHORT; RISK AB Aims To compare change in dietary intake, with an emphasis on food groups and food intake behaviour, over time across treatment arms in a diabetes prevention trial and to assess the differences in dietary intake among demographic groups within treatment arms. Methods Data are from the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. Participants were randomized to a lifestyle intervention (n = 1079), metformin (n = 1073) or placebo (n = 1082) for an average of 3 years, after which the initial results regarding the benefits of the lifestyle intervention were released and all participants were offered a modified lifestyle intervention. Dietary intake was assessed using a food frequency questionnaire at baseline and at 1, 5, 6 and 9 years after randomization. Results Compared with the metformin and placebo arms, participants in the lifestyle arm maintained a lower total fat and saturated fat and a higher fibre intake up to 9 years after randomization and lower intakes of red meat and sweets were maintained for up to 5 years. Younger participants had higher intakes of poultry and lower intakes of fruits compared with their older counterparts, particularly in the lifestyle arm. Black participants tended to have lower dairy and higher poultry intakes compared with white and Hispanic participants. In the lifestyle arm, men tended to have higher grain, fruit and fish intakes than women. Conclusions Changes in nutrient intake among participants in the lifestyle intervention were maintained for up to 9 years. Younger participants reported more unhealthy diets over time and thus may benefit from additional support to achieve and maintain dietary goals. C1 [Jaacks, L. M.; Mayer-Davis, E. J.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Ma, Y.] George Washington Univ, Washington, DC USA. [Davis, N.; Brown-Friday, J.; Wylie-Rosett, J.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Delahanty, L. M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Delahanty, L. M.] Harvard Univ, Sch Med, Boston, MA USA. [Mayer-Davis, E. J.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Franks, P. W.] Lund Univ, Malmo, Sweden. [Franks, P. W.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Isonaga, M.] Univ Hawaii, Honolulu, HI 96822 USA. [Kriska, A. M.; Venditti, E. M.] Univ Pittsburgh, Pittsburgh, PA USA. RP Wylie-Rosett, J (reprint author), Albert Einstein Coll Med, Bronx, NY 10467 USA. EM judith.wylie-rosett@einstein.yu.edu OI Franks, Paul/0000-0002-0520-7604; Kriska, Andrea/0000-0002-3522-0869 FU DPPOS, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health [U01 DK048489]; NIDDK; Indian Health Service; National Institute of Child Health and Human Development; National Institute on Aging; National Eye Institute; National Heart Lung and Blood Institute; Office of Research on Women's Health; National Institute on Minority Health and Health Disparities; Centers for Disease Control and Prevention; American Diabetes Association; Bristol-Myers Squibb; Parke-Davis FX During the DPPOS, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centres and the coordinating centre for the design and conduct of the study, and collection, management, analysis and interpretation of the data (U01 DK048489). The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centres. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the Office of Research on Women's Health, the National Institute on Minority Health and Health Disparities, the Centers for Disease Control and Prevention and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided additional funding and material support during the DPP, Lipha (Merck-Sante) provided medication and LifeScan Inc. donated materials during the DPP and the DPPOS. The opinions expressed are those of the investigators and do not necessarily reflect the views of the funding agencies. A complete list of centres, investigators and staff can be found in the Appendix S2. NR 29 TC 3 Z9 3 U1 2 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0742-3071 EI 1464-5491 J9 DIABETIC MED JI Diabetic Med. PD DEC PY 2014 VL 31 IS 12 BP 1631 EP 1642 DI 10.1111/dme.12500 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AU0GQ UT WOS:000345302100024 PM 24824893 ER PT J AU Muzes, G Sipos, F Furi, I Constantinovits, M Spisak, S Wichmann, B Valcz, G Tulassay, Z Molnar, B AF Muzes, Gyoergyi Sipos, Ferenc Furi, Istvan Constantinovits, Miklos Spisak, Sandor Wichmann, Barnabas Valcz, Gabor Tulassay, Zsolt Molnar, Bela TI Preconditioning with Intravenous Colitic Cell-Free DNA Prevents DSS-Colitis by Altering TLR9-Associated Gene Expression Profile SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Preconditioning; Cell-free DNA; DSS-colitis; Toll-like receptor 9; Cytokines; Tissue regeneration ID DEXTRAN SULFATE SODIUM; TOLL-LIKE RECEPTORS; INFLAMMATORY BOWEL DISEASES; MATERNAL PERIPHERAL-BLOOD; ACTIVE ULCERATIVE-COLITIS; NF-KAPPA-B; NUCLEIC-ACIDS; COLORECTAL-CANCER; FETAL DNA; IN-VIVO AB Background Presence of cell-free-circulating DNA (fcDNA) sequences in sera of patients with inflammatory bowel diseases (IBD) is a well-established phenomenon. Potential roles of fcDNA in diagnosis, prognosis and therapy monitoring of chronic inflammatory colonic disorders have already been examined, albeit its actual biological function still remains unclear. Aims and Methods In the present experiment, we studied the immunobiological effects of isolated fcDNA of normal and inflammatory origin administered intravenously to mice prior to induction of dextran sulfate sodium (DSS)-colitis. In addition to evaluate the current disease and histological activity, changes of the gene expression profile in isolated lamina propria cells upon TLR9 ligation were assayed. Results A single intravenous dose of fcDNA pretreatment with colitic fcDNA exhibited beneficial response concerning the clinical and histological severity of DSS-colitis as compared to effects of normal fcDNA. Pretreatment with colitic fcDNA substantially altered the expression of several TLR9-related and inflammatory cytokine genes in a clinically favorable manner. Conclusions During the process of acute colitis, the subsequent inflammatory environment presumably results in changes of fcDNA with the potential to facilitate the downregulation of inflammation and improvement of regeneration. Thus, preconditioning of mice with colitis-derived fcDNA via TLR9 signaling could exert a tissue-protective effect and influence beneficially the course of DSS-colitis. Elucidating mechanisms of immune response alterations by nucleic acids may provide further insight into the etiology of IBD and develop the basis of novel immunotherapies. C1 [Muzes, Gyoergyi; Sipos, Ferenc; Furi, Istvan; Constantinovits, Miklos; Wichmann, Barnabas; Valcz, Gabor; Tulassay, Zsolt; Molnar, Bela] Semmelweis Univ, Dept Internal Med 2, H-1088 Budapest, Hungary. [Spisak, Sandor] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Spisak, Sandor; Tulassay, Zsolt; Molnar, Bela] Hungarian Acad Sci, Mol Med Res Unit, Budapest, Hungary. RP Muzes, G (reprint author), Semmelweis Univ, Dept Internal Med 2, Szentkiralyi St 46, H-1088 Budapest, Hungary. EM muzes.gyorgyi@med.semmelweis-univ.hu OI Valcz, Gabor/0000-0002-7109-3529 NR 82 TC 0 Z9 0 U1 1 U2 6 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 DEC PY 2014 VL 59 IS 12 BP 2935 EP 2946 DI 10.1007/s10620-014-3325-x PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU0OG UT WOS:000345322100012 PM 25217236 ER PT J AU Oh, HC Kang, H Brugge, WR AF Oh, Hyoung-Chul Kang, Hyun Brugge, William R. TI Cyst Fluid Amylase and CEA Levels in the Differential Diagnosis of Pancreatic Cysts: A Single-Center Experience with Histologically Proven Cysts SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Pancreatic cyst; Amylase; Carcinoembryonic antigen; Diagnosis ID PAPILLARY MUCINOUS NEOPLASMS; FINE-NEEDLE-ASPIRATION; CARCINOEMBRYONIC ANTIGEN; LESIONS; PERFORMANCE; PREVALENCE AB Objective Cyst fluid amylase is a potential marker for pseudocysts and intraductal papillary mucinous neoplasms (IPMN). This study aimed to evaluate the diagnostic role of cyst fluid amylase and to determine the optimal cutoff values of cyst fluid amylase and carcinoembryonic antigen (CEA) for the differential diagnosis of pancreatic cysts. Methods Based on the pancreatic cyst database at Massachusetts General Hospital, a total of 78 patients with histologically proven cysts [pancreatic pseudocyst (PP), n = 16; mucinous cystic neoplasm, mucinous cystic neoplasm (MCN), n = 22; IPMN, n = 40] were selected. Complete cyst fluid amylase and CEA values were analyzed. Results Thirty two of 78 patients were male with median age of 60.4 years (range, 24-84). Cyst diameter ranged from 5 to 130 mm. For cyst fluid amylase, there was significant difference between PP and MCN (median, 30,034.50 vs. 4,723.50 U/L; p < 0.05) or IPMN (30,034.50 vs. 1,585.00; p = 0.001), but no difference between MCN and IPMN. For cyst fluid CEA, there was a significant difference between PP and MCN (median, 26.00 vs. 627.50 ng/mL; p < 0.001) or IPMN (26.00 vs. 356.50; p < 0.001). Median amylase and CEA values were significantly different between PP and mucinous neoplasms (MCN/IPMN) (p < 0.01 and p < 0.001). Optimal cutoff values of 6,800 U/mL for amylase and 50 ng/mL for CEA correlated with the crossover of the sensitivity and specificity curves for differentiating PP and mucinous neoplasms. The overall accuracies of cyst fluid amylase and CEA were 69 and 85 %, respectively. Conclusions Cyst fluid amylase analysis does not differentiate between MCN and IPMN. The combination of cyst fluid CEA and amylase value may increase the diagnostic accuracy for differentiating mucinous neoplasms from pseudocysts. C1 [Oh, Hyoung-Chul; Brugge, William R.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Oh, Hyoung-Chul] Chung Ang Univ, Coll Med, Div Gastroenterol, Seoul 156756, South Korea. [Kang, Hyun] Chung Ang Univ, Coll Med, Dept Anesthesiol, Seoul 156756, South Korea. RP Oh, HC (reprint author), Chung Ang Univ, Coll Med, Div Gastroenterol, Seoul 156756, South Korea. EM ohcgi@cau.ac.kr NR 24 TC 8 Z9 8 U1 1 U2 5 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 DEC PY 2014 VL 59 IS 12 BP 3111 EP 3116 DI 10.1007/s10620-014-3254-8 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AU0OG UT WOS:000345322100034 PM 24965184 ER PT J AU Ambwani, S Slane, JD Thomas, KM Hopwood, CJ Grilo, CM AF Ambwani, Suman Slane, Jennifer D. Thomas, Katherine M. Hopwood, Christopher J. Grilo, Carlos M. TI Interpersonal dysfunction and affect-regulation difficulties in disordered eating among men and women SO EATING BEHAVIORS LA English DT Article DE Interpersonal functioning; Negative affect; Emotion regulation; Disordered eating; Gender differences ID ANOREXIA-NERVOSA; BODY DISSATISFACTION; EMOTIONAL EXPRESSION; MODEL; MAINTENANCE; PSYCHOPATHOLOGY; QUESTIONNAIRE; DYSREGULATION; VALIDATION; PATHOLOGY AB Although several studies suggest that negative affect and interpersonal problems serve as important contributors for eating-related problems, much of this research has been conducted among women and less is known about their roles in precipitating and maintaining eating problems among men. Previous studies with undergraduate men suggest that difficulties in emotion regulation are associated with disordered eating even after controlling for differences in body mass index (BMI) and negative affect. The present study sought to replicate these findings and extend them to assess any unique variance explained by problems in interpersonal functioning among both men and women. Participants were men (n = 213) and women (n = 521) undergraduates at a large Midwestern university who completed a demographic information form, the Eating Disorder Examination-Questionnaire (EDE-Q), the Difficulties in Emotion Regulation Scale (DERS), the Positive and Negative Affect Schedule, and the Inventory of Interpersonal Problems-Short Circumplex Form(IIP-SC). A series of hierarchical regression analyses indicated that DERS and IIP-SC significantly predicted EDE-Q global scores after controlling for variability in BMI and negative affect and that the results were similar for men and women. Our findings offer preliminary support for models that highlight emotional vulnerability and interpersonal problems for disordered eating for young adult men. Future research extending these findings among treatment-seeking samples and employing multi-method assessment would serve to further clarify the tenability of these theoretical models for both men and women. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Ambwani, Suman] Dickinson Coll, Dept Psychol, Carlisle, PA 17013 USA. [Slane, Jennifer D.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15261 USA. [Slane, Jennifer D.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15213 USA. [Thomas, Katherine M.; Hopwood, Christopher J.] Michigan State Univ, Dept Psychol, E Lansing, MI 48824 USA. [Grilo, Carlos M.] Yale Univ, Dept Psychiat, Sch Med, New Haven, CT 06511 USA. RP Ambwani, S (reprint author), Dickinson Coll, Dept Psychol, POB 1773, Carlisle, PA 17013 USA. EM Ambwanis@dickinson.edu NR 34 TC 5 Z9 5 U1 3 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1471-0153 EI 1873-7358 J9 EAT BEHAV JI Eat. Behav. PD DEC PY 2014 VL 15 IS 4 BP 550 EP 554 DI 10.1016/j.eatbeh.2014.08.005 PG 5 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AU1TJ UT WOS:000345402700007 PM 25194562 ER PT J AU Kwan, MY Gordon, KH Eddy, KT Thomas, JJ Franko, DL Troop-Gordon, W AF Kwan, Mun Yee Gordon, Kathryn H. Eddy, Kamryn T. Thomas, Jennifer J. Franko, Debra L. Troop-Gordon, Wendy TI Gender differences in coping responses and bulimic symptoms among undergraduate students SO EATING BEHAVIORS LA English DT Article DE Coping; Involuntary disengagement; Bulimic symptoms; Social stress ID EATING-DISORDERS; BODY DISSATISFACTION; STRESS; ADOLESCENCE; VALIDATION; INVENTORY; STYLE; WOMEN AB This prospective study examined the predictive role of three types of coping responses (i.e., voluntary disengagement, involuntary engagement, and involuntary disengagement) in response to social stress on bulimic symptoms among undergraduate women and men. A total of 883 (308 men; 35%) participants completed the Response to Stress Questionnaire, the Beck Depression Inventory, and the Eating Disorder Inventory (EDI) at baseline assessment and the EDI at follow-up assessment 8-12 weeks later. After controlling for baseline bulimic symptoms, depression, and body dissatisfaction, involuntary disengagement predicted bulimic symptoms at follow-up among men (b = .21, p < .001), but not among women (b = .06, p > .05). Results indicated that men who responded to social stress through involuntary disengagement (e. g., emotional numbing, inaction) had higher risk for increased bulimic symptoms. Future studies are needed to replicate these findings and to further understand the role of these coping responses on bulimic symptoms. Published by Elsevier Ltd. C1 [Kwan, Mun Yee; Gordon, Kathryn H.; Troop-Gordon, Wendy] N Dakota State Univ, Dept Psychol, Fargo, ND 58108 USA. [Gordon, Kathryn H.] Neuropsychiat Res Inst, Fargo, ND 58102 USA. [Eddy, Kamryn T.; Thomas, Jennifer J.; Franko, Debra L.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Eddy, Kamryn T.; Thomas, Jennifer J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Franko, Debra L.] Northwestern Univ, Dept Counseling & Appl Educ Psychol, Boston, MA 02115 USA. RP Kwan, MY (reprint author), N Dakota State Univ, Dept Psychol, Minard 232, Fargo, ND 58108 USA. EM munyee.kwan@my.ndsu.edu NR 32 TC 1 Z9 1 U1 3 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1471-0153 EI 1873-7358 J9 EAT BEHAV JI Eat. Behav. PD DEC PY 2014 VL 15 IS 4 BP 632 EP 637 DI 10.1016/j.eatbeh.2014.08.020 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AU1TJ UT WOS:000345402700023 PM 25248128 ER PT J AU Ducrocq, G Bhatt, DL Labreuche, J Corbalan, R Porath, A Gao, R Panchenko, E Liau, CS Ikeda, Y Goto, S Amarenco, P Steg, PG AF Ducrocq, G. Bhatt, D. L. Labreuche, J. Corbalan, R. Porath, A. Gao, R. Panchenko, E. Liau, C. S. Ikeda, Y. Goto, S. Amarenco, P. Steg, P. G. TI Geographic differences in outcomes in outpatients with established atherothrombotic disease: results from the REACH Registry SO EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY LA English DT Article DE Geographic differences; atherothrombotic disease; ischemic outcomes; bleeding ID ACUTE CORONARY SYNDROMES; CARDIOVASCULAR EVENT RATES; EURO HEART SURVEY; BODY-MASS INDEX; SECONDARY PREVENTION; STABLE OUTPATIENTS; INCOME COUNTRIES; MIDDLE-INCOME; GLOBAL BURDEN; MANAGEMENT AB Aims There are major differences in the prevalence and management of patients with atherothrombotic disease including coronary artery disease (CAD), cerebrovascular disease (CVD) and peripheral artery disease (PAD) across different geographical regions. There is, however, little data allowing comparisons of management and outcomes across broad geographic regions. We aimed to describe geographical differences in baseline characteristics, management and outcomes in stable outpatients with established atherothrombotic disease. Methods and results From the REACH Registry of atherothrombosis, patients with documented CAD, PAD or CVD and with 4-year follow-up were included. Baseline characteristics, treatments and 4-year outcomes were recorded. Event rates were compared between geographical regions and were adjusted for risk scores predicting ischemic and bleeding events. The analyses of baseline characteristics and medications according to geographical region showed marked differences. For the composite primary outcome (cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke), rates ranged from 12.1% in Japan to 18.2% in Eastern Europe. After adjustment, substantial variations remained: taking North America as a reference, patients from Western Europe and Japan had a lower risk of primary outcome event (hazard ratio (HR) 0.93; p=0.045, and HR=0.67; p<0.001 respectively) whereas patients from Eastern Europe had a higher risk (HR=1.24; p<0.001). There were no obvious differences between patients from North America and those from Latin America, the Middle East and Asia. Conclusion There are important variations in the outcomes of patients with atherothrombotic across geographic regions. These observations have important implications for public health and clinical research. C1 [Ducrocq, G.; Labreuche, J.; Amarenco, P.; Steg, P. G.] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France. [Ducrocq, G.; Labreuche, J.; Amarenco, P.; Steg, P. G.] Hop Bichat Paris, AP HP, Paris, France. [Ducrocq, G.; Labreuche, J.; Amarenco, P.; Steg, P. G.] INSERM, U698, F-75877 Paris 18, France. [Bhatt, D. L.] Harvard Univ, Brigham & Womens Hosp, VA Boston Healthcare Syst, Sch Med, Cambridge, MA 02138 USA. [Corbalan, R.] Pontificia Univ Catolica Chile, Santiago, Chile. [Porath, A.] Ben Gurion Univ Negev, Dept Epidemiol, IL-84105 Beer Sheva, Israel. [Gao, R.] Cardiovasc Inst, Beijing, Peoples R China. [Gao, R.] Fuwai Hosp, Beijing, Peoples R China. [Panchenko, E.] Cardiol Res Ctr, Moscow, Russia. [Liau, C. S.] Natl Taiwan Univ Hosp, Taipei, Taiwan. [Ikeda, Y.] Kokura Mem Hosp, Fukuoka, Japan. [Goto, S.] Tokai Univ, Hiratsuka, Kanagawa 25912, Japan. RP Ducrocq, G (reprint author), INSERM, U698, 46 Rue Henri Huchard, F-75877 Paris 18, France. EM gregory.ducrocq@bch.aphp.fr FU Astra Zeneca; Departement Hospitalo-Universitaire FIRE of Universite Paris-Diderot and Assistance Publique - Hopitaux de Paris FX This analysis was supported by Astra Zeneca and by the Departement Hospitalo-Universitaire FIRE of Universite Paris-Diderot and Assistance Publique - Hopitaux de Paris. NR 27 TC 6 Z9 7 U1 2 U2 7 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 DEC PY 2014 VL 21 IS 12 BP 1509 EP 1516 DI 10.1177/2047487313501278 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT9CF UT WOS:000345224900008 PM 23965467 ER PT J AU Yip, WK Fier, H DeMeo, DL Aryee, M Laird, N Lange, C AF Yip, Wai-Ki Fier, Heide DeMeo, Dawn L. Aryee, Martin Laird, Nan Lange, Christoph TI A Novel Method for Detecting Association Between DNA Methylation and Diseases Using Spatial Information SO GENETIC EPIDEMIOLOGY LA English DT Article DE DNA methylation; spatial analysis; genetic analysis; Genome-Wide Association Test (GWAS); differentially methylated regions (DMRs) ID EPIGENETIC EPIDEMIOLOGY; MISSING HERITABILITY; CANCER AB DNA methylation may represent an important contributor to the missing heritability described in complex trait genetics. However, technology to measure DNA methylation has outpaced statistical methods for analysis. Taking advantage of the recent finding that methylated sites cluster together, we propose a Spatial Clustering Method (SCM) to detect differentially methylated regions (DMRs) in the genome in case and control studies using spatial location information. This new method compares the distribution of distances in cases and controls between DNA methylation marks in the genomic region of interest. A statistic is computed based on these distances. Proper type I error rate is maintained and statistical significance is evaluated using permutation test. The effectiveness of the SCM we propose is evaluated by a simulation study. By simulating a simple disease model, we demonstrate that SCM has good power to detect DMRs associated with the disease. Finally, we applied the SCM to an exploratory analysis of chromosome 14 from a colorectal cancer data set and identified statistically significant genomic regions. Identification of these regions should lead to a better understanding of methylated sites and their contribution to disease. The SCM can be used as a reliable statistical method for the identification of DMRs associated with disease states in exploratory epigenetic analyses. C1 [Yip, Wai-Ki] Harvard Univ, Boston, MA 02115 USA. [Fier, Heide] Univ Bonn, Dept Genom Math, Bonn, Germany. [DeMeo, Dawn L.] Brigham & Women Hosp, Channing Div Network Med, Boston, MA USA. [Aryee, Martin] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Laird, Nan; Lange, Christoph] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Yip, WK (reprint author), BioStat Dept, 855 Huntington Ave,Bldg II,4th Floor, Boston, MA 02115 USA. EM wkyip@hsph.harvard.edu FU Clinical Epidemiology of Lung Diseases Training Grant [T32 HL 007427] FX We would like to thank Dr. Emily Wan for her assistance in the preparation of the COPD data set and the TCGA Research Network for making the COAD data set publicly available. Generation of the methylation data included in the simulation (es_ICGN) was supported by NIH/NHLBI R01 HL089438. DLD is additionally supported by P01 HL 105339 and P01 HL 083069. We would also like to acknowledge the support of Wai-Ki Yip by the Clinical Epidemiology of Lung Diseases Training Grant (T32 HL 007427). NR 18 TC 1 Z9 2 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 EI 1098-2272 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2014 VL 38 IS 8 BP 714 EP 721 DI 10.1002/gepi.21851 PG 8 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA AU0DD UT WOS:000345292600007 PM 25250875 ER PT J AU Tamers, SL Allen, J Yang, M Stoddard, A Harley, A Sorensen, G AF Tamers, Sara L. Allen, Jennifer Yang, May Stoddard, Anne Harley, Amy Sorensen, Glorian TI Does Concern Motivate Behavior Change? Exploring the Relationship Between Physical Activity and Body Mass Index Among Low-Income Housing Residents SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE body mass index; concerns; low-income; physical activity; racial; ethnic minorities ID RISK PERCEPTIONS; UNREALISTIC OPTIMISM; HEALTH BEHAVIOR; WEIGHT STATUS; FEAR APPEALS; WOMEN; SUSCEPTIBILITY; MODEL; OVERWEIGHT; BARRIERS AB Objective. To explore relationships between concerns and physical activity and body mass index (BMI) among a racially/ethnically diverse low-income population. Method. A cross-sectional survey documented behavioral risks among racially/ethnically diverse low-income residents in the Boston area (2005-2009). Multivariable logistic regressions were conducted in 2012 for each concern, using SAS version 9.2. Results. Those very/moderately concerned about weight were more likely to have higher BMIs, be in the preparation/action stage, received behavioral counseling, participated in a weight management program, and be interested in participating in one in the future. Those very/moderately concerned about physical activity were more likely to have higher BMIs, received behavioral counseling, and participated in a physical activity program. Conclusion. Individuals with elevated BMIs or low levels of physical activity are concerned. While level of concern is important, these findings suggest that it is not likely to be a sufficient catalyst to behavior change. C1 [Tamers, Sara L.; Allen, Jennifer; Sorensen, Glorian] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Tamers, Sara L.; Allen, Jennifer; Sorensen, Glorian] Dana Farber Canc Inst, Boston, MA 02115 USA. [Yang, May; Stoddard, Anne] New England Res Inst Inc, Watertown, MA USA. [Harley, Amy] Univ Wisconsin Milwaukee, Milwaukee, WI USA. RP Tamers, SL (reprint author), Harvard Univ, Sch Publ Hlth, 677 Huntington Ave, Boston, MA 02115 USA. EM stamers@post.harvard.edu RI Allen, Jennifer/M-2113-2015 FU NCI NIH HHS [R25 CA057711, R25 CA057713, K05 CA108663, K05 CA108663-05, R01 CA111310, R01CA111310-01A1] NR 37 TC 0 Z9 0 U1 1 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 EI 1552-6127 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD DEC PY 2014 VL 41 IS 6 BP 642 EP 650 DI 10.1177/1090198114532289 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT8ZU UT WOS:000345218300009 PM 24786794 ER PT J AU Anderson, JA Godwin, KM Saleem, JJ Russell, S Robinson, JJ Kimmel, B AF Anderson, Jane A. Godwin, Kyler M. Saleem, Jason J. Russell, Scott Robinson, Joshua J. Kimmel, Barbara TI Accessibility, usability, and usefulness of a Web-based clinical decision support tool to enhance provider-patient communication around Self-management TO Prevent (STOP) Stroke SO HEALTH INFORMATICS JOURNAL LA English DT Article DE Clinical decision support tool; clinical-practice guidelines; prevention; provider-patient communication; stroke ID CARE; IMPACT AB This article reports redesign strategies identified to create a Web-based user-interface for the Self-management TO Prevent (STOP) Stroke Tool. Members of a Stroke Quality Improvement Network (N = 12) viewed a visualization video of a proposed prototype and provided feedback on implementation barriers/facilitators. Stroke-care providers (N = 10) tested the Web-based prototype in think-aloud sessions of simulated clinic visits. Participants' dialogues were coded into themes. Access to comprehensive information and the automated features/systematized processes were the primary accessibility and usability facilitator themes. The need for training, time to complete the tool, and computer-centric care were identified as possible usability barriers. Patient accountability, reminders for best practice, goal-focused care, and communication/counseling themes indicate that the STOP Stroke Tool supports the paradigm of patient-centered care. The STOP Stroke Tool was found to prompt clinicians on secondary stroke-prevention clinical-practice guidelines, facilitate comprehensive documentation of evidence-based care, and support clinicians in providing patient-centered care through the shared decision-making process that occurred while using the action-planning/goal-setting feature of the tool. C1 [Anderson, Jane A.; Godwin, Kyler M.] Baylor Coll Med, VA Hlth Serv Res & Dev, Houston Ctr Innovat Qual Effectiveness & Safety, Michael E Debark VAMC, Houston, TX 77030 USA. [Saleem, Jason J.] Regenstrief Inst Inc, VA Hlth Serv Res & Dev, Ctr Implementing Evidence Based Practice, Richard Roudebush VAMC, Indianapolis, IN USA. [Russell, Scott] Richard L Roudebush Vet Affairs Med Ctr, Hlth Serv Res & Dev, Ctr Implementing Evidence Based Practice, Indianapolis, IN USA. [Robinson, Joshua J.] US Dept Vet Affairs, Washington, DC 20420 USA. [Kimmel, Barbara] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. RP Anderson, JA (reprint author), Baylor Coll Med, Michael E DeBakey VA Med Ctr, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM Jane.Anderson@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service [RRP 09-147]; Health Services Research & Development Houston VA Center of Excellence [HFP90-020]; National Research Service Award [T32 HP10031] FX This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (RRP 09-147). This work was partly supported by the Health Services Research & Development Houston VA Center of Excellence (HFP90-020) and by the National Research Service Award (T32 HP10031). NR 18 TC 0 Z9 0 U1 2 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1460-4582 EI 1741-2811 J9 HEALTH INFORM J JI Health Inform. J. PD DEC PY 2014 VL 20 IS 4 BP 261 EP 274 DI 10.1177/1460458213493195 PG 14 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA AU0UB UT WOS:000345339000003 PM 24352597 ER PT J AU Pandit, LM Lloyd, EE Reynolds, JO Lawrence, WS Reynolds, C Wehrens, XHT Bryan, RM AF Pandit, Lavannya M. Lloyd, Eric E. Reynolds, Julia O. Lawrence, William S. Reynolds, Corey Wehrens, Xander H. T. Bryan, Robert M. TI TWIK-2 Channel Deficiency Leads to Pulmonary Hypertension Through a Rho-Kinase-Mediated Process SO HYPERTENSION LA English DT Article DE KCNK6; potassium channel; pulmonary hypertension; Rho-kinase; TWIK-2 ID ARTERY SMOOTH-MUSCLE; DOMAIN POTASSIUM CHANNELS; K+ CHANNELS; VASOCONSTRICTION; MICE; INHIBITOR; CELLS; TASK-1; PATHOGENESIS; CONTRACTION AB TWIK-2 (KCNK6) is a member of the 2-pore domain (K-2P) family of potassium channels, which are highly expressed in the vascular system. We tested the hypothesis that TWIK-2 deficiency leads to pulmonary hypertension. TWIK-2 knockout mice and their wildtype littermates at 8 weeks of age had similar mean right ventricular systolic pressures (24 +/- 3 and 21 +/- 3 mm Hg, respectively.) Significantly, by 20 weeks of age, the mean right ventricular systolic pressures in TWIK-2 knockout mice increased to 35 +/- 3 mm Hg (P <= 0.036), whereas mean right ventricular systolic pressures in wildtype littermates remained at 22 +/- 3 mm Hg. Elevated mean right ventricular systolic pressures in the TWIK-2 knockout mice was accompanied by pulmonary vascular remodeling as determined by a 25% increase in the cross-sectional area of the vessels occupied by the vessel wall. Additionally, secondary branches of the pulmonary artery from 20-week-old TWIK-2 knockout mice showed an enhanced contractile response to U46619 (10(-6) moles/L), a thromboxane A2 mimetic, which was completely abolished with the Rho-kinase inhibitor, Y27632 (10(-6) and 10(-5) moles/L). Treatment of TWIK-2 knockout mice with the Rho-kinase inhibitor, fasudil, in the drinking water for 12 weeks, abolished the development of pulmonary hypertension and attenuated the vessel remodeling. We concluded that mice deficient in the TWIK-2 channel develop pulmonary hypertension between 8 and 20 weeks of age through a mechanism involving Rho-kinase. Our results suggest that downregulation of TWIK-2 in the pulmonary vasculature may be an underlying mechanism in the development of pulmonary hypertension. C1 [Pandit, Lavannya M.; Wehrens, Xander H. T.; Bryan, Robert M.] Baylor Coll Med, Dept Internal Med, Houston, TX 77030 USA. [Lloyd, Eric E.; Bryan, Robert M.] Baylor Coll Med, Dept Anesthesiol, Houston, TX 77030 USA. [Reynolds, Julia O.; Reynolds, Corey; Wehrens, Xander H. T.; Bryan, Robert M.] Baylor Coll Med, Cardiovasc Res Inst, Dept Mol Physiol & Biophys, Houston, TX 77030 USA. [Lawrence, William S.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX USA. RP Pandit, LM (reprint author), Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, One Baylor Plaza,Jones Bldg Suite 535e, Houston, TX 77030 USA. EM lpandit@bcm.edu FU Baylor College of Medicine; Veterans Affairs Career Development Award Program; [R21 HL098921] FX The studies were supported by R21 HL098921 (R. M. Bryan), Baylor College of Medicine Seed Funding Award 2011-2012 (L. M. Pandit), and Veterans Affairs Career Development Award Program (L. M. Pandit). NR 42 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD DEC PY 2014 VL 64 IS 6 BP 1260 EP U216 DI 10.1161/HYPERTENSIONAHA.114.03406 PG 13 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AT7PL UT WOS:000345129900024 PM 25245387 ER PT J AU McDonald, CC Sommers, MS Fargo, JD AF McDonald, Catherine C. Sommers, Marilyn S. Fargo, Jamison D. TI Risky driving, mental health, and health-compromising behaviours: risk clustering in late adolescents and adults SO INJURY PREVENTION LA English DT Article ID HIGH-SCHOOL-STUDENTS; RANDOMIZED CONTROLLED-TRIAL; MOTOR-VEHICLE CRASHES; EMERGENCY-DEPARTMENT; TEENAGE DRIVERS; NOVICE DRIVERS; SLEEP QUALITY; UNITED-STATES; YOUNG-ADULTS; ALCOHOL AB Background Health-compromising behaviours in adolescents and adults co-occur. Because motor vehicle crashes are the leading cause of death and disability for these age groups, understanding the association between risky driving and other health-compromising behaviours is critical. Methods We performed a secondary analysis of data from a randomised controlled trial of an intervention for participants who screened positive for risky driving and problem drinking. Using baseline data, we examined relationships among conduct behaviour problems before and after age 15 years, depressive symptoms, sleep, problem drinking, and risky driving (hostile, reckless and drinking and driving) in late adolescents ages 18-24 (n=110) years, and adults ages 25-44 (n=202) years. We developed a measurement model for the entire sample using confirmatory factor analysis, which was then specified as a multigroup structural equation model. Results Late adolescents and adults had some similar associations for pathways through problem drinking to drinking and driving; depression to reckless driving; and conduct behaviour problems after 15 years of age to hostile driving. Late adolescents, however, had more complex relationships: depressive symptoms and conduct behaviour problems before 15 years of age were associated with more risky driving behaviours through multiple pathways, and males reported more risky driving. Conclusions Risky driving is associated with other health-compromising behaviours and mental health factors. It is a multidimensional phenomenon more pronounced in late adolescence than adulthood. In order to promote safe driving, the findings support the need to consider behaviours that are a health threat in the late adolescent population during driving training and licensure. C1 [McDonald, Catherine C.; Sommers, Marilyn S.] Univ Penn, Sch Nursing, Ctr Global Womens Hlth, Philadelphia, PA 19104 USA. [McDonald, Catherine C.] Univ Penn, Ctr Hlth Equ Res, Philadelphia, PA 19104 USA. [Fargo, Jamison D.] Utah State Univ, Dept Psychol, Logan, UT 84322 USA. RP McDonald, CC (reprint author), Univ Penn, Sch Nursing, Ctr Global Womens Hlth, Claire Fagin Hall,418 Curie Blvd,4012a, Philadelphia, PA 19104 USA. EM mcdonalc@nursing.upenn.edu FU Centers for Disease Control and Prevention [R49CE523225]; University of Pennsylvania, School of Nursing through the National Institute of Nursing Research [T32NR007100, K99NR013548] FX We would like to acknowledge that the study was funded by the Centers for Disease Control and Prevention, Grants for Unintentional Injury Prevention and Control Research (R49CE523225) (PI: Marilyn S. Sommers). The analyses presented here was supported by the postdoctoral research training for Catherine C. McDonald at the University of Pennsylvania, School of Nursing on T32NR007100 (PI: Marilyn S. Sommers) and K99NR013548 (PI: Catherine C. McDonald) through the National Institute of Nursing Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Nursing Research or the National Institutes of Health. NR 44 TC 2 Z9 2 U1 2 U2 21 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1353-8047 EI 1475-5785 J9 INJURY PREV JI Inj. Prev. PD DEC PY 2014 VL 20 IS 6 BP 365 EP 372 DI 10.1136/injuryprev-2014-041150 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT9XB UT WOS:000345276000001 PM 24814717 ER PT J AU Dursun, A Hodin, R Bordeianou, L AF Dursun, Abdulmetin Hodin, Richard Bordeianou, Liliana TI Impact of perineal Crohn's disease on utilization of care in the absence of modifiable predictors of treatment failure SO INTERNATIONAL JOURNAL OF COLORECTAL DISEASE LA English DT Article DE Perineal Crohn's disease; Anal fistula; Infliximab; Diversion for anal fistula ID INFLIXIMAB INFUSION; SETON PLACEMENT; FISTULAS AB The burden of perineal Crohn's disease (PCD) remains poorly characterized, and many patients ultimately require fecal diversion or proctectomy. Our goal was to characterize the clinical course of patients presenting with perineal Crohn's disease, focusing on the cohort of patients ultimately requiring fecal diversion, and identify modifiable predictors for this unfortunate outcome. We performed a retrospective review of 81 consecutive patients who underwent 172 operations to address complications of PCD. Diverted patients were compared to those who did not require diversion in regard to demographics, surgical procedure, postoperative infliximab, and presence of proctitis (chi square, t tests). Logistic regression was utilized to predict the need for fecal diversion. The number of visits needed to undergo care for this condition was quantified. Eight-one patients underwent a total of 172 surgical procedures and had a total of 2713 outpatient visits (range 1-118) to address symptoms of perineal Crohn's disease. Following first intervention, only 57.1 % healed at 3 months. These rates were highest in patients treated with fistulotomies and were not impacted by whether patients received postoperative infliximab (p = 0.703). Patients (23.5 %) underwent three or more surgical procedures to control their PCD and ultimately only 60 % healed without diversion, which was performed in 19 (23.5 %) patients. Patients undergoing more than three operations (OR = 10.9, p = 0.006) and women with rectovaginal fistula (OR = 3.88, p < 0.01) were at a high risk for diversion. Modifiable factors such as infliximab, smoking, proctitis, and surgery aimed at closing the internal anal opening did not alter outcome. In the patients with perineal Crohn's, complex fistulas healing rates appear to be independent of postoperative infliximab or procedures aimed at closing the internal anal opening. Those who do not heal require numerous specialist visits. C1 [Dursun, Abdulmetin; Hodin, Richard; Bordeianou, Liliana] Massachusetts Gen Hosp, Div Gastrointestinal Surg, Crohns & Colitis Ctr, Boston, MA 02114 USA. [Dursun, Abdulmetin; Hodin, Richard; Bordeianou, Liliana] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Bordeianou, L (reprint author), Massachusetts Gen Hosp, Div Gastrointestinal Surg, Crohns & Colitis Ctr, 15 Parkman St,ACC 460, Boston, MA 02114 USA. EM lbordeianou@mgh.harvard.edu NR 15 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0179-1958 EI 1432-1262 J9 INT J COLORECTAL DIS JI Int. J. Colorectal Dis. PD DEC PY 2014 VL 29 IS 12 BP 1535 EP 1539 DI 10.1007/s00384-014-2013-9 PG 5 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AT7ES UT WOS:000345100400012 PM 25269618 ER PT J AU Mitchell, KS Wolf, EJ Reardon, AF Miller, MW AF Mitchell, Karen S. Wolf, Erika J. Reardon, Annemarie F. Miller, Mark W. TI Association of Eating Disorder Symptoms with Internalizing and Externalizing Dimensions of Psychopathology among Men and Women SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE eating disorders; internalizing; externalizing; gender; comorbidity ID NATIONAL-COMORBIDITY-SURVEY; PSYCHIATRIC-DISORDERS; GENDER-DIFFERENCES; UNITED-STATES; PREVALENCE; VETERANS; LIFETIME; PERSONALITY; PATHOLOGY; 12-MONTH AB ObjectiveA large body of factor analytic research supports the idea that common mental disorders are organized along correlated latent dimensions termed internalizing and externalizing. Eating disorders (EDs) have been associated with both internalizing (mood and anxiety disorders) and externalizing (substance use, antisocial personality disorder) forms of psychopathology. Previous studies found that EDs are most strongly related to internalizing disorders. However, no previous factor analytic studies of EDs and the internalizing/externalizing dimensions have evaluated if EDs align with these spectra similarly for men and women. We examined the location of anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED) symptoms within this model of psychopathology among a sample of veterans, a population traditionally understudied in EDs. MethodData were from two studies of veterans and their intimate partners (N=453 men and 307 women). Participants were administered the Structured Clinical Interview for DSM-IV without skip-outs. Lifetime symptom severity scores were used in confirmatory factor analytic models. ResultsA model with AN, BN, and BED symptoms loading onto the distress subfactor of the internalizing domain fit the data best in the full sample and the male and female subsamples. This model was statistically equivalent for men and women. DiscussionAll three EDs loaded onto distress, indicating that these conditions overlap with psychopathology characterized by negative affect. Investigating latent dimensions of psychopathology is one approach to identifying common factors that partially account for patterns of comorbidity among psychiatric disorders, which may aid in translating research findings into clinical practice. (c) 2014 Wiley Periodicals, Inc. (Int J Eat Disord 2014; 47:860-869) C1 [Mitchell, Karen S.; Wolf, Erika J.; Reardon, Annemarie F.; Miller, Mark W.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Mitchell, Karen S.; Wolf, Erika J.; Miller, Mark W.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. RP Mitchell, KS (reprint author), VA Boston Healthcare Syst 116B 3, Natl Ctr PTSD, Womens Hlth Sci Div, 150 South Huntington Ave, Boston, MA 02130 USA. EM Ksmitche@bu.edu; mark.miller5@va.gov RI Miller, Mark/G-7322-2011; OI Miller, Mark/0000-0001-6393-8563; Wolf, Erika/0000-0003-2666-2435 FU VA CSRD Merit Award [5I01CX000431-02]; VA CSR&D Career Development Award; [R01MH079806]; [K01MH093750] FX Supported by R01MH079806, 5I01CX000431-02 from VA CSR&D Merit Award, K01MH093750, and VA CSR&D Career Development Award. NR 32 TC 4 Z9 4 U1 3 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 EI 1098-108X J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD DEC PY 2014 VL 47 IS 8 BP 860 EP 869 DI 10.1002/eat.22300 PG 10 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA AU0XL UT WOS:000345345400003 PM 24849585 ER PT J AU Vaillant, GE Okereke, OI Mukamal, K Waldinger, RJ AF Vaillant, George E. Okereke, Olivia I. Mukamal, Kenneth Waldinger, Robert J. TI Antecedents of intact cognition and dementia at age 90 years: a prospective study SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE longitudinal; prospective; dementia; Alzheimer's disease; risk factors; cognitive reserve; MCI ID MINI-MENTAL-STATE; ALZHEIMERS-DISEASE; OLDER PERSONS; INDIVIDUAL-DIFFERENCES; DEPRESSIVE SYMPTOMS; NATURAL-HISTORY; RISK-FACTORS; LATE MIDLIFE; FOLLOW-UP; LATE-LIFE AB ObjectivesThis study aimed to examine the possible antecedents of both dementia and sustained intact cognition at age 90years among men who underwent a prospective, multidisciplinary assessment from ages 19 to 90years, with little attrition. MethodsWe conducted a prospective 20-year reassessment of 196 (out of 268) former Harvard college sophomores who survived until age 70years. Since 1939, the study gathered measurements of childhood environment, dominant personality traits, objective mental and physical health over time, smoking in pack-years, alcohol abuse, and depression. Questionnaires were obtained every 2years and physical exams every 5years. Cognitive status was assessed at ages 80, 85, and 90years. ResultsDespite addressing a wide variety of health, behavioral, and social factors over the lifespan, we observed few predictors with strong association with either intact cognition at age 90years (n=40) or dementia (n=44). Univariate analysis revealed seven suggestive predictors of intact cognition at age 90years or of dementia: warm childhood relationship with mother, exercise at age 60years, high maternal education, young age of mother at subject's birth, low body mass index, good physical health at 60years, and late retirement. Only the first three variables, warm childhood relationship with mother, exercise at age 60years, and high maternal education, remained significant with logistic regression. ConclusionsIn this prospective study of long-lived, highly educated men, several well-known putative predictors of Alzheimer's disease did not distinguish those who over the next 20years developed dementia from those with unimpaired cognition until age 90years. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Vaillant, George E.; Waldinger, Robert J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Okereke, Olivia I.] Harvard Univ, Sch Med, Dept Psychiat, Brigham & Womens Hosp, Boston, MA 02115 USA. [Mukamal, Kenneth] Harvard Univ, Sch Med, Dept Med, Beth Israel Deaconess Hosp, Boston, MA USA. RP Vaillant, GE (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM gvaillant@partners.org RI Okereke, Olivia/R-9934-2016 FU National Institute of Health [K05-MH00364, MH42248, AG034554] FX This work was supported by research grants K05-MH00364, MH42248, and AG034554 from the National Institute of Health. NR 54 TC 1 Z9 2 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-6230 EI 1099-1166 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD DEC PY 2014 VL 29 IS 12 BP 1278 EP 1285 DI 10.1002/gps.4108 PG 8 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AT8YJ UT WOS:000345214600012 PM 24733646 ER PT J AU Li, JS Tsai, TY Wang, SB Li, PY Kwon, YM Freiberg, A Rubash, HE Li, GA AF Li, Jing-Sheng Tsai, Tsung-Yuan Wang, Shaobai Li, Pingyue Kwon, Young-Min Freiberg, Andrew Rubash, Harry E. Li, Guoan TI Prediction of In Vivo Knee Joint Kinematics Using a Combined Dual Fluoroscopy Imaging and Statistical Shape Modeling Technique SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article DE statistical shape model; automatic matching; knee kinematics; DFIS ID SINGLE-PLANE FLUOROSCOPY; MATCHING METHOD; RECONSTRUCTION; MOTION; VALIDATION; SURFACE; IMAGES; 2D; VARIABILITY; DEFICIENCY AB Using computed tomography (CT) or magnetic resonance (MR) images to construct 3D knee models has been widely used in biomedical engineering research. Statistical shape modeling (SSM) method is an alternative way to provide a fast, cost-efficient, and subject-specific knee modeling technique. This study was aimed to evaluate the feasibility of using a combined dual-fluoroscopic imaging system (DFIS) and SSM method to investigate in vivo knee kinematics. Three subjects were studied during a treadmill walking. The data were compared with the kinematics obtained using a CT-based modeling technique. Geometric root-mean-square (RMS) errors between the knee models constructed using the SSM and CT-based modeling techniques were 1.16 mm and 1.40 mm for the femur and tibia, respectively. For the kinematics of the knee during the treadmill gait, the SSM model can predict the knee kinematics with RMS errors within 3.3 deg for rotation and within 2.4 mm for translation throughout the stance phase of the gait cycle compared with those obtained using the CT-based knee models. The data indicated that the combined DFIS and SSM technique could be used for quick evaluation of knee joint kinematics. C1 [Li, Jing-Sheng; Tsai, Tsung-Yuan; Wang, Shaobai; Li, Pingyue; Li, Guoan] Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, Boston, MA 02114 USA. [Li, Jing-Sheng; Tsai, Tsung-Yuan; Wang, Shaobai; Li, Pingyue; Kwon, Young-Min; Freiberg, Andrew; Rubash, Harry E.; Li, Guoan] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Li, Jing-Sheng] Boston Univ, Sargent Coll, Coll Hlth & Rehabil Sci, Boston, MA 02215 USA. [Kwon, Young-Min; Freiberg, Andrew; Rubash, Harry E.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Li, GA (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, Boston, MA 02114 USA. EM gli1@mgh.harvard.edu OI Tsai, Tsung-Yuan/0000-0003-1522-2987 FU National Institutes of Health [R01 AR055612] FX The authors would like to gratefully acknowledge the financial support of the National Institutes of Health (R01 AR055612). NR 31 TC 3 Z9 4 U1 2 U2 14 PU ASME PI NEW YORK PA TWO PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 EI 1528-8951 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD DEC PY 2014 VL 136 IS 12 AR 124503 DI 10.1115/1.4028819 PG 6 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA AT7ZU UT WOS:000345154300013 PM 25320846 ER PT J AU Simner, PJ Hyle, EP Buckwalter, SP Branda, JA Brown-Elliott, BA Franklin, J Toney, NC de Man, TJB Wallace, RJ Vasireddy, R Gandhi, RT Wengenack, NL AF Simner, Patricia J. Hyle, Emily P. Buckwalter, Seanne P. Branda, John A. Brown-Elliott, Barbara A. Franklin, Jameelah Toney, Nadege C. de Man, Tom J. B. Wallace, Richard J., Jr. Vasireddy, Ravikiran Gandhi, Rajesh T. Wengenack, Nancy L. TI Tenosynovitis Caused by a Novel Nontuberculous Mycobacterium Species Initially Misidentified as a Member of the Mycobacterium tuberculosis Complex SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID DNA PROBES; PNCA GENE; IDENTIFICATION; PYRAZINAMIDE; SYSTEM; STRAIN; ASSAY AB We present a case of tenosynovitis caused by a novel, slowly growing, nonchromogenic, nontuberculous mycobacterium (NTM). Originally misidentified as Mycobacterium tuberculosis complex, the NTM cross-reacts with the M. tuberculosis complex nucleic acid hybridization probe, a M. tuberculosis gamma interferon release assay, and is closely related to M. tuberculosis by 16S rRNA gene sequencing. C1 [Simner, Patricia J.; Buckwalter, Seanne P.; Wengenack, Nancy L.] Mayo Clin, Dept Lab Med & Pathol, Div Clin Microbiol, Rochester, MN 55905 USA. [Hyle, Emily P.; Gandhi, Rajesh T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Branda, John A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Brown-Elliott, Barbara A.; Wallace, Richard J., Jr.; Vasireddy, Ravikiran] Univ Texas Hlth Ctr Tyler, Dept Microbiol, Mycobacteria Nocardia Lab, Tyler, TX 75710 USA. [Toney, Nadege C.; de Man, Tom J. B.] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA USA. [Franklin, Jameelah] Ctr Dis Control & Prevent, Div TB Eliminat, Atlanta, GA USA. [Gandhi, Rajesh T.] Ragon Inst MGH & Harvard, Boston, MA USA. RP Wengenack, NL (reprint author), Mayo Clin, Dept Lab Med & Pathol, Div Clin Microbiol, Rochester, MN 55905 USA. EM wengenack.nancy@mayo.edu FU Carter Foundation FX This study was supported in part by a grant from the Carter Foundation to the Mycobacteria/Nocardia Laboratory at the University of Texas Health Science Center. NR 16 TC 2 Z9 2 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 EI 1098-660X J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD DEC PY 2014 VL 52 IS 12 BP 4414 EP 4418 DI 10.1128/JCM.00967-14 PG 5 WC Microbiology SC Microbiology GA AT9BM UT WOS:000345222900056 PM 25253791 ER PT J AU Dick, AM Niles, BL Street, AE DiMartino, DM Mitchell, KS AF Dick, Alexandra M. Niles, Barbara L. Street, Amy E. DiMartino, Dawn M. Mitchell, Karen S. TI Examining Mechanisms of Change in a Yoga Intervention for Women: The Influence of Mindfulness, Psychological Flexibility, and Emotion Regulation on PTSD Symptoms SO JOURNAL OF CLINICAL PSYCHOLOGY LA English DT Article DE yoga; PTSD; mindfulness; acceptance; emotion regulation; complementary and alternative medicine ID POSTTRAUMATIC-STRESS-DISORDER; NATIONAL COMORBIDITY SURVEY; ACTION QUESTIONNAIRE-II; EXPERIENTIAL AVOIDANCE; SURVEY-REPLICATION; TRAUMATIC EVENTS; ACCEPTANCE; SURVIVORS; VETERANS; PREDICTORS AB Objective: This study explored possible mechanisms through which symptoms of posttraumatic stress disorder (PTSD) were reduced in a randomized controlled trial comparing the effect of a yoga intervention with an assessment control. Method: We examined whether changes in psychological flexibility, mindfulness, and emotion regulation strategies (expressive suppression and reappraisal) were associated with posttreatment PTSD symptoms for 38 women with Diagnostic and Statistical Manual of Mental Disorders Fourth Edition full or subthreshold PTSD. Results: Hierarchical linear regression models revealed that expressive suppression significantly decreased for the yoga group relative to the assessment control. Psychological flexibility increased significantly for the control but not yoga group. However, increases in psychological flexibility were associated with decreases in PTSD symptoms for the yoga but not control group. Conclusion: Preliminary findings suggest that yoga may reduce expressive suppression and may improve PTSD symptoms by increasing psychological flexibility. More research is needed to replicate and extend these findings. Published 2014. This article is a U.S. Government work and is in the public domain in the USA C1 [Dick, Alexandra M.] Suffolk Univ, Boston, MA USA. [Niles, Barbara L.; Street, Amy E.; Mitchell, Karen S.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Niles, Barbara L.; Street, Amy E.; Mitchell, Karen S.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [DiMartino, Dawn M.] Simmons Coll, Sch Social Work, Boston, MA USA. RP Mitchell, KS (reprint author), VA Boston Healthcare Syst 116B 3, Natl Ctr PTSD, Womens Hlth Sci Div, 150 South Huntington Ave, Boston, MA 02130 USA. EM Karen.Mitchell5@va.gov NR 56 TC 4 Z9 4 U1 16 U2 66 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9762 EI 1097-4679 J9 J CLIN PSYCHOL JI J. Clin. Psychol. PD DEC PY 2014 VL 70 IS 12 BP 1170 EP 1182 DI 10.1002/jclp.22104 PG 13 WC Psychology, Clinical SC Psychology GA AT9EG UT WOS:000345230200004 PM 24888209 ER PT J AU Giordano, S Dodson, M Ravi, S Redmann, M Ouyang, XS Usmar, VMD Zhang, JH AF Giordano, Samantha Dodson, Matthew Ravi, Saranya Redmann, Matthew Ouyang, Xiaosen Usmar, Victor M. Darley Zhang, Jianhua TI Bioenergetic adaptation in response to autophagy regulators during rotenone exposure SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE 3-methyladenine; autophagy; mitochondria; primary neuron; rapamycin; rotenone ID MITOCHONDRIAL QUALITY-CONTROL; PARKINSONS-DISEASE; OXIDATIVE STRESS; COMPLEX-I; CELLULAR BIOENERGETICS; CELLS; MITOPHAGY; MECHANISMS; SH-SY5Y; MODEL AB Parkinson's disease is the second most common neurodegenerative disorder with both mitochondrial dysfunction and insufficient autophagy playing a key role in its pathogenesis. Among the risk factors, exposure to the environmental neurotoxin rotenone increases the probability of developing Parkinson's disease. We previously reported that in differentiated SH-SY5Y cells, rotenone-induced cell death is directly related to inhibition of mitochondrial function. How rotenone at nM concentrations inhibits mitochondrial function, and whether it can engage the autophagy pathway necessary to remove damaged proteins and organelles, is unknown. We tested the hypothesis that autophagy plays a protective role against rotenone toxicity in primary neurons. We found that rotenone (10-100nM) immediately inhibited cellular bioenergetics. Concentrations that decreased mitochondrial function at 2h, caused cell death at 24h with an LD50 of 10nM. Overall, autophagic flux was decreased by 10nM rotenone at both 2 and 24h, but surprisingly mitophagy, or autophagy of the mitochondria, was increased at 24h, suggesting that a mitochondrial-specific lysosomal degradation pathway may be activated. Up-regulation of autophagy by rapamycin protected against cell death while inhibition of autophagy by 3-methyladenine exacerbated cell death. Interestingly, while 3-methyladenine exacerbated the rotenone-dependent effects on bioenergetics, rapamycin did not prevent rotenone-induced mitochondrial dysfunction, but caused reprogramming of mitochondrial substrate usage associated with both complex I and complex II activities. Taken together, these data demonstrate that autophagy can play a protective role in primary neuron survival in response to rotenone; moreover, surviving neurons exhibit bioenergetic adaptations to this metabolic stressor. C1 [Giordano, Samantha; Dodson, Matthew; Ravi, Saranya; Redmann, Matthew; Ouyang, Xiaosen; Usmar, Victor M. Darley; Zhang, Jianhua] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Giordano, Samantha; Dodson, Matthew; Ravi, Saranya; Redmann, Matthew; Ouyang, Xiaosen; Usmar, Victor M. Darley; Zhang, Jianhua] Univ Alabama Birmingham, Ctr Free Radical Biol, Birmingham, AL 35294 USA. [Ouyang, Xiaosen; Zhang, Jianhua] Birmingham VA Med Ctr, Dept Vet Affairs, Birmingham, AL USA. 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 [NIHR01-NS064090]; VA merit award FX We thank members of the Zhang and the Darley-Usmar laboratories for discussions and technical help. This work was supported by NIH (NIHR01-NS064090) and a VA merit award (to JZ). NR 42 TC 7 Z9 7 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2014 VL 131 IS 5 BP 625 EP 633 DI 10.1111/jnc.12844 PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AU0YQ UT WOS:000345348500010 PM 25081478 ER PT J AU Linfante, I Mack, W Chen, M Rai, A Albuquerque, F Gupta, R Hirsch, JA Mocco, J Fiorella, D Tarr, R AF Linfante, Italo Mack, Willian Chen, Michael Rai, Ansaar Albuquerque, Felipe Gupta, Rishi Hirsch, Joshua A. Mocco, J. Fiorella, Dave Tarr, Robert TI Best articles published in 2014 in Journal of NeuroInterventional Surgery SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Editorial Material DE Stroke ID FEASIBILITY; ANEURYSMS; TRIAL C1 [Linfante, Italo] Baptist Cardiac & Vasc Inst, Miami, FL 33176 USA. [Mack, Willian] Univ So Calif, Dept Neurosurg, Los Angeles, CA USA. [Chen, Michael] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Rai, Ansaar] West Virginia Univ Hosp, Dept Intervent Neuroradiol, Morgantown, WV USA. [Albuquerque, Felipe] Barrow Neurol Inst, Div Neurol Surg, Phoenix, AZ 85013 USA. [Gupta, Rishi] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, NeuroEndovasc Program, Boston, MA 02114 USA. [Mocco, J.] Vanderbilt Univ, Dept Neurosurg, Nashville, TN 37235 USA. [Fiorella, Dave] SUNY Stony Brook, Dept Neurosurg, Stony Brook, NY 11794 USA. [Tarr, Robert] Univ Hosp Case Med Ctr, Dept Radiol, Cleveland, OH USA. RP Linfante, I (reprint author), Baptist Cardiac & Vasc Inst, Miami, FL 33176 USA. EM linfante.italo@gmail.com NR 11 TC 0 Z9 0 U1 1 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD DEC PY 2014 VL 6 IS 10 BP 722 EP 723 DI 10.1136/neurintsurg-2014-011489 PG 2 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA AT4UU UT WOS:000344939800006 PM 25381218 ER PT J AU Mehan, WA Romero, JM Hirsch, JA Sabbag, DJ Gonzalez, RG Heit, JJ Schaefer, PW AF Mehan, William A., Jr. Romero, Javier M. Hirsch, Joshua A. Sabbag, David J. Gonzalez, Ramon G. Heit, Jeremy J. Schaefer, Pamela W. TI Unruptured intracranial aneurysms conservatively followed with serial CT angiography: could morphology and growth predict rupture? SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article DE Aneurysm; CT Angiography ID MAGNETIC-RESONANCE ANGIOGRAPHY; RISK-FACTORS; CEREBRAL ANEURYSMS; NATURAL-HISTORY; JAPANESE POPULATION; PREVALENCE; METAANALYSIS; ENLARGEMENT; AGE AB Background and purpose Despite several landmark studies, the natural history of unruptured intracranial aneurysms (UIA) remains uncertain. Our aim was to identify or confirm factors predictive of rupture of UIA being observed conservatively with serial CT angiography (CTA) in a North American patient population. Methods We performed a retrospective review of patients with UIA being followed with serial CTA studies from 1999 to 2010. The following features for each aneurysm were cataloged from the official radiologic reports and CTA images: maximum diameter, growth between follow-up studies, location, multiplicity, wall calcification, intraluminal thrombus and morphology. Univariate logistic regression analysis of the potential independent risk factors for aneurysm rupture was performed. Statistically significant risk factors from the univariate analysis were then entered into a multivariate logistic regression analysis. Results 152 patients with a total of 180 UIA had at least two CTA studies. Six aneurysms in six different patients ruptured during the CTA follow-up period for an overall rupture rate of 3.3% and an annual rupture rate of 0.97%. All ruptured aneurysms were 9mm. In the univariate analysis, the statistically significant predictors of aneurysm rupture were aneurysm size (p=0.003), aneurysm growth (p<0.0001) and aneurysm multilobulation (p=0.001). The risk factors that remained significant following the multivariate analysis were growth (OR 55.9; 95% CI 4.47 to 700.08; p=0.002) and multilobulation (OR 17.4; 95% CI 1.52 to 198.4; p=0.022). Conclusions Aneurysm morphology and interval growth are characteristics predictive of a higher risk of subsequent rupture during conservative CTA follow-up. C1 [Mehan, William A., Jr.; Romero, Javier M.; Hirsch, Joshua A.; Heit, Jeremy J.; Schaefer, Pamela W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Sabbag, David J.] Baylor Coll Med, Dept Radiol, Houston, TX 77030 USA. RP Mehan, WA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Gray B285,Fruit St, Boston, MA 02114 USA. EM will.mehan@gmail.com FU Harvard Catalyst grant [8UL1TR000170-05] FX This work was conducted with support from Harvard Catalyst grant number 8UL1TR000170-05. NR 23 TC 12 Z9 13 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD DEC PY 2014 VL 6 IS 10 BP 761 EP 766 DI 10.1136/neurintsurg-2013-010944 PG 6 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA AT4UU UT WOS:000344939800014 PM 24275611 ER PT J AU Feres, M Teles, F AF Feres, M. Teles, F. TI Anne D. Haffajee, DDS, 1947-2013 In Memoriam SO JOURNAL OF PERIODONTAL RESEARCH LA English DT Biographical-Item C1 [Feres, M.] Univ Guarulhos, Guarulhos, SP, Brazil. [Teles, F.] Forsyth Inst, Cambridge, MA USA. RP Feres, M (reprint author), Univ Guarulhos, Guarulhos, SP, Brazil. EM mferes@ung.br RI Feres, Magda/H-7964-2012 NR 1 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3484 EI 1600-0765 J9 J PERIODONTAL RES JI J. Periodont. Res. PD DEC PY 2014 VL 49 IS 6 BP 681 EP 682 DI 10.1111/jre.12198 PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AT7ZC UT WOS:000345152300001 PM 24948197 ER PT J AU Tsugawa, D Oya, Y Masuzaki, R Ray, K Engers, DW Dib, M Do, N Kuramitsu, K Ho, K Frist, A Yu, PB Bloch, KD Lindsley, CW Hopkins, CR Hong, CC Karp, SJ AF Tsugawa, Daisuke Oya, Yuki Masuzaki, Ryota Ray, Kevin Engers, Darren W. Dib, Martin Do, Nhue Kuramitsu, Kaori Ho, Karen Frist, Audrey Yu, Paul B. Bloch, Kenneth D. Lindsley, Craig W. Hopkins, Corey R. Hong, Charles C. Karp, Seth J. TI Specific Activin Receptor-Like Kinase 3 Inhibitors Enhance Liver Regeneration SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PARTIAL-HEPATECTOMY; HEPCIDIN EXPRESSION; SIGNAL-TRANSDUCTION; GROWTH-FACTOR; CELL-CYCLE; IN-VIVO; MICE; DORSOMORPHIN; REPLICATION; FAILURE AB Pharmacologic agents to enhance liver regeneration after injury would have wide therapeutic application. Based on previous work suggesting inhibition of bone morphogenetic protein (BMP) signaling stimulates liver regeneration, we tested known and novel BMP inhibitors for their ability to accelerate regeneration in a partial hepatectomy (PH) model. Compounds were produced based on the 3,6-disubstituted pyrazolo[1,5-a] pyrimidine core of the BMP antagonist dorsomorphin and evaluated for their ability to inhibit BMP signaling and enhance liver regeneration. Antagonists of the BMP receptor activin receptor-like kinase 3 (ALK3), including LDN-193189 (LDN; 4-[6-[4-(1-piperazinyl)phenyl] pyrazolo[1,5-a]pyrimidin-3-yl]-quinoline), DMH2 (4-(2-(4-(3-(quinolin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)phenoxy)ethyl)morpholine; VU0364849), and the novel compound VU0465350 (7-(4-isopropoxyphenyl)-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine; VU5350), blocked SMAD phosphorylation in vitro and in vivo, and enhanced liver regeneration after PH. In contrast, an antagonist of the BMP receptor ALK2, VU0469381 (5-(6-(4-methoxyphenyl)pyrazolo[1,5-a] pyrimidin-3-yl)quinolone; 1LWY), did not affect liver regeneration. LDN did not affect liver synthetic or metabolic function. Mechanistically, LDN increased serum interleukin-6 levels and signal transducer and activator of transcription 3 phosphorylation in the liver, and modulated other factors known to be important for liver regeneration, including suppressor of cytokine signaling 3 and p53. These findings suggest that inhibition of ALK3 may be part of a therapeutic strategy for treating human liver disease. C1 [Tsugawa, Daisuke; Oya, Yuki; Masuzaki, Ryota; Ray, Kevin; Karp, Seth J.] Vanderbilt Univ, Med Ctr, Transplant Ctr, Nashville, TN 37212 USA. [Tsugawa, Daisuke; Oya, Yuki; Masuzaki, Ryota; Ray, Kevin; Karp, Seth J.] Vanderbilt Univ, Med Ctr, Dept Surg, Nashville, TN 37212 USA. [Engers, Darren W.; Lindsley, Craig W.; Hopkins, Corey R.] Vanderbilt Ctr Neurosci Drug Discovery, Dept Pharmacol, Nashville, TN USA. [Dib, Martin; Do, Nhue] Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. [Kuramitsu, Kaori] Kobe Univ, Dept Surg, Kobe, Hyogo 657, Japan. [Ho, Karen] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Yu, Paul B.] Brigham & Womens Hosp, Dept Med, Div Cardiol, Boston, MA 02115 USA. [Bloch, Kenneth D.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Ctr Crit Care Res, Boston, MA 02114 USA. [Lindsley, Craig W.] Vanderbilt Univ, Dept Chem, Nashville, TN 37212 USA. [Frist, Audrey; Hong, Charles C.] Tennessee Valley Healthcare Syst, Dept Vet Affairs, Nashville, TN USA. RP Karp, SJ (reprint author), Vanderbilt Univ, Sch Med, Dept Surg, 805 Oxford House,1313 21st Ave South, Nashville, TN 37212 USA. EM seth.karp@vanderbilt.edu OI Yu, Paul/0000-0003-2145-4944 FU National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [7R01-DK081387, R01-DK0829710]; Vanderbilt University Medical Center; Foundation LeDucq FX This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants 7R01-DK081387 and R01-DK0829710]; Vanderbilt University Medical Center; and the Foundation LeDucq. NR 32 TC 8 Z9 8 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD DEC PY 2014 VL 351 IS 3 BP 549 EP 558 DI 10.1124/jpet.114.216903 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AT9AK UT WOS:000345219800008 PM 25271257 ER PT J AU Jesinkey, SR Korrapati, MC Rasbach, KA Beeson, CC Schnellmann, RG AF Jesinkey, Sean R. Korrapati, Midhun C. Rasbach, Kyle A. Beeson, Craig C. Schnellmann, Rick G. TI Atomoxetine Prevents Dexamethasone-Induced Skeletal Muscle Atrophy in Mice SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID MITOCHONDRIAL BIOGENESIS; BETA(2)-ADRENOCEPTOR AGONISTS; CELLULAR MECHANISMS; UBIQUITIN LIGASES; GENE-EXPRESSION; ERR-ALPHA; HYPERTROPHY; NOREPINEPHRINE; METABOLISM; FORMOTEROL AB Skeletal muscle atrophy remains a clinical problem in numerous pathologic conditions. beta(2)-Adrenergic receptor agonists, such as formoterol, can induce mitochondrial biogenesis (MB) to prevent such atrophy. Additionally, atomoxetine, an FDA-approved norepinephrine reuptake inhibitor, was positive in a cellular assay for MB. We used a mouse model of dexamethasone-induced skeletal muscle atrophy to investigate the potential role of atomoxetine and formoterol to prevent muscle mass loss. Mice were administered dexamethasone once daily in the presence or absence of formoterol (0.3 mg/kg), atomoxetine (0.1 mg/kg), or sterile saline. Animals were euthanized at 8, 16, and 24 hours or 8 days later. Gastrocnemius muscle weights, changes in mRNA and protein expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) isoforms, ATP synthase beta, cytochrome c oxidase subunit I, NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8, ND1, insulin-like growth factor 1 (IGF-1), myostatin, muscle Ring-finger protein-1 (muscle atrophy), phosphorylated forkhead box protein O 3a (p-FoxO3a), Akt, mammalian target of rapamycin (mTOR), and ribosomal protein S6 (rp-S6; muscle hypertrophy) in naive and muscle-atrophied mice were measured. Atomoxetine increased p-mTOR 24 hours after treatment in naive mice, but did not change any other biomarkers. Formoterol robustly activated the PGC-1 alpha-4-IGF1-Akt-mTOR-rp-S6 pathway and increased p-FoxO3a as early as 8 hours and repressed myostatin at 16 hours. In contrast to what was observed with acute treatment, chronic treatment (7 days) with atomoxetine increased p-Akt and p-FoxO3a, and sustained PGC-1 alpha expression and skeletal muscle mass in dexamethasone-treated mice, in a manner comparable to formoterol. In conclusion, chronic treatment with a low dose of atomoxetine prevented dexamethasone-induced skeletal muscle wasting and supports a potential role in preventing muscle atrophy. C1 [Jesinkey, Sean R.; Korrapati, Midhun C.; Rasbach, Kyle A.; Beeson, Craig C.; 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 Institutes of Health National Institute of General Medical Sciences [R01-GM084147]; National Institutes of Health National Center for Research Resources [UL1-RR029882, C06-RR015455]; Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs [BX-000851]; SC COBRE in Oxidants, Redox Balance, and Stress Signaling [P20 GM103542-02]; South Carolina Clinical and Translational Research Institute at the Medical University of South Carolina FX This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM084147]; the National Institutes of Health National Center for Research Resources [Grant UL1-RR029882]; the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs [BX-000851]; an SC COBRE in Oxidants, Redox Balance, and Stress Signaling [P20 GM103542-02]; and the South Carolina Clinical and Translational Research Institute, which has an academic home at the Medical University of South Carolina. Animal facilities were funded by National Institutes of Health National Center for Research Resources [Grant C06-RR015455]. NR 43 TC 7 Z9 7 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 EI 1521-0103 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD DEC PY 2014 VL 351 IS 3 BP 663 EP 673 DI 10.1124/jpet.114.217380 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AT9AK UT WOS:000345219800019 PM 25292181 ER PT J AU Teunis, T Lubberts, B Reilly, BT Ring, D AF Teunis, Teun Lubberts, Bart Reilly, Brian T. Ring, David TI A systematic review and pooled analysis of the prevalence of rotator cuff disease with increasing age SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Review DE Rotator cuff; abnormalities; prevalence; age ID ANTERIOR SHOULDER DISLOCATION; ASYMPTOMATIC SHOULDERS; CORACOACROMIAL ARCH; TEAR ARTHROPATHY; REPAIR; ARTHROGRAPHY; REGRESSION; FAILURE; MR; ABNORMALITIES AB Hypothesis and background: Abnormalities of the rotator cuff are more common with age, but the exact prevalence of abnormalities and the extent to which the presence of an abnormality is associated with symptoms are topics of debate. Our aim was to review the published literature to establish the prevalence of abnormalities of the rotator cuff and to determine if the prevalence of abnormalities increases with older age in 10-year intervals. In addition, we assessed prevalence in 4 separate groups: (1) asymptomatic patients, (2) general population, (3) symptomatic patients, and (4) patients after shoulder dislocation. Methods: We searched PubMed, EMBASE, and the Cochrane Library up to February 24, 2014, and included studies reporting rotator cuff abnormalities by age. Thirty studies including 6112 shoulders met our criteria. We pooled the individual patient data and calculated proportions of patients with and without abnormalities per decade (range, younger than 20 years to 80 years and older). Results: Overall prevalence of abnormalities increased with age, from 9.7% (29 of 299) in patients aged 20 years and younger to 62% (166 of 268) in patients aged 80 years and older (P < .001) (odds ratio, 15; 95% confidence interval, 9.6-24; P < .001). There was a similar increasing prevalence of abnormalities regardless of symptoms or shoulder dislocation. Discussion and conclusion: The prevalence of rotator cuff abnormalities in asymptomatic people is high enough for degeneration of the rotator cuff to be considered a common aspect of normal human aging and to make it difficult to determine when an abnormality is new (e. g., after a dislocation) or is the cause of symptoms. Level of evidence: Level III, Systematic Review. (C) 2014 Journal of Shoulder and Elbow Surgery Board of Trustees. C1 [Teunis, Teun; Lubberts, Bart; Reilly, Brian T.; Ring, David] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Ring, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, 55 Fruit St, Boston, MA 02114 USA. EM dring@mgh.harvard.edu OI Ring, David/0000-0002-6506-4879 NR 51 TC 13 Z9 13 U1 2 U2 10 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1058-2746 J9 J SHOULDER ELB SURG JI J. Shoulder Elbow Surg. PD DEC PY 2014 VL 23 IS 12 BP 1913 EP 1921 DI 10.1016/j.jse.2014.08.001 PG 9 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA AT4WL UT WOS:000344942300027 PM 25441568 ER PT J AU Mehta, BP Leslie-Mazwi, TM Chandra, RV Bell, DL Sun, CHJ Hirsch, JA Rabinov, JD Rost, NS Schwamm, LH Goldstein, JN Levine, WC Gupta, R Yoo, AJ AF Mehta, Brijesh P. Leslie-Mazwi, Thabele M. Chandra, Ronil V. Bell, Donnie L. Sun, Chung-Huan J. Hirsch, Joshua A. Rabinov, James D. Rost, Natalia S. Schwamm, Lee H. Goldstein, Joshua N. Levine, Wilton C. Gupta, Rishi Yoo, Albert J. TI Reducing Door-to-Puncture Times for Intra-Arterial Stroke Therapy: A Pilot Quality Improvement Project SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE acute ischemic stroke; endovascular stroke thrombectomy; quality improvement; stroke process improvement ID ACUTE ISCHEMIC-STROKE; ACUTE MYOCARDIAL-INFARCTION; PLASMINOGEN-ACTIVATOR; TREATMENT RATES; POOLED ANALYSIS; THROMBOLYSIS; REPERFUSION; SELECTION; ONSET; RECANALIZATION AB Background-Delays to intra-arterial therapy (IAT) lead to worse outcomes in stroke patients with proximal occlusions. Little is known regarding the magnitude of, and reasons for, these delays. In a pilot quality improvement (QI) project, we sought to examine and improve our door-puncture times. Methods and Results-For anterior-circulation stroke patients who underwent IAT, we retrospectively calculated in-hospital time delays associated with various phases from patient arrival to groin puncture. We formulated and then implemented a process change targeted to the phase with the greatest delay. We examined the impact on time to treatment by comparing the pre- and post-QI cohorts. One hundred forty-six patients (93 pre- vs. 51 post-QI) were analyzed. In the pre- QI cohort (ie, sequential process), the greatest delay occurred from imaging to the neurointerventional (NI) suite ("picture-suite": median, 62 minutes; interquartile range [IQR], 40 to 82). A QI measure was instituted so that the NI team and anesthesiologist were assembled and the suite set up in parallel with completion of imaging and decision making. The post-QI (ie, parallel process) median picture-to-suite time was 29 minutes (IQR, 21 to 41; P<0.0001). There was a 36-minute reduction in median door-to-puncture time (143 vs. 107 minutes; P<0.0001). Parallel workflow and presentation during work hours were independent predictors of shorter door-puncture times. Conclusions- In-hospital delays are a major obstacle to timely IAT. A simple approach for achieving substantial time savings is to mobilize the NI and anesthesia teams during patient evaluation and treatment decision making. This parallel workflow resulted in a >30-minute (25%) reduction in median door-to-puncture times. C1 [Yoo, Albert J.] Massachusetts Gen Hosp, Div Diagnost Neuroradiol, Boston, MA 02114 USA. [Mehta, Brijesh P.; Leslie-Mazwi, Thabele M.; Chandra, Ronil V.; Bell, Donnie L.; Hirsch, Joshua A.; Rabinov, James D.; Yoo, Albert J.] Massachusetts Gen Hosp, Dept Radiol, Div Intervent Neuroradiol, Boston, MA 02114 USA. [Mehta, Brijesh P.; Leslie-Mazwi, Thabele M.; Rost, Natalia S.; Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Levine, Wilton C.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Sun, Chung-Huan J.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Gupta, Rishi] Kennestone Hosp, Wellstar Neurosurg, Marietta, GA USA. RP Mehta, BP (reprint author), Mem Neurosci Inst, 3501 Johnson St, Hollywood, FL 33021 USA. EM brmehta@mhs.net RI Goldstein, Joshua/H-8953-2016 FU CPIP FX The CPIP at our hospital provided strategic guidance and administrative funding during the course of this project. NR 30 TC 7 Z9 7 U1 1 U2 9 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 DEC PY 2014 VL 3 IS 6 AR e000963 DI 10.1161/JAHA.114.000963 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT6RY UT WOS:000345067600013 PM 25389281 ER PT J AU Klassert, TE Hanisch, A Brauer, J Klaile, E Heyl, KA Mansour, MM Tam, JM Vyas, JM Slevogt, H AF Klassert, Tilman E. Hanisch, Anja Braeuer, Julia Klaile, Esther Heyl, Kerstin A. Mansour, Michael M. Tam, Jenny M. Vyas, Jatin M. Slevogt, Hortense TI Modulatory role of vitamin A on the Candida albicans-induced immune response in human monocytes SO MEDICAL MICROBIOLOGY AND IMMUNOLOGY LA English DT Article DE Vitamin A; Retinoic acid; Candida albicans; Dectin-1 ID RETINOIC ACID; IN-VITRO; CYTOKINE PRODUCTION; INNATE IMMUNITY; HOST-DEFENSE; RT-PCR; DECTIN-1; EPIDEMIOLOGY; MACROPHAGES; CELLS AB Beyond its well-documented role in reproduction, embryogenesis and maintenance of body tissues, vitamin A has attracted considerable attention due to its immunomodulatory effects on both the innate and the adaptive immune responses. In infectious diseases, vitamin A has been shown to have a host-protective effect in infections of bacterial, viral or protozoan origin. Nevertheless, its impact in fungal infections remains unknown. Meanwhile, the frequency of invasive mycoses keeps on growing, with Candida albicans being the major opportunistic fungal pathogen and associated with high mortality. In the present work, we explored the impact of all-trans retinoic acid (atRA), the most active metabolite of vitamin A, on the innate immune response against C. albicans in human monocytes. Our results show a strong immunomodulatory role for atRA, leading to a significant down-regulation of the fungi-induced expression and secretion of the pro-inflammatory cytokines TNF alpha, IL6 and IL12. Moreover, atRA significantly suppressed the expression of Dectin-1, a major fungal pattern recognition receptor, as well as the Dectin-1-dependent cytokine production. Both RAR-dependent and RAR-independent mechanisms seem to play a role in the atRA-mediated immunomodulation. Our findings open a new direction to elucidate the role of vitamin A on the immune function during fungal infections. C1 [Klassert, Tilman E.; Hanisch, Anja; Braeuer, Julia; Klaile, Esther; Heyl, Kerstin A.; Slevogt, Hortense] Jena Univ Hosp, Sept Res Ctr, D-07745 Jena, Germany. [Hanisch, Anja; Klaile, Esther] Jena Univ Hosp, CSCC, D-07747 Jena, Germany. [Mansour, Michael M.; Tam, Jenny M.; Vyas, Jatin M.] Harvard Univ, Sch Med, Dept Med, Div Infect Dis,Massachusetts Gen Hosp, Boston, MA USA. RP Slevogt, H (reprint author), Jena Univ Hosp, Sept Res Ctr, Albert Einstein Str 10, D-07745 Jena, Germany. EM hortense.slevogt@med.uni-jena.de FU German Research Foundation (Collaborative Research Center) [Transregio 124]; German Federal Ministry of Education and Research [BMBF 03Z2JN22, 01EO1002]; German Federal Ministry of Education and Research (Center for Sepsis Control and Care); NIH/NIAID [1K08AI110655, 1R01AI092084, 1R01AI097519] FX We want to thank Simone Tanzer for excellent technical assistance. This work was funded by the German Research Foundation (Collaborative Research Center/Transregio 124-Pathogenic fungi and their human host: Networks of Interaction, Project A5), by the German Federal Ministry of Education and Research (BMBF 03Z2JN22 to H. S. and 01EO1002 to A. H. and E.K./Center for Sepsis Control and Care), and the grants NIH/NIAID 1K08AI110655 to M. K. M., 1R01AI092084 to J.M.T. and 1R01AI097519 to J.M.V. NR 47 TC 5 Z9 6 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0300-8584 EI 1432-1831 J9 MED MICROBIOL IMMUN JI Med. Microbiol. Immunol. PD DEC PY 2014 VL 203 IS 6 BP 415 EP 424 DI 10.1007/s00430-014-0351-4 PG 10 WC Immunology; Microbiology SC Immunology; Microbiology GA AT7FC UT WOS:000345101300006 PM 25129478 ER PT J AU Klassert, TE Hanisch, A Brauer, J Klaile, E Heyl, KA Mansour, MK Tam, JM Vyas, JM Slevogt, H AF Klassert, Tilman E. Hanisch, Anja Braeuer, Julia Klaile, Esther Heyl, Kerstin A. Mansour, Michael K. Tam, Jenny M. Vyas, Jatin M. Slevogt, Hortense TI Erratum to: Modulatory role of vitamin A on the Candida albicans-induced immune response in human monocytes (vol 203, pg 415, 2014) SO MEDICAL MICROBIOLOGY AND IMMUNOLOGY LA English DT Correction C1 [Klassert, Tilman E.; Hanisch, Anja; Braeuer, Julia; Klaile, Esther; Heyl, Kerstin A.; Slevogt, Hortense] Jena Univ Hosp, Sept Res Ctr, D-07745 Jena, Germany. [Hanisch, Anja; Klaile, Esther] Jena Univ Hosp, CSCC, D-07747 Jena, Germany. [Mansour, Michael K.; Tam, Jenny M.; Vyas, Jatin M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis,Dept Med, Boston, MA USA. RP Slevogt, H (reprint author), Jena Univ Hosp, Sept Res Ctr, Albert Einstein Str 10, D-07745 Jena, Germany. EM hortense.slevogt@med.uni-jena.de NR 1 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0300-8584 EI 1432-1831 J9 MED MICROBIOL IMMUN JI Med. Microbiol. Immunol. PD DEC PY 2014 VL 203 IS 6 BP 425 EP 425 DI 10.1007/s00430-014-0362-1 PG 1 WC Immunology; Microbiology SC Immunology; Microbiology GA AT7FC UT WOS:000345101300007 ER PT J AU Farr, OM Sloan, DM Keane, TM Mantzoros, CS AF Farr, Olivia M. Sloan, Denise M. Keane, Terence M. Mantzoros, Christos S. TI Stress- and PTSD-associated obesity and metabolic dysfunction: A growing problem requiring further research and novel treatments SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Editorial Material ID DORSOLATERAL PREFRONTAL CORTEX; COMBAT-RELATED PTSD; WORLD-TRADE-CENTER; MYOCARDIAL-INFARCTION; MEDICAL EXPENDITURES; PSYCHOSOCIAL STRESS; CHILDHOOD ADVERSITY; ALCOHOL DEPENDENCE; INSULIN-RESISTANCE; AMYGDALA ACTIVITY C1 [Farr, Olivia M.; Mantzoros, Christos S.] Harvard Univ, Sch Med, Div Endocrinol, Boston VA Healthcare Syst, Boston, MA USA. [Sloan, Denise M.; Keane, Terence M.] Boston Univ, Sch Med, VA Boston Healthcare Syst, VA Natl Ctr PTSD, Boston, MA 02118 USA. RP Farr, OM (reprint author), VA Boston Healthcare Syst, Div Endocrinol, 9-B,150 S Huntington Ave, Boston, MA 02130 USA. EM Olivia.Farr@va.gov OI Farr, Olivia/0000-0002-5182-3432 FU NICHD NIH HHS [5T32HD052961, T32 HD052961] NR 99 TC 11 Z9 11 U1 5 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD DEC PY 2014 VL 63 IS 12 BP 1463 EP 1468 DI 10.1016/j.metabol.2014.08.009 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AT8QE UT WOS:000345196500001 PM 25267015 ER PT J AU Lartey, FM Ahn, GO Ali, R Rosenblum, S Miao, Z Arksey, N Shen, B Colomer, MV Rafat, M Liu, HG Alejandre-Alcazar, MA Chen, JW Palmer, T Chin, FT Guzman, R Loo, BW Graves, E AF Lartey, Frederick M. Ahn, G-One Ali, Rehan Rosenblum, Sahar Miao, Zheng Arksey, Natasha Shen, Bin Colomer, Marta Vilalta Rafat, Marjan Liu, Hongguang Alejandre-Alcazar, Miguel A. Chen, John W. Palmer, Theo Chin, Frederick T. Guzman, Raphael Loo, Billy W., Jr. Graves, Edward TI The Relationship Between Serial [(18) F]PBR06 PET Imaging of Microglial Activation and Motor Function Following Stroke in Mice SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Stroke; [F-18]PBR06 PET imaging; Microglia; Neuroinflammation; Mice; Motor function; Minocycline ID PROTEIN 18 KDA; FOCAL CEREBRAL-ISCHEMIA; POSITRON-EMISSION-TOMOGRAPHY; NEURAL STEM-CELLS; IN-VIVO; INFLAMMATORY RESPONSE; RAT-BRAIN; MINOCYCLINE; IMPAIRMENT; NEUROINFLAMMATION AB Using [(18) F]PBR06 positron emission tomography (PET) to characterize the time course of stroke-associated neuroinflammation (SAN) in mice, to evaluate whether brain microglia influences motor function after stroke, and to demonstrate the use of [(18) F]PBR06 PET as a therapeutic assessment tool. Stroke was induced by transient middle cerebral artery occlusion (MCAO) in Balb/c mice (control, stroke, and stroke with poststroke minocycline treatment). [18 F]PBR06 PET/CT imaging, rotarod tests, and immunohistochemistry (IHC) were performed 3, 11, and 22 days poststroke induction (PSI). The stroke group exhibited significantly increased microglial activation, and impaired motor function. Peak microglial activation was 11 days PSI. There was a strong association between microglial activation, motor function, and microglial protein expression on IHC. Minocycline significantly reduced microglial activation and improved motor function by day 22 PSI. [18 F]PBR06 PET imaging noninvasively characterizes the time course of SAN, and shows increased microglial activation is associated with decreased motor function. C1 [Lartey, Frederick M.; Ali, Rehan; Colomer, Marta Vilalta; Rafat, Marjan; Loo, Billy W., Jr.; Graves, Edward] Stanford Univ, Dept Radiat Oncol, Sch Med, Stanford, CA 94305 USA. [Loo, Billy W., Jr.; Graves, Edward] Stanford Canc Inst, Stanford, CA USA. [Miao, Zheng; Arksey, Natasha; Shen, Bin; Liu, Hongguang; Chin, Frederick T.] Stanford Univ, Dept Radiol, Sch Med, Stanford, CA 94305 USA. [Rosenblum, Sahar; Palmer, Theo; Guzman, Raphael] Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA. [Alejandre-Alcazar, Miguel A.] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA. [Ahn, G-One] Pohang Univ Sci & Technol, Kyungbuk, South Korea. [Chen, John W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Chen, John W.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Guzman, Raphael] Univ Basel, Dept Neurosurg, Basel, Switzerland. [Guzman, Raphael] Univ Basel, Dept Biomed, Basel, Switzerland. RP Loo, BW (reprint author), Stanford Univ, Dept Radiat Oncol, Sch Med, Stanford, CA 94305 USA. EM BWLoo@Stanford.edu; EGraves@Stanford.edu RI Rafat, Marjan/D-8348-2015 OI Rafat, Marjan/0000-0002-9444-4379 FU Stanford Bio-X Interdisciplinary Initiatives Program (IIP) Award; Stanford Bio-X Interdisciplinary Initiatives Cancer Research Award; NCI ICMIC P50 Award [CA114747]; AHA [AHA-0835274 N]; CIRM [RC1-0134]; NRF; Ministry of Education, Science and Technology, Korea [R31-10105, NRF-2012M3A9C6049796]; Li Ka Shing Foundation; Department of Radiation Oncology, Stanford University FX Sources of funds were Stanford Bio-X Interdisciplinary Initiatives Program (IIP) Award and Cancer Research Award (to BWL), an NCI ICMIC P50 Award (CA114747 to Dr. Sanjiv Sam Gambhir), an AHA Grant (AHA-0835274 N to RG), a CIRM Grant (RC1-0134 to TDP), NRF and the Ministry of Education, Science and Technology, Korea grants (R31-10105 and NRF-2012M3A9C6049796 to GOA), the Li Ka Shing Foundation and the Department of Radiation Oncology, Stanford University. NR 36 TC 3 Z9 3 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 EI 1860-2002 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD DEC PY 2014 VL 16 IS 6 BP 821 EP 829 DI 10.1007/s11307-014-0745-0 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AT9ZC UT WOS:000345281600009 PM 24865401 ER PT J AU Xie, T Lim, SM Westover, KD Dodge, ME Ercan, D Ficarro, SB Udayakumar, D Gurbani, D Tae, HS Riddle, SM Sim, T Marto, JA Janne, PA Crews, CM Gray, NS AF Xie, Ting Lim, Sang Min Westover, Kenneth D. Dodge, Michael E. Ercan, Dalia Ficarro, Scott B. Udayakumar, Durga Gurbani, Deepak Tae, Hyun Seop Riddle, Steven M. Sim, Taebo Marto, Jarrod A. Jaenne, Pasi A. Crews, Craig M. Gray, Nathanael S. TI Pharmacological targeting of the pseudokinase Her3 SO NATURE CHEMICAL BIOLOGY LA English DT Article ID HER2-POSITIVE BREAST-CANCER; TYROSINE KINASE; LUNG-CANCER; EXTENDED 5-SUBSTITUENT; ADJUVANT CHEMOTHERAPY; SELECTIVE INHIBITORS; MET AMPLIFICATION; OVARIAN-CANCER; PROTEIN; DOMAIN AB Her3 (also known as ErbB3) belongs to the epidermal growth factor receptor tyrosine kinases and is well credentialed as an anti-cancer target but is thought to be 'undruggable' using ATP-competitive small molecules because it lacks appreciable kinase activity. Here we report what is to our knowledge the first selective Her3 ligand, TX1-85-1, that forms a covalent bond with Cys721 located in the ATP-binding site of Her3. We demonstrate that covalent modification of Her3 inhibits Her3 signaling but not proliferation in some Her3-dependent cancer cell lines. Subsequent derivatization with a hydrophobic adamantane moiety demonstrates that the resultant bivalent ligand (TX2-121-1) enhances inhibition of Her3-dependent signaling. Treatment of cells with TX2-121-1 results in partial degradation of Her3 and serendipitously interferes with productive heterodimerization between Her3 with either Her2 or c-Met. These results suggest that small molecules will be capable of perturbing the biological function of Her3 and -60 other pseudokinases found in human cells. C1 [Xie, Ting; Lim, Sang Min; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Xie, Ting; Lim, Sang Min; Ficarro, Scott B.; Marto, Jarrod A.; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Xie, Ting; Lim, Sang Min] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Westover, Kenneth D.; Udayakumar, Durga; Gurbani, Deepak] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Westover, Kenneth D.; Udayakumar, Durga; Gurbani, Deepak] Univ Texas SW Med Ctr Dallas, Dept Radiat Oncol, Dallas, TX 75390 USA. [Dodge, Michael E.; Ercan, Dalia; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Ficarro, Scott B.; Marto, Jarrod A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Ficarro, Scott B.; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. [Tae, Hyun Seop; Crews, Craig M.] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT USA. [Riddle, Steven M.] Life Technol Corp, Primary & Stem Cell Syst, Madison, WI USA. [Sim, Taebo] Korea Inst Sci & Technol, Chem Kin Res Ctr, Seoul, South Korea. [Sim, Taebo] KU KIST Grad Sch Converging Sci & Technol, Seoul, South Korea. RP Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. EM pjanne@partners.org; craig.crews@yale.edu; nathanael_gray@dfci.harvard.edu FU Dana Farber Cancer Institute Lander Fellowship; Claudia Adams Barr Program Award; US National Institutes of Health (NIH) [AI 084140-03]; Cancer Prevention Research Institute of Texas [R1207]; National Research Foundation of Korea [NRF-2011-0028676]; NIH [P01 CA154303] FX We wish to thank staff at The Institute of Chemistry and Cell Biology for the guidance of screening equipment and assay development discussion. We thank J. Minna and M. Peyton of UT Southwestern Medical Center for providing the HCC2935 cell line. This work is supported by the Dana Farber Cancer Institute Lander Fellowship (T.X.), Claudia Adams Barr Program Award (N.S.G.), US National Institutes of Health (NIH) grant AI 084140-03 (C.M.C.), Cancer Prevention Research Institute of Texas grant R1207 (K.D.W.), creative/challenging research program of National Research Foundation of Korea NRF-2011-0028676 (T.S.) and NIH grant P01 CA154303 (P.A.J. and N.S.G.). NR 50 TC 23 Z9 23 U1 6 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD DEC PY 2014 VL 10 IS 12 BP 1006 EP + DI 10.1038/nchembio.1658 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT7MT UT WOS:000345122300007 PM 25326665 ER PT J AU Li, LY Yin, Q Kuss, P Maliga, Z Millan, JL Wu, H Mitchison, TJ AF Li, Lingyin Yin, Qian Kuss, Pia Maliga, Zoltan Millan, Jose L. Wu, Hao Mitchison, Timothy J. TI Hydrolysis of 2 ' 3 '-cGAMP by ENPP1 and design of nonhydrolyzable analogs SO NATURE CHEMICAL BIOLOGY LA English DT Article ID CYCLIC GMP-AMP; MEMBRANE GLYCOPROTEIN PC-1; CYTOSOLIC DNA; NUCLEOTIDE PHOSPHODIESTERASES; ENDOPLASMIC-RETICULUM; ALKALINE-PHOSPHATASE; BONE MINERALIZATION; SIGNALING PATHWAY; RESISTANCE; SENSOR AB Agonists of mouse STING (TMEM173) shrink and even cure solid tumors by activating innate immunity; human STING (hSTING) agonists are needed to test this therapeutic hypothesis in humans. The endogenous STING agonist is 2'3'-cGAMP, a second messenger that signals the presence of cytosolic double-stranded DNA. We report activity-guided partial purification and identification of ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) to be the dominant 2'3'-cGAMP hydrolyzing activity in cultured cells. The hydrolysis activity of ENPP1 was confirmed using recombinant protein and was depleted in tissue extracts and plasma from Enpp1-/- mice. We synthesized a hydrolysis-resistant bisphosphothioate analog of 2'3'-cGAMP (2'3'-cGsAsMP) that has similar affinity for hSTING in vitro and is ten times more potent at inducing IFN-beta secretion from human THP1 monocytes. Studies in mouse Enpp1-/- lung fibroblasts indicate that resistance to hydrolysis contributes substantially to its higher potency. 2'3'-cGsAsMP is therefore improved over natural 2'3'-cGAMP as a model agonist and has potential as a vaccine adjuvant and cancer therapeutic. C1 [Li, Lingyin; Maliga, Zoltan; Mitchison, Timothy J.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02138 USA. [Yin, Qian; Wu, Hao] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Kuss, Pia; Millan, Jose L.] Sanford Burnham Med Res Inst, Sanford Childrens Hlth Res Ctr, La Jolla, CA USA. RP Li, LY (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02138 USA. EM lingyin_li@hms.harvard.edu FU National Cancer Institute [CA139980, AR53102, AI050872, 1K99AI108793-01] FX We thank P. Koch, P. Choi, K. Krukenberg, A. Groen, M. Loose, S. Kim and S. Gruver for helpful discussions. We thank R. Jiang for help with data analysis. We thank K. Chu for providing mouse livers. We thank S. Walker for sharing the MicroBeta plate reader and C. Fan for technical assistance. We thank J.J. Mekalanos for providing the DncV expression plasmid and T. Bernhard (both from Harvard Medical School) for providing the pTB146 plasmid. We thank G. Heffron and C. Sheahan for assistance with the NMR data collection and analysis. We thank R. Ward for help with manuscript preparation. This research was supported by the National Cancer Institute (CA139980, AR53102, AI050872 and 1K99AI108793-01). L. Li thanks the Jane Coffin Childs Fund for her postdoctoral fellowship. NR 43 TC 21 Z9 22 U1 5 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD DEC PY 2014 VL 10 IS 12 BP 1043 EP + DI 10.1038/NChemBio.1661 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT7MT UT WOS:000345122300012 PM 25344812 ER PT J AU Zanni, MV Schouten, J Grinspoon, SK Reiss, P AF Zanni, Markella V. Schouten, Judith Grinspoon, Steven K. Reiss, Peter TI Risk of coronary heart disease in patients with HIV infection SO NATURE REVIEWS CARDIOLOGY LA English DT Review ID IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; PROTEASE INHIBITOR RITONAVIR; ACUTE MYOCARDIAL-INFARCTION; HUMAN ENDOTHELIAL-CELLS; MONOCYTE CHEMOATTRACTANT PROTEIN-1; INTERCELLULAR-ADHESION MOLECULE-1; INTIMA-MEDIA THICKNESS; CHRONIC KIDNEY-DISEASE; TISSUE FACTOR EXPRESSION AB The lives of individuals infected with HIV who have access to combination antiretroviral therapy (cART) are substantially prolonged, which increases the risk of developing non-AIDS comorbidities, including coronary heart disease (CHD). In Europe and the USA, individuals with HIV infection have a similar to 1.5-fold increased risk of myocardial infarction relative to uninfected individuals. In Africa, the relative risk of myocardial infarction is unknown, but broadened access to life-extending cART suggests that rates of CHD will rise in this and other resource-constrained regions. Atherogenesis in HIV is affected by complex interactions between traditional and immune risk factors. cART has varied, regimen-specific effects on metabolic risk factors. Overall, cART seems to lessen proatherogenic immune activation, but does not eliminate it even in patients in whom viraemia is suppressed. Current strategies to decrease the risk of CHD in individuals infected with HIV include early initiation of cART regimens with the fewest metabolic adverse effects, and careful management of traditional CHD risk factors throughout treatment. Future strategies to prevent CHD in patients with HIV infection might involve the use of HIV-tailored CHD risk-prediction paradigms and the administration of therapies alongside cART that will further decrease proatherogenic HIV-specific immune activation. C1 [Zanni, Markella V.; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Zanni, Markella V.; Grinspoon, Steven K.] Harvard Univ, Boston, MA 02114 USA. [Schouten, Judith; Reiss, Peter] Univ Amsterdam, Acad Med Ctr, Dept Global Hlth, NL-1105 AZ Amsterdam, Netherlands. [Schouten, Judith; Reiss, Peter] Amsterdam Inst Global Hlth & Dev, NL-1105 AZ Amsterdam, Netherlands. RP Reiss, P (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Global Hlth, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM p.reiss@amc.uva.nl FU NIDDK NIH HHS [P30 DK040561] NR 208 TC 19 Z9 22 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 EI 1759-5010 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD DEC PY 2014 VL 11 IS 12 BP 728 EP 741 DI 10.1038/nrcardio.2014.167 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AU0DE UT WOS:000345292800006 PM 25331088 ER PT J AU Malnar, M Hecimovic, S Mattsson, N Zetterberg, H AF Malnar, Martina Hecimovic, Silva Mattsson, Niklas Zetterberg, Henrik TI Bidirectional links between Alzheimer's disease and Niemann-Pick type C disease SO NEUROBIOLOGY OF DISEASE LA English DT Review DE Alzheimer's disease; Amyloid-beta; Niemann-Pick type C disease; NPC1; Tau; Cholesterol; Lipids ID AMYLOID-PRECURSOR-PROTEIN; INTRACELLULAR CHOLESTEROL TRANSPORT; GENOME-WIDE ASSOCIATION; A-BETA PRODUCTION; APOLIPOPROTEIN-E; NEUROFIBRILLARY TANGLES; IN-VIVO; ENDOCYTIC PATHWAY; ALPHA-SYNUCLEIN; DOWN-SYNDROME AB Alzheimer's disease (AD) and Niemann-Pick type C (NPC) disease are progressive neurodegenerative diseases with very different epidemiology and etiology. AD is a common cause of dementia with a complex polyfactorial etiology, including both genetic and environmental risk factors, while NPC is a very rare autosomal recessive disease. However, the diseases share some disease-related molecular pathways, including abnormal cholesterol metabolism, and involvement of amyloid-beta (A beta) and tau pathology. Here we review recent studies on these pathological traits, focusing on studies of A beta and tau pathology in NPC, and the importance of the NPC1 gene in AD. Further studies of similarities and differences between AD and NPC may be useful to increase the understanding of both these devastating neurological diseases. (C) 2014 Elsevier Inc. All rights reserved. C1 [Malnar, Martina; Hecimovic, Silva] Rudjer Boskovic Inst, Div Mol Med, Zagreb 10000, Croatia. [Mattsson, Niklas; Zetterberg, Henrik] Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Clin Neurochem Lab,Inst Neurosci & Physiol, Gothenburg, Sweden. [Mattsson, Niklas] San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA USA. [Mattsson, Niklas] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Zetterberg, Henrik] UCL Inst Neurol, London WC1N 3BG, England. RP Hecimovic, S (reprint author), Rudjer Boskovic Inst, Div Mol Med, Zagreb 10000, Croatia. EM silva.hecimovic@irb.hr; henrik.zetterberg@gu.se FU Swedish Research Council Formas; Knut and Alice Wallenberg Foundation; Wolfson Foundation; Ministry of Science, Education and Sports of the Republic of Croatia; Unity through Knowledge Fund; Swedish State Support for Clinical Research FX Work in the authors' laboratories is supported by the Swedish Research Council Formas, Swedish State Support for Clinical Research, the Knut and Alice Wallenberg Foundation, the Wolfson Foundation (to N.M. and H.Z.), the Ministry of Science, Education and Sports of the Republic of Croatia and the Unity through Knowledge Fund (to S.H.). NR 122 TC 13 Z9 13 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD DEC PY 2014 VL 72 SI SI BP 37 EP 47 DI 10.1016/j.nbd.2014.05.033 PN A PG 11 WC Neurosciences SC Neurosciences & Neurology GA AT8QX UT WOS:000345198300005 PM 24907492 ER PT J AU Ernst, M Romero, JM Buhk, JH Kemmling, A Fiehler, J Groth, M AF Ernst, M. Romero, J. M. Buhk, J. H. Kemmling, A. Fiehler, J. Groth, M. TI Sensitivity of visual and quantitative detection of middle cerebral artery occlusion on non-contrast-enhanced computed tomography SO NEURORADIOLOGY LA English DT Article DE NECT; Hyperdense artery sign; Middle cerebral artery occlusion; Accuracy ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN-ACTIVATOR; EARLY CT SIGNS; INTRAVENOUS THROMBOLYSIS; STATISTICAL-METHODS; HYPERACUTE STROKE; PROGNOSTIC VALUE; PREDICTIVE-VALUE; ANGIOGRAPHY; DENSITY AB This study aims to investigate diagnostic sensitivity and reliability for the detection of middle cerebral artery occlusion (MCAO) on non-contrast-enhanced computed tomography (NECT) by visual assessment (VA), Hounsfield unit (HU) measurement, calculation of the Hounsfield unit/hematocrit (HU/Hct) ratio, and combination of visual assessment and attenuation measurement (VA + HU). NECT of 18 patients with angiographically proven MCAO and 18 patients without MCAO were reviewed by two blinded observers. Visual assessment of presence or absence of a hyperdense sign was followed by HU measurement of both middle cerebral arteries (MCA). Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for VA, HU measurement, HU/Hct ratio, and VA + HU measurement. Receiver operating characteristic curve analysis (ROC) was performed to determine the optimal cut-off values for MCAO using attenuation measurements or HU/Hct ratio. Diagnostic sensitivity/specificity was 63 %/91 % for VA, 56 %/88 % for attenuation measurement, 68 %/81 % for HU/Hct ratio, and 75 %/78 % for VA + HU. ROC curve analysis revealed cut-off values of > 42.5 HU for attenuation measurements and > 1.12 HU/Hct for HU/Hct ratio. Combination of visual assessment with additional attenuation measurement with a cut-off value of 42.5 HU is recommended for most sensitive and reliable detection of MCAO on NECT. C1 [Ernst, M.; Buhk, J. H.; Kemmling, A.; Fiehler, J.; Groth, M.] Univ Med Ctr Hamburg Eppendorf, Ctr Radiol & Endoscopy, Dept Diagnost & Intervent Neuroradiol, D-20246 Hamburg, Germany. [Romero, J. M.] Harvard Univ, Sch Med, Dept Radiol, Div Neuroradiol,Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Ernst, M (reprint author), Univ Med Ctr Hamburg Eppendorf, Ctr Radiol & Endoscopy, Dept Diagnost & Intervent Neuroradiol, Haus Ost 22 O 22 Martinistr 52, D-20246 Hamburg, Germany. EM m.ernst@uke.de NR 35 TC 3 Z9 3 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0028-3940 EI 1432-1920 J9 NEURORADIOLOGY JI Neuroradiology PD DEC PY 2014 VL 56 IS 12 BP 1063 EP 1068 DI 10.1007/s00234-014-1443-y PG 6 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU0ET UT WOS:000345297100006 PM 25274137 ER PT J AU Dabaghyan, M Muradyan, I Hrovat, A Butler, J Frederick, E Zhou, F Kyriazis, A Hardin, C Patz, S Hrovat, M AF Dabaghyan, Mikayel Muradyan, Iga Hrovat, Alan Butler, James Frederick, Eric Zhou, Feng Kyriazis, Angelos Hardin, Charles Patz, Samuel Hrovat, Mirko TI A portable single-sided magnet system for remote NMR measurements of pulmonary function SO NMR IN BIOMEDICINE LA English DT Article DE Spectroscopic imaging; MR Spectroscopy (MRS) and Spectroscopic Imaging (MRSI) Methods; Methods and Engineering; RF Pulse design; Acquisition Methods; Methods and Engineering Magnets; MR Engineering; Post-acquisition Processing ID ACUTE RESPIRATORY-DISTRESS; ACUTE LUNG INJURY; END-EXPIRATORY PRESSURE; RESONANCE; FIELDS; METAANALYSIS AB In this work, we report initial results from a light-weight, low field magnetic resonance device designed to make relative pulmonary density measurements at the bedside. The development of this device necessarily involves special considerations for the magnet, RF and data acquisition schemes as well as a careful analysis of what is needed to provide useful information in the ICU. A homogeneous field region is created remotely from the surface of the magnet such that when the magnet is placed against the chest, an NMR signal is measured from a small volume in the lung. In order to achieve portability, one must trade off field strength and therefore spatial resolution. We report initial measurements from a ping-pong ball size region in the lung as a function of lung volume. As expected, we measured decreased signal at larger lung volumes since lung density decreases with increasing lung volume. Using a CPMG sequence with TE=3.5 ms and a 20 echo train, a signal to noise ratio similar to 1100 was obtained from an 8.8mT planar magnet after signal averaging for 43s. This is the first demonstration of NMR measurements made on a human lung with a light-weight planar NMR device. We argue that very low spatial resolution measurements of different lobar lung regions will provide useful diagnostic information for clinicians treating Acute Respiratory Distress Syndrome as clinicians want to avoid ventilator pressures that cause either lung over distension (too much pressure) or lung collapse (too little pressure). Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Dabaghyan, Mikayel; Hrovat, Alan; Hrovat, Mirko] Mirtech Inc, Brockton, MA USA. [Muradyan, Iga; Butler, James; Kyriazis, Angelos; Hardin, Charles; Patz, Samuel] Harvard Univ, Sch Med, Boston, MA USA. [Muradyan, Iga; Butler, James; Kyriazis, Angelos; Patz, Samuel] Brigham & Womens Hosp, Boston, MA 02115 USA. [Frederick, Eric; Zhou, Feng] Univ Massachusetts Lowell, Lowell, MA USA. [Hardin, Charles] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Patz, S (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM patz@bwh.harvard.edu OI Patz, Samuel/0000-0002-4500-1918 FU NIH [1RC1HL100606, 1P50HL110790, 1R41HL117339]; Center for Integration of Medicine and Innovative Technology (CIMIT) Innovator Award FX We would like to acknowledge Michael Hrovat for his contributions to the construction and assembly of components used in this study. We would also like to thank Dr. Matt Rosen for allowing us to make some initial measurements on his low-field imaging system. This work was supported by the following grants: NIH 1RC1HL100606, NIH 1P50HL110790, NIH 1R41HL117339, and a Center for Integration of Medicine and Innovative Technology (CIMIT) Innovator Award. NR 36 TC 1 Z9 1 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD DEC PY 2014 VL 27 IS 12 SI SI BP 1479 EP 1489 DI 10.1002/nbm.3149 PG 11 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA AT8ZY UT WOS:000345218600007 PM 24953556 ER PT J AU Nogueira, I Hrovat, K AF Nogueira, Isadora Hrovat, Kathleen TI Adolescent Bariatric Surgery: Review on Nutrition Considerations SO NUTRITION IN CLINICAL PRACTICE LA English DT Review DE bariatric surgery; weight loss; adolescent; nutrition assessment ID WEIGHT-LOSS SURGERY; Y GASTRIC BYPASS; SLEEVE GASTRECTOMY; NATIONAL TRENDS; SUPPORT GROUP; OBESITY; PREDICTORS; CHILDREN; PATIENT AB The prevalence of obesity in adolescents has dramatically increased over the past 3 decades in the United States. Weight loss surgery is becoming a viable treatment option for obese adolescents. The number of surgeries being performed yearly is rising, and this trend is likely to continue. Adolescent patients present a unique challenge to clinicians. There are currently best-practice recommendations and evidence-based nutrition guidelines for the treatment of the adolescent bariatric patient. A review of the current literature was performed to discuss bariatric surgery and nutrition for the adolescent patient. Studies show that most adolescents with obesity will become obese adults, thus increasing their risk of developing serious and debilitating health conditions. It is recommended that the candidates for surgery be referred to a practice that has a multidisciplinary team experienced in meeting the distinct physical and psychological needs of adolescents. Specific nutrition concerns for the adolescent bariatric patient include preoperative educational pathway, postoperative dietary progression, female reproduction, compliance with vitamin/supplementation recommendations, laboratory tests, and long-term monitoring. The medical literature has reported positive outcomes of bariatric surgery in adolescents with severe obesity. Before surgery is offered as an option, unique factors to adolescents must be addressed. The multidisciplinary clinical team must consider the adolescents' cognitive, social, and emotional development when considering their candidacy for surgery. As the number of adolescent bariatric surgery programs increases, continued research and long-term outcome data need to be collected and shared to base future treatment decisions. C1 [Nogueira, Isadora] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hrovat, Kathleen] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. RP Nogueira, I (reprint author), Massachusetts Gen Hosp, 50 Staniford St,4th Floor, Boston, MA 02114 USA. EM inogueira@partners.org NR 35 TC 3 Z9 3 U1 0 U2 5 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 DEC PY 2014 VL 29 IS 6 BP 740 EP 746 DI 10.1177/0884533614552851 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AT8XQ UT WOS:000345212800003 PM 25332015 ER PT J AU Remenschneider, AK Lookabaugh, S Aliphas, A Brodsky, JR Devaiah, AK Dagher, W Grundfast, KM Heman-Ackah, SE Rubin, S Sillman, J Tsai, AC Vecchiotti, M Kujawa, SG Lee, DJ Quesnel, AM AF Remenschneider, Aaron K. Lookabaugh, Sarah Aliphas, Avner Brodsky, Jacob R. Devaiah, Anand K. Dagher, Walid Grundfast, Kenneth M. Heman-Ackah, Selena E. Rubin, Samuel Sillman, Jonathan Tsai, Angela C. Vecchiotti, Mark Kujawa, Sharon G. Lee, Daniel J. Quesnel, Alicia M. TI Otologic Outcomes After Blast Injury: The Boston Marathon Experience SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Blast injury; Boston Marathon bombings; Hearing loss; Quality of life; Tympanoplasty; Tympanic membrane perforation ID INDUCED HEARING-LOSS; TYMPANIC MEMBRANE; HANDICAP INVENTORY; TINNITUS; CONSEQUENCES; EXPOSURE; PERFORATIONS; RUPTURE; EAR AB Objective: Otologic trauma was the most common physical injury sustained after the April 15, 2013, Boston Marathon bombings. The goal of this study is to describe the resultant otologic morbidity and to report on early outcomes. Study Design: Multi-institutional prospective cohort study. Methods: Children and adults seen for otologic complaints related to the Boston Marathon bombings comprised the study population. Participants completed symptom assessments, quality-of-life questionnaires, and audiograms at initial and 6-month visits. Otologic evaluation and treatment, including tympanoplasty results, were reviewed. Results: More than 100 patients from eight medical campuses have been evaluated for blast-related otologic injuries; 94 have enrolled. Only 7% had any otologic symptoms before the blasts. Ninety percent of hospitalized patients sustained tympanic membrane perforation. Proximity to blast (RR = 2.7, p < 0.01) and significant nonotologic injury (RR = 2.7, p < 0.01) were positive predictors of perforation. Spontaneous healing occurred in 38% of patients, and tympanoplasty success was 86%. After oral steroid therapy in eight patients, improvement in hearing at 2 and 4 kHz was seen, although changes did not reach statistical significance. Hearing loss, tinnitus, hyperacusis, and difficulty hearing in noise remain persistent and, in some cases, progressive complaints for patients. Otologic-specific quality of life was impaired in this population. Conclusion: Blast-related otologic injuries constitute a major source of ongoingmorbidity after the BostonMarathon bombings. Continued follow-up and care of this patient population are warranted. C1 [Remenschneider, Aaron K.; Brodsky, Jacob R.; Heman-Ackah, Selena E.; Kujawa, Sharon G.; Lee, Daniel J.; Quesnel, Alicia M.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Remenschneider, Aaron K.; Lookabaugh, Sarah; Lee, Daniel J.; Quesnel, Alicia M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Remenschneider, Aaron K.; Lee, Daniel J.; Quesnel, Alicia M.] Massachusetts Gen Hosp, Dept Otolaryngol, Boston, MA 02114 USA. [Aliphas, Avner; Devaiah, Anand K.; Grundfast, Kenneth M.; Rubin, Samuel; Tsai, Angela C.] Boston Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Boston Med Ctr, Boston, MA 02118 USA. [Brodsky, Jacob R.] Boston Childrens Hosp, Dept Otolaryngol & Commun Enhancement, Boston, MA USA. [Dagher, Walid; Sillman, Jonathan; Vecchiotti, Mark] Tufts Univ, Sch Med, Tufts Med Ctr, Dept Otolaryngol Head & Neck Surg, Boston, MA 02111 USA. [Heman-Ackah, Selena E.] Beth Israel Deaconess Med Ctr, Dept Surg, Div Otolaryngol, Boston, MA 02215 USA. [Kujawa, Sharon G.] Massachusetts Eye & Ear Infirm, Dept Audiol, Boston, MA 02114 USA. [Lee, Daniel J.] Brigham & Womens Hosp, Dept Surg, Div Otolaryngol, Boston, MA 02115 USA. RP Quesnel, AM (reprint author), 243 Charles St, Boston, MA 02114 USA. EM Alicia_Quesnel@meei.harvard.edu FU Massachusetts Eye and Ear Institutional Review Board FX This study would not have been possible without the significant support of the Massachusetts Eye and Ear Institutional Review Board and Fariba Houman, Ph.D. The authors thank Dr. Michael Hoffer for assistance in guiding clinical care as well as the study design. Staff across all eight institutions provided extensive clerical support and facilitated recruitment for the study. Patients in this study were evaluated, cared for, and continue to be managed by 30 treating otolaryngologists and affiliated audiologists. Most of all, the authors thank the patients who continue to impress the authors every day with their inner strength and willingness to participate in this research. NR 34 TC 13 Z9 13 U1 3 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD DEC PY 2014 VL 35 IS 10 BP 1825 EP 1834 PG 10 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA AT8AX UT WOS:000345157200039 PM 25393974 ER PT J AU McKay, RR Zukotynski, KA Werner, L Voznesensky, O Wu, JS Smith, SE Jiang, Z Melnick, K Yuan, X Kantoff, PW Montgomery, B Balk, SP Taplin, ME AF McKay, R. R. Zukotynski, K. A. Werner, L. Voznesensky, O. Wu, J. S. Smith, S. E. Jiang, Z. Melnick, K. Yuan, X. Kantoff, P. W. Montgomery, B. Balk, S. P. Taplin, M-E TI Imaging, procedural and clinical variables associated with tumor yield on bone biopsy in metastatic castration-resistant prostate cancer SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article ID MARROW BIOPSY; VERTEBRAL BIOPSY; GUIDED BIOPSY; CARCINOMA; SPINE AB BACKGROUND: Understanding the mechanisms driving disease progression is fundamental to identifying new therapeutic targets for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). Owing to the prevalence of bone metastases in mCRPC, obtaining sufficient tumor tissue for analysis has historically been a challenge. In this exploratory analysis, we evaluated imaging, procedural and clinical variables associated with tumor yield on image-guided bone biopsy in men with mCRPC. METHODS: Clinical data were collected prospectively from men with mCRPC enrolled on a phase II trial with serial metastasis biopsies performed according to standard clinical protocol. Imaging was retrospectively reviewed. We evaluated the percent positive biopsy cores (PPC), calculated as the number of positive cores divided by the total number of cores collected per biopsy. RESULTS: Twenty-nine men had 39 bone biopsies. Seventy-seven percent of bone biopsies had at least one positive biopsy core. We determined that lesion size and distance from the skin to the lesion edge correlated with tumor yield on biopsy (median PPC 75% versus 42% for lesions > 8.8 cm(3) versus <= 8.8 cm(3), respectively, P = 0.05; median PPC 33% versus 71% for distance >= 6.1 versus < 6.1 cm, respectively, P = 0.02). There was a trend towards increased tumor yield in patients with increased uptake on radionuclide bone scan, higher calcium levels and shorter duration of osteoclast-targeting therapy, although this was not statistically significant. Ten men had 14 soft tissue biopsies. All soft tissue biopsies had at least one positive biopsy core. CONCLUSIONS: This exploratory analysis suggests that there are imaging, procedural and clinical variables that have an impact on image-guided bone biopsy yield. In order to maximize harvest of prostate cancer tissue, we have incorporated a prospective analysis of the metrics described here as part of a multi-institutional project aiming to use the molecular characterization of mCRPC tumors to direct individual therapy. C1 [McKay, R. R.; Werner, L.; Smith, S. E.; Jiang, Z.; Melnick, K.; Kantoff, P. W.; Taplin, M-E] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Zukotynski, K. A.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Zukotynski, K. A.; Smith, S. E.; Yuan, X.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Voznesensky, O.; Wu, J. S.; Balk, S. P.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Montgomery, B.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. RP Taplin, ME (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM mtaplin@partners.org FU Janssen; Fairweather Family Fund; Prostate Cancer Foundation Challenge Award FX The clinical trial described in this manuscript was funded by Janssen. GlaxoSmithKline provided dutasteride for this trial. The cost of the tumor biopsies was funded through the Fairweather Family Fund and the Prostate Cancer Foundation Challenge Award. NR 15 TC 2 Z9 2 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 EI 1476-5608 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD DEC PY 2014 VL 17 IS 4 BP 325 EP 331 DI 10.1038/pcan.2014.28 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AT3LC UT WOS:000344835400005 PM 25091040 ER PT J AU Liu, Y Zhang, Y Wang, JH AF Liu, Ying Zhang, Yan Wang, Jia-Huai TI Crystal structure of human Ankyrin G death domain SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE apoptosis; axon initial segment; 3(10)-helix; hydrophobic pocket; monomer ID AXON INITIAL SEGMENT; NEURONAL POLARITY; PROTEINS; MAINTENANCE; APOPTOSIS; RANVIER; COMPLEX; SYSTEM; GENE AB Ankyrins (Ank) are a ubiquitously expressed family of multifunctional membrane adapter proteins. Ankyrin G (AnkG) is critical for assembling and maintenance of the axon initial segment. Here we present the 2.1 angstrom crystal structure of human AnkG death domain (hAnkG-DD). The core death domain is composed of six -helices and three 3(10)-helices. It forms a hydrophobic pocket on the surface of the molecule. The C-terminal tail of the hAnkG-DD curves back to have the aromatic ring of a phenylalanine residue, Phe100 insert into this pocket, which anchors the flexible tail onto the core domain. Related DDs were selected for structure comparison. The major variations are at the C-terminal region, including the 6 and the long C-terminal extension. The results of size exclusion chromatography and analytical ultracentrifugation suggest that hAnkG-DD exists as monomer in solution. Our work should help for the future investigation of the structure-function of AnkG. Proteins 2014; 82:3476-3482. (c) 2014 Wiley Periodicals, Inc. C1 [Liu, Ying; Zhang, Yan; Wang, Jia-Huai] Peking Univ, Coll Life Sci, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100871, Peoples R China. [Zhang, Yan] PKU IDG McGovern Inst Brain Res, Beijing 100871, Peoples R China. [Wang, Jia-Huai] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Wang, JH (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02225 USA. EM jwang@red.dfci.harvard.edu FU Ministry of Education of China; National Science Foundation of China (NSFC) [91132718]; Beijing Natural Science Foundation [7142085]; NIH [HL48675]; Peking-Tsinghua Center for Life Sciences FX Grant sponsor: Ministry of Education of China (to J.-H.W. and Y.Z.); Grant sponsor: National Science Foundation of China (NSFC) Major Research; Grant number: 91132718; Grant sponsor: Beijing Natural Science Foundation (to Y.Z.); Grant number: 7142085; Grant sponsor: NIH grant; Grant number: HL48675; Grant sponsor: Peking-Tsinghua Center for Life Sciences (to J.-H.W.). NR 28 TC 0 Z9 0 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD DEC PY 2014 VL 82 IS 12 BP 3476 EP 3482 DI 10.1002/prot.24702 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AU0HZ UT WOS:000345305400020 PM 25307106 ER PT J AU Yakabi, K Harada, Y Takayama, K Ro, S Ochiai, M Iizuka, S Hattori, T Wang, LX Tache, Y AF Yakabi, Koji Harada, Yumi Takayama, Kiyoshige Ro, Shoki Ochiai, Mitsuko Iizuka, Seiichi Hattori, Tomohisa Wang, Lixin Tache, Yvette TI Peripheral alpha(2)-beta(1) adrenergic interactions mediate the ghrelin response to brain urocortin 1 in rats SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Atylated ghrelin; Adrenergit receptors; Food intake; Urocortin 1; Stress; Rikkunshito ID CORTICOTROPIN-RELEASING-FACTOR; EDINGER-WESTPHAL NUCLEUS; AUTONOMIC NERVOUS-SYSTEM; DES-ACYL GHRELIN; FOOD-INTAKE; CRF2 RECEPTORS; GASTROINTESTINAL-TRACT; CIRCULATING GHRELIN; ENERGY-METABOLISM; INDUCED ANOREXIA AB The autonomic nervous system (ANS) conveys neuronal input from the brain to the stomach. We investigated mechanisms through which urocortin 1 (UCN1) injected intracerebroventricularly (ICV, 300 pmol/rat) inhibits circulating ghrelin in rats. This was achieved by assessing (1) the induction of c-fos gene expression as a marker of neuronal activation in specific hypothalamic and caudal brainstem regulating ANS; (2) the influence of vagotomy and pharmacological blockade of central and peripheral alpha- and beta-adrenergic receptor (AR) on ICY UCN1-induced reduction of plasma ghrelin levels (determined by ELISA); and (3) the relevance of this pathway in the feeding response to a fast in rats. UCN1 increased c-fos mRNA expression in key brain sites influencing sympathetic activity namely the hypothalamic paraventricular and ventromedial nuclei, locus coeruleus, nucleus of the solitary tract, and rostral ventrolateral medulla, by 16-, 29-, 6-, 37-, and 13-fold, respectively. In contrast, the dorsal motor nucleus of the vagus had little c-fos mRNA expression and ICY UCN1 induced a similar reduction in acylated ghrelin in the sham-operated (31%) and vagotomized (41%) rats. An intraperitoneal (IP) injection of either a non-selective alpha- or selective alpha(2)-AR antagonist reduced, while a selective alpha(2)-AR agonist enhanced ICV UCN1-induced suppression of plasma acylated ghrelin levels. In addition, IP injection of a non-selective beta- or selective beta(1)-AR agonist blocked, and selective beta(1)-AR antagonist augmented, the ghrelin response to ICV UCN1. The IP injections of a selective alpha(1)- or non-selective beta or beta(2)-AR antagonists, or any of the pretreatments given ICV had no effect. ICV UCN1 reduced the 2-h food intake in response to a fast by 80%, and this effect was partially prevented by a selective alpha(2)-AR antagonist. These data suggest that ICV UCN1 reduces plasma ghrelin mainly through the brain sympathetic component of the ANS and peripheral AR specifically alpha(2)-AR activation and inactivation of beta(1)-AR. The alpha(2)-AR pathway contributes to the associated reduction in food intake. (C) 2014 The Authors. Published by Elsevier Ltd. C1 [Yakabi, Koji; Harada, Yumi; Takayama, Kiyoshige; Ro, Shoki; Ochiai, Mitsuko] Saitama Med Univ, Dept Gastroenterol & Hepatol, Saitama Med Ctr, Saitama 3508550, Japan. [Harada, Yumi; Iizuka, Seiichi; Hattori, Tomohisa] Tsumura & Co, Tsumura Res Labs, Ami, Ibaraki 3001192, Japan. [Takayama, Kiyoshige] Gunma Univ, Sch Hlth Sci, Dept Lab Sci, Gunma 3718511, Japan. [Ro, Shoki] Teikyo Univ, Chiba Med Ctr, Cent Res Labs, Chiba 2990111, Japan. [Wang, Lixin; Tache, Yvette] Univ Calif Los Angeles, CURE Digest Dis Ctr, Dept Med, Div Digest Dis, Los Angeles, CA 90078 USA. [Wang, Lixin; Tache, Yvette] Univ Calif Los Angeles, Ctr Neurobiol Stress, Dept Med, Div Digest Dis, Los Angeles, CA 90078 USA. [Wang, Lixin; Tache, Yvette] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90078 USA. RP Harada, Y (reprint author), Tsumura & Co, Tsumura Res Labs, 3586 Yoshiwara, Ami, Ibaraki 3001192, Japan. EM harada_yumi@mail.tsumura.co.jp FU Saitama Medical Center, Saitama Medical University (Japan); Tsumura Co. (Japan); Senior Research Career Scientist Award FX This work was supported in part by Saitama Medical Center, Saitama Medical University (Japan), a grant from Tsumura & Co. (Japan) and the Senior Research Career Scientist Award (YT). NR 53 TC 2 Z9 2 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD DEC PY 2014 VL 50 BP 300 EP 310 DI 10.1016/j.psyneuen.2014.09.003 PG 11 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA AT6PJ UT WOS:000345061000029 PM 25265283 ER PT J AU Raj, RS Bonney, EA Phillippe, M AF Raj, Renju S. Bonney, Elizabeth A. Phillippe, Mark TI Influenza, Immune System, and Pregnancy SO REPRODUCTIVE SCIENCES LA English DT Review DE influenza; pregnancy; innate immunity; adaptive immunity ID TUMOR-NECROSIS-FACTOR; TOLL-LIKE RECEPTORS; 1918 PANDEMIC VIRUS; PLASMACYTOID DENDRITIC CELLS; BRONCHIAL EPITHELIAL-CELLS; HUMAN GESTATIONAL TISSUES; MATERNAL-FETAL INTERFACE; VIRAL GENE REPLICATION; MEMBRANE CHORION CELLS; NATURAL-KILLER-CELLS AB Influenza is a major health problem worldwide. Both seasonal influenza and pandemics take a major toll on the health and economy of our country. The present review focuses on the virology and complex immunology of this RNA virus in general and in relation to pregnancy. The goal is to attempt to explain the increased morbidity and mortality seen in infection during pregnancy. We discuss elements of innate and adaptive immunity as well as placental cellular responses to infection. In addition, we delineate findings in animal models as well as human disease. Increased knowledge of maternal and fetal immunologic responses to influenza is needed. However, enhanced understanding of nonimmune, pregnancy-specific factors influencing direct interaction of the virus with host cells is also important for the development of more effective prevention and treatment options in the future. C1 [Raj, Renju S.; Bonney, Elizabeth A.] Univ Vermont, Coll Med, Dept Obstet Gynecol & Reprod Sci, Burlington, VT USA. [Phillippe, Mark] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. RP Phillippe, M (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, 55 Fruit St,Founders Bldg 520-A, Boston, MA 02114 USA. EM mphillippe@mgh.harvard.edu FU Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont College of Medicine [NIHP20 RR021905]; Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard School of Medicine; [NIHK12HD063082] FX The author(s) received the following financial support for the research, authorship, and/or publication of this article: Supported by NIHK12HD063082 (all authors), NIHP20 RR021905 (EAB, through the Vermont Center for Immunology and Infectious Disease), The Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont College of Medicine (RSR, EAB), and the Vincent Center for Reproductive Biology, Massachusetts General Hospital, Harvard School of Medicine(MP). NR 215 TC 4 Z9 4 U1 1 U2 21 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD DEC PY 2014 VL 21 IS 12 BP 1434 EP 1451 DI 10.1177/1933719114537720 PG 18 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AT8YK UT WOS:000345214700001 PM 24899469 ER PT J AU Lin, HZ Zhou, L Zhou, XH AF Lin, Huazhen Zhou, Ling Zhou, Xiaohua TI Semiparametric Regression Analysis of Longitudinal Skewed Data SO SCANDINAVIAN JOURNAL OF STATISTICS LA English DT Article DE additive model; longitudinal data; multiplicative model; semiparametric; transformation model ID TRANSFORMATION MODELS; CENSORED-DATA; RETRANSFORMATION AB In this paper, we develop a semiparametric regression model for longitudinal skewed data. In the new model, we allow the transformation function and the baseline function to be unknown. The proposed model can provide a much broader class of models than the existing additive and multiplicative models. Our estimators for regression parameters, transformation function and baseline function are asymptotically normal. Particularly, the estimator for the transformation function converges to its true value at the rate n(-1/2), the convergence rate that one could expect for a parametric model. In simulation studies, we demonstrate that the proposed semiparametric method is robust with little loss of efficiency. Finally, we apply the new method to a study on longitudinal health care costs. C1 [Lin, Huazhen; Zhou, Ling] Southwestern Univ Finance & Econ, Sch Stat, Ctr Stat Res, Chengdu, Peoples R China. [Zhou, Xiaohua] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Zhou, Xiaohua] VA Puget Sound Hlth Care Syst, HSR&D Ctr Excellence, Seattle, WA USA. RP Zhou, XH (reprint author), Univ Washington, Dept Biostat, Seattle, WA 98195 USA. EM azhou@u.washington.edu FU Chinese Natural Science Foundation [11125104, 30728019]; Fundamental Research Funds for the Central Universities of China; US Department of Veterans Affairs, Veterans Affairs Health Administration, HSRD [IIR 07-235-1] FX Lin's research is supported in part by the Chinese Natural Science Foundation (11125104) and the Fundamental Research Funds for the Central Universities of China. Zhou's work was supported in part by the Chinese Natural Science Foundation (30728019), and US Department of Veterans Affairs, Veterans Affairs Health Administration, HSR&D grant IIR 07-235-1. This paper presents the findings and conclusions of the authors. It does not necessarily represent those of VA HSR&D Service. We would like to thank Dr Liu at University of Virginia for providing us the data set used in this paper and Shili Fan for her help in analysing the real data. This paper presents the findings and conclusions of the authors. NR 35 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0303-6898 EI 1467-9469 J9 SCAND J STAT JI Scand. J. Stat. PD DEC PY 2014 VL 41 IS 4 BP 1031 EP 1050 DI 10.1111/sjos.12080 PG 20 WC Statistics & Probability SC Mathematics GA AT3UO UT WOS:000344860800010 ER PT J AU Shirozu, K Hirai, S Tanaka, T Hisaka, S Kaneki, M Ichinose, F AF Shirozu, Kazuhiro Hirai, Shuichi Tanaka, Tomokazu Hisaka, Shinsuke Kaneki, Masao Ichinose, Fumito TI FARNESYL TRANSFERASE INHIBITOR, TIPIFARNIB, PREVENTS GALACTOSAMINE/LIPOPOLYSACCHARIDE-INDUCED ACUTE LIVER FAILURE SO SHOCK LA English DT Article DE Farnesyltransferase; falnesylation; liver failure ID ACUTE HEPATIC-FAILURE; ANIMAL-MODELS; MICE; GALACTOSAMINE; INFLAMMATION; CYCLOPHILIN; ENDOTOXIN; BIOMARKER; PROTECTS; DEATH AB Acute liver failure (ALF) is a fatal syndrome associated with massive hepatocyte death. There is no cure for ALF except liver transplantation. Protein farnesylation is a lipid modification of cysteine residues that is catalyzed by farnesyltransferase (FTase) and has been proposed as an integral component of acute inflammation. Previously, we have demonstrated that FTase inhibitors improve survival in mouse models of endotoxemia and sepsis. Here we studied the effects of FTase inhibitor, tipifarnib, on galactosamine (GalN)/lipopolysaccharide (LPS)-induced ALF. The effects of tipifarnib (10 mg/kg, i.p.) were studied in GalN (400 mg/kg, i.p.)- and LPS (3 mu g/kg) -challenged mice by histological and biochemical analyses. Galactosamine/LPS administration caused prominent liver injury characterized by the increased plasma alanine aminotransferase and aspartic aminotransferase levels, leading to significant mortality in mice. Tipifarnib inhibited GalN/LPS-induced caspase 3 activation, inflammatory cytokine production, and c-Jun N-terminal kinase phosphorylation in the liver. On the other hand, tipifarnib upregulated antiapoptotic protein, Bcl-xL, in the liver after GalN/LPS challenge. Tipifarnib also protected primary hepatocytes from GalN/tumor necrosis factor alpha-induced cell death by inhibiting caspase 3 activation and upregulating antiapoptotic proteins. Galactosamine/LPS-induced liver injury was associated with increased protein farnesylation in the liver. Tipifarnib prevented protein farnesylation in the liver and markedly attenuated liver injury and mortality in GalN/LPS-challenged mice. These results suggest that protein farnesylation is a novel potential molecular target to prevent hepatocyte death and acute inflammatory liver failure in fulminant hepatitis. C1 [Shirozu, Kazuhiro; Hirai, Shuichi; Ichinose, Fumito] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, Charlestown, MA USA. [Tanaka, Tomokazu; Hisaka, Shinsuke; Kaneki, Masao] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Shriners Hosp Children, Charlestown, MA USA. [Tanaka, Tomokazu; Hisaka, Shinsuke; Kaneki, Masao] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA USA. RP Kaneki, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 149 13th St,Room 6604, Charlestown, MA 02129 USA. EM mkaneki@helix.mgh.harvard.edu; fichinose@mgh.harvard.edu FU Shriners Hospitals for Children; National Institutes of Health [HL101930] FX This work was supported by grants from Shriners Hospitals for Children to M. K. and National Institutes of Health grants HL101930 to F.I. NR 26 TC 3 Z9 3 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 EI 1540-0514 J9 SHOCK JI Shock PD DEC PY 2014 VL 42 IS 6 BP 570 EP 577 DI 10.1097/SHK.0000000000000239 PG 8 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA AT9FX UT WOS:000345234400012 PM 25046541 ER PT J AU Chen, YF Hodin, RA Pandolfi, C Ruan, DT McKenzie, TJ AF Chen, Yufei Hodin, Richard A. Pandolfi, Chiara Ruan, Daniel T. McKenzie, Travis J. TI Hypoglycemia after resection of pheochromocytoma SO SURGERY LA English DT Article ID INSULIN; REMOVAL; EPINEPHRINE; GLUCOSE; DESENSITIZATION; NOREPINEPHRINE; SECRETION; RESPONSES; GLUCAGON; SURGERY AB Background. Hypoglycemia after resection of pheochromocytoma is a rare and poorly understood complication thought to be secondary to rebound hyperinsulinemia and increased peripheral glucose uptake. We examined the incidence of this complication and aimed to identify predisposing risk factors. Methods. Patients who underwent pheochromocytoma resection between 1993 and 2013 at 2 large academic medical centers were identified retrospectively from a research patient data registry. The primary end point was postoperative hypoglycemia defined as blood glucose <55 mg/dL. Results. A total of 213 patients underwent resection of pheochromocytoma for a total of 215 operations. Nine patients (4.2%) experienced postoperative hypoglycemia, with 8 of 9 episodes occurring in the first 24 hours. Patients who developed hypoglycemia were more likely to have greater preoperative 24-hour urinary metanephrine (4,726 vs 2,461 mu g/24 h, P = .05) and experienced longer operative times (270 vs 142 minutes, P < .01) with larger neoplasms (7.6 vs 4.6 cm, P = .02). Postoperatively, patients with hypoglycemia required intensive care level monitoring more frequently (88.9% vs 34.5%, P < .01), but there was no difference in duration of hospital stay (5 vs 3 days, P =.10). Conclusion. Our data demonstrate that hypoglycemia is a rare complication after resection of pheochromocytoma and may be more common in patients with epinephrine-predominant neoplasms and longer operative times. C1 [Chen, Yufei; Hodin, Richard A.; McKenzie, Travis J.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Pandolfi, Chiara; Ruan, Daniel T.; McKenzie, Travis J.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. RP Chen, YF (reprint author), Massachusetts Gen Hosp, Dept Surg, 55 Fruit St,GRB-425, Boston, MA 02114 USA. EM ychen49@partners.org NR 24 TC 4 Z9 4 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD DEC PY 2014 VL 156 IS 6 BP 1404 EP 1409 DI 10.1016/j.surg.2014.08.020 PG 6 WC Surgery SC Surgery GA AT9OF UT WOS:000345255700016 PM 25456920 ER PT J AU McKinley, SK Brunt, LM Schwaitzberg, SD AF McKinley, Sophia K. Brunt, L. Michael Schwaitzberg, Steven D. TI Prevention of bile duct injury: the case for incorporating educational theories of expertise SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article DE Cholecystectomy; Education; G-I; Training/courses; Common bile duct (CBD); Complications ID COGNITIVE TASK-ANALYSIS; LAPAROSCOPIC CHOLECYSTECTOMY; LEARNING-CURVE; INTRAOPERATIVE CHOLANGIOGRAPHY; SIMULATION APPLICATIONS; SLOWING-DOWN; LITIGATION; JUDGMENT; ERRORS; SKILLS AB Over 700,000 laparoscopic cholecystectomies are performed yearly in the US. Despite multiple advantages of laparoscopic surgery, the increased rate of bile duct injury (BDI) compared to the traditional, open approach to cholecystectomy remains problematic. Due to the seriousness of bile duct injury, the time has come for an aggressive educational campaign to better train laparoscopic surgeons in order to reduce the incidence of this life-threatening and expensive complication. We performed a literature review of what is currently known about the causes of bile duct injury during laparoscopic cholecystectomy. Based on these reviews, we identified educational theories of expertise that may be relevant in understanding variable rates of BDI between surgeons. Finally, we applied educational theories of expertise to the problem of BDI in laparoscopic cholecystectomy to propose how to develop and design an effective educational approach for the prevention of BDI. Multiple studies demonstrate that the primary causes of BDI during laparoscopic cholecystectomy are non-technical. Additionally, there exists a learning curve in which the rates of BDI are higher in a surgeon's earlier cases compared to later cases and that some surgeons perform laparoscopic cholecystectomy with significantly fewer injuries than others. Educational theories indicate that interventions that optimize novice to expert development require (1) revealing expert knowledge to novices and (2) scaffolding the mental habits of expert-like learners. BDI is an appropriate target for the application of educational theories of expertise. Designing better educational interventions for the prevention of BDI will require uncovering the hidden knowledge of expert surgeons and incorporating the processes of reinvestment and progressive problem solving that are inherent to expert performance. C1 [McKinley, Sophia K.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Brunt, L. Michael] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Schwaitzberg, Steven D.] Cambridge Hlth Alliance, Dept Surg, Cambridge, MA USA. RP McKinley, SK (reprint author), Massachusetts Gen Hosp, Dept Surg, 55 Fruit St, Boston, MA 02114 USA. EM skmckinley@gmail.com NR 51 TC 5 Z9 6 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0930-2794 EI 1432-2218 J9 SURG ENDOSC JI Surg. Endosc. PD DEC PY 2014 VL 28 IS 12 BP 3385 EP 3391 DI 10.1007/s00464-014-3605-8 PG 7 WC Surgery SC Surgery GA AT7XK UT WOS:000345147500018 PM 24939158 ER PT J AU Turowski, EE Shen, Z Ducore, RM Parry, NMA Kirega, A Dewhirst, FE Fox, JG AF Turowski, E. E. Shen, Z. Ducore, R. M. Parry, N. M. A. Kirega, A. Dewhirst, F. E. Fox, J. G. TI Isolation of a Campylobacter lanienae-like Bacterium from Laboratory Chinchillas (Chinchilla laniger) SO ZOONOSES AND PUBLIC HEALTH LA English DT Article DE Campylobacter lanienae; chinchilla; DNA sequence analysis; 16S ribosomal RNA; rpoB ID DRINKING-WATER; CATTLE; JEJUNI; COLONIZATION; FECES; SPP.; PREVALENCE; INTESTINES; INFECTION; SWINE AB Routine necropsies of 27 asymptomatic juvenile chinchillas revealed a high prevalence of gastric ulcers with microscopic lymphoplasmacytic gastroenteritis and typhlocolitis. Polymerase chain reaction (PCR) analysis using Campylobacter genus-specific partial 16S rRNA primers revealed the presence of Campylobacter spp. DNA in the faeces of 12 of 27 animals (44.4%). Species-specific partial 16S rRNA PCR and sequencing confirmed that these animals were colonized with Campylobacter lanienae, a gram-negative, microaerophilic bacterium that was first identified on routine faecal screening of slaughterhouse employees and subsequently isolated from faeces of livestock. Campylobacter lanienae was isolated from the faeces of six PCR-positive animals and identified with species-specific PCR and full 16S rRNA sequencing. Phylogenetic analysis showed that these isolates clustered with C.lanienae strain NCTC 13004. PCR analysis of DNA extracted from gastrointestinal tissues revealed the presence of C.lanienae DNA in the caecum and colon of these chinchillas. Gastrointestinal lesions were scored and compared between C.lanienae-positive and C.lanienae-negative animals. There was no correlation between colonization status and lesion severity in the stomach, liver, duodenum, or colon. Possible routes of C.lanienae infection in chinchillas could include waterborne transmission and faecal-oral transmission from wild mice and rats or livestock. Based on these findings, the authors conclude that C.lanienae colonizes the lower bowel of chinchillas in the absence of clinical disease. This is the first report of C.lanienae in any rodent species. Campylobacter lanienae isolates from different mammalian species demonstrate heterogeneity by 16S rRNA sequence comparison. Analysis using rpoB suggests that isolates and clones currently identified as C.lanienae may represent multiple species or subspecies. C1 [Turowski, E. E.; Shen, Z.; Ducore, R. M.; Parry, N. M. A.; Fox, J. G.] MIT, Div Comparat Med, Cambridge, MA 02139 USA. [Ducore, R. M.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR USA. [Kirega, A.; Dewhirst, F. E.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Dewhirst, F. E.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP Fox, JG (reprint author), MIT, Div Comparat Med, Bldg 16,Room 825,77 Massachusetts Ave, Cambridge, MA 02139 USA. EM jgfox@mit.edu OI Ducore, Rebecca/0000-0001-5223-2266; Turowski, Erin/0000-0001-7913-5220 FU Ruth L. Kirschstein National Research Service Award from the National Institutes of Health [T32-OD007036, R01-OD011141, P30-ES02109] FX Special thanks to Alison Hayward, Catrina Wong, Wayne Au, and Homer Chang for their assistance in acquiring the tissue and faecal samples used in this study. The authors would also like to thank Zhongming Ge, Ellen Buckley, Carolyn Madden, Kvin Lertpiriyapong, and Laura Cacioppo for their assistance in performing the aforementioned laboratory techniques. This work was supported by a Ruth L. Kirschstein National Research Service Award, grants T32-OD007036 (JGF), R01-OD011141 (JGF), and P30-ES02109 (JGF) from the National Institutes of Health. NR 28 TC 1 Z9 1 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1863-1959 EI 1863-2378 J9 ZOONOSES PUBLIC HLTH JI Zoonoses Public Health PD DEC PY 2014 VL 61 IS 8 BP 571 EP 580 DI 10.1111/zph.12107 PG 10 WC Public, Environmental & Occupational Health; Infectious Diseases; Veterinary Sciences SC Public, Environmental & Occupational Health; Infectious Diseases; Veterinary Sciences GA AU0LI UT WOS:000345313800006 PM 24628887 ER PT J AU Lam, HM Ouyang, B Chen, J Ying, J Wang, J Wu, CL Jia, L Medvedovic, M Vessella, RL Ho, SM AF Lam, Hung-Ming Ouyang, Bin Chen, Jing Ying, Jun Wang, Jiang Wu, Chin-Lee Jia, Li Medvedovic, Mario Vessella, Robert L. Ho, Shuk-Mei TI Targeting GPR30 with G-1: a new therapeutic target for castration-resistant prostate cancer SO ENDOCRINE-RELATED CANCER LA English DT Article DE androgen deprivation therapy; androgen-repressed gene; metastases; tumor-infiltrating neutrophils ID PROTEIN-COUPLED RECEPTOR-30; ESTROGEN-RECEPTOR; BREAST-CANCER; ANDROGEN RECEPTOR; METASTATIC CARCINOMA; PLASMA-MEMBRANE; GENE-EXPRESSION; SIPULEUCEL-T; CELLS; NEUTROPHILS AB Castration-resistant prostate cancer (CRPC) is an advanced-stage prostate cancer (PC) associated with high mortality. We reported that G-1, a selective agonist of G protein-coupled receptor 30 (GPR30), inhibited PC cell growth by inducing G2 cell cycle arrest and arrested PC-3 xenograft growth. However, the therapeutic actions of G-1 and their relationships with androgen in vivo are unclear. Using the LNCaP xenograft to model PC growth during the androgen-sensitive (AS) versus the castration-resistant (CR) phase, we found that G-1 inhibited growth of CR but not AS tumors with no observable toxicity to the host. Substantial necrosis (approximately 65%) accompanied by marked intratumoral infiltration of neutrophils was observed only in CR tumors. Global transcriptome profiling of human genes identified 99 differentially expressed genes with 'interplay between innate and adaptive immune responses' as the top pathway. Quantitative PCR confirmed upregulation of neutrophil-related chemokines and inflammation-mediated cytokines only in the G-1-treated CR tumors. Expression of murine neutrophil-related cytokines also was elevated in these tumors. GPR30 (GPER1) expression was significantly higher in CR tumors than in AS tumors. In cell-based experiments, androgen repressed GPR30 expression, a response reversible by anti-androgen or siRNA-induced androgen receptor silencing. Finally, in clinical specimens, 80% of CRPC metastases (n=123) expressed a high level of GPR30, whereas only 54% of the primary PCs (n=232) showed high GPR30 expression. Together, these results provide the first evidence, to our knowledge, that GPR30 is an androgen-repressed target and G-1 mediates the anti-tumor effect vianeutrophil-infiltration-associated necrosis in CRPC. Additional studies are warranted to firmly establish GPR30 as a therapeutic target in CRPC. C1 [Lam, Hung-Ming; Ouyang, Bin; Chen, Jing; Ying, Jun; Medvedovic, Mario; Ho, Shuk-Mei] Univ Cincinnati, Med Ctr, Dept Environm Hlth, Cincinnati, OH 45267 USA. [Wang, Jiang] Univ Cincinnati, Med Ctr, Dept Pathol & Lab Med, Cincinnati, OH 45267 USA. [Wu, Chin-Lee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Wu, Chin-Lee] Harvard Univ, Sch Med, Boston, MA USA. [Jia, Li] Washington Univ, Sch Med, Ctr Pharmacogen, Dept Med, St Louis, MO USA. [Medvedovic, Mario; Ho, Shuk-Mei] Univ Cincinnati, Med Ctr, Ctr Environm Genet, Cincinnati, OH 45267 USA. [Vessella, Robert L.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Ho, Shuk-Mei] Cincinnati Vet Affairs Med Ctr, Cincinnati, OH USA. [Ho, Shuk-Mei] Cincinnati Canc Ctr, Cincinnati, OH USA. RP Ho, SM (reprint author), Univ Cincinnati, Med Ctr, Dept Environm Hlth, Room 128 Kettering Complex, Cincinnati, OH 45267 USA. EM Shuk-mei.Ho@uc.edu FU Veteran Affairs (Merit Award) [I01BX000675]; National Institutes of Health [P30ES006096, U01ES019480, U01ES020988, P50CA097186]; Prostate Cancer Foundation (Young Investigator Award) FX This work was supported by Veteran Affairs (Merit Award I01BX000675 to S-M Ho), the National Institutes of Health (grant numbers P30ES006096, U01ES019480, and U01ES020988 to S-M Ho and P50CA097186 Pacific Northwest SPORE Career Development Award to H-M Lam), and the Prostate Cancer Foundation (Young Investigator Award to H-M Lam). NR 59 TC 9 Z9 10 U1 0 U2 5 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 EI 1479-6821 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD DEC PY 2014 VL 21 IS 6 BP 903 EP 914 DI 10.1530/ERC-14-0402 PG 12 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA AT2TI UT WOS:000344788600013 PM 25287069 ER PT J AU Simoni, JM Huh, D Wang, Y Wilson, IB Reynolds, NR Remien, RH Goggin, K Gross, R Rosen, MI Schneiderman, N Arnsten, J Golin, CE Erlen, JA Bangsberg, DR Liu, HH AF Simoni, Jane M. Huh, David Wang, Yan Wilson, Ira B. Reynolds, Nancy R. Remien, Robert H. Goggin, Kathy Gross, Robert Rosen, Marc I. Schneiderman, Neil Arnsten, Julia Golin, Carol E. Erlen, Judith A. Bangsberg, David R. Liu, Honghu TI The Validity of Self-Reported Medication Adherence as an Outcome in Clinical Trials of Adherence-Promotion Interventions: Findings from the MACH14 Study SO AIDS AND BEHAVIOR LA English DT Article DE HIV/AIDS; Medication adherence assessment; Intervention studies; Social desirability AB In medication adherence-promotion trials, participants in the intervention arm are often cognizant of the researcher's aim to improve adherence; this may lead to their inflating reports of their own adherence compared to control arm participants. Using data from 1,247 HIV-positive participants across eight U.S. Studies in the Multi-site Adherence Collaboration on HIV (MACH14) collaboration, we evaluated the validity of self-reported adherence by examining whether its association with two more objective outcomes [1], electronically monitored adherence and [2] viral load, varied by study arm. After adjusting for potential confounders, there was no evidence of greater overestimation of self-reported adherence among intervention arm participants, supporting its potential as a trial outcome indicator. C1 [Simoni, Jane M.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Huh, David] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Wang, Yan] Univ Calif Los Angeles, Dept Biostat, Fielding Sch Publ Hlth, Los Angeles, CA USA. [Wilson, Ira B.] Brown Univ, Sch Publ Hlth, Dept Hlth Serv Policy & Practice, Providence, RI 02912 USA. [Reynolds, Nancy R.] Yale Univ, Sch Nursing, New Haven, CT 06536 USA. [Remien, Robert H.] New York State Psychiat Inst & Hosp, HIV Ctr Clin & Behav Studies, New York, NY 10032 USA. [Remien, Robert H.] Columbia Univ, New York, NY USA. [Goggin, Kathy] Univ Missouri, Sch Med, Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA. [Goggin, Kathy] Univ Missouri, Sch Pharm, Childrens Mercy Hosp & Clin, Kansas City, MO 64110 USA. [Gross, Robert] Univ Penn, Perelman Sch Med, Dept Med Infect Dis, Philadelphia, PA 19104 USA. [Gross, Robert] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Gross, Robert] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Rosen, Marc I.] VA Connecticut Healthcare Syst, New Haven, CT USA. [Rosen, Marc I.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Schneiderman, Neil] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. [Arnsten, Julia] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Arnsten, Julia] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Psychiat, Bronx, NY USA. [Arnsten, Julia] Albert Einstein Coll Med, Dept Epidemiol, Bronx, NY 10467 USA. [Arnsten, Julia] Montefiore Med Ctr, Bronx, NY 10467 USA. [Golin, Carol E.] Univ N Carolina, Sch Med, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Erlen, Judith A.] Univ Pittsburgh, Sch Nursing, Dept Hlth & Community Syst, Pittsburgh, PA USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Boston, MA USA. [Bangsberg, David R.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Bangsberg, David R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Liu, Honghu] Univ Calif Los Angeles, David Geffen Sch Med, Div Publ Hlth & Community Dent, Sch Dent,Fielding Sch Publ Hlth, Los Angeles, CA 90095 USA. RP Simoni, JM (reprint author), Univ Washington, Dept Psychol, Box 351525, Seattle, WA 98195 USA. EM jsimoni@uw.edu RI Wilson, Ira/F-9190-2016; OI Wilson, Ira/0000-0002-0246-738X; Simoni, Jane/0000-0002-8711-1576; Huh, David/0000-0002-6357-4883 FU NIAID NIH HHS [P30 AI027757, AI069419, AI38858, P30 AI050410, P30AI050410, P30AI27757, R01AI41413, U01 AI038858, U01 AI069419, UM1 AI069419]; NIDA NIH HHS [K02 DA017277, K02DA017277, R01 DA011869, R01 DA013826, R01 DA015215, R01 DA015679, R01DA015679, R01DA11869, R01DA13826, R01DA15215]; NIMH NIH HHS [K08 MH001584, K08 MH01584, K23 MH001862, K23MH01862, K24 MH093243, K24MH093243, P01 MH049548, P01MH49548, P30 MH043520, R01 MH054907, R01 MH058986, R01 MH061173, R01 MH061695, R01 MH068197, R01 MH078773, R01MH068197, R01MH078773, R01MH54907, R01MH58986, R01MH61173, R01MH61695]; NINR NIH HHS [2R01NR04749, R01 NR004749, R01NR04749]; ODCDC CDC HHS [CC02-SD-003, CC99-SD003] NR 11 TC 11 Z9 11 U1 1 U2 3 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD DEC PY 2014 VL 18 IS 12 BP 2285 EP 2290 DI 10.1007/s10461-014-0905-x PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA AT1ZY UT WOS:000344731300004 PM 25280447 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 Ruiz-Arguelles, G Undurraga, MS Martinez, L 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 Silvia Ruiz-Argueelles, Guillermo Soledad Undurraga, Maria Martinez, Lem 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 Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukemia study SO ANNALS OF HEMATOLOGY LA English DT Article DE Acute promyelocytic leukemia; IC-APL; FLT3-ITD mutations; Developing countries; ATRA ID ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; TYROSINE KINASE INHIBITOR; RISK-ADAPTED TREATMENT; PML-RAR-ALPHA; FLT3-ACTIVATING MUTATIONS; PROGNOSTIC IMPLICATION; CLINICAL-FEATURES; ARSENIC TRIOXIDE; PML/RAR-ALPHA AB Activating internal tandem duplication (ITD) mutations in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor outcome in acute myeloid leukemia, but their prognostic impact in acute promyelocytic leukemia (APL) remains controversial. Here, we screened for FLT3-ITD mutations in 171 APL patients, treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. We identified FLT3-ITD mutations in 35 patients (20 %). FLT3-ITD mutations were associated with higher white blood cell counts (P < 0.0001), relapse-risk score (P = 0.0007), higher hemoglobin levels (P = 0.0004), higher frequency of the microgranular morphology (M3v) subtype (P = 0.03), and the short PML/RARA (BCR3) isoform (P < 0.0001). After a median follow-up of 38 months, FLT3-ITDpositive patients had a lower 3-year overall survival rate (62 %) compared with FLT3-ITDnegative patients (82 %) (P = 0.006). The prognostic impact of FLT3-ITD on survival was retained in multivariable analysis (hazard ratio: 2.39, 95 % confidence interval [CI] 1.17-4.89; P = 0.017). Nevertheless, complete remission (P = 0.07), disease-free survival (P = 0.24), and the cumulative incidence of relapse (P = 0.94) rates were not significantly different between groups. We can conclude that FLT3-ITD mutations are associated with several hematologic features in APL, in particular with high white blood cell counts. In addition, FLT3-ITD may independently predict a shorter survival in patients with APL treated with ATRA and anthracycline-based chemotherapy. C1 [Lucena-Araujo, Antonio R.; Jacomo, Rafael H.; Lima, Ana Silvia; Rego, Eduardo M.] Med Sch Ribeirao Preto, Ribeirao Preto, Brazil. [Lucena-Araujo, Antonio R.; Jacomo, Rafael H.; Lima, Ana Silvia; Rego, Eduardo M.] Ctr Cell Based Therapy, Ribeirao Preto, 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. [Ruiz-Argueelles, Guillermo] Clin Ruiz Puebla, Puebla, Mexico. [Soledad Undurraga, Maria] Hosp Salvador, Santiago, Chile. [Martinez, Lem] Asociac Espanola Primera Socorros Mutuos, Montevideo, Uruguay. [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.] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, New York, NY 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. [Lo-Coco, Francesco] Univ Roma Tor Vergata, Rome, Italy. [Lo-Coco, Francesco] Santa Lucia Fdn, Rome, Italy. [Lowenberg, Bob] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Sanz, Miguel A.] Univ Valencia, Sch Med, Valencia, Spain. [Rego, Eduardo M.] Univ Sao Paulo, Med Sch Ribeirao Preto, BR-14048900 Ribeirao Preto, SP, Brazil. 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) [1998/14247-6]; 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 Leukemia of the American Society of Hematology. This investigation was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP-Grant #1998/14247-6) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNpQ - #573754/2008-0). In addition, ARLA received a fellowship from FAPESP (#2007/55067-1). NR 54 TC 4 Z9 5 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-5555 EI 1432-0584 J9 ANN HEMATOL JI Ann. Hematol. PD DEC PY 2014 VL 93 IS 12 BP 2001 EP 2010 DI 10.1007/s00277-014-2142-9 PG 10 WC Hematology SC Hematology GA AT2ZJ UT WOS:000344803100006 PM 24981688 ER PT J AU Li, TT Liao, XY Lochhead, P Morikawa, T Yamauchi, M Nishihara, R Inamura, K Kim, SA Mima, K Sukawa, Y Kuchiba, A Imamura, Y Baba, Y Shima, K Meyerhardt, JA Chan, AT Fuchs, CS Ogino, S Qian, ZR AF Li, Tingting Liao, Xiaoyun Lochhead, Paul Morikawa, Teppei Yamauchi, Mai Nishihara, Reiko Inamura, Kentaro Kim, Sun A. Mima, Kosuke Sukawa, Yasutaka Kuchiba, Aya Imamura, Yu Baba, Yoshifumi Shima, Kaori Meyerhardt, Jeffrey A. Chan, Andrew T. Fuchs, Charles S. Ogino, Shuji Qian, Zhi Rong TI SMO Expression in Colorectal Cancer: Associations with Clinical, Pathological, and Molecular Features SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; HEDGEHOG SIGNALING PATHWAY; COLON-CANCER; MICROSATELLITE INSTABILITY; BRAF MUTATION; LINE-1 HYPOMETHYLATION; PROMOTER METHYLATION; PIK3CA MUTATION; ACTIVATION; DIFFERENTIATION AB Smoothened, frizzled family receptor (SMO) is an important component of the hedgehog signaling pathway, which has been implicated in various human carcinomas. However, clinical, molecular, and prognostic associations of SMO expression in colorectal cancer remain unclear. Using a database of 735 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study, we examined the relationship of tumor SMO expression (assessed by immunohistochemistry) to prognosis, and to clinical, pathological, and tumor molecular features, including mutations of KRAS, BRAF, and PIK3CA, microsatellite instability, CpG island methylator phenotype (CIMP), LINE-1 methylation, and expression of phosphorylated AKT and CTNNB1. SMO expression was detected in 370 tumors (50 %). In multivariate logistic regression analysis, SMO expression was independently inversely associated with phosphorylated AKT expression [odds ratio (OR) 0.48; 95 % confidence interval (CI) 0.34-0.67] and CTNNB1 nuclear localization (OR 0.48; 95 % CI 0.35-0.67). SMO expression was not significantly associated with colorectal cancer-specific or overall survival. However, in CIMP-high tumors, but not CIMP-low/0 tumors, SMO expression was significantly associated with better colorectal cancer-specific survival (log-rank P = 0.012; multivariate hazard ratio, 0.36; 95 % CI 0.13-0.95; P (interaction) = 0.035, for SMO and CIMP status). Our data reveal novel potential associations between the hedgehog, the WNT/CTNNB1, and the PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase)/AKT pathways, supporting pivotal roles of SMO and hedgehog signaling in pathway networking. SMO expression in colorectal cancer may interact with tumor CIMP status to affect patient prognosis, although confirmation by future studies is needed. C1 [Li, Tingting; Liao, Xiaoyun; Lochhead, Paul; Yamauchi, Mai; Nishihara, Reiko; Inamura, Kentaro; Kim, Sun A.; Mima, Kosuke; Sukawa, Yasutaka; Kuchiba, Aya; Imamura, Yu; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Ogino, Shuji; Qian, Zhi Rong] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Li, Tingting; Liao, Xiaoyun; Lochhead, Paul; Yamauchi, Mai; Nishihara, Reiko; Inamura, Kentaro; Kim, Sun A.; Mima, Kosuke; Sukawa, Yasutaka; Kuchiba, Aya; Imamura, Yu; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Ogino, Shuji; Qian, Zhi Rong] Harvard Univ, Sch Med, Boston, MA USA. [Li, Tingting] Chinese Peoples Liberat Army Gen Hosp, Dept Geriatr Gastroenterol, Beijing, Peoples R China. [Morikawa, Teppei] Tokyo Univ Hosp, Dept Pathol, Tokyo 113, Japan. [Nishihara, Reiko; Kuchiba, Aya] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Inamura, Kentaro] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Baba, Yoshifumi] Kumamoto Univ, Dept Surg Gastroenterol, Kumamoto, Japan. [Shima, Kaori] Kagoshima Univ, Dept Oral Pathol, Kagoshima 890, Japan. [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [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 Li, TT (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu; zhirong_qian@dfci.harvard.edu FU USA National Institute of Health (NIH) [P01 CA87969, UM1 CA167552, P01 CA55075, R01 CA137178, P50 CA127003, R01 CA151993]; Bennett Family Fund for Targeted Therapies Research; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance; Harvard University Frank Knox Memorial Fellowship; Chief Scientist Office, Scotland FX Supported in part by USA National Institute of Health (NIH) [P01 CA87969 (to S. E. Hankinson), UM1 CA167552 and P01 CA55075 (to W. C. Willett), R01 CA137178 (to A. T. C.), P50 CA127003 (to C. S. F.), and R01 CA151993 (to S.O.)]; the Bennett Family Fund for Targeted Therapies Research; and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. PL was supported by a Harvard University Frank Knox Memorial Fellowship and a fellowship from the Chief Scientist Office, Scotland. A. T. C is a Damon Runyon Clinical Investigator. 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 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 design of the study; the collection, analysis, or interpretation of the data; the decision to submit the article for publication; or the writing of the article. NR 69 TC 8 Z9 8 U1 0 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD DEC PY 2014 VL 21 IS 13 BP 4164 EP 4173 DI 10.1245/s10434-014-3888-y PG 10 WC Oncology; Surgery SC Oncology; Surgery GA AT0LA UT WOS:000344626400019 PM 25023548 ER PT J AU Smoller, JW Gallagher, PJ Duncan, LE McGrath, LM Haddad, SA Holmes, AJ Wolf, AB Hilker, S Block, SR Weill, S Young, S Choi, EY Rosenbaum, JF Biederman, J Faraone, SV Roffman, JL Manfro, GG Blaya, C Hirshfeld-Becker, DR Stein, MB Van Ameringen, M Tolin, DF Otto, MW Pollack, MH Simon, NM Buckner, RL Ongur, D Cohen, BM AF Smoller, Jordan W. Gallagher, Patience J. Duncan, Laramie E. McGrath, Lauren M. Haddad, Stephen A. Holmes, Avram J. Wolf, Aaron B. Hilker, Sidney Block, Stefanie R. Weill, Sydney Young, Sarah Choi, Eun Young Rosenbaum, Jerrold F. Biederman, Joseph Faraone, Stephen V. Roffman, Joshua L. Manfro, Gisele G. Blaya, Carolina Hirshfeld-Becker, Dina R. Stein, Murray B. Van Ameringen, Michael Tolin, David F. Otto, Michael W. Pollack, Mark H. Simon, Naomi M. Buckner, Randy L. Oenguer, Dost Cohen, Bruce M. TI The Human Ortholog of Acid-Sensing Ion Channel Gene ASIC1a Is Associated With Panic Disorder and Amygdala Structure and Function SO BIOLOGICAL PSYCHIATRY LA English DT Article DE ACCN2; amygdala; ASIC1a; association; genetic; panic disorder ID CARBON-DIOXIDE; ANXIETY; FEAR; REGIONS; BRAIN; NORMALIZATION; BEHAVIOR; DISEASE; IMAGES; VOLUME AB Background: Individuals with panic disorder (PD) exhibit a hypersensitivity to inhaled carbon dioxide, possibly reflecting a lowered threshold for sensing signals of suffocation. Animal studies have shown that carbon dioxide-mediated fear behavior depends on chemosensing of acidosis in the amygdala via the acid-sensing ion channel ASIC1a. We examined whether the human ortholog of the ASIC1a gene, ACCN2, is associated with the presence of PD and with amygdala structure and function. Methods: We conducted a case-control analysis (n = 414 PD cases and 846 healthy controls) of ACCN2 single nucleotide polymorphisms and PD. We then tested whether variants showing significant association with PD are also associated with amygdala volume (n = 1048) or task-evoked reactivity to emotional stimuli (n = 103) in healthy individuals. Results: Two single nucleotide polymorphisms at the ACCN2 locus showed evidence of association with PD: rs685012 (odds ratio = 1.32, gene-wise corrected p = .011) and rs10875995 (odds ratio = 1.26, gene-wise corrected p = .046). The association appeared to be stronger when early-onset (age < 20 years) PD cases and when PD cases with prominent respiratory symptoms were compared with controls. The PD risk allele at rs10875995 was associated with increased amygdala volume (p = .035) as well as task-evoked amygdala reactivity to fearful and angry faces (p = .0048). Conclusions: Genetic variation at ACCN2 appears to be associated with PD and with amygdala phenotypes that have been linked to proneness to anxiety. These results support the possibility that modulation of acid-sensing ion channels may have therapeutic potential for PD. C1 [Smoller, Jordan W.; Gallagher, Patience J.; Duncan, Laramie E.; McGrath, Lauren M.; Haddad, Stephen A.; Wolf, Aaron B.; Hilker, Sidney; Weill, Sydney] Massachusetts Gen Hosp, Psychiat & Neurodevelopmental Genet Unit, Boston, MA 02114 USA. [Holmes, Avram J.; Rosenbaum, Jerrold F.; Biederman, Joseph; Roffman, Joshua L.; Hirshfeld-Becker, Dina R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Holmes, Avram J.; Rosenbaum, Jerrold F.; Buckner, Randy L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Simon, Naomi M.] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Boston, MA 02114 USA. [Smoller, Jordan W.; Duncan, Laramie E.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Duncan, Laramie E.; Rosenbaum, Jerrold F.; Hirshfeld-Becker, Dina R.; Oenguer, Dost; Cohen, Bruce M.] Harvard Univ, Sch Med, Boston, MA USA. [Holmes, Avram J.; Choi, Eun Young; Buckner, Randy L.] Harvard Univ, Dept Psychol, Ctr Brain Sci, Boston, MA 02115 USA. [Hilker, Sidney] Harvard Univ, Harvard Coll, Boston, MA 02115 USA. [Duncan, Laramie E.] Broad Inst, Cambridge, MA USA. [Block, Stefanie R.] Univ Michigan, Dept Psychol, Ann Arbor, MI USA. [Young, Sarah; Oenguer, Dost; Cohen, Bruce M.] McClean Hosp, Belmont, MA USA. [Young, Sarah] Massachusetts Sch Profess Psychol, Boston, MA USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Physiol, Syracuse, NY 13210 USA. [Manfro, Gisele G.] Univ Fed Rio Grande do Sul, Hosp Clin Porto Alegre, Anxiety Disorders Outpatient Program, Porto Alegre, RS, Brazil. [Manfro, Gisele G.] Univ Fed Rio Grande do Sul, Post Grad Program Med Sci Psychiat, Porto Alegre, RS, Brazil. [Blaya, Carolina] Univ Fed Ciencias Saude Porto Alegre, Dept Psychiat, Porto Alegre, RS, Brazil. [Stein, Murray B.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stein, Murray B.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Van Ameringen, Michael] McMaster Univ, Dept Psychiat & Behav Neurosci, Hamilton, ON, Canada. [Tolin, David F.] Hartford Hosp, Inst Living, Hartford, CT 06115 USA. [Tolin, David F.] Yale Univ, Sch Med, New Haven, CT USA. [Otto, Michael W.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Pollack, Mark H.] Rush Univ, Med Ctr, Dept Psychiat, Chicago, IL 60612 USA. RP Smoller, JW (reprint author), Ctr Human Genet Res, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM jsmoller@hms.harvard.edu OI Choi, Eun Young/0000-0003-3226-1486; Faraone, Stephen/0000-0002-9217-3982 FU National Institutes of Health (NIH) [K24MH094614, T32-MH16259, T32MH017119, R01 47077, R01 63683, MH64122, R01 MH081116]; Jonathan Edwards Brooking Mental Health Fellowship; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [301553/2006-7]; Fundo de Incentivo a Pesquisa e Eventos-Hospital de Clinicas de Porto Alegre (FIPE-HCPA); Highland Foundation; Frazier Research Institute at McLean; Merck; Endo Pharmaceuticals; Eli Lilly; Forest Laboratories; Hamilton Academic Health Sciences Organization Innovation Grant (Academic Funding Plan [AFP] Innovation Grant); Janssen-Ortho, Inc; National Institutes of Health; Pfizer, Inc; Servier; Pamlab; American Professional Society of ADHD and Related Disorders; U.S. Department of Defense; ElMindA; Janssen; McNeil; Shire; VayaPharma/Enzymotec; Pfizer; Johnson Johnson; Bristol-Myers Squibb; Euthymics; GlaxoSmithKline; National Center for Complementary and Alternative Medicine; National Institute on Drug Abuse; National Institute of Mental Health; American Foundation for Suicide Prevention; Department of Defense; MicroTransponder, Inc; Concert Pharmaceuticals; ProPhase FX This work was supported in part by National Institutes of Health (NIH) Grant No. K24MH094614 (JWS), NIH Grant No. T32-MH16259 (LMM), Jonathan Edwards Brooking Mental Health Fellowship and NIH Grant No. T32MH017119 (LED), NIH Grant No. R01 47077 (JFR), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) Grant No. 301553/2006-7, Fundo de Incentivo a Pesquisa e Eventos-Hospital de Clinicas de Porto Alegre (FIPE-HCPA) (GGM), NIH Grant No. R01 63683 (DRH-B), NIH Grant No. MH64122 (MBS), NIH Grant No. R01 MH081116 (MWO), the Highland Foundation (MHP, NMS), and the Frazier Research Institute at McLean (BMC). We thank Ahmad Hariri for assistance with constructing the functional magnetic resonance imaging task.; JWS is on the Scientific Advisory Board of PsyBrain, Inc. DO is a Principal Investigator (PI) on research contract with Myriad Genetics, Inc, and served on the advisory board for Lilly Pharmaceuticals. DFT has received research support from Merck, Endo Pharmaceuticals, and Eli Lilly. MVA has received grant/research support from Forest Laboratories, Hamilton Academic Health Sciences Organization Innovation Grant (Academic Funding Plan [AFP] Innovation Grant), Janssen-Ortho, Inc, National Institutes of Health, Pfizer, Inc, and Servier; is part of the Speaker's Bureau for Janssen-Ortho, Inc, Lundbeck, Pfizer, Inc, and Shire; and is on advisory boards for Forest Laboratories, Janssen-Ortho, Inc, Labo Pharm, Lundbeck, Pfizer, Inc, Servier, Shire, Sunovion, and Valeant. JFR has equity in Medavante. JR has received research support from Pamlab. JB currently is receiving research support from American Professional Society of ADHD and Related Disorders, U.S. Department of Defense, ElMindA, Janssen, McNeil, Shire, and VayaPharma/Enzymotec; in 2012, he received an honorarium from Massachusetts General Hospital Psychiatry Academy and The Children's Hospital of Southwest Florida/Lee Memorial Health System for tuition-funded continuing medical education courses; in 2011, he gave a single unpaid talk for Juste Pharmaceutical Spain, received honoraria from Massachusetts General Hospital Psychiatry Academy for a tuition-funded continuing medical education course, and received honoraria for presenting at an international scientific conference on attention-deficit/hyperactivity disorder; he received an honorarium from Cambridge University Press for a chapter publication; and he received departmental royalties from a copyrighted rating scale used for attention-deficit/hyperactivity disorder diagnoses, paid by Eli Lilly, Shire, and AstraZeneca to the Department of Psychiatry, Massachusetts General Hospital. RLB is a paid consultant for Pfizer and Johnson & Johnson. MHP is on advisory boards and serves as a consultant for Corcept Therapeutics, Eli Lilly, Ironwood Pharmaceuticals, Medavante, Otsuka, Targia Pharmaceuticals, and Transcept Pharmaceuticals; has received research grants from Bristol-Myers Squibb, Euthymics, Forest Laboratories, GlaxoSmithKline, Eli Lilly, National Center for Complementary and Alternative Medicine, National Institute on Drug Abuse, and National Institute of Mental Health; participated in continuing medical education-supported activities from Pfizer; has equity in Doyen Medical, Mensante Corporation, Mindsite, and Targia Pharmaceuticals; and has received royalty/patent from Structured Interview Guide for the Hamilton Anxiety Scale and SAFER interviews. NMS has received research support in the past 3 years from American Foundation for Suicide Prevention, Forest Laboratories, National Institutes of Health, Department of Defense, and Highland Foundation, and honoraria for speaking/continuing medical education from Massachusetts General Hospital Psychiatry Academy; her spouse has equity in Elan, Dandreon, G Zero, and Gatekeeper. MWO has served in the past 3 years as a paid consultant for MicroTransponder, Inc, Concert Pharmaceuticals, and ProPhase and received royalty support for use of the Structured Interview Guide for the Hamilton Anxiety Scale from ProPhase. The remaining authors report no biomedical financial interests or potential conflicts of interest. NR 34 TC 20 Z9 20 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD DEC 1 PY 2014 VL 76 IS 11 BP 902 EP 910 DI 10.1016/j.biopsych.2013.12.018 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AT2AO UT WOS:000344733200013 PM 24529281 ER PT J AU Poppendieck, W Sossalla, A Krob, MO Welsch, C Nguyen, TAK Gong, W DiGiovanna, J Micera, S Merfeld, DM Hoffmann, KP AF Poppendieck, Wigand Sossalla, Adam Krob, Marc-Oliver Welsch, Christine Nguyen, T. A. Khoa Gong, Wangsong DiGiovanna, Jack Micera, Silvestro Merfeld, Daniel M. Hoffmann, Klaus-Peter TI Development, manufacturing and application of double-sided flexible implantable microelectrodes SO BIOMEDICAL MICRODEVICES LA English DT Article DE Microelectromechanical systems; Neural microtechnology; Neural prosthesis; Polyimides; Vestibular implant ID NEURAL INTERFACES; ELECTRICAL-STIMULATION; ELECTRODE ARRANGEMENTS; PERIPHERAL-NERVE; POLYIMIDE; PROSTHESIS; SYSTEM; ARRAYS AB Many neuroprosthetic applications require the use of very small, flexible multi-channel microelectrodes (e.g. polyimide-based film-like electrodes) to fit anatomical constraints. By arranging the electrode contacts on both sides of the polyimide film, selectivity can be further increased without increasing size. In this work, two approaches to create such double-sided electrodes are described and compared: sandwich electrodes prepared by precisely gluing two single-sided structures together, and monolithic electrodes created using a new double-sided photolithography process. Both methods were successfully applied to manufacture double-sided electrodes for stimulation of the vestibular system. In a case study, the electrodes were implanted in the semicircular canals of three guinea pigs and proven to provide electrical stimulation of the vestibular nerve. For both the monolithic electrodes and the sandwich electrodes, long-term stability and functionality was observed over a period of more than 12 months. Comparing the two types of electrodes with respect to the manufacturing process, it can be concluded that monolithic electrodes are the preferred solution for very thin electrodes (<20 mu m), while sandwich electrode technology is especially suitable for thicker electrodes (4050 mu m). C1 [Poppendieck, Wigand; Sossalla, Adam; Krob, Marc-Oliver; Welsch, Christine; Hoffmann, Klaus-Peter] Fraunhofer Inst Biomed Engn, Dept Med Engn & Neuroprosthet, St Ingbert, Germany. [Nguyen, T. A. Khoa; DiGiovanna, Jack; Micera, Silvestro] Ecole Polytech Fed Lausanne, Translat Neural Engn Lab, Lausanne, Switzerland. [Gong, Wangsong; Merfeld, Daniel M.] Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, Boston, MA 02114 USA. [Micera, Silvestro] Scuola Super Sant Anna, BioRobot Inst, Pisa, Italy. RP Poppendieck, W (reprint author), Fraunhofer Inst Biomed Engn, Dept Med Engn & Neuroprosthet, 66386Ensheimer Str 48, St Ingbert, Germany. EM wigand.poppendieck@ibmt.fraunhofer.de FU European Commission in the Future & Emerging Technologies Open Scheme [225929] FX This work was supported by the European Commission in the Future & Emerging Technologies Open Scheme, Project 225929 (CLONS - A Closed-Loop Neural Prosthesis for Vestibular Disorders). NR 37 TC 5 Z9 5 U1 2 U2 17 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1387-2176 EI 1572-8781 J9 BIOMED MICRODEVICES JI Biomed. Microdevices PD DEC PY 2014 VL 16 IS 6 BP 837 EP 850 DI 10.1007/s10544-014-9887-8 PG 14 WC Engineering, Biomedical; Nanoscience & Nanotechnology SC Engineering; Science & Technology - Other Topics GA AS9BK UT WOS:000344538200005 PM 25078417 ER PT J AU Lai, LP Lotinun, S Bouxsein, ML Baron, R McMahon, AP AF Lai, Lick Pui Lotinun, Sutada Bouxsein, Mary L. Baron, Roland McMahon, Andrew P. TI Stk11 (Lkb1) deletion in the osteoblast lineage leads to high bone turnover, increased trabecular bone density and cortical porosity SO BONE LA English DT Article DE Serine/threonine kinase 11 (Stk11/Lkb1); Osteoblast differentiation; Histomorphometry; Peritrabecular marrow fibrosis; Woven bone; mTOR signaling ID CHONDROCYTE DIFFERENTIATION; ENDOCHONDRAL SKELETON; HEDGEHOG; HYPERPARATHYROIDISM; ROLES; SOX9; HISTOMORPHOMETRY; PROLIFERATION; PROGENITORS; RECEPTOR AB The mTOR pathway couples energy homeostasis to growth, division and survival of the cell. Stk11/Lkb1 is a critical serine-threonine protein kinase in the inhibition of mTOR pathway action. In the mammalian skeleton, Stk11 regulates the transition between immature and hypertrophic chondrocytes. Here, we have focused on the action of Stk11 in the osteoblast lineage through osteoblast specific-removal of Stk11 activity. In the mouse model system, specification and primary organization of the neonatal honey skeleton is independent of Stk11. However, histological, molecular and micro-CT analysis revealed a marked perturbation of normal bone development evident in the immediate post-natal period. Cortical bone was unusually porous displaying a high rate of turnover with new trabeculae forming in the endosteal space. Trabecular bone also showed enhanced turnover and marked increase in the density of trabeculae and number of osteoclasts. Though mutants showed an expansion of bone volume and trabecular number, their bone matrix comprised large amounts of osteoid and irregularly deposited woven bone highlighted by diffuse fluorochrome labeling. Additionally, we observed an increase in fibroblast-like cells associated with trabecular bone in Stk11 mutants. Stk11 down-regulates mTORC1 activity through control of upstream modulators of the AMP kinase family: an increase in the levels of the phosphorylated ribosomal protein S6, a target of mTORC1-mediated kinase activity, on osteoblast removal of Stk11 suggests deregulated mTORC1 activity contributes to the osteoblast phenotype. These data demonstrate Stk11 activity within osteoblasts is critical for the development of normally structured bone regulating directly the number and coordinated actions of osteoblasts, and indirectly osteoclast number. (C) 2014 Elsevier Inc. All rights reserved. C1 [Lai, Lick Pui; McMahon, Andrew P.] Univ So Calif, WM Keck Sch Med, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA 90089 USA. [Lai, Lick Pui; McMahon, Andrew P.] Univ So Calif, WM Keck Sch Med, Broad CIRM Ctr Regenerat Med & Stem Cell Res, Los Angeles, CA 90089 USA. [Lotinun, Sutada; Baron, Roland] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Lotinun, Sutada] Chulalongkorn Univ, Dept Physiol, Fac Dent, Bangkok 10330, Thailand. [Bouxsein, Mary L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Ctr Adv Orthopaed Studies, Boston, MA 02215 USA. [Bouxsein, Mary L.] Harvard Univ, Sch Med, Dept Orthoped Surg, Boston, MA 02215 USA. [Baron, Roland] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Baron, Roland] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP McMahon, AP (reprint author), 1425 San Pablo St,BCC 312, Los Angeles, CA 90033 USA. EM amcmahon@med.usc.edu FU National Institutes of Health [NIH/NIDDK P01 DK056246]; Arthritis Foundation Postdoctoral fellowship FX We thank Dr. R.A. DePhino for sharing the Stk11 conditional knock-out mouse. We also thank members and advisors of the Tabin, Kronenberg and McMahon P01 group for discussions and ongoing support during the preparation of the manuscript. Work in A.P.M.'s laboratory was supported by a grant from the National Institutes of Health (NIH/NIDDK P01 DK056246). L.P.L. was supported by an Arthritis Foundation Postdoctoral fellowship. NR 32 TC 3 Z9 3 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 EI 1873-2763 J9 BONE JI Bone PD DEC PY 2014 VL 69 BP 98 EP 108 DI 10.1016/j.bone.2014.09.010 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AT1TO UT WOS:000344717000013 PM 25240456 ER PT J AU Beamer, BS Morgan, JH Barr, C Weaver, MJ Vrahas, MS AF Beamer, Brandon S. Morgan, Jordan H. Barr, Christopher Weaver, Michael J. Vrahas, Mark S. TI Does Fluoroscopy Improve Acetabular Component Placement in Total Hip Arthroplasty? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID POLYETHYLENE WEAR; ORIENTATION; REPLACEMENT; DISLOCATION; RISK AB Background The success of THA largely depends on correct placement of the individual components. Traditionally, these have been placed freehand using anatomic landmarks, but studies have shown poor accuracy with this method. Questions/purposes Specifically, we asked (1) does using fluoroscopy lead to more accurate and greater likelihood of cup placement with the Lewinnek safe zone than does freehand cup placement; (2) is there a learning curve associated with the use of fluoroscopy for cup placement; (3) does the use of fluoroscopy increase operative time; and (4) is there a difference in leg length discrepancy between freehand and fluoroscopic techniques? Methods This series consisted of 109 consecutive patients undergoing primary THA, conversion of a previous hip surgery to THA, and revision THA during a 24-month period. No patients were excluded from analysis during this time. The first 52 patients had cups placed freehand, and then the next 57 patients had acetabular components placed using fluoroscopy; the analysis began with the first patient treated using fluoroscopy, to include our initial experience with the technique. The abduction, version, and limb length discrepancy were measured on 6-week postoperative pelvic radiographs obtained with the patient in the supine position. Operative time, sex, age, BMI, diagnosis, operative side, and femoral head size were recorded as possible confounders. Results Cups inserted freehand were placed in the ideal range of abduction (30 degrees-45 degrees) and anteversion (5 degrees-25 degrees) 44% of the time. With fluoroscopy, placement in the Lewinnek safe zone for both measures significantly increased to 65%. The odds of placing the cup in the Lewinnek safe zone for abduction and version were 2.3 times greater with the use of fluoroscopy (95% CI, 1.2-5.0; p = 0.03). Patients undergoing primary THAs (32 freehand, 35 C-arm) had cup placement in the safe zone for abduction and version 44% of the time freehand and 57% of the time with fluoroscopy, which failed to reach statistical significance. There was no difference in operative time, patient age, sex, operative side, diagnosis, limb length discrepancy, or femoral head size between the two groups. Conclusions The use of fluoroscopy to directly observe pelvic position and acetabular component placement increased the success of placement in the Lewinnek safe zone in this cohort of patients having complex and primary THAs. This is a simple, low-cost, and quick method for increasing successful acetabular component alignment. The study population included a large proportion of patients having complex THAs, and further validation of this technique in patients undergoing straightforward, primary THAs needs to be done to understand if similar gains in accuracy for component placement can be expected in that group. C1 [Beamer, Brandon S.; Morgan, Jordan H.; Weaver, Michael J.; Vrahas, Mark S.] Harvard Univ, Brigham & Womens Hosp, Dept Orthopaed Surg, Sch Med, Boston, MA 02114 USA. [Beamer, Brandon S.; Morgan, Jordan H.; Vrahas, Mark S.] Harvard Univ, Massachusetts Gen Hosp, Dept Orthopaed Surg, Sch Med, Boston, MA 02114 USA. [Barr, Christopher] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. RP Beamer, BS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Orthopaed Surg, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM bbeamer@partners.org NR 22 TC 8 Z9 8 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD DEC PY 2014 VL 472 IS 12 BP 3953 EP 3962 DI 10.1007/s11999-014-3944-8 PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AT0TH UT WOS:000344647200048 PM 25238804 ER PT J AU Chan, JJ Teunis, T Ring, D AF Chan, Jimmy J. Teunis, Teun Ring, David TI Prevalence of Triangular Fibrocartilage Complex Abnormalities Regardless of Symptoms Rise With Age: Systematic Review and Pooled Analysis SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID SIDED WRIST PAIN; ARTHROGRAPHY; ARTHROSCOPY; MRI; SURGERY; TEARS; JOINT; DIAGNOSIS; INJURIES AB Background Triangular fibrocartilage complex abnormalities seem to be more common with age, but the degree to which this is so, and the degree to which the presence of an abnormality is associated with symptoms, are topics of controversy. Questions/purposes We wished to perform a systematic review to determine the prevalence of triangular fibrocartilage complex abnormalities, and to determine if the prevalence of abnormalities are greater with increasing age. In addition, we stratified age groups based on symptoms. Methods We searched MEDLINE, EMBASE, and the Cochrane Library through August 15, 2013. Studies that reported triangular fibrocartilage complex abnormalities by age were included. Fifteen studies including 977 wrists met our criteria and reported a total of 368 (38%) triangular fibrocartilage complex abnormalities. Eight studies included symptomatic patients; the remainder studied cadavers (six studies) or asymptomatic volunteers (one study). Patients were divided into four age groups (<30, 30-49, 50-69, and 70 years and older) for pooled analysis, comparing the proportions of patients with and without abnormalities between groups using chi-square analysis. We also evaluated the proportions after stratifying each age group by symptoms. Results Overall, the prevalence of triangular fibrocartilage complex abnormalities increased with age, from 27% (80/301) in patients younger than 30 years to 49% (130/265) in patients 70 years and older (p < 0.001), odds ratio (OR), 2.7, 95% CI, 1.9-3.8 (p < 0.001). In asymptomatic patients, triangular fibrocartilage complex prevalence abnormality increased from 15% (24/159) to 49% (129/263) in the same age groups (p < 0.001), OR, 5.4, 95% CI, 3.3-8.9 (p < 0.001). For symptomatic patients prevalence ranged from 39% (56/142) to 70% (14/20) in patients between 50 and 69 years old (p < 0.034), OR, 3.6, 95% CI, 1.3-9.9 (p < 0.014). Conclusion Triangular fibrocartilage complex abnormalities are common in symptomatic and asymptomatic wrists, and they are increasingly common with age. As in all situations where abnormalities are so common that they may be incidental, we need (1) a reliable and accurate method for determining whether these abnormalities are the cause of symptoms; and (2) evidence that treatment of these abnormalities improves symptoms better than placebo. Level of Evidence Level III, prognostic study. See the Instructions for Authors for a complete description of levels of evidence. C1 [Chan, Jimmy J.; Teunis, Teun; Ring, David] Harvard Univ, Orthopaed Hand & Upper Extrem Serv, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Ring, D (reprint author), Harvard Univ, Orthopaed Hand & Upper Extrem Serv, Massachusetts Gen Hosp, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM dring@mgh.harvard.edu FU Prince Bernhard Culture Fund & Kuitse Fung (Amsterdam, The Netherlands); Fundatie van de Vrijvrouwe van Renswoude te's-Gravenhage (The Hague, The Netherlans); Wright Medical (Memphis, TN, USA); Skeletal Dynamics (Miami, FL, USA); Biomet (Warsaw, IN, USA); AO North America (Paoli, PA, USA); AO International (Dubendorf, Switzerland) FX One of the authors (TT) received research grants from the Prince Bernhard Culture Fund & Kuitse Fung (USD less than 10,000) (Amsterdam, The Netherlands), Fundatie van de Vrijvrouwe van Renswoude te's-Gravenhage (USD less than 10,000) (The Hague, The Netherlans).; One of the authors (DR) certifies that he, or a member of his immediate family, has or may receive payments or benefits, during the study period from Wright Medical (USD less than 10,000) (Memphis, TN, USA); Skeletal Dynamics (USD less than 10,000) (Miami, FL, USA); Biomet (USD less than 10,000) (Warsaw, IN, USA); AO North America (USD less than 10,000) (Paoli, PA, USA); and AO International (USD less than 10,000) (Dubendorf, Switzerland). NR 29 TC 0 Z9 0 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD DEC PY 2014 VL 472 IS 12 BP 3987 EP 3994 DI 10.1007/s11999-014-3825-1 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AT0TH UT WOS:000344647200053 PM 25091224 ER PT J AU Gallagher, MW Bentley, KH Barlow, DH AF Gallagher, Matthew W. Bentley, Kate H. Barlow, David H. TI Perceived Control and Vulnerability to Anxiety Disorders: A Meta-analytic Review SO COGNITIVE THERAPY AND RESEARCH LA English DT Review DE Perceived control; Anxiety; Vulnerability; Meta-analysis; Transdiagnostic ID OBSESSIVE-COMPULSIVE SYMPTOMS; CONTROL QUESTIONNAIRE; CHILDHOOD ANXIETY; PANIC DISORDER; POSTTRAUMATIC-STRESS; EMOTION REGULATION; PERSONAL CONTROL; CONTROL BELIEFS; MEDIATING ROLE; SELF-EFFICACY AB Contemporary theories of psychopathology suggest a lack of perceived control as central to the experience of negative emotion and to be particularly relevant to the development of anxiety disorders. The present study meta-analytically reviewed the relationship between perceived control and both trait and disorder-specific measures of anxiety in order to determine whether current evidence is consistent with perceived control functioning as a transdiagnostic vulnerability factor. A comprehensive literature review identified 51 studies with a total of 11,218 participants that were determined to meet eligibility criteria. The mean effect sizes between perceived control and trait measures of anxiety (k = 29) and disorder specific measures of anxiety (k = 37) were calculated using random-effects methods. Results indicated a large, negative association between perceived control and both trait measures of anxiety and disorder-specific measures of anxiety, with the largest associations being between perceived control and generalized anxiety disorder. Moderator analyses indicated that the associations between perceived control and trait anxiety were greater in adults than children, and varied across different measures of perceived control. These results underscore the importance of perceived control as a transdiagnostic vulnerability factor across the anxiety disorders. C1 [Gallagher, Matthew W.] VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA 02130 USA. [Gallagher, Matthew W.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Bentley, Kate H.; Barlow, David H.] Boston Univ, Ctr Anxiety & Related Disorders, Boston, MA 02215 USA. RP Gallagher, MW (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, 150 South Huntington Ave,116B-2, Boston, MA 02130 USA. EM mwg@bu.edu NR 91 TC 13 Z9 13 U1 11 U2 52 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-5916 EI 1573-2819 J9 COGNITIVE THER RES JI Cogn. Ther. Res. PD DEC PY 2014 VL 38 IS 6 BP 571 EP 584 DI 10.1007/s10608-014-9624-x PG 14 WC Psychology, Clinical SC Psychology GA AT5TN UT WOS:000345005100001 ER PT J AU Stevenson, W Chen, YH Lee, SM Lee, HS Hua, J Dohlman, T Shiang, T Dana, R AF Stevenson, William Chen, Yihe Lee, Sang-Mok Lee, Hyun Soo Hua, Jing Dohlman, Thomas Shiang, Tina Dana, Reza TI Extraorbital Lacrimal Gland Excision: A Reproducible Model of Severe Aqueous Tear-Deficient Dry Eye Disease SO CORNEA LA English DT Article DE dry eye disease; keratoconjunctivitis sicca; aqueous tear deficiency; lacrimal gland; scopolamine; ocular surface inflammation; mouse ID OCULAR-SURFACE; MOUSE MODEL; KERATOCONJUNCTIVITIS SICCA; DESICCATING STRESS; SJOGRENS-SYNDROME; EPITHELIAL-CELLS; ANIMAL-MODELS; RABBIT; MICE; LIMITATIONS AB Purpose: The aim of this study was to establish and characterize extraorbital lacrimal gland excision (LGE) as a model of aqueous tear-deficient dry eye disease in mice. Methods: Female C57BL/6 mice at 6 to 8 weeks of age were randomized to extraorbital LGE, sham surgery, or scopolamine groups. Mice that underwent extraorbital LGE or sham surgery were housed in the standard vivarium. Scopolamine-treated mice were housed in a controlled environment chamber that allowed for the continuous regulation of airflow (15 L/min), relative humidity (30%), and temperature (21-23 degrees C). Clinical disease severity was assessed over the course of 14 days using the phenol red thread test and corneal fluorescein staining. Real-time polymerase chain reaction was performed to assess corneal mRNA expression of interleukin 1 beta, tumor necrosis factor alpha, and matrix metalloproteinase 9. Flow cytometry was used to assess T helper cell frequencies in the conjunctivae and draining lymph nodes. Results: Extraorbital LGE markedly reduced aqueous tear secretion as compared with the sham procedure and induced a more consistent decrease in aqueous tear secretion than was observed in mice that received scopolamine while housed in the controlled environment chamber. Extraorbital LGE significantly increased corneal fluorescein staining scores as compared with those of both the sham surgery and scopolamine-treated groups. Extraorbital LGE significantly increased the corneal expression of interleukin 1 beta, tumor necrosis factor alpha, and matrix metalloproteinase 9. Further, extraorbital LGE increased T helper 17-cell frequencies in the conjunctivae and draining lymph nodes. Conclusions: Extraorbital LGE induces aqueous tear-deficient dry eye disease in mice as evidenced by decreased aqueous tear secretion, increased corneal epitheliopathy, and induced ocular surface inflammation and immunity. C1 [Stevenson, William; Chen, Yihe; Lee, Sang-Mok; Lee, Hyun Soo; Hua, Jing; Dohlman, Thomas; Shiang, Tina; Dana, Reza] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Schepens Eye Res Inst, Boston, MA USA. RP Dana, R (reprint author), Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM reza_dana@meei.harvard.edu OI Lee, Sang-Mok/0000-0002-9018-8216 FU National Institutes of Health [EY-20889] FX Supported by the National Institutes of Health Grant EY-20889. NR 35 TC 9 Z9 9 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD DEC PY 2014 VL 33 IS 12 BP 1336 EP 1341 PG 6 WC Ophthalmology SC Ophthalmology GA AT3ZM UT WOS:000344875600017 PM 25255136 ER PT J AU Wilson, MT Hamilos, DL AF Wilson, Michael T. Hamilos, Daniel L. TI The Nasal and Sinus Microbiome in Health and Disease SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Review DE Nasal; Microbiome; Bacterial; Chronic rhinosinusitis ID CHRONIC RHINOSINUSITIS; STAPHYLOCOCCUS-AUREUS; EXTRACELLULAR VESICLES; MAXILLARY SINUSITIS; BACTERIAL BIOFILMS; COMPLEXITY; DIVERSITY AB There has been great interest in unraveling the complex inter-relationships between microbes and humans as they relate to human health and disease. This review will focus on recent advances in the appreciation and understanding of these relationships in terms of the upper respiratory tract, specifically the nose and paranasal sinuses. C1 [Wilson, Michael T.; Hamilos, Daniel L.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Hamilos, DL (reprint author), Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Bulfinch 422, Boston, MA 02114 USA. EM dhamilos@partners.org NR 32 TC 15 Z9 15 U1 1 U2 36 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1529-7322 EI 1534-6315 J9 CURR ALLERGY ASTHM R JI Curr. Allergy Asthma Rep. PD DEC PY 2014 VL 14 IS 12 AR 485 DI 10.1007/s11882-014-0485-x PG 10 WC Allergy; Immunology SC Allergy; Immunology GA AS9IU UT WOS:000344557400007 PM 25342392 ER PT J AU Chinot, OL Reardon, DA AF Chinot, Oliver L. Reardon, David A. TI The future of antiangiogenic treatment in glioblastoma SO CURRENT OPINION IN NEUROLOGY LA English DT Review DE angiogenesis; bevacizumab; glioblastoma; vascular endothelial growth factor ID NEWLY-DIAGNOSED GLIOBLASTOMA; RECURRENT MALIGNANT GLIOMA; PHASE-II TRIAL; HIGH-GRADE GLIOMAS; BEVACIZUMAB PLUS IRINOTECAN; RESPONSE ASSESSMENT CRITERIA; ENDOTHELIAL GROWTH-FACTOR; PROGRESSION-FREE SURVIVAL; SINGLE-AGENT BEVACIZUMAB; BRAIN-TUMOR CONSORTIUM AB Purpose of review A major recent clinical research focus for glioblastoma has been the therapeutic evaluation of antiangiogenic agents. Several vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors and a soluble decoy VEGF receptor have demonstrated nominal benefit among patients. In contrast, bevacizumab, a humanized VEGF monoclonal antibody, exhibits evidence of apparent antitumor benefit, although these data remain controversial. In this review, we summarize how results of clinical trials evaluating bevacizumab to date influence the future of this therapeutic for recurrent and newly diagnosed glioblastoma patients. Recent findings Recently reported, placebo-controlled phase III studies demonstrate a meaningful progression-free survival increment, but no overall survival benefit among newly diagnosed patients treated with bevacizumab. For unclear reasons, quality-of-life surveys from these studies revealed divergent results. Among recurrent patients, uncontrolled trials demonstrate improved overall radiographic response and progression-free survival rates, although the impact of bevacizumab on overall survival remains to be defined by an ongoing randomized phase III trial. Summary The role of bevacizumab for glioblastoma remains uncertain but will likely be strongly influenced by results of a randomized phase III study among recurrent patients as well as further investigation of gene expression biomarker profiles to identify newly diagnosed patients more likely to derive survival benefit. C1 [Chinot, Oliver L.] Aix Marseille Univ, CHU Timone, AP HM, Serv Neurooncol, Marseille, France. [Reardon, David A.] Dana Farber Canc Inst, Ctr Neurooncol, Dept Med Oncol, Boston, MA 02215 USA. [Reardon, David A.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Reardon, DA (reprint author), Dana Farber Canc Inst, Ctr Neurooncol, 450 Brookline Ave, Boston, MA 02215 USA. EM david_reardon@dfci.harvard.edu FU Merck/Schering-Plough; Roche/Genentech; Midatech; Novartis; Stemline Therapeutics; Amgen; Momenta Pharmaceuticals; Merck KGaA/EMD Serono (G) FX David A. Reardon, MD, has received financial compensation as a consultant for Merck/Schering-Plough, Roche/Genentech, Midatech, Novartis, Stemline Therapeutics, Amgen, Momenta Pharmaceuticals, and Merck KGaA/EMD Serono (G). He is a member of the speakers' bureau for Merck/Schering-Plough and Roche/Genentech. NR 68 TC 5 Z9 5 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1350-7540 EI 1473-6551 J9 CURR OPIN NEUROL JI Curr. Opin. Neurol. PD DEC PY 2014 VL 27 IS 6 BP 675 EP 682 DI 10.1097/WCO.0000000000000142 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AS8XG UT WOS:000344527800009 PM 25313693 ER PT J AU Chadha, R Leonard, DA Kurtz, JM Cetrulo, CL AF Chadha, Radhika Leonard, David A. Kurtz, Josef M. Cetrulo, Curtis L., Jr. TI The unique immunobiology of the skin: implications for tolerance of vascularized composite allografts SO CURRENT OPINION IN ORGAN TRANSPLANTATION LA English DT Review DE immunosuppression; skin immunobiology; tolerance; transplant; vascularized composite allograft ID REGULATORY T-CELLS; BONE-MARROW-TRANSPLANTATION; HUMAN LANGERHANS CELLS; TISSUE ALLOTRANSPLANTATION; FOLLOW-UP; MAINTENANCE IMMUNOSUPPRESSION; RENAL-TRANSPLANTATION; HAND TRANSPLANTATION; DENDRITIC CELLS; IN-VIVO AB Purpose of review Vascularized composite allograft (VCA) transplantation restores function and form following major soft tissue and musculoskeletal injury. Lifelong immunosuppression is necessary for graft function and survival but acute skin-targeted rejection episodes remain common. We review recent advances in skin immunobiology, emphasizing findings in clinical and experimental VCAs. We also highlight advances in immunotherapy and tolerance protocols with implications for the prevention of VCA rejection, and ultimately, induction of clinically applicable strategies for VCA tolerance. Recent findings There is now an increasing appreciation for the role of skin-specific mechanisms, including lymphoid neogenesis, in VCA rejection. In contrast, expression of the regulatory master-switch FOXP3 was demonstrated to be significantly upregulated in the skin of tolerant VCAs in large animal models compared with normal skin and rejecting controls. Summary Most VCA transplant centers continue to utilize antibody-mediated induction therapy and triple agent maintenance immunosuppression. Skin remains the primary target of rejection in VCAs, and current multicenter studies hope to elucidate the mechanisms involved. Proposed standardized procedures for skin biopsies, and diligent reporting of clinical data to the international registry, will be important to maximize the strength of these studies. C1 [Chadha, Radhika] Univ Oxford, Oxford, England. [Leonard, David A.; Kurtz, Josef M.; Cetrulo, Curtis L., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. [Leonard, David A.; Cetrulo, Curtis L., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast & Reconstruct Surg, Boston, MA USA. [Leonard, David A.] Univ Manchester, Dept Plast & Reconstruct Surg Res, Manchester, Lancs, England. [Kurtz, Josef M.] Emmanuel Coll, Dept Biol, Boston, MA USA. RP Cetrulo, CL (reprint author), Transplantat Biol Res Ctr, Vascularized Composite Allotransplantat Lab, MGH East Bldg 149-9019,13th St, Boston, MA 02129 USA. EM ccetrulo@partners.org FU American Society of Transplant Surgeons FX D.A.L. is a recipient of a Novartis Scientist Scholarship from the American Society of Transplant Surgeons. For the remaining authors there are no conflicts of interest. NR 50 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1087-2418 EI 1531-7013 J9 CURR OPIN ORGAN TRAN JI Curr. Opin. Organ Transpl. PD DEC PY 2014 VL 19 IS 6 BP 566 EP 572 DI 10.1097/MOT.0000000000000136 PG 7 WC Transplantation SC Transplantation GA AT5XC UT WOS:000345012100005 PM 25333830 ER PT J AU Moser, PT Ott, HC AF Moser, Philipp T. Ott, Harald C. TI Recellularization of organs: what is the future for solid organ transplantation? SO CURRENT OPINION IN ORGAN TRANSPLANTATION LA English DT Review DE acellular scaffolds; bioartificial organs; biomimetic culture; recellularization; stem cells ID PLURIPOTENT STEM-CELLS; REGENERATIVE MEDICINE APPROACH; DECELLULARIZED PORCINE LIVER; PERFUSION DECELLULARIZATION; ORTHOTOPIC TRANSPLANTATION; CODING MUTATIONS; PROGENITOR CELLS; SMALL-MOLECULE; HEART-VALVES; NEURAL CELLS AB Purpose of review Allogeneic organ transplantation is burdened by donor shortage, graft rejection and adverse effects of lifelong immune suppression. Engineering bioartificial organs from acellular organ scaffolds and patient-derived cells are a new approach to potentially overcome these limitations. Recent findings Decellularized organs yield a scaffold of extracellular matrix on which cells can adhere, integrate and ultimately form functional tissue. Various cell sources are currently used to repopulate acellular scaffolds, however, all have limitations. Patient-derived pluripotent stem cells hold great promise for tissue and organ engineering, when robust and mature cells can be directed in a reliable and safe manner. Finally, to produce mature organotypic tissue from a nonfunctional seeded scaffold, cellular scaffolds are cultured under biomimetic conditions in vitro. Alternatively, organs may be implanted at an immature stage to harness the recipient's body's regenerative capacity. In proof of principle experiments to date, bioengineered small animal organs have shown rudimentary function and maintained patency for limited time when transplanted in vivo. Summary Recent advances in bioengineering organs raise the hope that we can overcome organ donor shortage and eliminate the need for livelong immunosuppression. However, significant challenges remain in generating mature large-scale donor-like bioartificial organs. C1 [Moser, Philipp T.; Ott, Harald C.] Massachusetts Gen Hosp, Dept Surg, Div Thorac Surg, Boston, MA 02114 USA. [Moser, Philipp T.; Ott, Harald C.] Harvard Univ, Sch Med, Boston, MA USA. [Ott, Harald C.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Ott, Harald C.] Harvard Stem Cell Inst, Boston, MA USA. RP Ott, HC (reprint author), 185 Cambridge St,CPZN 4800, Boston, MA 02114 USA. EM hott@mgh.harvard.edu FU United Therapeutics Corporation FX P.M. is supported through a research grant by the United Therapeutics Corporation. NR 66 TC 4 Z9 4 U1 2 U2 36 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1087-2418 EI 1531-7013 J9 CURR OPIN ORGAN TRAN JI Curr. Opin. Organ Transpl. PD DEC PY 2014 VL 19 IS 6 BP 603 EP 609 DI 10.1097/MOT.0000000000000131 PG 7 WC Transplantation SC Transplantation GA AT5XC UT WOS:000345012100011 PM 25304814 ER PT J AU Chau, NG Rabinowits, G Haddad, RI AF Chau, Nicole G. Rabinowits, Guilherme Haddad, Robert I. TI Human Papillomavirus-Associated Oropharynx Cancer (HPV-OPC): Treatment Options SO CURRENT TREATMENT OPTIONS IN ONCOLOGY LA English DT Article DE Oropharynx squamous cell carcinoma; Human papillomavirus; De-intensification; Surgery; Chemotherapy; Radiotherapy ID SQUAMOUS-CELL CARCINOMA; LOCALLY ADVANCED HEAD; RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; PHASE-III TRIAL; NECK-CANCER; RADIATION-THERAPY; UNITED-STATES; ROBOTIC SURGERY; TOBACCO SMOKING AB Human papillomavirus-associated oropharynx cancer (HPV-OPC) is growing in incidence and has distinct clinical, pathologic, molecular, and epidemiologic features. However, the management of HPV-OPC does not presently differ from HPV-negative OPC based on the current evidence and requires complex multidisciplinary approaches. The superior prognosis of HPV-OPC and the toxicities of current multimodality treatment in a young population serve as the impetus to evaluate de-intensification treatment regimens aimed at reducing toxicity while maintaining therapeutic efficacy. Clinical trials are underway to evaluate reduced doses of radiation or less toxic systemic therapy regimens in HPV-OPC. Minimally invasive surgical approaches in the HPV-OPC population with early tumor stage also are being investigated. De-intensification strategies should only be employed in the context of clinical trials, and HPV-OPC patients should be offered clinical trials' participation. Appropriate patient selection is critical to the development of de-intensification regimens, and this requires greater understanding of risk factors within the HPV-OPC population, HPV-OPC biology, and how HPV modulates response to specific therapies. Smoking history and bulky nodal disease have been shown to impact negatively the favorable prognosis of HPV association. Validated biomarkers within the HPV-OPC population are lacking, although alterations in the PI3K pathway and markers of immune response may emerge as important considerations in the future. Novel therapeutic strategies are desperately needed particularly for HPV-OPC patients who fail definitive therapy, and select patients with recurrent or metastatic disease may benefit from aggressive approaches. C1 [Chau, Nicole G.; Rabinowits, Guilherme; Haddad, Robert I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Head & Neck Oncol, Boston, MA 02215 USA. RP Chau, NG (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Head & Neck Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM Nicole_chau@dfci.harvard.edu NR 74 TC 4 Z9 4 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1527-2729 EI 1534-6277 J9 CURR TREAT OPTION ON JI Curr. Treat. Options Oncol. PD DEC PY 2014 VL 15 IS 4 BP 595 EP 610 DI 10.1007/s11864-014-0309-1 PG 16 WC Oncology SC Oncology GA AS8ZG UT WOS:000344532800007 PM 25240410 ER PT J AU Boronat, S Caruso, P Thiele, EA AF Boronat, Susana Caruso, Paul Thiele, Elizabeth A. TI Absence of subependymal nodules in patients with tubers suggests possible neuroectodermal mosaicism in tuberous sclerosis complex SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Article ID GENOTYPE-PHENOTYPE CORRELATIONS; NEURAL CREST; DIAGNOSTIC-CRITERIA; MUTATIONAL ANALYSIS; TSC1; PATHOGENESIS; TUMORS; MRI AB AimPatients with tuberous sclerosis complex (TSC) with brain involvement usually have both tubers and subependymal nodules (SENs) and the occurrence of one lesion without the other seems to be rare. The aim of this study was to assess the specific clinical manifestations and genotype of patients with one type of lesion or the other but not both. MethodThe magnetic resonance images of 220 patients with TSC were reviewed, and patients with either tubers or SENs, but not both, were identified. ResultsOut of a total of 220 patients (95 males, 125 females; mean age 22y 9mo, range 9mo-81y), six (3%) had tubers without SENs (two males; four females; mean age 34y 10mo, range 11-48y); however, no patients with SENs and without tubers were identified. No mutation was identified (NMI) in any of the six patients who underwent mutational analysis of TSC1 and TSC2. Five of the six patients had three or fewer tubers. InterpretationWe found no patients with SENs but without tubers among our cohort. In all patients with tubers but without SENs, mutational studies of TSC1/TSC2 were negative, and the majority of these had three or fewer tubers. A possible mechanism for patients with NMI and an absence of SENs is a mosaicism with a first postzygotic mutation in the neuroectoderm. C1 [Boronat, Susana; Thiele, Elizabeth A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Boronat, Susana] Univ Autonoma Barcelona, Vall dHebron Hosp, Dept Paediat Neurol, E-08193 Barcelona, Spain. [Caruso, Paul] Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. RP Thiele, EA (reprint author), Massachusetts Gen Hosp, Pediat Epilepsy Program, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM ethiele@partners.org NR 25 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1622 EI 1469-8749 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD DEC PY 2014 VL 56 IS 12 BP 1207 EP 1211 DI 10.1111/dmcn.12523 PG 5 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AT2SS UT WOS:000344786500016 PM 24954233 ER PT J AU Huynh, J Xiong, G Bentley-Lewis, R AF Huynh, Jennifer Xiong, Grace Bentley-Lewis, Rhonda TI A systematic review of metabolite profiling in gestational diabetes mellitus SO DIABETOLOGIA LA English DT Review DE Amino acids; Gestational diabetes mellitus; Metabolite profiling; Metabolites; Metabolomics; Systematic review ID ASYMMETRIC DIMETHYLARGININE ADMA; SERUM HOMOCYSTEINE LEVELS; AMINO-ACID-CONCENTRATIONS; TRIMESTER MATERNAL URINE; OXIDE SYNTHASE INHIBITOR; FREE FATTY-ACIDS; INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; GLUCOSE-METABOLISM; ENDOTHELIAL DYSFUNCTION AB Gestational diabetes mellitus is associated with adverse maternal and fetal outcomes during, as well as subsequent to, pregnancy, including increased risk of type 2 diabetes and cardiovascular disease. Because of the importance of early risk stratification in preventing these complications, improved first-trimester biomarker determination for diagnosing gestational diabetes would enhance our ability to optimise both maternal and fetal health. Metabolomic profiling, the systematic study of small molecule products of biochemical pathways, has shown promise in the identification of key metabolites associated with the pathogenesis of several metabolic diseases, including gestational diabetes. This article provides a systematic review of the current state of research on biomarkers and gestational diabetes and discusses the clinical relevance of metabolomics in the prediction, diagnosis and management of gestational diabetes. We conducted a systematic search of MEDLINE (PubMed) up to the end of February 2014 using the key term combinations of 'metabolomics,' 'metabonomics,' 'nuclear magnetic spectroscopy,' 'mass spectrometry,' 'metabolic profiling' and 'amino acid profile' combined (AND) with 'gestational diabetes'. Additional articles were identified through searching the reference lists from included studies. Quality assessment of included articles was conducted through the use of QUADOMICS. This systematic review included 17 articles. The biomarkers most consistently associated with gestational diabetes were asymmetric dimethylarginine and NEFAs. After QUADOMICS analysis, 13 of the 17 included studies were classified as 'high quality'. Existing metabolomic studies of gestational diabetes present inconsistent findings regarding metabolite profile characteristics. Further studies are needed in larger, more racially/ethnically diverse populations. C1 [Huynh, Jennifer; Xiong, Grace; Bentley-Lewis, Rhonda] Massachusetts Gen Hosp, Dept Med, Diabet Unit, Boston, MA 02114 USA. RP Bentley-Lewis, R (reprint author), Massachusetts Gen Hosp, Dept Med, Diabet Unit, 55 Fruit St,Bulfinch 4-415, Boston, MA 02114 USA. EM rbentleylewis@mgh.harvard.edu FU National Institutes of Health [R03DK096152]; Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program; Massachusetts General Hospital Executive Committee on Research/Multicultural Affairs Office Physician-Scientist Development Award FX This study was supported in part by the following grants awarded to RB-L: National Institutes of Health R03DK096152; the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program; and the Massachusetts General Hospital Executive Committee on Research/Multicultural Affairs Office Physician-Scientist Development Award. NR 80 TC 11 Z9 11 U1 11 U2 65 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD DEC PY 2014 VL 57 IS 12 BP 2453 EP 2464 DI 10.1007/s00125-014-3371-0 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AT0MR UT WOS:000344630700007 PM 25193282 ER PT J AU Preston, MA Riis, AH Ehrenstein, V Breau, RH Batista, JL Olumi, AF Mucci, LA Adami, HO Sorensen, HT AF Preston, Mark A. Riis, Anders H. Ehrenstein, Vera Breau, Rodney H. Batista, Julie L. Olumi, Aria F. Mucci, Lorelei A. Adami, Hans-Olov Sorensen, Henrik T. TI Metformin Use and Prostate Cancer Risk SO EUROPEAN UROLOGY LA English DT Article DE Chemoprevention; Danish registry; Epidemiology; Incidence; Metformin; Prostate cancer ID DIABETES-MELLITUS; RADICAL PROSTATECTOMY; COHORT; HYPERINSULINEMIA; METAANALYSIS; ASSOCIATION; OBESITY; TRIAL AB Background: Metformin may decrease prostate cancer (PCa) risk by reducing hyperinsulinemia-associated carcinogenesis or through direct effects on cancer cells. Objective: To evaluate the association between metformin use and PCa diagnosis. Design, setting, and participants: We used the Danish Cancer Registry and the Aarhus University Prescription Database to conduct a nested case-control study among men residing in northern Denmark from 1989 to 2011. We identified 12 226 cases of PCa and used risk-set sampling to select 10 population controls per case (n = 122 260) from among men alive on the index date and born in the same year. A sensitivity analysis was conducted using subjects who had prostate-specific antigen (PSA) testing prior to 1 yr before the index date. Intervention: Metformin exposure was assessed using prescriptions redeemed before the index date. Outcome measurements and statistical analysis: Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. The association between metformin use and PCa diagnosis was determined, controlling for diabetes severity and other potential confounders. Results and limitations: Metformin users were at decreased risk of PCa diagnosis compared with never-users (adjusted OR [aOR]: 0.84; 95% CI, 0.74-0.96). Diabetics on no medication (aOR: 0.98; 95% CI, 0.89-1.09) or on other oral hypoglycemics (aOR: 0.98; 95% CI, 0.86-1.10) did not have a reduced risk of PCa, while users of insulin did have a reduced risk (aOR: 0.77; 95% CI, 0.64-0.93). In the PSA-tested group, metformin use was associated with decreased risk of PCa compared with nonuse (aOR: 0.66; 95% CI, 0.51-0.86). Diabetics on no medication (aOR: 1.03; 95% CI, 0.86-1.24), diabetics on other oral hypoglycemics (aOR: 0.92; 95% CI, 0.70-1.20), and insulin users (aOR: 0.83; 95% CI, 0.56-1.24) did not have a statistically significant reduced risk of cancer. Conclusions: Metformin use was associated with decreased risk of PCa diagnosis, whereas diabetics using other oral hypoglycemics had no decreased risk. Patient summary: We studied the relationship between metformin (a diabetic medication) and prostate cancer in Denmark. We found that metformin reduced the risk of prostate cancer diagnosis, whereas other oral antidiabetic medications did not. (C) 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Preston, Mark A.; Olumi, Aria F.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Riis, Anders H.; Ehrenstein, Vera; Sorensen, Henrik T.] Aarhus Univ, Dept Clin Epidemiol, Aarhus, Denmark. [Breau, Rodney H.] Univ Ottawa, Ottawa Hosp Res Inst, Ottawa, ON, Canada. [Batista, Julie L.; Mucci, Lorelei A.; Adami, Hans-Olov] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Batista, Julie L.; Mucci, Lorelei A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Batista, Julie L.; Mucci, Lorelei A.] Harvard Univ, Sch Med, Boston, MA USA. [Adami, Hans-Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. RP Preston, MA (reprint author), Massachusetts Gen Hosp, Dept Urol, 55 Fruit St, Boston, MA 02114 USA. EM preston.mark@gmail.com OI Riis, Anders Hammerich/0000-0002-6684-4068 FU Danish Cancer Society [R73-A4284-13-S17]; Karen Elise Jensen Foundation; Aarhus University Research Foundation; Danish Research Council [09-075724, 10-079102] FX This study (management of the data) was supported by a grant from the Danish Cancer Society (R73-A4284-13-S17), the Karen Elise Jensen Foundation, and a grant from Aarhus University Research Foundation. The Department of Clinical Epidemiology is a member of the Danish Center for Strategic Research in Type 2 Diabetes (Danish Research Council, grant nos. 09-075724 and 10-079102). NR 32 TC 25 Z9 27 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD DEC PY 2014 VL 66 IS 6 BP 1012 EP 1020 DI 10.1016/j.eururo.2014.04.027 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AT1LF UT WOS:000344694300020 PM 24857538 ER PT J AU Preston, MA Batista, J Breau, RH Adami, HO Sorensen, HT AF Preston, Mark A. Batista, Julie Breau, Rodney H. Adami, Hans-Olov Sorensen, Henrik T. TI Metformin to Prevent Prostate Cancer: A Call to Unite Reply SO EUROPEAN UROLOGY LA English DT Editorial Material ID COHORT C1 [Preston, Mark A.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Batista, Julie; Adami, Hans-Olov] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Batista, Julie] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Batista, Julie] Harvard Univ, Sch Med, Boston, MA USA. [Breau, Rodney H.] Univ Ottawa, Ottawa Hosp Res Inst, Ottawa, ON, Canada. [Adami, Hans-Olov] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Sorensen, Henrik T.] Aarhus Univ, Dept Clin Epidemiol, Aarhus, Denmark. RP Preston, MA (reprint author), Massachusetts Gen Hosp, Dept Urol, 55 Fruit St, Boston, MA 02114 USA. EM preston.mark@gmail.com NR 6 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD DEC PY 2014 VL 66 IS 6 BP 1022 EP 1023 DI 10.1016/j.eururo.2014.08.005 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA AT1LF UT WOS:000344694300022 PM 25139199 ER PT J AU Gandaglia, G Sun, M Huc, JC Novara, G Choueiri, TK Nguyen, PL Schiffmann, J Graefen, M Shariat, SF Abdollah, F Briganti, A Montorsi, F Trinh, QD Karakiewicz, PI AF Gandaglia, Giorgio Sun, Maxine Huc, Jim C. Novara, Giacomo Choueiri, Toni K. Nguyen, Paul L. Schiffmann, Jonas Graefen, Markus Shariat, Shahrokh F. Abdollah, Firas Briganti, Alberto Montorsi, Francesco Quoc-Dien Trinh Karakiewicz, Pierre I. TI Gonadotropin-releasing Hormone Agonists and Acute Kidney Injury in Patients with Prostate Cancer SO EUROPEAN UROLOGY LA English DT Article DE Androgen deprivation therapy; Prostate cancer; Side effects; Renal failure; Competing risks; Acute kidney injury ID ANDROGEN-DEPRIVATION THERAPY; ACUTE-RENAL-FAILURE; CARDIOVASCULAR-DISEASE; MEN; RISK; MORTALITY; CARCINOMA; GNRH AB Background: Androgen deprivation therapy (ADT) might increase the risk of acute kidney injury (AKI) in patients with prostate cancer (PCa). Objective: To examine the impact of ADT on AKI in a large contemporary cohort of patients with nonmetastatic PCa representing the US population. Design, setting, and participants: Overall, 69 292 patients diagnosed with nonmetastatic PCa between 1995 and 2009 were abstracted from the Surveillance Epidemiology and End Results-Medicare database. Outcomes measurements and statistical analyses: Patient in both treatment arms (ADT vs no ADT) were matched using propensity-score methodology. Ten-year AKI rates were estimated. Competing-risks regression analyses tested the association between ADT and AKI, after adjusting for the risk of death during follow-up. Results and limitations: Overall, the 10-yr AKI rates were 24.9% versus 30.7% for ADT-naive patients versus those treated with ADT, respectively (p < 0.001). When patients were stratified according to the type of ADT, the 10-yr AKI rates were 31.1% versus 26.0% for men treated with gonadotropin-releasing hormone (GnRH) agonists and bilateral orchiectomy, respectively (p < 0.001). In multivariable analyses, the administration of GnRH agonists (hazard ratio [HR]: 1.24; 95% confidence interval [CI], 1.18-1.31; p < 0.001), but not bilateral orchiectomy (HR: 1.11; 95% CI, 0.96-1.29; p = 0.1), was associated with the risk of experiencing AKI. Our study is limited by its retrospective design. Conclusions: ADT is associated with an increased risk of AKI in patients with nonmetastatic PCa. In particular, the administration of GnRH agonists, but not surgical castration, may substantially increase the risk of experiencing AKI. These observations should help provide physicians with better patient selection to reduce the risk of AKI. Patient summary: The administration of gonadotropin-releasing hormone agonists, but not bilateral orchiectomy, increases the risk of acute kidney injury (AKI) in patients with prostate cancer (PCa). These observations should help provide physicians with better patient selection to reduce the risk of AKI in PCa patients. (C) 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Gandaglia, Giorgio; Sun, Maxine; Schiffmann, Jonas; Karakiewicz, Pierre I.] Univ Montreal, Ctr Hlth, Canc Prognost & Hlth Outcomes Unit, Montreal, PQ H2X 3J4, Canada. [Gandaglia, Giorgio; Abdollah, Firas; Briganti, Alberto; Montorsi, Francesco] Univ Vita Salute San Raffaele, Urol Res Inst, Milan, Italy. [Huc, Jim C.] Calif State Univ Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90032 USA. [Novara, Giacomo] Univ Padua, Dept Surg Oncol & Gastroenterol, Urol Clin, Padua, Italy. [Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Nguyen, Paul L.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol,Div Urol,Med Sch, Boston, MA 02115 USA. [Graefen, Markus] Univ Hosp Hamburg Eppendorf, Martini Klin, Hamburg, Germany. [Shariat, Shahrokh F.] Med Univ Vienna, Dept Urol, Vienna, Austria. [Quoc-Dien Trinh] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Surg,Div Urol,Med Sch, Boston, MA 02115 USA. RP Gandaglia, G (reprint author), Univ Montreal, Ctr Hlth, Canc Prognost & Hlth Outcomes Unit, 1058 Rue St Denis, Montreal, PQ H2X 3J4, Canada. EM giorgio.gandaglia@gmail.com FU University of Montreal Health Centre Urology Specialists; Fonds de la Recherche en Sante du Quebec; University of Montreal Department of Surgery; University of Montreal Health Centre (CHUM) Foundation FX Pierre I. Karakiewicz is partially supported by the University of Montreal Health Centre Urology Specialists, Fonds de la Recherche en Sante du Quebec, the University of Montreal Department of Surgery, and the University of Montreal Health Centre (CHUM) Foundation. NR 30 TC 11 Z9 11 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD DEC PY 2014 VL 66 IS 6 BP 1125 EP 1132 DI 10.1016/j.eururo.2014.01.026 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AT1LF UT WOS:000344694300036 PM 24495466 ER PT J AU Meng, N Zhang, XM Liao, AY Tian, SQ Ran, WQ Gao, Y Wang, JJ AF Meng, Na Zhang, Xiaomeng Liao, Anyan Tian, Suqing Ran, Weiqiang Gao, Yang Wang, Jun Jie TI Management of recurrent alveolar soft-part sarcoma of the tongue after external beam radiotherapy with iodine-125 seed brachytherapy SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE I-125 seed; brachytherapy; ultrasound guidance; alveolar soft-part sarcoma; outcome ID IMPLANTATION; CHILDREN; HEAD; NECK AB BackgroundAlveolar soft part sarcoma (ASPS) is a rare type of soft tissue sarcoma. The infrequency of ASPS is such that it accounts for <1% of all soft tissue sarcomas and <0.1% of sarcomas concerning the head and neck, primarily those involving the orbit (48%) and tongue (25%). Traditional chemotherapy or radiotherapy of ASPS is often associated with poor outcome, even after comprehensive interventions. Methods and ResultsWe performed iodine-125 (I-125) seed brachytherapy under ultrasound guidance through a submandibular puncture in a 4-year-old boy with recurrent ASPS of the tongue. The prescription dose was 120 Gy; therefore, 35 I-125 seeds were implanted with 0.77 mCi per seed, the total amount of activity being 26.95 mCi. CT scans confirmed a complete response after the treatment. ConclusionOur patient now has a recurrent-free survival of >30 months, an amount of time longer than the median rate described in the literature. (c) 2014 Wiley Periodicals, Inc. Head Neck 36: E125-E128, 2014 C1 [Meng, Na; Liao, Anyan; Tian, Suqing; Gao, Yang; Wang, Jun Jie] Peking Univ Third Hosp, Dept Radiat Oncol, Beijing 100191, Peoples R China. [Zhang, Xiaomeng] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Adv Med Imaging Sci, Boston, MA 02115 USA. [Ran, Weiqiang] Peking Univ Third Hosp, Dept Ultrasound, Beijing 100191, Peoples R China. RP Wang, JJ (reprint author), Peking Univ Third Hosp, Dept Radiat Oncol, Beijing 100191, Peoples R China. EM junjiewang_edu@sina.cn NR 11 TC 1 Z9 3 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD DEC PY 2014 VL 36 IS 12 BP E125 EP E128 DI 10.1002/hed.23648 PG 4 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AT2YR UT WOS:000344801200001 PM 24585519 ER PT J AU Sieuwerts, AM Willis, S Burns, MB Look, MP Meijer-Van Gelder, ME Schlicker, A Heideman, MR Jacobs, H Wessels, L Leyland-Jones, B Gray, KP Foekens, JA Harris, RS Martens, JWM AF Sieuwerts, Anieta M. Willis, Scooter Burns, Michael B. Look, Maxime P. Meijer-Van Gelder, Marion E. Schlicker, Andreas Heideman, Marinus R. Jacobs, Heinz Wessels, Lodewyk Leyland-Jones, Brian Gray, Kathryn P. Foekens, John A. Harris, Reuben S. Martens, John W. M. TI Elevated APOBEC3B Correlates with Poor Outcomes for Estrogen-Receptor-Positive Breast Cancers SO HORMONES & CANCER LA English DT Article ID MUTATIONAL PROCESSES; MOLECULAR PORTRAITS; RESTRICTION FACTORS; CYTIDINE DEAMINASE; DELETION; GENOMES; FAMILY; TUMORS; DNA; MUTAGENESIS AB Recent observations connected DNA cytosine deaminase APOBEC3B to the genetic evolution of breast cancer. We addressed whether APOBEC3B is associated with breast cancer clinical outcomes. APOBEC3B messenger RNA (mRNA) levels were related in 1,491 primary breast cancers to disease-free (DFS), metastasis-free (MFS), and overall survival (OS). For independent validation, APOBEC3B mRNA expression was associated with patient outcome data in five additional cohorts (over 3,500 breast cancer cases). In univariate Cox regression analysis, increasing APOBEC3B expression as a continuous variable was associated with worse DFS, MFS, and OS (hazard ratio [HR] = 1.20, 1.21, and 1.24, respectively; all P < .001). Also, in untreated ER-positive (ER+), but not in ER-, lymph-node-negative patients, high APOBEC3B levels were associated with a poor DFS (continuous variable: HR = 1.29, P = .001; dichotomized at the median level, HR = 1.66, P = .0002). This implies that APOBEC3B is a marker of pure prognosis in ER + disease. These findings were confirmed in the analyses of five independent patient sets. In these analyses, APOBEC3B expression dichotomized at the median level was associated with adverse outcomes (METABRIC discovery and validation, 788 and 706 ER + cases, disease-specific survival (DSS), HR = 1.77 and HR = 1.77, respectively, both P < .001; Affymetrix dataset, 754 ER + cases, DFS, HR = 1.57, P = 2.46E-04; NKI295, 181 ER + cases, DFS, HR = 1.72, P = .054; and BIG 1-98, 1,219 ER + cases, breast-cancer-free interval (BCFI), HR = 1.42, P = 0.0079). APOBEC3B is a marker of pure prognosis and poor outcomes for ER + breast cancer, which strongly suggests that genetic aberrations induced by APOBEC3B contribute to breast cancer progression. C1 [Sieuwerts, Anieta M.; Look, Maxime P.; Meijer-Van Gelder, Marion E.; Foekens, John A.; Martens, John W. M.] Erasmus MC Canc Inst, Dept Med Oncol & Canc Genom, NL-3015 GE Rotterdam, Netherlands. [Burns, Michael B.; Harris, Reuben S.] Univ Minnesota, Inst Mol Virol, Masonic Canc Ctr, Dept Biochem Mol Biol & Biophys, Minneapolis, MN USA. [Schlicker, Andreas; Heideman, Marinus R.; Jacobs, Heinz; Wessels, Lodewyk] Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands. [Willis, Scooter; Leyland-Jones, Brian] Avera Canc Inst, Dept Mol & Expt Med, Sioux Falls, SD 57105 USA. [Gray, Kathryn P.] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Stat Ctr,Dept Biostat & Computat Biol,IBCSG, Boston, MA 02215 USA. RP Martens, JWM (reprint author), Erasmus MC Canc Inst, Dept Med Oncol & Canc Genom, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands. EM j.martens@erasmusmc.nl OI Jacobs, Heinz/0000-0001-6227-9850; Burns, Michael/0000-0001-9791-4359 FU International Breast Cancer Study Group through Susan G. Komen for the Cure Promise Grant [KG080081]; United States National Cancer Institute [CA-75362]; Department of Defense Breast Cancer Research Program Predoctoral Fellowship [BC101124]; University of Minnesota Clinical and Translational Science Institute; NIH [1UL1RR033183]; Jimmy V Foundation; Cancer Genomics Netherlands - Netherlands Organisation for Scientific Research (NWO) FX Funding for the BIG 1-98 trial was provided by the International Breast Cancer Study Group through grants from Susan G. Komen for the Cure Promise Grant (KG080081) and United States National Cancer Institute (CA-75362). M. B. B. was supported by a Department of Defense Breast Cancer Research Program Predoctoral Fellowship (BC101124). Harris laboratory operational support for these studies was provided by a seed grant from the University of Minnesota Clinical and Translational Science Institute (supported by NIH 1UL1RR033183) and a Translational Research Grant from the Jimmy V Foundation. A. M. S. was supported by Cancer Genomics Netherlands funded by the Netherlands Organisation for Scientific Research (NWO). NR 40 TC 30 Z9 31 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-8497 EI 1868-8500 J9 HORM CANCER-US JI Horm. Cancer PD DEC PY 2014 VL 5 IS 6 BP 405 EP 413 DI 10.1007/s12672-014-0196-8 PG 9 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA AT2DW UT WOS:000344742800006 PM 25123150 ER PT J AU Rosness, TA Engedal, K Chemali, Z AF Rosness, Tor Atle Engedal, Knut Chemali, Zeina TI Raising the bar: a comparative analysis of patients with Early Onset Alzheimer's disease SO INTERNATIONAL PSYCHOGERIATRICS LA English DT Letter ID DEMENTIA C1 [Rosness, Tor Atle] Univ Oslo, Inst Hlth & Soc, N-0316 Oslo, Norway. [Engedal, Knut] Ullevaal Univ Hosp, Dept Geriatr Med, Norwegian Ctr Dementia Res, Oslo, Norway. [Chemali, Zeina] Harvard Univ, Sch Med, Dept Neurol, Neuropsychiat Clin,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Chemali, Zeina] Harvard Univ, Sch Med, Dept Psychiat, Neuropsychiat Clin,Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Rosness, TA (reprint author), Univ Oslo, Inst Hlth & Soc, N-0316 Oslo, Norway. EM t.a.rosness@medisin.uio.no NR 5 TC 1 Z9 1 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1041-6102 EI 1741-203X J9 INT PSYCHOGERIATR JI Int. Psychogeriatr. PD DEC PY 2014 VL 26 IS 12 SI SI BP 2103 EP 2104 DI 10.1017/S1041610214000064 PG 2 WC Psychology, Clinical; Geriatrics & Gerontology; Gerontology; Psychiatry; Psychology SC Psychology; Geriatrics & Gerontology; Psychiatry GA AT4YG UT WOS:000344948000020 PM 24472377 ER PT J AU Akgun, KM Tate, JP Crothers, K Crystal, S Leaf, DA Womack, J Brown, TT Justice, AC Oursler, KK AF Akguen, Kathleen M. Tate, Janet P. Crothers, Kristina Crystal, Stephen Leaf, David A. Womack, Julie Brown, Todd T. Justice, Amy C. Oursler, Krisann K. TI An Adapted Frailty-Related Phenotype and the VACS Index as Predictors of Hospitalization and Mortality in HIV-Infected and Uninfected Individuals SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE adapted frailty-related phenotype; physiologic frailty; HIV; VACS risk index; hospitalization; mortality ID VETERANS AGING COHORT; HUMAN-IMMUNODEFICIENCY-VIRUS; INDEPENDENT RISK-FACTOR; ANTIRETROVIRAL THERAPY; DEFICIT ACCUMULATION; ELDERLY-PEOPLE; OLDER-ADULTS; MEN; CARE; ASSOCIATION AB Background: Frailty is a geriatric syndrome of decreased physiologic reserve and a risk factor for hospitalization and mortality. We hypothesized that an adapted survey-based frailty-related phenotype (aFRP) predicts hospitalization and mortality among HIV-infected and uninfected individuals in adjusted models but is uncommon among those achieving undetectable HIV-1 RNA. Methods: Defined from self-reported domains of physical shrinking, exhaustion, slowness, and low physical activity in Veterans Aging Cohort Study (VACS) participants, aFRP was considered present with >= 3 domains and prefrailty with 1-2 domains. Cox survival analysis determined hazard ratios (HRs) for 5-year hospitalization and mortality risk adjusting for frailty states, demographics, health behaviors, comorbidities, and a validated risk index incorporating HIV-specific and general organ system biomarkers, the VACS Index. Model discrimination was assessed. Results: Participants with complete data were included [6515/7324 (89%)]. Of these, 3.9% of HIV-infected individuals with HIV-1 RNA >400 copies per milliliter; 2.0% of HIV-infected individuals with HIV-1 RNA <= 400 copies per milliliter; and 2.8% of uninfected individuals met aFRP criteria (P = 0.01). After adjustment for other covariates, aFRP was associated with hospitalization (HR = 1.78; 95% confidence interval: 1.48 to 2.13) and mortality (HR = 1.75; 95% confidence interval: 1.28 to 2.40). C-statistics for the VACS Index for hospitalization (0.633) and for mortality (0.756) were higher than for aFRP (0.565 and 0.584, respectively). C-statistic for hospitalization improved modestly when VACS Index and aFRP were both included (0.646) and minimally for mortality (0.761). Conclusions: aFRP was independently associated with adverse health outcomes among HIV-infected and uninfected individuals. aFRP modestly improved prediction for hospitalization. However, the aFRP is rare among HIV-infected individuals with undetectable HIV-1 RNA. C1 [Akguen, Kathleen M.] VA Connecticut Healthcare Syst, Dept Internal Med & Gen Internal Med, West Haven, CT 06516 USA. [Akguen, Kathleen M.; Tate, Janet P.; Justice, Amy C.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Tate, Janet P.; Justice, Amy C.] VA Connecticut Healthcare Syst, Dept Internal Med, West Haven, CT USA. [Crothers, Kristina] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Crystal, Stephen] Rutgers State Univ, Inst Hlth Healthcare Policy & Aging Res, New Brunswick, NJ 08903 USA. [Leaf, David A.] Univ Calif Los Angeles, Sch Med, Dept Med, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90024 USA. [Womack, Julie] Yale Univ, Sch Nursing, New Haven, CT 06536 USA. [Brown, Todd T.] Johns Hopkins Univ, Div Endocrinol Diabet & Metab, Baltimore, MD USA. [Oursler, Krisann K.] Univ Maryland SOM, VA Maryland Hlth Care Syst, Dept Med, Baltimore, MD USA. RP Akgun, KM (reprint author), VA Connecticut West Haven, 950 Campbell Ave,MS 11 ACSLG, West Haven, CT 06516 USA. EM kathleen.akgun@yale.edu OI Crothers, Kristina/0000-0001-9702-0371 FU Department of Veterans Affairs, Veterans Health Administration [V1CDA2012-20, I01 RX000667]; Association of Subspecialty Physicians; CHEST Foundation of the American College of Chest Physicians T. Franklin Williams Award; National Institute on Alcohol Abuse and Alcoholism [U24-AA020794, U01-AA020790, U10 AA013566]; National Institutes of Health and National Heart, Lung, and Blood Institute [R01 HL090342]; National Institutes of Health [K23 AG02489] FX K.M.A. is currently receiving a grant [VISN 1 Career Development Award (V1CDA2012-20)] from the Department of Veterans Affairs, Veterans Health Administration, and previously was supported with a grant from the Association of Subspecialty Physicians and CHEST Foundation of the American College of Chest Physicians T. Franklin Williams Award. A.C.J. is currently receiving a grant [U24-AA020794, U01-AA020790, and U10 AA013566-completed] from the National Institute on Alcohol Abuse and Alcoholism. K. C. was receiving a grant (R01 HL090342) from the National Institutes of Health and National Heart, Lung, and Blood Institute. K.K.O. is currently receiving a grant (I01 RX000667) from the Department of Veterans Affairs, Veterans Health Administration, and previously was supported with a grant (K23 AG02489) from the National Institutes of Health. The remaining authors have no funding or conflicts of interest to disclose. NR 37 TC 15 Z9 16 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 1 PY 2014 VL 67 IS 4 BP 397 EP 404 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AT2NR UT WOS:000344771900010 PM 25202921 ER PT J AU O'Laughlin, KN Kasozi, J Walensky, RP Parker, RA Faustin, ZM Doraiswamy, S Owino, CO Bassett, IV AF O'Laughlin, Kelli N. Kasozi, Julius Walensky, Rochelle P. Parker, Robert A. Faustin, Zikama M. Doraiswamy, Sathyanarayanan Owino, Chris Omara Bassett, Ingrid V. TI Clinic-Based Routine Voluntary HIV Testing in a Refugee Settlement in Uganda SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV testing; refugees; routine testing; Uganda; Africa; HIV ID SOUTH-AFRICA; KNOWLEDGE; TANZANIA AB We implemented and evaluated a clinic-based routine voluntary HIV testing intervention in Nakivale Refugee Settlement in Uganda. Comparing the standard of care period (40 d) with the intervention period (168 d), the mean HIV-infected clients identified per week increased from 0.9 to 5.6, and there was no significant difference between the HIV prevalence in the 2 periods (standard of care: 3.3%; intervention: 4.5%; P > 0.5). Clinic-based routine HIV testing in a refugee settlement is effective and should be considered for implementation in refugee settlements in other high-prevalence regions in sub-Saharan Africa. C1 [O'Laughlin, Kelli N.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [O'Laughlin, Kelli N.; Walensky, Rochelle P.; Parker, Robert A.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [O'Laughlin, Kelli N.; Walensky, Rochelle P.; Parker, Robert A.; Bassett, Ingrid V.] Harvard Univ, Sch Med, Boston, MA USA. [O'Laughlin, Kelli N.] Harvard Humanitarian Initiat, Cambridge, MA USA. [Kasozi, Julius] United Nations High Commissioner Refugees, Representat Uganda, Kampala, Uganda. [Walensky, Rochelle P.; Parker, Robert A.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Walensky, Rochelle P.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.; Parker, Robert A.; Bassett, Ingrid V.] Harvard Univ, Ctr AIDS Res, Boston, MA 02115 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Parker, Robert A.] Massachusetts Gen Hosp, MGH Biostat Ctr, Boston, MA 02114 USA. [Faustin, Zikama M.] Bugema Univ, Kampala, Uganda. [Doraiswamy, Sathyanarayanan] United Nations High Commissioner Refugees, Geneva, Switzerland. [Owino, Chris Omara] Med Teams Int, Mbarara, Uganda. RP O'Laughlin, KN (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM kolaughlin@partners.org FU National Institutes of Health: Harvard University Center for AIDS Research NIH/NIAID [5P30AI060354-08, R01 MH090326, R01 AI058736] FX Supported by the National Institutes of Health: Harvard University Center for AIDS Research NIH/NIAID 5P30AI060354-08, R01 MH090326, R01 AI058736. NR 24 TC 2 Z9 2 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 1 PY 2014 VL 67 IS 4 BP 409 EP 413 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AT2NR UT WOS:000344771900012 PM 25162817 ER PT J AU Srinivasa, S Fitch, KV Petrow, E Burdo, TH Williams, KC Lo, J Cote, HCF Grinspoon, SK AF Srinivasa, Suman Fitch, Kathleen V. Petrow, Eva Burdo, Tricia H. Williams, Kenneth C. Lo, Janet Cote, Helene C. F. Grinspoon, Steven K. TI Soluble CD163 Is Associated With Shortened Telomere Length in HIV-Infected Patients SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE sCD163; telomeres; HIV; immune activation; immunosenescence; aging ID ANTIRETROVIRAL THERAPY; NONINVASIVE BIOMARKER; IMMUNE ACTIVATION; DISEASE; RISK; MEN; ATHEROSCLEROSIS; PATHOGENESIS; MONOCYTES; MARKER AB Telomere length (TL) and immune activation markers were measured in a cohort of HIV-infected (n = 102) and age-matched non-HIV-infected (n = 41) men. TL was significantly shorter in HIV-infected compared with non-HIV-infected subjects (P = 0.04). Univariate analysis revealed a strong inverse relationship of TL to sCD163, and thus, monocyte/macrophage activation, among the HIV group (r = 20.30, P = 0.003). In multivariate modeling among the whole group, HIV-positive serostatus (P = 0.06) and sCD163 (P = 0.05) remained predictors of TL controlling for age and smoking status. Our data demonstrate that increased immune activation relates to shorter TL in HIV. C1 [Srinivasa, Suman; Fitch, Kathleen V.; Petrow, Eva; Lo, Janet; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Srinivasa, Suman; Fitch, Kathleen V.; Petrow, Eva; Lo, Janet; Grinspoon, Steven K.] Harvard Univ, Sch Med, Boston, MA USA. [Burdo, Tricia H.; Williams, Kenneth C.] Boston Univ, Dept Biol, Chestnut Hill, MA USA. [Cote, Helene C. F.] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON207, Boston, MA 02114 USA. EM sgrinspoon@mgh.harvard.edu FU National Institutes of Health [R01 HL095123-04, K23 HL092792, NS37654, NS40237]; Harvard Clinical and Translational Science Center from the National Center for Research Resources; Nutrition Obesity Research Center at Harvard [P30 DK040561]; NIH [M01-RR-01066, 1 UL1 RR025758-01]; Bristol-Myers Squibb; Immunex; Gilead; EMD Serono FX Supported by the National Institutes of Health R01 HL095123-04 to S. K. G., K23 HL092792 to J.L., NS37654 and NS40237 to K. C. W, NIH M01-RR-01066 and 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center, from the National Center for Research Resources and P30 DK040561, Nutrition Obesity Research Center at Harvard. Funding sources had no role in the design of the study, data analysis or the writing of the manuscript.; K. C. W. served as a consultant for Navidea Biopharmaceuticals Inc. unrelated to this manuscript. S. K. G. has received research funding from Bristol-Myers Squibb, Immunex, Gilead, and EMD Serono and served as a consultant for Navidea Inc., Aileron, Inc., NovoNordisk and BMS/AstraZeneca unrelated to this manuscript. The remaining authors have no conflicts of interest to disclose. NR 34 TC 2 Z9 2 U1 5 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 1 PY 2014 VL 67 IS 4 BP 414 EP 418 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AT2NR UT WOS:000344771900013 PM 25197827 ER PT J AU Robertson, NG O'Malley, JT Ong, CA Giersch, ABS Shen, J Stankovic, KM Morton, CC AF Robertson, Nahid G. O'Malley, Jennifer T. Ong, Cheng Ai Giersch, Anne B. S. Shen, Jun Stankovic, Konstantina M. Morton, Cynthia C. TI Cochlin in Normal Middle Ear and Abnormal Middle Ear Deposits in DFNA9 and Coch (G88E/G88E) Mice SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE COCH; cochlin; DFNA9; middle ear; deposits ID TUMOR-NECROSIS-FACTOR; GLAUCOMATOUS TRABECULAR MESHWORK; II COLLAGEN DISTRIBUTION; OTITIS-MEDIA; VESTIBULAR DYSFUNCTION; HEARING-LOSS; INNER-EAR; PERILYMPHATIC FISTULA; DEAFNESS DISORDER; FACTOR-ALPHA AB DFNA9 sensorineural hearing loss and vestibular disorder, caused by mutations in COCH, has a unique identifying histopathology including prominent acellular deposits in cochlear and vestibular labyrinths. A recent study has shown presence of deposits also in middle ear structures of DFNA9-affected individuals (McCall et al., J Assoc Res Otolaryngol 12:141-149, 2004). To investigate the possible role of cochlin in the middle ear and in relation to aggregate formation, we evaluated middle ear histopathology in our Coch knock-in (Coch (G88E/G88E) ) mouse model, which harbors one of the DFNA9-causative mutations. Our findings reveal accumulation of acellular deposits in the incudomalleal and incudostapedial joints in Coch (G88E/G88E) mice, similar to those found in human DFNA9-affected temporal bones. Aggregates are absent in negative control Coch (+/+) and Coch (-/-) mice. Thickening of the tympanic membrane (TM) found in humans with DFNA9 was not appreciably detected in Coch (G88E/G88E) mice at the evaluated age. We investigated cochlin localization first in the Coch (+/+)mouse and in normal human middle ears, and found prominent and specific cochlin staining in the incudomalleal joint, incudostapedial joint, and the pars tensa of the TM, which are the three sites where abnormal deposits are detected in DFNA9-affected middle ears. Cochlin immunostaining of Coch (G88E/G88E) and DFNA9-affected middle ears showed mutant cochlin localization within areas of aggregates. Cochlin staining was heterogeneous throughout DFNA9 middle ear deposits, which appear as unorganized and overlapping mixtures of both eosinophilic and basophilic substances. Immunostaining for type II collagen colocalized with cochlin in pars tensa of the tympanic membrane. In contrast, immunostaining for type II collagen did not overlap with cochlin in interossicular joints, where type II collagen was localized in the region of the chondrocytes, but not in the thin layer of the articular surface of the ossicles nor in the eosinophilic deposits with specific cochlin staining. C1 [Robertson, Nahid G.; Morton, Cynthia C.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Giersch, Anne B. S.; Shen, Jun; Morton, Cynthia C.] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. [O'Malley, Jennifer T.; Ong, Cheng Ai; Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Ong, Cheng Ai; Stankovic, Konstantina M.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Morton, CC (reprint author), Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. EM nrobertson@research.bwh.harvard.edu; Jennifer_O'Malley@meei.harvard.edu; ongca181@hotmail.com; agiersch@research.bwh.harvard.edu; jshen5@partners.org; Konstantina_Stankovic@meei.harvard.edu; cmorton@partners.org FU National Institutes of Health [R01 DC03402, K08 DC010419]; Bertarelli Foundation FX We would like to dedicate this work to the memory of our beloved friend and colleague, Dr. Saumil Merchant. We are grateful to the individuals and families who have participated in this study and for their generous donations of temporal bones. We thank Dr. John Rosowski and Melissa McKinnon for sharing their expertise in mouse middle ear. This work was supported by National Institutes of Health grants R01 DC03402 (to C. C. M.), K08 DC010419 (to K. M. S.), and the Bertarelli Foundation (to K.M.S.). NR 42 TC 3 Z9 3 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 EI 1438-7573 J9 JARO-J ASSOC RES OTO JI JARO PD DEC PY 2014 VL 15 IS 6 BP 961 EP 974 DI 10.1007/s10162-014-0481-9 PG 14 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA AT2OU UT WOS:000344775000007 PM 25049087 ER PT J AU Faul, LA Luta, G Sheppard, V Isaacs, C Cohen, HJ Muss, HB Yung, R Clapp, JD Winer, E Hudis, C Tallarico, M Wang, J Barry, WT Mandelblatt, JS AF Faul, Leigh Anne Luta, Gheorghe Sheppard, Vanessa Isaacs, Claudine Cohen, Harvey J. Muss, Hyman B. Yung, Rachel Clapp, Jonathan D. Winer, Eric Hudis, Clifford Tallarico, Michelle Wang, Julhy Barry, William T. Mandelblatt, Jeanne S. TI Associations among survivorship care plans, experiences of survivorship care, and functioning in older breast cancer survivors: CALGB/Alliance 369901 SO JOURNAL OF CANCER SURVIVORSHIP LA English DT Article DE Survivorship care plan; Breast cancer; Cancer survivors; Older adults; Cancer survivorship and aging ID QUALITY-OF-LIFE; FOLLOW-UP; EUROPEAN-ORGANIZATION; NATIONAL-SURVEY; HOSPITAL-CARE; HEALTH SURVEY; PHYSICIANS; PATIENT; WOMEN; QUESTIONNAIRE AB Survivorship care plans (SCP) are recommended for all cancer patients and could be especially useful to survivors 65 years and over ("older"). This study examined receipt of SCPs among older breast cancer survivors and whether SCPs were associated with improved patient-reported outcomes. Three hundred and twenty-eight older women diagnosed with invasive, nonmetastatic breast cancer between 2007-2011 were recruited from 78 cooperative-group sites. Participants completed telephone interviews at baseline and 1-year posttreatment. Regression analyses examined SCP receipt (yes/no) and functioning (EORTC-QLQ-C30), cancer worry, and experiences of survivorship care (care coordination, knowledge). Only 35 % of women received SCPs. For each 1-year increase in age, there was a 5 % lower odds of receiving an SCP (odds ratio (OR) = 0.94, 95 % confidence interval (CI) 0.91-0.98, p = 0.007). Besides age, no other factor predicted SCPs. SCP receipt was associated with greater knowledge and understanding of requisite follow-up care (p < 0.05); however, functioning was not significantly different among those with vs. without SCPs. Receipt of care plans was limited. SCPs improved understanding of breast cancer follow-up care among older survivors, but did not impact functioning one year post-treatment. To impact functioning and salient needs of the growing cohort of older survivors, survivorship care plans likely should be tailored to geriatric-specific issues. To improve functioning, SCP content should expand to include exercise, nutrition, polypharmacy, social support and management of symptom burden from cancer, and other comorbid conditions. To improve follow-up care for cancer survivors, SCPs should delineate shared care roles between oncology and primary care in managing recurrence surveillance, screening, and cancer sequelae. C1 [Faul, Leigh Anne; Sheppard, Vanessa; Isaacs, Claudine; Wang, Julhy; Mandelblatt, Jeanne S.] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Faul, Leigh Anne; Clapp, Jonathan D.; Tallarico, Michelle; Wang, Julhy; Mandelblatt, Jeanne S.] Georgetown Lombardi Comprehens Canc Ctr, Canc Prevent & Control Program, Washington, DC USA. [Luta, Gheorghe] Georgetown Univ, Med Ctr, Dept Biostat Bioinformat & Biomath, Washington, DC 20007 USA. [Luta, Gheorghe] Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA. [Sheppard, Vanessa; Isaacs, Claudine] Georgetown Lombardi Comprehens Canc Ctr, Breast Canc Program, Washington, DC USA. [Isaacs, Claudine] Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. [Cohen, Harvey J.] Duke Univ, Dept Med, Durham, NC USA. [Cohen, Harvey J.] Duke Univ, Ctr Study Aging & Human Dev, Durham, NC USA. [Muss, Hyman B.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Yung, Rachel; Winer, Eric] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hudis, Clifford] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Barry, William T.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Faul, LA (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. EM laf56@georgetown.edu OI Luta, George/0000-0001-9013-2207; Luta, George/0000-0002-4035-7632 FU National Cancer Institute (NCI) [U10-CA 84131, R01-CA127617]; NCI [K07-CA166342, K05 CA096940, CA31946, CA33601]; NTSR; Biostatistics and Bioinformatics Shared Resources at Lombardi Comprehensive Cancer Center under NCI [P30CA51008]; Amgen Pharmaceuticals FX This research was supported by grants from the National Cancer Institute (NCI), including U10-CA 84131 (JSM), R01-CA127617 (JSM). This work was also supported in part by NCI grants K07-CA166342 (LAF) and K05 CA096940 (JSM). This research was also supported by the Clinical and Molecular Epidemiology(now NTSR) and Biostatistics and Bioinformatics Shared Resources at Lombardi Comprehensive Cancer Center under NCI grant P30CA51008 (Weiner). The Cancer and Leukemia Group B (CALGB) protocol #369901 was supported, in part, by NCI grant CA31946 to the Cancer and Leukemia Group B (Monica Bernagnoli, MD, Chairman) and grant CA33601 to the CALGB Statistical Center (Stephen George, PhD). The content of this manuscript is solely the responsibility of the authors and does not represent official views of the NCI at the National Institutes of Health or CALGB. Cancer and Leukemia Group B is presently part of the Alliance for Clinical Trials in Oncology. The research was also funded, in part, by a grant to support patient accrual from Amgen Pharmaceuticals to the CALGB Foundation. NR 62 TC 4 Z9 4 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 EI 1932-2267 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD DEC PY 2014 VL 8 IS 4 BP 627 EP 637 DI 10.1007/s11764-014-0371-5 PG 11 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA AT0IF UT WOS:000344619400012 PM 24917307 ER PT J AU Rajimehr, R Bilenko, NY Vanduffel, W Tootell, RBH AF Rajimehr, Reza Bilenko, Natalia Y. Vanduffel, Wim Tootell, Roger B. H. TI Retinotopy versus Face Selectivity in Macaque Visual Cortex SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID LATERAL OCCIPITAL CORTEX; HUMAN OBJECT AREAS; CEREBRAL-CORTEX; CORTICAL CONNECTIONS; TEMPORAL CORTEX; CONTRAST AGENT; FIELD MAPS; BODY PARTS; ORGANIZATION; MONKEYS AB Retinotopic organization is a ubiquitous property of lowertier visual cortical areas in human and nonhuman primates. In macaque visual cortex, the retinotopic maps extend to higher-order areas in the ventral visual pathway, including area TEO in the inferior temporal (IT) cortex. Distinct regions within IT cortex are also selective to specific object categories such as faces. Here we tested the topographic relationship between retinotopic maps and face-selective patches in macaque visual cortex using high-resolution fMRI and retinotopic face stimuli. Distinct subregions within face-selective patches showed either (1) a coarse retinotopic map of eccentricity and polar angle, (2) a retinotopic bias to a specific location of visual field, or (3) nonretinotopic selectivity. In general, regions along the lateral convexity of IT cortex showed more overlap between retinotopic maps and face selectivity, compared with regions within the STS. Thus, face patches in macaques can be subdivided into smaller patches with distinguishable retinotopic properties. C1 [Rajimehr, Reza; Bilenko, Natalia Y.; Vanduffel, Wim; Tootell, Roger B. H.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Rajimehr, Reza] MIT, Cambridge, MA 02139 USA. [Vanduffel, Wim] KU Leuven Med Sch, Leuven, Belgium. RP Rajimehr, R (reprint author), Massachusetts Gen Hosp, NMR Martinos Ctr, 149 Thirteenth St,Room 2301, Charlestown, MA 02129 USA. EM reza@nmr.mgh.harvard.edu FU National Institutes of Health [R01 MH67529, R01 EY017081]; Martinos Center for Biomedical Imaging; NCRR; MIND Institute FX We thank Leeland Ekstrom for help with the monkey fMRI and two anonymous reviewers for comments on this manuscript. This research was supported by the National Institutes of Health (grants R01 MH67529 and R01 EY017081 to R. B. H. T.), the Martinos Center for Biomedical Imaging, the NCRR, and the MIND Institute. NR 49 TC 7 Z9 7 U1 0 U2 4 PU MIT PRESS PI CAMBRIDGE PA ONE ROGERS ST, CAMBRIDGE, MA 02142-1209 USA SN 0898-929X EI 1530-8898 J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD DEC PY 2014 VL 26 IS 12 BP 2691 EP 2700 DI 10.1162/jocn_a_00672 PG 10 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AS9PE UT WOS:000344573500004 PM 24893745 ER PT J AU Trinh, NHT Hagan, PN Flaherty, K Traeger, LN Inamori, A Brill, CD Hails, K Chang, TE Bedoya, CA Fava, M Yeung, A AF Trinh, Nhi-Ha T. Hagan, Patrick N. Flaherty, Katherine Traeger, Lara N. Inamori, Aya Brill, Charlotte D. Hails, Katherine Chang, Trina E. Bedoya, C. Andres Fava, Maurizio Yeung, Albert TI Evaluating Patient Acceptability of a Culturally Focused Psychiatric Consultation Intervention for Latino Americans with Depression SO JOURNAL OF IMMIGRANT AND MINORITY HEALTH LA English DT Article DE Depression; Latino Americans; Primary care; Culturally appropriate care ID MENTAL-HEALTH-SERVICES; PRIMARY-CARE PATIENTS; UNITED-STATES; DISPARITIES; COMPETENCE; FRAMEWORK; SYMPTOMS AB Significant disparities exist in both access to and quality of mental health care for Latino Americans with depression compared to Caucasians, resulting in a greater burden of disability in this underserved population. Our aim is to evaluate participant acceptability of a Culturally Focused Psychiatric (CFP) consultation program for depressed Latino Americans. Latino American adult primary care patients endorsing depressive symptoms on a screening questionnaire were targeted in their primary care clinic. The intervention addressed participants' depressive symptoms using culturally adapted clinical assessments and toolkits. Acceptability was evaluated using a treatment satisfaction scale and in-depth semi-structured interviews. Overall, 85 % of participants responded positively to all questions of the satisfaction scale. In in-depth interviews, the vast majority of participants reported the program met expectations, all stated providers were culturally sensitive, and most stated recommendations were culturally sensitive. The CFP program was found to be acceptable to a group of depressed Latino American primary care patients. Further research is needed to evaluate if the CFP intervention can improve depressive symptoms and outcomes. C1 [Trinh, Nhi-Ha T.; Inamori, Aya; Brill, Charlotte D.; Hails, Katherine; Chang, Trina E.; Fava, Maurizio; Yeung, Albert] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Hagan, Patrick N.] Massachusetts Gen Hosp, Ctr Community Hlth Improvement, Boston, MA 02114 USA. [Flaherty, Katherine] Abt Associates Inc, Cambridge, MA 02138 USA. [Traeger, Lara N.; Bedoya, C. Andres] Massachusetts Gen Hosp, Behav Med Serv, Boston, MA 02114 USA. RP Trinh, NHT (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, One Bowdoin Sq,Sixth Floor, Boston, MA 02114 USA. EM ntrinh@partners.org NR 27 TC 1 Z9 1 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1912 EI 1557-1920 J9 J IMMIGR MINOR HEALT JI J. Immigr. Minor. Health PD DEC PY 2014 VL 16 IS 6 BP 1271 EP 1277 DI 10.1007/s10903-013-9924-3 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AS9FZ UT WOS:000344549800029 PM 24097287 ER PT J AU Gajdosik, M Chmelik, M Just-Kukurova, I Bogner, W Valkovic, L Trattnig, S Krssak, M AF Gajdosik, Martin Chmelik, Marek Just-Kukurova, Ivica Bogner, Wolfgang Valkovic, Ladislav Trattnig, Siegfried Krssak, Martin TI In Vivo Relaxation Behavior of Liver Compounds at 7 Tesla, Measured by Single-Voxel Proton MR Spectroscopy SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE magnetic resonance spectroscopy; STEAM; hepatic lipids; relaxation times; J-coupling; 7 T ID MAGNETIC-RESONANCE-SPECTROSCOPY; SKELETAL-MUSCLE METABOLITES; HEPATIC STEATOSIS; LIPID-COMPOSITION; BONE-MARROW; 3 T; FAT; QUANTIFICATION; SEQUENCES; H-1-NMR AB PurposeTo assess the proton T-1 and T-2 relaxation of in vivo hepatic water, choline and lipid resonances with possible J-coupling behavior of lipids in healthy volunteers at 7 Tesla (T). Materials and MethodsRelaxation measurements were conducted on corn oil phantoms and on the hepatic tissue of 11 healthy volunteers at 7 T using a surface coil and a STEAM sequence. T-1's were determined by monoexponential fitting, and T-2's by both monoexponential and enhanced-exponential fitting (empirically designed to consider J-coupling of lipid resonances). ResultsIn vivo T-1's at 7 T were estimated as follows: water (4.70 ppm), 1362 83 ms; methyl- (0.90 ppm), 1026 +/- 162 ms; methylene- (1.30 ppm), 514 +/- 25 ms; -olefinic- (2.02 ppm), 488 +/- 220 ms; -carboxyl- (2.24 ppm), 476 +/- 89 ms; diacyl- (2.77 ppm), 479 +/- 260 ms group of lipid chains; and choline compounds (3.22 ppm), 1084 +/- 52 ms. The T-2's calculated with enhanced fitting were as follows: water, 15 +/- 2 ms; methyl-, 34 +/- 10 ms; methylene-, 41 +/- 8 ms; -olefinic-, 44 +/- 19 ms; -carboxyl-, 39 +/- 15 ms; diacyl-, 44 +/- 5 ms group of lipid chains; and choline compounds, 32 +/- 9 ms. ConclusionAn accurate knowledge of in vivo relaxation and J-coupling behavior will significantly improve the quantification of an extended number of resolved liver metabolites at 7 T. J. Magn. Reson. Imaging 2014;40:1365-1374. (c) 2013 Wiley Periodicals, Inc. C1 [Gajdosik, Martin; Chmelik, Marek; Just-Kukurova, Ivica; Bogner, Wolfgang; Valkovic, Ladislav; Trattnig, Siegfried; Krssak, Martin] Med Univ Vienna, MR Ctr Excellence, Dept Biomed Imaging & Image Guided Therapy, A-1090 Vienna, Austria. [Just-Kukurova, Ivica] Slovak Tech Univ, Dept NMR & MS, Bratislava, Slovakia. [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, Dept Imaging Methods, Inst Measurement Sci, Bratislava, Slovakia. [Krssak, Martin] Med Univ Vienna, Div Endocrinol & Metab, Dept Internal Med 3, A-1090 Vienna, Austria. RP Krssak, M (reprint author), Med Univ Vienna, Div Endocrinol & Metab, Dept Internal Med 3, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. EM martin.krssak@meduniwien.ac.at OI Valkovic, Ladislav/0000-0003-2567-3642; Gajdosik, Martin/0000-0003-1570-2825; Bogner, Wolfgang/0000-0002-0130-3463 FU Vienna Spots of Excellence of the Vienna Science and Technology Fund (WWTF); Vienna Advanced Clinical Imaging Center (VIACLIC) [FA102A0017]; Oesterreichische Nationalbank [15363] FX Contract grant sponsor: Vienna Spots of Excellence of the Vienna Science and Technology Fund (WWTF); Contract grant sponsor: Vienna Advanced Clinical Imaging Center (VIACLIC); Contract grant number: FA102A0017; Contract grant sponsor: Supported by funds of the Oesterreichische Nationalbank (Anniversary Fund, project number: 15363). NR 44 TC 4 Z9 4 U1 1 U2 9 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 DEC PY 2014 VL 40 IS 6 BP 1365 EP 1374 DI 10.1002/jmri.24489 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AT2SQ UT WOS:000344786200013 PM 24222653 ER PT J AU Lewis, MS McMillan, GP Hutter, M Folmer, RL Wilmington, D Casiana, L Fitzpatrick, M Lilly, DJ Bourdette, D Overs, S Cameron, M Fausti, S AF Lewis, M. Samantha McMillan, Garnett P. Hutter, Michele Folmer, Robert L. Wilmington, Debra Casiana, Linda Fitzpatrick, Mary Lilly, David J. Bourdette, Dennis Overs, Shannon Cameron, Michelle Fausti, Stephen TI Does Interferon Beta-1a Impact Pure-Tone Hearing Sensitivity Among Individuals With Multiple Sclerosis? SO JOURNAL OF NEUROSCIENCE NURSING LA English DT Article DE adverse effects; disease attributes; hearing; hearing loss; interferon beta-1a; multiple sclerosis; toxicology ID CHRONIC HEPATITIS-C; RIBAVIRIN COMBINATION THERAPY; PEGYLATED INTERFERON/RIBAVIRIN; AURAL ATTENUATION; OTOTOXICITY; PATIENT; THRESHOLDS; ALPHA; PEGINTERFERON; DEAFNESS AB Background: Previous studies reported that particular types of interferon medications might contribute to hearing loss in some patients. The package insert included in the original Food and Drug Administration application for intramuscular interferon beta-1a (Avonex) stated that some patients in the treatment group reported decreased hearing sensitivity. Objective: The purpose of the present investigation was to assess if individuals with multiple sclerosis (MS) taking intramuscular interferon beta-1a have significantly poorer hearing thresholds than those not currently using any disease-modifying therapies. Methods: This was a secondary analysis of data collected as part of two larger studies evaluating auditory function in patients with MS. The goal of this analysis was to determine if users of interferon beta-1a do not have significantly worse hearing thresholds than nonusers of disease-modifying therapies, after adjusting for potential confounders. A linear mixed model was fit to the audiometric thresholds of our subjects. This model included interferon beta-1a use, MS disease subtype, gender, test frequency, age, disease duration (number of years), and the Expanded Disability Status Scale score. Results and Conclusions: With all subjects included, there is insufficient evidence to say that intramuscular interferon-beta 1a is not ototoxic (in relation to nonuse of a disease-modifying therapy) at all frequencies tested except 3000 and 6000 Hz. After removing two influential subjects, the results indicated that there is statistical support for no ototoxic effect of intramuscular interferon beta-1a at test frequencies from 250 to 6000 Hz. There is insufficient evidence, however, to rule out an ototoxic effect at 8000 Hz. Future studies should further evaluate the effect of interferon on auditory function in patients with MS. Neuroscience nurses should monitor their patients' hearing throughout the course of treatment. C1 [Lewis, M. Samantha; McMillan, Garnett P.; Hutter, Michele; Folmer, Robert L.; Wilmington, Debra; Casiana, Linda; Lilly, David J.; Fausti, Stephen] Portland VA Med Ctr, NCRAR, Portland, OR 97239 USA. [Lewis, M. Samantha] Oregon Hlth & Sci Univ, Dept Otolarynol Head Neck Surg, Portland, OR 97201 USA. [Folmer, Robert L.; Wilmington, Debra; Fausti, Stephen] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97201 USA. [Fitzpatrick, Mary; Overs, Shannon; Cameron, Michelle] Portland VA Med Ctr, Neurol Serv, Portland, OR USA. [Lilly, David J.] Univ Iowa, Dept Otolaryngol Head & Neck Surg, Iowa City, IA 52242 USA. [Bourdette, Dennis] Portland VA Med Ctr, Multiple Sclerosis Ctr Excellence West, Portland, OR USA. [Bourdette, Dennis; Overs, Shannon; Cameron, Michelle; Fausti, Stephen] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Overs, Shannon] Novant Hlth Neurol Specialists, Charlotte, NC USA. RP Lewis, MS (reprint author), Portland VA Med Ctr, NCRAR, Portland, OR 97239 USA. EM Michele.Lewis3@med.va.gov FU U.S. Department of Veterans Affairs (VA) Rehabilitation Research and Development (RR&D) Service Merit Review grants [B2568R, C4488R]; VA RR&D Career Development Awards [C3293H, C3758V, C7067W, E7244-W]; VA RR&D National Center for Rehabilitative Auditory Research [C9230C]; Biogen Idec FX This work was supported by U.S. Department of Veterans Affairs (VA) Rehabilitation Research and Development (RR&D) Service Merit Review grants (#B2568R, #C4488R), VA RR&D Career Development Awards to the 1st (M. S. L.) author (#C3293H, #C3758V, #C7067W) and the 11th (M. C.) author (#E7244-W), and the VA RR&D National Center for Rehabilitative Auditory Research (#C9230C). In addition, some of the members of the study team were recognized with the Biogen Idec award for best poster presentation at the 2008 meeting of the Consortium of Multiple Sclerosis Centers in Denver, CO, which resulted in travel funds for the first author to attend the 2009 meeting The 9th (D. B.) and 10th (S. O.) authors of this article, also, have received honoraria for speaking, consultant fees, and/or educational grants from Biogen Idec. The 7th (M. F.) author now works for Biogen Idec. NR 64 TC 0 Z9 0 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0888-0395 EI 1945-2810 J9 J NEUROSCI NURS JI J. Neurosci. Nurs. PD DEC PY 2014 VL 46 IS 6 BP 351 EP 360 DI 10.1097/JNN.0000000000000096 PG 10 WC Clinical Neurology; Nursing SC Neurosciences & Neurology; Nursing GA AT4XK UT WOS:000344945200010 PM 25365049 ER PT J AU Hage, FG AF Hage, Fadi G. TI Regadenoson for myocardial perfusion imaging: Is it safe? (vol 21, pg 871, 2014) SO JOURNAL OF NUCLEAR CARDIOLOGY LA English DT Correction C1 [Hage, Fadi G.] Univ Alabama Birmingham, Div Cardiovasc Dis, Dept Med, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Cardiol Sect, Birmingham, AL USA. RP Hage, FG (reprint author), Univ Alabama Birmingham, Div Cardiovasc Dis, Dept Med, Lyons Harrison Res Bldg 314,1900 Univ BLVD, Birmingham, AL 35294 USA. EM fadihage@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 1 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-3581 EI 1532-6551 J9 J NUCL CARDIOL JI J. Nucl. Cardiol. PD DEC PY 2014 VL 21 IS 6 BP 1266 EP 1266 DI 10.1007/s12350-014-9993-2 PG 1 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA AT2GG UT WOS:000344750700026 ER PT J AU Pan, E Goldberg, SI Chen, YL Giraud, C Hornick, JL Nielsen, GP Hornicek, FJ Raut, CP DeLaney, TF Baldini, EH AF Pan, Elizabeth Goldberg, Saveli I. Chen, Yen-Lin Giraud, Christine Hornick, Jason L. Nielsen, Gunnlaugur P. Hornicek, Francis J. Raut, Chandrajit P. DeLaney, Thomas F. Baldini, Elizabeth H. TI Role of Post-Operative Radiation Boost for Soft Tissue Sarcomas with Positive Margins Following Pre-Operative Radiation and Surgery SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE radiation therapy; post-operative boost; sarcoma; local control; positive margin; extremity ID LONG-TERM OUTCOMES; SURGICAL MARGINS; PROGNOSTIC-FACTORS; RANDOMIZED-TRIAL; LOCAL RECURRENCE; SPARING SURGERY; EXTREMITIES; THERAPY; RADIOTHERAPY; RESECTION AB Background and ObjectivesThe role of a radiation therapy (RT) boost for positive margins following pre-operative RT and surgery in extremity soft tissue sarcomas (STS) is unclear. We assessed the contribution of a boost to local control (LC), disease-free survival (DFS), and overall survival (OS). MethodsWe identified 67 patients treated from 1987 to 2011 with pre-operative RT and surgery with positive margin(s). Select patients received a boost delivered as peri-operative Iridium-192 brachytherapy (BRT), intra-operative electrons (IORT), or post-operative external beam RT (EBRT). ResultsTen patients received no RT boost, 10 received a BRT or IORT boost, and 47 received an EBRT boost. Five-year LC rates for no boost, BRT/IORT boost, and EBRT boost were 100%, 78%, and 71% (P=0.5). On multivariate analysis, there were no significant predictors for LC. Variables associated with improved DFS rates were single positive margin (P=0.007) and low tumor grade (P=0.03). Tumor size <5cm (P=0.003), low grade (P=0.001), and boost (P=0.02) were associated with longer survival. ConclusionsWe did not identify a LC advantage for an RT boost. Given the unidentified selection factors for delivery of boost and its potential toxicities, its role in this setting remains unproven. J. Surg. Oncol. 2014 110:817-822. (c) 2014 Wiley Periodicals, Inc. C1 [Pan, Elizabeth; Chen, Yen-Lin; Giraud, Christine; DeLaney, Thomas F.; Baldini, Elizabeth H.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Pan, Elizabeth; Goldberg, Saveli I.; Chen, Yen-Lin; Giraud, Christine; Nielsen, Gunnlaugur P.; Hornicek, Francis J.; DeLaney, Thomas F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pan, Elizabeth] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Goldberg, Saveli I.] Dept Biostat & Biomath, Boston, MA USA. [Hornick, Jason L.; Nielsen, Gunnlaugur P.] Dept Pathol, Boston, MA USA. [Hornick, Jason L.; Raut, Chandrajit P.; Baldini, Elizabeth H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Hornick, Jason L.; Raut, Chandrajit P.; Baldini, Elizabeth H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hornicek, Francis J.; Raut, Chandrajit P.] Dept Surg, Boston, MA USA. RP DeLaney, TF (reprint author), Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, 55 Fruit St, Boston, MA 02114 USA. EM tdelaney@partners.org NR 36 TC 5 Z9 6 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4790 EI 1096-9098 J9 J SURG ONCOL JI J. Surg. Oncol. PD DEC 1 PY 2014 VL 110 IS 7 BP 817 EP 822 DI 10.1002/jso.23741 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA AS9GW UT WOS:000344552200009 PM 25111884 ER PT J AU Hayden, R Tanrikut, C AF Hayden, Russell Tanrikut, Cigdem TI Manipulation of a Locally Expressed Renin-Angiotensin System in the Testis: Implications for Steroidogenesis SO JOURNAL OF UROLOGY LA English DT Editorial Material ID LEYDIG-CELLS; CONVERTING ENZYME; RAT TESTIS; MICE C1 [Hayden, Russell; Tanrikut, Cigdem] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA 02163 USA. RP Hayden, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA 02163 USA. NR 10 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 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD DEC PY 2014 VL 192 IS 6 BP 1599 EP 1600 DI 10.1016/j.juro.2014.09.022 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA AT9AF UT WOS:000345219300003 PM 25240221 ER PT J AU Sui, JH Deming, M Rockx, B Liddington, RC Zhu, QK Baric, RS Marasco, WA AF Sui, Jianhua Deming, Meagan Rockx, Barry Liddington, Robert C. Zhu, Quan Karen Baric, Ralph S. Marasco, Wayne A. TI Effects of Human Anti-Spike Protein Receptor Binding Domain Antibodies on Severe Acute Respiratory Syndrome Coronavirus Neutralization Escape and Fitness SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODY; ANGIOTENSIN-CONVERTING ENZYME-2; SARS-CORONAVIRUS; IN-VITRO; POTENT NEUTRALIZATION; STRUCTURAL BASIS; S2 DOMAIN; AGED MICE; B-CELLS; IDENTIFICATION AB The receptor binding domain (RBD) of the spike (S) glycoprotein of severe acute respiratory syndrome coronavirus (SARS-CoV) is a major target of protective immunity in vivo. Although a large number of neutralizing antibodies (nAbs) have been developed, it remains unclear if a single RBD-targeting nAb or two in combination can prevent neutralization escape and, if not, attenuate viral virulence in vivo. In this study, we used a large panel of human nAbs against an epitope that overlaps the interface between the RBD and its receptor, angiotensin-converting enzyme 2 (ACE2), to assess their cross-neutralization activities against a panel of human and zoonotic SARS-CoVs and neutralization escape mutants. We also investigated the neutralization escape profiles of these nAbs and evaluated their effects on receptor binding and virus fitness in vitro and in mice. We found that some nAbs had great potency and breadth in neutralizing multiple viral strains, including neutralization escape viruses derived from other nAbs; however, no single nAb or combination of two blocked neutralization escape. Interestingly, in mice the neutralization escape mutant viruses showed either attenuation (Urbani background) or increased virulence (GD03 background) consistent with the different binding affinities between their RBDs and the mouse ACE2. We conclude that using either single nAbs or dual nAb combinations to target a SARS-CoV RBD epitope that shows plasticity may have limitations for preventing neutralization escape during in vivo immunotherapy. However, RBD-directed nAbs may be useful for providing broad neutralization and prevention of escape variants when combined with other nAbs that target a second conserved epitope with less plasticity and more structural constraint. IMPORTANCE The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 has resulted in severe human respiratory disease with high death rates. Their zoonotic origins highlight the likelihood of reemergence or further evolution into novel human coronavirus pathogens. Broadly neutralizing antibodies (nAbs) that prevent infection of related viruses represent an important immunostrategy for combating coronavirus infections; however, for this strategy to succeed, it is essential to uncover nAb-mediated escape pathways and to pioneer strategies that prevent escape. Here, we used SARS-CoV as a research model and examined the escape pathways of broad nAbs that target the receptor binding domain (RBD) of the virus. We found that neither single nAbs nor two nAbs in combination blocked escape. Our results suggest that targeting conserved regions with less plasticity and more structural constraint rather than the SARS-CoV RBD-like region(s) should have broader utility for antibody-based immunotherapy. C1 [Sui, Jianhua; Zhu, Quan Karen; Marasco, Wayne A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med,Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Deming, Meagan; Rockx, Barry; Baric, Ralph S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Deming, Meagan; Rockx, Barry; Baric, Ralph S.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC USA. [Liddington, Robert C.] Stanford Burnham Med Res Inst, Infect & Inflammatory Dis Ctr, La Jolla, CA USA. RP Baric, RS (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med,Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. EM rbaric@email.unc.edu; wayne_marasco@dfci.harvard.edu OI Deming, Meagan/0000-0003-2574-0542; SUI, JIANHUA/0000-0002-1272-9662 FU NIH [U01-AI061318, R01AI085524] FX This work was supported by NIH U01-AI061318 and R01AI085524 to W.A.M. NR 53 TC 6 Z9 7 U1 2 U2 20 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD DEC PY 2014 VL 88 IS 23 BP 13769 EP 13780 DI 10.1128/JVI.02232-14 PG 12 WC Virology SC Virology GA AT3CI UT WOS:000344812800022 PM 25231316 ER PT J AU Sprinkhuizen, SM Ackerman, JL Song, YQ AF Sprinkhuizen, Sara M. Ackerman, Jerome L. Song, Yi-Qiao TI Influence of Bone Marrow Composition on Measurements of Trabecular Microstructure Using Decay Due to Diffusion in the Internal Field MRI: Simulations and Clinical Studies SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE trabecular bone; marrow; osteoporosis; stimulated echo; diffusion; Monte Carlo ID MAGNETIC-RESONANCE; IN-VIVO; CANCELLOUS BONE; OSTEOPOROSIS; AGE; SUSCEPTIBILITY; VOLUME; FAT; SEX; SPECTROSCOPY AB PurposeDecay due to diffusion in the internal field (DDIF) MRI allows for measurements of microstructures of porous materials at low spatial resolution and thus has potential for trabecular bone quality measurements. In trabecular bone, solid bone changes (osteoporosis) as well as changes in bone marrow composition occur. The influence of such changes on DDIF MRI was studied by simulations and in vivo measurements. MethodsMonte Carlo simulations of DDIF in various trabecular bone models were conducted. Changes in solid bone and marrow composition were simulated with numerical bone erosion and marrow susceptibility variations. Additionally, in vivo measurements were performed in the lumbar spine of healthy volunteers aged 23-62 years. ResultsSimulations and in vivo results showed that 1) DDIF decay times decrease with increasing marrow fat and 2) the marrow fat percentage needs to be incorporated in the DDIF analysis to discriminate between healthy and osteoporotic solid bone structures. ConclusionsBone marrow composition plays an important role in DDIF MRI: incorporation of marrow fat percentage into DDIF MRI allowed for differentiation of young and old age groups (in vivo experiments). DDIF MRI may develop into a means of assessing osteoporosis and disorders that affect marrow composition. Magn Reson Med 72:1499-1508, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Sprinkhuizen, Sara M.; Ackerman, Jerome L.; Song, Yi-Qiao] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Song, Yi-Qiao] Schlumberger Doll Res Ctr, Cambridge, MA USA. RP Sprinkhuizen, SM (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM sara@nmr.mgh.harvard.edu RI Ackerman, Jerome/E-2646-2015 OI Ackerman, Jerome/0000-0001-5176-7496 FU Schlumberger-Doll Research; Athinoula A. Martinos Center for Biomedical Imaging; Center for Functional Neuroimaging Technologies [P41EB015896] FX Grant sponsor: Schlumberger-Doll Research; Grant sponsor: The Athinoula A. Martinos Center for Biomedical Imaging; Grant sponsor: The Center for Functional Neuroimaging Technologies; Grant number: P41EB015896. NR 39 TC 1 Z9 1 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD DEC PY 2014 VL 72 IS 6 BP 1499 EP 1508 DI 10.1002/mrm.25061 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AT2XS UT WOS:000344798300002 PM 24382681 ER PT J AU Valkovic, L Bogner, W Gajdosik, M Povazan, M Kukurova, IJ Krssak, M Gruber, S Frollo, I Trattnig, S Chmelik, M AF Valkovic, Ladislav Bogner, Wolfgang Gajdosik, Martin Povazan, Michal Kukurova, Ivica Just Krssak, Martin Gruber, Stephan Frollo, Ivan Trattnig, Siegfried Chmelik, Marek TI One-Dimensional Image-Selected In Vivo Spectroscopy Localized Phosphorus Saturation Transfer at 7T SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE energy metabolism; P-31-MRS; saturation transfer; 7T ID MAGNETIC-RESONANCE-SPECTROSCOPY; HUMAN CALF MUSCLE; P-31 SPECTROSCOPY; HUMAN LIVER; 3 T; ABSOLUTE QUANTIFICATION; ATP SYNTHESIS; HUMAN BRAIN; METABOLITES; KINETICS AB PurposeTo evaluate the feasibility of a one-dimensional image-selected in vivo spectroscopy (1D-ISIS) saturation transfer (ST) sequence at 7T for localized in vivo measurements of energy metabolism in different tissues in clinically reasonable examination times. MethodsThe performance of a gradient offset independent adiabacity-based 1D-ISIS localization was tested on phantom and the localized ST sequence was compared with the nonlocalized version in vivo. We performed localized measurements of basal metabolism of human liver and different muscle groups of the calf. Localized ST experiments took 15-25 minutes. ResultsThe selectivity of the 1D-ISIS sequence was 81.63% and the outer volume suppression was 97.57%. The ST parameters acquired with the 1D-ISIS sequence and with the nonlocalized acquisition in the muscle were not statistically different. The forward rate constants for phosphocreatine (PCr)-adenosine triphosphate (ATP) and inorganic phosphate (Pi)-ATP exchange reactions were measured in the soleus (k(CK)=0.300.06 s(-1) and k(ATP)=0.11 +/- 0.02 s(-1), respectively) and in the medial gastrocnemius (k(CK)=0.27 +/- 0.06 s(-1) and k(ATP)=0.09 +/- 0.03s(-1), respectively) in 15 minutes per muscle group. The corresponding fluxes were F-CK=6.26 +/- 1.28 mol/g/s, F-ATP=0.22 +/- 0.05 mol/g/s and F-CK=6.29 +/- 1.66 mol/g/s, F-ATP=0.21 +/- 0.07 mol/g/s, for soleus and gastrocnemius, respectively. The hepatic ATP synthesis measurement was feasible in 24 minutes. ConclusionThe fast assessment of PCr-ATP and Pi-ATP exchange rates at 7T makes the 1D-ISIS ST sequence a promising tool for examining local resting-state metabolism in clinically acceptable measurement times. Magn Reson Med 72:1509-1515, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Valkovic, Ladislav; Bogner, Wolfgang; Gajdosik, Martin; Povazan, Michal; Kukurova, Ivica Just; Krssak, Martin; Gruber, Stephan; Trattnig, Siegfried; Chmelik, Marek] Med Univ Vienna, High Field MR Ctr, Dept Biomed Imaging & Image Guided Therapy, A-1090 Vienna, Austria. [Valkovic, Ladislav; Frollo, Ivan] Slovak Acad Sci, Dept Imaging Methods, Inst Measurement Sci, Bratislava, Slovakia. [Bogner, Wolfgang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Boston, MA USA. [Kukurova, Ivica Just] Slovak Univ Technol Bratislava, Fac Chem & Food Technol, Dept NMR & MS, Bratislava, Slovakia. [Krssak, Martin] Med Univ Vienna, Div Endocrinol & Metab, Dept Internal Med 3, Vienna, Austria. RP Trattnig, S (reprint author), Med Univ Vienna, High Field MR Ctr, Dept Biomed Imaging & Image Guided Therapy, Lazarettgasse 14, A-1090 Vienna, Austria. EM siegfried.trattnig@meduniwien.ac.at OI Povazan, Michal/0000-0002-5498-5162; Valkovic, Ladislav/0000-0003-2567-3642; Gajdosik, Martin/0000-0003-1570-2825; Bogner, Wolfgang/0000-0002-0130-3463 FU Vienna Spots of Excellence des Wiener Wissenschafts-und Technologie-Fonds [FA102A0017-Vienna Advanced Imaging Center]; OeNB Jubilaeumsfond [13629, 13834, 15455]; Slovak Grant Agency VEGA [2/0013/14]; Slovak Research and Development Agency [0513-10] FX Grant sponsor: Vienna Spots of Excellence des Wiener Wissenschafts-und Technologie-Fonds; Grant number: FA102A0017-Vienna Advanced Imaging Center (to S.T.); Grant sponsor: OeNB Jubilaeumsfond; Grant numbers: 13629 (to M.C.), 13834 (to W.B.), and 15455 (to L.V.); Grant sponsor: Slovak Grant Agency VEGA; Grant number: 2/0013/14 (to I.F.); Grant sponsor: Slovak Research and Development Agency; Grant number: 0513-10. NR 32 TC 6 Z9 6 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD DEC PY 2014 VL 72 IS 6 BP 1509 EP 1515 DI 10.1002/mrm.25058 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AT2XS UT WOS:000344798300003 PM 24470429 ER PT J AU Blum, K Oscar-Berman, M Demetrovics, Z Barh, D Gold, MS AF Blum, Kenneth Oscar-Berman, Marlene Demetrovics, Zsolt Barh, Debmalya Gold, Mark S. TI Genetic Addiction Risk Score (GARS): Molecular Neurogenetic Evidence for Predisposition to Reward Deficiency Syndrome (RDS) SO MOLECULAR NEUROBIOLOGY LA English DT Review DE Genetic Addiction Risk Score (GARS)(TM); Polymorphisms; brain reward circuitry; Reward Deficiency Syndrome (RDS); Neurogenetics ID DOPAMINE TRANSPORTER GENE; VENTRAL TEGMENTAL AREA; GENOME-WIDE ASSOCIATION; RECEPTOR KNOCKOUT MICE; PROMOTER MAOA-UVNTR; ALCOHOL DEPENDENCE; SEROTONIN TRANSPORTER; MONOAMINE-OXIDASE; A118G POLYMORPHISM; GABA(A) RECEPTOR AB We have published extensively on the neurogenetics of brain reward systems with reference to the genes related to dopaminergic function in particular. In 1996, we coined "Reward Deficiency Syndrome" (RDS), to portray behaviors found to have gene-based association with hypodopaminergic function. RDS as a useful concept has been embraced in many subsequent studies, to increase our understanding of Substance Use Disorder (SUD), addictions, and other obsessive, compulsive, and impulsive behaviors. Interestingly, albeit others, in one published study, we were able to describe lifetime RDS behaviors in a recovering addict (17 years sober) blindly by assessing resultant Genetic Addiction Risk Score (GARS (TM)) data only. We hypothesize that genetic testing at an early age may be an effective preventive strategy to reduce or eliminate pathological substance and behavioral seeking activity. Here, we consider a select number of genes, their polymorphisms, and associated risks for RDS whereby, utilizing GWAS, there is evidence for convergence to reward candidate genes. The evidence presented serves as a plausible brain-print providing relevant genetic information that will reinforce targeted therapies, to improve recovery and prevent relapse on an individualized basis. The primary driver of RDS is a hypodopaminergic trait (genes) as well as epigenetic states (methylation and deacetylation on chromatin structure). We now have entered a new era in addiction medicine that embraces the neuroscience of addiction and RDS as a pathological condition in brain reward circuitry that calls for appropriate evidence-based therapy and early genetic diagnosis and that requires further intensive investigation. C1 [Blum, Kenneth; Gold, Mark S.] Univ Florida, Dept Psychiat, Coll Med, Gainesville, FL 32611 USA. [Blum, Kenneth; Gold, Mark S.] Univ Florida, Coll Med, McKnight Brain Inst, Gainesville, FL USA. [Oscar-Berman, Marlene] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Oscar-Berman, Marlene] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Oscar-Berman, Marlene] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Oscar-Berman, Marlene] Boston VA Healthcare Syst, Boston, MA 02118 USA. [Blum, Kenneth] Natl Inst Holist Addict Studies, Dept Holist Med, North Miami Beach, FL USA. [Blum, Kenneth] Univ Vermont, Coll Med, Ctr Clin & Translat Sci, Human Integrated Serv Unit, Burlington, VT USA. [Blum, Kenneth] Domin Diagnost LLC, North Kingstown, RI USA. [Blum, Kenneth] Malibu Beach Recovery Ctr, Dept Addict Res & Therapy, Malibu Beach, CA USA. [Blum, Kenneth] PATH Fdn, Dept Clin Neurol, New York, NY USA. [Blum, Kenneth; Barh, Debmalya] Inst Integrat Omics & Appl Biotechnol, Purba Medinipur, W Bengal, India. [Blum, Kenneth] IGENE LLC, Austin, TX USA. [Demetrovics, Zsolt] Eotvos Lorand Univ, Inst Psychol, Dept Clin Psychol & Addict, Budapest, Hungary. RP Blum, K (reprint author), Univ Florida, Dept Psychiat, Coll Med, Gainesville, FL 32611 USA. EM drd2gene@gmail.com RI Barh, Debmalya/O-4246-2015 OI Barh, Debmalya/0000-0002-2557-7768 FU National Institutes of Health, NIAAA [RO1-AA07112, K05-AA00219]; Medical Research Service of the US Department of Veterans Affairs; Life Extension Foundation, Ft/Lauderdale, Florida FX The writing of this paper was supported in part by funds from the National Institutes of Health, NIAAA (RO1-AA07112 and K05-AA00219) and the Medical Research Service of the US Department of Veterans Affairs (MOB). The authors appreciate the editorial assistance of Margaret A. Madigan and Paula J. Edge. Kenneth Blum is the recipient of a grant to PATH FOUNDATION NY, by Life Extension Foundation, Ft/Lauderdale, Florida. NR 186 TC 6 Z9 7 U1 4 U2 32 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD DEC PY 2014 VL 50 IS 3 BP 765 EP 796 DI 10.1007/s12035-014-8726-5 PG 32 WC Neurosciences SC Neurosciences & Neurology GA AT3WU UT WOS:000344865700005 PM 24878765 ER PT J AU Ji, MH Dong, L Jia, M Liu, WX Zhang, MQ Ju, LS Yang, JJ Xie, ZC Yang, JJ AF Ji, MuHuo Dong, Lin Jia, Min Liu, WenXue Zhang, MingQiang Ju, LinSha Yang, JiaoJiao Xie, Zhongcong Yang, JianJun TI Epigenetic Enhancement of Brain-Derived Neurotrophic Factor Signaling Pathway Improves Cognitive Impairments Induced by Isoflurane Exposure in Aged Rats SO MOLECULAR NEUROBIOLOGY LA English DT Article DE Cognition; Histone acetylation; Brain-derived neurotrophic factor; Inflammation; Apoptosis ID MOUSE MODEL; SYNAPTIC PLASTICITY; ALZHEIMERS-DISEASE; GENERAL-ANESTHESIA; MEMORY IMPAIRMENT; DYSFUNCTION; ADULT; NEUROGENESIS; DESFLURANE; INHIBITORS AB Isoflurane-induced cognitive impairments are well documented in animal models; yet, the molecular mechanisms remain largely to be determined. In the present study, 22-month-old male Sprague-Dawley rats received 2 h of 1.5 % isoflurane or 100 % oxygen daily for 3 consecutive days. For the intervention study, the rats were intraperitoneally injected with 1.2 g/kg sodium butyrate 2 h before isoflurane exposure. Our data showed that repeated isoflurane exposure significantly decreased the freezing time to context and the freezing time to tone in the fear conditioning test, which was associated with upregulated histone deacetylase 2, reduced histone acetylation, and increased inflammation and apoptosis in the hippocampus, and impairments of brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) and the downstream signaling pathway phospho-calmodulin-dependent protein kinase and phospho-cAMP response element-binding protein. These results suggest that isoflurane-induced cognitive impairments are associated with the declines in chromatin histone acetylation and the resulting downregulation of BDNF-TrkB signaling pathway. Moreover, the cognitive impairments and the signaling deficits can be rescued by histone deacetylase inhibitor sodium butyrate. Therefore, epigenetic enhancement of BDNF-TrkB signaling may be a promising strategy for reversing isoflurane-induced cognitive impairments. C1 [Ji, MuHuo; Dong, Lin; Jia, Min; Liu, WenXue; Zhang, MingQiang; Ju, LinSha; Yang, JiaoJiao; Yang, JianJun] Nanjing Univ, Sch Med, Jinling Hosp, Dept Anesthesiol, Nanjing 210008, Jiangsu, Peoples R China. [Xie, Zhongcong] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Geriatr Anesthesia Res Unit, Charlestown, MA 02129 USA. [Xie, Zhongcong] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Yang, JJ (reprint author), Nanjing Univ, Sch Med, Jinling Hosp, Dept Anesthesiol, Nanjing 210008, Jiangsu, Peoples R China. EM yjyangjj@126.com FU National Natural Science Foundation of China [81271216, 81300946]; Natural Science Foundation of Jiangsu Province [BK2012778] FX The authors declare no conflict of interest. This work was supported by the National Natural Science Foundation of China (no. 81271216 and 81300946) and the Natural Science Foundation of Jiangsu Province (no. BK2012778). NR 33 TC 23 Z9 24 U1 2 U2 14 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 EI 1559-1182 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD DEC PY 2014 VL 50 IS 3 BP 937 EP 944 DI 10.1007/s12035-014-8659-z PG 8 WC Neurosciences SC Neurosciences & Neurology GA AT3WU UT WOS:000344865700017 PM 24553857 ER PT J AU O'Connor, KL Westover, MB Phillips, MT Iftimia, NA Buckley, DA Ogilvy, CS Shafi, MM Rosenthal, ES AF O'Connor, Kathryn L. Westover, M. Brandon Phillips, Michael T. Iftimia, Nicolae A. Buckley, Deidre A. Ogilvy, Christopher S. Shafi, Mouhsin M. Rosenthal, Eric S. TI High Risk for Seizures Following Subarachnoid Hemorrhage Regardless of Referral Bias SO NEUROCRITICAL CARE LA English DT Article DE Subarachnoid hemorrhage; Non-convulsive seizures; Continuous electroencephalography ID RUPTURED CEREBRAL ANEURYSMS; CRITICALLY-ILL; CONTINUOUS EEG; EPILEPSY; COILING AB To investigate the frequency, predictors, and clinical impact of electrographic seizures in patients with high clinical or radiologic grade non-traumatic subarachnoid hemorrhage (SAH), independent of referral bias. We compared rates of electrographic seizures and associated clinical variables and outcomes in patients with high clinical or radiologic grade non-traumatic SAH. Rates of electrographic seizure detection before and after institution of a guideline which made continuous EEG monitoring routine in this population were compared. Electrographic seizures occurred in 17.6 % of patients monitored expressly because of clinically suspected subclinical seizures. In unselected patients, seizures still occurred in 9.6 % of all cases, and in 8.6 % of cases in which there was no a priori suspicion of seizures. The first seizure detected occurred 5.4 (IQR 2.9-7.3) days after onset of subarachnoid hemorrhage with three of eight patients (37.5 %) having the first recorded seizure more than 48 h following EEG initiation, and 2/8 (25 %) at more than 72 h following EEG initiation. High clinical grade was associated with poor outcome at time of hospital discharge; electrographic seizures were not associated with poor outcome. Electrographic seizures occur at a relatively high rate in patients with non-traumatic SAH even after accounting for referral bias. The prolonged time to the first detected seizure in this cohort may reflect dynamic clinical features unique to the SAH population. C1 [O'Connor, Kathryn L.; Westover, M. Brandon; Iftimia, Nicolae A.; Shafi, Mouhsin M.; Rosenthal, Eric S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Phillips, Michael T.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Buckley, Deidre A.; Ogilvy, Christopher S.] Beth Israel Deaconess Med Ctr, Dept Neurosurg, Boston, MA 02215 USA. [Shafi, Mouhsin M.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. RP Rosenthal, ES (reprint author), Massachusetts Gen Hosp, Dept Neurol, Lunder 6 Neurosci ICU,55 Fruit St, Boston, MA 02114 USA. EM koconnor13@mgh.harvard.edu; mwestover@mgh.harvard.edu; MPHILLIPS8@partners.org; nickiftimia@gmail.com; dabuckle@bidmc.harvard.edu; cogilvy@bidmc.harvard.edu; mouhsin.shafi@gmail.com; erosenthal@partners.org OI Rosenthal, Eric/0000-0003-3900-356X; O'Connor, Kathryn/0000-0002-5494-2357 FU NINDS NIH HHS [K23 NS090900] NR 23 TC 5 Z9 5 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 EI 1556-0961 J9 NEUROCRIT CARE JI Neurocrit. Care PD DEC PY 2014 VL 21 IS 3 BP 476 EP 482 DI 10.1007/s12028-014-9974-y PG 7 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA AT2TY UT WOS:000344790100014 PM 24723663 ER PT J AU Minzenberg, MJ Yoon, JH Cheng, YA Carter, CS AF Minzenberg, Michael J. Yoon, Jong H. Cheng, Yaoan Carter, Cameron S. TI Modafinil Effects on Middle-Frequency Oscillatory Power During Rule Selection in Schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article ID INDEPENDENT COMPONENT ANALYSIS; INTERNEURON DIVERSITY SERIES; PREFRONTAL CORTEX; COGNITIVE CONTROL; WORKING-MEMORY; THETA OSCILLATIONS; LOCUS-COERULEUS; NETWORK OSCILLATIONS; BAND OSCILLATIONS; DOUBLE-BLIND AB Control-related cognitive processes such as rule selection are associated with cortical oscillations in the theta, alpha and, beta ranges, and modulated by catecholamine neurotransmission. Thus, a potential strategy for improving cognitive control deficits in schizophrenia would be to use pro-catecholamine pharmacological agents to augment these control-related oscillations. In a double-blind, placebo-controlled (within-subjects) study, we tested the effects of adjunctive single-dose modafinil 200 mg on rule-related 4-30 Hz oscillations in 23 stable schizophrenia patients, using EEG during cognitive control task performance. EEG data underwent time-frequency decomposition with Morlet wavelets to determine the power of 4-30 Hz oscillations. Modafinil (relative to placebo) enhanced oscillatory power associated with high-control rule selection in theta, alpha, and beta ranges, with modest effects during rule maintenance. Modafinil treatment in schizophrenia augments middle-frequency cortical oscillatory power associated with rule selection, and may subserve diverse subcomponent processes in proactive cognitive control. C1 [Minzenberg, Michael J.; Cheng, Yaoan] Univ Calif San Francisco, Dept Psychiat, San Francisco Sch Med, San Francisco, CA USA. [Minzenberg, Michael J.; Cheng, Yaoan] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Yoon, Jong H.] Stanford Univ, Sch Med, Dept Psychiat, Palo Alto, CA 94304 USA. [Yoon, Jong H.] Palo Alto Vet Affairs Med Ctr, Palo Alto, CA USA. [Carter, Cameron S.] Calif State Univ Sacramento, Davis Sch Med, Dept Psychiat, Sacramento, CA 95819 USA. [Carter, Cameron S.] Univ Calif Davis, Ctr Neurosci, Davis, CA 95616 USA. RP Minzenberg, MJ (reprint author), San Francisco VA Med Ctr, Outpatient Mental Hlth Serv, 116C,4150 Clement St, San Francisco, CA 94121 USA. EM Michael.minzenberg@ucsf.edu FU Clinical Scientist Development Award from the Doris Duke Charitable Foundation; Young Investigator award from NARSAD (Brain and Behavior Foundation); [5RO1 MH059883] FX This work was supported by a Clinical Scientist Development Award from the Doris Duke Charitable Foundation, and a Young Investigator award from NARSAD (Brain and Behavior Foundation), both to MJM, and 5RO1 MH059883 to CSC. The authors have no competing financial interests. NR 69 TC 2 Z9 2 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2014 VL 39 IS 13 BP 3018 EP 3026 DI 10.1038/npp.2014.155 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AT3KT UT WOS:000344834600010 PM 24964814 ER PT J AU Slade, EP Becker, KD AF Slade, Eric P. Becker, Kimberly D. TI Understanding Proximal-Distal Economic Projections of the Benefits of Childhood Preventive Interventions SO PREVENTION SCIENCE LA English DT Article DE Prevention; Proximal-distal modeling; Economic projection ID PERRY PRESCHOOL PROGRAM; COST-EFFECTIVENESS; FOLLOW-UP; SCHOOL; CRIME; METAANALYSIS; 1ST-GRADE; CHILDREN; VIOLENCE; HEALTH AB This paper discusses the steps and decisions involved in proximal-distal economic modeling, in which social, behavioral, and academic outcomes data for children may be used to inform projections of the economic consequences of interventions. Economic projections based on proximal-distal modeling techniques may be used in cost-benefit analyses when information is unavailable for certain long-term outcomes data in adulthood or to build entire cost-benefit analyses. Although examples of proximal-distal economic analyses of preventive interventions exist in policy reports prepared for governmental agencies, such analyses have rarely been completed in conjunction with research trials. The modeling decisions on which these prediction models are based are often opaque to policymakers and other end-users. This paper aims to illuminate some of the key steps and considerations involved in constructing proximal-distal prediction models and to provide examples and suggestions that may help guide future proximal-distal analyses. C1 [Slade, Eric P.] US Dept Vet Affairs, VA Capitol Healthcare Network VISN5 Mental Illnes, Educ & Clin Ctr, Baltimore, MD 21201 USA. [Slade, Eric P.; Becker, Kimberly D.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. RP Slade, EP (reprint author), US Dept Vet Affairs, VA Capitol Healthcare Network VISN5 Mental Illnes, Educ & Clin Ctr, 737 W Lombard St,Room 526, Baltimore, MD 21201 USA. EM eslade@psych.umaryland.edu FU NIMH NIH HHS [P30 MH086043] NR 44 TC 1 Z9 1 U1 3 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 EI 1573-6695 J9 PREV SCI JI Prev. Sci. PD DEC PY 2014 VL 15 IS 6 BP 807 EP 817 DI 10.1007/s11121-013-0445-z PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AT3AN UT WOS:000344806700004 PM 24337979 ER PT J AU Ford, JM AF Ford, Judith M. TI Decomposing P300 to identify its genetic basis SO PSYCHOPHYSIOLOGY LA English DT Article DE EEG; P300 amplitude; Genetic basis; SNPs ID SCHIZOPHRENIA; AMPLITUDE; ENDOPHENOTYPES; DISORDERS; RISK AB In this commentary, I explore reasons why it has been difficult to associate P300 amplitude with a gene or a single nucleotide polymorphism (SNP). I suggest we decompose P300 into the factors that contribute to it to get better traction on its genetic basis. Specifically, I note that we can improve the measurement of P300 to remove state-dependent contributions by including more than one measurement occasion; we can identify and extract the neural components contributing to P300 amplitude by estimating EEG power in specific bands of the P300; we can adjust P300 for single-trial variability; we can extract single-trial variability; and we can refine the tasks to isolate the separate psychological processes that P300 reflects. In the end, each of these factors that contribute to the conglomerate P300 may be a separate endophenotype mapping onto a separate SNP or gene. C1 [Ford, Judith M.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Ford, Judith M.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Ford, JM (reprint author), San Francisco VA Med Ctr, Psychiat Serv 116D, 4150 Clement St, San Francisco, CA 94121 USA. EM Judith.Ford@ucsf.edu NR 20 TC 2 Z9 2 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD DEC PY 2014 VL 51 IS 12 SI SI BP 1325 EP 1326 DI 10.1111/psyp.12353 PG 2 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA AT2SL UT WOS:000344785500014 PM 25387713 ER PT J AU Fujisawa, D Umezawa, S Basaki-Tange, A Fujimori, M Miyashita, M AF Fujisawa, Daisuke Umezawa, Shino Basaki-Tange, Ado Fujimori, Maiko Miyashita, Mitsunori TI Smoking status, service use and associated factors among Japanese cancer survivors-a web-based survey SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Cancer survivor; Smoking cessation; Risk factor; Health behavior; Exercise ID CELL LUNG-CANCER; QUALITY-OF-LIFE; PERCEIVED SOCIAL SUPPORT; HEALTH BEHAVIORS; NECK-CANCER; CIGARETTE-SMOKING; UNITED-STATES; RISK-FACTORS; CESSATION; DIAGNOSIS AB This study aims to investigate smoking status and its associated factors among Japanese cancer survivors. We stretched our focus on association with health-related behaviors other than smoking (alcohol intake, physical exercise, and social activity) and the smoking cessation strategies used by cancer survivors. An anonymous cross-sectional web-based survey was conducted, enrolling survivors of various types of cancer up to 10 years after diagnosis. Smoking status, socioeconomic status, health-related behaviors other than smoking, and smoking cessation resource that the participants used were evaluated. Factors associated with continuous smoking after cancer diagnosis were explored using multivariate analysis. Among 168 participants who were smoking at the time of cancer diagnosis, 96 participants (57.1 %) continued smoking. Sixty-seven survivors (69.8 %) were willing to reduce or quit smoking, however, only 39 survivors (40.6 %) were provided with counseling or intervention on smoking cessation. Male gender, shorter time after cancer diagnosis, and lack of regular physical exercise associated with continuous smoking. Higher level of fear of cancer recurrence had trend-level significance of association with smoking cessation. Substantial proportions of Japanese cancer survivors continue smoking after diagnosis of cancer. The majority of them are not provided with relevant information or support, despite their willingness of reducing or quitting smoking. Smoking cessation is associated with other health behaviors (i.e., physical exercise). This suggests considerable missed opportunities for health-care providers to provide cancer survivors with counseling and evidence-based interventions. Promotion of professional support on smoking cessation and education to encourage healthy behaviors are needed. C1 [Fujisawa, Daisuke; Umezawa, Shino; Basaki-Tange, Ado; Fujimori, Maiko] Natl Canc Ctr East, Psychooncol Div, Kashiwa, Chiba, Japan. [Fujisawa, Daisuke] Massachusetts Gen Hosp, Ctr Psychiat Oncol & Behav Sci, Boston, MA 02114 USA. [Fujisawa, Daisuke] Keio Univ, Sch Med, Dept Neuropsychiat, Tokyo, Japan. [Umezawa, Shino] Tokyo Med & Dent Univ, Sect Liaison Psychiat & Palliat Med, Div Comprehens Patient Care, Tokyo, Japan. [Fujimori, Maiko] Natl Ctr Neurol & Psychiat, Tokyo, Japan. [Miyashita, Mitsunori] Tohoku Univ, Grad Sch Med, Div Palliat Nursing, Sendai, Miyagi 980, Japan. RP Fujisawa, D (reprint author), Keio Univ, Sch Med, Dept Neuropsychiat, Tokyo, Japan. EM dai_fujisawa@yahoo.co.jp FU Japanese Ministry of Health Labor and Welfare FX This study was fully supported by a Grant-in-Aid from Japanese Ministry of Health Labor and Welfare. The authors express gratitude to Professors Yosuke Uchitomi and Masatoshi Inagaki (Okayama University) and Ms. Junko Ueda-Nouno (National Cancer Center East) for their valuable inputs. NR 51 TC 1 Z9 1 U1 2 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD DEC PY 2014 VL 22 IS 12 BP 3125 EP 3134 DI 10.1007/s00520-014-2284-2 PG 10 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA AT0SB UT WOS:000344644100003 PM 24848577 ER PT J AU Koole, O Tsui, S Wabwire-Mangen, F Kwesigabo, G Menten, J Mulenga, M Auld, A Agolory, S Mukadi, YD Colebunders, R Bangsberg, DR van Praag, E Torpey, K Williams, S Kaplan, J Zee, A Denison, J AF Koole, Olivier Tsui, Sharon Wabwire-Mangen, Fred Kwesigabo, Gideon Menten, Joris Mulenga, Modest Auld, Andrew Agolory, Simon Mukadi, Ya Diul Colebunders, Robert Bangsberg, David R. van Praag, Eric Torpey, Kwasi Williams, Seymour Kaplan, Jonathan Zee, Aaron Denison, Julie TI Retention and risk factors for attrition among adults in antiretroviral treatment programmes in Tanzania, Uganda and Zambia SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Article DE ART; HIV; retention; sub-Saharan Africa; VIH; ART; retention; Afrique subsaharienne; VIH; TAR; retencion; africa sub-Sahariana ID SUB-SAHARAN AFRICA; FOLLOW-UP; THERAPY PROGRAMS; RURAL DISTRICT; HIV-INFECTION; SOUTH-AFRICA; 1ST YEAR; OUTCOMES; MORTALITY; SURVIVAL AB ObjectivesWe assessed retention and predictors of attrition (recorded death or loss to follow-up) in antiretroviral treatment (ART) clinics in Tanzania, Uganda and Zambia. MethodsWe conducted a retrospective cohort study among adults (18years) starting ART during 2003-2010. We purposefully selected six health facilities per country and randomly selected 250 patients from each facility. Patients who visited clinics at least once during the 90days before data abstraction were defined as retained. Data on individual and programme level risk factors for attrition were obtained through chart review and clinic manager interviews. Kaplan-Meier curves for retention across sites were created. Predictors of attrition were assessed using a multivariable Cox-proportional hazards model, adjusted for site-level clustering. ResultsFrom 17 facilities, 4147 patients were included. Retention ranged from 52.0% to 96.2% at 1year to 25.8%-90.4% at 4years. Multivariable analysis of ART initiation characteristics found the following independent risk factors for attrition: younger age [adjusted hazard ratio (aHR) and 95% confidence interval (95%CI)=1.30 (1.14-1.47)], WHO stage 4 ([aHR (95% CI): 1.56 (1.29-1.88)], >10% bodyweight loss [aHR (95%CI)=1.17 (1.00-1.38)], poor functional status [ambulatory aHR (95%CI)=1.29 (1.09-1.54); bedridden aHR1.54 (1.15-2.07)], and increasing years of clinic operation prior to ART initiation in government facilities [aHR (95%CI)=1.17 (1.10-1.23)]. Patients with higher CD4 cell count were less likely to experience attrition [aHR (95%CI)=0.88 (0.78-1.00)] for every log (tenfold) increase. Sites offering community ART dispensing [aHR (95%CI)=0.55 (0.30-1.01) for women; 0.40 (0.21-0.75) for men] had significantly less attrition. ConclusionsPatient retention to an individual programme worsened over time especially among males, younger persons and those with poor clinical indicators. Community ART drug dispensing programmes could improve retention. ObjectifsNous avons evalue la retention et les predicteurs de l'attrition (deces ou pertes au suivi enregistres) dans le traitement antiretroviral (ART) dans des cliniques en Tanzanie, en Ouganda et en Zambie. MethodesNous avons mene une etude de cohorte retrospective chez les adultes (18 ans) ayant debute l'ART au cours de 2003-2010. Nous avons deliberement choisi six etablissements de sante par pays et avons choisi au hasard 250 patients dans chaque etablissement. Les patients qui ont visite les cliniques au moins une fois au cours des 90 jours avant l'extraction des donnees ont ete definis comme retenus. Les donnees sur les facteurs de risque individuels et a l'echelle du programme pour l'attrition ont ete obtenues par l'examen des dossiers et des entrevues avec les directeur des cliniques. Les courbes de Kaplan-Meier pour la retention a travers les sites ont ete creees. Les predicteurs de l'attrition ont ete evalues a l'aide d'un modele multivarie des risques proportionnels de Cox, corriges par le regroupement au niveau du site. ResultatsDe 17 etablissements, 4147 patients ont ete inclus. La retention variait de 52,0% a 96,2% a un an et de 25,8% a 90,4% a 4 ans. L'analyse multivariee des caracteristiques a l'initiation de l'ART a trouve les facteurs independants de risque pour l'attrition suivants: le plus jeune age [Hazard Ratio ajuste (aHR) et intervalle de confiance a 95% (IC 95%)=1,30 (1,14 a 1,47)], le stade 4 de l'OMS ([aHR (IC 95%): 1,56 (1,29 a 1,88)], > 10% de perte de poids corporel [aHR (IC 95%)=1,17 (1,00 a 1,38)], un mauvais etat fonctionnel [aHR ambulatoire=1,29 (1,09-1,54); aHR alite=1,54 (01,15 a 02,07)] et de plus en plus d'annees d'operations en clinique avant le debut de l'ART dans les etablissements publics [aHR(IC 95%)=1,17 (1,10 a 1,23)]. Les patients avec un taux plus eleve de cellules CD4 etaient moins susceptibles a l'attrition [aHR (IC 95%) = 0,88 (0,78 a 1,00)] pour chaque augmentation logarithmique. Les sites offrant la distribution communautaire de l'ART [aHR (IC 95%)=0,55 (0,30 a 1,01) pour les femmes; =0,40 (0,21 a 0,75) pour les hommes] avaient significativement moins d'attrition. ConclusionsLa retention des patients dans un programme individuel empirait au fil du temps surtout chez les hommes, les personnes plus jeunes et ceux avec de mauvais indicateurs cliniques. Les programmes de distribution communautaire de l'ART pourraient ameliorer la retention. ObjetivosHemos evaluado la retencion y los vaticinadores de abandono (muerte registrada o perdida durante el seguimiento) en centros de tratamiento antirretroviral (TAR) en Tanzania, Uganda y Zambia. MetodosHemos realizado un estudio retrospectivo de cohortes con adultos (18 anos) en TAR durante el 2003-2010. Seleccionamos seis centros sanitarios por pais, y de forma aleatoria a 250 pacientes de cada centro. Los pacientes que visitaron los centros al menos una vez durante los 90 dias anteriores a la fecha de obtencion de los datos se definieron como retenidos. Se obtuvieron datos sobre los factores de riesgo de abandono de los individuos y el nivel del programa mediante la revision de graficos y entrevistas con el gestor del centro. Se realizaron curvas de Kaplan-Meier para la retencion en los distintos centros. Los vaticinadores de abandono se evaluaron utilizando un modelo de riesgos proporcionales de Cox, ajustado para agrupacion a nivel de centros. ResultadosSe incluyeron 4147 pacientes de 17 centros. La retencion estaba entre 52.0%-96.2% al ano y 25.8%-90.4% a los 4 anos. En un analisis multivariante de las caracteristicas presentes en el momento de iniciar TAR, se encontraron los siguientes factores de riesgo de abandono independientes: ser mas joven [razon de riesgo ajustada (RRa) and IC 95=1.30 (1.14-1.47)], estadio 4 de la OMS ([RRa(IC 95%): 1.56 (1.29-1.88)], > 10% perdida de peso corporal [RRa (IC 95%)=1.17 (1.00-1.38)], un estatus funcional pobre [RRa ambulatorio (IC 95%)=1.29 (1.09-1.54); estar en cama RRa 1.54 (1.15-2.07) ], y un mayor numero de anos en clinicas privadas antes de comenzar TAR en un centro gubernamental [RRa (IC 95%)=1.17 (1.10-1.23)]. Los pacientes con un mayor conteo de CD4 tenian una menor probabilidad de experimentar abandono [RRa (IC 95%)=0.88 (0.78-1.00)] para un aumento logaritmico (x10). Los centros que ofrecian dispensarios comunitarios de TAR [aHR (IC95%)=0.55 (0.30-1.01) para mujeres; 0.40 (0.21-0.75) para hombres] tenian significativamente menos abandono. ConclusionesLa retencion de pacientes en un programa individual empeoro a lo largo del tiempo, especialmente entre los hombres, personas jovenes y aquellos con indicadores clinicos pobres. Los programas comunitarios de dispensacion de TAR podrian mejorar la retencion. C1 [Koole, Olivier] London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London WC1E 7HT, England. [Koole, Olivier; Menten, Joris; Colebunders, Robert] Inst Trop Med, Dept Clin Sci, B-2000 Antwerp, Belgium. [Tsui, Sharon; Mukadi, Ya Diul; van Praag, Eric; Torpey, Kwasi; Denison, Julie] FHI 360, Durham, NC USA. [Tsui, Sharon; Denison, Julie] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Wabwire-Mangen, Fred] Makerere Univ, Infect Dis Inst, Coll Hlth Sci, Kampala, Uganda. [Kwesigabo, Gideon] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. [Mulenga, Modest] Trop Dis Res Ctr, Ndola, Zambia. [Auld, Andrew; Agolory, Simon; Williams, Seymour; Kaplan, Jonathan; Zee, Aaron] US Ctr Dis Control & Prevent, Div Global AIDS, Atlanta, GA USA. [Colebunders, Robert] Univ Antwerp, B-2020 Antwerp, Belgium. [Bangsberg, David R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Boston, MA USA. RP Koole, O (reprint author), London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, Keppel St, London WC1E 7HT, England. EM olivier.koole@lshtm.ac.uk OI Koole, Olivier/0000-0002-1122-5382; Auld, Andrew/0000-0001-5089-9163 FU PEPFAR through CDC; PEPFAR through HRSA FX We wish to acknowledge the study participants and participating clinics for their critical role in this study. This research was been supported by PEPFAR through CDC and HRSA. The views, opinions and content of this publication are those of the authors and do not necessarily reflect the views, opinions or policies of the CDC, HRSA or any other federal agency or office. This paper was presented in part at the XIX International AIDS Conference 2012, 22-27 July, Washington DC, USA. NR 33 TC 17 Z9 17 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1360-2276 EI 1365-3156 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD DEC PY 2014 VL 19 IS 12 BP 1397 EP 1410 DI 10.1111/tmi.12386 PG 14 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA AT2TO UT WOS:000344789200002 PM 25227621 ER PT J AU Pai, SY Cowan, MJ AF Pai, Sung-Yun Cowan, Morton J. TI Stem cell transplantation for primary immunodeficiency diseases: the North American experience SO CURRENT OPINION IN ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Review DE chronic granulomatous disease; hematopoietic stem cell transplantation; immune reconstitution; severe combined immunodeficiency; Wiskott-Aldrich syndrome ID WISKOTT-ALDRICH-SYNDROME; CHRONIC GRANULOMATOUS-DISEASE; BONE-MARROW-TRANSPLANTATION; SPEAKING NATIVE-AMERICANS; IMMUNE-DEFICIENCY; EUROPEAN EXPERIENCE; EXCELLENT SURVIVAL; SOYBEAN AGGLUTININ; UNRELATED DONOR; RECONSTITUTION AB Purpose of reviewThis review describes recent studies on outcomes after allogeneic hematopoietic cell transplantation for primary immunodeficiency in North America, including severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome and chronic granulomatous disease.Recent findingsUsing uniform diagnostic criteria, the Primary Immune Deficiency Treatment Consortium described the baseline characteristics of newly diagnosed infants with SCID in North America. Analysis of outcomes of hematopoietic cell transplantation for SCID in North America from 2000 to 2009 showed that young infants, and older infants without active infection, had excellent survival irrespective of type of donor or transplant approach with regard to conditioning. Although pretransplant conditioning with chemotherapy had a clear and strong negative impact on survival in infants with active infection at the time of transplant, among survivors, conditioning was associated with improved immune reconstitution. However, the potential late effects of conditioning in these infants remain to be characterized. Advances in transplant outcomes for Wiskott-Aldrich syndrome and chronic granulomatous disease support the strategy of early transplantation before the onset of severe complications; additional multicenter studies are needed to fully define optimal approaches.SummaryThe formation of the Primary Immune Deficiency Treatment Consortium, a multiinstitutional North American consortium, has contributed to our understanding of outcomes after transplant for primary immunodeficiency. C1 [Pai, Sung-Yun] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Pai, Sung-Yun] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Pai, Sung-Yun] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Cowan, Morton J.] Univ Calif San Francisco, Benioff Childrens Hosp, Div Pediat Allergy Immunol & Blood & Marrow Trans, San Francisco, CA 94143 USA. RP Pai, SY (reprint author), Boston Childrens Hosp, Div Hematol Oncol, 1 Blackfan Circle, Boston, MA 02115 USA. EM sung-yun.pai@childrens.harvard.edu FU NIH NIAID; NIH Office of Rare Diseases Research (ORDR) [U54 AI082973, R13 AI094943]; Boston Children's Hospital Translational Research Program (Translational Investigator Service Award) FX This work was in part supported by grants from NIH NIAID and the NIH Office of Rare Diseases Research (ORDR) (U54 AI082973 and R13 AI094943) and from Boston Children's Hospital Translational Research Program (Translational Investigator Service Award to S.-Y.P.). NR 45 TC 6 Z9 6 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-4050 EI 1473-6322 J9 CURR OPIN ALLERGY CL JI Curr. Opin. Allergy Clin. Immunol. PD DEC PY 2014 VL 14 IS 6 BP 521 EP 526 DI 10.1097/ACI.0000000000000115 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA AS9DS UT WOS:000344544000005 PM 25259542 ER PT J AU Persson, L Witt, RM Galligan, M Greer, PL Eisner, A Pazyra-Murphy, MF Datta, SR Segal, RA AF Persson, Laura Witt, Rochelle M. Galligan, Meghan Greer, Paul L. Eisner, Adriana Pazyra-Murphy, Maria F. Datta, Sandeep R. Segal, Rosalind A. TI Shh-Proteoglycan Interactions Regulate Maturation of Olfactory Glomerular Circuitry SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Article DE Shh; olfactory bulb; calbindin; proteoglycan; glomeruli; axon pruning ID ADULT SUBVENTRICULAR ZONE; SONIC-HEDGEHOG; INTERNEURON DIVERSITY; RECEPTOR NEURONS; TRANSGENIC MICE; BULB OUTPUT; SYSTEM; NEUROGENESIS; PROJECTIONS; SWITCH AB The olfactory system relies on precise circuitry connecting olfactory sensory neurons (OSNs) and appropriate relay and processing neurons of the olfactory bulb (OB). In mammals, the exact correspondence between specific olfactory receptor types and individual glomeruli enables a spatially precise map of glomerular activation that corresponds to distinct odors. However, the mechanisms that govern the establishment and maintenance of the glomerular circuitry are largely unknown. Here we show that high levels of Sonic Hedgehog (Shh) signaling at multiple sites enable refinement and maintenance of olfactory glomerular circuitry. Mice expressing a mutant version of Shh (Shh(Ala/Ala)), with impaired binding to proteoglycan co-receptors, exhibit disproportionately small olfactory bulbs containing fewer glomeruli. Notably, in mutant animals the correspondence between individual glomeruli and specific olfactory receptors is lost, as olfactory sensory neurons expressing different olfactory receptors converge on the same glomeruli. These deficits arise at late stages in post-natal development and continue into adulthood, indicating impaired pruning of erroneous connections within the olfactory bulb. In addition, mature Shh(Ala/Ala) mice exhibit decreased proliferation in the subventricular zone (SVZ), with particular reduction in neurogenesis of calbindin-expressing periglomerular cells. Thus, Shh interactions with proteoglycan co-receptors function at multiple locations to regulate neurogenesis and precise olfactory connectivity, thereby promoting functional neuronal circuitry. (c) 2014 Wiley Periodicals, Inc. Develop Neurobiol 74: 1255-1267, 2014 C1 [Persson, Laura; Witt, Rochelle M.; Galligan, Meghan; Eisner, Adriana; Pazyra-Murphy, Maria F.; Segal, Rosalind A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Persson, Laura; Witt, Rochelle M.; Galligan, Meghan; Greer, Paul L.; Eisner, Adriana; Pazyra-Murphy, Maria F.; Datta, Sandeep R.; Segal, Rosalind A.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. RP Segal, RA (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM Rosalind_segal@dfci.harvard.edu FU Emerald Foundation, Inc.; NIH Director's Pioneer Award [DP1 OD000839, T32CA009361]; NIDCD [RO1DC011558]; Nancy Lurie Marks Foundation; Lefler Center FX Contract grant sponsor: The Emerald Foundation, Inc.; Contract grant sponsor: NIH Director's Pioneer Award; contract grant numbers: DP1 OD000839 (to R.A.S.), T32CA009361 (to A.E.).; Contract grant sponsor: NIDCD; contract grant number: RO1DC011558.; Contract grant sponsor: Nancy Lurie Marks Foundation (to P.L.G.) and Lefler Center. NR 34 TC 2 Z9 2 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1932-8451 EI 1932-846X J9 DEV NEUROBIOL JI Dev. Neurobiol. PD DEC PY 2014 VL 74 IS 12 BP 1255 EP 1267 DI 10.1002/dneu.22202 PG 13 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA AS5QO UT WOS:000344325100008 PM 24913191 ER PT J AU Brodowska, K Theodoropoulou, S Horste, MMZ Paschalis, EI Takeuchi, K Scott, G Ramsey, DJ Kiernan, E Hoang, M Cichy, J Miller, JW Gragoudas, ES Vavvas, DG AF Brodowska, Katarzyna Theodoropoulou, Sofia Hoerste, Melissa Meyer Zu Paschalis, Eleftherios I. Takeuchi, Kimio Scott, Gordon Ramsey, David J. Kiernan, Elizabeth Hoang, Mien Cichy, Joanna Miller, Joan W. Gragoudas, Evangelos S. Vavvas, Demetrios G. TI Effects of metformin on retinoblastoma growth in vitro and in vivo SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE toxicity; autophagy; proliferation; apoptosis; cyclin ID ACTIVATED PROTEIN-KINASE; BREAST-CANCER CELLS; INTRAARTERIAL CHEMOTHERAPY; PANCREATIC-CANCER; DECREASED RISK; OVARIAN-CANCER; LUNG-CANCER; P38 MAPK; AUTOPHAGY; INHIBITION AB Recent studies suggest that the anti-diabetic drug metformin may reduce the risk of cancer and have anti-proliferative effects for some but not all cancers. In this study, we examined the effects of metformin on human retinoblastoma cell proliferation in vitro and in vivo. Two different human retinoblastoma cell lines (Y79, WERI) were treated with metformin in vitro and xenografts of Y79 cells were established in nu/nu immune-deficient mice and used to assess the effects of pharmacological levels of metformin in vivo. Metformin inhibited proliferation of the retinoblastoma cells in vitro. Similar to other studies, high concentrations of metformin (mM) blocked the cell cycle in GO-G1, indicated by a strong decrease of G1 cyclins, especially cyclin D, cyclin-dependent kinases (4 and 6), and flow cytometry assessment of the cell cycle. This was associated with activation of AMPK, inhibition of the mTOR pathways and autophagy marker LC3B. However, metformin failed to suppress growth of xenografted tumors of Y79 human retinoblastoma cells in nu/nu mice, even when treated with a maximally tolerated dose level achieved in human patients. In conclusion, supra-pharmacological levels (mM) of metformin, well above those tolerated in vivo, inhibited the proliferation of retinoblastoma cells in vitro. However, physiological levels of metformin, such as seen in the clinical setting, did not affect the growth of retinoblastoma cells in vitro or in vivo. This suggests that the potential beneficial effects of metformin seen in epidemiological studies may be limited to specific tumor types or be related to indirect effects/mechanisms not observed under acute laboratory conditions. C1 [Brodowska, Katarzyna; Theodoropoulou, Sofia; Hoerste, Melissa Meyer Zu; Paschalis, Eleftherios I.; Takeuchi, Kimio; Scott, Gordon; Ramsey, David J.; Kiernan, Elizabeth; Hoang, Mien; Miller, Joan W.; Gragoudas, Evangelos S.; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Angiogenesis Lab,Retina Serv,Dept Ophthalmol, Boston, MA 02114 USA. [Cichy, Joanna] Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Immunol, Krakow, Poland. RP Vavvas, DG (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Angiogenesis Lab,Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM vavvas@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 FU National Eye Institute [EY014104]; Research to Prevent Blindness Foundation (RPB); RPB; Massachusetts Lions Eye Research Fund FX This study was supported by National Eye Institute grant EY014104 (MEEI Core Grant), an unrestricted grant to the institution by the Research to Prevent Blindness Foundation (RPB), a Physician Scientist Award by RPB to D.G.V. and by the Massachusetts Lions Eye Research Fund. NR 80 TC 6 Z9 7 U1 1 U2 12 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 EI 1791-2423 J9 INT J ONCOL JI Int. J. Oncol. PD DEC PY 2014 VL 45 IS 6 BP 2311 EP 2324 DI 10.3892/ijo.2014.2650 PG 14 WC Oncology SC Oncology GA AS3TJ UT WOS:000344200700015 PM 25215935 ER PT J AU Sridhar, BV Doyle, NR Randolph, MA Anseth, KS AF Sridhar, Balaji V. Doyle, Nicholas R. Randolph, Mark A. Anseth, Kristi S. TI Covalently tethered TGF-beta 1 with encapsulated chondrocytes in a PEG hydrogel system enhances extracellular matrix production SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A LA English DT Article DE cartilage tissue engineering; chondrocytes; protein conjugation; hydrogels; transforming growth factor-1 ID POLY(ETHYLENE GLYCOL) HYDROGELS; TISSUE-ENGINEERED CARTILAGE; GROWTH-FACTOR; ARTICULAR-CARTILAGE; DELIVERY; REPAIR; REGENERATION; SCAFFOLD; STRATEGIES; CULTURE AB Healing articular cartilage defects remains a significant clinical challenge because of its limited capacity for self-repair. While delivery of autologous chondrocytes to cartilage defects has received growing interest, combining cell-based therapies with growth factor delivery that can locally signal cells and promote their function is often advantageous. We have previously shown that PEG thiol-ene hydrogels permit covalent attachment of growth factors. However, it is not well known if embedded chondrocytes respond to tethered signals over a long period. Here, chondrocytes were encapsulated in PEG hydrogels functionalized with transforming growth factor-beta 1 (TGF-1) with the goal of increasing proliferation and matrix production. Tethered TGF-1 was found to be distributed homogenously throughout the gel, and its bioactivity was confirmed with a TGF-1 responsive reporter cell line. Relative to solubly delivered TGF-1, chondrocytes presented with immobilized TGF-1 showed significantly increased DNA content, and GAG and collagen production over 28 days, while maintaining markers of articular cartilage. These results indicate the potential of thiol-ene chemistry to covalently conjugate TGF-1 to PEG to locally influence chondrocyte function over 4 weeks. Scaffolds with other or multiple tethered growth factors may prove broadly useful in the design of chondrocyte delivery vehicles for cartilage tissue engineering applications. (c) 2014 The Authors. Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc.: 102A: 4464-4472, 2014. C1 [Sridhar, Balaji V.; Doyle, Nicholas R.; Anseth, Kristi S.] Univ Colorado, Dept Chem & Biol Engn, Boulder, CO 80309 USA. [Sridhar, Balaji V.; Doyle, Nicholas R.; Anseth, Kristi S.] Univ Colorado, Biofrontiers Inst, Boulder, CO 80309 USA. [Randolph, Mark A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Lab Musculoskeletal Tissue En, Boston, MA USA. [Randolph, Mark A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast Surg,Plast Surg Res Lab, Boston, MA USA. [Anseth, Kristi S.] Univ Colorado, Howard Hughes Med Inst, Boulder, CO 80309 USA. RP Sridhar, BV (reprint author), Univ Colorado, Dept Chem & Biol Engn, Boulder, CO 80309 USA. EM balaji.sridhar@colorado.edu RI Randolph, Mark/A-4406-2009 FU Howard Hughes Medical Institute and Department of Defense [W81XWH-10-1-0791]; US Army Medical Research Acquisition Activity FX Contract grant sponsor: Howard Hughes Medical Institute and Department of Defense; contract grant number: W81XWH-10-1-0791; Contract grant sponsor: The US Army Medical Research Acquisition Activity NR 45 TC 12 Z9 12 U1 4 U2 54 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1549-3296 EI 1552-4965 J9 J BIOMED MATER RES A JI J. Biomed. Mater. Res. Part A PD DEC PY 2014 VL 102 IS 12 BP 4464 EP 4472 DI 10.1002/jbm.a.35115 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA AS6OL UT WOS:000344382500028 PM 24616326 ER PT J AU Underhill, ML Sheldon, LK Halpenny, B Berry, DL AF Underhill, Meghan L. Sheldon, Lisa Kennedy Halpenny, Barbara Berry, Donna L. TI Communication About Symptoms and Quality of Life Issues in Patients With Cancer: Provider Perceptions SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Cancer; Symptom and quality of life issues; Patient and provider communication ID MANAGEMENT; HEALTH AB This study used qualitative data collection and analysis methods to describe provider perceptions of addressing patient-initiated communication about common or sensitive symptom and quality of life issues (SQIs) in oncology. Eligible participants were health care providers who had participated in a larger trial testing a patient-centered technology to assess cancer SQIs and support self-care. Audio-recorded vignettes were simulated based on recorded clinic visits from the larger trial and presented during semi-structured cognitive interviews with each participant. Transcripts of the interviews were content analyzed. Twelve providers participated. Participants' responses included four themes: the institutional and clinical context, the complexity of addressing SQIs, strategies used to understand SQIs, and creating a plan to address SQIs. Participants felt that approaching SQIs inside and outside of the clinic required ongoing communication within a multidisciplinary team both to gather information and manage the SQI. Forming a relationship with the patient was one strategy to facilitate assessing SQIs. Most participants expressed a need for guidance about effective SQI communication. Providers perceived approaching SQIs as a routine part of interdisciplinary clinical care. The specific symptom and the complexity of its management influenced the process of assessing and managing SQIs. Findings have implications for institutional processes, training, evaluation, and program development. C1 [Underhill, Meghan L.; Halpenny, Barbara; Berry, Donna L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Sheldon, Lisa Kennedy] Univ Massachusetts, Boston, MA 02125 USA. RP Underhill, ML (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM meghanl_underhill@dfci.harvard.edu OI Sheldon, Lisa Kennedy/0000-0002-5958-8529 FU National Institute of Nursing Research [R01 NR008726]; National Cancer Institute [1U54 CA156732] FX National Institute of Nursing Research, R01 NR008726; National Cancer Institute, 1U54 CA156732 NR 28 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 EI 1543-0154 J9 J CANCER EDUC JI J. Cancer Educ. PD DEC PY 2014 VL 29 IS 4 BP 753 EP 761 DI 10.1007/s13187-014-0651-9 PG 9 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA AS6BW UT WOS:000344350800022 PM 24748096 ER PT J AU Guerrero-Berroa, E Kluger, A Schmeidler, J Sailor, K Lizardi, H Golomb, J Ferris, S Reisberg, B AF Guerrero-Berroa, Elizabeth Kluger, Alan Schmeidler, James Sailor, Kevin Lizardi, Humberto Golomb, James Ferris, Steven Reisberg, Barry TI Neuropsychological and Neuropsychiatric Prediction of Global Cognitive Status Among Older Spanish-Speaking Hispanics and English-Speaking Whites SO JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY LA English DT Article DE neuropsychology; neuropsychiatric symptoms; depression; cognitive status; dementia; Hispanic elderly ID LATE-LIFE DEPRESSION; PRIMARY DEGENERATIVE DEMENTIA; ALZHEIMERS-DISEASE; TEST-PERFORMANCE; DETERIORATION SCALE; MEXICAN-AMERICANS; MEMORY IMPAIRMENT; AFRICAN-AMERICAN; ELDERLY PERSONS; PRIMARY-CARE AB Background: Neuropsychological and depression measures have been found to predict cognitive functioning. We compared these associations among whites and Spanish-speaking Hispanics. Methods: Fifty-two pairs of whites and Hispanics were matched demographically and clinically in a cross-sectional study. Hierarchical regression analyses predicted Global Deterioration Scale (GDS) rating by baseline neuropsychological tests and depression symptoms. Results: Neuropsychological tests predicted GDS better in whites; depression symptomsspecifically retardationpredicted well in Hispanics but not whites. Immediate recall of the New York University (NYU)-Paragraph Test and the Retardation item of the Hamilton Depression Rating Scale were associated with GDS in Hispanics and delayed recall of the NYU-Paragraph Test and Wechsler Adult Intelligence Scale-Digit Symbol in whites. Neuropsychological tests and depression symptoms predicted GDS differently in Hispanics and whites. Discussion: These results suggest that other measures should be considered to increase the predictive accuracy of neuropsychological tests when assessing cognitive status in Spanish-speaking Hispanics. Additional studies of specific ethnic/racial and sociodemographic subgroups are warranted. C1 [Guerrero-Berroa, Elizabeth; Schmeidler, James] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Kluger, Alan; Sailor, Kevin; Lizardi, Humberto] CUNY Herbert H Lehman Coll, Dept Psychol, New York, NY USA. [Kluger, Alan; Golomb, James; Ferris, Steven; Reisberg, Barry] NYU, Langone Med Ctr, Comprehens Ctr Brain Aging, Alzheimers Dis Ctr, New York, NY USA. RP Guerrero-Berroa, E (reprint author), James J Peters VA Med Ctr, 130 West Kingsbridge Rd,Room 1F-01, Bronx, NY 10468 USA. EM elizabeth.guerrero-berroa@mssm.edu OI Reisberg, Barry/0000-0002-9104-7423; Ferris, Steven/0000-0001-8641-6223 FU NIH [S06 GM 08225, 12, P30 AG 08051, AG-R01-03051, MH R29 44697]; National Science Foundation/ Alliance for Graduate Education and the Professoriate [HRD 0450360] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by NIH grants S06 GM 08225 (Project 12); P30 AG 08051; AG-R01-03051; MH R29 44697; and the National Science Foundation/ Alliance for Graduate Education and the Professoriate (HRD 0450360). NR 64 TC 0 Z9 0 U1 2 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0891-9887 EI 1552-5708 J9 J GERIATR PSYCH NEUR JI J. Geriatr. Psychiatry Neurol. PD DEC PY 2014 VL 27 IS 4 BP 266 EP 275 DI 10.1177/0891988714532020 PG 10 WC Geriatrics & Gerontology; Clinical Neurology; Psychiatry SC Geriatrics & Gerontology; Neurosciences & Neurology; Psychiatry GA AS9MW UT WOS:000344567700006 PM 24759088 ER PT J AU Sumner, JA Pietrzak, RH Danielson, CK Adams, ZW Ruggiero, KJ AF Sumner, Jennifer A. Pietrzak, Robert H. Danielson, Carla Kmett Adams, Zachary W. Ruggiero, Kenneth J. TI Elucidating dimensions of posttraumatic stress symptoms and their functional correlates in disaster-exposed adolescents SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Posttraumatic stress disorder; Disasters; Adolescents; Dysphoric arousal model; Confirmatory factor analysis ID CONFIRMATORY FACTOR-ANALYSIS; DISORDER SYMPTOMS; FACTORIAL INVARIANCE; EARTHQUAKE SURVIVORS; DYSPHORIC AROUSAL; 5-FACTOR MODEL; PTSD; SAMPLE; VETERANS; CHILDREN AB The aim of this study was to elucidate the dimensional structure of posttraumatic stress disorder (PTSD) and potential moderators and functional correlates of this structure in disaster-affected adolescents. A population-based sample of 2000 adolescents aged 12-17 years (M = 14.5 years; 51% female) completed interviews on post-tornado PTSD symptoms, substance use, and parent adolescent conflict between 4 and 13 months (M = 8.8, SD = 2.6) after tornado exposure. Confirmatory factor analyses revealed that all models fit well but a 5-factor dysphoric arousal model provided a statistically significantly better representation of adolescent PTSD symptoms compared to 4-factor dysphoria and emotional numbing models. There was evidence of measurement invariance of the dysphoric arousal model across gender and age, although girls and older adolescents aged 15-17 years had higher mean scores than boys and younger adolescents aged 12-14 years, respectively, on some PTSD dimensions. Differential magnitudes of association between PTSD symptom dimensions and functional correlates were observed, with emotional numbing symptoms most strongly positively associated with problematic substance use since the tornado, and dysphoric arousal symptoms most strongly positively associated with parent-adolescent conflict; both correlations were significantly larger than the corresponding correlations with anxious arousal. Taken together, these results suggest that the dimensional structure of tornado-related PTSD symptomatology in adolescents is optimally characterized by five separate clusters of re-experiencing, avoidance, numbing, dysphoric arousal, and anxious arousal symptoms, which showed unique associations with functional correlates. Findings emphasize that PTSD in disaster-exposed adolescents is not best conceptualized as a homogenous construct and highlight potential differential targets for post-disaster assessment and intervention. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Sumner, Jennifer A.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Pietrzak, Robert H.] Natl Ctr Posttraumat Stress Disorder, Vet Affairs Connecticut Healthcare Syst, Clin Neurosci Div, West Haven, CT 06516 USA. [Pietrzak, Robert H.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06511 USA. [Danielson, Carla Kmett; Adams, Zachary W.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Ruggiero, Kenneth J.] Med Univ S Carolina, Coll Nursing, Charleston, SC 29425 USA. [Ruggiero, Kenneth J.] Ralph H Johnson VA Med Ctr, Charleston, SC 29401 USA. RP Sumner, JA (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, 722 W 168th St, New York, NY 10032 USA. EM js4456@columbia.edu FU National Institute of Mental Health [R01-MH081056, T32-MH18869, R21-MH086313]; National Institute on Drug Abuse [R01-DA031285] FX This work was supported by National Institute of Mental Health grants R01-MH081056, T32-MH18869, R21-MH086313 and National Institute on Drug Abuse grant R01-DA031285. The funding sources did not have any involvement in study design, data collection, analysis, or interpretation, writing of the manuscript, or the decision to submit the manuscript for publication. NR 48 TC 6 Z9 6 U1 6 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD DEC PY 2014 VL 59 BP 85 EP 92 DI 10.1016/j.jpsychires.2014.09.003 PG 8 WC Psychiatry SC Psychiatry GA AS3WJ UT WOS:000344205700012 PM 25248557 ER PT J AU Erickson, CA Ray, B Maloney, B Wink, LK Bowers, K Schaefer, TL McDougle, CJ Sokol, DK Lahiri, DK AF Erickson, Craig A. Ray, Balmiki Maloney, Bryan Wink, Logan K. Bowers, Katherine Schaefer, Tori L. McDougle, Christopher J. Sokol, Deborah K. Lahiri, Debomoy K. TI Impact of acamprosate on plasma amyloid-beta precursor protein in youth: A pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Amyloid precursor protein; Autism spectrum disorder; Acamprosate; Glutamate; Biomarker; GABA ID BRAIN OVERGROWTH; MESSENGER-RNAS; GLUTAMATE RECEPTORS; ALZHEIMERS-DISEASE; MENTAL-RETARDATION; HEAD CIRCUMFERENCE; SECRETED FORMS; OPEN-LABEL; RAT-BRAIN; FMRP AB Background: Understanding of the pathophysiology of autism spectrum disorder (ASD) remains limited. Brain overgrowth has been hypothesized to be associated with the development of ASD. A derivative of amyloid-beta precursor protein (APP), secreted APP alpha (sAPP alpha), has neuroproliferative effects and has been shown to be elevated in the plasma of persons with ASD compared to control subjects. Reduction in sAPP alpha holds promise as a novel molecular target of treatment in ASD. Research into the neurochemistry of ASD has repeatedly implicated excessive glutamatergic and deficient GABAergic neurotransmission in the disorder. With this in mind, acamprosate, a novel modulator of glutamate and GABA function, has been studied in ASD. No data is available on the impact of glutamate or GABA modulation on sAPP alpha function. Methods: Plasma APP derivative levels pre- and post-treatment with acamprosate were determined in two pilot studies involving youth with idiopathic and fragile X syndrome (FXS)-associated ASD. We additionally compared baseline APP derivative levels between youth with FXS-associated or idiopathic ASD. Results: Acamprosate use was associated with a significant reduction in plasma sAPP(total) and sAPP alpha. levels but no change occurred in A beta 40 or A beta 42 levels in 15 youth with ASD (mean age: 11.1 years). Youth with FXS-associated ASD (n = 12) showed increased sAPP alpha processing compared to age-, gender- and IQ-match youth with idiopathic ASD (n = 11). Conclusions: Plasma APP derivative analysis holds promise as a potential biomarker for use in ASD targeted treatment. Reduction in sAPP (total) and sAPP alpha may be a novel pharmacodynamic property of acamprosate. Future study is required to address limitations of the current study to determine if baseline APP derivative analysis may predict subgroups of persons with idiopathic or FXS-associated ASD who may respond best to acamprosate or to potentially other modulators of glutamate and/or GABA neurotransmission. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Erickson, Craig A.; Wink, Logan K.; Bowers, Katherine; Schaefer, Tori L.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Ray, Balmiki; Maloney, Bryan; Sokol, Deborah K.; Lahiri, Debomoy K.] Indiana Univ Sch Med, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA. [McDougle, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lurie Ctr Autism, Boston, MA USA. RP Lahiri, DK (reprint author), Indiana Univ Sch Med, Dept Psychiat, Inst Psychiat Res, Neurosci Res Bldg,320 West 15th St,NB 200C, Indianapolis, IN 46202 USA. EM dlahiri@iupui.edu RI Bowers, Katherine/N-5226-2015; Maloney, Bryan/C-4924-2011 OI Maloney, Bryan/0000-0003-2364-9649 FU United States Department of Defense; American Academy of Child and Adolescent Psychiatry; John Merck Fund; Cincinnati Children's Hospital Medical Center; Simons Foundation; Angelman Syndrome Foundation; National Fragile X Foundation/United States Centers for Disease Control; Baxter Healthcare FX None (TS, KB, CJM, BR, DKS); Logan Wink, Consultant to Otsuka Pharmaceuticals; Craig Erickson, Equity in Confluence Pharmaceuticals, Consultant to the Roche Group and Alcobra Pharmaceuticals, Research Grant Support from the United States Department of Defense, The American Academy of Child and Adolescent Psychiatry, The John Merck Fund, Cincinnati Children's Hospital Medical Center, The Simons Foundation, the Angelman Syndrome Foundation, and the National Fragile X Foundation/United States Centers for Disease Control; Debomoy Lahiri: Scientific advisory board- QR Pharma, Yuma Therapeutics, Entia Biosciences; International advisory board- Drug Discovery and Therapy World Congress; Stock options, QR Pharma; Patent involving memantine (mode of action is not related to that of acamprosate); Editor in Chief, Current Alzheimer Research; Research Grant Support from Baxter Healthcare. NR 76 TC 10 Z9 10 U1 1 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD DEC PY 2014 VL 59 BP 220 EP 228 DI 10.1016/j.jpsychires.2014.07.011 PG 9 WC Psychiatry SC Psychiatry GA AS3WJ UT WOS:000344205700030 PM 25300441 ER PT J AU Draberova, L Bugajev, V Potuckova, L Halova, I Bambouskova, M Polakovicova, I Xavier, RJ Seed, B Draber, P AF Draberova, Lubica Bugajev, Viktor Potuckova, Lucie Halova, Ivana Bambouskova, Monika Polakovicova, Iva Xavier, Ramnik J. Seed, Brian Draber, Petr TI Transmembrane Adaptor Protein PAG/CBP Is Involved in both Positive and Negative Regulation of Mast Cell Signaling SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID FC-EPSILON-RI; AFFINITY IGE RECEPTOR; GLYCOSPHINGOLIPID-ENRICHED MICRODOMAINS; THY-1 MEMBRANE MICRODOMAINS; CAPACITATIVE CALCIUM-ENTRY; BASOPHILIC LEUKEMIA-CELLS; TYROSINE KINASE; IMMUNOGLOBULIN-E; LIPID RAFTS; FYN KINASE AB The transmembrane adaptor protein PAG/CBP (here, PAG) is expressed in multiple cell types. Tyrosine-phosphorylated PAG serves as an anchor for C-terminal SRC kinase, an inhibitor of SRC-family kinases. The role of PAG as a negative regulator of immunoreceptor signaling has been examined in several model systems, but no functions in vivo have been determined. Here, we examined the activation of bone marrow-derived mast cells (BMMCs) with PAG knockout and PAG knockdown and the corresponding controls. Our data show that PAG-deficient BMMCs exhibit impaired antigen-induced degranulation, extracellular calcium uptake, tyrosine phosphorylation of several key signaling proteins (including the high-affinity IgE receptor subunits, spleen tyrosine kinase, and phospholipase C), production of several cytokines and chemokines, and chemotaxis. The enzymatic activities of the LYN and FYN kinases were increased in nonactivated cells, suggesting the involvement of a LYN- and/or a FYN-dependent negative regulatory loop. When BMMCs from PAG-knockout mice were activated via the KIT receptor, enhanced degranulation and tyrosine phosphorylation of the receptor were observed. In vivo experiments showed that PAG is a positive regulator of passive systemic anaphylaxis. The combined data indicate that PAG can function as both a positive and a negative regulator of mast cell signaling, depending upon the signaling pathway involved. C1 [Draberova, Lubica; Bugajev, Viktor; Potuckova, Lucie; Halova, Ivana; Bambouskova, Monika; Polakovicova, Iva; Draber, Petr] Acad Sci Czech Republic, Inst Mol Genet, Dept Signal Transduct, Prague, Czech Republic. [Xavier, Ramnik J.; Seed, Brian] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA. [Xavier, Ramnik J.] Broad Inst Harvard Univ & Massachusetts Inst Tech, Cambridge, MA USA. RP Draber, P (reprint author), Acad Sci Czech Republic, Inst Mol Genet, Dept Signal Transduct, Prague, Czech Republic. EM draberpe@img.cas.cz RI Halova, Ivana/G-3512-2014 OI Halova, Ivana/0000-0003-3078-7986 FU Czech Science Foundation [301/09/1826, P302/10/1759, P302-14-09807S, P302/12/G101, P305-14-00703S, 204/09/H084]; European Co-operation in Science and Technology [Action BM1007]; Ministry of Education, Youth, and Sports of the Czech Republic [LD12073 COST-CZ-MAST]; Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic [RVO 68378050]; Faculty of Science, Charles University, Prague, Czech Republic FX This work was supported by projects 301/09/1826, P302/10/1759, P302-14-09807S, P302/12/G101, P305-14-00703S, and 204/09/H084 from the Czech Science Foundation, by Action BM1007 from European Co-operation in Science and Technology, by project LD12073 COST-CZ-MAST from the Ministry of Education, Youth, and Sports of the Czech Republic, and by the Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic (RVO 68378050). L. P., M. B., and I. P. were supported in part by the Faculty of Science, Charles University, Prague, Czech Republic. NR 76 TC 8 Z9 9 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2014 VL 34 IS 23 BP 4285 EP 4300 DI 10.1128/MCB.00983-14 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AT0NA UT WOS:000344631500006 PM 25246632 ER PT J AU Raciborska, A Bilska, K Drabko, K Chaber, R Sobol, G Pogorzala, M Wyrobek, E Polczynska, K Rogowska, E Rodriguez-Galindo, C Wozniak, W AF Raciborska, Anna Bilska, Katarzyna Drabko, Katarzyna Chaber, Radoslaw Sobol, Grazyna Pogorzala, Monika Wyrobek, Elzbieta Polczynska, Katarzyna Rogowska, Elzbieta Rodriguez-Galindo, Carlos Wozniak, Wojciech TI Validation of a Multi-Modal Treatment Protocol for Ewing Sarcoma-A Report from the Polish Pediatric Oncology Group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE children; Ewing sarcoma; survival; treatment ID WHOLE-LUNG IRRADIATION; PROGNOSTIC-FACTORS; PULMONARY METASTASES; LOCAL TREATMENT; TUMORS; FAMILY; MANAGEMENT; SURVIVAL; THERAPY; MULTIDISCIPLINARY AB BackgroundEwing sarcoma (ES) is the second most common paediatric malignant bone tumor. Advances in multi-disciplinary care have resulted in significant improvement in cure rates over the last decades. However, the generalization of those results in countries traditionally excluded from large cooperative trials has yet to be demonstrated. We report the results of modern multi-disciplinary care for patients with ES in Poland. ProceduresOne hundred and thirty-two patients with ES were treated using modern multi-modal therapy during the period 2000-2009. Overall survival was estimated by Kaplan-Meier methods and compared using long-rank test and Cox models. Factors predictive of outcome in our setting were analyzed to identify distinct risk groups that could help identify areas for improvement. ResultsThe median age at the time of diagnosis was 12.3 years. With a median follow-up of 5.0 years, the 5-year event-free survival (EFS) and OS estimates for localized disease were 54.88% and 68.29%, respectively. For patients with metastatic disease, 5-year EFS and OS estimates were 36% and 42%, respectively. There was no correlation between age and stage or site. Patients with localized, non-pelvic disease had better outcome than patients with axial tumors (71% vs. 44%, respectively, P=0.00073). Treatment failure was associated with stage, pelvic primary, poor histological response, and type of local control. ConclusionsSuccessful treatment of ES requires optimal systemic and local therapy. We were able to replicate the results of modern multi-modal protocols. Validation of current treatment protocols in countries with more limited cancer treatment resources is required. Pediatr Blood Cancer 2014;61:2170-2174. (c) 2014 Wiley Periodicals, Inc. C1 [Raciborska, Anna; Bilska, Katarzyna; Rogowska, Elzbieta; Wozniak, Wojciech] Inst Mother & Child Hlth, Dept Surg Oncol Children & Youth, PL-01211 Warsaw, Poland. [Drabko, Katarzyna] Med Univ Lublin, Dept Pediat Hematol Oncol & Bone Marrow Transplan, Lublin, Poland. [Chaber, Radoslaw] Wroclaw Med Univ, Dept & Clin Pediat Oncol Hematol & Bone Marrow Tr, Wroclaw, Poland. [Sobol, Grazyna] Med Univ Silesia, Unit Pediat Oncol Hematol & Chemotherapy, Katowice, Poland. [Pogorzala, Monika] Nicholas Copernicus Univ, Dept Pediat Hematol & Oncol, Coll Med, Bydgoszcz, Poland. [Wyrobek, Elzbieta] Univ Childrens Hosp Kracow, Dept Oncol & Hematol, Krakow, Poland. [Polczynska, Katarzyna] Med Univ Gdansk, Dept Pediat Hematol & Oncol, Gdansk, Poland. [Rodriguez-Galindo, Carlos] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Rodriguez-Galindo, Carlos] Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. RP Raciborska, A (reprint author), Inst Mother & Child Hlth, Dept Surg Oncol Children & Youth, Ul Kasprzaka 17a, PL-01211 Warsaw, Poland. EM anna.raciborska@hoga.pl NR 23 TC 4 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 IS 12 BP 2170 EP 2174 DI 10.1002/pbc.25167 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AS4EP UT WOS:000344226300006 PM 25163763 ER PT J AU Alexander, S Kraveka, JM Weitzman, S Lowe, E Smith, L Lynch, JC Chang, M Kinney, MC Perkins, SL Laver, J Gross, TG Weinstein, H AF Alexander, Sarah Kraveka, Jacqueline M. Weitzman, Sheila Lowe, Eric Smith, Lynette Lynch, James C. Chang, Myron Kinney, Marsha C. Perkins, Sherrie L. Laver, Joseph Gross, Thomas G. Weinstein, Howard TI Advanced Stage Anaplastic Large Cell Lymphoma in Children and Adolescents: Results of ANHL0131, a Randomized Phase III Trial of APO Versus a Modified Regimen With Vinblastine: A Report From the Children's Oncology Group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE anaplastic large cell lymphoma; vinblastine ID NON-HODGKIN-LYMPHOMA; CANCER-STUDY-GROUP; CLINICAL-FEATURES; PEDIATRIC-ONCOLOGY; CHILDHOOD; ALK; CHEMOTHERAPY; LEUKEMIA; SURVIVAL; THERAPY AB BackgroundOptimal therapy for children and adolescents with advanced stage anaplastic large cell lymphoma (ALCL) is unknown. ANHL0131 examined whether a maintenance regimen including vinblastine compared to the standard APO (doxorubicin, prednisone, vincristine, methotrexate, 6-mercaptopurine) regimen would result in superior event-free survival. ProcedureOne hundred and twenty five eligible patients were enrolled. Induction was identical for both arms. Post induction patients were randomized to receive APO with vincristine every 3 weeks or a regimen that substituted vincristine with weekly vinblastine (APV). ResultsThere was no difference between the patients randomized to the APO versus APV arms in either event free survival (EFS) or overall survival (OS) (three year EFS 74% vs. 79%, P=0.68 and three years OS of 84% vs. 86%, P=0.87, respectively). Patients in the APV arm required dose reduction secondary to myelosuppression and had a higher incidence of neutropenia as well as infection with neutropenia compared to those in the APO arm (P<0.001, P=0.019, respectively). ConclusionsTreatment with weekly vinblastine instead of every three week vincristine as part of multi-agent maintenance therapy did not result in improvement in EFS or OS. Weekly vinblastine was associated with increased toxicity. ( Identifier NCT00059839) Pediatr Blood Cancer 2014;61:2236-2242. (c) 2014 Wiley Periodicals, Inc. C1 [Alexander, Sarah; Weitzman, Sheila] Hosp Sick Children, Div Pediat Hematol Oncol, Toronto, ON M5G 1X8, Canada. [Kraveka, Jacqueline M.] Med Univ S Carolina, Div Pediat Hematol Oncol, Charleston, SC 29425 USA. [Lowe, Eric] Childrens Hosp Kings Daughters, Div Pediat Hematol Oncol, Norfolk, VA USA. [Smith, Lynette; Lynch, James C.] COG Data Ctr, Omaha, NE USA. [Smith, Lynette; Lynch, James C.] Univ Nebraska Med Ctr, Omaha, NE USA. [Chang, Myron] Univ Florida, Dept Biostat, Gainesville, FL USA. [Kinney, Marsha C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Perkins, Sherrie L.] Univ Utah Hlth Sci, Dept Pathol, Salt Lake City, UT USA. [Perkins, Sherrie L.] ARUP Inst, Salt Lake City, UT USA. [Laver, Joseph] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Gross, Thomas G.] Nationwide Childrens Hosp, Dept Pediat Hematol Oncol, Columbus, OH USA. [Weinstein, Howard] Massachusetts Gen Hosp, Div Pediat Hematol Oncol, Boston, MA 02114 USA. RP Alexander, S (reprint author), Univ Toronto, Hosp Sick Children, Div Hematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM sarah.alexander@sickkids.ca FU NCI NIH HHS [U10 CA180899, U10 CA098413, U10 CA098543, U10 CA180886] NR 35 TC 9 Z9 9 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 IS 12 BP 2236 EP 2242 DI 10.1002/pbc.25187 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AS4EP UT WOS:000344226300018 PM 25156886 ER PT J AU Alcasabas, AP Caranto, K Rodriguez-Galindo, C Wilson, MW Lam, CG Sundar, G Quah, TC Dolendo, MC AF Alcasabas, A. P. Caranto, K. Rodriguez-Galindo, C. Wilson, M. W. Lam, C. G. Sundar, G. Quah, T. C. Dolendo, M. C. TI IMPACT OF IMPLEMENTING A RETINOBLASTOMA PROGRAM IN A PUBLIC TERTIARY HOSPITAL IN A RESOURCE LIMITED SETTING SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Alcasabas, A. P.] Philippine Gen Hosp, Dept Pediat, Sect Hematol Oncol, Manila, Philippines. [Caranto, K.; Dolendo, M. C.] Southern Philippines Med Ctr, Dept Pediat, Childrens Canc & Blood Dis Unit, Davao, Philippines. [Rodriguez-Galindo, C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wilson, M. W.] St Jude Childrens Res Hosp, Dept Surg, Div Ophthalmol & Pathol, Memphis, TN 38105 USA. [Lam, C. G.] St Jude Childrens Res Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA. [Lam, C. G.] St Jude Childrens Res Hosp, Int Outreach Program, Memphis, TN 38105 USA. [Sundar, G.] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore. [Quah, T. C.] Khoo Teck Puat Natl Univ Childrens Med Inst, Sect Pediat Hematol Oncol, Singapore, Singapore. RI Quah, Thuan Chong/D-8469-2015 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA EP-566 BP S378 EP S379 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932101217 ER PT J AU Ananth, P Melvin, P Berry, JG Wolfe, J AF Ananth, P. Melvin, P. Berry, J. G. Wolfe, J. TI HEALTH CARE UTILIZATION AND COSTS IN THE LAST YEAR OF LIFE FOR CHILDREN WITH MALIGNANCIES SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Ananth, P.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Melvin, P.] Boston Childrens Hosp, Program Patient Safety & Qual, Boston, MA USA. [Berry, J. G.] Boston Childrens Hosp, Div Gen Pediat, Boston, MA USA. [Wolfe, J.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA P-297 BP S238 EP S238 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100538 ER PT J AU Brand, S Chordas, C Liptak, C Manley, P Recklitis, C AF Brand, S. Chordas, C. Liptak, C. Manley, P. Recklitis, C. TI USING THE FATIGUE THERMOMETER TO SCREEN ADOLESCENT AND YOUNG ADULT BRAIN TUMOR SURVIVORS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Brand, S.; Chordas, C.; Liptak, C.; Manley, P.; Recklitis, C.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA EP-222 BP S303 EP S303 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100824 ER PT J AU Brennan, R Wilson, MW Mao, S Wu, J Qaddoumi, I Rodriguez-Galindo, C AF Brennan, R. Wilson, M. W. Mao, S. Wu, J. Qaddoumi, I. Rodriguez-Galindo, C. TI A PROSPECTIVE SINGLE INSTITUTION TRIAL USING TOPOTECAN BASED CHEMOTHERAPY FOR THE TREATMENT OF BILATERAL INTRAOCULAR RETINOBLASTOMA SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Brennan, R.; Mao, S.; Wu, J.; Qaddoumi, I.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Wilson, M. W.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Rodriguez-Galindo, C.] Dana Farber Canc Inst, Boston, MA 02115 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA O-111 BP S135 EP S135 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100112 ER PT J AU Chow, C Liptak, C Manley, P Recklitis, C AF Chow, C. Liptak, C. Manley, P. Recklitis, C. TI HISTORY OF RELAPSED DISEASE IN PEDIATRIC BRAIN TUMOR SURVIVORS: PSYCHOSOCIAL OUTCOMES AND QUALITY OF LIFE SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Chow, C.; Liptak, C.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Manley, P.; Recklitis, C.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA P-348 BP S249 EP S250 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100587 ER PT J AU Eaton, B Esiashvili, N Kim, S Weyman, E Thornton, L Kasper, H Mazewski, C MacDonald, T Ebb, D MacDonald, S Tarbell, N Yock, T AF Eaton, B. Esiashvili, N. Kim, S. Weyman, E. Thornton, L. Kasper, H. Mazewski, C. MacDonald, T. Ebb, D. MacDonald, S. Tarbell, N. Yock, T. TI CLINICAL OUTCOMES OF CHILDREN WITH STANDARD RISK MEDULLOBLASTOMA TREATED WITH PROTON AND PHOTON RADIOTHERAPY SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Eaton, B.; Esiashvili, N.; Kim, S.] Emory Univ, Atlanta, GA 30322 USA. [Weyman, E.; Thornton, L.; Kasper, H.; Ebb, D.; MacDonald, S.; Tarbell, N.; Yock, T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mazewski, C.; MacDonald, T.] Childrens Healthcare Atlanta, Aflac Canc & Blood Disorders Ctr, Atlanta, GA USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA O-021 BP S111 EP S112 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100022 ER PT J AU Fay-McClymont, T Walsh, K Mabbott, D Smith, A Madden, J Chi, S Wells, E Owen, E Packer, R Foreman, N Bouffet, E Lafay-Cousin, L AF Fay-McClymont, T. Walsh, K. Mabbott, D. Smith, A. Madden, J. Chi, S. Wells, E. Owen, E. Packer, R. Foreman, N. Bouffet, E. Lafay-Cousin, L. TI LONG TERM NEUROPSYCHOLOGICAL FOLLOW UP OF YOUNG CHILDREN WITH MEDULLOBLASTOMA TREATED ACCORDING TO THE CCG 99703 REGIMEN SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Fay-McClymont, T.; Lafay-Cousin, L.] Alberta Childrens Prov Gen Hosp, Calgary, AB T2T 5C7, Canada. [Walsh, K.; Wells, E.; Packer, R.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Mabbott, D.; Bouffet, E.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Smith, A.; Owen, E.] Arnold Palmer Hosp Children, Orlando, FL USA. [Madden, J.; Foreman, N.] Childrens Hosp Colorado, Denver, CO USA. [Chi, S.] Dana Farber Canc Inst, Boston, MA 02115 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA O-024 BP S112 EP S112 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100025 ER PT J AU Frederick, N Recklitis, C AF Frederick, N. Recklitis, C. TI FATIGUE IN CHILDHOOD CANCER SURVIVORS: A REPORT FROM PROJECT REACH SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Frederick, N.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Recklitis, C.] Dana Farber Canc Inst, Perini Family Survivors Ctr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA P-121 BP S196 EP S196 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100363 ER PT J AU Geoerger, B Bourdeaut, F DuBois, SG Geller, JI Marabelle, A Pearson, AD Kan, R Matano, A Bhansali, SG Parasuraman, S Chi, SN AF Geoerger, B. Bourdeaut, F. DuBois, S. G. Geller, J. I. Marabelle, A. Pearson, A. D. Kan, R. Matano, A. Bhansali, S. G. Parasuraman, S. Chi, S. N. TI PHASE I STUDY OF THE CDK4/6 INHIBITOR LEE011 IN PATIENTS WITH MALIGNANT RHABDOID TUMORS OR NEUROBLASTOMA SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Geoerger, B.] Inst Gustave Roussy, Dept Pediat, Villejuif, France. [Bourdeaut, F.] Inst Curie, Dept Pediat, Paris, France. [Bourdeaut, F.] Inst Curie, INSERM, U830, Paris, France. [DuBois, S. G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Geller, J. I.] Cincinnati Childrens Hosp Med Ctr, Div Hematol Oncol, Cincinnati, OH 45229 USA. [Marabelle, A.] Leon Berard Comprehens Canc Ctr, Inst Pediat Hematooncol, Lyon, France. [Pearson, A. D.] Royal Marsden Hosp, Children & Young Peoples Unit, London SW3 6JJ, England. [Pearson, A. D.] Inst Canc Res, London SW3 6JB, England. [Kan, R.; Parasuraman, S.] Novartis Inst BioMed Res, Cambridge, MA USA. [Matano, A.] Novartis Pharma AG, Oncol Translat Med, Basel, Switzerland. [Bhansali, S. G.] Novartis Pharmaceut, Clin Pharmacol, E Hanover, NJ USA. [Chi, S. N.] Dana Farber Canc Inst, Pediat Neurooncol Program, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 4 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA O-125 BP S138 EP S139 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100126 ER PT J AU Kenney, LB Melvin, P Fishman, L O'Sullivan-Oliveira, J Sawicki, GS Ziniel, S Diller, L Fernandes, SM AF Kenney, L. B. Melvin, P. Fishman, L. O'Sullivan-Oliveira, J. Sawicki, G. S. Ziniel, S. Diller, L. Fernandes, S. M. TI TRANSITIONING CHILDHOOD CANCER SURVIVORS TO ADULT CARE: A SURVEY OF PEDIATRIC ONCOLOGISTS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Kenney, L. B.; Diller, L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Melvin, P.; Ziniel, S.] Boston Childrens Hosp, Program Patient Safety & Qual, Boston, MA USA. [Fishman, L.; Sawicki, G. S.] Boston Childrens Hosp, Dept Med, Boston, MA USA. [O'Sullivan-Oliveira, J.] Boston Childrens Hosp, Dept Surg, Boston, MA USA. [Fernandes, S. M.] Lucile Packard Childrens Hosp Stanford, Dept Pediat, Palo Alto, CA 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA P-129 BP S198 EP S198 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100371 ER PT J AU Ladra, M Edgington, S Moteabbed, M Mahajan, A Grosshans, D MacDonald, S Tarbell, N Yock, T AF Ladra, M. Edgington, S. Moteabbed, M. Mahajan, A. Grosshans, D. MacDonald, S. Tarbell, N. Yock, T. TI A DOSIMETRIC COMPARISON OF PROTON RADIOTHERAPY AND IMRT IN PEDIATRIC RMS PATIENTS ENROLLED ON A PHASE II PROTON STUDY SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Ladra, M.; Edgington, S.; Moteabbed, M.; MacDonald, S.; Tarbell, N.; Yock, T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mahajan, A.; Grosshans, D.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA P-289 BP S236 EP S236 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100530 ER PT J AU Ladra, M Mandeville, H Niemierko, A MacDonald, S Friedmann, A Tarbell, N Yock, T AF Ladra, M. Mandeville, H. Niemierko, A. MacDonald, S. Friedmann, A. Tarbell, N. Yock, T. TI THE IMPACT OF RESPONSE TO INDUCTION CHEMOTHERAPY ON SURVIVAL AND LOCAL CONTROL IN EMBRYONAL PARAMENINGEAL RHABDOMYOSARCOMA SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Ladra, M.; Niemierko, A.; MacDonald, S.; Friedmann, A.; Tarbell, N.; Yock, T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mandeville, H.] Royal Marsden Hosp, London SW3 6JJ, England. 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA P-287 BP S235 EP S235 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100528 ER PT J AU Lafay-Cousin, L Chi, S Madden, J Smith, A Wells, E Owen, E Strother, D Foreman, N Packer, R Bouffet, E AF Lafay-Cousin, L. Chi, S. Madden, J. Smith, A. Wells, E. Owen, E. Strother, D. Foreman, N. Packer, R. Bouffet, E. TI LONG TERM FOLLOW UP OF INFANTS WITH MEDULLOBLASTOMA TREATED WITH SEQUENTIAL HIGH DOSE CHEMOTHERAPY SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Lafay-Cousin, L.; Strother, D.] Alberta Childrens Prov Gen Hosp, Calgary, AB, Canada. [Chi, S.] Dana Farber Inst, Boston, MA USA. [Madden, J.; Foreman, N.] Childrens Hosp Colorado, Denver, CO USA. [Smith, A.; Owen, E.] Arnold Palmer Hosp Children, Orlando, FL USA. [Wells, E.; Packer, R.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Bouffet, E.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA P-047 BP S178 EP S178 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100290 ER PT J AU Lucas, J Kuhlthau, K Delahaye, J Pulsifer, M Weyman, E McBride, S MacDonald, S Tarbell, N Yock, T AF Lucas, J. Kuhlthau, K. Delahaye, J. Pulsifer, M. Weyman, E. McBride, S. MacDonald, S. Tarbell, N. Yock, T. TI LONGITUDINAL CHILD AND PARENT REPORTED HEALTH RELATED QUALITY OF LIFE IN CHILDREN ENROLLED ON A PROTON RADIOTHERAPY PHASE II MEDULLOBLASTOMA STUDY SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Lucas, J.] Wake Forest Baptist Med Ctr, Winston Salem, NC USA. [Kuhlthau, K.; Delahaye, J.; Pulsifer, M.; Weyman, E.; MacDonald, S.; Tarbell, N.; Yock, T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [McBride, S.] Mem Sloan Kettering, Radiat Oncol, New York, NY USA. RI Lucas Jr., John/K-5243-2013 OI Lucas Jr., John/0000-0002-4139-4160 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA P-052 BP S179 EP S179 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100294 ER PT J AU Mak, K Lee, SW Balboni, TA Marcus, KJ AF Mak, K. Lee, S. W. Balboni, T. A. Marcus, K. J. TI PALLIATIVE RADIOTHERAPY FOR CHILDHOOD CANCERS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Mak, K.] Harvard Radiat Oncol Program, Dept Radiat Oncol, Boston, MA USA. [Mak, K.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Lee, S. W.; Balboni, T. A.; Marcus, K. J.] Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA USA. [Balboni, T. A.] Dana Farber Brigham & Womens Canc Ctr, Dept Psychosocial Oncol & Palliat Care, Boston, MA USA. [Balboni, T. A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Marcus, K. J.] Dana Farber Brigham & Womens Canc Ctr, Dept Pediat Oncol, Boston, MA USA. [Marcus, K. J.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA EP-644 BP S396 EP S396 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932101295 ER PT J AU Mody, R Van Ryn, C London, WB Park, JR Hogarty, MD Diller, L AF Mody, R. Van Ryn, C. London, W. B. Park, J. R. Hogarty, M. D. Diller, L. TI LATE RECURRENCES, MORTALITY AND SECOND CANCERS IN FIVE-YEAR SURVIVORS OF HIGH RISK NEUROBLASTOMA SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Mody, R.] Univ Michigan, Ann Arbor, MI 48109 USA. [Van Ryn, C.] Univ Florida, Gainesville, FL USA. [London, W. B.; Diller, L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Park, J. R.] Seattle Childrens Hosp, Seattle, WA USA. [Hogarty, M. D.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA O-002 BP S106 EP S106 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100003 ER PT J AU Northman, L Morris, M Ross, S Ullrich, N Manley, P AF Northman, L. Morris, M. Ross, S. Ullrich, N. Manley, P. TI SUPPORTING THE ACADEMIC NEEDS OF PEDIATRIC CANCER SURVIVORS: A MODEL OF CARE SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Northman, L.; Morris, M.; Ross, S.; Manley, P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ullrich, N.] Boston Childrens Hosp, 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA P-126 BP S197 EP S197 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100368 ER PT J AU O'Neill, AF Malogolowkin, MH Brugieres, L Casanova, M Geller, JI Schmid, I Venkatramani, R Thompson, P Feusner, J Rangaswami, AA AF O'Neill, A. F. Malogolowkin, M. H. Brugieres, L. Casanova, M. Geller, J. I. Schmid, I. Venkatramani, R. Thompson, P. Feusner, J. Rangaswami, A. A. TI GEMCITABINE AND OXALIPLATIN FOR THE TREATMENT OF PEDIATRIC PATIENTS WITH HEPATOCELLULAR CARCINOMA SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [O'Neill, A. F.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Malogolowkin, M. H.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Brugieres, L.] Inst Gustave Roussy, Villejuif, France. [Casanova, M.] IRCCS Fdn Ist Nazl Tumori, Milan, Italy. [Geller, J. I.] Univ Cincinnati, Cincinnati, OH USA. [Schmid, I.] Dr von Hauner Childrens Hosp, Munich, Germany. [Venkatramani, R.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Thompson, P.] Texas Childrens Canc Ctr, Houston, TX USA. [Thompson, P.] Texas Childrens Hematol Ctr, Houston, TX USA. [Feusner, J.] Childrens Hosp & Res Ctr Oakland, Oakland, CA USA. [Rangaswami, A. A.] Stanford Univ, Palo Alto, CA 94304 USA. 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA O-087 BP S128 EP S129 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100088 ER PT J AU Rangaswami, A Rinaldi, E O'Neill, A Haeberle, B Maibach, R Roebuck, D Lopez-Terrada, D Hiiyama, EISO Meyers, R Czauderna, P AF Rangaswami, A. Rinaldi, E. O'Neill, A. Haeberle, B. Maibach, R. Roebuck, D. Lopez-Terrada, D. Hiiyama, E. I. S. O. Meyers, R. Czauderna, P. TI DEVELOPMENT OF A NOVEL WEB-BASED CONSULTATION SERVICE FOR A PAEDIATRIC RARE TUMOR: THE SIOPEL CLINICIAN ONLINE CONSULTATION SERVICE SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Rangaswami, A.] Stanford Univ, Palo Alto, CA 94304 USA. [Rinaldi, E.] Cineca, PMP, Bologna, Italy. [O'Neill, A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Haeberle, B.] Univ Munich, Munich, Germany. [Maibach, R.] IBCSG, Bern, Switzerland. [Roebuck, D.] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Lopez-Terrada, D.] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Hiiyama, E. I. S. O.] Hiroshima Univ, Nat Sci Ctr Basic Res & Dev, Hiroshima, Japan. [Meyers, R.] Univ Utah, Dept Surg, Salt Lake City, UT USA. [Czauderna, P.] Med Univ Gdansk, Dept Surg, Gdansk, Poland. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA O-090 BP S129 EP S129 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100091 ER PT J AU Samiee, S Ahmed, S Hui, K Gryfe, R Pollett, A Cino, M Gingras-Hill, G Ng, A Hodgson, D AF Samiee, S. Ahmed, S. Hui, K. Gryfe, R. Pollett, A. Cino, M. Gingras-Hill, G. Ng, A. Hodgson, D. TI COLORECTAL CANCER SCREENING IN CANCER SURVIVORS TREATED WITH RADIATION THERAPY SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Samiee, S.; Ahmed, S.; Hui, K.; Gingras-Hill, G.; Hodgson, D.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Gryfe, R.] Mt Sinai Hosp, Dept Surg, Toronto, ON M5G 1X5, Canada. [Pollett, A.] Mt Sinai Hosp, Dept Pathol, Toronto, ON M5G 1X5, Canada. [Cino, M.] Toronto Western Hosp, Dept Gastroenterol, Toronto, ON M5T 2S8, Canada. [Ng, A.] Harvard Univ, Sch Med, Farber Canc Inst, Boston, MA 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA O-232 BP S164 EP S164 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100230 ER PT J AU Shyirambere, C Elmore, S May, L Umuhizi, D Tapela, N Lehmann, L Mpunga, T AF Shyirambere, C. Elmore, S. May, L. Umuhizi, D. Tapela, N. Lehmann, L. Mpunga, T. TI PRELIMINARY TREATMENT OUTCOMES UTILIZING SIOP GUIDELINES IN A NOVEL ONCOLOGIC CARE MODEL FOR WILMS' TUMOR IN RWANDA SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Shyirambere, C.; Tapela, N.] Inshuti Mu Buzima Partners Hlth Rwanda, Noncommunicable Dis, Butaro, Rwanda. [Elmore, S.] Harvard Univ, Sch Med, Boston, MA USA. [May, L.] Boston Childrens Hosp, Boston, MA USA. [Umuhizi, D.; Mpunga, T.] Minist Hlth, Butaro Canc Ctr Excellence, Butaro, Rwanda. [Lehmann, L.] Dana Farber Canc Inst, Clin Pediat Stem Cell Transplantat Ctr, Boston, MA 02115 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA P-264 BP S230 EP S230 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100505 ER PT J AU Vrooman, LM Blackmon, JE Kenney, LB Silverman, LB Recklitis, CJ Diller, L AF Vrooman, L. M. Blackmon, J. E. Kenney, L. B. Silverman, L. B. Recklitis, C. J. Diller, L. TI BONE FRACTURE IN PEDIATRIC AND ADOLESCENT SURVIVORS OF CHILDHOOD CANCER: A REPORT FROM PROJECT REACH AT DANA-FARBER CANCER INSTITUTE (DFCI) SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Vrooman, L. M.; Blackmon, J. E.; Kenney, L. B.; Silverman, L. B.; Recklitis, C. J.; Diller, L.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA P-112 BP S194 EP S194 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100354 ER PT J AU Yock, T Indelicato, DJ Hartsell, W Kasper, HSH Perkins, S Hill-Kayser, C Mahajan, A Chang, AL Childs, S Laurie, F Buchsbaum, J Raeke, L Neville, C Ladra, M Yeap, BY AF Yock, T. Indelicato, D. J. Hartsell, W. Kasper, H. Symecko H. Perkins, S. Hill-Kayser, C. Mahajan, A. Chang, A. L. Childs, S. Laurie, F. Buchsbaum, J. Raeke, L. Neville, C. Ladra, M. Yeap, B. Y. TI PRELIMINARY RESULTS FROM THE PEDIATRIC PROTON CONSORTIUM REGISTRY (PPCR): A COLLABORATION OF US PROTON CENTERS TO ACCELERATE PROTON THERAPY RESEARCH SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Yock, T.; Kasper, H. Symecko H.; Raeke, L.; Neville, C.; Ladra, M.; Yeap, B. Y.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Indelicato, D. J.] Univ Florida, Dept Radiat Oncol, Proton Therapy Inst, Jacksonville, FL USA. [Hartsell, W.] CDH Proton Ctr Chicago, Dept Radiat Oncol, Chicago, IL USA. [Perkins, S.] Washington Univ, Dept Radiat Oncol, St Louis, MO USA. [Hill-Kayser, C.] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Mahajan, A.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Chang, A. L.] Hampton Univ, Dept Radiat Oncol, Hampton, VA 23668 USA. [Childs, S.] Mayo Clin & Mayo Grad Sch Med, Dept Radiat Oncol, Rochester, MN USA. [Laurie, F.] Qarc Univ Massachusetts, Dept Radiat Oncol, Providence, RI USA. [Buchsbaum, J.] Indiana Univ, Dept Radiat Oncol, Providence, RI USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA O-234 BP S164 EP S164 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100232 ER PT J AU Zhou, E Vrooman, LM Manley, PE Recklitis, CJ AF Zhou, E. Vrooman, L. M. Manley, P. E. Recklitis, C. J. TI COGNITIVE-BEHAVIORAL TREATMENT FOR INSOMNIA IN ADOLESCENT AND YOUNG ADULT SURVIVORS OF CHILDHOOD CANCER SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Zhou, E.; Vrooman, L. M.; Recklitis, C. J.] Dana Farber Canc Inst, Perini Family Survivors Ctr, Boston, MA 02115 USA. [Manley, P. E.] Dana Farber Canc Inst, Boston, MA 02115 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 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA O-217 BP S160 EP S160 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100215 ER PT J AU Zhu, S Wood, A Yang, G Zhang, X Weichert, N He, S Tao, T Oldridge, D Maris, J Look, T AF Zhu, S. Wood, A. Yang, G. Zhang, X. Weichert, N. He, S. Tao, T. Oldridge, D. Maris, J. Look, T. TI ROLE OF LMO1 IN NEUROBLASTOMA INITIATION AND MAINTENANCE: ANALYSIS IN THE ZEBRAFISH MODEL OF CHILDHOOD NEUROBLASTOMA SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Zhu, S.; Yang, G.; Zhang, X.] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN USA. [Wood, A.; Oldridge, D.; Maris, J.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Wood, A.; Oldridge, D.; Maris, J.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA. [Weichert, N.; He, S.; Tao, T.; Look, T.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC PY 2014 VL 61 SU 2 MA P-154 BP S205 EP S205 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AR9YA UT WOS:000343932100396 ER PT J AU Madenci, AL Lehmann, LE Weldon, CB AF Madenci, Arin L. Lehmann, Leslie E. Weldon, Christopher B. TI Surgical consultation and intervention during pediatric hematopoietic stem cell transplantation SO PEDIATRIC TRANSPLANTATION LA English DT Article DE hematopoietic stem cell transplantation; referral and consultation; interdisciplinary communication; pediatrics; health services; central venous catheters ID ALLOGENEIC BLOOD-TRANSFUSION; ONCOLOGY PATIENTS; BONE-MARROW; RISK-FACTORS; COMPLICATIONS; MANAGEMENT; CHILDREN; PREVENTION; STRATEGIES; RECIPIENTS AB Children undergoing HSCT are at risk for complications due to immune system impairment, toxicity from prior therapies and conditioning regimens, and long-term use of indwelling catheters. These problems may require assessment by the surgical team. We sought to characterize the role of surgical consultation during primary hospital stay for HSCT. We retrospectively reviewed the records of consecutive patients undergoing HSCT between September 2010 and September 2012. One hundred and seventy-three patients underwent 189 HSCTs. General surgery consultations occurred during 33% (n=62) of primary hospitalizations for HSCT, with a total of 85 consults. Sixty-three (73%) consults resulted in an intervention in the operating room or at the bedside. The majority of consults were for CVL issues (59%, n=50), followed by abdominal complaints (16%, n=14). Patients requiring surgical consultation had significantly higher in-hospital mortality (16% vs. 2%, p<0.01) and 100-day TRM (10% vs. 2%, p<0.01), compared with those not requiring consultation. Patients undergoing HSCT often require surgical consultation, most commonly for line-related issues. Surgical consultation heralded an increased risk of in-hospital and 100-day TRM. Issues among this high-risk cohort of children who have undergone HSCT must be familiar to the general surgeon and oncologist alike. C1 [Madenci, Arin L.; Weldon, Christopher B.] Boston Childrens Hosp, Dept Surg, Boston, MA USA. [Madenci, Arin L.; Lehmann, Leslie E.; Weldon, Christopher B.] Harvard Univ, Sch Med, Boston, MA USA. [Madenci, Arin L.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Lehmann, Leslie E.] Boston Childrens Hosp, Dept Med, Div Hematol Oncol, Boston, MA USA. [Lehmann, Leslie E.; Weldon, Christopher B.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Weldon, CB (reprint author), Dept Surg, 300 Longwood Ave,Fegan 3, Boston, MA 02115 USA. EM christopher.weldon@childrens.harvard.edu OI Madenci, Arin/0000-0003-1258-7278 NR 17 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1397-3142 EI 1399-3046 J9 PEDIATR TRANSPLANT JI Pediatr. Transplant. PD DEC PY 2014 VL 18 IS 8 BP 875 EP 881 DI 10.1111/petr.12360 PG 7 WC Pediatrics; Transplantation SC Pediatrics; Transplantation GA AS6FS UT WOS:000344360500022 PM 25224384 ER PT J AU Peters, A Sylvia, LG da Silva Magalhaes, PV Miklowitz, DJ Frank, E Otto, MW Hansen, NS Dougherty, DD Berk, M Nierenberg, AA Deckersbach, T AF Peters, A. Sylvia, L. G. da Silva Magalhaes, P. V. Miklowitz, D. J. Frank, E. Otto, M. W. Hansen, N. S. Dougherty, D. D. Berk, M. Nierenberg, A. A. Deckersbach, T. TI Age at onset, course of illness and response to psychotherapy in bipolar disorder: results from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Bipolar disorder; mood episodes; psychotherapy; staging ID RANDOMIZED CONTROLLED-TRIAL; SOCIAL RHYTHM THERAPY; PSYCHOSOCIAL INTERVENTIONS; RELAPSE PREVENTION; COGNITIVE THERAPY; MOOD DISORDERS; I DISORDER; FOLLOW-UP; NUMBER; MODERATORS AB Background. The course of bipolar disorder progressively worsens in some patients. Although responses to pharmacotherapy appear to diminish with greater chronicity, less is known about whether patients' prior courses of illness are related to responses to psychotherapy. Method. Embedded in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was a randomized controlled trial of psychotherapy for bipolar depression comparing the efficacy of intensive psychotherapy with collaborative care (a three-session psycho-educational intervention). We assessed whether the number of previous mood episodes, age of illness onset, and illness duration predicted or moderated the likelihood of recovery and time until recovery from a depressive episode in patients in the two treatments. Results. Independently of treatment condition, participants with one to nine prior depressive episodes were more likely to recover and had faster time to recovery than those with 20 or more prior depressive episodes. Participants with fewer than 20 prior manic episodes had faster time to recovery than those with 20 or more episodes. Longer illness duration predicted a longer time to recovery. Participants were more likely to recover in intensive psychotherapy than collaborative care if they had 10-20 prior episodes of depression [number needed to treat (NNT)=2.0], but equally likely to respond to psychotherapy and collaborative care if they had one to nine (NNT=32.0) or >20 (NNT=9.0) depressive episodes. Conclusions. Number of previous mood episodes and illness duration are associated with the likelihood and speed of recovery among bipolar patients receiving psychosocial treatments for depression. C1 [Peters, A.] Univ Illinois, Chicago, IL USA. [Sylvia, L. G.; Hansen, N. S.; Dougherty, D. D.; Nierenberg, A. A.; Deckersbach, T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sylvia, L. G.; Dougherty, D. D.; Nierenberg, A. A.; Deckersbach, T.] Harvard Univ, Sch Med, Boston, MA USA. [da Silva Magalhaes, P. V.] Univ Fed Rio Grande do Sul, Porto Alegre, Brazil. [Miklowitz, D. J.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Frank, E.] Univ Pittsburgh, Pittsburgh, PA USA. [Otto, M. W.] Boston Univ, Boston, MA 02215 USA. [Berk, M.] Deakin Univ, Melbourne, Vic, Australia. [Berk, M.] Univ Melbourne, Melbourne, Vic, Australia. RP Deckersbach, T (reprint author), Massachusetts Gen Hosp, Bldg 149,13th St,2nd Floor, Charlestown, MA 02129 USA. EM tdeckersbach@partners.org RI Magalhaes, Pedro/A-8519-2008; OI Magalhaes, Pedro/0000-0002-5644-6357; Miklowitz, David/0000-0002-9647-6147; Berk, Michael/0000-0002-5554-6946 FU NIMH [N01MH80001, MH29618 l, MH43931, MH55101]; National Alliance for Research on Schizophrenia and Depression (NARSAD) FX The STEP-BD was funded in part by the NIMH (no. N01MH80001). Support for the development of the psychosocial treatments was provided by grants from the NIMH (no. MH29618 l, MH43931, MH55101) and by the National Alliance for Research on Schizophrenia and Depression (NARSAD). NR 44 TC 5 Z9 5 U1 8 U2 31 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD DEC PY 2014 VL 44 IS 16 BP 3455 EP 3467 DI 10.1017/S0033291714000804 PG 13 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA AS7ZC UT WOS:000344469400009 PM 25066366 ER PT J AU Alonso, D Plourde, J Weininger, S Goldman, JM AF Alonso, Diego Plourde, Jeffrey Weininger, Sandy Goldman, Julian M. TI Web-Based Clinical Scenario Repository (TM) (CSR (TM)) SO ANESTHESIA AND ANALGESIA LA English DT Meeting Abstract C1 [Alonso, Diego; Plourde, Jeffrey; Goldman, Julian M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Goldman, Julian M.] Harvard Med Sch, Boston, MA USA. [Weininger, Sandy] US FDA, Rockville, MD 20857 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2014 VL 119 SU 1 PG 2 WC Anesthesiology SC Anesthesiology GA V45PE UT WOS:000209827700065 ER PT J AU Arney, D Rentachinthala, V Troup, D Maji, A Fillinger, A Diduch, L Sayrafian, K Goldman, JM AF Arney, Dave Rentachinthala, Venkata Troup, Dennis Maji, Anand Fillinger, Antoine Diduch, Lukas Sayrafian, Kamran Goldman, Julian M. TI ICE Data Logger Prototype SO ANESTHESIA AND ANALGESIA LA English DT Meeting Abstract C1 [Arney, Dave; Goldman, Julian M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Goldman, Julian M.] Harvard Med Sch, Boston, MA USA. [Sayrafian, Kamran] NIST, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2014 VL 119 SU 1 PG 2 WC Anesthesiology SC Anesthesiology GA V45PE UT WOS:000209827700064 ER PT J AU Goldman, JM Arney, D Plourde, J AF Goldman, Julian M. Arney, David Plourde, Jeffrey TI OpenICE Prototype: A New, Open Interoperable Medical Device Clinical Research Platform SO ANESTHESIA AND ANALGESIA LA English DT Meeting Abstract C1 [Goldman, Julian M.; Arney, David; Plourde, Jeffrey] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Goldman, Julian M.] Harvard Med Sch, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2014 VL 119 SU 1 PG 2 WC Anesthesiology SC Anesthesiology GA V45PE UT WOS:000209827700062 ER PT J AU Goldman, JM Jaffe, MB Osborn, D Weininger, S AF Goldman, Julian M. Jaffe, Michael B. Osborn, David Weininger, Sandy TI The Integrated Clinical Environment (ICE) Standards (ASTM F2761-09) - The First Ten Years SO ANESTHESIA AND ANALGESIA LA English DT Meeting Abstract C1 [Goldman, Julian M.; Jaffe, Michael B.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Osborn, David] Philips Healthcare, Andover, MA USA. [Weininger, Sandy] US FDA, Silver Spring, MD USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2014 VL 119 SU 1 PG 2 WC Anesthesiology SC Anesthesiology GA V45PE UT WOS:000209827700063 ER PT J AU Jaffe, M Arney, D Weininger, S Dain, S Goldman, JM AF Jaffe, Michael Arney, David Weininger, Sandy Dain, Steven Goldman, Julian M. TI The Integrated Clinical Environment (ICE) Data Logger-Opportunities and Advantages Relative to Individual Device Data Logging SO ANESTHESIA AND ANALGESIA LA English DT Meeting Abstract C1 [Jaffe, Michael; Arney, David; Goldman, Julian M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Weininger, Sandy; Goldman, Julian M.] Harvard Med Sch, Boston, MA USA. [Weininger, Sandy; Goldman, Julian M.] US FDA, Rockville, MD 20857 USA. [Dain, Steven] Western Univ, Schulich Med & Dent, London, ON, Canada. NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2014 VL 119 SU 1 PG 2 WC Anesthesiology SC Anesthesiology GA V45PE UT WOS:000209827700061 ER PT J AU DeLisi, LE AF DeLisi, Lynn E. TI Pursuit of the "truth" about mental illness: the significance of findings in neuropsychiatric research, and lessons from the past SO DIALOGUES IN CLINICAL NEUROSCIENCE LA English DT Editorial Material DE GWAS; PGC; pharmacogenetics; genetic risk; ethical issues in genetics AB Technology in genetics and brain imaging has advanced so rapidly that it is difficult to be knowledgeable about all the new tools being used in the pursuit of progress toward understanding and treating mental illness. While findings from new studies remain promising, caution is needed with regard to their current applicability to clinical use, both to predict who is likely to become ill and who is likely to respond to medication. A perspective on the past, using schizophrenia as an example, illustrates important findings that were published, had much visibility, and caused a flurry of new related studies, but then slowly disappeared, either to be abandoned as an artifact of the assay or study design, an epiphenomenon, or as simply nonreplicated findings not leading to further progress. Remembering that good science is "the pursuit of the truth" and not joining the latest "bandwagon fad" of "believers" is an important principle to adhere to when participating in the politics of science. C1 [DeLisi, Lynn E.] Harvard Med Sch, VA Boston Healthcare Syst, Brockton, MA USA. [DeLisi, Lynn E.] Harvard Med Sch, Dept Psychiat, Brockton, MA USA. RP DeLisi, LE (reprint author), VA Boston Healthcare Syst, Dept Psychiat, Bldg 2,940 Belmont Ave, Brockton, MA 02010 USA. EM DeLisi76@aol.com NR 28 TC 1 Z9 1 U1 0 U2 0 PU INST CONFERENCE HIPPOCRATE PI SURESNESS-CEDEX PA 50 RUE CARNOT, SURESNESS-CEDEX, 92284, FRANCE SN 1294-8322 EI 1958-5969 J9 DIALOGUES CLIN NEURO JI Dialogues Clin. Neurosci. PD DEC PY 2014 VL 16 IS 4 BP 447 EP 450 PG 4 WC Neurosciences SC Neurosciences & Neurology GA V45QS UT WOS:000209831700001 PM 25733950 ER PT J AU Thase, ME AF Thase, Michael E. TI Using biomarkers to predict treatment response in major depressive disorder: evidence from past and present studies SO DIALOGUES IN CLINICAL NEUROSCIENCE LA English DT Article DE biomarker; antidepressant; cognitive behavior therapy; prediction; treatment response AB Major depressive disorder (MDD) is a heterogeneous condition with a variable response to a wide range of treatments. Despite intensive efforts, no biomarker has been identified to date that can reliably predict response or nonresponse to any form of treatment, nor has one been identified that can be used to identify those at high risk of developing treatment-resistant depression (ie, nonresponse to a sequence of treatments delivered for adequate duration and intensity). This manuscript reviews some past areas of research that have proved informative, such as studies using indexes of hypercortisolism or sleep disturbance, and more recent research findings using measures of inflammation and different indicators of regional cortical activation to predict treatment response. It is concluded that, although no method has yet been demonstrated to be sufficiently accurate to be applied in clinical practice, progress has been made. It thus seems likely that-at some point in the not-too-distant future-it will be possible to prospectively identify, at least for some MDD patients, the likelihood of response or nonresponse to cognitive therapy or various antidepressant medications. (C) 2014, AICH - Servier Research Group C1 [Thase, Michael E.] Univ Penn, Philadelphia Vet Affairs Med Ctr, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Thase, Michael E.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. RP Thase, ME (reprint author), Dept Psychiat, Mood & Anxiety Disorders Sect, 3535 Market St,Suite 670, Philadelphia, PA 19104 USA. EM thase@mail.med.upenn.edu FU Agency for Healthcare Research and Quality; Eli Lilly Company; National Institute of Mental Health; Otsuka Pharmaceuticals; PharmaNeuroboost [03/13]; Roche [06/13] FX Dr Thase has provided scientific consultation to Alkermes, Astra-Zeneca, Bristol-Myers Squibb Company, Eli Lilly & Company, Forest Pharmaceuticals, Inc, Gerson Lehman Group, GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante, Inc, Merck and Co. Inc, Neronetics, Inc, Novartis, Otsuka, Ortho-McNeil Pharmaceuticals, Pfizer (formerly Wyeth-Ayerst Laboratories), Shire US Inc, Sunovion Pharmaceuticals, Inc, and Takeda. Dr Thase receives grant funding from the Agency for Healthcare Research and Quality, Eli Lilly & Company, National Institute of Mental Health, Otsuka Pharmaceuticals, PharmaNeuroboost (ended 03/13), and Roche (ended 06/13). He has equity holdings in MedAvante, Inc and receives royalty income from American Psychiatric Foundation, Inc, Guilford Publications, Herald House, Oxford University Press, and W.W. Norton & Company. His wife is employed as the Group Scientific Director for Peloton Advantage which does business with Pfizer. NR 29 TC 5 Z9 5 U1 1 U2 2 PU INST CONFERENCE HIPPOCRATE PI SURESNESS-CEDEX PA 50 RUE CARNOT, SURESNESS-CEDEX, 92284, FRANCE SN 1294-8322 EI 1958-5969 J9 DIALOGUES CLIN NEURO JI Dialogues Clin. Neurosci. PD DEC PY 2014 VL 16 IS 4 BP 539 EP 544 PG 6 WC Neurosciences SC Neurosciences & Neurology GA V45QS UT WOS:000209831700008 PM 25733957 ER PT J AU Elwy, AR Johnston, JM Bormann, JE Hull, A Taylor, SL AF Elwy, A. Rani Johnston, Jennifer M. Bormann, Jill E. Hull, Amanda Taylor, Stephanie L. TI A Systematic Scoping Review of Complementary and Alternative Medicine Mind and Body Practices to Improve the Health of Veterans and Military Personnel SO MEDICAL CARE LA English DT Review DE complementary and alternative medicine (CAM); veterans; military; systematic review; methods AB Background: Meditation, imagery, acupuncture, and yoga are the most frequently offered mind and body practices in the Department of Veterans Affairs. Yet, the research on mind and body practices has been critiqued as being too limited in evidence and scope to inform clinical treatment. Objectives: We conducted a systematic scoping review of mind and body practices used with veterans or active duty military personnel to identify gaps in the literature and make recommendations for future primary research. Research Design: Following systematic literature review methodology, we searched 5 databases using 27 different National Center for Complementary and Alternative Medicine-defined mind and body practices as text words, keywords, and MeSH terms through June 30, 2014. We also conducted handsearches of 4 previous reviews. Subjects: Active duty military members or veterans 18 years or older participating in mind and body practice interventions globally. Measures: Data were extracted from studies meeting 5 inclusion criteria. The quality of randomized controlled trials (RCTs) was assessed using an existing checklist. Results: Of 1819 studies identified, 89 interventions (50 RCTs) published between 1976 and 2014, conducted in 9 countries, using 152 different measures to assess 65 health and well-being outcomes met our inclusion criteria. Most interventions took place in the United States (n = 78). Meditation practices (n = 25), relaxation techniques including imagery (n = 20), spinal manipulation including physical therapy (n = 16), and acupuncture (n = 11) were the most frequently studied practices. Methodological quality of most RCTs was rated poorly. Conclusions: Meditation and acupuncture practices are among the most frequently offered and studied mind and body practices. Future research should include yoga as it is currently understudied among veterans and military personnel. A repository of mind and body intervention outcome measures may further future research efforts, as would conducting pragmatic trials and more robust RCTs. C1 [Elwy, A. Rani] Edith Nourse Rogers Mem Vet Hosp, Ctr Healthcare Org & Implementat Res, 200 Springs Rd,Mailstop 152, Bedford, MA 01730 USA. [Elwy, A. Rani] Boston Univ, Sch Med, Dept Hlth Policy & Management, Boston, MA 02118 USA. [Johnston, Jennifer M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Bormann, Jill E.] VA San Diego Healthcare Syst, Ctr Excellence Stress & Mental Hlth, San Diego, CA USA. [Bormann, Jill E.] Univ San Diego, Hahn Sch Nursing & Hlth Sci, San Diego, CA 92110 USA. [Hull, Amanda] Washington DC VA Med Ctr, Integrat Hlth & Wellness Program, War Related Injuries & Illness Ctr, Washington, DC USA. [Taylor, Stephanie L.] Greater Los Angeles VA Med Ctr, Ctr Study Healthcare Innovat Implementat & Policy, North Hills, CA USA. [Taylor, Stephanie L.] RAND Corp, Santa Monica, CA USA. RP Elwy, AR (reprint author), Edith Nourse Rogers Mem Vet Hosp, Ctr Healthcare Org & Implementat Res, 200 Springs Rd,Mailstop 152, Bedford, MA 01730 USA. EM rani.elwy@va.gov FU Department of Veterans Affairs, Health Services Research and Development Service [SDR 13-424]; National Institute of Mental Health [R25 MH080916-01A2]; Department of Veterans Affairs, Health Services Research & Development Service, Quality Enhancement Research Initiative FX Supported by the Department of Veterans Affairs, Health Services Research and Development Service, SDR 13-424.; A.R.E. is also an investigator with the Implementation Research Institute, 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. The remaining authors declare no conflict of interest. NR 127 TC 6 Z9 6 U1 3 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD DEC PY 2014 VL 52 IS 12 SU 5 BP S70 EP S82 PG 13 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V45TM UT WOS:000209838900013 PM 25397827 ER PT J AU Goldstein, JN Long, JA Arevalo, D Ibrahim, SA Mao, JJ AF Goldstein, Jennifer N. Long, Judith A. Arevalo, Doris Ibrahim, Said A. Mao, Jun J. TI US Veterans Use Vitamins and Supplements as Substitutes for Prescription Medication SO MEDICAL CARE LA English DT Article AB Background: Vitamins and supplements are the most commonly used form of complementary and alternative medicine in the United States. Growing research suggests that patients substitute vitamins and supplements for their prescription medications. The reasons might include cost of prescription medications and discordant patient and doctor health belief systems. Objectives: To investigate the prevalence of substitution of vitamins and supplements for prescription medications among veterans who receive care in the VA health care system and whether substitution is associated with prescription rationing due to cost, treatment beliefs, or distrust of the health system. Research Design: Cross-sectional observational survey. Subjects: Primary care patients (n = 275) at the Philadelphia VA Medical Center. Measures: Medication substitution, prescription medication rationing, treatment beliefs, and health system distrust were measured with structured instruments. Multivariate logistic regression was performed with substitution as the dependent variable. Results: A significant number of primary care patients in the VA system use vitamins and supplements 206 (75%). The prevalence of medication substitution is high 48 (18%). Medication substitution is strongly associated with prescription rationing due to cost (adjusted odds ratio 6.3, 95% confidence interval: 2.0-19.5, P = 0.001). Similarly, greater belief in complementary and alternative approaches to care positively predicts medication substitution (adjusted odds ratio 1.08, 95% confidence interval: 1.01-1.15, P = 0.011). There is no significant association between health system distrust and likelihood of medication substitution. Conclusions: Medication substitution is prevalent in this sample of inner city primary care patients who receive care in the VA system. Cost of prescriptions and belief in the value of complementary and alternative approaches to care appear to be associated with this patient-driven treatment decision. C1 [Goldstein, Jennifer N.] Christiana Hosp, Dept Med, Ammon Bldg,Suite 2E72A,4755 Ogletown Stanton Rd, Newark, DE 19718 USA. [Long, Judith A.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Long, Judith A.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Arevalo, Doris] Univ Illinois, Urbana, IL 61801 USA. [Ibrahim, Said A.] Philadelphia VA Med Ctr, Ctr Hlth Equ & Promot, Philadelphia, PA USA. [Mao, Jun J.] Univ Penn, Dept Family & Community Med, Philadelphia, PA 19104 USA. RP Goldstein, JN (reprint author), Christiana Hosp, Dept Med, Ammon Bldg,Suite 2E72A,4755 Ogletown Stanton Rd, Newark, DE 19718 USA. EM jennifer.n.goldstein@gmail.com FU Ruth L. Kirschstein National Research Service Award (NRSA) [T32HP10026] FX The Ruth L. Kirschstein National Research Service Award (NRSA): Grant #: T32HP10026 funded the fellowship of J.N.G. and therefore this research. NR 24 TC 1 Z9 1 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD DEC PY 2014 VL 52 IS 12 SU 5 BP S65 EP S69 PG 5 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V45TM UT WOS:000209838900012 PM 25397826 ER PT J AU Kearney, DJ McManus, C Malte, CA Martinez, ME Felleman, B Simpson, TL AF Kearney, David J. McManus, Carolyn Malte, Carol A. Martinez, Michelle E. Felleman, Benjamin Simpson, Tracy L. TI Loving-Kindness Meditation and the Broaden-and-Build Theory of Positive Emotions Among Veterans Disorder SO MEDICAL CARE LA English DT Article DE emotions; meditation; social support; post-traumatic stress disorder (PTSD); veterans AB Background: Loving-kindness meditation (LKM) is a practice intended to enhance feelings of kindness and compassion for self and others. Objectives: To assess whether participation in a 12-week course of LKM for veterans with posttraumatic stress disorder (PTSD) is associated with improved positive emotions, decentering, and personal resources. Research Design: In an open-pilot trial, veterans were assessed at baseline, after the course, and 3 months later. Effect sizes were calculated from baseline to each follow-up point for each construct of interest. Measures were chosen as an initial investigation of the broaden-and-build theory of positive emotions. Subjects: A total of 42 veterans with active PTSD (40% female) participated. Measures: Emotions, decentering, psychological wellbeing including autonomy, environmental mastery, personal growth, positive relations, purpose in life, self-acceptance, and sense of social support were measured at each time point. Results: Significant increases in unactivated pleasant (d = 0.73), but not activated pleasant, emotions were found over time. Activated and unactivated unpleasant emotions decreased over time (d = -0.69 and -0.53, respectively). There were also increases in environmental mastery (d = 0.61), personal growth (d = 0.54), purpose in life (d = 0.71), self-acceptance (d = 0.68), and decentering (d = 0.96) at 3-month follow-up. Conclusions: Overall, positive emotions increased, and enhancement of personal resources occurred over time. Further investigation of LKM for PTSD is warranted. C1 [Kearney, David J.] VA Puget Sound Hlth Care Syst, Dept Med, Seattle, WA USA. [Kearney, David J.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [McManus, Carolyn] Swedish Med Ctr, Dept Phys Therapy, Seattle, WA USA. [Malte, Carol A.] CESATE, Seattle, WA USA. [Martinez, Michelle E.; Felleman, Benjamin] VA Puget Sound Hlth Care Syst, Dept Res & Dev, Seattle, WA USA. [Simpson, Tracy L.] VA Puget Sound Hlth Care Syst, Dept Mental Hlth, Seattle, WA USA. [Simpson, Tracy L.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Kearney, DJ (reprint author), VA Puget Sound Hlth Care Syst, 1660 South Columbian Way,S-111-GI, Seattle, WA 98108 USA. EM david.kearney@va.gov NR 50 TC 5 Z9 5 U1 4 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD DEC PY 2014 VL 52 IS 12 SU 5 BP S32 EP S38 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V45TM UT WOS:000209838900007 PM 25397820 ER PT J AU Lisi, AJ Khorsan, R Smith, MM Mittman, BS AF Lisi, Anthony J. Khorsan, Raheleh Smith, Monica M. Mittman, Brian S. TI Variations in the Implementation and Characteristics of Chiropractic Services in VA SO MEDICAL CARE LA English DT Article DE Department of Veterans Affairs; chiropractic; health services research; rehabilitation services; complementary therapies; program evaluation AB Background: In 2004, the US Department of Veterans Affairs expanded its delivery of chiropractic care by establishing onsite chiropractic clinics at select facilities across the country. Systematic information regarding the planning and implementation of these clinics and describing their features and performance is lacking. Objectives: To document the planning, implementation, key features and performance of VA chiropractic clinics, and to identify variations and their underlying causes and key consequences as well as their implications for policy, practice, and research on the introduction of new clinical services into integrated health care delivery systems. Research Design, Methods, and Subjects: Comparative case study of 7 clinics involving site visit-based and telephone-based interviews with 118 key stakeholders, including VA clinicians, clinical leaders and administrative staff, and selected external stakeholders, as well as reviews of key documents and administrative data on clinic performance and service delivery. Interviews were recorded, transcribed, and analyzed using a mixed inductive (exploratory) and deductive approach. Results and Conclusions: Interview data revealed considerable variations in clinic planning and implementation processes and clinic features, as well as perceptions of clinic performance and quality. Administrative data showed high variation in patterns of clinic patient care volume over time. A facility's initial willingness to establish a chiropractic clinic, along with a higher degree of perceived evidence-based and collegial attributes of the facility chiropractor, emerged as key factors associated with higher and more consistent delivery of chiropractic services and higher perceived quality of those services. C1 [Lisi, Anthony J.] Vet Hlth Adm, Chiropract Serv, Rehabil Serv, Washington, DC USA. [Lisi, Anthony J.] Vet Hlth Adm, Chiropract Serv, Prosthet Serv, Washington, DC USA. [Lisi, Anthony J.] VA Connecticut Healthcare Syst, Chiropract Serv, 950 Campbell Ave, West Haven, CT 06516 USA. [Khorsan, Raheleh] Samueli Inst, Mil Med Res Program, Corona Del Mar, CA USA. [Khorsan, Raheleh; Smith, Monica M.; Mittman, Brian S.] VA Greater Los Angeles Healthcare Syst, VA Ctr Implementat Practice & Res Support, Los Angeles, CA USA. [Mittman, Brian S.] Kaiser Permanente Southern Calif, Dept Res & Evaluat, Pasadena, CA USA. RP Lisi, AJ (reprint author), VA Connecticut Healthcare Syst, Chiropract Serv, 950 Campbell Ave, West Haven, CT 06516 USA. EM anthony.lisi@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research Development Service; Samueli Institute; US Army Medical Research and Materiel Command [W81XWH-06-1-0279]; National Institutes of Health National Center for Complementary and Alternative Medicine (NIH-NCCAM) [K01-AT002391] FX This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research Development Service. In addition, this work was supported, in part, by a grant to Brian S. Mittman by the Samueli Institute. This grant is supported by the US Army Medical Research and Materiel Command under Award no. W81XWH-06-1-0279. M.M.S. was supported in this work by Grant no. K01-AT002391, a grant from National Institutes of Health National Center for Complementary and Alternative Medicine (NIH-NCCAM). NR 15 TC 2 Z9 2 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD DEC PY 2014 VL 52 IS 12 SU 5 BP S97 EP S104 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V45TM UT WOS:000209838900016 PM 25397831 ER PT J AU Reinhard, MJ Nassif, TH Bloeser, K Dursa, EK Barth, SK Benetato, B Schneiderman, A AF Reinhard, Matthew J. Nassif, Thomas H. Bloeser, Katharine Dursa, Erin K. Barth, Shannon K. Benetato, Bonnie Schneiderman, Aaron TI CAM Utilization Among OEF/OIF Veterans Findings From the National Health Study for a New Generation of US Veterans SO MEDICAL CARE LA English DT Article DE complementary therapies; alternative medicine; veterans health; health surveys; population characteristics; CAM AB Background: Complementary and alternative medicine (CAM) is increasingly seen as an adjunct to traditional plans of care. This study utilized a representative sample of Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) veterans and OEF/OIF-era veterans to explore the prevalence and characteristics of CAM users. Research Design: The National Health Study for a New Generation of US Veterans (NewGen) is a longitudinal health study of a population-based cohort of OEF/OIF (deployed) and OEF/OIF-era (nondeployed) veterans. Data from the 2009-2011 NewGen survey (n = 20,563) were analyzed to determine prevalence of CAM use by demographic and military characteristics, the types of CAM modalities used, and where the modalities were sought. Results were weighted to the entire population of OEF/OIF and OEF/OIF-era veterans. Results: There was no statistically significant association between CAM use and deployment. Those who used Department of Veterans Affairs (VA) health care after separation were more likely to be CAM users compared with those who did not use VA care; however, the majority of veterans using CAM are using it outside the VA health care system. Massage was the most prevalent CAM modality followed by chiropractic treatment; males were less likely to use CAM than women. Conclusions: CAM modalities are being utilized by OEF/OIF veterans for health problems mainly outside the VA. Policy-makers should determine appropriate use of these modalities. C1 [Reinhard, Matthew J.; Nassif, Thomas H.; Bloeser, Katharine] Washington DC Vet Affairs Med Ctr, WRIISC, Washington, DC USA. [Reinhard, Matthew J.] Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC USA. [Nassif, Thomas H.] Amer Univ, Sch Educ Teaching & Hlth, Washington, DC 20016 USA. [Dursa, Erin K.; Barth, Shannon K.; Schneiderman, Aaron] US Dept Vet Affairs, Off Publ Hlth, Post Deployment Hlth, Program Epidemiol, Washington, DC USA. [Benetato, Bonnie] Vet Affairs Greenville NC CBOC, Greenville, NC USA. [Benetato, Bonnie] East Carolina Univ, Coll Nursing, Greenville, NC USA. RP Reinhard, MJ (reprint author), Vet Affairs Med Ctr, War Related Illness & Injury Study Ctr, Room 3B 203,Mail Stop 127,50 Irving St NW, Washington, DC 20422 USA. EM matthew.reinhard@va.gov FU Department of Veterans Affairs Office of Public Health; War Related Illness and Injury Study Center FX Supported by the Department of Veterans Affairs Office of Public Health and the War Related Illness and Injury Study Center. NR 50 TC 4 Z9 4 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD DEC PY 2014 VL 52 IS 12 SU 5 BP S45 EP S49 PG 5 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V45TM UT WOS:000209838900009 PM 25397822 ER PT J AU Serpa, JG Taylor, SL Tillisch, K AF Serpa, J. Greg Taylor, Stephanie L. Tillisch, Kirsten TI Mindfulness-based Stress Reduction (MBSR) Reduces Anxiety, Depression, and Suicidal Ideation in Veterans SO MEDICAL CARE LA English DT Article DE mindfulness; meditation; veterans; depression; anxiety; pain; suicidal ideation AB Introduction: Anxiety, depression, and pain are major problems among veterans, despite the availability of standard medical options within the Veterans Health Administration. Complementary and alternative approaches for these symptoms have been shown to be appealing to veterans. One such complementary and alternative approach is mindfulness-based stress reduction (MBSR), a brief course that teaches mindfulness meditation with demonstrated benefits for mood disorders and pain. Methods: We prospectively collected data on MBSR's effectiveness among 79 veterans at an urban Veterans Health Administration medical facility. The MBSR course had 9 weekly sessions that included seated and walking meditations, gentle yoga, body scans, and discussions of pain, stress, and mindfulness. Pre-MBSR and post-MBSR questionnaires investigating pain, anxiety, depression, suicidal ideation, and physical and mental health functioning were obtained and compared for individuals. We also conducted a mediation analysis to determine whether changes in mindfulness were related to changes in the other outcomes. Results: Significant reductions in anxiety, depression, and suicidal ideation were observed after MBSR training. Mental health functioning scores were improved. Also, mindfulness interacted with other outcomes such that increases in mindfulness were related to improvements in anxiety, depression, and mental health functionality. Pain intensity and physical health functionality did not show improvements. Discussion: This naturalistic study in veterans shows that completing an MBSR program can improve symptoms of anxiety and depression, in addition to reducing suicidal ideations, all of which are of critical importance to the overall health of the patients. C1 [Serpa, J. Greg; Taylor, Stephanie L.; Tillisch, Kirsten] Vet Adm Greater Los Angeles, Los Angeles, CA USA. [Serpa, J. Greg] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA USA. [Taylor, Stephanie L.] RAND Corp, Santa Monica, CA USA. [Tillisch, Kirsten] Univ Calif Los Angeles, David Geffen Sch Med, Oppenheimer Ctr Neurobiol Stress, Los Angeles, CA 90095 USA. RP Serpa, JG (reprint author), VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd 116B, Los Angeles, CA 90073 USA. EM john.serpa@va.gov FU VA Office of Patient Centered Care & Cultural Transformation FX The authors thank Sandy Robertson RN, MSN, PH-CNS for her support in the delivery of MBSR and the preparation of this manuscript and the VA Office of Patient Centered Care & Cultural Transformation for funding to provide MBSR and prepare the manuscript. We also would like to thank Christiane Wolf, MD, PhD, lead consultant of VA-CALM and Insight LA MBSR teacher trainer as well as the co-facilitators of the MBSR classes: Najwa Culver, PhD; Sarah Duman, PhD; Sara Gilbert, PhD; Morgan Kay, PhD; Jeanette Lantz, PhD; Shirley Pakdaman, Psy. D; Nissa Perez, MD; Debra Sobol, PhD. We also grateful to Alexis Huynh, PhD; Michele Solloway, PhD; and Nui Brown MA for their assistance. NR 38 TC 11 Z9 11 U1 4 U2 23 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD DEC PY 2014 VL 52 IS 12 SU 5 BP S19 EP S24 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V45TM UT WOS:000209838900005 PM 25397818 ER PT J AU Taylor, SL Elwy, AR AF Taylor, Stephanie L. Elwy, A. Rani TI Complementary and Alternative Medicine for US Veterans and Active Duty Military Personnel Promising Steps to Improve Their Health SO MEDICAL CARE LA English DT Editorial Material C1 [Taylor, Stephanie L.] Greater Los Angeles VA Healthcare Syst, Ctr Study Healthcare Innovat Implementat & Policy, 16111 Plummer St,Mailstop 152, North Hills, CA 91343 USA. [Elwy, A. Rani] Edith Nourse Rogers Mem Vet Hosp, Ctr Healthcare Org & Implementat Res, Bedford, MA USA. [Elwy, A. Rani] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. RP Taylor, SL (reprint author), Greater Los Angeles VA Healthcare Syst, Ctr Study Healthcare Innovat Implementat & Policy, 16111 Plummer St,Mailstop 152, North Hills, CA 91343 USA. EM stephanie.taylor8@va.gov FU Department of Veterans Affairs, Office of Patient Centered Care and Cultural Transformation FX Funding for this research was provided by the Department of Veterans Affairs, Office of Patient Centered Care and Cultural Transformation. NR 72 TC 2 Z9 2 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD DEC PY 2014 VL 52 IS 12 SU 5 BP S1 EP S4 PG 4 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA V45TM UT WOS:000209838900001 PM 25397816 ER PT J AU Gilbert, JA Ball, M Blainey, P Blaser, MJ Bohannan, BJ Bateman, A Bunge, J Dominguez-Bello, MG Epstein, S Fierer, N Gevers, D Grikscheit, T Hamdan, LJ Harvey, J Huttenhower, C Kirkup, B Kong, HH Lauber, C Lemon, KP Lynch, SV Martin, L Mello, C Palma, J Parker, R Petrosino, J Segre, JA Vosshall, L Yi, R Knight, R AF Gilbert, Jack A. Ball, Madeleine Blainey, Paul Blaser, Martin J. Bohannan, Brendan Jm Bateman, Ashley Bunge, John Dominguez-Bello, Maria Gloria Epstein, Slava Fierer, Noah Gevers, Dirk Grikscheit, Tracy Hamdan, Leila J. Harvey, James Huttenhower, Curtis Kirkup, Benjamin Kong, Heidi H. Lauber, Christian Lemon, Katherine P. Lynch, Susan V. Martin, Lance Mello, Charlene Palma, Joseph Parker, Roy Petrosino, Joseph Segre, Julia A. Vosshall, Leslie Yi, Rui Knight, Rob TI Meeting report for the 1st skin microbiota workshop, boulder, CO October 15-16 2012 SO STANDARDS IN GENOMIC SCIENCES LA English DT Article DE Skin microbiome; Army; Bioinformatics AB This report details the outcome of the 1st Skin Microbiota Workshop, Boulder, CO, held on October 15th-16th 2012. The workshop was arranged to bring Department of Defense personnel together with experts in microbial ecology, human skin physiology and anatomy, and computational techniques for interrogating the microbiome to define research frontiers at the intersection of these important areas. The workshop outlined a series of questions and created several working groups to address those questions, specifically to promote interdisciplinary activity and potential future collaboration. The US Army provided generous grant support and the meeting was organized and hosted by the University of Colorado at Boulder. A primary forward vision of the meeting was the importance of understanding skin microbial communities to improve the health and stealth of US Army warfighters. C1 [Gilbert, Jack A.] Argonne Natl Lab, 9700 S Cass Ave, Argonne, IL 60439 USA. [Gilbert, Jack A.] Univ Chicago, Dept Ecol & Evolut, Chicago, IL 60637 USA. [Ball, Madeleine] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. Broad Inst & MIT Dept Biol Engn, Cambridge, MA USA. [Blaser, Martin J.] NYU Langone Med Ctr, Dept Med, New York, NY USA. New York Harbor VA Med Ctr, New York, NY USA. [Bohannan, Brendan Jm; Bateman, Ashley] Univ Oregon, Inst Ecol & Evolut, Eugene, OR 97403 USA. [Bunge, John] Cornell Univ, Dept Stat Sci, Ithaca, NY USA. [Dominguez-Bello, Maria Gloria] NYU, Dept Med, New York, NY 10016 USA. [Dominguez-Bello, Maria Gloria] Univ Puerto Rico, Dept Biol, Mayaguez, PR USA. [Epstein, Slava] Northeastern Univ, Dept Biol, Boston, MA 02115 USA. [Fierer, Noah] Univ Colorado, Dept Ecol & Evolutionary Biol, Boulder, CO 80309 USA. [Fierer, Noah; Lauber, Christian] Univ Colorado, CIRES, Boulder, CO 80309 USA. [Gevers, Dirk] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Grikscheit, Tracy] Childrens Hosp Los Angeles, Saban Res Inst, USC, Div Pediat Surg,Keck Sch Med, Los Angeles, CA 90027 USA. [Hamdan, Leila J.] George Mason Univ, Manassas, VA 20110 USA. [Harvey, James] US Army Res Off, Res Triangle Pk, NC USA. [Huttenhower, Curtis] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kirkup, Benjamin] Walter Reed Army Inst Res, Dept Wound Infect, Silver Spring, MD USA. [Kirkup, Benjamin] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Kong, Heidi H.] NCI, NIH, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Lemon, Katherine P.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Lemon, Katherine P.] Boston Childrens Hosp, Div Infect Dis, Boston, MA USA. [Lynch, Susan V.] Univ Calif San Francisco, Dept Med, Div Gastroenterol, San Francisco, CA USA. [Martin, Lance] Stanford Univ, Sch Med, Dept Bioengn, Program Epithelial Biol, Stanford, CA 94305 USA. [Martin, Lance] Stanford Univ, Stanford, CA 94305 USA. [Mello, Charlene; Palma, Joseph] US Natick Soldier Ctr, Natick, MA USA. [Parker, Roy; Knight, Rob] Howard Hughes Med Inst, Boulder, CO USA. [Parker, Roy; Knight, Rob] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Parker, Roy; Knight, Rob] Univ Colorado, BioFrontiers Inst, Boulder, CO 80309 USA. [Petrosino, Joseph] Baylor Coll Med, Dept Mol Virol & Microbiol, Alkek Ctr Metagen & Microbiome Res, Houston, TX 77030 USA. [Segre, Julia A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Vosshall, Leslie] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. [Yi, Rui] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. RP Gilbert, JA (reprint author), Argonne Natl Lab, 9700 S Cass Ave, Argonne, IL 60439 USA. EM gilbertjack@gmail.com OI Blainey, Paul/0000-0002-4889-8783; Kirkup, Benjamin/0000-0002-8722-6218; Kong, Heidi/0000-0003-4424-064X FU U.S. Army Research Laboratory; U.S. Army Research Office [W911NF-12-1-0513] FX This workshop was supported in part by the U.S. Army Research Laboratory and the U.S. Army Research Office under grant number W911NF-12-1-0513. We thank Wally Buchholtz, who is the program manager for this program, and Jerry Kennedy and Ulla Westermann for superb assistance on the logistics. NR 26 TC 0 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1944-3277 J9 STAND GENOMIC SCI JI Stand. Genomic Sci. PD DEC PY 2014 VL 9 IS 1 AR 13 DI 10.1186/1944-3277-9-13 PG 7 WC Genetics & Heredity; Microbiology SC Genetics & Heredity; Microbiology GA V45LA UT WOS:000209816900013 ER PT J AU Bhattacharyya, S Darby, R Berkowitz, AL AF Bhattacharyya, Shamik Darby, Ryan Berkowitz, Aaron L. TI Antibiotic-Induced Neurotoxicity SO CURRENT INFECTIOUS DISEASE REPORTS LA English DT Article DE Neurotoxicity; Antibiotics; Seizures; Encephalopathy; Neuropathy; Myasthenia gravis ID INDUCED PERIPHERAL NEUROPATHY; TOXIC OPTIC NEUROPATHY; BETA-LACTAM ANTIBIOTICS; MYASTHENIA-GRAVIS; NEUROMUSCULAR-TRANSMISSION; TRIMETHOPRIM-SULFAMETHOXAZOLE; SAFETY PROFILE; METRONIDAZOLE; DRUGS; INTOXICATION AB Antibiotic neurotoxicity is rare but can cause significant morbidity when it occurs. The risk of antibiotic neurotoxicity appears to be highest in patients who are older, have impaired renal function, or have preexisting neurologic conditions. This review describes the clinical features of the most common antibiotic toxicities affecting the nervous system: seizures, encephalopathy, optic neuropathy, peripheral neuropathy, and exacerbation of myasthenia gravis. C1 [Bhattacharyya, Shamik; Darby, Ryan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Bhattacharyya, Shamik; Darby, Ryan; Berkowitz, Aaron L.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. RP Bhattacharyya, S (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. EM sbhattacharyya3@partners.org OI Bhattacharyya, Shamik/0000-0001-8047-3622 NR 68 TC 2 Z9 2 U1 3 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3847 EI 1534-3146 J9 CURR INFECT DIS REP JI Curr. Infect. Dis. Rep. PD DEC PY 2014 VL 16 IS 12 AR 448 DI 10.1007/s11908-014-0448-3 PG 6 WC Infectious Diseases SC Infectious Diseases GA AS0HO UT WOS:000343958800004 PM 25348743 ER PT J AU Jacobs, CS Etherton, MR Lyons, JL AF Jacobs, Claire S. Etherton, Mark R. Lyons, Jennifer L. TI Fungal Infections of the Central Nervous System SO CURRENT INFECTIOUS DISEASE REPORTS LA English DT Article DE Meningitis; Cryptococcus; Cryptococcal meningitis; Endemic Fungi; Yeast; CNS infection ID RECONSTITUTION INFLAMMATORY SYNDROME; CLINICAL-PRACTICE GUIDELINES; SOCIETY-OF-AMERICA; CRYPTOCOCCAL MENINGITIS; IMMUNE RECONSTITUTION; ANTIRETROVIRAL THERAPY; DISEASES-SOCIETY; CEREBROSPINAL-FLUID; COCCIDIOIDAL MENINGITIS; UNITED-STATES AB Fungal infections of the central nervous system have manifold presentations and courses that depend largely on both host and organism characteristics. Although subjects with impaired immunity are generally at higher risk for severe disease, several fungal organisms are considered primary pathogens and can also cause disease in otherwise immunocompetent individuals. Herein, we describe the epidemiology, presentation, diagnosis, and management of central nervous system complications of several fungal pathogens. C1 [Jacobs, Claire S.; Etherton, Mark R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Jacobs, Claire S.; Etherton, Mark R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Jacobs, Claire S.; Etherton, Mark R.] Harvard Univ, Sch Med, Boston, MA USA. [Lyons, Jennifer L.] Brigham & Womens Hosp, Dept Neurol, Div Neurol Infect, Boston, MA 02115 USA. [Lyons, Jennifer L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Lyons, JL (reprint author), Brigham & Womens Hosp, Dept Neurol, Div Neurol Infect, 45 Francis St, Boston, MA 02115 USA. EM jlyons5@partners.org NR 61 TC 0 Z9 0 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3847 EI 1534-3146 J9 CURR INFECT DIS REP JI Curr. Infect. Dis. Rep. PD DEC PY 2014 VL 16 IS 12 AR 449 DI 10.1007/s11908-014-0449-2 PG 7 WC Infectious Diseases SC Infectious Diseases GA AS0HO UT WOS:000343958800005 PM 25348744 ER PT J AU Raibagkar, P Neagu, MR Lyons, JL Klein, JP AF Raibagkar, Pooja Neagu, Martha R. Lyons, Jennifer L. Klein, Joshua P. TI Imaging in Neurologic Infections I: Bacterial and Parasitic Diseases SO CURRENT INFECTIOUS DISEASE REPORTS LA English DT Article DE Imaging; Nervous system; Infection; Magnetic resonance imaging; Computed tomography; Meningitis ID CENTRAL-NERVOUS-SYSTEM; CEREBRAL MALARIA; SPINAL-CORD; COMPUTED-TOMOGRAPHY; LUMBAR PUNCTURE; MENINGITIS; ADULTS; NEUROCYSTICERCOSIS; NEUROBORRELIOSIS; VENTRICULITIS AB Often presenting as medical emergencies, nervous system infections can be diagnostically challenging. Knowledgeable utilization of neuroimaging modalities and the understanding of characteristic imaging findings facilitate early diagnosis and treatment. In the first part of this two-part review, we address common and unique diagnostic imaging features of bacterial and parasitic nervous system infections. C1 [Raibagkar, Pooja; Neagu, Martha R.; Lyons, Jennifer L.; Klein, Joshua P.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Klein, Joshua P.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Raibagkar, Pooja; Neagu, Martha R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. [Raibagkar, Pooja; Neagu, Martha R.; Lyons, Jennifer L.; Klein, Joshua P.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Klein, JP (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM jpklein@partners.org FU Journal of Neuroimaging; AAN Continuum journal FX Pooja Raibagkar and Martha Neagu have no conflicts of interest. Joshua Klein served as a board member for the American Society of Neuroimaging; received an Associate Editor stipend from the Journal of Neuroimaging; received honoraria from the American Academy of Neurology and honoraria from the Neurological Society of Pune, India; received payment for manuscript preparation from the AAN Continuum journal; and received royalties from the "Adams and Victor's Principles of Neurology" textbook, 10th edition (McGraw-Hill). Jennifer Lyons received honoraria from Springer for working as a section editor. NR 57 TC 0 Z9 0 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3847 EI 1534-3146 J9 CURR INFECT DIS REP JI Curr. Infect. Dis. Rep. PD DEC PY 2014 VL 16 IS 12 AR 443 DI 10.1007/s11908-014-0443-8 PG 13 WC Infectious Diseases SC Infectious Diseases GA AS0HO UT WOS:000343958800002 PM 25348741 ER PT J AU Shukla, S Meeran, SM Katiyar, SK AF Shukla, Samriddhi Meeran, Syed M. Katiyar, Santosh K. TI Epigenetic regulation by selected dietary phytochemicals in cancer chemoprevention SO CANCER LETTERS LA English DT Review DE Epigenetics; Phytochemicals; DNA methylation; Histone deacetylation; Cancer ID TUMOR-SUPPRESSOR GENES; GREEN TEA POLYPHENOL; HISTONE DEACETYLASE INHIBITORS; MOUSE ERYTHROLEUKEMIA-CELLS; FACTOR-KAPPA-B; BREAST-CANCER; DNA METHYLATION; PROSTATE-CANCER; SKIN-CANCER; PREVENTS PHOTOCARCINOGENESIS AB The growing interest in cancer epigenetics is largely due to the reversible nature of epigenetic changes which tend to alter during the course of carcinogenesis. Major epigenetic changes including DNA methylation, chromatin modifications and miRNA regulation play important roles in tumorigenic process. There are several epigenetically active synthetic molecules such as DNA methyltransferase (DNMTs) and histone deacetylases (HDACs) inhibitors, which are either approved or, are under clinical trials for the treatment of various cancers. However, most of the synthetic inhibitors have shown adverse side effects, narrow in their specificity and also expensive. Hence, bioactive phytochemicals, which are widely available with lesser toxic effects, have been tested for their role in epigenetic modulatory activities in gene regulation for cancer prevention and therapy. Encouragingly, many bioactive phytochemicals potentially altered the expression of key tumor suppressor genes, tumor promoter genes and oncogenes through modulation of DNA methylation and chromatin modification in cancer. These bioactive phytochemicals either alone or in combination with other phytochemicals showed promising results against various cancers. Here, we summarize and discuss the role of some commonly investigated phytochemicals and their epigenetic targets that are of particular interest in cancer prevention and cancer therapy. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Shukla, Samriddhi; Meeran, Syed M.] CSIR, Cent Drug Res Inst, Canc Epigenet Lab, Div Endocrinol, Lucknow 226021, Uttar Pradesh, India. [Katiyar, Santosh K.] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. RP Katiyar, SK (reprint author), Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. EM skatiyar@uab.edu FU National Institutes of Health/NCI [CA140832, CA140197]; Veterans Administration Merit Review Award [1I01BX001410]; Council of Scientific and Industrial Research (CSIR), Government of India, India [EpiHeD (BSC0118), UNDO (BSC0103), BioPROS (BSC0106)] FX The work reported from Dr. Katiyar's laboratory was supported by National Institutes of Health/NCI (CA140832, CA140197) and Veterans Administration Merit Review Award (1I01BX001410). The work reported from Dr. Meeran's laboratory was supported in part by grants from the Council of Scientific and Industrial Research (CSIR), Government of India, India network grants-EpiHeD (BSC0118), UNDO (BSC0103), and BioPROS (BSC0106). CSIR-CDRI communication #8790. The content of this article does not necessarily reflect the views or policies of the funding sources. NR 109 TC 27 Z9 27 U1 1 U2 42 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD DEC 1 PY 2014 VL 355 IS 1 BP 9 EP 17 DI 10.1016/j.canlet.2014.09.017 PG 9 WC Oncology SC Oncology GA AR7TO UT WOS:000343782900002 PM 25236912 ER PT J AU Dhillon, A Tardini, F Bittner, E Schmidt, U Allain, R Bigatello, L AF Dhillon, Anahat Tardini, Francesca Bittner, Edward Schmidt, Ulrich Allain, Rae Bigatello, Luca TI Benefit of using a "bundled" consent for intensive care unit procedures as part of an early family meeting SO JOURNAL OF CRITICAL CARE LA English DT Article DE Quality improvement; Patient satisfaction; Patient-centered care; Critical care; Decision making ID SURGICAL INFORMED-CONSENT; CRITICALLY-ILL; CLINICAL-TRIAL; SATISFACTION; QUALITY; ICU; COMPREHENSION; MULTICENTER AB Purpose: Relatives of patients in the intensive care unit (ICU) are often dissatisfied with family-physician communication. Our prospective preintervention and postintervention study tested the hypothesis that introducing this informed consent process would improve family satisfaction with the ICU process of care. Materials and methods: We developed a consent form that included an introductory explanation of the main ICU interventions and a description of 8 common procedures in a surgical ICU. We administered it early in the ICU course during a scheduled family meeting. The study was a prospective preintervention and postintervention design. Results: The "Family Satisfaction in the Intensive Care Unit" (FS-ICU) score was higher in the intervention than in the control group (95.4 +/- 4 vs 78.2 +/- 22, P < .001). The nursing perception of satisfaction with care was also higher in the intervention group (95.8 +/- 13 vs 71.9 +/- 28, P < .001). Conclusion: A bundled informed consent resulted in higher family satisfaction with the process of care in ICU. (C) 2014 Elsevier Inc. All rights reserved. C1 [Dhillon, Anahat] UCLA, Dept Anesthesiol & Perioperat Med, Los Angeles, CA USA. [Tardini, Francesca; Allain, Rae; Bigatello, Luca] St Elizabeths Med Ctr, Crit Care & Pain Med, Dept Anesthesiol, Boston, MA USA. [Bittner, Edward; Schmidt, Ulrich] Massachusetts Gen Hosp, Dept Anesthesia, Crit Care & Pain Med, Boston, MA 02114 USA. RP Dhillon, A (reprint author), 757 Westwood Plaza Suite 3325, Los Angeles, CA 90095 USA. EM adhillon@mednet.ucla.edu NR 26 TC 2 Z9 2 U1 3 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 0883-9441 EI 1557-8615 J9 J CRIT CARE JI J. Crit. Care PD DEC PY 2014 VL 29 IS 6 BP 919 EP 922 DI 10.1016/j.jcrc.2014.07.004 PG 4 WC Critical Care Medicine SC General & Internal Medicine GA AR4WZ UT WOS:000343588100007 PM 25168636 ER PT J AU Lee, S Dong, DX Jindal, R Maguire, T Mitra, B Schloss, R Yarmush, M AF Lee, Serom Dong, David Xu Jindal, Rohit Maguire, Tim Mitra, Bhaskar Schloss, Rene Yarmush, Martin TI Predicting full thickness skin sensitization using a support vector machine SO TOXICOLOGY IN VITRO LA English DT Article DE MUTZ-3; Skin equivalent; Co-culture; In vitro; Skin sensitization; Support vector machine ID EPIDERMAL EQUIVALENT ASSAY; DENDRITIC CELLS; CONTACT SENSITIZERS; CHEMICAL SENSITIZATION; IL-18 PRODUCTION; ALLERGENS; LINE; HYPERSENSITIVITY; CYTOKINE; MODEL AB To assess the public's propensity for allergic contact dermatitis (ACD), many alternatives to in vivo chemical screening have been developed which generally incorporate a small panel of cell surface and secreted dendritic cell biomarkers. However, given the underlying complexity of ACD, one cell type and limited cellular metrics may be insufficient to predict contact sensitizers accurately. To identify a molecular signature that can further characterize sensitization, we developed a novel system using RealSkin, a full thickness skin equivalent, in co-culture with MUTZ-3 derived Langerhan's cells. This system was used to distinguish a model moderate pro-hapten isoeugenol (IE) and a model strong pre-hapten p-phenylenediamine (PPD) from irritant, salicylic acid (SA). Commonly evaluated metrics such as CD86, CD54, and IL-8 secretion were assessed, in concert with a 27-cytokine multi-plex screen and a functional chemotaxis assay. Data were analyzed with feature selection methods using ANOVA, hierarchical cluster analysis, and a support vector machine to identify the best molecular signature for sensitization. A panel consisting of IL-12, IL-9, VEGF, and IFN-gamma predicted sensitization with over 90% accuracy using this co-culture system analysis. Thus, a multi-metric approach that has the potential to identify a molecular signature may be more predictive of contact sensitization. (C) 2014 Published by Elsevier Ltd. C1 [Lee, Serom; Dong, David Xu; Jindal, Rohit; Maguire, Tim; Mitra, Bhaskar; Schloss, Rene; Yarmush, Martin] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. [Yarmush, Martin] Massachusettes Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. [Yarmush, Martin] Massachusettes Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Yarmush, Martin] Shriners Burns Hosp, Boston, MA 02114 USA. RP Yarmush, M (reprint author), Rutgers Biomed Engn, 599 Taylor Rd, Piscataway, NJ 08854 USA. EM yarmush@rci.rutgers.edu FU NIH Biotechnology Training Grant [T32GM8339-21] FX The authors would like to thank L'Oreal for their generous gift of RealSkin and the NIH Biotechnology Training Grant T32GM8339-21. NR 34 TC 0 Z9 0 U1 1 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD DEC PY 2014 VL 28 IS 8 BP 1413 EP 1423 DI 10.1016/j.tiv.2014.07.002 PG 11 WC Toxicology SC Toxicology GA AR5QT UT WOS:000343639400009 PM 25025180 ER PT J AU Oral, E Neils, AL Wannomae, KK Muratoglu, OK AF Oral, Ebru Neils, Andrew L. Wannomae, Keith K. Muratoglu, Orhun K. TI Novel active stabilization technology in highly crosslinked UHMWPEs for superior stability SO RADIATION PHYSICS AND CHEMISTRY LA English DT Article; Proceedings Paper CT 17th International Meeting on Radiation Processing (IMRP) CY NOV 04-08, 2013 CL IIA, Shanghai, PEOPLES R CHINA SP Jaingsu Dasheng Electron Accelerator Co Ltd, SQHL HO IIA DE UHMWPE; Polyethylene; Crosslinking ID MOLECULAR-WEIGHT POLYETHYLENE; HAP-PAUL-AWARD; VITAMIN-E; PROPAGATION RESISTANCE; MECHANICAL-PROPERTIES; FATIGUE RESISTANCE; VIVO OXIDATION; FREE-RADICALS; LOW WEAR; IN-VIVO AB Radiation cross-linked ultrahigh molecular weight polyethylene (UHMWPE) is the bearing of choice in joint arthroplasty. The demands on the longevity of this polymer are likely to increase with the recently advancing deterioration of the performance of alternative metal-on-metal implants. Vitamin E-stabilized, cross-linked UHMWPEs are considered the next generation of improved UHMWPE bearing surfaces for improving the oxidation resistance of the polymer. It was recently discovered that in the absence of radiation-induced free radicals, lipids absorbed into UHMWPE from the synovial fluid can initiate oxidation and result in new free radical-mediated oxidation mechanisms. In the presence of radiation-induced free radicals, it is possible for the polymer to oxidize through both existing free radicals at the time of implantation and through newly formed free radicals in vivo. Thus, we showed that reducing the radiation-induced free radicals in vitamin E-stabilized UHMWPE would increase its oxidative stability and presumably lead to improved longevity. We describe mechanical annealing and warm irradiation of irradiated vitamin E blends as novel methods to eliminate 99% of radiation-induced free radicals without sacrificing crystallinity. These are significant improvements in the processing of highly cross-linked UHMWPE for joint implants with improved longevity. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Oral, Ebru; Neils, Andrew L.; Wannomae, Keith K.; Muratoglu, Orhun K.] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Oral, Ebru; Muratoglu, Orhun K.] Harvard Univ, Sch Med, Dept Orthopaed Surg, Cambridge, MA 02138 USA. EM eoral@partners.org FU Laboratory Funds FX This study was funded by Laboratory Funds. More than one co-author receives royalties for intellectual property licenses based on technology described here. This manuscript won the am 'HAP' Paul Award of the International Society for Technology in Arthroplasty. NR 47 TC 7 Z9 7 U1 0 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0969-806X J9 RADIAT PHYS CHEM JI Radiat. Phys. Chem. PD DEC PY 2014 VL 105 BP 6 EP 11 DI 10.1016/j.radphyschem.2014.05.017 PG 6 WC Chemistry, Physical; Nuclear Science & Technology; Physics, Atomic, Molecular & Chemical SC Chemistry; Nuclear Science & Technology; Physics GA AQ7TO UT WOS:000343022300003 ER PT J AU Baek, JH Kang, ES Fava, M Mischoulon, D Nierenberg, AA Lee, D Heo, JY Jeon, HJ AF Baek, Ji Hyun Kang, Eun-Suk Fava, Maurizio Mischoulon, David Nierenberg, Andrew A. Lee, Dongsoo Heo, Jung-Yoon Jeon, Hong Jin TI Thyroid stimulating hormone and serum, plasma, and platelet brain-derived neurotrophic factor during a 3-month follow-up in patients with major depressive disorder SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Thyroid hormone; Thyroid-stimulating hormone; BDNF; Major depressive disorder ID SEROTONIN REUPTAKE INHIBITORS; FACTOR BDNF; ANTIDEPRESSANT ACTION; HYPOTHYROIDISM; TRIIODOTHYRONINE; EXPRESSION; THYROXINE; INSUFFICIENCY; AUGMENTATION; INCREASE AB Background: Thyroid dysfunction and elevated thyroid stimulating hormone (TSH) are common in patients with depression. TSH might exert ifs function in the brain through blood levels of brain derived neurotrophic factor (BDNF). BDNF decreases during depressed states and normalize after treatment. The gap is that the association between TSH and BDNF in patients with major depressive disorder (MDD) is unknown. Methods.: We studied 105 subjects >= 18 years of age with MDD and measured serum, plasma, and platelet BDNF at baseline, 1 month and 3 months during antidepressant treatment. Other baseline measurements included hypothalamic-pituitary-thyroid axis hormones such as TSH, triiodothyronine (T3) and thyroxine (T4); hypothalamic-pituitary-adrenal (HPA) axis hormones and hypothalamic-pituitary-gonadal (HPG) axis hormones and prolactin. Results: Linear mixed model effect analyses revealed that baseline TSH level was negatively associated with changes of serum BDNF from baseline to 3 months (F=7.58, p=0.007) after adjusting for age, sex, and body mass index, but was not associated with plasma and platelet BDNF. In contrast, T3 and T4, HPA axis hormones, HPG axis hormones, and prolactin were not associated with serum, plasma, or platelet BDNF levels. Patients in the highest quartile of TSH showed significantly lower serum BDNF than in the other quartiles (F=4.54, p=0.038), but no significant differences were found based on T3 and T4 levels. Limitations: TSH was only measured at baseline. Conclusions: Higher TSH is associated with lower baseline and reduced the increase of serum BDNF levels during antidepressant treatment in patients with MDD. (C) 2014 Elsevier B.V. All rights reserved. C1 [Baek, Ji Hyun; Lee, Dongsoo; Heo, Jung-Yoon; Jeon, Hong Jin] Sungkyunkwan Univ, Sch Med, Dept Psychiat, Depress Ctr,Samsung Med Ctr, Seoul 135710, South Korea. [Jeon, Hong Jin] SAIHST, Seoul, South Korea. [Kang, Eun-Suk] Sungkyunkwan Univ, Sch Med, Dept Lab Med, Samsung Med Ctr, Seoul 135710, South Korea. [Fava, Maurizio; Mischoulon, David; Nierenberg, Andrew A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. [Baek, Ji Hyun; Nierenberg, Andrew A.; Jeon, Hong Jin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bipolar Clin, Boston, MA USA. [Baek, Ji Hyun; Nierenberg, Andrew A.; Jeon, Hong Jin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Res Program, Boston, MA USA. RP Jeon, HJ (reprint author), Sungkyunkwan Univ, Sch Med, Dept Psychiat, Depress Ctr,Samsung Med Ctr, 50 Irwon Dong, Seoul 135710, South Korea. EM jeonhj@skku.edu FU Samsung Social Mental Health Institute [SMHI 2010-04]; National Research Foundation of Korea (NRF); Samsung Medical Center Clinical Research Development Program(CRDP) Grant [SMO1131461] FX Funding for this study was provided by Samsung Social Mental Health Institute (SMHI 2010-04), National Research Foundation of Korea (NRF) and the Samsung Medical Center Clinical Research Development Program(CRDP) Grant SMO1131461. They had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 37 TC 6 Z9 7 U1 3 U2 27 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD DEC 1 PY 2014 VL 169 BP 112 EP 117 DI 10.1010/j.jad.2014.08.009 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AQ2LB UT WOS:000342616400018 PM 25189990 ER PT J AU Sylvia, LG Rabideau, DJ Nierenberg, AA Bowden, CL Friedman, ES Iosifescu, DV Thase, ME Ketter, T Greiter, EA Calabrese, JR Leon, AC Ostacher, MJ Reilly-Harrington, N AF Sylvia, Louisa G. Rabideau, Dustin J. Nierenberg, Andrew A. Bowden, Charles L. Friedman, Edward S. Iosifescu, Dan V. Thase, Michael E. Ketter, Terence Greiter, Elizabeth A. Calabrese, Joseph R. Leon, Andrew C. Ostacher, Michael J. Reilly-Harrington, Noreen TI The effect of personalized guideline-concordant treatment on quality of life and functional impairment in bipolar disorder SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Life functioning; Quality of life; Lithium ID PROSPECTIVE FOLLOW-UP; LITHIUM-TREATMENT; SUICIDE; DEPRESSION; SCALE; CARBAMAZEPINE; MANIA AB Objectives: The aims of this study were to evaluate correlates and predictors of life functioning and quality of life in bipolar disorder during a comparative effectiveness trial of moderate doses of lithium. Methods: In the Lithium treatment moderate-dose use study (LiTMUS), 283 symptomatic outpatients with bipolar disorder type l or II were randomized to receive lithium plus "optimal personalized treatment (OPT)", or OPT alone. Participants were assessed using structured diagnostic interviews, clinician-rated blinded assessments, and questionnaires. We employ linear mixed effects models to test the effect of treatment overall and adjunct lithium specifically on quality of life or functioning. Similar models are used to examine the association of baseline demographics and clinical features with quality of lift and life functioning. Results: Quality of life and impaired functioning at baseline were associated with lower income, higher depressive severity, and more psychiatric comorbid conditions. Over 6 months, patients in both treatment groups improved in quality of life and life functioning (p-Values < 0.0001); without a statistically significant difference between the two treatment groups (p-Values > 0.05). Within the lithium group, improvement in quality of life and functioning was not associated with concurrent lithium levels at week 12 or week 24 (p-Values > 0.05). Lower baseline depressive severity and younger age of onset predicted less improvement in functioning over 6 months. Conclusions: Optimized care for bipolar disorder improves overall quality of life and life functioning, with no additional benefit from adjunct moderate doses of lithium. Illness burden and psychosocial stressors were associated with worse quality of life and lower functioning in individuals with bipolar disorder. (C) 2014 Elsevier B.V. All rights reserved C1 [Sylvia, Louisa G.; Rabideau, Dustin J.; Nierenberg, Andrew A.; Greiter, Elizabeth A.; Reilly-Harrington, Noreen] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bowden, Charles L.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Friedman, Edward S.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. [Iosifescu, Dan V.] Mt Sinai Sch Med, New York, NY USA. [Thase, Michael E.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Ketter, Terence; Ostacher, Michael J.] Stanford Univ, Stanford, CA 94305 USA. [Calabrese, Joseph R.] Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA. [Leon, Andrew C.] Weill Cornell Med Coll, New York, NY USA. [Ostacher, Michael J.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. RP Sylvia, LG (reprint author), Massachusetts Gen Hosp, 50 Staniford St,Suite 580, Boston, MA 02114 USA. EM lsylvia2@partners.org OI Ostacher, Michael/0000-0003-0353-7535 FU NIMH FX NIMH covered the costs of the study. NR 28 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD DEC 1 PY 2014 VL 169 BP 144 EP 148 DI 10.1016/j.jad.2014.08.019 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AQ2LB UT WOS:000342616400021 PM 25194782 ER PT J AU Heesters, BA Das, A Chatterjee, P Carroll, MC AF Heesters, Balthasar A. Das, Abhishek Chatterjee, Priyadarshini Carroll, Michael C. TI Do follicular dendritic cells regulate lupus-specific B cells? SO MOLECULAR IMMUNOLOGY LA English DT Article DE Autoimmunity; Germinal center; Lupus nucleolar antigen; Negative selection ID COMPLEMENT COMPONENT C4; RAY CRYSTAL-STRUCTURE; APOPTOTIC CELLS; IMMUNE-COMPLEXES; AUTOIMMUNE-DISEASE; GERMINAL-CENTERS; RECEPTOR; MICE; ACTIVATION; ANTIGEN AB The factors that allow self-reactive B cells to escape negative selection and become activated remain poorly defined. In this review we describe recently published results in which a B cell receptor-knock-in mouse strain specific for nucleolar self-antigens was bred with mice deficient in complement C4 and discuss the implications for the lupus field. Absence of C4 leads to a breakdown in the elimination of autoreactive B cell clones at the transitional stage. This is characterized by a relative increase in their response to a range of stimuli, entrance into follicles and a greater propensity to form self-reactive germinal centers. In this review, a model is proposed in which, in the absence of complement C4, inappropriate clearance of apoptotic debris promotes chronic activation of myeloid cells and follicular dendritic cells, resulting in secretion of Type I interferon. This allows for the maturation and activation of self-reactive B cell clones leading to increased spontaneous formation of germinal centers and subsequent generation of autoantibodies. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Heesters, Balthasar A.; Das, Abhishek; Carroll, Michael C.] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Carroll, Michael C.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Chatterjee, Priyadarshini] Reg Ctr Biotechnol, New Delhi, India. RP Carroll, MC (reprint author), PCMM, Room 251 Warren Alpert Bldg,200 Long Wood Ave, Boston, MA 02115 USA. EM Michael.carroll@Childrens.harvard.edu FU NIH [R01 AI039246, R37 AI054636] FX The authors thank Ms. Carlien Frijlink for administrative assistance and members of the Carroll lab in helpful discussions of the project. In particular, we thank Dr. Soren Degn for discussions of pathways involving C4 and clearance of apoptotic cells. This work was supported by NIH grants R01 AI039246 and R37 AI054636 (to MCC). NR 48 TC 6 Z9 6 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD DEC PY 2014 VL 62 IS 2 SI SI BP 283 EP 288 DI 10.1016/j.molimm.2014.02.010 PG 6 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA AQ3SQ UT WOS:000342714200004 PM 24636642 ER PT J AU Sung, YJ Xu, L Nagarkar, V Gupta, R AF Sung, Yongjin Xu, Ling Nagarkar, Vivek Gupta, Rajiv TI Compressed X-ray phase-contrast imaging using a coded source SO OPTICS COMMUNICATIONS LA English DT Article DE X-ray phase-contrast imaging; Inverse scattering; Coded aperture imaging; Computational imaging ID RESTRICTED ISOMETRY PROPERTY; DARK-FIELD; RECONSTRUCTION; INTERFEROMETER; NOISE AB X-ray phase-contrast imaging (XPCI) holds great promise for medical X-ray imaging with high soft-tissue contrast. Obviating optical elements in the imaging chain, propagation-based XPCI (PB-XPCI) has definite advantages over other XPCI techniques in terms of cost, alignment and scalability. However, it imposes strict requirements on the spatial coherence of the source and the resolution of the detector. In this study, we demonstrate that using a coded X-ray source and sparsity-based reconstruction, we can significantly relax these requirements. Using numerical simulation, we assess the feasibility of our approach and study the effect of system parameters on the reconstructed image. The results are demonstrated with images obtained using a bench-top micro-focus XPCI system. (C) 2014 Elsevier B.V. All rights reserved. C1 [Sung, Yongjin; Gupta, Rajiv] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sung, Yongjin; Gupta, Rajiv] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Xu, Ling] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Nagarkar, Vivek] Radiat Monitoring Devices Inc, Watertown, MA 02472 USA. RP Sung, YJ (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM yongjin.sung@gmail.com FU DARPA AXiS program [N66001-11-4204, 1300217190] FX This research was funded by the DARPA AXiS program (Grant no. N66001-11-4204, P.R. no. 1300217190). The authors thank Dr. Synho Do, Dr. W. Clem Karl, and Dr. George Barbastathis for helpful discussions, and Dr. Bipin Singh and Dr. Haris Kudrolli for the help with the micro-focus XPCI system. NR 35 TC 1 Z9 1 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0030-4018 EI 1873-0310 J9 OPT COMMUN JI Opt. Commun. PD DEC 1 PY 2014 VL 332 BP 370 EP 378 DI 10.1016/j.optcom.2014.07.041 PG 9 WC Optics SC Optics GA AP7NI UT WOS:000342263600059 ER PT J AU Kaiser, NC Liang, LJ Melrose, RJ Wilkins, SS Sultzer, DL Mendez, MF AF Kaiser, Natalie C. Liang, Li-Jung Melrose, Rebecca J. Wilkins, Stacy S. Sultzer, David L. Mendez, Mario F. TI Differences in Anxiety Among Patients With Early- Versus Late-Onset Alzheimer's Disease SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID BEHAVIOR RATING-SCALE; NEUROPSYCHIATRIC INVENTORY; PSYCHIATRIC-SYMPTOMS; VASCULAR DEMENTIA; CACHE COUNTY; PREVALENCE; DISTURBANCES; DEPRESSION; MEMORY; PSYCHOPATHOLOGY AB The authors sought to evaluate the incidence and correlates of anxiety in early-onset Alzheimer's disease (EOAD) versus the more typical late-onset AD (LOAD). A group of 23 EOAD and 22 LOAD patients were compared by the Neuropsychiatric Inventory Anxiety subscale. Demographic and disease-related relationships with anxiety were evaluated, as well as types of anxiety symptoms that were endorsed. EOAD patients had significantly more anxiety symptoms than LOAD patients. Among those with EOAD, anxiety was associated with male gender, higher Mini-Mental State Exam score, and separation from caregivers. Among LOAD patients, anxiety was associated with psychotic and activating psychiatric symptoms. These results have implications for the management and alleviation of anxiety in AD. C1 [Kaiser, Natalie C.; Wilkins, Stacy S.; Sultzer, David L.; Mendez, Mario F.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Liang, Li-Jung; Melrose, Rebecca J.; Sultzer, David L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Kaiser, NC (reprint author), VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. EM Natalie.Kaiser@va.gov FU National Institutes of Health [R01AG034499-3]; Dept. of Veterans Affairs VA Merit Review; Career Development Award; National Institute of Mental Health [R01-MH56031]; GRECC Fellowship Award FX This research was supported by National Institutes of Health Grant #R01AG034499-3 (M. Mendez PI); Dept. of Veterans Affairs VA Merit Review (two separate awards; one to M. Mendez and one to D. Sultzer); Career Development Award to R. Melrose; National Institute of Mental Health #R01-MH56031 (D. Sultzer, PI); GRECC Fellowship Award to N. Kaiser. NR 46 TC 5 Z9 6 U1 4 U2 163 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 EI 1545-7222 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD WIN PY 2014 VL 26 IS 1 BP 73 EP 80 PG 8 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AB9OW UT WOS:000332125500041 PM 24515678 ER PT J AU Izquierdo, A Sarkisian, C Ryan, G Wells, KB Miranda, J AF Izquierdo, Adriana Sarkisian, Catherine Ryan, Gery Wells, Kenneth B. Miranda, Jeanne TI OLDER DEPRESSED LATINOS' EXPERIENCES WITH PRIMARY CARE VISITS FOR PERSONAL, EMOTIONAL AND/OR MENTAL HEALTH PROBLEMS: A QUALITATIVE ANALYSIS SO ETHNICITY & DISEASE LA English DT Article DE Depression; Aging; Latino; Primary Care ID RANDOMIZED CONTROLLED-TRIAL; POPULATION; SYMPTOMS; IMPACT AB Objective: To describe salient experiences with a primary care visit (eg, the context leading up to the visit, the experience and/or outcomes of that visit) for emotional, personal and/or mental health problems older Latinos with a history of depression and recent depressive symptoms and/or antidepressant medication use reported 10 years after enrollment into a randomized controlled trial of quality-improvement for depression in primary care. Design: Secondary analysis of existing qualitative data from the second stage of the continuation study of Partners in Care (PIC). Participants: Latino ethnicity, aged >= 50 years, recent depressive symptoms and/or antidepressant medication use, and a recent primary care visit for mental health problems. Of 280 second-stage participants, 47 were eligible. Both stages of the continuation study included participants from the PIC parent study control and 2 intervention groups, and all had a history of depression. Methods: Data analyzed by a multidisciplinary team using grounded theory methodology. Results: Five themes were identified: beliefs about the nature of depression; prior experiences with mental health disorders/treatments; sociocultural context (eg, social relationships, caregiving, the media); clinic-related features (eg, accessibility of providers, staff continuity, amount of visit time); and provider attributes (eg, interpersonal skills, holistic care approach). Conclusions: Findings emphasize the importance of key features for shaping the context leading up to primary care visits for help-seeking for mental health problems, and the experience and/or outcomes of those visits, among older depressed Latinos at long-term follow-up, and may help tailor chronic depression care for the clinical management of this vulnerable population. C1 [Izquierdo, Adriana] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA 90095 USA. [Sarkisian, Catherine] Univ Calif Los Angeles, David Geffen Sch Med, Div Geriatr, Los Angeles, CA 90095 USA. [Sarkisian, Catherine] VA Greater Los Angeles Healthcare Syst, Geriatr Res Educ Clin Ctr, Los Angeles, CA USA. [Ryan, Gery] RAND Corp, Santa Monica, CA USA. [Izquierdo, Adriana; Wells, Kenneth B.; Miranda, Jeanne] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Ctr Hlth Serv & Soc, Los Angeles, CA 90024 USA. RP Izquierdo, A (reprint author), 10920 Wilshire Blvd,Suite 300, Los Angeles, CA 90024 USA. EM aizquierdo@mednet.ucla.edu FU Diversity Supplement (NIMH) [P30-MH082760-04]; UCLA Resource Centers for Minority Aging Research/Center for Health Improvement of Minority Elderly (RCMAR/CHIME) (NIH/NIA) [P30-AG021684]; UCLA-CTSI (NIH/NCRR/NCATS [ULITR000124] FX Dr. Izquierdo was supported by a Diversity Supplement (NIMH Grant P30-MH082760-04), the UCLA Resource Centers for Minority Aging Research/Center for Health Improvement of Minority Elderly (RCMAR/CHIME) (NIH/NIA Grant P30-AG021684), and the UCLA-CTSI (NIH/NCRR/NCATS Grant ULITR000124). NR 16 TC 1 Z9 1 U1 3 U2 99 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X EI 1945-0826 J9 ETHNIC DIS JI Ethn. Dis. PD WIN PY 2014 VL 24 IS 1 BP 84 EP 91 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AB3IA UT WOS:000331683300013 PM 24620453 ER PT J AU Laposata, M AF Laposata, Michael TI Putting the Patient First - Using the Expertise of Laboratory Professionals to Produce Rapid and Accurate Diagnoses SO LABMEDICINE LA English DT Editorial Material C1 [Laposata, Michael] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Laposata, Michael] Vanderbilt Univ Sch Med, Nashville, TN USA. [Laposata, Michael] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Laposata, Michael] Massachusetts Gen Hosp, Clin Labs, Boston, MA 02114 USA. [Laposata, Michael] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Laposata, M (reprint author), Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. NR 0 TC 1 Z9 1 U1 1 U2 10 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0007-5027 EI 1943-7730 J9 LABMEDICINE JI Labmedicine PD WIN PY 2014 VL 45 IS 1 BP 4 EP 5 DI 10.1309/LM31UQ3NJCQXJUCC PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 294AN UT WOS:000330014900001 PM 24719977 ER PT J AU Lennerz, JK AF Lennerz, Jochen K. TI Double-punching PMBL SO ONCOTARGET LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02163 USA. RP Lennerz, JK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02163 USA. EM JLennerz@partners.org NR 7 TC 0 Z9 0 U1 0 U2 0 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 30 PY 2014 VL 5 IS 22 BP 10965 EP 10966 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ2AQ UT WOS:000348037400004 PM 25473898 ER PT J AU Blumenthal, DM Bernard, K Fraser, TN Bohnen, J Zeidman, J Stone, VE AF Blumenthal, Daniel M. Bernard, Ken Fraser, Traci N. Bohnen, Jordan Zeidman, Jessica Stone, Valerie E. TI Implementing a pilot leadership course for internal medicine residents: design considerations, participant impressions, and lessons learned SO BMC MEDICAL EDUCATION LA English DT Article DE Leadership development; Management; Quality of care; Teamwork; Patient safety ID HEALTH-CARE; EMOTIONAL INTELLIGENCE; PHYSICIAN LEADERSHIP; MANAGEMENT; CURRICULUM; TEAMS; EDUCATION.; HOSPITALS; PROGRAMS; PATHWAY AB Background: Effective clinical leadership is associated with better patient care. We implemented and evaluated a pilot clinical leadership course for second year internal medicine residents at a large United States Academic Medical Center that is part of a multi-hospital health system. Methods: The course met weekly for two to three hours during July, 2013. Sessions included large group discussions and small group reflection meetings. Topics included leadership styles, emotional intelligence, and leading clinical teams. Course materials were designed internally and featured "business school style" case studies about everyday clinical medicine which explore how leadership skills impact care delivery. Participants evaluated the course's impact and quality using a post-course survey. Questions were structured in five point likert scale and free text format. Likert scale responses were converted to a 1-5 scale (1 = strongly disagree; 3 = neither agree nor disagree; 5 = strongly agree), and means were compared to the value 3 using one-way T-tests. Responses to free text questions were analyzed using the constant comparative method. Results: All sixteen pilot course participants completed the survey. Participants overwhelmingly agreed that the course provided content and skills relevant to their clinical responsibilities and leadership roles. Most participants also acknowledged that taking the course improved their understanding of their strengths and weaknesses as leaders, different leadership styles, and how to manage interpersonal conflict on clinical teams. 88% also reported that the course increased their interest in pursuing additional leadership training. Conclusions: A clinical leadership course for internal medicine residents designed by colleagues, and utilizing case studies about clinical medicine, resulted in significant self-reported improvements in clinical leadership competencies. C1 [Blumenthal, Daniel M.; Fraser, Traci N.; Zeidman, Jessica] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. [Blumenthal, Daniel M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Internal Med, Boston, MA 02114 USA. [Bernard, Ken] Harvard Univ, Sch Med, Partners Healthcare, Dept Emergency Med, Boston, MA 02114 USA. [Zeidman, Jessica] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Internal Med, Boston, MA 02114 USA. [Bohnen, Jordan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Gen Surg, Boston, MA 02114 USA. [Stone, Valerie E.] Harvard Univ, Sch Med, Mt Auburn Hosp, Dept Med, Boston, MA 02114 USA. RP Blumenthal, DM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, 55 Fruit St,GRB 800, Boston, MA 02114 USA. EM dblumenthal1@partners.org NR 51 TC 6 Z9 7 U1 3 U2 20 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6920 J9 BMC MED EDUC JI BMC Med. Educ. PD NOV 30 PY 2014 VL 14 AR UNSP 257 DI 10.1186/s12909-014-0257-2 PG 11 WC Education & Educational Research; Education, Scientific Disciplines SC Education & Educational Research GA AY1KJ UT WOS:000347351900001 PM 25433680 ER PT J AU Miller, CJ Li, MF Penfold, RB Lee, AF Smith, EG Osser, DN Bajor, L Bauer, MS AF Miller, Christopher J. Li, Mingfei Penfold, Robert B. Lee, Austin F. Smith, Eric G. Osser, David N. Bajor, Laura Bauer, Mark S. TI Patterns of initiation of second generation antipsychotics for bipolar disorder: a month-by-month analysis of provider behavior SO BMC PSYCHIATRY LA English DT Article DE Bipolar disorder; Antipsychotics; Veterans ID RANDOMIZED CONTROLLED-TRIALS; UNITED-STATES; ATYPICAL ANTIPSYCHOTICS; PRESCRIPTION PATTERNS; TREATMENT GUIDELINES; TREAT SCHIZOPHRENIA; RACIAL DISPARITY; MEDICATION USE; MIXED STATES; VETERANS AB Background: Several second generation antipsychotics (SGAs) received FDA approval for bipolar disorder in the 2000s. Although efficacious, they have been costly and may cause significant side effects. Little is known about the factors associated with prescribers' decisions to initiate SGA prescriptions for this condition. Methods: We gathered administrative data from the Department of Veterans Affairs on 170,713 patients with bipolar disorder between fiscal years 2003-2010. Patients without a prior history of taking SGAs were considered eligible for SGA initiation during the study (n = 126,556). Generalized estimating equations identified demographic, clinical, and comorbidity variables associated with initiation of an SGA prescription on a month-by-month basis. Results: While the number of patients with bipolar disorder using SGAs nearly doubled between 2003 and 2010, analyses controlling for patient characteristics and the rise in the bipolar population revealed a 1.2% annual decline in SGA initiation during this period. Most medical comorbidities were only modestly associated with overall SGA initiation, although significant differences emerged among individual SGAs. Several markers of patient severity predicted SGA initiation, including previous hospitalizations, psychotic features, and a history of other antimanic prescriptions; these severity markers became less firmly linked to SGA initiation over time. Providers in the South were somewhat more likely to initiate SGA treatment. Conclusions: The number of veterans with bipolar disorder prescribed SGAs is rising steadily, but this increase appears primarily driven by a corresponding increase in the bipolar population. Month-by-month analyses revealed that higher illness severity predicted SGA initiation, but that this association may be weakening over time. C1 [Miller, Christopher J.; Li, Mingfei; Lee, Austin F.; Smith, Eric G.; Bajor, Laura; Bauer, Mark S.] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Bedford, MA 02130 USA. [Miller, Christopher J.; Li, Mingfei; Lee, Austin F.; Bajor, Laura; Bauer, Mark S.] Edith Nourse Rogers Mem VA Med Ctr, Bedford, MA USA. [Bauer, Mark S.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Li, Mingfei; Lee, Austin F.] Bentley Univ, Dept Math Sci, Waltham, MA USA. [Penfold, Robert B.] Grp Hlth Res Inst, Seattle, WA USA. [Penfold, Robert B.] Univ Washington, Dept Hlth Serv Res, Seattle, WA 98195 USA. [Lee, Austin F.] Xian Univ Finance & Econ, Res Ctr Med Stat & Actuarial Sci, Xian, Peoples R China. [Lee, Austin F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Smith, Eric G.] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA. [Osser, David N.] VA Boston Healthcare Syst, Brockton, MA USA. RP Miller, CJ (reprint author), VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Bedford, MA 02130 USA. EM christopher.miller8@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research Development [IIR-10-314] FX This study was funded by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research & Development grant #IIR-10-314, "Spatiotemporal Spread of Newer Antipsychotics for Bipolar Disorder and PTSD." The funding organization provided competitive grant support for these analyses but was not otherwise involved in the design or conduct of the study, or review or approval of this manuscript. The opinions expressed in this manuscript represent the views of the authors and do not necessarily reflect the views of the Department of Veterans Affairs. These data have not yet been presented at a scientific meeting. Special thanks to Samuel S. Nordberg, PhD and Fang Zhang, PhD for their help in preparing this manuscript. NR 50 TC 3 Z9 3 U1 5 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-244X J9 BMC PSYCHIATRY JI BMC Psychiatry PD NOV 30 PY 2014 VL 14 AR 339 DI 10.1186/s12888-014-0339-z PG 10 WC Psychiatry SC Psychiatry GA AU8SZ UT WOS:000345868000001 PM 25433807 ER PT J AU Lee, DJ Liverant, GI Lowmaster, SE Gradus, JL Sloan, DM AF Lee, Daniel J. Liverant, Gabrielle I. Lowmaster, Sara E. Gradus, Jaimie L. Sloan, Denise M. TI PTSD and reasons for living: Associations with depressive symptoms and alcohol use SO PSYCHIATRY RESEARCH LA English DT Article DE PTSD; Trauma; Depression; Alcohol Use; Reasons for living ID POSTTRAUMATIC-STRESS-DISORDER; NATIONAL COMORBIDITY SURVEY; IDENTIFICATION TEST AUDIT; MAJOR DEPRESSION; SUICIDAL IDEATION; SELF-HARM; INVENTORY; BEHAVIOR; ADULTS; TRIAL AB Posttraumatic stress disorder (PTSD) is associated with suicidal ideation and behavior, and is found to frequently co-occur with other conditions that exacerbate the risk for suicidal behavior. Despite these findings, few individuals with PTSD engage in suicidal acts, and there has been little research to examine those factors that protect against such behaviors. The current study used path analysis to examine the association among PTSD, depression, hazardous alcohol consumption, and beliefs about suicide (i.e., reasons for living) in a community sample with motor vehicle accident related-PTSD (N=50). Reasons for living were inversely associated with PTSD, depression, and alcohol use. Further, depression symptom severity accounted for the association between PTSD symptom severity and reasons for living. In contrast, hazardous alcohol consumption only demonstrated a trend for accounting for the association between PTSD and reasons for living. Our findings highlight the importance of clinicians assessing co-occurring depression symptoms and suggest the potential use of interventions that promote adaptive cognitions about suicide among people with PTSD. Published by Elsevier Ireland Ltd. C1 [Lee, Daniel J.] Auburn Univ, Dept Psychol, Auburn, AL 36849 USA. [Liverant, Gabrielle I.; Lowmaster, Sara E.; Sloan, Denise M.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Liverant, Gabrielle I.; Lowmaster, Sara E.; Gradus, Jaimie L.; Sloan, Denise M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Gradus, Jaimie L.; Sloan, Denise M.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. [Gradus, Jaimie L.] Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Sloan, DM (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD 116B 2, 150 South Huntington Ave, Boston, MA 02130 USA. EM Denise.Sloan@va.gov OI Gradus, Jaimie/0000-0003-1459-5327 FU National Institute of Mental Health [R34MH077658-02] FX This study was supported by a National Institute of Mental Health under Grant (R34MH077658-02) awarded to the last author. NR 45 TC 2 Z9 2 U1 7 U2 34 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD NOV 30 PY 2014 VL 219 IS 3 BP 550 EP 555 DI 10.1016/j.psychres.2014.06.016 PG 6 WC Psychiatry SC Psychiatry GA AP2KR UT WOS:000341901600022 PM 24984579 ER PT J AU Mitchell, KS Rasmusson, A Bartlett, B Gerber, MR AF Mitchell, Karen S. Rasmusson, Ann Bartlett, Brooke Gerber, Megan R. TI Eating disorders and associated mental health comorbidities in female veterans SO PSYCHIATRY RESEARCH LA English DT Article DE Disordered eating; Women; Mental health ID WOMEN VETERANS; POSTTRAUMATIC-STRESS; SURVEY-REPLICATION; SEXUAL TRAUMA; DEPRESSION; PREVALENCE AB Eating disorders (EDs) remain understudied among veterans, possibly due to the perception that primarily male population does not suffer from EDs. However, previous research suggests that male and female veterans do experience EDs. The high rates of posttraumatic stress disorder (PTSD), depression, and obesity observed among veterans may make this group vulnerable to disordered eating. Retrospective chart review was used to obtain data from 492 female veterans who were presented to a women's primary care center at a large, urban VA medical center between 2007 and 2009. A total of 2.8% of this sample had been diagnosed with an ED. In bivariate analyses, presence of PTSD and depression were significantly associated with having an ED diagnosis. However, when these two disorders were included in a multivariate model controlling for age, only depression diagnosis and lower age were significantly related to ED status. In sum, the rate of EDs in this sample is comparable to prevalence estimates of EDs in the general population. Current findings underscore the importance of assessing for EDs among VA patients and the need for further research among veterans. Published by Elsevier Ireland Ltd. C1 [Mitchell, Karen S.; Rasmusson, Ann; Bartlett, Brooke] VA Boston Healthcare Syst, Womens Hlth Sci Div 116B 3, Natl Ctr PTSD, Boston, MA 02130 USA. [Mitchell, Karen S.; Rasmusson, Ann; Bartlett, Brooke] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Gerber, Megan R.] VA Boston Healthcare Syst, Womens Hlth, Boston, MA 02130 USA. [Gerber, Megan R.] Boston Univ, Sch Med, Div Gen Internal Med, Boston, MA 02118 USA. RP Mitchell, KS (reprint author), VA Boston Healthcare Syst, Womens Hlth Sci Div 116B 3, Natl Ctr PTSD, 150 South Huntington Ave, Boston, MA 02130 USA. EM ksmitche@bu.edu OI Gerber, Megan/0000-0002-8444-5554 FU NIMH NIH HHS [K01 MH093750] NR 16 TC 3 Z9 3 U1 1 U2 28 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD NOV 30 PY 2014 VL 219 IS 3 BP 589 EP 591 DI 10.1016/j.psychres.2014.06.018 PG 3 WC Psychiatry SC Psychiatry GA AP2KR UT WOS:000341901600028 PM 25015710 ER PT J AU Taylor, JJ Neitzke, DJ Khouri, G Borckardt, JJ Acierno, R Tuerk, PW Schmidt, M George, MS AF Taylor, Joseph J. Neitzke, Daniel J. Khouri, George Borckardt, Jeffrey J. Acierno, Ron Tuerk, Peter W. Schmidt, Matthew George, Mark S. TI A pilot study to investigate the induction and manipulation of learned helplessness in healthy adults SO PSYCHIATRY RESEARCH LA English DT Article DE Learned helplessness; Stress; rTMS; Prefrontal cortex; Post-traumatic stress disorder; Depression ID TRANSCRANIAL MAGNETIC STIMULATION; POSTTRAUMATIC-STRESS-DISORDER; MEDIAL PREFRONTAL CORTEX; DORSAL RAPHE NUCLEUS; BRAIN ACTIVATION; PRIMARY-CARE; DEPRESSION; RTMS; PTSD; CONTROLLABILITY AB Eliminating the controllability of a noxious stimulus may induce a learned helplessness (LH) that resembles aspects of depression and post-traumatic stress disorder (PTSD). This study examined whether repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) promotes resilience in an aversive stimulus model of LH. All 55 participants were told that an undisclosed sequence of button presses would terminate an aversive stimulus on their forearm. In truth, only half had control (+C). The other half had no control (-C). All participants received real (R) or sham (S) left DLPFC rTMS during the paradigm (+C/R, -C/S, +C/S, -C/R). We evaluated the cognitive effects of LH using an anagram task. The LH paradigm successfully reduced perceived control in the -C groups. As predicted, the +C/R and +C/S groups tended to give up less quickly and take less time to solve each anagram than did the -C/S group. Superior anagram performance in the -C/R group approached statistical significance. Our preliminary results suggest that manipulating the controllability of an aversive stimulus may induce an LH effect that manifests as impaired anagram performance. Further research is needed to refine this model and determine if DLPFC rTMS mitigates any LH effects. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Taylor, Joseph J.; Neitzke, Daniel J.; Khouri, George; Borckardt, Jeffrey J.; Acierno, Ron; Tuerk, Peter W.; Schmidt, Matthew; George, Mark S.] Med Univ S Carolina, Charleston, SC 29425 USA. [Acierno, Ron; Tuerk, Peter W.; George, Mark S.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP George, MS (reprint author), Med Univ S Carolina, Brain Stimulat Lab, 67 President St, Charleston, SC 29425 USA. EM georgem@musc.edu FU NIDA [F30DA033748]; NIGMS [T32 GM008716]; USAMRAA/TATRC [W81XWH-10-2-0194] FX JT was funded by NIDA (Grant no. F30DA033748). DN was funded by NIGMS (Grant no. T32 GM008716). MG was partially funded through USAMRAA/TATRC W81XWH-10-2-0194. MG would like to acknowledge Dr. John Carney for many interesting brainstorming sessions about resiliency and brain circuits and stimulation. NR 37 TC 1 Z9 1 U1 2 U2 27 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD NOV 30 PY 2014 VL 219 IS 3 BP 631 EP 637 DI 10.1016/j.psychres.2014.05.045 PG 7 WC Psychiatry SC Psychiatry GA AP2KR UT WOS:000341901600035 PM 25023370 ER PT J AU Glass, K Quackenbush, J Silverman, EK Celli, B Rennard, SI Yuan, GC DeMeo, DL AF Glass, Kimberly Quackenbush, John Silverman, Edwin K. Celli, Bartolome Rennard, Stephen I. Yuan, Guo-Cheng DeMeo, Dawn L. TI Sexually-dimorphic targeting of functionally-related genes in COPD SO BMC SYSTEMS BIOLOGY LA English DT Article DE Network modeling; Gene regulation; Regulatory networks; Sexual-dimorphism; Chronic Obstructive Lung Disease ID OBSTRUCTIVE PULMONARY-DISEASE; ESTROGEN-RECEPTOR-BETA; SEX-DIFFERENCES; CIGARETTE-SMOKE; SKELETAL-MUSCLE; NETWORK RECONSTRUCTION; MITOCHONDRIAL-FUNCTION; TRANSCRIPTION FACTORS; MATERNAL INHERITANCE; EXPRESSION DATA AB Background: There is growing evidence that many diseases develop, progress, and respond to therapy differently in men and women. This variability may manifest as a result of sex-specific structures in gene regulatory networks that influence how those networks operate. However, there are few methods to identify and characterize differences in network structure, slowing progress in understanding mechanisms driving sexual dimorphism. Results: Here we apply an integrative network inference method, PANDA (Passing Attributes between Networks for Data Assimilation), to model sex-specific networks in blood and sputum samples from subjects with Chronic Obstructive Pulmonary Disease (COPD). We used a jack-knifing approach to build an ensemble of likely networks for each sex. By adapting statistical methods to compare these network ensembles, we were able to identify strong differential-targeting patterns associated with functionally-related sets of genes, including those involved in mitochondrial function and energy metabolism. Network analysis also identified several potential sex-and disease-specific transcriptional regulators of these pathways. Conclusions: Network analysis yielded insight into potential mechanisms driving sexual dimorphism in COPD that were not evident from gene expression analysis alone. We believe our ensemble approach to network analysis provides a principled way to capture sex-specific regulatory relationships and could be applied to identify differences in gene regulatory patterns in a wide variety of diseases and contexts. C1 [Glass, Kimberly; Quackenbush, John; Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Glass, Kimberly; Quackenbush, John; Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Glass, Kimberly; Quackenbush, John; Silverman, Edwin K.; DeMeo, Dawn L.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Glass, Kimberly; Quackenbush, John; Silverman, Edwin K.; DeMeo, Dawn L.] Harvard Univ, Sch Med, Boston, MA USA. [Silverman, Edwin K.; Celli, Bartolome; DeMeo, Dawn L.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Rennard, Stephen I.] Univ Nebraska, Med Ctr, Div Pulm Crit Care Sleep & Allergy, Omaha, NE USA. RP Glass, K (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM rekrg@channing.harvard.edu FU [R01 HL089438]; [R01 HL111759-01A1]; [R01 HL111759-02S1]; [P01 HL105339] FX This project has been supported by R01 HL089438, R01 HL111759-01A1, R01 HL111759-02S1 and P01 HL105339. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ECLIPSE clinical Investigators - Bulgaria: Y. Ivanov, Pleven; K. Kostov, Sofia. Canada: J. Bourbeau, Montreal; M. Fitzgerald, Vancouver, BC; P. Hernandez, Halifax, NS; K. Killian, Hamilton, ON; R. Levy, Vancouver, BC; F. Maltais, Montreal; D. O'Donnell, Kingston, ON. Czech Republic: J. Krepelka, Prague. Denmark: J. Vestbo, Hvidovre. The Netherlands: E. Wouters, Horn-Maastricht. New Zealand: D. Quinn, Wellington. Norway: P. Bakke, Bergen. Slovenia: M. Kosnik, Golnik. Spain: A. Agusti, J. Sauleda, P. de Mallorca. Ukraine: Y. Feschenko, V. Gavrisyuk, L. Yashina, Kiev; N. Monogarova, Donetsk. United Kingdom: P. Calverley, Liverpool; D. Lomas, Cambridge; W. MacNee, Edinburgh; D. Singh, Manchester; J. Wedzicha, London. United States: A. Anzueto, San Antonio, TX; S. Braman, Providence, RI; R. Casaburi, Torrance CA; B. Celli, Boston; G. Giessel, Richmond, VA; M. Gotfried, Phoenix, AZ; G. Greenwald, Rancho Mirage, CA; N. Hanania, Houston; D. Mahler, Lebanon, NH; B. Make, Denver; S. Rennard, Omaha, NE; C. Rochester, New Haven, CT; P. Scanlon, Rochester, MN; D. Schuller, Omaha, NE; F. Sciurba, Pittsburgh; A. Sharafkhaneh, Houston; T. Siler, St. Charles, MO; E. Silverman, Boston; A. Wanner, Miami; R. Wise, Baltimore; R. ZuWallack, Hartford, CT. NR 85 TC 6 Z9 6 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD NOV 28 PY 2014 VL 8 AR 118 DI 10.1186/s12918-014-0118-y PG 17 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AY4OP UT WOS:000347558500001 PM 25431000 ER PT J AU Gomez-Cabrero, D Menche, J Cano, I Abugessaisa, I Huertas-Miguelanez, M Tenyi, A de Mas, IM Kiani, NA Marabita, F Falciani, F Burrowes, K Maier, D Wagner, P Selivanov, V Cascante, M Roca, J Barabasi, AL Tegner, J AF Gomez-Cabrero, David Menche, Joerg Cano, Isaac Abugessaisa, Imad Huertas-Miguelanez, Mercedes Tenyi, Akos Marin de Mas, Igor Kiani, Narsis A. Marabita, Francesco Falciani, Francesco Burrowes, Kelly Maier, Dieter Wagner, Peter Selivanov, Vitaly Cascante, Marta Roca, Josep Barabasi, Albert-Laszlo Tegner, Jesper TI Systems Medicine: from molecular features and models to the clinic in COPD SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; PROTEIN INTERACTION NETWORK; COMPREHENSIVE RESOURCE; INTERACTION DATABASE; GENE-EXPRESSION; CANDIDATE GENES; INTERACTOME; INTEGRATION; MECHANISMS; UPDATE AB Background and hypothesis: Chronic Obstructive Pulmonary Disease (COPD) patients are characterized by heterogeneous clinical manifestations and patterns of disease progression. Two major factors that can be used to identify COPD subtypes are muscle dysfunction/wasting and co-morbidity patterns. We hypothesized that COPD heterogeneity is in part the result of complex interactions between several genes and pathways. We explored the possibility of using a Systems Medicine approach to identify such pathways, as well as to generate predictive computational models that may be used in clinic practice. Objective and method: Our overarching goal is to generate clinically applicable predictive models that characterize COPD heterogeneity through a Systems Medicine approach. To this end we have developed a general framework, consisting of three steps/objectives: (1) feature identification, (2) model generation and statistical validation, and (3) application and validation of the predictive models in the clinical scenario. We used muscle dysfunction and co-morbidity as test cases for this framework. Results: In the study of muscle wasting we identified relevant features (genes) by a network analysis and generated predictive models that integrate mechanistic and probabilistic models. This allowed us to characterize muscle wasting as a general de-regulation of pathway interactions. In the co-morbidity analysis we identified relevant features (genes/pathways) by the integration of gene-disease and disease-disease associations. We further present a detailed characterization of co-morbidities in COPD patients that was implemented into a predictive model. In both use cases we were able to achieve predictive modeling but we also identified several key challenges, the most pressing being the validation and implementation into actual clinical practice. Conclusions: The results confirm the potential of the Systems Medicine approach to study complex diseases and generate clinically relevant predictive models. Our study also highlights important obstacles and bottlenecks for such approaches (e.g. data availability and normalization of frameworks among others) and suggests specific proposals to overcome them. C1 [Gomez-Cabrero, David; Abugessaisa, Imad; Kiani, Narsis A.; Marabita, Francesco; Tegner, Jesper] Karolinska Inst, Unit Computat Med, Ctr Mol Med, Dept Med, Stockholm, Sweden. [Gomez-Cabrero, David; Abugessaisa, Imad; Kiani, Narsis A.; Marabita, Francesco; Tegner, Jesper] Karolinska Univ Hosp, Stockholm, Sweden. [Menche, Joerg; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Ctr Complex Network Res, Boston, MA 02115 USA. [Menche, Joerg; Barabasi, Albert-Laszlo] Budapest Univ Technol & Econ, Dept Theoret Phys, H-1111 Budapest, Hungary. [Cano, Isaac; Roca, Josep] Univ Barcelona, Hosp Clin, IDIBAPS, CIBERES, Barcelona, Catalunya, Spain. [Huertas-Miguelanez, Mercedes] Barcelona Digital Technol Ctr, Barcelona 08018, Spain. [Tenyi, Akos; Marin de Mas, Igor; Selivanov, Vitaly; Cascante, Marta] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain. [Falciani, Francesco] Univ Liverpool, Inst Integrat Biol, Liverpool L69 3BX, Merseyside, England. [Burrowes, Kelly] Univ Oxford, Dept Comp Sci, Oxford OX1 3QD, England. [Maier, Dieter] Biomax Informat AG, Munich, Germany. [Wagner, Peter] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Barabasi, Albert-Laszlo] Cent European Univ, Ctr Network Sci, H-1051 Budapest, Hungary. [Barabasi, Albert-Laszlo] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. RP Barabasi, AL (reprint author), Karolinska Inst, Unit Computat Med, Ctr Mol Med, Dept Med, Stockholm, Sweden. EM alb@neu.edu; jesper.tegner@ki.se RI Roca, Josep/J-2583-2015; Menche, Jorg/G-3994-2015; OI Roca, Josep/0000-0003-4768-8722; Menche, Jorg/0000-0002-1583-6404; Burrowes, Kelly/0000-0002-6369-2951; Kiani, Narsis/0000-0002-0949-046X; Abugessaisa, Imad/0000-0001-7458-801X; Marabita, Francesco/0000-0001-6180-0106 FU Synergy-COPD European project [FP7-ICT-270086] FX Publication of this article has been funded by the Synergy-COPD European project (FP7-ICT-270086). The opinions expressed in this manuscript are those of the authors and are not necessarily those of Synergy-COPD project's partners or the European Commission NR 70 TC 8 Z9 8 U1 0 U2 261 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD NOV 28 PY 2014 VL 12 SU 2 AR S4 DI 10.1186/1479-5876-12-S2-S4 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AW3TA UT WOS:000346207800004 PM 25471042 ER PT J AU Auld, AF Agolory, SG Shiraishi, RW Wabwire-Mangen, F Kwesigabo, G Mulenga, M Hachizovu, S Asadu, E Tuho, MZ Ettiegne-Traore, V Mbofana, F Okello, V Azih, C Denison, JA Tsui, S Koole, O Kamiru, H Nuwagaba-Biribonwoha, H Alfredo, C Jobarteh, K Odafe, S Onotu, D Ekra, KA Kouakou, JS Ehrenkranz, P Bicego, G Torpey, K Mukadi, YD van Praag, E Menten, J Mastro, T Hamilton, CD Swaminathan, M Dokubo, EK Baughman, AL Spira, T Colebunders, R Bangsberg, D Marlink, R Zee, A Kaplan, J Ellerbrock, TV AF Auld, Andrew F. Agolory, Simon G. Shiraishi, Ray W. Wabwire-Mangen, Fred Kwesigabo, Gideon Mulenga, Modest Hachizovu, Sebastian Asadu, Emeka Tuho, Moise Zanga Ettiegne-Traore, Virginie Mbofana, Francisco Okello, Velephi Azih, Charles Denison, Julie A. Tsui, Sharon Koole, Olivier Kamiru, Harrison Nuwagaba-Biribonwoha, Harriet Alfredo, Charity Jobarteh, Kebba Odafe, Solomon Onotu, Dennis Ekra, Kunomboa A. Kouakou, Joseph S. Ehrenkranz, Peter Bicego, George Torpey, Kwasi Mukadi, Ya Diul van Praag, Eric Menten, Joris Mastro, Timothy Hamilton, Carol Dukes Swaminathan, Mahesh Dokubo, E. Kainne Baughman, Andrew L. Spira, Thomas Colebunders, Robert Bangsberg, David Marlink, Richard Zee, Aaron Kaplan, Jonathan Ellerbrock, Tedd V. TI Antiretroviral Therapy Enrollment Characteristics and Outcomes Among HIV-Infected Adolescents and Young Adults Compared with Older Adults - Seven African Countries, 2004-2013 SO MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT LA English DT Article C1 [Auld, Andrew F.; Agolory, Simon G.; Shiraishi, Ray W.; Swaminathan, Mahesh; Dokubo, E. Kainne; Baughman, Andrew L.; Spira, Thomas; Zee, Aaron; Kaplan, Jonathan; Ellerbrock, Tedd V.] CDC, Ctr Global Hlth, Div Global HIV AIDS, Atlanta, GA 30333 USA. [Wabwire-Mangen, Fred] Makerere Univ, Coll Hlth Sci, Infect Dis Inst, Kampala, Uganda. [Kwesigabo, Gideon] Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania. [Mulenga, Modest; Hachizovu, Sebastian] Trop Dis Res Ctr, Ndola, Zambia. [Asadu, Emeka] Minist Hlth, Abuja, Nigeria. [Tuho, Moise Zanga; Ettiegne-Traore, Virginie] Minist Hlth, Abidjan, Cote Ivoire. [Mbofana, Francisco] Natl Inst Hlth, Maputo, Mozambique. [Okello, Velephi; Azih, Charles] Minist Hlth, Manzini, Swaziland. [Denison, Julie A.; Tsui, Sharon] FHI 360, Social & Behav Hlth Sci, Washington, DC USA. [Koole, Olivier; Menten, Joris; Colebunders, Robert] Inst Trop Med, Dept Clin Sci, Antwerp, Belgium. [Kamiru, Harrison; Nuwagaba-Biribonwoha, Harriet] Columbia Univ, Int Ctr AIDS Care, New York, NY USA. [Kamiru, Harrison; Nuwagaba-Biribonwoha, Harriet] Columbia Univ, Treatment Programs, New York, NY USA. [Alfredo, Charity; Jobarteh, Kebba] CDC, Ctr Global Hlth, Div Global HIV AIDS, Maputo, Mozambique. [Odafe, Solomon; Onotu, Dennis] CDC, Ctr Global Hlth, Div Global HIV AIDS, Lagos, Nigeria. [Ekra, Kunomboa A.; Kouakou, Joseph S.] CDC, Ctr Global Hlth, Div Global HIV AIDS, Abidjan, Cote Ivoire. [Ehrenkranz, Peter; Bicego, George] CDC, Ctr Global Hlth, Div Global HIV AIDS, Mbabane, Swaziland. [Torpey, Kwasi] FHI 360, Lusaka, Zambia. [Mukadi, Ya Diul] FHI 360, Port Au Princ, Haiti. [van Praag, Eric] FHI 360, Dar Es Salaam, Tanzania. [Mastro, Timothy; Hamilton, Carol Dukes] FHI 360, Global Hlth Populat & Nutr, Durham, NC USA. [Bangsberg, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Marlink, Richard] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Auld, AF (reprint author), CDC, Ctr Global Hlth, Div Global HIV AIDS, Atlanta, GA 30333 USA. EM aauld@cdc.gov FU NIMH NIH HHS [F31 MH095665] NR 10 TC 17 Z9 17 U1 0 U2 3 PU CENTER DISEASE CONTROL & PREVENTION PI ATLANTA PA MAILSTOP E-90, ATLANTA, GA 30333 USA SN 0149-2195 EI 1545-861X J9 MMWR-MORBID MORTAL W JI MMWR-Morb. Mortal. Wkly. Rep. PD NOV 28 PY 2014 VL 63 IS 47 BP 1097 EP 1103 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AU3LR UT WOS:000345515200001 PM 25426651 ER PT J AU Li, JZ Heisey, A Ahmed, H Wang, HY Zheng, L Carrington, M Wrin, T Schooley, RT Lederman, MM Kuritzkes, DR AF Li, Jonathan Z. Heisey, Andrea Ahmed, Hayat Wang, Hongying Zheng, Lu Carrington, Mary Wrin, Terri Schooley, Robert T. Lederman, Michael M. Kuritzkes, Daniel R. CA ACTG A5197 Study Team TI Relationship of HIV reservoir characteristics with immune status and viral rebound kinetics in an HIV therapeutic vaccine study SO AIDS LA English DT Article DE analytic treatment interruption; HIV; reservoir; therapeutic vaccine ID ACTIVE ANTIRETROVIRAL THERAPY; STRUCTURED TREATMENT INTERRUPTIONS; VIRUS TYPE-1 RNA; T-CELL RESPONSES; NEUTRALIZING ANTIBODIES; PCR ASSAY; INFECTION; PLASMA; DNA; NONPROGRESSORS AB Objectives: The objective of this study is to evaluate the impact of therapeutic HIV vaccination on the HIV reservoir and assess the relationship of the viral reservoir with HIV-specific immune status and viral rebound kinetics. Design: A retrospective analysis of ACTG A5197, a randomized, placebo-controlled trial of a therapeutic rAd5 HIV-1 gag vaccine. Methods: Participants received vaccine/placebo at weeks 0, 4 and 26 prior to a 16-week analytic treatment interruption (ATI) at week 38. Cell-associated HIV-1 RNA and DNA (CA-RNA and CA-DNA) and HIV-1 residual viremia were quantified at weeks 0, 8 and 38. HIV-specific CD4(+)/CD8(+) activity was assessed by an intracellular cytokine staining assay. Results: At study entry, CA-RNA and CA-DNA levels were correlated inversely with the numbers of HIV-specific CD4(+) interferon-g producing cells (CA-RNA: r = -0.23, P = 0.03 and CA-DNA: r = -0.28, P < 0.01, N = 93). Therapeutic HIV vaccination induced HIV-specific CD4(+) activity, but did not significantly affect levels of CA-RNA or CA-DNA. Vaccine recipients with undetectable residual viremia at week 8 had higher frequencies of HIV-specific CD4(+) and CD8(+) interferon-g producing cells (undetectable versus detectable residual viremia: 277 versus 161 CD4(+) cells/10(6) lymphocytes, P = 0.03 and 1326 versus 669 CD8(+) cells/10 6 lymphocytes, P = 0.04). Pre-ATI CARNA and CA-DNA were associated with post-ATI plasma HIV set point (CA-RNA: r = 0.51, P < 0.01 and CA-DNA: r = 0.47, P < 0.01). Conclusion: Vaccine-induced T-cell responses were associated with a modest transient effect on residual viremia, but more potent immune responses and/or combination treatment with latency-reversing agents are needed to reduce the HIV reservoir. HIV reservoir measures may act as biomarkers of post-ATI viral rebound kinetics. C1 [Li, Jonathan Z.; Heisey, Andrea; Ahmed, Hayat; Kuritzkes, Daniel R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Wang, Hongying; Zheng, Lu] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Carrington, Mary] Frederick Natl Lab Canc Res, Leidos Biomed Res Inst, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. [Carrington, Mary] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Carrington, Mary] Harvard Univ, Cambridge, MA 02138 USA. [Wrin, Terri] Monogram Biosci, La Jolla, CA USA. [Schooley, Robert T.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Lederman, Michael M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Li, JZ (reprint author), Brigham & Womens Hosp, Div Infect Dis, 65 Landsdowne St,Rm 421, Cambridge, MA 02139 USA. EM Jli22@partners.org FU Harvard University Center for AIDS Research [NIAID 5P30AI060354-08]; National Institutes of Health (NIH) [UM1 AI068634, UM1 AI068636]; federal funds from the Frederick National Laboratory for Cancer Research [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research; Abbott; Avexa; Bristol-Myers Squibb; Gilead; GlaxoSmithKline; Merck; ViiV Healthcare FX This work was supported in part by a grant from the Harvard University Center for AIDS Research (to Dr Li, NIAID 5P30AI060354-08), National Institutes of Health (NIH) grants UM1 AI068634 (Statistical and Data Management Center of the AIDS Clinical Trials Group), UM1 AI068636 (AIDS Clinical Trials Group) and a subcontract from UM1 AI068636 to the Harvard Virology Support Laboratory (to Dr Kuritzkes). Merck provided the A5197 study vaccine and performed the assays characterizing HIV-specific T-cell activity. The NAb assays were performed by Monogram Biosciences. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research.; J.Z.L. has served as a consultant for Therapy Edge, Quest Diagnostics and SeraCare Life Sciences. D. R. K. has served as a consultant to and/or has received research grant support from Abbott, Avexa, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck and ViiV Healthcare; he has also received speaking honoraria from Gilead and ViiV. NR 37 TC 13 Z9 13 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD NOV 28 PY 2014 VL 28 IS 18 BP 2649 EP 2657 DI 10.1097/QAD.0000000000000478 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AT9XO UT WOS:000345277300002 PM 25254301 ER PT J AU Chetty, S Porichis, F Govender, P Zupkosky, J Ghebremichael, M Pillay, M Walker, BD Ndung'u, T Kaufmann, DE Kasprowicz, VO AF Chetty, Shivan Porichis, Filippos Govender, Pamla Zupkosky, Jennifer Ghebremichael, Musie Pillay, Mona Walker, Bruce D. Ndung'u, Thumbi Kaufmann, Daniel E. Kasprowicz, Victoria O. TI Tuberculosis distorts the inhibitory impact of interleukin-10 in HIV infection SO AIDS LA English DT Article DE HIV coinfection; interleukin-10 receptor alpha blockade; immune regulation; interleukin-10; Mycobacterium tuberculosis ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4 T-CELL; CYTOKINE PRODUCTION; IL-10; MACROPHAGES; DYSFUNCTION; RESPONSES; ALPHA AB Objectives: This study aimed to assess how Mycobacterium tuberculosis (MTB) coinfection alters the impact of interleukin-10 in chronic HIV infection. Design: We assessed plasma cytokine levels (interleukin-10, interferon-g, tumor necrosis factor-a, interleukin-2, interleukin-6 and interleukin-13) in 82 individuals presenting with HIV monoinfection, HIV-LTBI (latent MTB infection) coinfection or HIV-TB (active tuberculosis) coinfection. We also assessed the influence of MTB on the functional impact of interleukin-10 receptor alpha (interleukin-10R alpha) blockade on HIV and MTB-specific CD4(+) T cells. Methods: Plasma cytokine levels were measured by high sensitivity Luminex. We used an ex-vivo interleukin-10R alpha blockade assay to assess if functional enhancement of HIV and MTB-specific CD4(+) T cells was possible following a 48-h stimulation with HIV gag or pooled ESAT-6 (6 kDa early secretory antigenic target) and CFP-10 (10-kDa culture filtrate protein) peptides. Cell supernatant was collected 48 h after stimulation and the cytokine profile was measured by Luminex. Results: Plasma interleukin-10 levels were elevated in HIV-TB as compared with HIV monoinfection (P < 0.05) and HIV-LTBI (P < 0.05). Plasma interleukin-10 levels correlated to HIV viral load in HIV monoinfection (P = 0.016) and HIV-LTBI (P = 0.042), but not HIV-TB. Ex-vivo blockade of interleukin-10R alpha significantly enhanced MTB and HIV-specific CD4+ T-cell function in HIV-LTBI individuals but not in HIV-TB individuals. Conclusion: Tuberculosis disrupts the correlation between interleukin-10 and markers of HIV disease progression. In addition, HIV-TB is associated with a more inflammatory cytokine milieu compared with HIV monoinfection. Interestingly, interleukin-10R alpha blockade can enhance both HIV and MTB-specific T-cell function in HIV-LTBI, but not in HIV-TB coinfection. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Chetty, Shivan; Govender, Pamla; Pillay, Mona; Ndung'u, Thumbi; Kasprowicz, Victoria O.] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. [Chetty, Shivan; Kasprowicz, Victoria O.] KwaZulu Natal Res Inst TB & HIV K RITH, Durban, South Africa. [Porichis, Filippos; Zupkosky, Jennifer; Ghebremichael, Musie; Walker, Bruce D.; Ndung'u, Thumbi; Kaufmann, Daniel E.; Kasprowicz, Victoria O.] MIT, MGH, Ragon Inst, Cambridge, MA 02139 USA. [Porichis, Filippos; Zupkosky, Jennifer; Ghebremichael, Musie; Walker, Bruce D.; Ndung'u, Thumbi; Kaufmann, Daniel E.; Kasprowicz, Victoria O.] Harvard, Cambridge, MA USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Kaufmann, Daniel E.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Kaufmann, Daniel E.] CRCHUM, Montreal, PQ, Canada. [Chetty, Shivan] Univ Cape Town, Div Med Virol, ZA-7925 Cape Town, South Africa. RP Kasprowicz, VO (reprint author), MIT, MGH, Ragon Inst, 400 Technol Sq,Room 894, Cambridge, MA 02139 USA. EM vkasprowicz@mgh.harvard.edu OI Ndung'u, Thumbi/0000-0003-2962-3992 FU Howard Hughes Medical Institute (HHMI); KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH); South African Medical Research Council (MRC); CU-SA Fogarty AITRP programme; NIH; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [PO1 AI-080192]; National Heart Lung and Blood Institute of the National Institutes of Health [RO1 HL-092565]; Research Scholar Career Award of the Quebec Health Research Fund (FRQS); Massachusetts General Hospital Executive Committee on Research; Harvard Global Health Institute (HGHI) FX The authors would like to thank the following funders: the Howard Hughes Medical Institute (HHMI), the KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), The South African Medical Research Council (MRC), The CU-SA Fogarty AITRP programme and the NIH. This study was also supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (PO1 AI-080192; D. E. K), the National Heart Lung and Blood Institute of the National Institutes of Health (RO1 HL-092565; D. E. K). D. E. K is supported by a Research Scholar Career Award of the Quebec Health Research Fund (FRQS). FP is supported by a fellowship grant of the Massachusetts General Hospital Executive Committee on Research and the Harvard Global Health Institute (HGHI). NR 23 TC 5 Z9 5 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD NOV 28 PY 2014 VL 28 IS 18 BP 2671 EP 2676 DI 10.1097/QAD.0000000000000437 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AT9XO UT WOS:000345277300004 PM 25211438 ER PT J AU Greene, M Covinsky, K Astemborski, J Piggott, DA Brown, T Leng, S Galai, N Mehta, SH Guralnik, J Patel, KV Kirk, GD AF Greene, Meredith Covinsky, Kenneth Astemborski, Jacquie Piggott, Damani A. Brown, Todd Leng, Sean Galai, Noya Mehta, Shruti H. Guralnik, Jack Patel, Kushang V. Kirk, Gregory D. TI The relationship of physical performance with HIV disease and mortality SO AIDS LA English DT Article DE aging; HIV; injection drug use; mortality; physical function ID LOWER-EXTREMITY FUNCTION; EFFECTIVE ANTIRETROVIRAL THERAPY; INJECTION-DRUG USERS; SUBSEQUENT DISABILITY; FUNCTIONAL IMPAIRMENT; OLDER PERSONS; IL-6 LEVELS; INFECTION; FRAILTY; AGE AB Objective: To evaluate whether HIV infection was associated with reduced physical performance, and to examine if reduced physical performance predicted mortality in our aging cohort of HIV-infected and HIV-uninfected persons. Design: Prospective, observational cohort of current and former injection drug users in the AIDS Linked to the IntraVenous Experience study in Baltimore, Maryland, USA. Methods: The Short Physical Performance Battery (SPPB) was used as an objective measure of physical performance and measured semiannually along with behavioral and demographic data. Correlates of reduced physical performance (SPPB score < 10) were identified and the relationship between reduced physical performance, HIV infection and mortality was analyzed by Cox regression. Results: Among 12 270 person-visits contributed by 1627 participants, the median age was 51, 30.3% were HIV-infected and 32.6% had an SPPB score 10 or less. In multivariable models, HIV infection was independently associated with 30% increased odds of reduced physical performance [odds ratio 1.30; 95% confidence interval (CI): 1.12-1.52]. Reduced physical performance predicted mortality in a dose-response manner and within all HIV disease strata. Whereas reduced physical performance alone (hazard ratio 2.52, 95% CI: 1.59-4.00) and HIV infection alone (hazard ratio 2.78, 95% CI: 1.70-4.54) increased mortality, HIV-infected participants with reduced physical performance had a six-fold increased mortality risk (hazard ratio 6.03, 95% CI: 3.80-10.0) compared with HIV-uninfected participants with higher physical performance. Conclusion: HIV infection was independently associated with reduced physical performance. HIV and reduced physical performance have independent and joint effects on mortality. Physical performance measurement may be an important research and clinical tool to predict adverse outcomes among aging HIV-infected persons. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Greene, Meredith; Covinsky, Kenneth] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA USA. [Greene, Meredith; Covinsky, Kenneth] San Francisco VA Med Ctr, San Francisco, CA USA. [Astemborski, Jacquie; Piggott, Damani A.; Galai, Noya; Mehta, Shruti H.; Kirk, Gregory D.] Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Piggott, Damani A.; Kirk, Gregory D.] Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. [Brown, Todd] Johns Hopkins Univ, Sch Med, Dept Med, Div Endocrinol & Metab, Baltimore, MD 21205 USA. [Leng, Sean] Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr & Gerontol, Baltimore, MD 21205 USA. [Galai, Noya] Univ Haifa, Dept Stat, Har Hakarmel, Israel. [Guralnik, Jack] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. RP Kirk, GD (reprint author), Johns Hopkins Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,E-6533, Baltimore, MD 21205 USA. EM gkirk@jhsph.edu FU National Institutes of Health [U01-DA-036297, R01-DA-0433, R01-DA-12568, RC1-AI-086053, 5-T32-AG000212] FX This work was supported by the National Institutes of Health (grants U01-DA-036297, R01-DA-0433, R01-DA-12568, RC1-AI-086053, and 5-T32-AG000212 [MG]). T. B. is a consultant for EMD-Serono, ViiV Healthcare, Gilead, Merck, and Abbvie. M. G. received one-time honoraria for reviewing IAS-USA cases on the web. NR 40 TC 10 Z9 10 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD NOV 28 PY 2014 VL 28 IS 18 BP 2711 EP 2719 DI 10.1097/QAD.0000000000000507 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AT9XO UT WOS:000345277300009 PM 25493597 ER PT J AU Akeju, O Loggia, ML Catana, C Pavone, KJ Vazquez, R Rhee, J Ramirez, VC Chonde, DB Izquierdo-Garcia, D Arabasz, G Hsu, S Habeeb, K Hooker, JM Napadow, V Brown, EN Purdon, PL AF Akeju, Oluwaseun Loggia, Marco L. Catana, Ciprian Pavone, Kara J. Vazquez, Rafael Rhee, James Ramirez, Violeta Contreras Chonde, Daniel B. Izquierdo-Garcia, David Arabasz, Grae Hsu, Shirley Habeeb, Kathleen Hooker, Jacob M. Napadow, Vitaly Brown, Emery N. Purdon, Patrick L. TI Disruption of Thalamic Functional Connectivity is a Neural Correlate of Dexmedetomidine-Induced Unconsciousness SO ELIFE LA English DT Article ID DEFAULT-MODE NETWORK; ANESTHETIC-INDUCED UNCONSCIOUSNESS; CEREBRAL METABOLIC-RATE; GENERAL-ANESTHESIA; RESTING-STATE; LOCUS-COERULEUS; HYPNOTIC RESPONSE; AWAKE CRANIOTOMY; HIGH-RISK; SLEEP AB Understanding the neural basis of consciousness is fundamental to neuroscience research. Disruptions in cortico-cortical connectivity have been suggested as a primary mechanism of unconsciousness. By using a novel combination of positron emission tomography and functional magnetic resonance imaging, we studied anesthesia-induced unconsciousness and recovery using the alpha(2)-agonist dexmedetomidine. During unconsciousness, cerebral metabolic rate of glucose and cerebral blood flow were preferentially decreased in the thalamus, the Default Mode Network (DMN), and the bilateral Frontoparietal Networks (FPNs). Cortico-cortical functional connectivity within the DMN and FPNs was preserved. However, DMN thalamo-cortical functional connectivity was disrupted. Recovery from this state was associated with sustained reduction in cerebral blood flow, and restored DMN thalamo-cortical functional connectivity. We report that loss of thalamo-cortical functional connectivity is sufficient to produce unconsciousness. C1 [Akeju, Oluwaseun; Pavone, Kara J.; Vazquez, Rafael; Rhee, James; Ramirez, Violeta Contreras; Brown, Emery N.; Purdon, Patrick L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Loggia, Marco L.; Catana, Ciprian; Chonde, Daniel B.; Izquierdo-Garcia, David; Arabasz, Grae; Hsu, Shirley; Hooker, Jacob M.; Napadow, Vitaly] MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02139 USA. [Loggia, Marco L.; Napadow, Vitaly] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Habeeb, Kathleen] Massachusetts Gen Hosp, Clin Res Ctr, Boston, MA 02114 USA. [Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Brown, Emery N.; Purdon, Patrick L.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Akeju, O (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM oluwaseun.akeju@mgh.harvard.edu; patrickp@nmr.harvard.edu FU Massachusetts General Hospital Physician Scientist Development Award; Foundation for Anesthesia Education and Research; NIH [DP2-OD006454, DP1-OD003646, TR01-GM104948]; Harvard Clinical and Translational Science Center, from the National Center for Advancing Translational Science [8 UL1 TR000170-05]; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital FX This work was funded by the Massachusetts General Hospital Physician Scientist Development Award (to O.A); Foundation for Anesthesia Education and Research (to O.A); NIH DP2-OD006454 (to P.L.P); DP1-OD003646 and TR01-GM104948 (to E.N.B); 8 UL1 TR000170-05, Harvard Clinical and Translational Science Center, from the National Center for Advancing Translational Science; and funds from the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital. NR 79 TC 16 Z9 16 U1 0 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 28 PY 2014 VL 3 AR e04499 DI 10.7554/eLife.04499 PG 49 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AU5JL UT WOS:000345642800002 PM 25432022 ER PT J AU Zhang, GL Keskin, DB Lin, HN Lin, HH DeLuca, DS Leppanen, S Milford, EL Reinherz, EL Brusic, V AF Zhang, Guang Lan Keskin, Derin B. Lin, Hsin-Nan Lin, Hong Huang DeLuca, David S. Leppanen, Scott Milford, Edgar L. Reinherz, Ellis L. Brusic, Vladimir TI Human leukocyte antigen typing using a knowledge base coupled with a high-throughput oligonucleotide probe array analysis SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE HLA typing; HLA disease association; population typing ID STEVENS-JOHNSON-SYNDROME; TOXIC EPIDERMAL NECROLYSIS; INDUCED HYPERSENSITIVITY REACTIONS; HLA CLASS-I; GENOME-WIDE ASSOCIATION; HLA-B-ASTERISK-1502 ALLELE; JAPANESE POPULATION; HAN CHINESE; RISK-FACTOR; CARBAMAZEPINE AB Human leukocyte antigens (HLA) are important biomarkers because multiple diseases, drug toxicity, and vaccine responses reveal strong HLA associations. Current clinical HLA typing is an elimination process requiring serial testing. We present an alternative in situ synthesized DNA-based microarray method that contains hundreds of thousands of probes representing a complete overlapping set covering 1,610 clinically relevant HLA class I alleles accompanied by computational tools for assigning HLA type to 4-digit resolution. Our proof-of-concept experiment included 21 blood samples, 18 cell lines, and multiple controls. The method is accurate, robust, and amenable to automation. Typing errors were restricted to homozygous samples or those with very closely related alleles from the same locus, but readily resolved by targeted DNA sequencing validation of flagged samples. High-throughput HLA typing technologies that are effective, yet inexpensive, can be used to analyze the world's populations, benefiting both global public health and personalized health care. C1 [Zhang, Guang Lan; Keskin, Derin B.; Lin, Hsin-Nan; Lin, Hong Huang; DeLuca, David S.; Reinherz, Ellis L.; Brusic, Vladimir] Harvard Univ, Sch Med, Canc Vaccine Ctr, Dana Farber Canc Inst, Boston, MA 02115 USA. [Zhang, Guang Lan; Brusic, Vladimir] Boston Univ, Dept Comp Sci, Metropolitan Coll, Boston, MA 02215 USA. [Keskin, Derin B.; Milford, Edgar L.; Reinherz, Ellis L.; Brusic, Vladimir] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Keskin, Derin B.; Reinherz, Ellis L.] Dana Farber Canc Inst, Dept Med Oncol, Immunobiol Lab, Boston, MA 02115 USA. [Lin, Hsin-Nan] Acad Sinica, Inst Informat Sci, Taipei, Taiwan. [Lin, Hong Huang] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Leppanen, Scott] Agilent Technol, Santa Clara, CA USA. [Milford, Edgar L.] Brigham & Womens Hosp, Histocompatibil & Tissue Typing Lab, Boston, MA 02115 USA. RP Brusic, V (reprint author), Harvard Univ, Sch Med, Canc Vaccine Ctr, Dana Farber Canc Inst, 77 Ave Louis Pasteur,HIM 401, Boston, MA 02115 USA. EM vladimir_brusic@dfci.harvard.edu OI Lin, Honghuang/0000-0003-3043-3942 FU NIH [U01 AI90043, U01 AI089859] FX This work was funded by the NIH grants U01 AI90043 and U01 AI089859. NR 58 TC 1 Z9 1 U1 0 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD NOV 27 PY 2014 VL 5 BP 1 EP 12 AR 597 DI 10.3389/fimmu.2014.00597 PG 12 WC Immunology SC Immunology GA CI1UX UT WOS:000354531500001 PM 25505899 ER PT J AU Beach, SR Kroshinsky, D Kontos, N AF Beach, Scott R. Kroshinsky, Daniela Kontos, Nicholas TI Case 37-2014: A 35-Year-Old Woman with Suspected Mite Infestation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DELUSIONAL PARASITOSIS; PSYCHOSIS; ANTIPSYCHOTICS; SCHIZOPHRENIA; SYMPTOMS; THERAPY C1 [Beach, Scott R.; Kontos, Nicholas] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Beach, Scott R.; Kontos, Nicholas] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Kroshinsky, Daniela] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Beach, SR (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. NR 25 TC 3 Z9 3 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD NOV 27 PY 2014 VL 371 IS 22 BP 2115 EP 2123 DI 10.1056/NEJMcpc1305989 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AU4KP UT WOS:000345580000013 PM 25427115 ER PT J AU Ghobrial, IM Landgren, O AF Ghobrial, Irene M. Landgren, Ola TI How I treat smoldering multiple myeloma SO BLOOD LA English DT Review ID MONOCLONAL GAMMOPATHY; UNDETERMINED SIGNIFICANCE; TUMOR-SUPPRESSOR; MELPHALAN-PREDNISONE; UNTREATED MYELOMA; PRECURSOR DISEASE; RANDOMIZED-TRIAL; ZOLEDRONIC ACID; EARLY-STAGE; PROGRESSION AB Smoldering myelomais a heterogeneous clinical entity where a subset of patients has an indolent course of disease that mimics monoclonal gammopathy of undermined significance, whereas others have a more aggressive course that has been described as "early myeloma." It is defined as either serum M-protein >= 3 g/L or >= 10% monoclonal plasma cells in the bone marrow. There are currently no molecular factors to differentiate risks of progression for these patients. Current recommendations of therapy continue to be patient observation or patient enrollment in clinical trials. However, new definitions of active multiple myeloma recently agreed upon by the International Myeloma Working Group may alter the timing of therapy. On the basis of emerging data of therapy in these patients, it seems reasonable to believe that future recommendations for therapy of patients with smoldering important topic. In this article, we review the current knowledge of this disease and risk factors associated with progression. We also examine biological insights and alterations that occur in the tumor clone and the surrounding bone marrow niche. Finally, we review clinical trials that have been performed in these patients and provide recommendations for follow-up of patients with this unique disease entity. C1 [Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. RP Ghobrial, IM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM Irene_ghobrial@dfci.harvard.edu; landgrec@mskcc.org FU National Institutes of Health, National Cancer Institute [R01CA 181683-01]; Leukemia and Lymphoma Society FX This work was supported by National Institutes of Health, National Cancer Institute grant R01CA 181683-01 and the Leukemia and Lymphoma Society. NR 76 TC 9 Z9 9 U1 1 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 NOV 27 PY 2014 VL 124 IS 23 BP 3380 EP 3388 DI 10.1182/blood-2014-08-551549 PG 9 WC Hematology SC Hematology GA AY3DQ UT WOS:000347465100010 PM 25298034 ER PT J AU Gu, LC Li, C Aach, J Hill, DE Vidal, M Church, GM AF Gu, Liangcai Li, Chao Aach, John Hill, David E. Vidal, Marc Church, George M. TI Multiplex single-molecule interaction profiling of DNA-barcoded proteins SO NATURE LA English DT Article ID COUPLED RECEPTOR; POLYMERASE COLONIES; IN-VITRO; DISCOVERY; BINDING; AMPLIFICATION; GENOME; ASSAYS; IDENTIFICATION; TRANSDUCTION AB In contrast with advances in massively parallel DNA sequencing(1), high-throughput protein analyses(2-4) are often limited by ensemble measurements, individual analyte purification and hence compromised quality and cost-effectiveness. Single-molecule protein detection using optical methods(5) is limited by the number of spectrally non-overlapping chromophores. Here we introduce a single-molecular-interaction sequencing (SMI-seq) technology for parallel protein interaction profiling leveraging single-molecule advantages. DNA barcodes are attached to proteins collectively via ribosome display(6) or individually via enzymatic conjugation. Barcoded proteins are assayed en masse in aqueous solution and subsequently immobilized in a polyacrylamide thin film to construct a random single-molecule array, where barcoding DNAs are amplified into in situ polymerase colonies (polonies)(7) and analysed by DNA sequencing. This method allows precise quantification of various proteins with a theoretical maximum array density of over one million polonies per square millimetre. Furthermore, protein interactions can be measured on the basis of the statistics of colocalized polonies arising from barcoding DNAs of interacting proteins. Two demanding applications, G-protein coupled receptor and antibody-binding profiling, are demonstrated. SMI-seq enables 'library versus library' screening in a one-pot assay, simultaneously interrogating molecular binding affinity and specificity. C1 [Gu, Liangcai; Aach, John; Hill, David E.; Vidal, Marc; Church, George M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Li, Chao; Church, George M.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Hill, David E.; Vidal, Marc] Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA. [Hill, David E.; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. RP Gu, LC (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM liangcaigu@gmail.com; gchurch@genetics.med.harvard.edu FU US Department of Energy [DE-FG02-02ER63445]; NIH NHGRI [HG001715]; Jane Coffin Childs Fund for Medical Research; Harvard Origins of Life Initiative FX This work was supported by a grant from the US Department of Energy (DE-FG02-02ER63445) to G.M.C. and a grant from the NIH NHGRI (HG001715) to M.V. and D.E.H.L.G. was supported by a postdoctoral fellowship from the Jane Coffin Childs Fund for Medical Research and a grant from Harvard Origins of Life Initiative. We thank W. Harper, L. Pontano Vaites, S. Elledge and J. Zhu for providing plasmids, F. Vigneault for comments on the manuscript, J. Lai and D. Breslau for assistance on imaging setup, and members of the Church and Vidal groups for constructive discussions. NR 50 TC 18 Z9 19 U1 6 U2 80 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 NOV 27 PY 2014 VL 515 IS 7528 BP 554 EP + DI 10.1038/nature13761 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AW4JP UT WOS:000346247600001 PM 25252978 ER PT J AU Powles, T Eder, JP Fine, GD Braiteh, FS Loriot, Y Cruz, C Bellmunt, J Burris, HA Petrylak, DP Teng, SL Shen, XD Boyd, Z Hegde, PS Chen, DS Vogelzang, NJ AF Powles, Thomas Eder, Joseph Paul Fine, Gregg D. Braiteh, Fadi S. Loriot, Yohann Cruz, Cristina Bellmunt, Joaquim Burris, Howard A. Petrylak, Daniel P. Teng, Siew-Leng Shen, Xiaodong Boyd, Zachary Hegde, Priti S. Chen, Daniel S. Vogelzang, Nicholas J. TI MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer SO NATURE LA English DT Article ID TRANSITIONAL-CELL CARCINOMA; ADVANCED UROTHELIAL CARCINOMA; PLATINUM-CONTAINING REGIMEN; PHASE-II; 2ND-LINE TREATMENT; SINGLE GROUP; TRIAL; VINFLUNINE; TRACT; PACLITAXEL AB There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30 years. Chemotherapy is still the standard of care. Patient outcomes, especially for those in whom chemotherapy is not effective or is poorly tolerated, remain poor(1,2). One hallmark of UBC is the presence of high rates of somatic mutations(3,5). These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens(6). However, these cancers may also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-Li; also called CD274 or B7-H1) in the tumour microenvironment(7,8). Therefore, we examined the anti-PDLi antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of metastatic UBC. MPDL3280A is a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-Gl antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7.1 (CD80)9. Because PD-L1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PD-Li. Here we show that MPDL3280A has noteworthy activity in metastatic UBC. Responses were often rapid, with many occurring at the time of the first response assessment (6 weeks) and nearly all were ongoing at the data cutoff. This phase I expansion study, with an adaptive design that allowed for biomarker-positive enriched cohorts, demonstrated that tumours expressing PD-L1 -positive tumour-infiltrating immune cells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC, who are often older and have a higher incidence of renal impairment, may be better able to tolerate MPDL3280A versus chemotherapy. These results suggest that MPDL3280A may have an important role in treating UBC-the drug received breakthrough designation status by the US Food and Drug Administration (FDA) in June 2014. C1 [Powles, Thomas] Queen Mary Univ London, Barts Canc Inst, Barts Expt Canc Med Ctr, London EC1M 6BQ, England. [Eder, Joseph Paul; Petrylak, Daniel P.] Yale Canc Ctr, New Haven, CT 06520 USA. [Fine, Gregg D.; Teng, Siew-Leng; Shen, Xiaodong; Boyd, Zachary; Hegde, Priti S.; Chen, Daniel S.] Genentech Inc, San Francisco, CA 94080 USA. [Braiteh, Fadi S.] Comprehens Canc Ctr Nevada, Las Vegas, NV 89169 USA. [Loriot, Yohann] Gustave Roussy, F-94805 Villejuif, France. [Cruz, Cristina] VHIO, Barcelona 08035, Spain. [Cruz, Cristina] Vall dHebron Univ Hosp, Barcelona 08035, Spain. [Bellmunt, Joaquim] Harvard Univ, Sch Med, Bladder Canc Ctr, Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02215 USA. [Burris, Howard A.] Sarah Cannon Res Inst, Nashville, TN 37203 USA. [Vogelzang, Nicholas J.] Univ Nevada, Sch Med, Las Vegas, NV 89169 USA. [Vogelzang, Nicholas J.] Univ Nevada, US Oncol Comprehens Canc Ctr Nevada, Las Vegas, NV 89169 USA. RP Powles, T (reprint author), Queen Mary Univ London, Barts Canc Inst, Barts Expt Canc Med Ctr, London EC1M 6BQ, England. EM Thomas.Powles@bartshealth.nhs.uk NR 27 TC 560 Z9 586 U1 23 U2 127 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 NOV 27 PY 2014 VL 515 IS 7528 BP 558 EP + DI 10.1038/nature13904 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AW4JP UT WOS:000346247600052 PM 25428503 ER PT J AU Herbst, RS Soria, JC Kowanetz, M Fine, GD Hamid, O Gordon, MS Sosman, JA McDermott, DF Powderly, JD Gettinger, SN Kohrt, HEK Horn, L Lawrence, DP Rost, S Leabman, M Xiao, YY Mokatrin, A Koeppen, H Hegde, PS Mellman, I Chen, DS Hodi, FS AF Herbst, Roy S. Soria, Jean-Charles Kowanetz, Marcin Fine, Gregg D. Hamid, Omid Gordon, Michael S. Sosman, Jeffery A. McDermott, David F. Powderly, John D. Gettinger, Scott N. Kohrt, Holbrook E. K. Horn, Leora Lawrence, Donald P. Rost, Sandra Leabman, Maya Xiao, Yuanyuan Mokatrin, Ahmad Koeppen, Hartmut Hegde, Priti S. Mellman, Ira Chen, Daniel S. Hodi, F. Stephen TI Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients SO NATURE LA English DT Article ID T-CELLS; IN-VIVO; SAFETY; TUMORS; PD-1; MELANOMA; CRITERIA; PATHWAY; DISEASE; B7-H1 AB The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system(1-4). However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironmen(5). Programmed death-ligand 1 (PD-Li; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing(6-10). The PD -LI-PD -1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections(11). Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (T(H)1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment. C1 [Herbst, Roy S.; Gettinger, Scott N.] Yale Univ, Sch Med, Yale Comprehens Canc Ctr, New Haven, CT 06520 USA. [Soria, Jean-Charles] Gustave Roussy South Paris Univ, F-94805 Villejuif, France. [Kowanetz, Marcin; Fine, Gregg D.; Rost, Sandra; Leabman, Maya; Xiao, Yuanyuan; Mokatrin, Ahmad; Koeppen, Hartmut; Hegde, Priti S.; Mellman, Ira; Chen, Daniel S.] Genentech Inc, San Francisco, CA 94080 USA. [Hamid, Omid] Angeles Clin & Res Inst, Los Angeles, CA 90025 USA. [Gordon, Michael S.] Pinnacle Oncol Hematol, Scottsdale, AZ 85258 USA. [Sosman, Jeffery A.; Horn, Leora] Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [McDermott, David F.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Powderly, John D.] Carolina BioOncol Inst, Huntersville, NC 28078 USA. [Kohrt, Holbrook E. K.] Stanford Univ, Stanford, CA 94305 USA. [Lawrence, Donald P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hodi, F. Stephen] Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02215 USA. RP Herbst, RS (reprint author), Yale Univ, Sch Med, Yale Comprehens Canc Ctr, 333 Cedar St,WWW221, New Haven, CT 06520 USA. EM roy.herbst@yale.edu FU NCI [1R01CA155196, P30 CA 016359] FX We thank the patients and their families. We also thank all of the investigators and their staff, including A. Balmanoukian and P. Boasberg from The Angeles Clinic and Research Institute; T. Powles from Barts Cancer Institute, QMUL, Barts Health NHS Trust; D. Cho from NYU Langone Medical Center; P. Cassier from Centre Leon-Berard; F. Braiteh from USON Research Network, Comprehensive Cancer Centers of Nevada; N. Vogelzang from USON Research Network, Comprehensive Cancer Centers of Nevada and University of Nevada; T. Choueiri, L. Gandhi, N. Ibrahim and P. Ott from Dana-Farber Cancer Institute; J.-P. Delord and C. Gomez-Rocca from Institut Claudius Regaud; A. Hollebecque and R. Bahleda from Gustave Roussy; L. Emens from Johns Hopkins Medicine, The Sidney Kimmel Comprehensive Cancer Center; K. Flaherty and R. Sullivan from Massachusetts General Hospital; S. Antonia from Moffitt Cancer Center; H. Burris, J. Infante and D. Spigel from Sarah Cannon Research Institute; G. Fisher from Stanford Medicine, Cancer Institute; P. Conkling and L. Garbo from US Oncology Research, Inc.; C. Cruz and J. Tabenero from Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital; W. Pao and I. Puzanov from Vanderbilt-Ingram Cancer Center; P. Eder, H. Kluger and M. Sznol from Yale Cancer Center. From Genentech, we thank M. Anderson, M. Boe, Z. Boyd, C. Chappey, M. Denker, R. Desai, L. Fu, B. Irving, D. Jin, W. Kadel, R. Nakamura, I. Rhee, X. Shen, M. Stroh, T. Sumiyoshi, J. Wu,Y. Xin and J. Yi. Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd. NCI grants 1R01CA155196 (Battle-2) and P30 CA 016359 (CCSG) to R.S.H. helped support the infrastructure for this trial and program. NR 31 TC 755 Z9 797 U1 43 U2 179 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 NOV 27 PY 2014 VL 515 IS 7528 BP 563 EP + DI 10.1038/nature14011 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AW4JP UT WOS:000346247600053 PM 25428504 ER PT J AU Gubin, MM Zhang, XL Schuster, H Caron, E Ward, JP Noguchi, T Ivanova, Y Hundal, J Arthur, CD Krebber, WJ Mulder, GE Toebes, M Vesely, MD Lam, SSK Korman, AJ Allison, JP Freeman, GJ Sharpe, AH Pearce, EL Schumacher, TN Aebersold, R Rammensee, HG Melief, CJM Mardis, ER Gillanders, WE Artyomov, MN Schreiber, RD AF Gubin, Matthew M. Zhang, Xiuli Schuster, Heiko Caron, Etienne Ward, Jeffrey P. Noguchi, Takuro Ivanova, Yulia Hundal, Jasreet Arthur, Cora D. Krebber, Willem-Jan Mulder, Gwenn E. Toebes, Mireille Vesely, Matthew D. Lam, Samuel S. K. Korman, Alan J. Allison, James P. Freeman, Gordon J. Sharpe, Arlene H. Pearce, Erika L. Schumacher, Ton N. Aebersold, Ruedi Rammensee, Hans-Georg Melief, Cornelis J. M. Mardis, Elaine R. Gillanders, William E. Artyomov, Maxim N. Schreiber, Robert D. TI Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens SO NATURE LA English DT Article ID EXOME ANALYSIS REVEALS; T-CELLS; QUANTITATIVE PROTEOMICS; MELANOMA; INFLAMMATION; IMMUNITY; PD-1; RESPONSES; IMMUNOGENICITY; EQUILIBRIUM AB The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity(1-6), but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion(1,2,7). Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD -1), two immunomodulatory receptors expressed on T cells(8,9). Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits including durable responses to patients with different malignancies(10-13). However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic C1 [Gubin, Matthew M.; Ward, Jeffrey P.; Noguchi, Takuro; Ivanova, Yulia; Arthur, Cora D.; Vesely, Matthew D.; Lam, Samuel S. K.; Pearce, Erika L.; Artyomov, Maxim N.; Schreiber, Robert D.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Zhang, Xiuli; Gillanders, William E.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Schuster, Heiko; Rammensee, Hans-Georg] German Canc Res Ctr, Dept Immunol, Inst Cell Biol, D-72076 Tubingen, Germany. [Schuster, Heiko; Rammensee, Hans-Georg] German Canc Res Ctr, German Canc Consortium DKTK, D-72076 Tubingen, Germany. [Caron, Etienne; Aebersold, Ruedi] ETH, Dept Biol, Inst Mol Syst Biol, CH-8093 Zurich, Switzerland. [Ward, Jeffrey P.] Washington Univ, Sch Med, Dept Med, Div Oncol, St Louis, MO 63110 USA. [Hundal, Jasreet; Mardis, Elaine R.] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA. [Krebber, Willem-Jan; Mulder, Gwenn E.; Melief, Cornelis J. M.] ISA Therapeut BV, NL-2333 CH Leiden, Netherlands. [Toebes, Mireille; Schumacher, Ton N.] Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands. [Korman, Alan J.] Bristol Myers Squibb Co, Redwood City, CA 94063 USA. [Allison, James P.] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sharpe, Arlene H.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Aebersold, Ruedi] Univ Zurich, Fac Sci, CH-8093 Zurich, Switzerland. [Melief, Cornelis J. M.] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2333 ZA Leiden, Netherlands. [Mardis, Elaine R.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. RP Schreiber, RD (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, 660 South Euclid Ave, St Louis, MO 63110 USA. EM schreiber@immunology.wustl.edu FU National Cancer Institute [R01 CA043059, U01 CA141541, T32 CA00954729]; Cancer Research Institute; WWWW Foundation; Siteman Cancer Center/Barnes-Jewish Hospital (Cancer Frontier Fund); Susan G. Komen for the Cure (Promise grant); National Human Genome Research Institute; National Institute of Health [P50 CA101942, P01 A1054456]; Dutch Cancer Society (Queen Wilhelmina Research Award); Marie Curie Intra-European Fellowship within the Seventh Framework Programme of the European Community for Research; postdoctoral training grant(Irvington Postdoctoral Fellowship)from the Cancer Research Institute FX We are grateful to K. Murphy for the Batf3-/- mice, T. Hansen for providing MHC class I antibodies and the H-2Kb construct, D. Fremont for the human beta 2m construct, and the National Institutes of Health (NIH) Tetramer Core Facility for producing MHC class I tetramers. We also thank R. Ahmed and M. Hashimoto for the multiplex staining strategy used to define functional and dysfunctional T cells. We thank A. Bensimon, O. Schubert and P. Kouvonen for instrument maintenance and for technical support with the mass spectrometry measurements and R. Vanganipuram, M. Selby and J. Valle for generating and supplying anti-PD-1 and anti-CTLA-4 in endotoxin-free sterile form. We also thank K. Sheehan, P. Allen, G. Dunn and R. Chan for constructive criticisms and comments, all members of the Schreiber laboratory for discussions, and the many members of The Genome Institute at Washington University School of Medicine. We would also like to thank W. Song for his assistance with the bioinformatics approaches, P. Kvistborg for assistance with tetramer combinatorial coding, and Christopher Nelson for advice with peptide-MHC monomer purification. This work was supported by grants to R.D.S. from the National Cancer Institute (R01 CA043059, U01 CA141541), the Cancer Research Institute and the WWWW Foundation; to R.D.S. and W.E.G. from The Siteman Cancer Center/Barnes-Jewish Hospital (Cancer Frontier Fund); to W.E.G. from Susan G. Komen for the Cure (Promise grant); to E.R.M. from the National Human Genome Research Institute; to G.J.F. from the National Institute of Health (P50 CA101942, P01 A1054456, P50 CA101942); to A.H.S. from the National Institute of Health (P50 CA101942); and to T.N.S. from the Dutch Cancer Society (Queen Wilhelmina Research Award). E.C. is supported by a Marie Curie Intra-European Fellowship within the Seventh Framework Programme of the European Community for Research. M.M.G. was supported by a postdoctoral training grant (T32 CA00954729) from the National Cancer Institute and is currently supported by a postdoctoral training grant(Irvington Postdoctoral Fellowship)from the Cancer Research Institute. Aspects of studies at Washington University were performed with assistance by the Immunomonitoring Laboratory of the Center for Human Immunology and Immunotherapy Programs and the Siteman Comprehensive Cancer Center. NR 46 TC 328 Z9 344 U1 48 U2 245 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 NOV 27 PY 2014 VL 515 IS 7528 BP 577 EP + DI 10.1038/nature13988 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AW4JP UT WOS:000346247600056 PM 25428507 ER PT J AU Spicer, TP Jiang, JW Taylor, AB Choi, JY Hart, PJ Roush, WR Fields, GB Hodder, PS Minong, D AF Spicer, Timothy P. Jiang, Jianwen Taylor, Alexander B. Choi, Jun Yong Hart, P. John Roush, William R. Fields, Gregg B. Hodder, Peter S. Minong, Dmitriy TI Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation in Vitro SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PYRIMIDINETRIONE-BASED INHIBITORS; CHELATING MMP-13 INHIBITORS; HUMAN COLLAGENASE-3 MMP-13; CRYSTAL-STRUCTURES; CATALYTIC DOMAIN; STRUCTURAL BASIS; DRUG DISCOVERY; CANCER-THERAPY; POTENT; OSTEOARTHRITIS AB Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. As a result of high-throughput screening and structureactivity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S-1' subsite and in an S-1/S-2* subsite. Type II collagen- and cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Finally, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drugdrug interactions in humans. C1 [Spicer, Timothy P.; Hodder, Peter S.; Minong, Dmitriy] Scripps Res Inst, Translat Res Inst, Lead Identificat Div, Jupiter, FL 33458 USA. [Hodder, Peter S.] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA. [Choi, Jun Yong; Roush, William R.] Scripps Res Inst, Scripps Florida, Dept Chem, Jupiter, FL 33458 USA. [Fields, Gregg B.; Minong, Dmitriy] Torrey Pines Inst Mol Studies, Dept Chem, Port St Lucie, FL 34987 USA. [Fields, Gregg B.; Minong, Dmitriy] Torrey Pines Inst Mol Studies, Dept Biol, Port St Lucie, FL 34987 USA. [Jiang, Jianwen; Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Jiang, Jianwen; Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Hart, P. John] South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX 78229 USA. RP Minong, D (reprint author), Scripps Res Inst, Translat Res Inst, Lead Identificat Div, Jupiter, FL 33458 USA. EM dminond@tpims.org FU National Institutes of Health (Florida) [MH078948-01, U54MH074404, CA098799, AR063795]; Robert A. Welch Foundation [AQ-1399]; National Center for Research Resources at the National Institutes of Health [RR-15301]; U.S. 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 The National Institutes of Health (Grants MH078948-01, U54MH074404, CA098799, and AR063795) supported this work (Florida). Dr. Louis Scampavia, Pierre Baillargeon, and Lina DeLuca (Lead Identification Division, Translational Research Institute, Scripps Florida) are thanked for their assistance with compound management. This work was also supported in part by a grant from the Robert A. Welch Foundation (AQ-1399) (to P.J.H.) and is based in part upon research conducted at the Northeastern Collaborative Access Team beamlines of the Advanced Photon Source, supported by Award RR-15301 from the National Center for Research Resources at the National Institutes of Health. Use of the Advanced Photon Source is supported by the U.S. Department of Energy, Office of Basic Energy Sciences, under Contract No. W-31-109-ENG-38. Support for the X-ray Crystallography Core Laboratory by the UTHSCSA Executive Research Committee and by a Cancer Therapy & Research Center (CTRC) Cancer Center Support Grant (NCI P30CA054174) is also acknowledged. NR 66 TC 9 Z9 9 U1 2 U2 7 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 NOV 27 PY 2014 VL 57 IS 22 BP 9598 EP 9611 DI 10.1021/jm501284e PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AU6ON UT WOS:000345722200027 PM 25330343 ER PT J AU Stitziel, NO Won, HH Morrison, AC Peloso, GM Do, R Lange, LA Fontanillas, P Gupta, N Duga, S Goel, A Farrall, M Saleheen, D Ferrario, P Konig, I Asselta, R Merlini, PA Marziliano, N Notarangelo, MF Schick, U Auer, P Assimes, TL Reilly, M Wilensky, R Rader, DJ Hovingh, GK Meitinger, T Kessler, T Kastrati, A Laugwitz, KL Siscovick, D Rotter, JI Hazen, SL Tracy, R Cresci, S Spertus, J Jackson, R Schwartz, SM Natarajan, P Crosby, J Muzny, D Ballantyne, C Rich, SS O'Donnell, CJ Abecasis, G Sunyaev, S Nickerson, DA Buring, JE Ridker, PM Chasman, DI Austin, E Ye, Z Kullo, IJ Weeke, PE Shaffer, CM Bastarache, LA Denny, JC Roden, DM Palmer, C Deloukas, P Lin, DY Tang, ZZ Erdmann, J Schunkert, H Danesh, J Marrugat, J Elosua, R Ardissino, D McPherson, R Watkins, H Reiner, AP Wilson, JG Altshuler, D Gibbs, RA Lander, ES Boerwinkle, E Gabriel, S Kathiresan, S AF Stitziel, Nathan O. Won, Hong-Hee Morrison, Alanna C. Peloso, Gina M. Do, Ron Lange, Leslie A. Fontanillas, Pierre Gupta, Namrata Duga, Stefano Goel, Anuj Farrall, Martin Saleheen, Danish Ferrario, Paola Koenig, Inke Asselta, Rosanna Merlini, Piera A. Marziliano, Nicola Notarangelo, Maria Francesca Schick, Ursula Auer, Paul Assimes, Themistocles L. Reilly, Muredach Wilensky, Robert Rader, Daniel J. Hovingh, G. Kees Meitinger, Thomas Kessler, Thorsten Kastrati, Adnan Laugwitz, Karl-Ludwig Siscovick, David Rotter, Jerome I. Hazen, Stanley L. Tracy, Russell Cresci, Sharon Spertus, John Jackson, Rebecca Schwartz, Stephen M. Natarajan, Pradeep Crosby, Jacy Muzny, Donna Ballantyne, Christie Rich, Stephen S. O'Donnell, Christopher J. Abecasis, Goncalo Sunyaev, Shamil Nickerson, Deborah A. Buring, Julie E. Ridker, Paul M. Chasman, Daniel I. Austin, Erin Ye, Zi Kullo, Iftikhar J. Weeke, Peter E. Shaffer, Christian M. Bastarache, Lisa A. Denny, Joshua C. Roden, Dan M. Palmer, Colin Deloukas, Panos Lin, Dan-Yu Tang, Zheng-zheng Erdmann, Jeanette Schunkert, Heribert Danesh, John Marrugat, Jaume Elosua, Roberto Ardissino, Diego McPherson, Ruth Watkins, Hugh Reiner, Alex P. Wilson, James G. Altshuler, David Gibbs, Richard A. Lander, Eric S. Boerwinkle, Eric Gabriel, Stacey Kathiresan, Sekar TI Inactivating Mutations in NPC1L1 and Protection from Coronary Heart Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INTESTINAL CHOLESTEROL ABSORPTION; MYOCARDIAL-INFARCTION; GENETIC-VARIANTS; EZETIMIBE; DESIGN; RISK; TRIAL; LDL; ASSOCIATION; SIMVASTATIN AB BACKGROUND Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann-Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug. METHODS We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease. RESULTS With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P = 0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P = 0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%). CONCLUSIONS Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. C1 [Stitziel, Nathan O.; Cresci, Sharon] Washington Univ, Sch Med, Dept Med, Div Cardiovasc, St Louis, MO 63130 USA. [Stitziel, Nathan O.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO 63130 USA. [Cresci, Sharon] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Won, Hong-Hee; Peloso, Gina M.; Do, Ron; Natarajan, Pradeep; Altshuler, David; Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Won, Hong-Hee; Peloso, Gina M.; Do, Ron; Natarajan, Pradeep; Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [O'Donnell, Christopher J.; Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Won, Hong-Hee; Peloso, Gina M.; Do, Ron; Natarajan, Pradeep; O'Donnell, Christopher J.; Altshuler, David; Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Sunyaev, Shamil] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Buring, Julie E.; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Won, Hong-Hee; Peloso, Gina M.; Do, Ron; Fontanillas, Pierre; Gupta, Namrata; Natarajan, Pradeep; Sunyaev, Shamil; Altshuler, David; Lander, Eric S.; Gabriel, Stacey; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Morrison, Alanna C.; Crosby, Jacy; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Muzny, Donna; Gibbs, Richard A.; Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Ballantyne, Christie] Baylor Coll Med, Sect Atherosclerosis & Vasc Med, Houston, TX 77030 USA. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Lin, Dan-Yu] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Duga, Stefano; Asselta, Rosanna] Univ Milan, Dipartimento Biotecnol Med & Med Traslaz, Milan, Italy. [Merlini, Piera A.; Marziliano, Nicola; Notarangelo, Maria Francesca; Ardissino, Diego] Azienda Osped Univ Parma, Parma, Italy. [Merlini, Piera A.; Ardissino, Diego] Assoc Studio Trombosi Cardiol, Pavia, Italy. [Goel, Anuj; Farrall, Martin; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England. [Goel, Anuj; Farrall, Martin; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Danesh, John] Univ Cambridge, Cambridge, England. [Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge, England. [Palmer, Colin] Univ Dundee, Med Res Inst, Dundee, Scotland. [Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Saleheen, Danish] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Reilly, Muredach; Wilensky, Robert] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [Ferrario, Paola; Koenig, Inke] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany. [Buring, Julie E.] Med Univ Lubeck, Inst Integrat & Expt Genom, D-23538 Lubeck, Germany. [Buring, Julie E.] DZHK German Res Ctr Cardiovasc Res Partner Site H, Lubeck, Germany. [Meitinger, Thomas] Helmholtz Zentrum, Inst Humangenet, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Humangenet, D-80290 Munich, Germany. [Laugwitz, Karl-Ludwig] Tech Univ Munich, Klinikum Rechts Isar, Med Klin, D-80290 Munich, Germany. [Kessler, Thorsten; Kastrati, Adnan; Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany. [Meitinger, Thomas; Kastrati, Adnan; Laugwitz, Karl-Ludwig; Schunkert, Heribert] Partner Site Munich Heart Alliance, German Ctr Cardiovasc Res DZHK, Munich, Germany. [Schick, Ursula; Schwartz, Stephen M.; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Siscovick, David] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Siscovick, David] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98195 USA. [Schwartz, Stephen M.; Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Auer, Paul] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53201 USA. [Assimes, Themistocles L.] Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA. [Assimes, Themistocles L.] Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Hovingh, G. Kees] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Hazen, Stanley L.] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Jackson, Rebecca] Ohio State Univ, Dept Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Tracy, Russell] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Tracy, Russell] Univ Vermont, Coll Med, Dept Biochem, Burlington, VT 05405 USA. [Spertus, John] Univ Missouri Kansas City, St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Abecasis, Goncalo] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Austin, Erin; Ye, Zi; Kullo, Iftikhar J.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Weeke, Peter E.; Shaffer, Christian M.; Denny, Joshua C.; Roden, Dan M.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Bastarache, Lisa A.; Denny, Joshua C.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37235 USA. [Roden, Dan M.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA. [Tang, Zheng-zheng] Vanderbilt Univ, Dept Biostat, Nashville, TN 37235 USA. [Weeke, Peter E.] Rigshosp, Copenhagen Univ Hosp, Mol Cardiol Lab, Dept Cardiol, DK-2100 Copenhagen, Denmark. [Deloukas, Panos] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia. [Marrugat, Jaume; Elosua, Roberto] Inst Hosp Mar Invest Med IMIM, Grp Epidemiol & Genet Cardiovasc, Barcelona, Spain. [McPherson, Ruth] Univ Ottawa Heart Inst, Div Cardiol, Ottawa, ON, Canada. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA. EM skathiresan@partners.org RI Palmer, Colin/C-7053-2008; Meitinger, Thomas/O-1318-2015; Kessler, Thorsten/O-7426-2015; Deloukas, Panos/B-2922-2013; Study, GoDARTS/K-9448-2016; Konig, Inke/A-4544-2009; Erdmann, Jeanette/P-7513-2014; OI Watkins, Hugh/0000-0002-5287-9016; Assimes, Themistocles/0000-0003-2349-0009; Palmer, Colin/0000-0002-6415-6560; Deloukas, Panos/0000-0001-9251-070X; Asselta, Rosanna/0000-0001-5351-0619; ELOSUA, ROBERTO/0000-0001-8235-0095; Natarajan, Pradeep/0000-0001-8402-7435; Erdmann, Jeanette/0000-0002-4486-6231; Stitziel, Nathan/0000-0002-4963-8211; Duga, Stefano/0000-0003-3457-1410 FU National Institutes of Health FX Funded by the National Institutes of Health and others. NR 38 TC 137 Z9 139 U1 6 U2 22 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 NOV 27 PY 2014 VL 371 IS 22 BP 2072 EP 2082 DI 10.1056/NEJMoa1405386 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AU4KP UT WOS:000345580000006 ER PT J AU Ryan, DP Hong, TS Bardeesy, N AF Ryan, David P. Hong, Theodore S. Bardeesy, Nabeel TI Pancreatic Adenocarcinoma REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID INTERNATIONAL CONSENSUS GUIDELINES; MANAGEMENT C1 [Ryan, David P.; Hong, Theodore S.; Bardeesy, Nabeel] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ryan, DP (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM dpryan@mgh.harvard.edu NR 3 TC 38 Z9 40 U1 0 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD NOV 27 PY 2014 VL 371 IS 22 BP 2140 EP 2141 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AU4KP UT WOS:000345580000027 PM 25427123 ER PT J AU Michmizos, KP Vaisman, L Krebs, HI AF Michmizos, Konstantinos P. Vaisman, Lev Krebs, Hermano Igo TI A comparative analysis of speed profile models for ankle pointing movements: evidence that lower and upper extremity discrete movements are controlled by a single invariant strategy SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE sensorimotor control; ankle movements; rehabilitation robotics; neurorehabilitation of motor function; stroke; cerebral palsy ID AMERICAN-HEART-ASSOCIATION; ROBOT-ASSISTED THERAPY; MOTOR RECOVERY; ARM MOVEMENTS; VESTIBULOOCULAR REFLEX; STROKE REHABILITATION; MECHANICAL IMPEDANCE; TRAJECTORY FORMATION; RAPID MOVEMENTS; SUBACUTE STROKE AB Little is known about whether our knowledge of how the central nervous system controls the upper extremities (UE), can generalize, and to what extent to the lower limbs. Our continuous efforts to design the ideal adaptive robotic therapy for the lower limbs of stroke patients and children with cerebral palsy highlighted the importance of analyzing and modeling the kinematics of the lower limbs, in general, and those of the ankle joints, in particular. We recruited 15 young healthy adults that performed in total 1,386 visually evoked, visually guided, and target-directed discrete pointing movements with their ankle in dorsal-plantar and inversion-eversion directions. Using a non-linear, least-squares error-minimization procedure, we estimated the parameters for 19 models, which were initially designed to capture the dynamics of upper limb movements of various complexity. We validated our models based on their ability to reconstruct the experimental data. Our results suggest a remarkable similarity between the top-performing models that described the speed profiles of ankle pointing movements and the ones previously found for the UE both during arm reaching and wrist pointing movements. Among the top performers were the support-bounded lognormal and the beta models that have a neurophysiological basis and have been successfully used in upper extremity studies with normal subjects and patients. Our findings suggest that the same model can be applied to different "human" hardware, perhaps revealing a key invariant in human motor control. These findings have a great potential to enhance our rehabilitation efforts in any population with lower extremity deficits by, for example, assessing the level of motor impairment and improvement as well as informing the design of control algorithms for therapeutic ankle robots. C1 [Michmizos, Konstantinos P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging,MIT, Charlestown, MA 02129 USA. [Michmizos, Konstantinos P.] MIT, McGovern Inst Brain Res, Cambridge, MA 02319 USA. [Vaisman, Lev] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Krebs, Hermano Igo] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Krebs, Hermano Igo] Univ Maryland, Sch Med, Dept Neurol, Div Rehabil, College Pk, MD 20742 USA. [Krebs, Hermano Igo] Fujita Hlth Univ, Dept Phys Med & Rehabil, Nagoya, Aichi, Japan. [Krebs, Hermano Igo] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. RP Michmizos, KP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging,MIT, 1115-Q,149 13th St, Charlestown, MA 02129 USA. EM konmic@mgh.harvard.edu FU Cerebral Palsy International Research Foundation (CPIRF); Niarchos Foundation; NIH [R01HD069776-02]; Foundation for Education and European Culture FX This work was supported in part by a grant from the Cerebral Palsy International Research Foundation (CPIRF) and the Niarchos Foundation, and by NIH Grant R01HD069776-02. Dr. Konstantinos P. Michmizos was partially supported by the Foundation for Education and European Culture. Dr. Hermano Igo Krebs is a co-inventor in the MIT-held patent for the robotic device used in this work. He holds equity positions in Interactive Motion Technologies, the company that manufactures this type of technology under license to MIT. NR 101 TC 4 Z9 4 U1 3 U2 20 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD NOV 27 PY 2014 VL 8 AR 962 DI 10.3389/fnhum.2014.00962 PG 15 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AU1HY UT WOS:000345372900001 PM 25505881 ER PT J AU Leykum, LK Lanham, HJ Provost, SM McDaniel, RR Pugh, J AF Leykum, Luci K. Lanham, Holly J. Provost, Shannon M. McDaniel, Reuben R., Jr. Pugh, Jacqueline TI Improving outcomes of hospitalized patients: the Physician Relationships, Improvising, and Sensemaking intervention protocol SO IMPLEMENTATION SCIENCE LA English DT Article DE Complexity science; Inpatient care; Physician teams ID QUALITY-OF-CARE; HEALTH-CARE; COMPLEXITY; MORTALITY; FAILURE; PROGRAM; SCIENCE; TEAMS; JAZZ AB Background: Our goal is to improve the safety and effectiveness of inpatient care. Rather than focus on improving process of care, we focus on the social structure within physician teams. We have developed the Physician Relationships, Improvising, and Sensemaking (PRISm) intervention to improve the way physician teams round, enabling them to better relate, make sense of their patients' conditions, and improvise in uncertain clinical situations. We are currently studying the impact of PRISm on adverse events and complications in hospitalized patients. This manuscript describes the PRISm intervention. Methods/design: PRISm is a structured communication tool consisting of three components: daily briefings before rounds; use of the Situation, Task, Intent, Concern, and Calibrate (STICC) framework during rounds as part of the discussion of individual patients; and debriefings after rounds. We are implementing the PRISm intervention on eight inpatient medical and surgical physician teams in the South Texas Veterans Health Care System. We are assessing PRISm impact on the way team members relate to each other, round, and discuss patients through pre- and post-implementation observations and surveys. We are also assessing PRISm impact on complications and adverse events. Finally, we are interviewing physicians regarding their experience using the intervention. Discussion: Our results will allow us to begin to understand the potential impact of interventions designed to improve how providers relate to each other, improvise, and make sense of what is happening as a strategy for improving inpatient care. Our in-depth data collection will enable us to assess how relationships, improvising, and sensemaking influence patient outcomes, potentially through creating shared mental models or enhancing distributed cognition during clinical reasoning. Finally, our results will lay the groundwork for larger implementation studies to improve clinical outcomes through improving how providers, and providers, patients, and caregivers, relate. C1 [Leykum, Luci K.; Lanham, Holly J.; Pugh, Jacqueline] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Leykum, Luci K.; Lanham, Holly J.; Pugh, Jacqueline] Univ Texas San Antonio, Hlth Sci Ctr, Sch Med, San Antonio, TX 78229 USA. [Leykum, Luci K.; Lanham, Holly J.; Provost, Shannon M.; McDaniel, Reuben R., Jr.] Univ Texas Austin, Austin, TX 78712 USA. RP Leykum, LK (reprint author), South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. EM Leykum@uthscsa.edu NR 38 TC 1 Z9 2 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD NOV 26 PY 2014 VL 9 AR 171 DI 10.1186/s13012-014-0171-3 PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AY2PR UT WOS:000347432400002 PM 25424007 ER PT J AU Rudd, ML Mohamed, H Price, JC O'Hara, AJ Le Gallo, M Urick, ME Cruz, P Zhang, SY Hansen, NF Godwin, AK Sgroi, DC Wolfsberg, TG Mullikin, JC Merino, MJ Bell, DW AF Rudd, Meghan L. Mohamed, Hassan Price, Jessica C. O'Hara, Andrea J. Le Gallo, Matthieu Urick, Mary Ellen Cruz, Pedro Zhang, Suiyuan Hansen, Nancy F. Godwin, Andrew K. Sgroi, Dennis C. Wolfsberg, Tyra G. Mullikin, James C. Merino, Maria J. Bell, Daphne W. CA NISC Comparative Sequencing TI Mutational analysis of the tyrosine kinome in serous and clear cell endometrial cancer uncovers rare somatic mutations in TNK2 and DDR1 SO BMC CANCER LA English DT Article DE Endometrial; Cancer; Mutation; TNK2; ACK1; DDR1; Copy number; Tyrosine kinase; Tyrosine kinome ID DISCOIDIN DOMAIN RECEPTOR-1; CHRONIC MYELOID-LEUKEMIA; LUNG-CANCER; EGF RECEPTOR; KINASE ACK1; CARCINOMA; MIGRATION; GENOMICS; COMPLEX; GROWTH AB Background: Endometrial cancer (EC) is the 8(th) leading cause of cancer death amongst American women. Most ECs are endometrioid, serous, or clear cell carcinomas, or an admixture of histologies. Serous and clear ECs are clinically aggressive tumors for which alternative therapeutic approaches are needed. The purpose of this study was to search for somatic mutations in the tyrosine kinome of serous and clear cell ECs, because mutated kinases can point to potential therapeutic targets. Methods: In a mutation discovery screen, we PCR amplified and Sanger sequenced the exons encoding the catalytic domains of 86 tyrosine kinases from 24 serous, 11 clear cell, and 5 mixed histology ECs. For somatically mutated genes, we next sequenced the remaining coding exons from the 40 discovery screen tumors and sequenced all coding exons from another 72 ECs (10 clear cell, 21 serous, 41 endometrioid). We assessed the copy number of mutated kinases in this cohort of 112 tumors using quantitative real time PCR, and we used immunoblotting to measure expression of these kinases in endometrial cancer cell lines. Results: Overall, we identified somatic mutations in TNK2 (tyrosine kinase non-receptor, 2) and DDR1 (discoidin domain receptor tyrosine kinase 1) in 5.3% (6 of 112) and 2.7% (3 of 112) of ECs. Copy number gains of TNK2 and DDR1 were identified in another 4.5% and 0.9% of 112 cases respectively. Immunoblotting confirmed TNK2 and DDR1 expression in endometrial cancer cell lines. Three of five missense mutations in TNK2 and one of two missense mutations in DDR1 are predicted to impact protein function by two or more in silico algorithms. The TNK2(P761Rfs)*(72) frameshift mutation was recurrent in EC, and the DDR1(R570Q) missense mutation was recurrent across tumor types. Conclusions: This is the first study to systematically search for mutations in the tyrosine kinome in clear cell endometrial tumors. Our findings indicate that high-frequency somatic mutations in the catalytic domains of the tyrosine kinome are rare in clear cell ECs. We uncovered ten new mutations in TNK2 and DDR1 within serous and endometrioid ECs, thus providing novel insights into the mutation spectrum of each gene in EC. C1 [Rudd, Meghan L.; Mohamed, Hassan; Price, Jessica C.; O'Hara, Andrea J.; Le Gallo, Matthieu; Urick, Mary Ellen; Bell, Daphne W.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.; NISC Comparative Sequencing] NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. [Cruz, Pedro; Zhang, Suiyuan; Hansen, Nancy F.; Wolfsberg, Tyra G.; Mullikin, James C.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66160 USA. [Sgroi, Dennis C.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. [Sgroi, Dennis C.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Merino, Maria J.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bell, DW (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM belldaph@mail.nih.gov FU Intramural Program of the National Human Genome Research Institute, National Institutes of Health; Ovarian Cancer Research Fund; Avon Foundation; National Institute of Health [R01CA112021]; Department of Defense Breast Cancer Research Program [W81XWH-04-1-0606]; NCI SPORE in breast cancer at Massachusetts General Hospital; NIH [R01CA140323] FX We thank Niraj Travedi for advice on statistical analyses. Funded in part by the Intramural Program of the National Human Genome Research Institute, National Institutes of Health (DWB, JGW, and JCM), by NIH R01CA140323 and the Ovarian Cancer Research Fund (AKG), The Avon Foundation (DCS), National Institute of Health (R01CA112021, DCS), The Department of Defense Breast Cancer Research Program (W81XWH-04-1-0606, DCS), and the NCI SPORE in breast cancer at Massachusetts General Hospital (DCS). NR 60 TC 1 Z9 1 U1 0 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 NOV 26 PY 2014 VL 14 AR 884 DI 10.1186/1471-2407-14-884 PG 9 WC Oncology SC Oncology GA AU9SC UT WOS:000345934000001 PM 25427824 ER PT J AU Naik, RP Derebail, VK Grams, ME Franceschini, N Auer, PL Peloso, GM Young, BA Lettre, G Peralta, CA Katz, R Hyacinth, HI Quarells, RC Grove, ML Bick, AG Fontanillas, P Rich, SS Smith, JD Boerwinkle, E Rosamond, WD Ito, K Lanzkron, S Coresh, J Correa, A Sarto, GE Key, NS Jacobs, DR Kathiresan, S Bibbins-Domingo, K Kshirsagar, AV Wilson, JG Reiner, AP AF Naik, Rakhi P. Derebail, Vimal K. Grams, Morgan E. Franceschini, Nora Auer, Paul L. Peloso, Gina M. Young, Bessie A. Lettre, Guillaume Peralta, Carmen A. Katz, Ronit Hyacinth, Hyacinth I. Quarells, Rakale C. Grove, Megan L. Bick, Alexander G. Fontanillas, Pierre Rich, Stephen S. Smith, Joshua D. Boerwinkle, Eric Rosamond, Wayne D. Ito, Kaoru Lanzkron, Sophie Coresh, Josef Correa, Adolfo Sarto, Gloria E. Key, Nigel S. Jacobs, David R. Kathiresan, Sekar Bibbins-Domingo, Kirsten Kshirsagar, Abhijit V. Wilson, James G. Reiner, Alexander P. TI Association of Sickle Cell Trait With Chronic Kidney Disease and Albuminuria in African Americans SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID GLOMERULAR-FILTRATION-RATE; STAGE RENAL-DISEASE; RACIAL-DIFFERENCES; DESIGN; PREVALENCE; VARIANTS; ATHEROSCLEROSIS; OBJECTIVES; DEFECT; RISK AB IMPORTANCE The association between sickle cell trait (SCT) and chronic kidney disease (CKD) is uncertain. OBJECTIVE To describe the relationship between SCT and CKD and albuminuria in self-identified African Americans. DESIGN, SETTING, AND PARTICIPANTS Using 5 large, prospective, US population-based studies (the Atherosclerosis Risk in Communities Study [ARIC, 1987-2013; n = 3402], Jackson Heart Study [JHS, 2000-2012; n = 2105], Coronary Artery Risk Development in Young Adults [CARDIA, 1985-2006; n = 848], Multi-Ethnic Study of Atherosclerosis [MESA, 2000-2012; n = 1620], and Women's Health Initiative [WHI, 1993-2012; n = 8000]), we evaluated 15 975 self-identified African Americans (1248 participants with SCT [SCT carriers] and 14 727 participants without SCT [noncarriers]). MAIN OUTCOMES AND MEASURES Primary outcomes were CKD (defined as an estimated glomerular filtration rate [eGFR] of <60 mL/min/1.73m(2) at baseline or follow-up), incident CKD, albuminuria (defined as a spot urine albumin: creatinine ratio of >30mg/g or albumin excretion rate >30mg/24 hours), and decline in eGFR (defined as a decrease of >3 mL/min/1.73m2 per year). Effect sizes were calculated separately for each cohort and were subsequently meta-analyzed using a random-effects model. RESULTS A total of 2233 individuals (239 of 1247 SCT carriers [19.2%] vs 1994 of 14 722 noncarriers [13.5%]) had CKD, 1298 (140 of 675 SCT carriers [20.7%] vs 1158 of 8481 noncarriers [13.7%]) experienced incident CKD, 1719 (150 of 665 SCT carriers [22.6%] vs 1569 of 8249 noncarriers [19.0%]) experienced decline in eGFR, and 1322 (154 of 485 SCT carriers [31.8%] vs 1168 of 5947 noncarriers [19.6%]) had albuminuria during the study period. Individuals with SCT had an increased risk of CKD (odds ratio [OR], 1.57 [95% CI, 1.34-1.84]; absolute risk difference [ARD], 7.6%[95% CI, 4.7%-10.8%]), incident CKD (OR, 1.79 [95% CI, 1.45-2.20]; ARD, 8.5%[95% CI, 5.1%-12.3%]), and decline in eGFR (OR, 1.32 [95% CI, 1.07-1.61]; ARD, 6.1%[95% CI, 1.4%-13.0%]) compared with noncarriers. Sickle cell trait was also associated with albuminuria (OR, 1.86 [95% CI, 1.49-2.31]; ARD, 12.6%[95% CI, 7.7%-17.7%]). CONCLUSIONS AND RELEVANCE Among African Americans in these cohorts, the presence of SCT was associated with an increased risk of CKD, decline in eGFR, and albuminuria, compared with noncarriers. These findings suggest that SCT may be associated with the higher risk of kidney disease in African Americans. C1 [Naik, Rakhi P.; Lanzkron, Sophie] Johns Hopkins Univ, Div Hematol, Dept Med, Baltimore, MD 21287 USA. [Derebail, Vimal K.; Kshirsagar, Abhijit V.] Univ N Carolina, Dept Med, Kidney Ctr, Div Nephrol & Hypertens, Chapel Hill, NC USA. [Grams, Morgan E.] Johns Hopkins Univ, Dept Med, Div Nephrol, Baltimore, MD USA. [Franceschini, Nora; Rosamond, Wayne D.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Auer, Paul L.] Univ Wisconsin Milwaukee, Zilber Sch Publ Hlth, Dept Biostat, Milwaukee, WI USA. [Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Program Med & Populat Genet, Boston & Broad Inst, Ctr Human Genet, Cambridge, MA USA. [Young, Bessie A.] Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Lettre, Guillaume] Univ Montreal, Montreal, PQ, Canada. [Peralta, Carmen A.] Univ Calif San Francisco, Dept Med, Div Nephrol, San Francisco, CA USA. [Katz, Ronit] Univ Washington, Kidney Res Inst, Seattle, WA 98195 USA. [Hyacinth, Hyacinth I.] Med Univ S Carolina, Dept Neurosci, Stroke Ctr, Charleston, SC USA. [Quarells, Rakale C.] Morehouse Sch Med, Cardiovasc Res Inst, Atlanta, GA 30310 USA. [Grove, Megan L.; Boerwinkle, Eric] Univ Texas Sch, Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX USA. [Bick, Alexander G.; Fontanillas, Pierre; Ito, Kaoru] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Smith, Joshua D.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Correa, Adolfo] Univ Mississippi, Med Ctr, Dept Med & Pediat, Jackson, MS USA. [Sarto, Gloria E.] Univ Wisconsin, Dept Obstet & Gynecol, Madison, WI 53706 USA. [Key, Nigel S.] Univ N Carolina, Dept Med, Div Hematol & Oncol, Chapel Hill, NC USA. [Jacobs, David R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Bibbins-Domingo, Kirsten] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS USA. [Reiner, Alexander P.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. RP Naik, RP (reprint author), Johns Hopkins Univ, Div Hematol, Dept Med, 1830 E Monument St,Ste 7300, Baltimore, MD 21287 USA. EM rakhi@jhmi.edu OI Grams, Morgan/0000-0002-4430-6023; Derebail, Vimal/0000-0002-7662-7497 FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367]; National Human Genome Research Institute (NHGRI) [U01HG004402]; National Institutes of Health (NIH) [HHSN268200625226C]; NIH through the American Recovery and Reinvestment Act (ARRA) [5RC2HL102419]; Baylor Genome Center [U54 HG003273]; Duke University Medical Center [5K12 HL087097-0]; University of North Carolina Clinical Hematology Research Career Development Program; NHLBI [AG0005, N01-HC-95159, 01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167]; National Institute on Minority Health and Health Disparities [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C, RC4MD005964]; University of Alabama at Birmingham [HHSN268201300025C, HSN268201300026C]; Northwestern University [HHSN268201300027C]; University of Minnesota [HHSN268201300028C]; Kaiser Foundation Research Institute [HHSN268201300029C]; Johns Hopkins University School of Medicine [HHSN268200900041C]; Intramural Research Program of the National Institute on Aging (NIA); NIA [AG0005]; National Center for Research Resources [UL1-TR-000040, UL1-RR-025005]; NIH [R01 DK089174, R01 DK076770-01, 1R01DK102134-01]; US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK085501, DK085524, DK085526, DK085545, DK085584]; NHGRI [5u54HG003067, U54 HG003067]; NIDDK [R01 DK089174, R01 DK076770-01]; NHLBI. [R01HL086694, N01-HC-95168, N01-HC-95169, RC2 HL-103010, RC2 HL-102923, RC2 HL-102924, RC2 HL-102925, RC2 HL-102926, R01HL107816, HL080494-05, 2K12HL087169-06, T32HL007208, 1UO1HL117659, R01HL071862] FX The Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (NHLBI; contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C and grants R01HL087641, R01HL59367, and R01HL086694); National Human Genome Research Institute (NHGRI; contract U01HG004402); and the National Institutes of Health (NIH; contract HHSN268200625226C). Funding for "Building on Genome Wide Association Studies for NHLBI-diseases: the US CHARGE Consortium" was provided by grant 5RC2HL102419 from the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA). Sequencing was funded by grant U54 HG003273 from the Baylor Genome Center. This ancillary study was supported by grant 5K12 HL087097-0 from the Duke University Medical Center and University of North Carolina Clinical Hematology Research Career Development Program (Dr. Derebail). The Jackson Heart Study (JHS) is supported by the NHLBI and the National Institute on Minority Health and Health Disparities (contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C). The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by NHLBI in collaboration with the University of Alabama at Birmingham (contracts HHSN268201300025C and HSN268201300026C), Northwestern University (contract HHSN268201300027C), University of Minnesota (contract HHSN268201300028C), Kaiser Foundation Research Institute (contract HHSN268201300029C), and Johns Hopkins University School of Medicine (contract HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and intra-agency agreement AG0005 between NIA and NHLBI. The Multi-Ethnic Study of Atherosclerosis (MESA) was supported by the NHLBI (contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169) and by grants UL1-TR-000040 and UL1-RR-025005 from National Center for Research Resources. The Women's Health Initiative (WHI) program is funded by NHLBI, NIH, and the US Department of Health and Human Services (contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C). Funding for the Grand Opportunity Exome Sequencing Project (GO ESP) was provided by NHLBI grants RC2 HL-103010 (HeartGO), RC2 HL-102923 (LungGO), and RC2 HL-102924 (WHISP). The exome sequencing was performed through NHLBI grants RC2 HL-102925 (BroadGO) and RC2 HL-102926 (SeattleGO). Exome sequencing was also performed through the Type 2 Diabetes Genetic Exploration by Next Generation Sequencing (T2D-GENES) consortium, with support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; contracts DK085501, DK085524, DK085526, DK085545, and DK085584). Additional exome sequencing was performed through the Minority Health Genomics and Translational Research Bio-repository Database (MH-GRID) with support from grant RC4MD005964 from the National Institute on Minority Health and Health Disparities. The MH-GRID investigators (Rakale C. Quarells, Donna K. Arnett, Gary H. Gibbons, Robert L. Davis, Suzanne M. Leal, Deborah A. Nickerson, James Perkins, Charles N. Rotimi, Joel H. Saltz, and Herman A. Taylor, James G. Wilson) collected and provided data for this study.; Chip genotyping and exome sequencing in JHS was also supported by grant R01HL107816 from NHLBI (Dr Kathiresan) and NHGRI (contract 5u54HG003067) (Drs Gabriel and Lander). Support for targeted sequencing was provided by grants U54 HG003067 from the NHGRI (Medical Sequencing Program) and HL080494-05 from NHLBI. Funding for cystatin C and APOL1 in ARIC was provided by grants R01 DK089174 for cystatin C (Dr Selvin) and R01 DK076770-01 for APOL1 from the NIH and NIDDK. Funding for this work was also provided by grant 1R01DK102134-01 from the NIH and NIDDK. This material is the result of work supported by resources from the Veterans Affairs Puget Sound Health Care System (Dr Young), Seattle, Washington. Funding was also provided in part by grant 2K12HL087169-06 (Dr Naik), by grant T32HL007208 (Dr Peloso), by grant 1UO1HL117659 (Dr Key), and by grant R01HL071862 (Dr Reiner) from NHLBI. Some of the data reported here have been supplied by the United States Renal Data System. NR 33 TC 26 Z9 26 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 NOV 26 PY 2014 VL 312 IS 20 BP 2115 EP 2125 DI 10.1001/jama.2014.15063 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AU5DG UT WOS:000345626800015 PM 25393378 ER PT J AU Cardillo, A Petri, G Nicosia, V Sinatra, R Gomez-Gardenes, J Latora, V AF Cardillo, Alessio Petri, Giovanni Nicosia, Vincenzo Sinatra, Roberta Gomez-Gardenes, Jesus Latora, Vito TI Evolutionary dynamics of time-resolved social interactions SO PHYSICAL REVIEW E LA English DT Article ID COMPLEX NETWORKS; STATISTICAL-MECHANICS; COOPERATION; DILEMMAS; MOBILITY; GRAPHS; ORIGIN; WORLD; GAMES AB Cooperation among unrelated individuals is frequently observed in social groups when their members combine efforts and resources to obtain a shared benefit that is unachievable by an individual alone. However, understanding why cooperation arises despite the natural tendency of individuals toward selfish behavior is still an open problem and represents one of the most fascinating challenges in evolutionary dynamics. Recently, the structural characterization of the networks in which social interactions take place has shed some light on the mechanisms by which cooperative behavior emerges and eventually overcomes the natural temptation to defect. In particular, it has been found that the heterogeneity in the number of social ties and the presence of tightly knit communities lead to a significant increase in cooperation as compared with the unstructured and homogeneous connection patterns considered in classical evolutionary dynamics. Here, we investigate the role of social-ties dynamics for the emergence of cooperation in a family of social dilemmas. Social interactions are in fact intrinsically dynamic, fluctuating, and intermittent over time, and they can be represented by time-varying networks. By considering two experimental data sets of human interactions with detailed time information, we show that the temporal dynamics of social ties has a dramatic impact on the evolution of cooperation: the dynamics of pairwise interactions favors selfish behavior. C1 [Cardillo, Alessio; Gomez-Gardenes, Jesus] Univ Zaragoza, Dept Fis Mat Condensada, E-50009 Zaragoza, Spain. [Cardillo, Alessio; Gomez-Gardenes, Jesus] Univ Zaragoza, Inst Biocomputat & Phys Complex Syst BIFI, E-50018 Zaragoza, Spain. [Petri, Giovanni] ISI, I-10126 Turin, Italy. [Nicosia, Vincenzo; Latora, Vito] Queen Mary Univ London, Sch Math Sci, London E14NS, England. [Sinatra, Roberta] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Sinatra, Roberta] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Sinatra, Roberta] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Latora, Vito] Univ Catania, Dipartimento Fis & Astron, I-95123 Catania, Italy. [Latora, Vito] Ist Nazl Fis Nucl, I-95123 Catania, Italy. RP Cardillo, A (reprint author), Univ Zaragoza, Dept Fis Mat Condensada, E-50009 Zaragoza, Spain. EM gardenes@gmail.com RI Cardillo, Alessio/F-3466-2011; Gomez-Gardenes, Jesus/B-5818-2009; Nicosia, Vincenzo/C-7890-2013; OI Cardillo, Alessio/0000-0003-4811-9978; Gomez-Gardenes, Jesus/0000-0001-5204-1937; Nicosia, Vincenzo/0000-0003-0636-3278; Latora, Vito/0000-0002-0984-8038; Sinatra, Roberta/0000-0002-7558-1028 FU EU LASAGNE Project [318132 (STREP)]; EU MULTIPLEX Project [317532 (STREP)]; EU PLEXMATH Project [317614 (STREP)]; Spanish MINECO [MTM2009-13848, FIS2011-25167]; FEDER; Comunidad de Aragon (Grupo FENOL); Italian INFN project [TO61]; Spanish MINECO through the Ramon y Cajal program; FET project "TOPDRIM" [IST-318121]; James S. McDonnell Foundation; EPSRC [GALE EP/K020633/1] FX This work was supported by the EU LASAGNE Project, Contract No. 318132 (STREP), by the EU MULTIPLEX Project, Contract No. 317532 (STREP), by the EU PLEXMATH Project, Contract No. 317614 (STREP), by the Spanish MINECO under Projects MTM2009-13848 and FIS2011-25167 (cofinanced by FEDER funds), by the Comunidad de Aragon (Grupo FENOL), and by the Italian TO61 INFN project. J.G.G. is supported by Spanish MINECO through the Ramon y Cajal program. G.P. is supported by the FET project "TOPDRIM" (IST-318121). R.S. is supported by a James S. McDonnell Foundation Postdoctoral Fellowship. V.L. was supported by the EPSRC project GALE EP/K020633/1. NR 63 TC 8 Z9 8 U1 1 U2 18 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 EI 1550-2376 J9 PHYS REV E JI Phys. Rev. E PD NOV 25 PY 2014 VL 90 IS 5 AR 052825 DI 10.1103/PhysRevE.90.052825 PG 11 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA AZ9KP UT WOS:000348533000003 ER PT J AU Kopans, DB AF Kopans, Daniel B. TI MAMMOGRAPHY SCREENING Study "guesstimated" how many cancers would have occurred without mammography screening SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Letter ID BREAST-CANCER C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Breast Imaging Div, Boston, MA 02114 USA. RP Kopans, DB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Breast Imaging Div, Boston, MA 02114 USA. EM dkopans@partners.org NR 5 TC 2 Z9 2 U1 0 U2 1 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 NOV 25 PY 2014 VL 349 AR g6824 DI 10.1136/bmj.g6824 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AW2KE UT WOS:000346115600004 PM 25424500 ER PT J AU Williams, JS Lynch, CP Knapp, RG Egede, LE AF Williams, Joni S. Lynch, Cheryl P. Knapp, Rebecca G. Egede, Leonard E. TI Technology-Intensified Diabetes Education Study (TIDES) in African Americans with type 2 diabetes: study protocol for a randomized controlled trial SO TRIALS LA English DT Article DE Diabetes; Education; Skills training; Technology; Telehealth; Telemedicine ID GLYCEMIC CONTROL; CARE MANAGEMENT; FOLLOW-UP; SUPPORT; SCALE; VETERANS; MELLITUS; VALIDITY; DESIGN; IMPACT AB Background: Compared to American Whites, African Americans have a higher prevalence of type 2 diabetes mellitus (T2DM), experiencing poorer metabolic control and greater risks for complications and death. Patient-level factors, such as diabetes knowledge, self-management skills, empowerment, and perceived control, account for > 90% of the variance observed in outcomes between these racial groups. There is strong evidence that self-management interventions that include telephone-delivered diabetes education and skills training are effective at improving metabolic control in diabetes. Web-based home telemonitoring systems in conjunction with active care management are also effective ways to lower glycosylated hemoglobin A1c values when compared to standard care, and provide feedback to patients; however, there are no studies in African Americans with poorly controlled T2DM that examine the use of technology-based feedback to tailor or augment diabetes education and skills training. This study provides a unique opportunity to address this gap in the literature. Methods: We describe an ongoing 4-year randomized clinical trial, which will test the efficacy of a technology intensified diabetes education and skills training (TIDES) intervention in African Americans with poorly controlled T2DM. Two hundred male and female AfricanAmerican participants, 21 years of age or older and with a glycosylated hemoglobin A1c level = 8%, will be randomized into one of two groups for 12 weeks of telephone interventions: (1) TIDES intervention group or (2) a usual-care group. Participants will be followed for 12 months to ascertain the effect of the interventions on glycemic control. Our primary hypothesis is that, among African Americans with poorly controlled T2DM, patients randomized to the TIDES intervention will have significantly greater reduction in glycosylated hemoglobin A1c at 12 months of follow-up compared to the usual-care group. Discussion: Results from this study will add to the current literature examining how best to deliver diabetes education and skills training and provide important insight into effective strategies to improve metabolic control and hence reduce diabetes complications and mortality rates in African Americans with poorly controlled T2DM. C1 [Williams, Joni S.; Lynch, Cheryl P.; Knapp, Rebecca G.; Egede, Leonard E.] Med Univ S Carolina, Div Gen Internal Med & Geriatr, Charleston, SC 29425 USA. [Williams, Joni S.; Lynch, Cheryl P.; Egede, Leonard E.] Med Univ S Carolina, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Lynch, Cheryl P.; Egede, Leonard E.] Ralph H Johnson VAMC, Hlth Equ & Rural Outreach Innovat Ctr, Charleston, SC 29401 USA. [Knapp, Rebecca G.] Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA. RP Egede, LE (reprint author), Med Univ S Carolina, Div Gen Internal Med & Geriatr, 135 Rutledge Ave, Charleston, SC 29425 USA. EM Egedel@musc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [R01DK098529, K24DK093699] FX The study is funded by grant #R01DK098529 from the National Institute of Diabetes and Digestive and Kidney Diseases. LEE is also partially supported by grant # K24DK093699 from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 33 TC 0 Z9 0 U1 2 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD NOV 25 PY 2014 VL 15 AR 460 DI 10.1186/1745-6215-15-460 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AW2DD UT WOS:000346097600001 PM 25425504 ER PT J AU Chavarri-Guerra, Y Higgins, MJ Szymonifka, J Cigler, T Liedke, P Partridge, A Ligibel, J Come, SE Finkelstein, D Ryan, PD Goss, PE AF Chavarri-Guerra, Y. Higgins, M. J. Szymonifka, J. Cigler, T. Liedke, P. Partridge, A. Ligibel, J. Come, S. E. Finkelstein, D. Ryan, P. D. Goss, P. E. TI Drug withdrawal in women with progressive metastatic breast cancer while on aromatase inhibitor therapy SO BRITISH JOURNAL OF CANCER LA English DT Article DE aromatase inhibitor; withdrawal response; breast cancer; hormone-receptor-positive tumours; metastatic; endocrine therapy ID FIRST-LINE THERAPY; POSTMENOPAUSAL WOMEN; PHASE-III; ESTRADIOL HYPERSENSITIVITY; ESTROGEN DEPRIVATION; TAMOXIFEN; ANASTROZOLE; EXEMESTANE; LETROZOLE; CELLS AB Background: Acquiring resistance to endocrine therapy is common in metastatic hormone-receptor-positive breast cancer (MBC). These patients most often transition either to next-line endocrine therapy or to systemic chemotherapy. However, withdrawal of endocrine therapy and observation as is selectively practiced in prostate cancer is another potential strategy for breast cancer patients. Methods: A prospective, single-arm phase II trial of aromatase inhibitor (AI) withdrawal was performed in women with MBC, who had disease progression on AI therapy. The primary objective was to estimate the clinical benefit rate (defined as complete or partial response, or stable disease for at least 24 weeks, by RECIST criteria). Participants were monitored clinically and radiographically off all therapy at 8, 16 and 24 weeks after treatment and every 12 weeks thereafter until disease progression. Results: Twenty-four patients (of 40 intended) were enrolled when the study was closed due to slow accrual. Clinical benefit rate overall was 46% (95% CI 26% to 67%). Median progression-free survival from time of AI withdrawal was 4 months. Two patients have remained progression free, off all treatment, for over 60 months. Conclusions: Despite suboptimal patient accrual, our results suggest that selected patients with metastatic breast cancer progressing on AI therapy can experience disease stabilisation and a period of observation after AI withdrawal. A randomised phase II trial is planned. C1 [Chavarri-Guerra, Y.] Inst Nacl Ciencias Med Nutr, Mexico City, DF, Mexico. [Higgins, M. J.; Szymonifka, J.; Liedke, P.; Finkelstein, D.; Goss, P. E.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Cigler, T.] Weill Cornell Med Coll, New York, NY USA. [Partridge, A.; Ligibel, J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Come, S. E.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Ryan, P. D.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. RP Goss, PE (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM pgoss@partners.org FU Avon Foundation, New York FX We are grateful to the women who agreed to participate in this study. This study was supported and funded by the Avon Foundation, New York. This funding source had no role in the planning or writing of this manuscript. NR 24 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD NOV 25 PY 2014 VL 111 IS 11 BP 2046 EP 2050 DI 10.1038/bjc.2014.502 PG 5 WC Oncology SC Oncology GA AU4QW UT WOS:000345597700003 PM 25233398 ER PT J AU Isakoff, SJ Wang, D Campone, M Calles, A Leip, E Turnbull, K Bardy-Bouxin, N Duvillie, L Calvo, E AF Isakoff, S. J. Wang, D. Campone, M. Calles, A. Leip, E. Turnbull, K. Bardy-Bouxin, N. Duvillie, L. Calvo, E. TI Bosutinib plus capecitabine for selected advanced solid tumours: results of a phase 1 dose-escalation study SO BRITISH JOURNAL OF CANCER LA English DT Article DE bosutinib; capecitabine; neoplasms; metastatic cancer; phase 1; safety ID METASTATIC BREAST-CANCER; TYROSINE KINASE INHIBITOR; SRC FAMILY KINASES; SQUAMOUS-CELL CARCINOMA; THYMIDYLATE SYNTHASE; IN-VITRO; ORAL CAPECITABINE; CLINICAL-TRIALS; DASATINIB BMS-354825; PROTEIN EXPRESSION AB Background: This phase 1 study evaluated the maximum tolerated dose (MTD), safety, and efficacy of bosutinib (competitive Src/Abl tyrosine kinase inhibitor) plus capecitabine. Methods: Patients with locally advanced/metastatic breast, pancreatic, or colorectal cancers; cholangiocarcinoma; or glioblastoma received bosutinib plus capecitabine at eight of nine possible dose combinations using an 'up-down' design to determine the toxicity contour of the combination. Results: Among 32 enrolled patients, none of the 9 patients receiving MTD (bosutinib 300 mg once daily plus capecitabine 1000 mg m(-2) twice daily) experienced dose-limiting toxicities (DLTs). Overall, 2 out of 31 (6%) evaluable patients experienced DLTs (grade 3 neurologic pain (n = 1); grade 3 pruritus/rash and increased alanine aminotransferase (n = 1)). Most common treatment-related adverse events (AEs) were diarrhoea, nausea, vomiting, palmar-plantar erythrodysesthesia (PPE), fatigue; most frequent grade 3/4 AEs: PPE, fatigue, and increased alanine/aspartate aminotransferase. Although diarrhoea was common, 91% of affected patients experienced maximum grade 1/2 events that resolved. Best overall confirmed partial response or stable disease 424 weeks (all tumour types) was observed in 6 and 13% of patients. Conclusions: In this population of patients with advanced solid tumours, bosutinib plus capecitabine demonstrated a safety profile similar to that previously reported for bosutinib or capecitabine monotherapy; limited efficacy was observed. C1 [Isakoff, S. J.] Massachusetts Gen Hosp, Ctr Canc, Div Hematol & Oncol, Boston, MA 02114 USA. [Isakoff, S. J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Wang, D.] Henry Ford Hosp, Phase Clin Trials Program 1, Detroit, MI 48202 USA. [Campone, M.] Inst Cancerol Quest Rene Gauducheau, F-44805 Nantes, France. [Calles, A.; Calvo, E.] Hosp Madrid Norte Sanchinarro, Ctr Integral Oncol Clara Campal, START Madrid, Madrid 28050, Spain. [Leip, E.; Turnbull, K.] Pfizer Inc, Cambridge, MA 02138 USA. [Bardy-Bouxin, N.; Duvillie, L.] Pfizer Global Res & Dev, F-75668 Paris, France. RP Isakoff, SJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Div Hematol & Oncol, 55 Fruit St, Boston, MA 02114 USA. EM sisakoff@partners.org OI Calles, Antonio/0000-0002-2547-1947 FU Pfizer; Pfizer Inc.; Novartis; Merck; Roche/Genentech; PsiOxus; GSK; BMS; Boehringer Ingelheim; PharmaMar FX We thank all of the participating patients and their families as well as the global network of investigators, research nurses, study coordinators, and operations staff. We also thank Drs Young Kim (formerly of Wyeth Research) and Charles Zacharchuk (Pfizer) for their contributions to the design and conduct of the study. Editorial/medical writing support was provided by Janetricks Chebukati, PhD of Scifluent, and Simon J. Slater, PhD, and Cynthia Gobbel, PhD, of Complete Healthcare Communications, Inc., and was funded by Pfizer. This study was sponsored by Pfizer Inc. SJI, DW, AC, and LD, nothing to disclose; MC, consultant and recipient of honoraria (Novartis and Servier); EL, KT, and NBB, employees of Pfizer and KT and NBB own stock in Pfizer; EC is the recipient of research funding (Pfizer, Novartis, Merck, Roche/Genentech, PsiOxus, GSK, BMS, Boehringer Ingelheim, PharmaMar), consultant/advisor (Novartis, GSK, Pfizer, Roche/Genentech, Astellas), participant in speakers' bureau (Novartis, Astellas), recipient of honoraria (Novartis). NR 54 TC 3 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD NOV 25 PY 2014 VL 111 IS 11 BP 2058 EP 2066 DI 10.1038/bjc.2014.508 PG 9 WC Oncology SC Oncology GA AU4QW UT WOS:000345597700005 PM 25290090 ER PT J AU Peterson, ED Ho, PM Barton, M Beam, C Burgess, LH Casey, DE Drozda, JP Fonarow, GC Goff, D Grady, KL King, DE King, ML Masoudi, FA Nielsen, DR Stanko, S AF Peterson, Eric D. Ho, P. Michael Barton, Mary Beam, Craig Burgess, L. Hayley Casey, Donald E., Jr. Drozda, Joseph P., Jr. Fonarow, Gregg C. Goff, David, Jr. Grady, Kathleen L. King, Dana E. King, Marjorie L. Masoudi, Frederick A. Nielsen, David R. Stanko, Stephen TI ACC/AHA/AACVPR/AAFP/ANA Concepts for Clinician-Patient Shared Accountability in Performance Measures A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures SO CIRCULATION LA English DT Article DE AHA Scientific Statements; quality indicators; quality measurement; shared accountability ID BEHAVIORAL ECONOMICS; OF-CARDIOLOGY; CARE; ADHERENCE; MEDICARE; QUALITY C1 [Ho, P. Michael] Denver VA Med Ctr, Denver, CO USA. [Ho, P. Michael] Univ Colorado Denver, Denver, CO USA. [Barton, Mary] Natl Comm Qual Assurance, Washington, DC USA. [Beam, Craig] Amer Heart Assoc, Dallas, TX USA. [Burgess, L. Hayley] HCA Clin Serv Grp, Nashville, TN USA. [Casey, Donald E., Jr.] NYUPN Clin Integrated Network, New York, NY USA. [Drozda, Joseph P., Jr.] Mercy Hlth Syst, Janesville, WI 53548 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. [Goff, David, Jr.] Colorado Sch Publ Hlth, Aurora, CO USA. [Grady, Kathleen L.] Northwestern Univ Feinberg, Sch Med, Chicago, IL USA. [Grady, Kathleen L.] NW Mem Hosp, Bluhm Cardiovasc Inst, Chicago, IL USA. [King, Dana E.] W Virginia Univ, Morgantown, WV 26506 USA. [King, Marjorie L.] Helen Hayes Hosp, West Haverstraw, NY USA. [Masoudi, Frederick A.] Univ Colorado, Denver, CO 80202 USA. [Nielsen, David R.] Amer Acad Otolaryngol, Alexandria, VA USA. [Stanko, Stephen] Mended Hearts Inc, Dallas, TX USA. FU NIGMS NIH HHS [U54 GM104942] NR 28 TC 12 Z9 12 U1 0 U2 2 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 NOV 25 PY 2014 VL 130 IS 22 BP 1984 EP + DI 10.1161/CIR.0000000000000139 PG 17 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AU3MJ UT WOS:000345517100014 PM 25366994 ER PT J AU Slaughter, A Jurado, KA Deng, NJ Feng, L Kessl, JJ Shkriabai, N Larue, RC Fadel, HJ Patel, PA Jena, N Fuchs, JR Poeschla, E Levy, RM Engelman, A Kvaratskhelia, M AF Slaughter, Alison Jurado, Kellie A. Deng, Nanjie Feng, Lei Kessl, Jacques J. Shkriabai, Nikoloz Larue, Ross C. Fadel, Hind J. Patel, Pratiq A. Jena, Nivedita Fuchs, James R. Poeschla, Eric Levy, Ronald M. Engelman, Alan Kvaratskhelia, Mamuka TI The mechanism of H171T resistance reveals the importance of N delta-protonated His171 for the binding of allosteric inhibitor BI-D to HIV-1 integrase SO RETROVIROLOGY LA English DT Article DE HIV-1 integrase; Allosteric inhibitors; Aberrant multimerization; Drug resistance ID IMMUNODEFICIENCY-VIRUS TYPE-1; SMALL-MOLECULE INHIBITORS; VIRAL-REPLICATION; DNA INTEGRATION; STRUCTURAL BASIS; FORCE-FIELD; FREE-ENERGY; HUMAN-CELLS; LEDGF/P75; SITE AB Background: Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an important new class of anti-HIV-1 agents. ALLINIs bind at the IN catalytic core domain (CCD) dimer interface occupying the principal binding pocket of its cellular cofactor LEDGF/p75. Consequently, ALLINIs inhibit HIV-1 IN interaction with LEDGF/p75 as well as promote aberrant IN multimerization. Selection of viral strains emerging under the inhibitor pressure has revealed mutations at the IN dimer interface near the inhibitor binding site. Results: We have investigated the effects of one of the most prevalent substitutions, H171T IN, selected under increasing pressure of ALLINI BI-D. Virus containing the H171T IN substitution exhibited an similar to 68-fold resistance to BI-D treatment in infected cells. These results correlated with similar to 84-fold reduced affinity for BI-D binding to recombinant H171T IN CCD protein compared to its wild type (WT) counterpart. However, the H171T IN substitution only modestly affected IN-LEDGF/p75 binding and allowed HIV-1 containing this substitution to replicate at near WT levels. The x-ray crystal structures of BI-D binding to WT and H171T IN CCD dimers coupled with binding free energy calculations revealed the importance of the Nd-protonated imidazole group of His171 for hydrogen bonding to the BI-D tert-butoxy ether oxygen and establishing electrostatic interactions with the inhibitor carboxylic acid, whereas these interactions were compromised upon substitution to Thr171. Conclusions: Our findings reveal a distinct mechanism of resistance for the H171T IN mutation to ALLINI BI-D and indicate a previously undescribed role of the His171 side chain for binding the inhibitor. C1 [Slaughter, Alison; Feng, Lei; Kessl, Jacques J.; Shkriabai, Nikoloz; Larue, Ross C.; Kvaratskhelia, Mamuka] Ohio State Univ, Ctr Retrovirus Res, Coll Pharm, Columbus, OH 43210 USA. [Slaughter, Alison; Feng, Lei; Kessl, Jacques J.; Shkriabai, Nikoloz; Larue, Ross C.; Kvaratskhelia, Mamuka] Ohio State Univ, Ctr Comprehens Canc, Coll Pharm, Columbus, OH 43210 USA. [Jurado, Kellie A.; Engelman, Alan] Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02215 USA. [Jurado, Kellie A.; Engelman, Alan] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Deng, Nanjie; Levy, Ronald M.] Temple Univ, Coll Sci & Technol, Dept Chem, Philadelphia, PA 19122 USA. [Deng, Nanjie; Levy, Ronald M.] Temple Univ, Coll Sci & Technol, Ctr Biophys & Computat Biol, Philadelphia, PA 19122 USA. [Fadel, Hind J.; Poeschla, Eric] Mayo Clin, Coll Med, Dept Mol Med, Rochester, MN 55905 USA. [Fadel, Hind J.; Poeschla, Eric] Mayo Clin, Coll Med, Div Infect Dis, Rochester, MN 55905 USA. [Patel, Pratiq A.; Jena, Nivedita; Fuchs, James R.] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA. RP Kvaratskhelia, M (reprint author), Ohio State Univ, Ctr Retrovirus Res, Coll Pharm, 496 W 12th Ave,508 Riffe Bldg, Columbus, OH 43210 USA. EM kvaratskhelia.1@osu.edu RI Kessl, Jacques/J-6073-2015; OI Slaughter, Alison/0000-0002-0683-9291 FU National Institutes of Health [AI062520, GM103368, AI039394, AI110310, AI110270, GM30580, AI77344]; John H. Tietze Foundation Trust FX We thank Dr. Dennis Bong (OSU, Chemistry Department) for the use of the DLS instrument and Dr. Drew Dangel for technical assistance with SPR experiments. The present study was supported by the National Institutes of Health (grants AI062520 to M.K., GM103368 to M.K., A.E., R.M.L. and J.R.F., AI039394 to A.E., AI110310 to M.K. and J.R.F., AI110270 to J.J.K., GM30580 to R. M.L., AI77344 and the John H. Tietze Foundation Trust to E.M.P.). NR 74 TC 11 Z9 11 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD NOV 25 PY 2014 VL 11 AR 100 DI 10.1186/s12977-014-0100-1 PG 14 WC Virology SC Virology GA AU6IG UT WOS:000345706400003 PM 25421939 ER PT J AU Barton, JL Koenig, CJ Evans-Young, G Trupin, L Anderson, J Ragouzeos, D Breslin, M Morse, T Schillinger, D Montori, VM Yelin, EH AF Barton, Jennifer L. Koenig, Christopher J. Evans-Young, Gina Trupin, Laura Anderson, Jennie Ragouzeos, Dana Breslin, Maggie Morse, Timothy Schillinger, Dean Montori, Victor M. Yelin, Edward H. TI The design of a low literacy decision aid about rheumatoid arthritis medications developed in three languages for use during the clinical encounter SO BMC MEDICAL INFORMATICS AND DECISION MAKING LA English DT Article DE Decision aid; Rheumatoid arthritis; Health literacy AB Background: Shared decision-making in rheumatoid arthritis (RA) care is a priority among policy makers, clinicians and patients both nationally and internationally. Demands on patients to have basic knowledge of RA, treatment options, and details of risk and benefit when making medication decisions with clinicians can be overwhelming, especially for those with limited literacy or limited English language proficiency. The objective of this study is to describe the development of a medication choice decision aid for patients with rheumatoid arthritis (RA) in three languages using low literacy principles. Methods: Based on the development of a diabetes decision aid, the RA decision aid (RA Choice) was developed through a collaborative process involving patients, clinicians, designers, decision-aid and health literacy experts. A combination of evidence synthesis and direct observation of clinician-patient interactions generated content and guided an iterative process of prototype development. Results: Three iterations of RA Choice were developed and field-tested before completion. The final tool organized data using icons and plain language for 12 RA medications across 5 issues: frequency of administration, time to onset, cost, side effects, and special considerations. The tool successfully created a conversation between clinician and patient, and garnered high acceptability from clinicians. Conclusions: The process of collaboratively developing an RA decision aid designed to promote shared decision making resulted in a graphically-enhanced, low literacy tool. The use of RA Choice in the clinical encounter has the potential to enhance communication for RA patients, including those with limited health literacy and limited English language proficiency. C1 [Barton, Jennifer L.; Koenig, Christopher J.; Evans-Young, Gina; Trupin, Laura; Schillinger, Dean; Yelin, Edward H.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Barton, Jennifer L.] Portland VA Med Ctr, Div Hosp & Specialty Med, Portland, OR 97239 USA. [Evans-Young, Gina; Trupin, Laura; Yelin, Edward H.] Phillip R Lee Inst Hlth Policy Studies, San Francisco, CA USA. [Montori, Victor M.] Mayo Clin, Knowledge & Evaluat Res Unit, Rochester, MN 55905 USA. RP Barton, JL (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA USA. EM Jennifer.Barton@va.gov OI Barton, Jennifer/0000-0002-6771-3465; Koenig, Christopher J./0000-0003-0884-4120; Montori, Victor/0000-0003-0595-2898 FU Agency for Healthcare Research and Quality [R18 HS019209-01]; NIH [P60 AR053308] FX Funding for this project was from the Agency for Healthcare Research and Quality (R18 HS019209-01, PI Yelin). AHRQ had no role in study design; in collection, analysis and interpretation of data; in the writing of this manuscript; or in the decision to submit this paper for publication. Dr. Yelin, Ms. Trupin and Ms. Evans-Young also received funding from the NIH (NIAMS P60 AR053308). NR 45 TC 6 Z9 7 U1 3 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6947 J9 BMC MED INFORM DECIS JI BMC Med. Inform. Decis. Mak. PD NOV 25 PY 2014 VL 14 AR 104 DI 10.1186/s12911-014-0104-8 PG 14 WC Medical Informatics SC Medical Informatics GA V42AA UT WOS:000209585500001 PM 25649726 ER PT J AU Choi, JK Carreras, I Aytan, N Jenkins-Sahlin, E Dedeoglu, A Jenkins, BG AF Choi, Ji-Kyung Carreras, Isabel Aytan, Nur Jenkins-Sahlin, Eric Dedeoglu, Alpaslan Jenkins, Bruce G. TI The effects of aging, housing and ibuprofen treatment on brain neurochemistry in a triple transgene Alzheimer's disease mouse model using magnetic resonance spectroscopy and imaging SO BRAIN RESEARCH LA English DT Article DE Alzheimer's disease; Magnetic resonance spectroscopy; Magnetic resonance imaging; Triple transgene; Animal model ID A-BETA; HUNTINGTONS-DISEASE; NEURODEGENERATIVE ILLNESS; PLAQUE-FORMATION; MICE; PATHOLOGY; PROFILE; PROTON; TAU; MRS AB We investigated a triple transgene Alzheimer's disease (AD) mouse model that recapitulates many of the neurochemical, anatomic, pathologic and behavioral defects seen in human AD. We studied the mice as a function of age and brain region and investigated potential therapy with the non-steroidal anti-inflammatory drug ibuprofen. Magnetic resonance spectroscopy (MRS) showed alterations characteristic of AD (i.e. increased myo-inositol and decreased N-acetylaspartate (NAA)). Mice at 6 months of age showed an increase in myo-inositol in the hippocampus at a time when the A beta is intracellular, but not in amygdala or cortex. Myo-inositol increased as a function of age in the amygdala, cortex and striatum while NAA decreased only in the hippocampus and cortex at 17-23 months of age. Ibuprofen protected the increase of myo-inositol at six months of age in the hippocampus, but had no effect at 17-23 months of age (a time when A beta is extracellular). In vivo MRI and MRS showed that at 17-23 months of age there was a significant protective effect of ibuprofen on hippocampal volume and NAA loss. Together, these data show the following: the increase in myo-inositol occurs before the decrease in NAA in hippocampus but not cortex; the hippocampus shows earlier changes than does the amygdale or cortex consistent with earlier deposition of A beta 40-42 in the hippocampus and ibuprofen protects against multiple components of the AD pathology. These data also show a profound effect of housing on this particular mouse model. Published by Elsevier B.V. C1 [Choi, Ji-Kyung; Jenkins-Sahlin, Eric; Dedeoglu, Alpaslan; Jenkins, Bruce G.] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Choi, Ji-Kyung; Jenkins-Sahlin, Eric; Dedeoglu, Alpaslan; Jenkins, Bruce G.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Carreras, Isabel; Aytan, Nur; Dedeoglu, Alpaslan] VA Boston Healthcare Syst, Dept Vet Affairs, Boston, MA 02130 USA. [Carreras, Isabel] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. [Aytan, Nur; Dedeoglu, Alpaslan] Boston Univ, Sch Med, Neurol & Alzheimers Dis Ctr, Boston, MA 02118 USA. RP Choi, JK (reprint author), Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Bldg 149,13th St, Charlestown, MA 02129 USA. EM jchoi@nmr.mgh.harvard.edu; bgj@nmr.mgh.harvard.edu FU NIA [R01AG031896]; Department of Veteran Affairs (Merit Award) FX This research is supported by Grants from NIA (R01AG031896) to A. Dedeoglu and the Department of Veteran Affairs (Merit Award) to A. Dedeoglu. NR 50 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD NOV 24 PY 2014 VL 1590 BP 85 EP 96 DI 10.1016/j.brainres.2014.09.067 PG 12 WC Neurosciences SC Neurosciences & Neurology GA AU6ST UT WOS:000345732800009 PM 25301691 ER PT J AU Kang, W Marasco, WA Tong, HI Byron, MM Wu, CX Shi, YL Sun, S Sun, YT Lu, YN AF Kang, Wen Marasco, Wayne A. Tong, Hsin-I Byron, Mary Margaret Wu, Chengxiang Shi, Yingli Sun, Si Sun, Yongtao Lu, Yuanan TI Anti-tat Hutat2:Fc mediated protection against tat-induced neurotoxicity and HIV-1 replication in human monocyte-derived macrophages SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE Anti-Tat antibody; HIV-1; HIV-associated neurocognitive disorders; Human monocyte-derived macrophages; Lentivirus; Neuroprotection ID IMMUNODEFICIENCY-VIRUS TYPE-1; CENTRAL-NERVOUS-SYSTEM; CLADE-SPECIFIC DIFFERENCES; BLOOD-BRAIN-BARRIER; FC-FUSION PROTEINS; CD4(+) T-CELLS; INDOLEAMINE 2,3-DIOXYGENASE; PARKINSONS-DISEASE; NEUROCOGNITIVE DISORDERS; LENTIVIRAL VECTORS AB Background: HIV-1 Tat is essential for HIV replication and is also a well-known neurotoxic factor causing HIV-associated neurocognitive disorder (HAND). Currently, combined antiretroviral therapy targeting HIV reverse transcriptase or protease cannot prevent the production of early viral proteins, especially Tat, once HIV infection has been established. HIV-infected macrophages and glial cells in the brain still release Tat into the extracellular space where it can exert direct and indirect neurotoxicity. Therefore, stable production of anti-Tat antibodies in the brain would neutralize HIV-1 Tat and thus provide an effective approach to protect neurons. Methods: We constructed a humanized anti-Tat Hutat2:Fc fusion protein with the goal of antagonizing HIV-1 Tat and delivered the gene into cell lines and primary human monocyte-derived macrophages (hMDM) by an HIV-based lentiviral vector. The function of the anti-Tat Hutat2:Fc fusion protein and the potential side effects of lentiviral vector-mediated gene transfer were evaluated in vitro. Results: Our study demonstrated that HIV-1-based lentiviral vector-mediated gene transduction resulted in a high-level, stable expression of anti-HIV-1 Tat Hutat2:Fc in human neuronal and monocytic cell lines, as well as in primary hMDM. Hutat2:Fc was detectable in both cells and supernatants and continued to accumulate to high levels within the supernatant. Hutat2:Fc protected mouse cortical neurons against HIV-1 Tat(86)-induced neurotoxicity. In addition, both secreted Hutat2:Fc and transduced hMDM led to reducing HIV-1(BaL) viral replication in human macrophages. Moreover, lentiviral vector-based gene introduction did not result in any significant changes in cytomorphology and cell viability. Although the expression of IL8, STAT1, and IDO1 genes was up-regulated in transduced hMDM, such alternation in gene expression did not affect the neuroprotective effect of Hutat2:Fc. Conclusions: Our study demonstrated that lentivirus-mediated gene transfer could efficiently deliver the Hutat2:Fc gene into primary hMDM and does not lead to any significant changes in hMDM immune-activation. The neuroprotective and HIV-1 suppressive effects produced by Hutat2:Fc were comparable to that of a full-length anti-Tat antibody. This study provides the foundation and insights for future research on the potential use of Hutat2:Fc as a novel gene therapy approach for HAND through utilizing monocytes/macrophages, which naturally cross the blood-brain barrier, for gene delivery. C1 [Kang, Wen; Sun, Yongtao] Fourth Mil Med Univ, Tangdu Hosp, Dept Infect Dis, Xian 710038, Shaanxi, Peoples R China. [Kang, Wen; Tong, Hsin-I; Wu, Chengxiang; Shi, Yingli; Sun, Si; Lu, Yuanan] Univ Hawaii, John A Burns Sch Med, Dept Publ Hlth Sci, Honolulu, HI 96822 USA. [Marasco, Wayne A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Byron, Mary Margaret] Univ Hawaii, John A Burns Sch Med, Hawaii Ctr AIDS, Honolulu, HI 96813 USA. RP Sun, YT (reprint author), Fourth Mil Med Univ, Tangdu Hosp, Dept Infect Dis, 569 Xinsi Rd, Xian 710038, Shaanxi, Peoples R China. EM yongtaos@hotmail.com; yuanan@hawaii.edu FU National Institutes of Health [R01 MH079717, S11NS043499] FX This study was supported by grants from the National Institutes of Health (R01 MH079717 and S11NS043499). The following reagents were obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: HIV-1 Tat (Cat#2222), rabbit antiserum to HIV-1 Tat from Dr. Bryan Cullen (Cat#705), HIV-1 Tat monoclonal antibody (1D9) from Dr. Dag E. Helland (Cat#7377), monoclonal antibody to HIV-1 p24 from Dr. Susan Zolla-Pazner (Cat#530), and HIV-1Ba-L from Dr. Suzanne Gartner, Dr. Mikulas Popovic, and Dr. Robert Gallo (Cat# 510). NR 108 TC 2 Z9 2 U1 0 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD NOV 22 PY 2014 VL 11 AR 195 DI 10.1186/s12974-014-0195-2 PG 21 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA AW6LG UT WOS:000346380400001 PM 25416164 ER PT J AU Reinherz, EL AF Reinherz, Ellis L. TI Revisiting the discovery of the alpha beta TCR complex and its co-receptors SO FRONTIERS IN IMMUNOLOGY LA English DT Editorial Material DE adaptive immunity; thymic development; co-receptors; TCR; CD3 ID MAJOR HISTOCOMPATIBILITY COMPLEX; T-CELL-RECEPTOR; RESTRICTED ANTIGEN RECEPTOR; TOXIC LYMPHOCYTES-T; MONOCLONAL-ANTIBODY; T3-MOLECULAR COMPLEX; PEPTIDE VARIABILITY; FUNCTIONAL SUBSETS; CLONES; RECOGNITION C1 Dana Farber Canc Inst, Dept Med Oncol, Immunobiol Lab, Boston, MA 02115 USA. RP Reinherz, EL (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Immunobiol Lab, Boston, MA 02115 USA. EM ellis_reinherz@dfci.harvard.edu NR 45 TC 1 Z9 1 U1 0 U2 2 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD NOV 21 PY 2014 VL 5 BP 1 EP 4 AR 583 DI 10.3389/fimmu.2014.00583 PG 4 WC Immunology SC Immunology GA CI1TL UT WOS:000354527400001 PM 25484883 ER PT J AU Bruckel, JT Gurm, HS Seth, M Prager, RL Jensen, A Nallamothu, BK AF Bruckel, Jeffrey T. Gurm, Hitinder S. Seth, Milan Prager, Richard L. Jensen, Andrea Nallamothu, Brahmajee K. TI Use of a Heart Team in Decision-Making for Patients with Complex Coronary Disease at Hospitals in Michigan Prior to Guideline Endorsement SO PLOS ONE LA English DT Article ID INTERVENTION; ASSOCIATION AB Background: Revascularization decisions can profoundly impact patient survival, quality of life, and procedural risk. Although use of Heart Teams to make revascularization decisions is growing, data on their implementation in the real-world are limited. Our objective was to assess the prevalence of Heart Teams and their association with collaboration in routine practice. Methods: A survey of cardiologists and cardiac surgeons at 31 hospitals in Michigan was performed in May, 2011 - prior to the recommendation for using Heart Teams in national guidelines. This survey included all percutaneous coronary intervention-performing hospitals in Michigan participating in the Blue Cross/Blue Shield of Michigan Cardiovascular Consortium and Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative. It targeted both the use of Heart Teams and multidisciplinary Case Conferences. Results: There were 53 physician survey respondents from 27 hospitals with 4 hospitals not responding. Among respondents, 11 (40.7%) hospitals reported no Heart Teams or Case Conferences while 7 (25.9%) hospitals reported either a Heart Team or Case Conference. However, there was disagreement about the presence of a Heart Team at seven hospitals, and about Case Conferences at nine hospitals. Hospitals with definite Heart Teams reported significantly greater levels of collaboration between cardiologists and cardiac surgeons. Conclusion: The overall presence of Heart Teams prior to their recommendation in national guidelines was limited. Even among hospitals with a potential Heart Team, there was substantial disagreement between respondents about their presence. Further refinement of the definition of a Heart Team and measures of successful implementation are needed. C1 [Bruckel, Jeffrey T.] Massachusetts Gen Hosp, Edward P Lawrence Ctr Qual & Safety, Boston, MA 02114 USA. [Bruckel, Jeffrey T.; Nallamothu, Brahmajee K.] Univ Michigan Hlth Syst, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Gurm, Hitinder S.; Seth, Milan; Jensen, Andrea] Blue Cross Blue Shield Michigan Cardiovasc Consor, Ann Arbor, MI USA. [Gurm, Hitinder S.] Univ Michigan Hlth Syst, Div Cardiovasc Med, Ann Arbor, MI USA. [Prager, Richard L.] Univ Michigan Hlth Syst, Dept Cardiac Surg, Ann Arbor, MI USA. [Prager, Richard L.] Michigan Soc Thorac & Cardiovasc Surg Qual Collab, Ann Arbor, MI USA. [Nallamothu, Brahmajee K.] Ann Arbor VA Ctr Clin Management & Res, Ann Arbor, MI USA. RP Nallamothu, BK (reprint author), Univ Michigan Hlth Syst, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. EM bnallamo@med.umich.edu OI Gurm, Hitinder/0000-0002-1646-0218 FU Blue Cross Blue Shield of Michigan FX Funding: The BMC2 registry is funded by Blue Cross Blue Shield of Michigan. The sponsor had no role in study design, review or the decision to submit the work for publication. There are no current funding sources for this specific study and no internal or external funding was used to support the work presented in this manuscript. NR 6 TC 1 Z9 1 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 21 PY 2014 VL 9 IS 11 AR e113241 DI 10.1371/journal.pone.0113241 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AX4MM UT WOS:000346906600034 PM 25415332 ER PT J AU Dudzinski, DM Hung, J AF Dudzinski, David M. Hung, Judy TI Echocardiographic assessment of ischemic mitral regurgitation SO CARDIOVASCULAR ULTRASOUND LA English DT Article DE Chronic Ischemic mitral regurgitation; Echocardiography; Ventricular remodelling; Papillary muscle displacement; Mitral valve tethering; Mitral valve tenting; Tethering angles; Tenting height; Tenting area; Mitral annulus dilatation; Myocardial infarction ID LEFT-VENTRICULAR DYSFUNCTION; PAPILLARY-MUSCLE DYSFUNCTION; INTRAOPERATIVE TRANSESOPHAGEAL ECHOCARDIOGRAPHY; TIME 3-DIMENSIONAL ECHOCARDIOGRAPHY; INFERIOR MYOCARDIAL-INFARCTION; EXERCISE-INDUCED CHANGES; COMPUTED-TOMOGRAPHY; HEART-DISEASE; VALVE; MECHANISM AB Ischemic mitral regurgitation is an important consequence of LV remodeling after myocardial infarction. Echocardiographic diagnosis and assessment of ischemic mitral regurgitation are critical to gauge its adverse effects on prognosis and to attempt to tailor rational treatment strategy. There is no single approach to the echocardiographic assessment of ischemic mitral regurgitation: standard echocardiographic measures of mitral regurgitation severity and of LV dysfunction are complemented by assessments of displacement of the papillary muscles and quantitative indices of mitral valve deformation. Development of novel approaches to understand mitral valve geometry by echocardiography may improve understanding of the mechanism, clinical trajectory, and reparability of ischemic mitral regurgitation. C1 [Dudzinski, David M.; Hung, Judy] Massachusetts Gen Hosp, Div Cardiol, Echocardiog Lab, Boston, MA 02114 USA. [Dudzinski, David M.] Massachusetts Gen Hosp, Div Crit Care Med, Boston, MA 02114 USA. RP Hung, J (reprint author), Massachusetts Gen Hosp, Div Cardiol, Echocardiog Lab, Boston, MA 02114 USA. EM jhung@partners.org FU NIH/NHLBI [R01 HL092101] FX This work was supported in part by grant NIH/NHLBI R01 HL092101 (JH). NR 57 TC 4 Z9 4 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-7120 J9 CARDIOVASC ULTRASOUN JI Cardiovasc. Ultrasound PD NOV 21 PY 2014 VL 12 AR 46 DI 10.1186/1476-7120-12-46 PG 16 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AX4ZK UT WOS:000346937000001 PM 25416497 ER PT J AU Das, F Ghosh-Choudhury, N Dey, N Bera, A Mariappan, MM Kasinath, BS Choudhury, GG AF Das, Falguni Ghosh-Choudhury, Nandini Dey, Nirmalya Bera, Amit Mariappan, Meenalakshmi M. Kasinath, Balakuntalam S. Choudhury, Goutam Ghosh TI High Glucose Forces a Positive Feedback Loop Connecting Akt Kinase and FoxO1 Transcription Factor to Activate mTORC1 Kinase for Mesangial Cell Hypertrophy and Matrix Protein Expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA TRANSLATION; DIABETIC-NEPHROPATHY; OSTEOBLAST DIFFERENTIATION; GENE-TRANSCRIPTION; SIGNALING PATHWAY; EPITHELIAL-CELLS; TRANSGENIC MICE; HIGH INSULIN; SMAD 3; DISEASE AB High glucose-induced Akt acts as a signaling hub for mesangial cell hypertrophy and matrix expansion, which are recognized as cardinal signatures for the development of diabetic nephropathy. How mesangial cells sustain the activated state of Akt is not clearly understood. Here we show Akt-dependent phosphorylation of the transcription factor FoxO1 by high glucose. Phosphorylation-deficient, constitutively active FoxO1 inhibited the high glucose-induced phosphorylation of Akt to suppress the phosphorylation/inactivation of PRAS40 and mTORC1 activity. In contrast, dominant negative FoxO1 increased the phosphorylation of Akt, resulting in increased mTORC1 activity similar to high glucose treatment. Notably, FoxO1 regulates high glucose-induced protein synthesis, hypertrophy, and expression of fibronectin and PAI-1. High glucose paves the way for complications of diabetic nephropathy through the production of reactive oxygen species (ROS). We considered whether the FoxO1 target antioxidant enzyme catalase contributes to sustained activation of Akt. High glucose-inactivated FoxO1 decreases the expression of catalase to increase the production of ROS. Moreover, we show that catalase blocks high glucose-stimulated Akt phosphorylation to attenuate the inactivation of FoxO1 and PRAS40, resulting in the inhibition of mTORC1 and mesangial cell hypertrophy and fibronectin and PAI-1 expression. Finally, using kidney cortices from type 1 diabetic OVE26 mice, we show that increased FoxO1 phosphorylation is associated with decreased catalase expression and increased fibronectin and PAI-1 expression. Together, our results provide the first evidence for the presence of a positive feedback loop for the sustained activation of Akt involving inactivated FoxO1 and a decrease in catalase expression, leading to increased ROS and mesangial cell hypertrophy and matrix protein expression. C1 [Ghosh-Choudhury, Nandini; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, Vet Affairs Res & Geriatr Res, San Antonio, TX 78229 USA. [Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, Educ & Clin Ctr, San Antonio, TX 78229 USA. [Das, Falguni; Dey, Nirmalya; Bera, Amit; Mariappan, Meenalakshmi M.; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Ghosh-Choudhury, Nandini] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. RP Choudhury, GG (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. EM choudhuryg@uthscsa.edu FU National Institutes of Health [RO1 DK50190]; Veterans Affairs Research Service Merit Review Grant [5I01BX000926, 5I01BX000150, 5I01BX001340]; Veterans Affairs Senior Research Career Scientist Award FX This work was supported, in whole or in part, by National Institutes of Health Grant RO1 DK50190. This work was also supported by Veterans Affairs Research Service Merit Review Grant 5I01BX000926 (to G. G. C.).; Supported by Veterans Affairs Merit Review Grant 5I01BX000150.; Supported by Veterans Affairs Merit Review Grant 5I01BX001340.; Recipient of the Veterans Affairs Senior Research Career Scientist Award. NR 50 TC 9 Z9 9 U1 1 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 NOV 21 PY 2014 VL 289 IS 47 DI 10.1074/jbc.M114.605196 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU0SO UT WOS:000345335000027 PM 25288788 ER PT J AU Sinha, A Kohrer, C Weber, MHW Masuda, I Mootha, VK Hou, YM RajBhandary, UL AF Sinha, Akesh Koehrer, Caroline Weber, Michael H. W. Masuda, Isao Mootha, Vamsi K. Hou, Ya-Ming RajBhandary, Uttam L. TI Biochemical Characterization of Pathogenic Mutations in Human Mitochondrial Methionyl-tRNA Formyltransferase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INITIATOR TRANSFER-RNA; FORMYLMETHIONINE TRANSFER-RNA; ACID INSERTION MODULE; COMPLEX I DEFICIENCY; ESCHERICHIA-COLI; PROTEIN-SYNTHESIS; MAMMALIAN MITOCHONDRIA; SUPPRESSOR MUTATIONS; CRYSTAL-STRUCTURE; MESSENGER-RNA AB N-Formylation of initiator methionyl-tRNA (Met-tRNA(Met)) by methionyl-tRNA formyltransferase (MTF) is important for translation initiation in bacteria, mitochondria, and chloroplasts. Unlike all other translation systems, the metazoan mitochondrial system is unique in using a single methionine tRNA (tRNA(Met)) for both initiation and elongation. A portion of Met-tRNA(Met) is formylated for initiation, whereas the remainder is used for elongation. Recently, we showed that compound heterozygous mutations within the nuclear gene encoding human mitochondrial MTF (mt-MTF) significantly reduced mitochondrial translation efficiency, leading to combined oxidative phosphorylation deficiency and Leigh syndrome in two unrelated patients. Patient P1 has a stop codon mutation in one of the MTF genes and an S209L mutation in the other MTF gene. P2 has a S125L mutation in one of the MTF genes and the same S209L mutation as P1 in the other MTF gene. Here, we have investigated the effect of mutations at Ser-125 and Ser-209 on activities of human mt-MTF and of the corresponding mutations, Ala-89 or Ala-172, respectively, on activities of Escherichia coli MTF. The S125L mutant has 653-fold lower activity, whereas the S209L mutant has 36-fold lower activity. Thus, both patients depend upon residual activity of the S209L mutant to support low levels of mitochondrial protein synthesis. We discuss the implications of these and other results for whether the effect of the S209L mutation on mitochondrial translational efficiency is due to reduced activity of the mutant mt-MTF and/or reduced levels of the mutant mt-MTF. C1 [Sinha, Akesh; Koehrer, Caroline; Weber, Michael H. W.; RajBhandary, Uttam L.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Masuda, Isao; Hou, Ya-Ming] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA. [Mootha, Vamsi K.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, Boston, MA 02114 USA. RP RajBhandary, UL (reprint author), MIT, Dept Biol, 77 Massachusetts Ave,Rm 68-671, Cambridge, MA 02139 USA. EM bhandary@mit.edu OI Hou, Ya-Ming/0000-0001-6546-2597 FU National Institutes of Health [GM17151, 5RNIAG042169, GM097136] FX This work was supported, in whole or in part, by National Institutes of Health Grants GM17151 (to U. L. R.), 5RNIAG042169 (to Y. M. H.), and GM097136 (to V. K. M.). NR 55 TC 4 Z9 4 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 NOV 21 PY 2014 VL 289 IS 47 DI 10.1074/jbc.M114.610626 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU0SO UT WOS:000345335000029 PM 25288793 ER PT J AU Lo, JA Fisher, DE AF Lo, Jennifer A. Fisher, David E. TI The melanoma revolution: From UV carcinogenesis to a new era in therapeutics SO SCIENCE LA English DT Review ID FREQUENT SOMATIC MUTATIONS; RAF INHIBITOR RESISTANCE; METASTATIC MELANOMA; MALIGNANT-MELANOMA; ULTRAVIOLET-RADIATION; HUMAN CANCER; CONFERS RESISTANCE; CUTANEOUS MELANOMA; IMPROVED SURVIVAL; MEK INHIBITION AB Melanoma, the deadliest form of skin cancer, is an a ressive disease that is rising in incidence. Although melanoma is a historically treatment-resistant malignancy, in recent years unprecedented breakthroughs in targeted therapies and immunotherapies have revolutionized the standard of care for patients with advanced disease. Here, we provide an overview of recent developments in our understanding of melanoma risk factors, genomics, and molecular pathogenesis and how these insights have driven advances in melanoma treatment. In addition, we review benefits and limitations of current therapies and look ahead to continued progress in melanoma prevention and therapy. Remarkable achievements in the field have already produced a paradigm shift in melanoma treatment: Metastatic melanoma, once considered incurable, can now be treated with potentially curative rather than palliative intent. C1 [Fisher, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cutaneous Biol Res Ctr,Dept Dermatol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, MGH Canc Ctr, Boston, MA 02114 USA. RP Fisher, DE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cutaneous Biol Res Ctr,Dept Dermatol, Boston, MA 02114 USA. EM dfisher3@partners.org OI , /0000-0002-9520-6874 FU NIH [T32GM007753, P01CA163222, R01AR043369, R01CA150226]; Melanoma Research Alliance, the U.S.-Israel Binational Science Foundation; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation FX We thank H. Tsao, C.-H. Won, and I. Kim for clinical images and K Robinson and K. Flaherty for useful comments and discussions. We extend our sincere apologies to those colleagues whose studies were not cited due to space constraints. This work was supported by the NIH under award numbers T32GM007753 (J.A.L.), P01CA163222, R01AR043369, and R01CA150226 and by grants tram the Melanoma Research Alliance, the U.S.-Israel Binational Science Foundation, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (D.E.F.). NR 75 TC 59 Z9 60 U1 6 U2 46 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 NOV 21 PY 2014 VL 346 IS 6212 BP 945 EP 949 DI 10.1126/science.1253735 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU6EL UT WOS:000345696000032 PM 25414302 ER PT J AU Vierstra, J Rynes, E Sandstrom, R Zhang, MH Canfield, T Hansen, RS Stehling-Sun, S Sabo, PJ Byron, R Humbert, R Thurman, RE Johnson, AK Vong, S Lee, K Bates, D Neri, F Diegel, M Giste, E Haugen, E Dunn, D Wilken, MS Josefowicz, S Samstein, R Chang, KH Eichler, EE De Bruijn, M Reh, TA Skoultchi, A Rudensky, A Orkin, SH Papayannopoulou, T Treuting, PM Selleri, L Kaul, R Groudine, M Bender, MA Stamatoyannopoulos, JA AF Vierstra, Jeff Rynes, Eric Sandstrom, Richard Zhang, Miaohua Canfield, Theresa Hansen, R. Scott Stehling-Sun, Sandra Sabo, Peter J. Byron, Rachel Humbert, Richard Thurman, Robert E. Johnson, Audra K. Vong, Shinny Lee, Kristen Bates, Daniel Neri, Fidencio Diegel, Morgan Giste, Erika Haugen, Eric Dunn, Douglas Wilken, Matthew S. Josefowicz, Steven Samstein, Robert Chang, Kai-Hsin Eichler, Evan E. De Bruijn, Marella Reh, Thomas A. Skoultchi, Arthur Rudensky, Alexander Orkin, Stuart H. Papayannopoulou, Thalia Treuting, Piper M. Selleri, Licia Kaul, Rajinder Groudine, Mark Bender, M. A. Stamatoyannopoulos, John A. TI Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution SO SCIENCE LA English DT Article ID TRANSCRIPTION FACTOR-BINDING; GENE-EXPRESSION; GENOME; EXPANSION; LINEAGES; ELEMENTS; ENHANCER; REGIONS; SITES AB To study the evolutionary dynamics of regulatory DNA, we mapped >1.3 million deoxyribonuclease I-hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-regulatory rewiring that combines branch-specific evolutionary innovation and loss with widespread repurposing of conserved DHSs to alternative cell fates, and that this process is mediated by turnover of transcription factor (TF) recognition elements. Despite pervasive evolutionary remodeling of the location and content of individual cis-regulatory regions, within orthologous mouse and human cell types the global fraction of regulatory DNA bases encoding recognition sites for each TF has been strictly conserved. Our findings provide new insights into the evolutionary forces shaping mammalian regulatory DNA landscapes. C1 [Vierstra, Jeff; Rynes, Eric; Sandstrom, Richard; Canfield, Theresa; Stehling-Sun, Sandra; Sabo, Peter J.; Humbert, Richard; Thurman, Robert E.; Johnson, Audra K.; Vong, Shinny; Lee, Kristen; Bates, Daniel; Neri, Fidencio; Diegel, Morgan; Giste, Erika; Haugen, Eric; Dunn, Douglas; Eichler, Evan E.; Kaul, Rajinder; Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Zhang, Miaohua; Byron, Rachel; Groudine, Mark; Bender, M. A.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Hansen, R. Scott; Kaul, Rajinder] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Wilken, Matthew S.; Reh, Thomas A.] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. [Josefowicz, Steven; Samstein, Robert; Rudensky, Alexander] Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10065 USA. [Josefowicz, Steven; Samstein, Robert; Eichler, Evan E.; Rudensky, Alexander; Orkin, Stuart H.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Chang, Kai-Hsin; Papayannopoulou, Thalia] Univ Washington, Dept Med, Div Hematol, Seattle, WA 98195 USA. [De Bruijn, Marella] John Radcliffe Hosp, Weatherall Inst Mol Med, Med Res Council MRC Mol Haematol Unit, Oxford OX3 9DS, England. [Skoultchi, Arthur] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Orkin, Stuart H.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Harvard Stem Cell Inst,Dept Pediat Oncol, Boston, MA 02115 USA. [Treuting, Piper M.] Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA. [Selleri, Licia] Cornell Univ, Weill Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA. [Groudine, Mark] Univ Washington, Dept Radiat Oncol, Seattle, WA 98109 USA. [Bender, M. A.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Stamatoyannopoulos, John A.] Univ Washington, Dept Med, Div Oncol, Seattle, WA 98195 USA. RP Stamatoyannopoulos, JA (reprint author), Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. EM jstam@uw.edu OI Samstein, Robert/0000-0001-6860-2401; Haugen, Eric/0000-0001-7444-8981 FU NIH grants [U54HG007010, 1RC2HG005654, R37DK44746, 2R01HD04399709]; NSF Graduate Research Fellowship [DGE-071824] FX Supported by NIH grants U54HG007010 (J.A.S.), 1RC2HG005654 (J.A.S. and M.G.), R37DK44746 (M.G. and M.A.B.), and 2R01HD04399709 (L.S.) and by NSF Graduate Research Fellowship DGE-071824 (J.V.). E.E.E. is on the scientific advisory boards for Pacific Biosciences Inc., SynapDx Corp., and DNAnexus Inc. J.V. and J.A.S. designed the experiments and analysis; E.R., R.S., and R.E.T. aided in data analysis and management; all other authors participated in data generation and sample collection; and J.V. and J.A.S. wrote the manuscript with help from E.R. We thank H. Wang and E. K. Salinas for help with figures. All sequence data generated in this study can be accessed with GEO accession numbers found within tables S1 and S2. NR 26 TC 58 Z9 58 U1 1 U2 12 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 NOV 21 PY 2014 VL 346 IS 6212 BP 1007 EP 1012 DI 10.1126/science.1246426 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU6EL UT WOS:000345696000047 PM 25411453 ER PT J AU Paganetti, H AF Paganetti, Harald TI Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Review DE relative biological effectiveness; cell survival; proton therapy; linear energy transfer ID DOUBLE-STRAND BREAKS; MELANOMA CELL-LINE; NATIONAL-CANCER-CENTER; CHINESE-HAMSTER CELLS; IN-VITRO IRRADIATION; OUT BRAGG PEAK; CHROMOSOME-ABERRATION FREQUENCIES; FIELD GEL-ELECTROPHORESIS; LUNG ADENOCARCINOMA CELLS; HUMAN PRIMARY FIBROBLASTS AB Proton therapy treatments are based on a proton RBE (relative biological effectiveness) relative to high-energy photons of 1.1. The use of this generic, spatially invariant RBE within tumors and normal tissues disregards the evidence that proton RBE varies with linear energy transfer (LET), physiological and biological factors, and clinical endpoint. Based on the available experimental data from published literature, this review analyzes relationships of RBE with dose, biological endpoint and physical properties of proton beams. The review distinguishes between endpoints relevant for tumor control probability and those potentially relevant for normal tissue complication. Numerous endpoints and experiments on subcellular damage and repair effects are discussed. Despite the large amount of data, considerable uncertainties in proton RBE values remain. As an average RBE for cell survival in the center of a typical spread-out Bragg peak (SOBP), the data support a value of similar to 1.15 at 2 Gy/fraction. The proton RBE increases with increasing LETd and thus with depth in an SOBP from similar to 1.1 in the entrance region, to similar to 1.15 in the center, similar to 1.35 at the distal edge and similar to 1.7 in the distal fall-off (when averaged over all cell lines, which may not be clinically representative). For small modulation widths the values could be increased. Furthermore, there is a trend of an increase in RBE as (alpha/beta)(x) decreases. In most cases the RBE also increases with decreasing dose, specifically for systems with low (alpha/beta)(x). Data on RBE for endpoints other than clonogenic cell survival are too diverse to allow general statements other than that the RBE is, on average, in line with a value of similar to 1.1. This review can serve as a source for defining input parameters for applying or refining biophysical models and to identify endpoints where additional radiobiological data are needed in order to reduce the uncertainties to clinically acceptable levels. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. RP Paganetti, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. EM hpaganetti@mgh.harvard.edu NR 257 TC 56 Z9 58 U1 9 U2 34 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 NOV 21 PY 2014 VL 59 IS 22 BP R419 EP R472 DI 10.1088/0031-9155/59/22/R419 PG 54 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AS2DY UT WOS:000344091000003 PM 25361443 ER PT J AU Bolanos-Meade, J Logan, BR Alousi, AM Antin, JH Barowski, K Carter, SL Goldstein, SC Hexner, EO Horowitz, MM Lee, SJ Levine, JE MacMillan, ML Martin, PJ Mendizabal, AM Nakamura, R Pasquini, MC Weisdorf, DJ Westervelt, P Ho, VT AF Bolanos-Meade, Javier Logan, Brent R. Alousi, Amin M. Antin, Joseph H. Barowski, Kate Carter, Shelly L. Goldstein, Steven C. Hexner, Elizabeth O. Horowitz, Mary M. Lee, Stephanie J. Levine, John E. MacMillan, Margaret L. Martin, Paul J. Mendizabal, Adam M. Nakamura, Ryotaro Pasquini, Marcelo C. Weisdorf, Daniel J. Westervelt, Peter Ho, Vincent T. TI Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802 SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; MARROW-TRANSPLANTATION; RANDOMIZED-TRIAL; BONE-MARROW; BLOOD; NETWORK; MYCOPHENOLATE; RISK AB Corticosteroids are the accepted primary therapy for acute graft-versus-host disease (GVHD), but durable responses are seen in only about half of the patients. Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0802, a phase 3 multicenter randomized double-blinded trial, was designed to test whether mycophenolate mofetil (MMF) plus corticosteroids was superior to corticosteroids alone as initial therapy for acute GVH D. Patients with newly diagnosed acute GVHD were eligible if they required systemic therapy. Patients were randomized to receive prednisone with either MMF or placebo. The primary end point was acute or chronic GVHD-free survival at day 56 after initiation of therapy. A futility rule for GVHD-free survival at day 56 was met at a planned interim analysis after 235 patients (of 372) were enrolled: 116 MMF, 119 placebo. Baseline characteristics were well balanced between treatment groups including grade and organ distribution of GVHD. GVHD-free survival at day 56, cumulative incidence of chronic GVHD at 12 months, overall survival, Epstein-Barr virus reactivation, severe, life-threatening infections, relapse at 12 months, and quality of life were similar. The addition of MMF to corticosteroids as initial therapy for acute GVHD does not improve GVHD-free survival compared with corticosteroids alone. This trial was registered at www.clinicaltrials.gov as #NCT01002742. C1 [Bolanos-Meade, Javier] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Bone Marrow Transplant Program, Baltimore, MD 21231 USA. [Bolanos-Meade, Javier] Johns Hopkins Univ, Sch Med, Dept Med Oncol, Baltimore, MD USA. [Logan, Brent R.] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Alousi, Amin M.] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplant & Cellular Therapies, Houston, TX 77030 USA. [Antin, Joseph H.; Ho, Vincent T.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Barowski, Kate; Carter, Shelly L.; Mendizabal, Adam M.] Emmes Corp, Rockville, MD USA. [Goldstein, Steven C.; Levine, John E.] Univ Michigan, Blood & Marrow Transplant Program, Ann Arbor, MI 48109 USA. [Hexner, Elizabeth O.] Univ Penn, Dept Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Horowitz, Mary M.; Pasquini, Marcelo C.] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Lee, Stephanie J.; Martin, Paul J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Lee, Stephanie J.; Martin, Paul J.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [MacMillan, Margaret L.] Univ Minnesota, Dept Pediat, Blood & Marrow Transplant Program, Minneapolis, MN 55455 USA. [Nakamura, Ryotaro] City Hope Natl Med Ctr, Dept Hematol Hematopoiet Cell Transplantat, Duarte, CA 91010 USA. [Weisdorf, Daniel J.] Univ Minnesota, Dept Med, Blood & Marrow Transplant Program, Minneapolis, MN 55455 USA. [Westervelt, Peter] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. RP Bolanos-Meade, J (reprint author), Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, CRB-I 2M87,1650 Orleans St, Baltimore, MD 21231 USA. EM fbolano2@jhmi.edu; vincent_ho@dfci.harvard.edu FU NHLBI [U10HL069294]; National Cancer Institute at the National Institutes of Health FX This work was supported by grant #U10HL069294 from the NHLBI and the National Cancer Institute at the National Institutes of Health. NR 15 TC 17 Z9 17 U1 1 U2 4 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 NOV 20 PY 2014 VL 124 IS 22 BP 3221 EP 3227 DI 10.1182/blood-2014-06-577023 PG 7 WC Hematology SC Hematology GA AY3CW UT WOS:000347463100010 PM 25170121 ER PT J AU Reagan, MR Mishima, Y Glavey, SV Zhang, Y Manier, S Lu, ZN Memarzadeh, M Zhang, Y Sacco, A Aljawai, Y Shi, JT Tai, YT Ready, JE Kaplan, DL Roccaro, AM Ghobrial, IM AF Reagan, Michaela R. Mishima, Yuji Glavey, Siobhan V. Zhang, Yong Manier, Salomon Lu, Zhi Ning Memarzadeh, Masoumeh Zhang, Yu Sacco, Antonio Aljawai, Yosra Shi, Jiantao Tai, Yu-Tzu Ready, John E. Kaplan, David L. Roccaro, Aldo M. Ghobrial, Irene M. TI Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model SO BLOOD LA English DT Article ID MESENCHYMAL STEM-CELLS; STROMAL CELLS; OSTEOBLAST DIFFERENTIATION; EXPRESSION; MICROENVIRONMENT; THERAPY; DISEASE; GROWTH; BISPHOSPHONATES; MECHANISMS AB Clonal proliferation of plasma cells within the bone marrow (BM) affects local cells, such as mesenchymal stromal cells (MSCs), leading to osteolysis and fatality in multiple myeloma (MM). Consequently, there is an urgent need to find better mechanisms of inhibiting myeloma growth and osteolytic lesion development. To meet this need and accelerate clinical translation, better models of myeloma within the BM are required. Herein we have developed a clinically relevant, three-dimensional (3D) myeloma BM coculture model that mimics bone cell/cancer cell interactions within the bone microenvironment. The coculture model and clinical samples were used to investigate myeloma growth, osteogenesis inhibition, and myeloma-induced abnormalities in MM-MSCs. This platform demonstrated myeloma support of capillarylike assembly of endothelial cells and cell adhesion mediated drug resistance (CAM-DR). Also, distinct normal donor (ND)and MM-MSC miRNA (miR) signatures were identified and used to uncover osteogenic miRs of interest for osteoblast differentiation. More broadly, our 3D platform provides a simple, clinically relevant tool to model cancer growth within the bone useful for investigating skeletal cancer biology, screening compounds, and exploring osteogenesis. Our identification and efficacy validation of novel bone anabolic miRs in MM opens more opportunities for novel approaches to cancer therapy via stromal miR modulation. C1 [Reagan, Michaela R.; Mishima, Yuji; Glavey, Siobhan V.; Zhang, Yong; Manier, Salomon; Lu, Zhi Ning; Memarzadeh, Masoumeh; Zhang, Yu; Sacco, Antonio; Aljawai, Yosra; Tai, Yu-Tzu; Ready, John E.; Roccaro, Aldo M.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Shi, Jiantao] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Ready, John E.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kaplan, David L.] Tufts Univ, Dept Biomed Engn, Medford, MA 02155 USA. RP Ghobrial, IM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM Irene_ghobrial@dfci.harvard.edu RI Sacco, Antonio/K-4681-2016; Reagan, Michaela/E-3549-2017; OI Sacco, Antonio/0000-0003-2945-9416; Roccaro, Aldo/0000-0002-1872-5128; Reagan, Michaela/0000-0003-2884-6481 FU Department of Defense, Peer-review Cancer Research Program [W81WH-13-1-0390]; National Institutes of Health P41 Center [EB002520]; National Cancer Institute [R01CA154648] FX This study was supported by the Department of Defense, Peer-review Cancer Research Program (W81WH-13-1-0390), the National Institutes of Health P41 Center (EB002520) and National Cancer Institute grant R01CA154648. NR 46 TC 17 Z9 17 U1 1 U2 14 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 NOV 20 PY 2014 VL 124 IS 22 BP 3250 EP 3259 DI 10.1182/blood-2014-02-558007 PG 10 WC Hematology SC Hematology GA AY3CW UT WOS:000347463100014 PM 25205118 ER PT J AU Guo, XH Chen, ZQ Liu, N Guo, ZQ Qi, Q Li, WS Zeng, Y Sun, CG AF Guo Xinhu Chen Zhongqiang Liu Ning Guo Zhaoqing Qi Qiang Li Weishi Zeng Yan Sun Chuiguo TI Comparison between two types of "Scheuermann disease-like people": thoracolumbar disc herniation patients and healthy volunteers with radiological signs of Scheuermann's disease SO CHINESE MEDICAL JOURNAL LA English DT Article DE intervertebral disc herniation; Scheuermann disease; Schmorl's node; thoracic vertebrae ID BACK-PAIN; JUVENILE KYPHOSIS; LUMBAR SPINE; DEGENERATION; INDIVIDUALS; PREVALENCE; NODES AB Background Scheuermann's disease (SD) is a spinal disorder and includes both a classic form and an atypical form. Interestingly, its existence among the general population as well as the disc disease patients is common. One of our previous studies showed that about 18% of the hospital staff members meet the SD criteria. On the other hand, another study has demonstrated that 95.2% of the symptomatic thoracolumbar disc herniation (STLDH) patients meet the SD criteria, which suggests that STLDH is very likely a special form of SD. The purpose of this study was to discriminate the factors contributing to the development of STLDH by comparing STLDH patients with the healthy SD-like hospital staff members. Methods This is a retrospective study including 33 STLDH patients who met the SD criteria and 30 SD-like hospital staff members. The STLDH group was chosen from a group of patients who underwent surgery after a diagnosis of STLDH (T10/11-L1/2) at our hospital between June 2007 and June 2010. SD-like hospital staff members were chosen from a database created in 2007, which contained a lumbar MR and low back pain (LBP) questionnaire of 188 hospital staff members. The demographic and radiologic characteristics were compared between groups. Results There was no statistical difference in sex, age, and height between the two groups. The STLDH patients had higher body weight, boby mass index, and thoracolumbar kyphotic angle than SD-like hospital staff members. In addition, STLDH patients had more levels of Schmorl's nodes (3.5 +/- 1.7 vs. 2.0 +/- 1.9, t=3.364, P=0.001) and irregular endplateson (4.0 +/- 1.9 vs. 2.7 +/- 1.9, t=2.667, P=0.010) compared to the SD-like hospital staff members. Conclusions Higher body weight, higher body mass index, larger thoracolumbar kyphosis, and more Schmorl's nodes and irregular endplates on MR may be associated with the development of STLDH in "SD-like people." C1 [Guo Xinhu; Chen Zhongqiang; Guo Zhaoqing; Qi Qiang; Li Weishi; Zeng Yan; Sun Chuiguo] Peking Univ Third Hosp, Dept Orthopaed, Beijing 100191, Peoples R China. [Liu Ning] Massachusetts Gen Hosp, Dept Orthopaed Surg, Spine Serv, Boston, MA 02114 USA. RP Chen, ZQ (reprint author), Peking Univ Third Hosp, Dept Orthopaed, Beijing 100191, Peoples R China. EM puh3_czq@bjmu.edu.cn NR 24 TC 0 Z9 0 U1 9 U2 10 PU CHINESE MEDICAL ASSOC PI BEIJING PA 42 DONGSI XIDAJIE, BEIJING 100710, PEOPLES R CHINA SN 0366-6999 J9 CHINESE MED J-PEKING JI Chin. Med. J. PD NOV 20 PY 2014 VL 127 IS 22 BP 3862 EP 3866 DI 10.3760/cma.j.issn.0366-6999.20141894 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA AW5QQ UT WOS:000346329600006 PM 25421181 ER PT J AU Koren, A Handsaker, RE Kamitaki, N Karlic, R Ghosh, S Polak, P Eggan, K McCarroll, SA AF Koren, Amnon Handsaker, Robert E. Kamitaki, Nolan Karlic, Rosa Ghosh, Sulagna Polak, Paz Eggan, Kevin McCarroll, Steven A. TI Genetic Variation in Human DNA Replication Timing SO CELL LA English DT Article ID COPY NUMBER; MYELOPROLIFERATIVE NEOPLASMS; JAK2 HAPLOTYPE; HUMAN MUTATION; CELL-TYPES; ARRAY-CGH; GENOME; INITIATION; PROFILES; CANCER AB Genomic DNA replicates in a choreographed temporal order that impacts the distribution of mutations along the genome. We show here that DNA replication timing is shaped by genetic polymorphisms that act in cis upon megabase-scale DNA segments. In genome sequences from proliferating cells, read depth along chromosomes reflected DNA replication activity in those cells. We used this relationship to analyze variation in replication timing among 161 individuals sequenced by the 1000 Genomes Project. Genome-wide association of replication timing with genetic variation identified 16 loci at which inherited alleles associate with replication timing. We call these "replication timing quantitative trait loci" (rtQTLs). rtQTLs involved the differential use of replication origins, exhibited allele-specific effects on replication timing, and associated with gene expression variation at megabase scales. Our results show replication timing to be shaped by genetic polymorphism and identify a means by which inherited polymorphism regulates the mutability of nearby sequences. C1 [Koren, Amnon; Handsaker, Robert E.; Kamitaki, Nolan; Ghosh, Sulagna; McCarroll, Steven A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Koren, Amnon; Handsaker, Robert E.; Kamitaki, Nolan; Ghosh, Sulagna; McCarroll, Steven A.] MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Koren, Amnon; Handsaker, Robert E.; Kamitaki, Nolan; Ghosh, Sulagna; Polak, Paz; Eggan, Kevin; McCarroll, Steven A.] Harvard, Cambridge, MA 02142 USA. [Handsaker, Robert E.; Kamitaki, Nolan; Ghosh, Sulagna; Eggan, Kevin; McCarroll, Steven A.] MIT, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Karlic, Rosa] Univ Zagreb, Fac Sci, Div Biol, Bioinformat Grp, Zagreb 10000, Croatia. [Ghosh, Sulagna; Eggan, Kevin] Harvard Univ, Harvard Stem Cell Inst, Howard Hughes Med Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Polak, Paz] MIT, Broad Inst, Canc Program, Cambridge, MA 02142 USA. [Polak, Paz] Harvard Univ, Sch Med, Dept Med, Ctr Canc, Boston, MA 02114 USA. [Polak, Paz] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP McCarroll, SA (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM mccarroll@genetics.med.harvard.edu OI McCarroll, Steven/0000-0002-6954-8184 FU National Human Genome Research Institute [R01 HG 006855]; Integra-Life Seventh Framework Programme [315997]; Stanley Center for Psychiatric Research; Howard Hughes Medical Institute; Harvard Stem Cell Institute FX We thank Vanessa Van Doren for technical assistance and David Altshuler, Chris Patil, Giulio Genovese, Sam Rose, and Itamar Simon for discussions and comments on the manuscript. This work was supported by the National Human Genome Research Institute (R01 HG 006855 to S. A. M.), the Integra-Life Seventh Framework Programme (grant 315997 to R. K.), the Stanley Center for Psychiatric Research, the Howard Hughes Medical Institute, and the Harvard Stem Cell Institute. NR 43 TC 23 Z9 24 U1 3 U2 25 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 NOV 20 PY 2014 VL 159 IS 5 BP 1015 EP 1026 DI 10.1016/j.cell.2014.10.025 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU3IP UT WOS:000345506300015 PM 25416942 ER PT J AU Chipumuro, E Marco, E Christensen, CL Kwiatkowski, N Zhang, TH Hatheway, CM Abraham, BJ Sharma, B Yeung, C Altabef, A Perez-Atayde, A Wong, KK Yuan, GC Gray, NS Young, RA George, RE AF Chipumuro, Edmond Marco, Eugenio Christensen, Camilla L. Kwiatkowski, Nicholas Zhang, Tinghu Hatheway, Clark M. Abraham, Brian J. Sharma, Bandana Yeung, Caleb Altabef, Abigail Perez-Atayde, Antonio Wong, Kwok-Kin Yuan, Guo-Cheng Gray, Nathanael S. Young, Richard A. George, Rani E. TI CDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer SO CELL LA English DT Article ID BET BROMODOMAIN INHIBITION; RNA-POLYMERASE-II; N-MYC; C-MYC; ACTIVATING KINASE; THERAPEUTIC TARGETS; CELLULAR GROWTH; GENE-EXPRESSION; LYMPHOMA-CELLS; NEUROBLASTOMA AB The MYC oncoproteins are thought to stimulate tumor cell growth and proliferation through amplification of gene transcription, a mechanism that has thwarted most efforts to inhibit MYC function as potential cancer therapy. Using a covalent inhibitor of cyclin-dependent kinase 7 (CDK7) to disrupt the transcription of amplified MYCN in neuroblastoma cells, we demonstrate downregulation of the oncoprotein with consequent massive suppression of MYCN-driven global transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without the introduction of systemic toxicity. The striking treatment selectivity of MYCN-overexpressing cells correlated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known oncogenic drivers in neuroblastoma. These results indicate that CDK7 inhibition, by selectively targeting the mechanisms that promote global transcriptional amplification in tumor cells, may be useful therapy for cancers that are driven by MYC family oncoproteins. C1 [Chipumuro, Edmond; Hatheway, Clark M.; Sharma, Bandana; Yeung, Caleb; George, Rani E.] Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02215 USA. [Chipumuro, Edmond; Hatheway, Clark M.; Sharma, Bandana; Yeung, Caleb; George, Rani E.] Boston Childrens Hosp, Boston, MA 02215 USA. [Chipumuro, Edmond; Yeung, Caleb; George, Rani E.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Marco, Eugenio; Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Marco, Eugenio; Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Christensen, Camilla L.; Altabef, Abigail; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Kwiatkowski, Nicholas; Abraham, Brian J.; Young, Richard A.] MIT, Whitehead Inst Biomed Res, Cambridge, MA 02139 USA. [Kwiatkowski, Nicholas; Abraham, Brian J.; Young, Richard A.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Zhang, Tinghu; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Zhang, Tinghu; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Perez-Atayde, Antonio] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. RP George, RE (reprint author), Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02215 USA. EM rani_george@dfci.harvard.edu RI Young, Richard/F-6495-2012 OI Young, Richard/0000-0001-8855-8647 FU NIH [R01CA148688, R01CA148688S1, R01CA179483-01, CA109901, HG002668, R21HG006778]; American Cancer Society [RSG-12-247-TBG]; Department of Defense [PR120741A]; Friends for Life Neuroblastoma Foundation FX We thank K. Ligon, D. Sabatini., W. Weiss, A. Kung, and the Children's Oncology Group for cell lines and plasmids and P. Baran for the dCA compound. We thank J.R. Gilbert and Takaomi Sanda for insightful discussions. This study was supported by NIH R01CA148688 (R. E. G.), R01CA148688S1 (E. C.), R01CA179483-01 (N.S.G. and T.H.Z.), CA109901, HG002668 (R. A. Y., N.K., B.A.), and R21HG006778 (G. C. Y.); American Cancer Society (RSG-12-247-TBG to R. E. G.); Department of Defense (PR120741A to R. E. G.); and Friends for Life Neuroblastoma Foundation (N.S.G. and R.E.G.). THZ1 has been licensed to Syros Pharmaceuticals for clinical development. N.S.G. and R.A.Y. are scientific founders of Syros Pharmaceuticals. NR 50 TC 67 Z9 69 U1 2 U2 15 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 NOV 20 PY 2014 VL 159 IS 5 BP 1126 EP 1139 DI 10.1016/j.cell.2014.10.024 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU3IP UT WOS:000345506300023 PM 25416950 ER PT J AU Rolland, T Tasan, M Charloteaux, B Pevzner, SJ Zhong, Q Sahni, N Yi, S Lemmens, I Fontanillo, C Mosca, R Kamburov, A Ghiassian, SD Yang, XP Ghamsari, L Balcha, D Begg, BE Braun, P Brehme, M Broly, MP Carvunis, AR Convery-Zupan, D Corominas, R Coulombe-Huntington, J Dann, E Dreze, M Dricot, A Fan, CY Franzosa, E Gebreab, F Gutierrez, BJ Hardy, MF Jin, M Kang, SL Kiros, R Lin, GN Luck, K MacWilliams, A Menche, JR Murray, RR Palagi, A Poulin, MM Rambout, X Rasla, J Reichert, P Romero, V Ruyssinck, E Sahalie, JM Scholz, A Shah, AA Sharma, A Shen, Y Spirohn, K Tam, S Tejeda, AO Trigg, SA Twizere, JC Vega, K Walsh, J Cusick, ME Xia, Y Barabasi, AL Iakoucheva, LM Aloy, P De Las Rivas, J Tavernier, J Calderwood, MA Hill, DE Hao, T Roth, FP Vidal, M AF Rolland, Thomas Tasan, Murat Charloteaux, Benoit Pevzner, Samuel J. Zhong, Quan Sahni, Nidhi Yi, Song Lemmens, Irma Fontanillo, Celia Mosca, Roberto Kamburov, Atanas Ghiassian, Susan D. Yang, Xinping Ghamsari, Lila Balcha, Dawit Begg, Bridget E. Braun, Pascal Brehme, Marc Broly, Martin P. Carvunis, Anne-Ruxandra Convery-Zupan, Dan Corominas, Roser Coulombe-Huntington, Jasmin Dann, Elizabeth Dreze, Matija Dricot, Amelie Fan, Changyu Franzosa, Eric Gebreab, Fana Gutierrez, Bryan J. Hardy, Madeleine F. Jin, Mike Kang, Shuli Kiros, Ruth Lin, Guan Ning Luck, Katja MacWilliams, Andrew Menche, Joerg Murray, Ryan R. Palagi, Alexandre Poulin, Matthew M. Rambout, Xavier Rasla, John Reichert, Patrick Romero, Viviana Ruyssinck, Elien Sahalie, Julie M. Scholz, Annemarie Shah, Akash A. Sharma, Amitabh Shen, Yun Spirohn, Kerstin Tam, Stanley Tejeda, Alexander O. Trigg, Shelly A. Twizere, Jean-Claude Vega, Kerwin Walsh, Jennifer Cusick, Michael E. Xia, Yu Barabasi, Albert-Laszlo Iakoucheva, Lilia M. Aloy, Patrick De Las Rivas, Javier Tavernier, Jan Calderwood, Michael A. Hill, David E. Hao, Tong Roth, Frederick P. Vidal, Marc TI A Proteome-Scale Map of the Human Interactome Network SO CELL LA English DT Article ID MOLECULAR INTERACTION DATABASE; GENOME-WIDE ASSOCIATION; POSTTRANSLATIONAL MODIFICATIONS; COMPREHENSIVE RESOURCE; HUMAN-DISEASE; CANCER GENES; UPDATE; EXPRESSION; PROTEINS; DISORDERS AB Just as reference genome sequences revolutionized human genetics, reference maps of interactome networks will be critical to fully understand geno-type- phenotype relationships. Here, we describe a systematic map of similar to 14,000 high-quality human binary protein-protein interactions. At equal quality, this map is similar to 30% larger than what is available from small-scale studies published in the literature in the last few decades. While currently available information is highly biased and only covers a relatively small portion of the proteome, our systematic map appears strikingly more homogeneous, revealing a "broader'' human interactome network than currently appreciated. The map also uncovers significant inter-connectivity between known and candidate cancer gene products, providing unbiased evidence for an expanded functional cancer landscape, while demonstrating how high-quality interactome models will help "connect the dots'' of the genomic revolution. C1 [Rolland, Thomas; Tasan, Murat; Charloteaux, Benoit; Pevzner, Samuel J.; Zhong, Quan; Sahni, Nidhi; Yi, Song; Kamburov, Atanas; Ghiassian, Susan D.; Yang, Xinping; Ghamsari, Lila; Balcha, Dawit; Begg, Bridget E.; Braun, Pascal; Brehme, Marc; Broly, Martin P.; Carvunis, Anne-Ruxandra; Convery-Zupan, Dan; Coulombe-Huntington, Jasmin; Dann, Elizabeth; Dreze, Matija; Dricot, Amelie; Fan, Changyu; Franzosa, Eric; Gebreab, Fana; Gutierrez, Bryan J.; Hardy, Madeleine F.; Jin, Mike; Kiros, Ruth; Luck, Katja; MacWilliams, Andrew; Menche, Joerg; Murray, Ryan R.; Palagi, Alexandre; Poulin, Matthew M.; Rambout, Xavier; Rasla, John; Reichert, Patrick; Romero, Viviana; Sahalie, Julie M.; Scholz, Annemarie; Shah, Akash A.; Sharma, Amitabh; Shen, Yun; Spirohn, Kerstin; Tam, Stanley; Tejeda, Alexander O.; Trigg, Shelly A.; Twizere, Jean-Claude; Vega, Kerwin; Walsh, Jennifer; Cusick, Michael E.; Xia, Yu; Barabasi, Albert-Laszlo; Calderwood, Michael A.; Hill, David E.; Hao, Tong; Roth, Frederick P.; Vidal, Marc] Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA. [Rolland, Thomas; Tasan, Murat; Charloteaux, Benoit; Pevzner, Samuel J.; Zhong, Quan; Sahni, Nidhi; Yi, Song; Kamburov, Atanas; Ghiassian, Susan D.; Yang, Xinping; Ghamsari, Lila; Balcha, Dawit; Begg, Bridget E.; Braun, Pascal; Brehme, Marc; Broly, Martin P.; Carvunis, Anne-Ruxandra; Convery-Zupan, Dan; Coulombe-Huntington, Jasmin; Dann, Elizabeth; Dreze, Matija; Dricot, Amelie; Fan, Changyu; Franzosa, Eric; Gebreab, Fana; Gutierrez, Bryan J.; Hardy, Madeleine F.; Jin, Mike; Kiros, Ruth; Luck, Katja; MacWilliams, Andrew; Menche, Joerg; Murray, Ryan R.; Palagi, Alexandre; Poulin, Matthew M.; Rambout, Xavier; Rasla, John; Reichert, Patrick; Romero, Viviana; Sahalie, Julie M.; Scholz, Annemarie; Shah, Akash A.; Sharma, Amitabh; Shen, Yun; Spirohn, Kerstin; Tam, Stanley; Tejeda, Alexander O.; Trigg, Shelly A.; Twizere, Jean-Claude; Vega, Kerwin; Walsh, Jennifer; Cusick, Michael E.; Xia, Yu; Barabasi, Albert-Laszlo; Calderwood, Michael A.; Hill, David E.; Hao, Tong; Roth, Frederick P.; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Rolland, Thomas; Charloteaux, Benoit; Pevzner, Samuel J.; Zhong, Quan; Sahni, Nidhi; Yi, Song; Kamburov, Atanas; Yang, Xinping; Ghamsari, Lila; Balcha, Dawit; Begg, Bridget E.; Braun, Pascal; Brehme, Marc; Broly, Martin P.; Carvunis, Anne-Ruxandra; Convery-Zupan, Dan; Dann, Elizabeth; Dreze, Matija; Dricot, Amelie; Fan, Changyu; Gebreab, Fana; Gutierrez, Bryan J.; Hardy, Madeleine F.; Jin, Mike; Kiros, Ruth; Lin, Guan Ning; Luck, Katja; MacWilliams, Andrew; Murray, Ryan R.; Palagi, Alexandre; Poulin, Matthew M.; Rambout, Xavier; Rasla, John; Reichert, Patrick; Romero, Viviana; Sahalie, Julie M.; Scholz, Annemarie; Shah, Akash A.; Shen, Yun; Spirohn, Kerstin; Tam, Stanley; Tejeda, Alexander O.; Trigg, Shelly A.; Twizere, Jean-Claude; Vega, Kerwin; Walsh, Jennifer; Cusick, Michael E.; Calderwood, Michael A.; Hill, David E.; Hao, Tong; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Tasan, Murat; Roth, Frederick P.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada. [Tasan, Murat; Roth, Frederick P.] Univ Toronto, Dept Comp Sci, Toronto, ON M5S 3E1, Canada. [Tasan, Murat; Roth, Frederick P.] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. [Tasan, Murat; Roth, Frederick P.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Pevzner, Samuel J.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Pevzner, Samuel J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Zhong, Quan] Wright State Univ, Dept Biol Sci, Dayton, OH 45435 USA. [Lemmens, Irma; Ruyssinck, Elien; Tavernier, Jan] VIB, Dept Med Prot Res, B-9000 Ghent, Belgium. [Fontanillo, Celia; De Las Rivas, Javier] Univ Salamanca, Canc Res Ctr, E-37008 Salamanca, Spain. [Fontanillo, Celia; De Las Rivas, Javier] CSIC, Salamanca 37008, Spain. [Mosca, Roberto; Aloy, Patrick] Inst Res Biomed IRB Barcelona, Joint IRB BSC Program Computat Biol, Barcelona 08028, Spain. [Menche, Joerg; Sharma, Amitabh; Barabasi, Albert-Laszlo] Northeastern Univ, CCNR, Boston, MA 02115 USA. [Menche, Joerg; Sharma, Amitabh; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Corominas, Roser; Kang, Shuli; Lin, Guan Ning; Iakoucheva, Lilia M.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Coulombe-Huntington, Jasmin; Franzosa, Eric; Xia, Yu] McGill Univ, Dept Bioengn, Montreal, PQ H3A 0C3, Canada. [Rambout, Xavier; Twizere, Jean-Claude] Univ Liege, GIGA R, Prot Signaling & Interact Lab, B-4000 Liege, Belgium. [Barabasi, Albert-Laszlo] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Aloy, Patrick] ICREA, Barcelona 08010, Spain. [Roth, Frederick P.] Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada. RP Roth, FP (reprint author), Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA. EM fritz.roth@utoronto.ca; marc_vidal@dfci.harvard.edu RI Roth, Frederick/H-6308-2011; Calderwood, Mike/B-2475-2014; Braun, Pascal/B-9669-2013; De Las Rivas, Javier/G-5936-2014; Corominas, Roser/H-4163-2016; Brehme, Marc/G-8697-2015; Menche, Jorg/G-3994-2015; OI Carvunis, Anne-Ruxandra/0000-0002-6474-6413; Mosca, Roberto/0000-0002-3244-1885; Calderwood, Mike/0000-0001-6475-1418; Braun, Pascal/0000-0003-2012-6746; De Las Rivas, Javier/0000-0002-0984-9946; Corominas, Roser/0000-0001-8888-5402; Brehme, Marc/0000-0003-0694-331X; Menche, Jorg/0000-0002-1583-6404; , /0000-0001-7002-8488; Aloy, Patrick/0000-0002-3557-0236; Iakoucheva, Lilia/0000-0002-4542-5219; Xia, Yu/0000-0002-5596-5518; Roth, Frederick/0000-0002-6628-649X FU NHGRI [R01/U01HG001715, P50HG004233]; NHLBI [U01HL098166, U01HL108630]; NCI [U54CA112962, R33CA132073]; NIH [RC4HG006066]; NICHD [R01HD065288, R21MH104766, R01MH105524]; NIMH [R01MH091350]; NSF [CCF-1219007]; NSERC [RGPIN-2014-03892]; Canada Excellence Research Chair; Krembil Foundation; Ontario Research Fund-Research Excellence Award; Avon Foundation; Junta de Castilla y Leon (Valladolid, Spain) [CSI07A09]; Ministerio de Economia y Competitividad (AES, ISCiii, Madrid, Spain) [PI12/00624]; Consejo Superior de Investigaciones Cientificas (CSIC, Madrid, Spain) [i-Link0398]; Spanish Ministerio de Ciencia e Innovacion [BIO2010-22073]; European Commission [306240]; Group-ID Multidisciplinary Research Partnerships of Ghent University; Fund for Scientific Research-Flanders [FWO-V G.0864.10]; ERC [340941]; EMBO long-term fellowship; Institute Sponsored Research funds from the Dana-Farber Cancer Institute Strategic Initiative FX The authors wish to acknowledge past and present members of the Center for Cancer Systems Biology (CCSB) and particularly H. Yu for helpful discussions. This work was supported primarily by NHGRI grant R01/U01HG001715 awarded to M.V., D.E.H., F.P.R., and J.T. and in part by the following grants and agencies: NHGRI P50HG004233 to M.V., F.P.R., and A.-L.B.; NHLBI U01HL098166 subaward to M.V.; NHLBI U01HL108630 subaward to A.-L. B.; NCI U54CA112962 subaward to M.V.; NCI R33CA132073 to M.V.; NIH RC4HG006066 to M.V., D.E.H., and T.H.; NICHD ARRA R01HD065288, R21MH104766, and R01MH105524 to L.M.I.; NIMH R01MH091350 to L.M.I. and T.H.; NSF CCF-1219007 and NSERC RGPIN-2014-03892 to Y.X.; Canada Excellence Research Chair, Krembil Foundation, Ontario Research Fund-Research Excellence Award, Avon Foundation, grant CSI07A09 from Junta de Castilla y Leon (Valladolid, Spain), grant PI12/00624 from Ministerio de Economia y Competitividad (AES 2012, ISCiii, Madrid, Spain), and grant i-Link0398 from Consejo Superior de Investigaciones Cientificas (CSIC, Madrid, Spain) to J.D.L.R.; Spanish Ministerio de Ciencia e Innovacion (BIO2010-22073) and the European Commission through the FP7 project SyStemAge grant agreement n:306240 to P.A.; Group-ID Multidisciplinary Research Partnerships of Ghent University, grant FWO-V G.0864.10 from the Fund for Scientific Research-Flanders and ERC Advanced Grant No 340941 to J.T.; EMBO long-term fellowship to A.K.; Institute Sponsored Research funds from the Dana-Farber Cancer Institute Strategic Initiative to M.V. I.L. is a postdoctoral fellow with the FWO-V. M.V. is a "Chercheur Qualifie Honoraire'' from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation, Belgium). Since performing the work described, C. Fontanillo has become an employee of Celgene Research SL, part of the Celgene Corporation. NR 56 TC 214 Z9 216 U1 23 U2 147 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 NOV 20 PY 2014 VL 159 IS 5 BP 1212 EP 1226 DI 10.1016/j.cell.2014.10.050 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU3IP UT WOS:000345506300029 PM 25416956 ER PT J AU Roussos, P Mitchell, AC Voloudakis, G Fullard, JF Pothula, VM Tsang, J Stahl, EA Georgakopoulos, A Ruderfer, DM Charney, A Okada, Y Siminovitch, KA Worthington, J Padyukov, L Klareskog, L Gregersen, PK Plenge, RM Raychaudhuri, S Fromer, M Purcell, SM Brennand, KJ Robakis, NK Schadt, EE Akbarian, S Sklar, P AF Roussos, Panos Mitchell, Amanda C. Voloudakis, Georgios Fullard, John F. Pothula, Venu M. Tsang, Jonathan Stahl, Eli A. Georgakopoulos, Anastasios Ruderfer, Douglas M. Charney, Alexander Okada, Yukinori Siminovitch, Katherine A. Worthington, Jane Padyukov, Leonid Klareskog, Lars Gregersen, Peter K. Plenge, Robert M. Raychaudhuri, Soumya Fromer, Menachem Purcell, Shaun M. Brennand, Kristen J. Robakis, Nikolaos K. Schadt, Eric E. Akbarian, Schahram Sklar, Pamela TI A Role for Noncoding Variation in Schizophrenia SO CELL REPORTS LA English DT Article ID GENOME-WIDE ASSOCIATION; BIPOLAR DISORDER; GENE-EXPRESSION; RISK LOCI; HEALTHY-INDIVIDUALS; PREFRONTAL CORTEX; CELL-TYPES; CACNA1C; IDENTIFICATION; TRANSCRIPTION AB A large portion of common variant loci associated with genetic risk for schizophrenia reside within noncoding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from the human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on colocalization of a risk SNP, eQTL, and regulatory element sequence. We identified potential physical interactions of noncontiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and -induced pluripotent stem cell-derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated noncoding SNPs and 3D genome architecture associated with chromosomal loopings and transcriptional regulation in the brain. C1 [Roussos, Panos; Mitchell, Amanda C.; Voloudakis, Georgios; Fullard, John F.; Pothula, Venu M.; Tsang, Jonathan; Stahl, Eli A.; Georgakopoulos, Anastasios; Ruderfer, Douglas M.; Charney, Alexander; Fromer, Menachem; Purcell, Shaun M.; Brennand, Kristen J.; Robakis, Nikolaos K.; Akbarian, Schahram; Sklar, Pamela] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Roussos, Panos; Stahl, Eli A.; Ruderfer, Douglas M.; Charney, Alexander; Fromer, Menachem; Purcell, Shaun M.; Schadt, Eric E.; Sklar, Pamela] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Roussos, Panos; Stahl, Eli A.; Ruderfer, Douglas M.; Charney, Alexander; Fromer, Menachem; Purcell, Shaun M.; Schadt, Eric E.; Sklar, Pamela] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Roussos, Panos; Mitchell, Amanda C.; Voloudakis, Georgios; Fullard, John F.; Pothula, Venu M.; Brennand, Kristen J.; Robakis, Nikolaos K.; Akbarian, Schahram; Sklar, Pamela] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Roussos, Panos] Mental Illness Res Educ & Clin Ctr, James J Peters VA Med Ctr, Bronx, NY 10468 USA. [Mitchell, Amanda C.; Voloudakis, Georgios; Pothula, Venu M.; Brennand, Kristen J.; Robakis, Nikolaos K.; Akbarian, Schahram; Sklar, Pamela] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Okada, Yukinori] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Human Genet & Dis Divers, Tokyo 2300045, Japan. [Okada, Yukinori] RIKEN Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa 2300045, Japan. [Siminovitch, Katherine A.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Siminovitch, Katherine A.] Toronto Gen Res Inst, Toronto, ON M5G 2M9, Canada. [Siminovitch, Katherine A.] Univ Toronto, Dept Med, Toronto, ON M5S 2J7, Canada. [Worthington, Jane] Univ Manchester, Arthrit Res UK Ctr Genet & Genom, Musculoskeletal Res Ctr, Inst Inflammat & Repair,Manchester Acad Hlth Sci, Manchester M13 9NT, Lancs, England. [Worthington, Jane] Cent Manchester Univ Hosp Natl Hlth Serv Fdn Trus, Natl Inst Hlth Res, Manchester Musculoskeletal Biomed Res Unit, Manchester Acad Hlth Sci Ctr, Manchester M13 9NT, Lancs, England. [Padyukov, Leonid; Klareskog, Lars] Karolinska Inst, Dept Med Solna, Rheumatol Unit, S-17176 Stockholm, Sweden. [Gregersen, Peter K.] North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY 11030 USA. [Plenge, Robert M.; Raychaudhuri, Soumya] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Plenge, Robert M.; Raychaudhuri, Soumya] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Plenge, Robert M.; Raychaudhuri, Soumya] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Raychaudhuri, Soumya] Cent Manchester NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, NIHR Manchester Musculoskeletal Biomed Res Unit, Manchester M13 9NT, Lancs, England. RP Roussos, P (reprint author), Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. EM panagiotis.roussos@mssm.edu; pamela.sklar@mssm.edu RI Brennand, Kristen/J-8704-2012; Siminovitch, Katherine/K-1475-2013; Ruderfer, Douglas/M-5795-2016; Roussos, Panos/J-7090-2013; OI Brennand, Kristen/0000-0003-0993-5956; Ruderfer, Douglas/0000-0002-2365-386X; Roussos, Panos/0000-0002-4640-6239; Klareskog, Lars/0000-0001-9601-6186; Padyukov, Leonid/0000-0003-2950-5670 FU NIH/National Institute of Mental Health (NIMH) grant [R01MH095034]; NIMH grant [R01MH097276, U01MH103392, P50 MH096890, R01 MH101454]; National Institute of Neurological Disorders and Stroke (NINDS) grant [R21 NS076958]; NINDS grant [R01 NS047229]; National Institute on Aging (NIA) grant [R37 AG017926]; NIA grant [P50 AG005138]; Veterans Affairs Merit grant [BX002395]; Brain Behavior Research Foundation; American Psychiatric Association-Merck & Co. Early Academic Career Research Award; New York Stem Cell Foundation; Alzheimer's Association grant [IIRG-11-205149]; Friedman Brain Institute at Icahn School of Medicine at Mount Sinai; Icahn Institute for Genomics and Multiscale Biology at Icahn School of Medicine at Mount Sinai; Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai FX We thank Iris Cheung and Yin Guo for ChIP-seq assays on sorted brain nuclei. We thank all members of the Rheumatoid Arthritis Consortium for providing access to the GWAS data. Members of Rheumatoid Arthritis Consortium are Steve Eyre, John Bowes, Dorothee Diogo, Annette Lee, Anne Barton, Paul Martin, Alexandra Zhernakova, E. A. S., Sebastien Viatte, Kate McAllister, Christopher I. Amos, L. P., Rene E. M. Toes, Tom W. J. Huizinga, Cisca Wijmenga, Gosia Trynka, Lude Franke, Harm-Jan Westra, Lars Alfredsson, Xinli Hu, Cynthia Sandor, Paul I. W. de Bakker, Sonia Davila, Chiea Chuen Khor, Khai Koon Heng, Robert Andrews, Sarah Edkins, Sarah E. Hunt, Cordelia Langford, Deborah Symmons, Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate, Wellcome Trust Case Control Consortium, Pat Concannon, Suna Onengut-Gumuscu, Stephen S. Rich, Panos Deloukas, Miguel A. Gonzalez-Gay, Luis Rodriguez-Rodriguez, Lisbeth Arlsetig, Javier Martin, Solbritt Rantapaa-Dahlqvist, R. M. P., S. R., L. K., P. K. G., J. W., the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS), and the Wellcome Trust Case Control Consortium (WTCCC). We thank Dr. Ron Zielke and staff from the Brain and Tissue Bank for Developmental Disorders, and Dr. Andree Lessard from the Maryland Psychiatric Research Center, University of Maryland, for providing postmortem brain tissue. We acknowledge funding support from NIH/National Institute of Mental Health (NIMH) grant R01MH095034 (to P. S.), NIMH grant R01MH097276 (to P. S. and E. E. S.), NIMH grant U01MH103392 (to. S. A. and P. S.), NIMH grant P50 MH096890 (to S. A.), National Institute of Neurological Disorders and Stroke (NINDS) grant R21 NS076958 (to S. A.), NINDS grant R01 NS047229 (to N.K.R.), National Institute on Aging (NIA) grant R37 AG017926 (to N.K.R.), NIA grant P50 AG005138 (to N.K.R. and A. G.), Veterans Affairs Merit grant BX002395 (to P. R.), the Brain Behavior Research Foundation (to P. R., A. C. M., S. A., E. A. S., and K. B.), the American Psychiatric Association-Merck & Co. Early Academic Career Research Award (to P. R.), NIMH grant R01 MH101454 (to K. B.), the New York Stem Cell Foundation (to K. B.), Alzheimer's Association grant IIRG-11-205149 (to A. G.), the Friedman Brain Institute at Icahn School of Medicine at Mount Sinai, and the Icahn Institute for Genomics and Multiscale Biology at Icahn School of Medicine at Mount Sinai. This work was supported in part through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. The funders had no role in study design, execution, analysis, or manuscript preparation. NR 58 TC 44 Z9 44 U1 1 U2 12 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 NOV 20 PY 2014 VL 9 IS 4 BP 1417 EP 1429 DI 10.1016/j.celrep.2014.10.015 PG 13 WC Cell Biology SC Cell Biology GA AU3QW UT WOS:000345529600023 PM 25453756 ER PT J AU Gasser, JA Inuzuka, H Lau, AW Wei, WY Beroukhim, R Toker, A AF Gasser, Jessica A. Inuzuka, Hiroyuki Lau, Alan W. Wei, Wenyi Beroukhim, Rameen Toker, Alex TI SGK3 Mediates INPP4B-Dependent PI3K Signaling in Breast Cancer SO MOLECULAR CELL LA English DT Article ID INDUCED PROTEIN-KINASE; 4-PHOSPHATASE TYPE-II; PIK3CA MUTATIONS; TUMOR-SUPPRESSOR; PROSTATE-CANCER; MTOR COMPLEX; PATHWAY; SERUM; PHOSPHORYLATION; ACTIVATION AB Oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), occur with high frequency in breast cancer. The protein kinase Akt is considered to be the primary effector of PIK3CA, although mechanisms by which PI3K mediates Akt-independent tumorigenic signals remain obscure. We show that serum and glucocorticoid-regulated kinase 3 (SGK3) is amplified in breast cancer and activated downstream of PIK3CA in a manner dependent on the phosphoinositide phosphatase INPP4B. Expression of INPP4B leads to enhanced SGK3 activation and suppression of Akt phosphorylation. Activation of SGK3 downstream of PIK3CA and INPP4B is required for 3D proliferation, invasive migration, and tumorigenesis in vivo. We further show that SGK3 targets the metastasis suppressor NDRG1 for degradation by Fbw7. We propose a model in which breast cancers harboring oncogenic PIK3CA activate SGK3 signaling while suppressing Akt, indicative of oncogenic functions for both INPP4B and SGK3 in these tumors. C1 [Gasser, Jessica A.; Inuzuka, Hiroyuki; Lau, Alan W.; Wei, Wenyi; Toker, Alex] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Beroukhim, Rameen] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA. [Beroukhim, Rameen] Broad Inst MIT & Harvard, Med & Populat Genet Grp, Cambridge, MA 02142 USA. [Beroukhim, Rameen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Beroukhim, Rameen] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Beroukhim, Rameen] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Beroukhim, Rameen] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Beroukhim, Rameen] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Beroukhim, Rameen] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Beroukhim, Rameen] Harvard Univ, Dept Med, Sch Med, Boston, MA 02215 USA. [Beroukhim, Rameen] Harvard Univ, Dept Pathol, Sch Med, Boston, MA 02215 USA. [Beroukhim, Rameen] Harvard Univ, Dept Pediat, Sch Med, Boston, MA 02215 USA. [Beroukhim, Rameen] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA 02215 USA. RP Toker, A (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. EM atoker@bidmc.harvard.edu FU Department of Defense Breast Cancer Research Program [BC093630]; NIH [CA177910, U54CA143798, GM089763, GM094777]; Men's Collaborative for Women's Cancers FX We thank Lewis Cantley, John Blenis, Wade Harper, and members of the A.T. and W.W. laboratories for productive discussions and Wade Harper, John Blenis, Lewis Cantley, Donald P. McDonnell, Sandra Marmiroli, Junying Yuan, Wei-Xing Zong, and Sushant Kachhap for providing reagents. This study was supported in part by grants from the Department of Defense Breast Cancer Research Program (J.A.G., BC093630), NIH (A.T., CA177910; R.B., U54CA143798; W.W., GM089763 and GM094777), and Men's Collaborative for Women's Cancers (R.B.). NR 60 TC 28 Z9 28 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD NOV 20 PY 2014 VL 56 IS 4 BP 595 EP 607 DI 10.1016/j.molcel.2014.09.023 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU3HE UT WOS:000345502200014 PM 25458846 ER PT J AU Yue, F Cheng, Y Breschi, A Vierstra, J Wu, WS Ryba, T Sandstrom, R Ma, ZH Davis, C Pope, BD Shen, Y Pervouchine, DD Djebali, S Thurman, RE Kaul, R Rynes, E Kirilusha, A Marinov, GK Williams, BA Trout, D Amrhein, H Fisher-Aylor, K Antoshechkin, I DeSalvo, G See, LH Fastuca, M Drenkow, J Zaleski, C Dobin, A Prieto, P Lagarde, J Bussotti, G Tanzer, A Denas, O Li, KW Bender, MA Zhang, MH Byron, R Groudine, MT McCleary, D Pham, L Ye, Z Kuan, S Edsall, L Wu, YC Rasmussen, MD Bansal, MS Kellis, M Keller, CA Morrissey, CS Mishra, T Jain, D Dogan, N Harris, RS Cayting, P Kawli, T Boyle, AP Euskirchen, G Kundaje, A Lin, S Lin, Y Jansen, C Malladi, VS Cline, MS Erickson, DT Kirkup, VM Learned, K Sloan, CA Rosenbloom, KR De Sousa, BL Beal, K Pignatelli, M Flicek, P Lian, J Kahveci, T Lee, D Kent, WJ Santos, MR Herrero, J Notredame, C Johnson, A Vong, S Lee, K Bates, D Neri, F Diegel, M Canfield, T Sabo, PJ Wilken, MS Reh, TA Giste, E Shafer, A Kutyavin, T Haugen, E Dunn, D Reynolds, AP Neph, S Humbert, R Hansen, RS De Bruijn, M Selleri, L Rudensky, A Josefowicz, S Samstein, R Eichler, EE Orkin, SH Levasseur, D Papayannopoulou, T Chang, KH Skoultchi, A Gosh, S Disteche, C Treuting, P Wang, Y Weiss, MJ Blobel, GA Cao, X Zhong, S Wang, T Good, PJ Lowdon, RF Adams, LB Zhou, XQ Pazin, MJ Feingold, EA Wold, B Taylor, J Mortazavi, A Weissman, SM Stamatoyannopoulos, JA Snyder, MP Guigo, R Gingeras, TR Gilbert, DM Hardison, RC Beer, MA Ren, B AF Yue, Feng Cheng, Yong Breschi, Alessandra Vierstra, Jeff Wu, Weisheng Ryba, Tyrone Sandstrom, Richard Ma, Zhihai Davis, Carrie Pope, Benjamin D. Shen, Yin Pervouchine, Dmitri D. Djebali, Sarah Thurman, Robert E. Kaul, Rajinder Rynes, Eric Kirilusha, Anthony Marinov, Georgi K. Williams, Brian A. Trout, Diane Amrhein, Henry Fisher-Aylor, Katherine Antoshechkin, Igor DeSalvo, Gilberto See, Lei-Hoon Fastuca, Meagan Drenkow, Jorg Zaleski, Chris Dobin, Alex Prieto, Pablo Lagarde, Julien Bussotti, Giovanni Tanzer, Andrea Denas, Olgert Li, Kanwei Bender, M. A. Zhang, Miaohua Byron, Rachel Groudine, Mark T. McCleary, David Pham, Long Ye, Zhen Kuan, Samantha Edsall, Lee Wu, Yi-Chieh Rasmussen, Matthew D. Bansal, Mukul S. Kellis, Manolis Keller, Cheryl A. Morrissey, Christapher S. Mishra, Tejaswini Jain, Deepti Dogan, Nergiz Harris, Robert S. Cayting, Philip Kawli, Trupti Boyle, Alan P. Euskirchen, Ghia Kundaje, Anshul Lin, Shin Lin, Yiing Jansen, Camden Malladi, Venkat S. Cline, Melissa S. Erickson, Drew T. Kirkup, Vanessa M. Learned, Katrina Sloan, Cricket A. Rosenbloom, Kate R. De Sousa, Beatriz Lacerda Beal, Kathryn Pignatelli, Miguel Flicek, Paul Lian, Jin Kahveci, Tamer Lee, Dongwon Kent, W. James Santos, Miguel Ramalho Herrero, Javier Notredame, Cedric Johnson, Audra Vong, Shinny Lee, Kristen Bates, Daniel Neri, Fidencio Diegel, Morgan Canfield, Theresa Sabo, Peter J. Wilken, Matthew S. Reh, Thomas A. Giste, Erika Shafer, Anthony Kutyavin, Tanya Haugen, Eric Dunn, Douglas Reynolds, Alex P. Neph, Shane Humbert, Richard Hansen, R. Scott De Bruijn, Marella Selleri, Licia Rudensky, Alexander Josefowicz, Steven Samstein, Robert Eichler, Evan E. Orkin, Stuart H. Levasseur, Dana Papayannopoulou, Thalia Chang, Kai-Hsin Skoultchi, Arthur Gosh, Srikanta Disteche, Christine Treuting, Piper Wang, Yanli Weiss, Mitchell J. Blobel, Gerd A. Cao, Xiaoyi Zhong, Sheng Wang, Ting Good, Peter J. Lowdon, Rebecca F. Adams, Leslie B. Zhou, Xiao-Qiao Pazin, Michael J. Feingold, Elise A. Wold, Barbara Taylor, James Mortazavi, Ali Weissman, Sherman M. Stamatoyannopoulos, John A. Snyder, Michael P. Guigo, Roderic Gingeras, Thomas R. Gilbert, David M. Hardison, Ross C. Beer, Michael A. Ren, Bing CA Mouse ENCODE Consortium TI A comparative encyclopedia of DNA elements in the mouse genome SO NATURE LA English DT Article ID TRANSCRIPTION FACTOR-BINDING; EMBRYONIC STEM-CELLS; PERVASIVE TRANSCRIPTION; CHROMATIN INTERACTIONS; EVOLUTIONARY DYNAMICS; TRANSPOSABLE ELEMENTS; ENCODE DATA; LANDSCAPE; GENE; EXPRESSION AB The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases. C1 [Yue, Feng; Shen, Yin; McCleary, David; Pham, Long; Ye, Zhen; Kuan, Samantha; Edsall, Lee; Ren, Bing] Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Yue, Feng; Shen, Yin; McCleary, David; Pham, Long; Ye, Zhen; Kuan, Samantha; Edsall, Lee; Ren, Bing] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Yue, Feng] Penn State Univ, Coll Med, Dept Biochem & Mol Biol, Hershey, PA 17033 USA. [Cheng, Yong; Ma, Zhihai; Cayting, Philip; Kawli, Trupti; Boyle, Alan P.; Euskirchen, Ghia; Kundaje, Anshul; Lin, Shin; Lin, Yiing; Malladi, Venkat S.; Erickson, Drew T.; Sloan, Cricket A.; Snyder, Michael P.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Breschi, Alessandra; Pervouchine, Dmitri D.; Djebali, Sarah; Prieto, Pablo; Lagarde, Julien; Bussotti, Giovanni; Tanzer, Andrea; Notredame, Cedric; Guigo, Roderic] Ctr Genom Regulat, Barcelona 08003, Catalonia, Spain. [Breschi, Alessandra; Pervouchine, Dmitri D.; Djebali, Sarah; Prieto, Pablo; Lagarde, Julien; Bussotti, Giovanni; Tanzer, Andrea; Notredame, Cedric; Guigo, Roderic] UPF, Barcelona 08003, Catalonia, Spain. [Vierstra, Jeff; Sandstrom, Richard; Thurman, Robert E.; Kaul, Rajinder; Rynes, Eric; Johnson, Audra; Vong, Shinny; Lee, Kristen; Bates, Daniel; Neri, Fidencio; Diegel, Morgan; Canfield, Theresa; Sabo, Peter J.; Giste, Erika; Shafer, Anthony; Kutyavin, Tanya; Haugen, Eric; Dunn, Douglas; Reynolds, Alex P.; Neph, Shane; Humbert, Richard; Hansen, R. Scott; Eichler, Evan E.; Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Wu, Weisheng; Keller, Cheryl A.; Morrissey, Christapher S.; Mishra, Tejaswini; Jain, Deepti; Dogan, Nergiz; Harris, Robert S.; Hardison, Ross C.] Penn State Univ, Huck Inst,Life Sci, Ctr Comparat Genom & Bioinformat, University Pk, PA 16802 USA. [Ryba, Tyrone; Pope, Benjamin D.; Gilbert, David M.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Davis, Carrie; See, Lei-Hoon; Fastuca, Meagan; Drenkow, Jorg; Zaleski, Chris; Dobin, Alex; Gingeras, Thomas R.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Kirilusha, Anthony; Marinov, Georgi K.; Williams, Brian A.; Trout, Diane; Amrhein, Henry; Fisher-Aylor, Katherine; Antoshechkin, Igor; DeSalvo, Gilberto; Wold, Barbara] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Tanzer, Andrea] Univ Vienna, Fac Chem, Dept Theoret Chem, A-1090 Vienna, Austria. [Denas, Olgert; Li, Kanwei; Taylor, James] Emory Univ, O Wayne Rollins Res Ctr, Dept Biol, Atlanta, GA 30322 USA. [Denas, Olgert; Li, Kanwei; Taylor, James] Emory Univ, O Wayne Rollins Res Ctr, Dept Math & Comp Sci, Atlanta, GA 30322 USA. [Bender, M. A.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Bender, M. A.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Zhang, Miaohua; Byron, Rachel; Groudine, Mark T.] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. [Groudine, Mark T.] Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA. [Wu, Yi-Chieh; Rasmussen, Matthew D.; Bansal, Mukul S.; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Kellis, Manolis] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Jansen, Camden; Mortazavi, Ali] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA. [Cline, Melissa S.; Kirkup, Vanessa M.; Learned, Katrina; Rosenbloom, Kate R.; Kent, W. James] Univ Calif Santa Cruz, Sch Engn, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [De Sousa, Beatriz Lacerda; Santos, Miguel Ramalho] Univ Calif San Francisco, Dept Obstet Gynecol, San Francisco, CA 94143 USA. [De Sousa, Beatriz Lacerda; Santos, Miguel Ramalho] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [De Sousa, Beatriz Lacerda; Santos, Miguel Ramalho] Univ Calif San Francisco, Ctr Reprod Sci, San Francisco, CA 94143 USA. [Beal, Kathryn; Pignatelli, Miguel; Flicek, Paul; Herrero, Javier; Levasseur, Dana] European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England. [Lian, Jin; Weissman, Sherman M.] Yale Univ, Dept Genet, New Haven, CT 06520 USA. [Kahveci, Tamer] Univ Florida, Gainesville, FL 32611 USA. [Lee, Dongwon; Beer, Michael A.] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Lee, Dongwon; Beer, Michael A.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21205 USA. [Herrero, Javier] UCL, UCL Canc Inst, Bill Lyons Informat Ctr, London WC1E 6DD, England. [Wilken, Matthew S.; Reh, Thomas A.; Wang, Yanli] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. [De Bruijn, Marella] Univ Oxford, MRC Mol Haemotol Unit, Oxford OX3 9DS, England. [Selleri, Licia] Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA. [Rudensky, Alexander; Josefowicz, Steven; Samstein, Robert] Mem Sloan Kettering Canc Ctr, Program Immunol, HHMI & Ludwig Ctr, New York, NY 10065 USA. [Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Cambridge, MA 02138 USA. [Levasseur, Dana] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. [Papayannopoulou, Thalia; Chang, Kai-Hsin] Univ Washington, Dept Med, Div Hematol, Seattle, WA 98195 USA. [Skoultchi, Arthur; Gosh, Srikanta] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Disteche, Christine] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Treuting, Piper] Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA. [Wang, Yanli] Penn State Univ, Bioinformat & Genom Program, University Pk, PA 16802 USA. [Weiss, Mitchell J.] St Jude Childrens Res Hosp, Dept Hematol, Memphis, TN 38105 USA. [Blobel, Gerd A.] Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 USA. [Blobel, Gerd A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Cao, Xiaoyi; Zhong, Sheng] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Wang, Ting] Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, Dept Genet, St Louis, MO 63108 USA. [Good, Peter J.; Lowdon, Rebecca F.; Adams, Leslie B.; Zhou, Xiao-Qiao; Pazin, Michael J.; Feingold, Elise A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Ren, B (reprint author), Ludwig Inst Canc Res, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM jstam@u.washington.edu; mpsnyder@stanford.edu; roderic.guigo@crg.cat; gingeras@cshl.edu; gilbert@bio.fsu.edu; ross@bx.psu.edu; mbeer@jhu.edu; biren@ucsd.edu RI Ma, Zhihai/E-7130-2015; Djebali, Sarah/O-9817-2014; cheng, yong/I-4270-2012; Pervouchine, Dmitri/H-5252-2015; Guigo, Roderic/D-1303-2010; Kumar, Swathi/I-7941-2015; Cao, Xiaoyi/D-4646-2017; Tanzer, Andrea/L-3147-2015; Fisher, Andrew/A-1113-2016; Boyle, Alan/I-1848-2014; Notredame, Cedric/G-3868-2010; Taylor, James/F-1026-2011; Prieto Barja, Pablo/H-2035-2015; OI Samstein, Robert/0000-0001-6860-2401; Edsall, Lee Elizabeth/0000-0002-0326-2829; Herrero, Javier/0000-0001-7313-717X; Haugen, Eric/0000-0001-7444-8981; Flicek, Paul/0000-0002-3897-7955; Zhou, Xiao-Qiao/0000-0002-0724-5153; Bussotti, Giovanni/0000-0002-4078-7413; Djebali, Sarah/0000-0002-0599-1267; Pervouchine, Dmitri/0000-0003-0543-9760; Guigo, Roderic/0000-0002-5738-4477; Kumar, Swathi/0000-0002-2770-5145; Cao, Xiaoyi/0000-0001-7222-5450; Tanzer, Andrea/0000-0003-2873-4236; Boyle, Alan/0000-0002-2081-1105; Notredame, Cedric/0000-0003-1461-0988; Taylor, James/0000-0001-5079-840X; Prieto Barja, Pablo/0000-0002-1615-3998; Pazin, Michael/0000-0002-7561-3640 FU National Institutes of Health [R01HG003991, 1U54HG007004, 3RC2HG005602, GM083337, GM085354, F31CA165863, RC2HG005573, R01DK065806]; Spanish Plan Nacional [BIO2011-26205]; ERC [BIO2011-26205, 294653]; National Science Foundation Graduate Research Fellowship [DGE-071824]; Wellcome Trust [095908]; NHGRI [U01HG004695]; [R01HD043997-09]; [F32HL110473]; [K99HL119617] FX This work is funded by grants R01HG003991 (B. R.), 1U54HG007004 (T. R. G.), 3RC2HG005602 (M. P. S.), GM083337 and GM085354 (D. M. G.), F31CA165863 (B. D. P.), RC2HG005573 and R01DK065806 (R. C. H.) from the National Institutes of Health, and BIO2011-26205 from the Spanish Plan Nacional and ERC 294653 (to R. G.). J.V. is supported by a National Science Foundation Graduate Research Fellowship under grant no. DGE-071824. K. B., M. P., J.H. and P. F. acknowledge the Wellcome Trust (grant number 095908), the NHGRI (grant number U01HG004695) and the European Molecular Biology Laboratory. We thank G. Hon for helping the analysis of high-throughput enhancer validation. L. S. is supported by R01HD043997-09. S. L. was supported by grants F32HL110473 and K99HL119617. NR 71 TC 197 Z9 199 U1 10 U2 58 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 NOV 20 PY 2014 VL 515 IS 7527 BP 355 EP + DI 10.1038/nature13992 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU7HE UT WOS:000345770600034 PM 25409824 ER PT J AU Swetter, SM Geller, AC AF Swetter, Susan M. Geller, Alan C. TI Catch melanoma early SO NATURE LA English DT Editorial Material C1 [Swetter, Susan M.] Stanford Univ, Med Ctr, Pigmented Lesion & Melanoma Program, Palo Alto, CA 94304 USA. [Swetter, Susan M.] Inst Canc Res, Palo Alto, CA USA. [Geller, Alan C.] Harvard Univ, Sch Publ Hlth, Boston, MA USA. [Geller, Alan C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Swetter, SM (reprint author), Stanford Univ, Med Ctr, Pigmented Lesion & Melanoma Program, Palo Alto, CA 94304 USA. EM sswetter@stanford.edu; ageller@hsph.harvard.edu NR 4 TC 3 Z9 3 U1 0 U2 2 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 NOV 20 PY 2014 VL 515 IS 7527 BP S117 EP S117 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU7HE UT WOS:000345770600004 PM 25407708 ER PT J AU Shaw, AT Ou, SHI Bang, YJ Camidge, DR Solomon, BJ Salgia, R Riely, GJ Varella-Garcia, M Shapiro, GI Costa, DB Doebele, RC Le, LP Zheng, ZL Tan, WW Stephenson, P Shreeve, SM Tye, LM Christensen, JG Wilner, KD Clark, JW Iafrate, AJ AF Shaw, Alice T. Ou, Sai-Hong I. Bang, Yung-Jue Camidge, D. Ross Solomon, Benjamin J. Salgia, Ravi Riely, Gregory J. Varella-Garcia, Marileila Shapiro, Geoffrey I. Costa, Daniel B. Doebele, Robert C. Long Phi Le Zheng, Zongli Tan, Weiwei Stephenson, Patricia Shreeve, S. Martin Tye, Lesley M. Christensen, James G. Wilner, Keith D. Clark, Jeffrey W. Iafrate, A. John TI Crizotinib in ROS1-Rearranged Non-Small-Cell Lung Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ANAPLASTIC LYMPHOMA KINASE; ROS GENE; INHIBITORS; RESISTANT; PROTEINS; FUSIONS; SAFETY; TUMORS AB Background Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET. Methods We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays. Results The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC. Conclusions In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. C1 [Shaw, Alice T.; Long Phi Le; Zheng, Zongli; Clark, Jeffrey W.; Iafrate, A. John] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Costa, Daniel B.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Ou, Sai-Hong I.] Univ Calif Irvine, Irvine, CA USA. [Tan, Weiwei; Shreeve, S. Martin; Tye, Lesley M.; Christensen, James G.; Wilner, Keith D.] Pfizer Oncol, La Jolla, CA USA. [Bang, Yung-Jue] Seoul Natl Univ Hosp, Seoul 110744, South Korea. [Camidge, D. Ross; Varella-Garcia, Marileila; Doebele, Robert C.] Univ Colorado, Aurora, CO USA. [Solomon, Benjamin J.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Salgia, Ravi] Univ Chicago, Chicago, IL 60637 USA. [Riely, Gregory J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Zheng, Zongli] Karolinska Inst, Stockholm, Sweden. [Stephenson, Patricia] Rho, Chapel Hill, NC USA. RP Shaw, AT (reprint author), Massachusetts Gen Hosp, Ctr Canc, Yawkey 7B,32 Fruit St, Boston, MA 02114 USA. EM ashaw1@mgh.harvard.edu RI zheng, zongli/B-2917-2011; OI zheng, zongli/0000-0003-4849-4903; Costa, Daniel/0000-0002-0689-395X FU Pfizer; National Cancer Institute [R21CA161590, K12CA086913, P50CA058187, P30CA046934]; Uniting against Lung Cancer; Swedish Research Council [350-2012-368]; Be a Piece of the Solution FX Supported by Pfizer, by grants from the National Cancer Institute (R21CA161590, to Dr. Iafrate; K12CA086913, to Dr. Doebele; P50CA058187, to Drs. Doebele and Camidge; and P30CA046934, to Dr. Varella-Garcia), by a research grant from Uniting against Lung Cancer (to Dr. Shaw), by the Swedish Research Council (postdoctoral fellowship 350-2012-368, to Dr. Zheng), and by Be a Piece of the Solution. NR 35 TC 280 Z9 296 U1 5 U2 29 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 NOV 20 PY 2014 VL 371 IS 21 BP 1963 EP 1971 DI 10.1056/NEJMoa1406766 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AT5ST UT WOS:000345002900005 PM 25264305 ER PT J AU Olson, KR Freitag, SK Johnson, JM Branda, JA AF Olson, Kristian R. Freitag, Suzanne K. Johnson, Jason M. Branda, John A. TI Case 36-2014: An 18-Year-Old Woman with Fever, Pharyngitis, and Double Vision SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID FUSOBACTERIUM-NECROPHORUM; INFECTIOUS-MONONUCLEOSIS; LEMIERRES-SYNDROME; NECROBACILLOSIS C1 [Olson, Kristian R.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Olson, Kristian R.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Johnson, Jason M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Branda, John A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Olson, Kristian R.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Olson, Kristian R.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Olson, Kristian R.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Johnson, Jason M.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Branda, John A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Freitag, Suzanne K.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. RP Olson, KR (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. FU Vodafone Foundation; Omidyar Network FX Dr. Olson reports receiving grant support through his institution from Vodafone Foundation and the Omidyar Network. No other potential conflict of interest relevant to this article was reported. NR 14 TC 1 Z9 1 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 NOV 20 PY 2014 VL 371 IS 21 BP 2018 EP 2027 DI 10.1056/NEJMcpc1310001 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AT5ST UT WOS:000345002900013 PM 25409375 ER PT J AU Johnson, DB Flaherty, KT Weber, JS Infante, JR Kim, KB Kefford, RF Hamid, O Schuchter, L Cebon, J Sharfman, WH McWilliams, RR Sznol, M Lawrence, DP Gibney, GT Burris, HA Falchook, GS Algazi, A Lewis, K Long, GV Patel, K Ibrahim, N Sun, P Little, S Cunningham, E Sosman, JA Daud, A Gonzalez, R AF Johnson, Douglas B. Flaherty, Keith T. Weber, Jeffrey S. Infante, Jeffrey R. Kim, Kevin B. Kefford, Richard F. Hamid, Omid Schuchter, Lynn Cebon, Jonathan Sharfman, William H. McWilliams, Robert R. Sznol, Mario Lawrence, Donald P. Gibney, Geoffrey T. Burris, Howard A., III Falchook, Gerald S. Algazi, Alain Lewis, Karl Long, Georgina V. Patel, Kiran Ibrahim, Nageatte Sun, Peng Little, Shonda Cunningham, Elizabeth Sosman, Jeffrey A. Daud, Adil Gonzalez, Rene TI Combined BRAF (Dabrafenib) and MEK Inhibition (Trametinib) in Patients With BRAF(V600)-Mutant Melanoma Experiencing Progression With Single-Agent BRAF Inhibitor SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID METASTATIC MELANOMA; ACQUIRED-RESISTANCE; IMPROVED SURVIVAL; RAF INHIBITION; VEMURAFENIB; MUTATIONS; MECHANISMS; OVERCOME; THERAPY AB Purpose Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAF(V600)-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment. Patients and Methods In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). Results In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease >= 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib >= 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%). Conclusion Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor-resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy >= 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy. (C) 2014 by American Society of Clinical Oncology C1 [Johnson, Douglas B.; Sosman, Jeffrey A.] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Weber, Jeffrey S.; Burris, Howard A., III] Sarah Cannon Res Inst, Nashville, TN USA. [Weber, Jeffrey S.; Burris, Howard A., III] Tennessee Oncol, Nashville, TN USA. [Flaherty, Keith T.; Lawrence, Donald P.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Weber, Jeffrey S.; Gibney, Geoffrey T.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Kim, Kevin B.; Falchook, Gerald S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kefford, Richard F.; Long, Georgina V.] Univ Sydney, Melanoma Inst Australia, Sydney, NSW 2006, Australia. [Kefford, Richard F.; Long, Georgina V.] Westmead Hosp, Sydney, NSW, Australia. [Cebon, Jonathan] Austin Hlth, Joint Ludwig Austin Oncol Unit, Melbourne, Vic, Australia. [Hamid, Omid] Angeles Clin & Res Inst, Los Angeles, CA USA. [Algazi, Alain; Daud, Adil] Univ Calif San Francisco, San Francisco, CA USA. [Schuchter, Lynn] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Ibrahim, Nageatte; Sun, Peng; Little, Shonda; Cunningham, Elizabeth] GlaxoSmithKline, Philadelphia, PA USA. [Sharfman, William H.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [McWilliams, Robert R.] Mayo Clin, Rochester, MN USA. [Sznol, Mario] Yale Univ, Sch Med, New Haven, CT USA. [Sznol, Mario] Yale New Haven Med Ctr, Smilow Canc Ctr, New Haven, CT 06504 USA. [Lewis, Karl; Gonzalez, Rene] Univ Colorado, Denver, CO 80202 USA. [Patel, Kiran] Incyte, Wilmington, DE USA. RP Johnson, DB (reprint author), 777 Preston Res Bldg,2220 Pierce Ave, Nashville, TN 37232 USA. EM douglas.b.johnson@vanderbilt.edu FU GlaxoSmithKline; National Institutes of Health [K12 CA 0906525]; Cancer Institute New South Wales; Royal Australasian College of Physicians FX Supported by GlaxoSmithKline, National Institutes of Health Grant No. K12 CA 0906525 (D.B.J.), and fellowships from the Cancer Institute New South Wales and the Royal Australasian College of Physicians (G.V.L.); editorial support provided by SciMentum, funded by GlaxoSmithKline. NR 31 TC 64 Z9 65 U1 0 U2 10 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 NOV 20 PY 2014 VL 32 IS 33 BP 3697 EP + DI 10.1200/JCO.2014.57.3535 PG 11 WC Oncology SC Oncology GA AT3US UT WOS:000344861400004 PM 25287827 ER PT J AU Taplin, ME Montgomery, B Logothetis, CJ Bubley, GJ Richie, JP Dalkin, BL Sanda, MG Davis, JW Loda, M True, LD Troncoso, P Ye, H Lis, RT Marck, BT Matsumoto, AM Balk, SP Mostaghel, EA Penning, TM Nelson, PS Xie, W Jiang, Z Haqq, CM Tamae, D Tran, N Peng, W Kheoh, T Molina, A Kantoff, PW AF Taplin, Mary-Ellen Montgomery, Bruce Logothetis, Christopher J. Bubley, Glenn J. Richie, Jerome P. Dalkin, Bruce L. Sanda, Martin G. Davis, John W. Loda, Massimo True, Lawrence D. Troncoso, Patricia Ye, Huihui Lis, Rosina T. Marck, Brett T. Matsumoto, Alvin M. Balk, Steven P. Mostaghel, Elahe A. Penning, Trevor M. Nelson, Peter S. Xie, Wanling Jiang, Zhenyang Haqq, Christopher M. Tamae, Daniel NamPhuong Tran Peng, Weimin Thian Kheoh Molina, Arturo Kantoff, Philip W. TI Intense Androgen-Deprivation Therapy With Abiraterone Acetate Plus Leuprolide Acetate in Patients With Localized High-Risk Prostate Cancer: Results of a Randomized Phase II Neoadjuvant Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RADICAL PROSTATECTOMY; HORMONAL-THERAPY; TRIAL; SUPPRESSION; EXPRESSION; INHIBITOR; SURVIVAL; ABLATION; OUTCOMES; SLCO1B3 AB Purpose Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone-releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression. Patients and Methods A neoadjuvant randomized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa (N = 58). For the first 12 weeks, patients were randomly assigned to LHRHa versus LHRHa plus AA. After a research prostate biopsy, all patients received 12 additional weeks of LHRHa plus AA followed by prostatectomy. Results The levels of intraprostatic androgens from 12-week prostate biopsies, including the primary end point (dihydrotestosterone/testosterone), were significantly lower (dehydroepiandrosterone, Delta(4)-androstene-3,17-dione, dihydrotestosterone, all P < .001; testosterone, P < .05) with LHRHa plus AA compared with LHRHa alone. Prostatectomy pathologic staging demonstrated a low incidence of complete responses and minimal residual disease, with residual T3- or lymph node-positive disease in the majority. Conclusion LHRHa plus AA treatment suppresses tissue androgens more effectively than LHRHa alone. Intensive intratumoral androgen suppression with LHRHa plus AA before prostatectomy for localized high-risk PCa may reduce tumor burden. (C) 2014 by American Society of Clinical Oncology C1 [Taplin, Mary-Ellen; Loda, Massimo; Lis, Rosina T.; Xie, Wanling; Jiang, Zhenyang; Kantoff, Philip W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Bubley, Glenn J.; Ye, Huihui; Balk, Steven P.] Beth Israel Deaconess Med Ctr, Boston, MA USA. [Richie, Jerome P.; Loda, Massimo; Lis, Rosina T.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Montgomery, Bruce; Dalkin, Bruce L.; True, Lawrence D.; Matsumoto, Alvin M.] Univ Washington, Seattle, WA 98195 USA. [Marck, Brett T.; Matsumoto, Alvin M.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Mostaghel, Elahe A.; Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Logothetis, Christopher J.; Davis, John W.; Troncoso, Patricia] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Sanda, Martin G.] Emory Univ, Sch Med, Atlanta, GA USA. [Loda, Massimo] Kings Coll London, London, England. [Penning, Trevor M.; Tamae, Daniel] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Haqq, Christopher M.; NamPhuong Tran; Peng, Weimin; Thian Kheoh; Molina, Arturo] Janssen Res & Dev, Los Angeles, CA USA. RP Taplin, ME (reprint author), Harvard Univ, Lank Ctr Genitourinary Oncol, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM mary_taplin@dfci.harvard.edu RI Sanda, Martin/B-2023-2015; OI Penning, Trevor/0000-0002-3937-1066 FU Janssen Research and Development; Pacific Northwest Prostate Cancer Specialized Program of Research Excellence (SPORE) [P50CA097186, RCICA146849, PC093509]; Dana-Farber Cancer Institute SPORE [5 P50 CA090381-10]; National Cancer Institute Cancer Pharmacology Training Fellowship [R25 CA101871]; Kohlberg Foundation; Prostate Cancer Foundation; Department of Defense [W81XWH-11-1-0295, W81XWH07-1-0443]; National Institutes of Health (NIH) [P01 CA163227]; Department of Veterans' Affairs Puget Sound Health Care System; Janssen Global Services FX Supported by Ortho Biotech Oncology Research and Development, unit of Cougar Biotechnology (now Janssen Research and Development); by Pacific Northwest Prostate Cancer Specialized Program of Research Excellence (SPORE) Grants No. P50CA097186, RCICA146849, and PC093509; by Dana-Farber Cancer Institute SPORE Grant No. 5 P50 CA090381-10; by National Cancer Institute Cancer Pharmacology Training Fellowship Grant No. R25 CA101871 (D.T.); by the Kohlberg Foundation; by a Challenge Award from the Prostate Cancer Foundation (P.S.N., S.P.B.); by Department of Defense Grants No. W81XWH-11-1-0295 and W81XWH07-1-0443 and National Institutes of Health (NIH) Grant No. P01 CA163227 (S.P.B.); by NIH Grant No. P01 CA163227 (S.P.B., P.S.N., E.A.M., T.M.P.); by the Department of Veterans' Affairs Puget Sound Health Care System (A.M.M.); and by Janssen Global Services, which funded writing assistance. The trial was conducted within the Prostate Cancer Clinical Trials Consortium. NR 29 TC 36 Z9 36 U1 0 U2 8 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 NOV 20 PY 2014 VL 32 IS 33 BP 3705 EP + DI 10.1200/JCO.2013.53.4578 PG 14 WC Oncology SC Oncology GA AT3US UT WOS:000344861400005 PM 25311217 ER PT J AU Perez, EA Romond, EH Suman, VJ Jeong, JH Sledge, G Geyer, CE Martino, S Rastogi, P Gralow, J Swain, SM Winer, EP Colon-Otero, G Davidson, NE Mamounas, E Zujewski, JA Wolmark, N AF Perez, Edith A. Romond, Edward H. Suman, Vera J. Jeong, Jong-Hyeon Sledge, George Geyer, Charles E., Jr. Martino, Silvana Rastogi, Priya Gralow, Julie Swain, Sandra M. Winer, Eric P. Colon-Otero, Gerardo Davidson, Nancy E. Mamounas, Eleftherios Zujewski, Jo Anne Wolmark, Norman TI Trastuzumab Plus Adjuvant Chemotherapy for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Planned Joint Analysis of Overall Survival From NSABP B-31 and NCCTG N9831 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID FOLLOW-UP; TRIAL; DOXORUBICIN; PACLITAXEL AB Purpose Positive interim analysis findings from four large adjuvant trials evaluating trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2) -positive breast cancer were first reported in 2005. One of these reports, the joint analysis of North Central Cancer Treatment Group NCCTG N9831 (Combination Chemotherapy With or Without Trastuzumab in Treating Women With HER2-Overexpressing Breast Cancer) and the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 (Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2), was updated in 2011. We now report the planned definitive overall survival (OS) results from this joint analysis along with updates on the disease-free survival (DFS) end point. Methods In all, 4,046 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The required number of events for the definitive statistical analysis for OS (710 events) was reached in September 2012. Updated analyses of overall DFS and related subgroups were also performed. Results Median time on study was 8.4 years. Adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.73; P < .001) and an increase in 10-year OS rate from 75.2% to 84%. These results were accompanied by an improvement in DFS of 40% (HR, 0.60; 95% CI, 0.53 to 0.68; P < .001) and increase in 10-year DFS rate from 62.2% to 73.7%. All patient subgroups benefited from addition of this targeted anti-HER2 agent. Conclusion The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence. (C) 2014 by American Society of Clinical Oncology C1 [Perez, Edith A.; Colon-Otero, Gerardo] Mayo Clin, Jacksonville, FL 32224 USA. [Mamounas, Eleftherios] Univ Florida, Hlth Canc Ctr Orlando Hlth, Orlando, FL USA. [Romond, Edward H.] Univ Kentucky, Lexington, KY USA. [Suman, Vera J.] Mayo Clin, Rochester, MN USA. [Jeong, Jong-Hyeon; Rastogi, Priya] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Davidson, Nancy E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. [Wolmark, Norman] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Sledge, George] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Martino, Silvana] Angeles Clin & Res Inst, Santa Monica, CA USA. [Geyer, Charles E., Jr.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Gralow, Julie] Univ Washington, Seattle Canc Care Alliance, Seattle, WA USA. [Swain, Sandra M.] MedStar Washington Hosp Ctr, Washington, DC USA. [Winer, Eric P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zujewski, Jo Anne] NIH, Rockville, MD USA. RP Perez, EA (reprint author), Mayo Clin, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM perez.edith@mayo.edu OI Jeong, Jong/0000-0003-0596-2201; Swain, Sandra/0000-0002-1320-3830 FU National Institutes of Health [U10-CA25224, CA129949]; National Surgical Adjuvant Breast and Bowel Project [U10-CA12027, U10-CA69651, U10-CA37377, U10-CA69974]; Breast Cancer Research Foundation; Genentech [35-03]; Cancer and Leukemia Group B FX Supported by Grants No. U10-CA25224 and CA129949 from the National Institutes of Health; Grants No. U10-CA12027, U10-CA69651, U10-CA37377, and U10-CA69974 from the National Surgical Adjuvant Breast and Bowel Project; by the Breast Cancer Research Foundation; and by Grant No. 35-03 from Genentech. P.A.K. received research funding from Cancer and Leukemia Group B. NR 11 TC 118 Z9 125 U1 1 U2 9 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 NOV 20 PY 2014 VL 32 IS 33 BP 3744 EP + DI 10.1200/JCO.2014.55.5730 PG 10 WC Oncology SC Oncology GA AT3US UT WOS:000344861400010 PM 25332249 ER PT J AU Ladra, MM Szymonifka, JD Mahajan, A Friedmann, AM Yeap, BY Goebel, CP MacDonald, SM Grosshans, DR Rodriguez-Galindo, C Marcus, KJ Tarbell, NJ Yock, TI AF Ladra, Matthew M. Szymonifka, Jackie D. Mahajan, Anita Friedmann, Alison M. Yeap, Beow Yong Goebel, Claire P. MacDonald, Shannon M. Grosshans, David R. Rodriguez-Galindo, Carlos Marcus, Karen J. Tarbell, Nancy J. Yock, Torunn I. TI Preliminary Results of a Phase II Trial of Proton Radiotherapy for Pediatric Rhabdomyosarcoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INTENSITY-MODULATED RADIOTHERAPY; CHILDRENS ONCOLOGY GROUP; INTERGROUP RHABDOMYOSARCOMA; NECK-RHABDOMYOSARCOMA; PARAMENINGEAL RHABDOMYOSARCOMA; STUDY-IV; IRS-IV; BLADDER/PROSTATE RHABDOMYOSARCOMA; RISK RHABDOMYOSARCOMA; PROGNOSTIC-FACTORS AB Purpose This prospective phase II study was designed to assess disease control and to describe acute and late adverse effects of treatment with proton radiotherapy in children with rhabdomyosarcoma (RMS). Patients and Methods Fifty-seven patients with localized RMS (age 21 years or younger) or metastatic embryonal RMS (age 2 to 10 years) were enrolled between February 2005 and August 2012. All patients were treated with chemotherapy based on either vincristine, actinomycin, and cyclophosphamide or vincristine, actinomycin, and ifosfamide-based chemotherapy and proton radiation. Surgical resection was based on tumor site and accessibility. Common Terminology Criteria for Adverse Events, Version 3.0, was used to assess and grade adverse effects of treatment. Concurrent enrollment onto Children's Oncology Group or European Pediatric Sarcoma Study Group protocols was allowed. All pathology and imaging were reviewed at the treating institution. Results Median follow-up was 47 months (range, 14 to 102 months) for survivors. Five-year event-free survival (EFS), overall survival (OS), and local control (LC) were 69%, 78%, and 81%, respectively, for the entire cohort. The 5-year LC by risk group was 93% for low-risk and 77% for intermediate-risk disease. There were 13 patients with grade 3 acute toxicity and three patients with grade 3 late toxicity. There were no acute or late toxicities higher than grade 3. Conclusion Five-year LC, EFS, and OS rates were similar to those observed in comparable trials that used photon radiation. Acute and late toxicity rates were favorable. Proton radiation appears to represent a safe and effective radiation modality for pediatric RMS. (C) 2014 by American Society of Clinical Oncology C1 [Ladra, Matthew M.; Szymonifka, Jackie D.; Friedmann, Alison M.; Yeap, Beow Yong; Goebel, Claire P.; MacDonald, Shannon M.; Tarbell, Nancy J.; Yock, Torunn I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Rodriguez-Galindo, Carlos; Marcus, Karen J.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Mahajan, Anita; Grosshans, David R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Yock, TI (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 55 Fruit St,Room 110, Boston, MA 02114 USA. EM tyock@partners.org FU Children's Oncology Group Chair [U10CA98543]; National Cancer Institute FX Supported by Children's Oncology Group Chair Grant No. U10CA98543 and other philantrhopic sources (cog-foundation.org). The Children's Oncology Group is primarily funded by the National Cancer Institute and also receives additional funding from other granting agencies. NR 31 TC 23 Z9 23 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 20 PY 2014 VL 32 IS 33 BP 3762 EP + DI 10.1200/JCO.2014.56.1548 PG 10 WC Oncology SC Oncology GA AT3US UT WOS:000344861400012 PM 25332253 ER PT J AU Maunsell, E Chlebowski, RT Ingle, JN Richardson, H Goss, PE AF Maunsell, Elizabeth Chlebowski, Rowan T. Ingle, James N. Richardson, Harriet Goss, Paul E. TI Aromatase Inhibitor Adverse Effects: Are We Sweeping Them Under the Rug? Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID BREAST-CANCER; PREVENTION; EXEMESTANE; WOMEN C1 [Maunsell, Elizabeth] Ctr Hosp Univ Quebec, Ctr Rech, Quebec City, PQ, Canada. [Chlebowski, Rowan T.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Ingle, James N.] Mayo Clin, Rochester, MN USA. [Richardson, Harriet] NCIC Clin Trials Grp, Kingston, ON, Canada. [Goss, Paul E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Maunsell, E (reprint author), Ctr Hosp Univ Quebec, Ctr Rech, Quebec City, PQ, Canada. NR 9 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 20 PY 2014 VL 32 IS 33 BP 3780 EP + DI 10.1200/JCO.2014.57.9235 PG 3 WC Oncology SC Oncology GA AT3US UT WOS:000344861400015 PM 25154825 ER PT J AU Leykum, LK Lanham, HJ Pugh, JA Parchman, M Anderson, RA Crabtree, BF Nutting, PA Miller, WL Stange, KC McDaniel, RR AF Leykum, Luci K. Lanham, Holly J. Pugh, Jacqueline A. Parchman, Michael Anderson, Ruth A. Crabtree, Benjamin F. Nutting, Paul A. Miller, William L. Stange, Kurt C. McDaniel, Reuben R., Jr. TI Manifestations and implications of uncertainty for improving healthcare systems: an analysis of observational and interventional studies grounded in complexity science SO IMPLEMENTATION SCIENCE LA English DT Article DE Complexity science; Relationships; Uncertainty; Healthcare systems; Implementation ID PREVENTIVE SERVICE DELIVERY; QUALITY-OF-CARE; CLINICAL-TRIAL; DIABETES CARE; NURSING-HOMES; MODEL; SCALE; IMPLEMENTATION; MEDICARE; INSIGHTS AB Background: The application of complexity science to understanding healthcare system improvement highlights the need to consider interdependencies within the system. One important aspect of the interdependencies in healthcare delivery systems is how individuals relate to each other. However, results from our observational and interventional studies focusing on relationships to understand and improve outcomes in a variety of healthcare settings have been inconsistent. We sought to better understand and explain these inconsistencies by analyzing our findings across studies and building new theory. Methods: We analyzed eight observational and interventional studies in which our author team was involved as the basis of our analysis, using a set theoretical qualitative comparative analytic approach. Over 16 investigative meetings spanning 11 months, we iteratively analyzed our studies, identifying patterns of characteristics that could explain our set of results. Our initial focus on differences in setting did not explain our mixed results. We then turned to differences in patient care activities and tasks being studied and the attributes of the disease being treated. Finally, we examined the interdependence between task and disease. Results: We identified system-level uncertainty as a defining characteristic of complex systems through which we interpreted our results. We identified several characteristics of healthcare tasks and diseases that impact the ways uncertainty is manifest across diverse care delivery activities. These include disease-related uncertainty (pace of evolution of disease and patient control over outcomes) and task-related uncertainty (standardized versus customized, routine versus non-routine, and interdependencies required for task completion). Conclusions: Uncertainty is an important aspect of clinical systems that must be considered in designing approaches to improve healthcare system function. The uncertainty inherent in tasks and diseases, and how they come together in specific clinical settings, will influence the type of improvement strategies that are most likely to be successful. Process-based efforts appear best-suited for low-uncertainty contexts, while relationship-based approaches may be most effective for high-uncertainty situations. C1 [Leykum, Luci K.; Lanham, Holly J.; Pugh, Jacqueline A.] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Leykum, Luci K.; Lanham, Holly J.; Pugh, Jacqueline A.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Leykum, Luci K.; Lanham, Holly J.; McDaniel, Reuben R., Jr.] Univ Texas Austin, Austin, TX 78712 USA. [Parchman, Michael] Grp Hlth Res Inst, MacColl Ctr Hlth Care Innovat, Seattle, WA USA. [Anderson, Ruth A.] Duke Univ, Durham, NC USA. [Crabtree, Benjamin F.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Family Med, New Brunswick, NJ USA. [Nutting, Paul A.] Univ Colorado, Dept Family Med, Sch Med, Aurora, CO USA. [Miller, William L.] Lehigh Valley Hlth Network, Lehigh, PA USA. [Stange, Kurt C.] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Leykum, LK (reprint author), South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. EM Leykum@uthscsa.edu OI Parchman, Michael/0000-0001-7129-2889 FU Department of Veterans Affairs, Veterans Health Administration, and Health Services Research and Development Service [CDA 07-022]; South Texas Veterans Health Care System; IC2 Institute of the University of Texas at Austin; Clinical Research Professorship from the American Cancer Society FX The research reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, and Health Services Research and Development Service (CDA 07-022). Investigator salary support is provided through this funding and through the South Texas Veterans Health Care System. 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. Dr. McDaniel receives support from the IC2 Institute of the University of Texas at Austin. Dr. Stange's time was supported in part by a Clinical Research Professorship from the American Cancer Society. NR 47 TC 7 Z9 7 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD NOV 19 PY 2014 VL 9 AR 165 DI 10.1186/s13012-014-0165-1 PG 13 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AY2PK UT WOS:000347431700001 PM 25407138 ER PT J AU Makene, CL Plotkin, M Currie, S Bishanga, D Ugwi, P Louis, H Winani, K Nelson, BD AF Makene, Christina Lulu Plotkin, Marya Currie, Sheena Bishanga, Dunstan Ugwi, Patience Louis, Henry Winani, Koheleth Nelson, Brett D. TI Improvements in newborn care and newborn resuscitation following a quality improvement program at scale: results from a before and after study in Tanzania SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article DE Essential newborn care; Newborn resuscitation; Newborn health; Quality of care; Tanzania ID NEONATAL DEATHS; MORTALITY; HEALTH AB Background: Every year, more than a million of the world's newborns die on their first day of life; as many as two-thirds of these deaths could be saved with essential care at birth and the early newborn period. Simple interventions to improve the quality of essential newborn care in health facilities - for example, improving steps to help newborns breathe at birth - have demonstrated up to 47% reduction in newborn mortality in health facilities in Tanzania. We conducted an evaluation of the effects of a large-scale maternal-newborn quality improvement intervention in Tanzania that assessed the quality of provision of essential newborn care and newborn resuscitation. Methods: Cross-sectional health facility surveys were conducted pre-intervention (2010) and post intervention (2012) in 52 health facilities in the program implementation area. Essential newborn care provided by health care providers immediately following birth was observed for 489 newborns in 2010 and 560 in 2012; actual management of newborns with trouble breathing were observed in 2010 (n = 18) and 2012 (n = 40). Assessments of health worker knowledge were conducted with case studies (2010, n = 206; 2012, n = 217) and a simulated resuscitation using a newborn mannequin (2010, n = 299; 2012, n = 213). Facility audits assessed facility readiness for essential newborn care. Results: Index scores for quality of observed essential newborn care showed significant overall improvement following the quality-of-care intervention, from 39% to 73% (p < 0.0001). Health worker knowledge using a case study significantly improved as well, from 23% to 41% (p < 0.0001) but skills in resuscitation using a newborn mannequin were persistently low. Availability of essential newborn care supplies, which was high at baseline in the regional hospitals, improved at the lower-level health facilities. Conclusions: Within two years, the quality improvement program was successful in raising the quality of essential newborn care services in the program facilities. Some gaps in newborn care were persistent, notably practical skills in newborn resuscitation. Continued investment in life-saving improvements to newborn care through the health services is a priority for reduction of newborn mortality in Tanzania. C1 [Makene, Christina Lulu; Plotkin, Marya; Bishanga, Dunstan] Jhpiego Tanzania, Dar Es Salaam, Tanzania. [Currie, Sheena] Jhpiego Baltimore, Baltimore, MD USA. [Ugwi, Patience; Louis, Henry; Nelson, Brett D.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Ugwi, Patience; Louis, Henry; Nelson, Brett D.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Winani, Koheleth] Tanzania Minist Hlth & Social Welf, Dar Es Salaam, Tanzania. [Nelson, Brett D.] Harvard Univ, Sch Med, Boston, MA USA. RP Plotkin, M (reprint author), Jhpiego Tanzania, POB 9170, Dar Es Salaam, Tanzania. EM Marya.plotkin@jhpiego.org OI Nelson, Brett/0000-0002-5049-1798 FU U.S. Agency for International Development (USAID) [621-A-00-08-00023-00]; Mothers and Infants, Safe Healthy Alive (MAISHA) program; Maternal and Child Health Integrated Program (MCHIP) [GHS-A-00-08-00002-00] FX This work was supported by the U.S. Agency for International Development (USAID), under the terms of the Cooperative Agreement No. 621-A-00-08-00023-00, Mothers and Infants, Safe Healthy Alive (MAISHA) program, and the Leader with Associates Cooperative Agreement GHS-A-00-08-00002-00 called the Maternal and Child Health Integrated Program (MCHIP). NR 32 TC 4 Z9 4 U1 0 U2 5 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 NOV 19 PY 2014 VL 14 AR 381 DI 10.1186/s12884-014-0381-3 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AX2BW UT WOS:000346749000001 PM 25406496 ER PT J AU Lane, JM Doyle, JR Fortin, JP Kopin, AS Ordovas, JM AF Lane, Jacqueline M. Doyle, Jamie R. Fortin, Jean-Philippe Kopin, Alan S. Ordovas, Jose M. TI Development of an OP9 Derived Cell Line as a Robust Model to Rapidly Study Adipocyte Differentiation SO PLOS ONE LA English DT Article ID ADIPOGENIC DIFFERENTIATION; CARDIOVASCULAR-DISEASE; GENE-EXPRESSION; 3T3-L1 CELLS; RISK-FACTORS; PPAR-GAMMA; STEM-CELLS; IN-VITRO; ADIPOSE; OBESITY AB One hallmark of obesity is adipocyte hypertrophy and hyperplasia. To gain novel insights into adipose biology and therapeutics, there is a pressing need for a robust, rapid, and informative cell model of adipocyte differentiation for potential RNAi and drug screens. Current models are prohibitive for drug and RNAi screens due to a slow differentiation time course and resistance to transfection. We asked if we could create a rapid, robust model of adipogenesis to potentially enable rapid functional and obesity therapeutic screens. We generated the clonal population OP9-K, which differentiates rapidly and reproducibly, and displays classic adipocyte morphology: rounded cell shape, lipid accumulation, and coalescence of lipids into a large droplet. We further validate the OP9-K cells as an adipocyte model system by microarray analysis of the differentiating transcriptome. OP9-K differentiates via known adipogenic pathways, involving the transcriptional activation and repression of common adipose markers Plin1, Gata2, C/Ebp alpha and C/Ebp beta and biological pathways, such as lipid metabolism, PPAR gamma signaling, and osteogenesis. We implemented a method to quantify lipid accumulation using automated microscopy and tested the ability of our model to detect alterations in lipid accumulation by reducing levels of the known master adipogenic regulator Ppar gamma. We further utilized our model to query the effects of a novel obesity therapeutic target, the transcription factor SPI1. We determine that reduction in levels of Spi1 leads to an increase in lipid accumulation. We demonstrate rapid, robust differentiation and efficient transfectability of the OP9-K cell model of adipogenesis. Together with our microscopy based lipid accumulation assay, adipogenesis assays can be achieved in just four days' time. The results of this study can contribute to the development of rapid screens with the potential to deepen our understanding of adipose biology and efficiently test obesity therapeutics. C1 [Lane, Jacqueline M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Lane, Jacqueline M.] Brigham & Womens Hosp, Div Sleep Med, Boston, MA 02115 USA. [Lane, Jacqueline M.; Ordovas, Jose M.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Doyle, Jamie R.; Fortin, Jean-Philippe; Kopin, Alan S.] Tufts Med Ctr, Mol Cardiol Res Inst, Mol Pharmacol Res Ctr, Boston, MA 02111 USA. RP Lane, JM (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St, Boston, MA 02114 USA. EM lane@chgr.mgh.harvard.edu FU U.S. Department of Agriculture [58-1950-0-014] FX This material is based upon work supported by the U.S. Department of Agriculture, under agreement No. 58-1950-0-014. Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the U.S. Department of Agriculture. 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 3 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 19 PY 2014 VL 9 IS 11 AR e112123 DI 10.1371/journal.pone.0112123 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU3SG UT WOS:000345533200015 PM 25409310 ER PT J AU Mega, JL Sabatine, MS Antman, EM AF Mega, Jessica L. Sabatine, Marc S. Antman, Elliott M. TI Population and Personalized Medicine in the Modern Era SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID STRATEGY; DISEASE; RISK C1 [Mega, Jessica L.; Sabatine, Marc S.; Antman, Elliott M.] Brigham & Womens Hosp, Div Cardiovasc Med, TIMI Study Grp, Boston, MA 02115 USA. [Mega, Jessica L.; Sabatine, Marc S.; Antman, Elliott M.] Harvard Univ, Sch Med, Boston, MA USA. [Antman, Elliott M.] Amer Heart Assoc, Dallas, TX USA. RP Mega, JL (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM jmega@partners.org NR 8 TC 12 Z9 12 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD NOV 19 PY 2014 VL 312 IS 19 BP 1969 EP 1970 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AU2LT UT WOS:000345450500006 PM 25399267 ER PT J AU Fu, WX Farache, J Clardy, SM Hattori, K Mander, P Lee, K Rioja, I Weissleder, R Prinjha, RK Benoist, C Mathis, D AF Fu, Wenxian Farache, Julia Clardy, Susan M. Hattori, Kimie Mander, Palwinder Lee, Kevin Rioja, Inmaculada Weissleder, Ralph Prinjha, Rab K. Benoist, Christophe Mathis, Diane TI Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and beta cells SO ELIFE LA English DT Article ID NF-KAPPA-B; T-CELL; NOD MICE; BROMODOMAIN INHIBITION; SELECTIVE-INHIBITION; SUPER-ENHANCERS; TRANSCRIPTION FACTORS; DEPENDENT GENES; PAUSE RELEASE; P-TEFB AB Epigenetic modifiers are an emerging class of anti-tumor drugs, potent in multiple cancer contexts. Their effect on spontaneously developing autoimmune diseases has been little explored. We report that a short treatment with I-BET151, a small-molecule inhibitor of a family of bromodomain-containing transcriptional regulators, irreversibly suppressed development of type-1 diabetes in NOD mice. The inhibitor could prevent or clear insulitis, but had minimal influence on the transcriptomes of infiltrating and circulating T cells. Rather, it induced pancreatic macrophages to adopt an anti-inflammatory phenotype, impacting the NF-kappa B pathway in particular. I-BET151 also elicited regeneration of islet beta-cells, inducing proliferation and expression of genes encoding transcription factors key to beta-cell differentiation/function. The effect on beta cells did not require T cell infiltration of the islets. Thus, treatment with I-BET151 achieves a "combination therapy," currently advocated by many diabetes investigators, operating by a novel mechanism that coincidentally dampens islet inflammation and enhances beta-cell regeneration. C1 [Fu, Wenxian; Farache, Julia; Hattori, Kimie; Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA. [Clardy, Susan M.; Weissleder, Ralph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Mander, Palwinder; Lee, Kevin; Rioja, Inmaculada; Prinjha, Rab K.] GlaxoSmithKline, Med Res Ctr, Immunoinflammat TA, Epinova DPU, Stevenage SG1 2NY, Herts, England. [Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA. [Benoist, Christophe; Mathis, Diane] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Mathis, D (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM cbdm@hms.harvard.edu FU NCI NIH HHS [T32 CA079443]; NIAID NIH HHS [P01 AI054904] NR 83 TC 9 Z9 10 U1 3 U2 6 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD NOV 19 PY 2014 VL 3 AR e04631 DI 10.7554/eLife.04631 PG 44 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AU5IA UT WOS:000345639000002 PM 25407682 ER PT J AU Abazari, A Chakraborty, N Hand, S Aksan, A Toner, M AF Abazari, Alireza Chakraborty, Nilay Hand, Steven Aksan, Alptekin Toner, Mehmet TI A Raman Microspectroscopy Study of Water and Trehalose in Spin-Dried Cells SO BIOPHYSICAL JOURNAL LA English DT Article ID MAMMALIAN-CELLS; DESICCATION TOLERANCE; ALPHA,ALPHA-TREHALOSE-WATER SOLUTIONS; DRY STATE; VITRIFICATION; ANHYDROBIOSIS; PRESERVATION; SPECTROSCOPY; STABILITY; LIPOSOMES AB Long-term storage of desiccated nucleated mammalian cells at ambient temperature may be accomplished in a stable glassy state, which can be achieved by removal of water from the biological sample in the presence of glass-forming agents including trehalose. The stability of the glass may be compromised due to a nonuniform distribution of residual water and trehalose within and around the desiccated cells. Thus, quantification of water and trehalose contents at the single-cell level is critical for predicting the glass formation and stability for dry storage. Using Raman microspectroscopy, we estimated the trehalose and residual water contents in the microenvironment of spin-dried cells. Individual cells with or without intracellular trehalose were embedded in a solid thin layer of extracellular trehalose after spin-drying. We found strong evidence suggesting that the residual water was bound at a 2:1 water/trehalose molar ratio in both the extracellular and intracellular milieus. Other than the water associated with trehalose, we did not find any more residual water in the spin-dried sample, intra- or extracellularly. The extracellular trehalose film exhibited characteristics of an amorphous state with a glass transition temperature of similar to 22 degrees C. The intracellular milieu also dried to levels suitable for glass formation at room temperature. These findings demonstrate a method for quantification of water and trehalose in desiccated specimens using confocal Raman microspectroscopy. This approach has broad use in desiccation studies to carefully investigate the relationship of water and trehalose content and distribution with the tolerance to drying in mammalian cells. C1 [Abazari, Alireza; Toner, Mehmet] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA USA. [Abazari, Alireza; Toner, Mehmet] Shriners Hosp Children, Boston, MA USA. [Chakraborty, Nilay] Univ Michigan, Dept Mech Engn, Dearborn, MI 48128 USA. [Hand, Steven] Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA. [Aksan, Alptekin] Univ Minnesota, Dept Mech Engn, Minneapolis, MN 55455 USA. RP Toner, M (reprint author), Ctr Engn Med, 114,16th St, Charlestown, MA 02129 USA. EM mtoner@hms.harvard.edu RI Aksan, Alptekin/C-1579-2014 OI Aksan, Alptekin/0000-0001-9891-1715 FU Natural Sciences and Engineering Research Council (NSERC) of Canada; National Institutes of Health (NIH) [2 R01 DK046270-14A1, 5 R01 GM086886] FX Alireza Abazari holds a postdoctoral fellowship award from Natural Sciences and Engineering Research Council (NSERC) of Canada. This research was also funded by National Institutes of Health (NIH) grants 2 R01 DK046270-14A1 and 5 R01 GM086886. NR 52 TC 1 Z9 1 U1 0 U2 24 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD NOV 18 PY 2014 VL 107 IS 10 BP 2253 EP 2262 DI 10.1016/j.bpj.2014.09.032 PG 10 WC Biophysics SC Biophysics GA AY3CU UT WOS:000347463000003 PM 25418294 ER PT J AU Crandall, CJ Newberry, SJ Diamant, A Lim, YW Gellad, WF Booth, MJ Motala, A Shekelle, PG AF Crandall, Carolyn J. Newberry, Sydne J. Diamant, Allison Lim, Yee-Wei Gellad, Walid F. Booth, Marika J. Motala, Aneesa Shekelle, Paul G. TI Comparative Effectiveness of Pharmacologic Treatments to Prevent Fractures An Updated Systematic Review SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID BONE-MINERAL DENSITY; BISPHOSPHONATE-RELATED OSTEONECROSIS; ATYPICAL FEMORAL FRACTURES; YEARLY ZOLEDRONIC ACID; LONG-TERM ALENDRONATE; POSTMENOPAUSAL WOMEN; PRIMARY OSTEOPOROSIS; ATRIAL-FIBRILLATION; ORAL BISPHOSPHONATES; VERTEBRAL FRACTURE AB Background: Osteoporosis is a major contributor to the propensity to fracture among older adults, and various pharmaceuticals are available to treat it. Purpose: To update a review about the benefits and harms of pharmacologic treatments used to prevent fractures in adults at risk. Data Sources: Multiple computerized databases were searched between 2 January 2005 and 4 March 2014 for English-language studies. Study Selection: Trials, observational studies, and systematic reviews. Data Extraction: Duplicate extraction and assessment of data about study characteristics, outcomes, and quality. Data Synthesis: From more than 52 000 titles screened, 315 articles were included in this update. There is high-strength evidence that bisphosphonates, denosumab, and teriparatide reduce fractures compared with placebo, with relative risk reductions from 0.40 to 0.60 for vertebral fractures and 0.60 to 0.80 for nonvertebral fractures. Raloxifene has been shown in placebo-controlled trials to reduce only vertebral fractures. Since 2007, there is a newly recognized adverse event of bisphosphonate use: atypical subtrochanteric femur fracture. Gastrointestinal side effects, hot flashes, thromboembolic events, and infections vary among drugs. Limitations: Few studies have directly compared drugs used to treat osteoporosis. Data in men are very sparse. Costs were not assessed. Conclusion: Good-quality evidence supports that several medications for bone density in osteoporotic range and/or preexisting hip or vertebral fracture reduce fracture risk. Side effects vary among drugs, and the comparative effectiveness of the drugs is unclear. C1 Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RAND Corp, Santa Monica, CA USA. Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. RAND Corp, Pittsburgh Vet Affairs Med Ctr, Pittsburgh, PA USA. Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. RP Crandall, CJ (reprint author), Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, David Geffen Sch Med, 911 Broxton Ave,1st Floor, Los Angeles, CA 90024 USA. EM ccrandall@mednet.ucla.edu FU Agency for Healthcare Research and Quality (AHRQ) [HHSA290200710062I] FX By the Agency for Healthcare Research and Quality (AHRQ) (HHSA290200710062I). No statement in this article should be construed as an official position of AHRQ or the U.S. Department of Health and Human Services. NR 157 TC 41 Z9 44 U1 1 U2 16 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD NOV 18 PY 2014 VL 161 IS 10 BP 711 EP U163 DI 10.7326/M14-0317 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA AX9TT UT WOS:000347245600028 PM 25199883 ER PT J AU Valcz, G Patai, AV Kalmar, A Peterfia, B Furi, I Wichmann, B Muzes, G Sipos, F Krenacs, T Mihaly, E Spisak, S Molnar, B Tulassay, Z AF Valcz, Gabor Patai, Arpad V. Kalmar, Alexandra Peterfia, Balint Furi, Istvan Wichmann, Barnabas Muzes, Gyoergyi Sipos, Ferenc Krenacs, Tibor Mihaly, Emese Spisak, Sandor Molnar, Bela Tulassay, Zsolt TI Myofibroblast-Derived SFRP1 as Potential Inhibitor of Colorectal Carcinoma Field Effect SO PLOS ONE LA English DT Article ID FRIZZLED-RELATED PROTEIN-1; WNT SIGNALING PATHWAY; RENAL-CELL CARCINOMA; COLON-CANCER; BETA-CATENIN; PROMOTER METHYLATION; SPEMANN ORGANIZER; WNT/BETA-CATENIN; EPITHELIAL-CELLS; PROSTATE-CANCER AB Epigenetic changes of stromal-epithelial interactions are of key importance in the regulation of colorectal carcinoma (CRC) cells and morphologically normal, but genetically and epigenetically altered epithelium in normal adjacent tumor (NAT) areas. Here we demonstrated retained protein expression of well-known Wnt inhibitor, secreted frizzled-related protein 1 (SFRP1) in stromal myofibroblasts and decreasing epithelial expression from NAT tissues towards the tumor. SFRP1 was unmethylated in laser microdissected myofibroblasts and partially hypermethylated in epithelial cells in these areas. In contrast, we found epigenetically silenced myofibroblast-derived SFRP1 in CRC stroma. Our results suggest that the myofibroblast-derived SFRP1 protein might be a paracrine inhibitor of epithelial proliferation in NAT areas and loss of this signal may support tumor proliferation in CRC. C1 [Valcz, Gabor; Wichmann, Barnabas; Molnar, Bela; Tulassay, Zsolt] Hungarian Acad Sci, Mol Med Res Unit, Budapest, Hungary. [Patai, Arpad V.; Kalmar, Alexandra; Peterfia, Balint; Furi, Istvan; Muzes, Gyoergyi; Sipos, Ferenc; Mihaly, Emese; Molnar, Bela; Tulassay, Zsolt] Semmelweis Univ, Dept Internal Med 2, H-1085 Budapest, Hungary. [Krenacs, Tibor] Semmelweis Univ, Dept Pathol & Expt Canc Res 1, H-1085 Budapest, Hungary. [Spisak, Sandor] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Patai, AV (reprint author), Semmelweis Univ, Dept Internal Med 2, H-1085 Budapest, Hungary. EM arpad.patai@gmail.com FU National Office for Research and Technology, Hungary [TECH08-AI/2-2008_0114] FX This study was supported in part by the National Office for Research and Technology, Hungary, Grant number: TECH08-AI/2-2008_0114. Funder's website:www.magzrt.hu. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no other funding to this study. NR 45 TC 9 Z9 9 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 18 PY 2014 VL 9 IS 11 AR e106143 DI 10.1371/journal.pone.0106143 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AX7UZ UT WOS:000347121300001 PM 25405986 ER PT J AU Min, CH Paganetti, H Winey, BA Adams, J MacDonald, SM Tarbell, NJ Yock, TI AF Min, Chul Hee Paganetti, Harald Winey, Brian A. Adams, Judith MacDonald, Shannon M. Tarbell, Nancy J. Yock, Torunn I. TI Evaluation of permanent alopecia in pediatric medulloblastoma patients treated with proton radiation SO RADIATION ONCOLOGY LA English DT Article DE Permanent alopecia; Proton therapy; Pediatric medulloblastoma; Monte Carlo simulation ID QUALITY-OF-LIFE; THERAPY; RADIOTHERAPY; CHILDHOOD; SURVIVORS AB Background: To precisely calculate skin dose and thus to evaluate the relationship between the skin dose and permanent alopecia for pediatric medulloblastoma patients treated with proton beams. Methods: The dosimetry and alopecia outcomes of 12 children with medulloblastoma (ages 4-15 years) comprise the study cohort. Permanent alopecia was assessed and graded after completion of the entire therapy. Skin threshold doses of permanent alopecia were calculated based on the skin dose from the craniospinal irradiation (CSI) plan using the concept of generalized equivalent uniform dose (gEUD) and accounting for chemotherapy intensity. Monte Carlo simulations were employed to accurately assess uncertainties due to beam range prediction and secondary particles. Results: Increasing the dose of the CSI field or the dose given by the boost field to the posterior fossa increased total skin dose delivered in that region. It was found that permanent alopecia could be correlated with CSI dose with a threshold of about 21 Gy (relative biological effectiveness, RBE) with high dose chemotherapy and 30 Gy (RBE) with conventional chemotherapy. Conclusions: Our results based on 12 patients provide a relationship between the skin dose and permanent alopecia for pediatric medulloblastoma patients treated with protons. The alopecia risk as assessed with gEUD could be predicted based on the treatment plan information. C1 [Min, Chul Hee; Paganetti, Harald; Winey, Brian A.; Adams, Judith; MacDonald, Shannon M.; Tarbell, Nancy J.; Yock, Torunn I.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Min, Chul Hee; Paganetti, Harald; Winey, Brian A.; Adams, Judith; MacDonald, Shannon M.; Tarbell, Nancy J.; Yock, Torunn I.] Harvard Univ, Sch Med, Boston, MA USA. [Min, Chul Hee] Yonsei Univ, Dept Radiat Convergence Engn, Wonju, South Korea. RP Yock, TI (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM TYOCK@mgh.harvard.edu FU National Cancer Institute [NIH/NCI PO1 CA21239]; National Institutes of Health FX This project was supported in part by a grant (NIH/NCI PO1 CA21239) from the National Cancer Institute and National Institutes of Health. NR 14 TC 3 Z9 3 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD NOV 18 PY 2014 VL 9 AR 220 DI 10.1186/s13014-014-0220-8 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW5FO UT WOS:000346301600001 PM 25403752 ER PT J AU Laulicht, B Traverso, G Deshpande, V Langer, R Karp, JM AF Laulicht, Bryan Traverso, Giovanni Deshpande, Vikram Langer, Robert Karp, Jeffrey M. TI Simple battery armor to protect against gastrointestinal injury from accidental ingestion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE coin cell battery ingestion; battery-induced injury; ingestion of foreign bodies; button battery safety; esophageal injury ID MANAGEMENT AB Inadvertent battery ingestion in children and the associated morbidity and mortality results in thousands of emergency room visits every year. Given the risk for serious electrochemical burns within hours of ingestion, the current standard of care for the treatment of batteries in the esophagus is emergent endoscopic removal. Safety standards now regulate locked battery compartments in toys, which have resulted in a modest reduction in inadvertent battery ingestion; specifically, 3,461 ingestions were reported in 2009, and 3,366 in 2013. Aside from legislation, minimal technological development has taken place at the level of the battery to limit injury. We have constructed a waterproof, pressure-sensitive coating, harnessing a commercially available quantum tunneling composite. Quantum tunneling composite coated (QTCC) batteries are nonconductive in the low-pressure gastrointestinal environment yet conduct within the higher pressure of standard battery housings. Importantly, this coating technology enables most battery-operated equipment to be powered without modification. If these new batteries are swallowed, they limit the external electrolytic currents responsible for tissue injury. We demonstrate in a large-animal model a significant decrease in tissue injury with QTCC batteries compared with uncoated control batteries. In summary, here we describe a facile approach to increasing the safety of batteries by minimizing the risk for electrochemical burn if the batteries are inadvertently ingested, without the need for modification of most battery-powered devices. C1 [Laulicht, Bryan; Karp, Jeffrey M.] Harvard Univ, Sch Med, Div Biomed Engn, Dept Med,Ctr Regenerat Therapeut,Brigham & Womens, Boston, MA 02115 USA. [Laulicht, Bryan; Langer, Robert; Karp, Jeffrey M.] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Traverso, Giovanni] Harvard Univ, Massachusetts Gen Hosp, Div Gastroenterol, Sch Med, Boston, MA 02114 USA. [Traverso, Giovanni; Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Traverso, Giovanni; Langer, Robert] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Deshpande, Vikram] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Karp, Jeffrey M.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Langer, R (reprint author), MIT, Harvard MIT Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM rlanger@mit.edu; jmkarp@partners.org FU NIH [DE013023, EB000244, GM086433, T32 DK 7191-38 S1] FX We thank Janet Freilich for her thoughtful discussions and writing assistance. We thank Hao-Yu Lin for his technical assistance with electron microscopy, and Richard Gedney and Ross Barman for their technical assistance. We thank Pentax for providing the endoscopic equipment used for this research, and in particular, Mike Fina for facilitating access to the equipment. This work was funded in part by NIH Grants DE013023 and EB000244 (to R. L.), Grant GM086433 (to J.M.K.), and Grant T32 DK 7191-38 S1 (to G.T.). NR 14 TC 2 Z9 2 U1 0 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 NOV 18 PY 2014 VL 111 IS 46 BP 16490 EP 16495 DI 10.1073/pnas.1418423111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT7ZL UT WOS:000345153300066 PM 25368176 ER PT J AU Yashiro-Ohtani, Y Wang, HF Zang, CZ Arnett, KL Bailis, W Ho, YG Knoechel, B Lanauze, C Louis, L Forsyth, KS Cheng, SJ Chung, Y Schug, J Blobel, GA Liebhaber, SA Bernstein, BE Blacklow, SC Liu, XS Aster, JC Pear, WS AF Yashiro-Ohtani, Yumi Wang, Hongfang Zang, Chongzhi Arnett, Kelly L. Bailis, Will Ho, Yugong Knoechel, Birgit Lanauze, Claudia Louis, Lumena Forsyth, Katherine S. Cheng, Sujun Chung, Yoonjie Schug, Jonathan Blobel, Gerd A. Liebhaber, Stephen A. Bernstein, Bradley E. Blacklow, Stephen C. Liu, Xiaole Shirley Aster, Jon C. Pear, Warren S. TI Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE enhancer; gene regulation; chromatin; transcription; Brd4 ID ACUTE LYMPHOBLASTIC-LEUKEMIA; MARGINAL ZONE LYMPHOMA; C-MYC; SUPER-ENHANCERS; TRANSCRIPTION; TARGET; EXPRESSION; COMPLEXES; CHROMATIN; GENOME AB Notch is needed for T-cell development and is a common oncogenic driver in T-cell acute lymphoblastic leukemia. The protooncogene c-Myc (Myc) is a critical target of Notch in normal and malignant pre-T cells, but how Notch regulates Myc is unknown. Here, we identify a distal enhancer located >1 Mb 3' of human and murine Myc that binds Notch transcription complexes and physically interacts with the Myc proximal promoter. The Notch1 binding element in this region activates reporter genes in a Notch-dependent, cell-context-specific fashion that requires a conserved Notch complex binding site. Acute changes in Notch activation produce rapid changes in H3K27 acetylation across the entire enhancer (a region spanning >600 kb) that correlate with Myc expression. This broad Notch-influenced region comprises an enhancer region containing multiple domains, recognizable as discrete H3K27 acetylation peaks. Leukemia cells selected for resistance to Notch inhibitors express Myc despite epigenetic silencing of enhancer domains near the Notch transcription complex binding sites. Notch-independent expression of Myc in resistant cells is highly sensitive to inhibitors of bromodomain containing 4 (Brd4), a change in drug sensitivity that is accompanied by preferential association of the Myc promoter with more 3' enhancer domains that are strongly dependent on Brd4 for function. These findings indicate that altered long-range enhancer activity can mediate resistance to targeted therapies and provide a mechanistic rationale for combined targeting of Notch and Brd4 in leukemia. C1 [Yashiro-Ohtani, Yumi; Bailis, Will; Lanauze, Claudia; Louis, Lumena; Forsyth, Katherine S.; Chung, Yoonjie; Pear, Warren S.] Univ Penn, Abramson Family Canc Res Inst, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Ho, Yugong; Schug, Jonathan; Liebhaber, Stephen A.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Blobel, Gerd A.] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Wang, Hongfang; Aster, Jon C.] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Arnett, Kelly L.; Blacklow, Stephen C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Knoechel, Birgit] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA 02115 USA. [Bernstein, Bradley E.] Harvard Univ, Sch Med, Broad Inst, Boston, MA 02115 USA. [Bernstein, Bradley E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. [Zang, Chongzhi; Liu, Xiaole Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Blacklow, Stephen C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Cheng, Sujun] Tongji Univ, Sch Life Sci & Technol, Dept Bioinformat, Shanghai 200092, Peoples R China. RP Aster, JC (reprint author), Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. EM jaster@partners.org; wpear@mail.med.upenn.edu RI Zang, Chongzhi/D-1445-2011 FU Leukemia and Lymphoma Society; St. Baldrick's Fellowship [T32HL007574]; National Institutes of Health [P01 CA119070, R01AI047833, R01HD25147, ENCODE U54 HG004570]; Leukemia and Lymphoma Society Specialized Center of Research; [T32HD007516]; [1F31CA165813] FX We thank Junwei Shi and Chris Vakoc (Cold Spring Harbor Laboratory) for sharing information prior to publication. The University of Pennsylvania Mouse Husbandry Core (University Laboratory Animal Resources), the Abramson Cancer Center Flow Cytometry Core (P30-CA016520), the Abramson Family Cancer Research Institute Core, the Functional Genomics Core, and the NIH/National Institute of Diabetes and Digestive and Kidney Diseases P30 Center for Molecular Studies in Digestive and Liver Diseases (P30-DK050306), contributed to this study. This work was supported by a Leukemia and Lymphoma Society fellowship (to C.Z.); Fellowships T32HD007516 and 1F31CA165813 (to W. B.); St. Baldrick's Fellowship T32HL007574 (to B. K.); National Institutes of Health Grants P01 CA119070 (to J.C.A., W. S. P., S. C. B., and X. S. L.), R01AI047833 (to W. S. P.), R01HD25147 (to S. A. L.), and ENCODE U54 HG004570 (to B. E. B.); and a Leukemia and Lymphoma Society Specialized Center of Research grant (to J.C.A. and B.E.B.). NR 39 TC 30 Z9 30 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD NOV 18 PY 2014 VL 111 IS 46 BP E4946 EP E4953 DI 10.1073/pnas.1407079111 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT7ZL UT WOS:000345153300009 PM 25369933 ER PT J AU Jubelt, LE Graham, J Maeng, DD Li, HL Epstein, AJ Metlay, JP AF Jubelt, Lindsay E. Graham, Jove Maeng, Daniel D. Li, Huilin Epstein, Andrew J. Metlay, Joshua P. TI Patient Ratings of Case Managers in a Medical Home: Associations With Patient Satisfaction and Health Care Utilization SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID VOLUNTARY DISENROLLMENT; REPORTED EXPERIENCE; COMMUNICATION; BENEFICIARIES; OUTCOMES; QUALITY; RISK; HOSPITALIZATION; PERCEPTIONS; PREDICTORS AB Background: Case managers are employed in medical homes to coordinate care for clinically complex patients. Objective: To measure the association of patient perceptions of case manager performance with overall satisfaction and subsequent health care utilization. Design: Retrospective cohort study. Setting: Integrated health system in Pennsylvania. Patients: Members of the health system-owned health plan who 1) received primary care in the health system's clinics, 2) were exposed to clinic-embedded case managers, and 3) completed a survey of satisfaction with care. Measurements: Survey assessment of case manager performance and overall satisfaction with care and claims-based assessment of case manager performance and subsequent hospitalizations or emergency department visits. Survey measures were dichotomized into very good versus less than very good. Results: A total of 1755 patients (44%) completed the survey and 1415 met study criteria. Survey respondents who reported very good ratings of case manager performance across all items had a higher probability of reporting very good overall satisfaction with care (92.2% vs. 62.5%; P < 0.001) and had a lower incidence of subsequent emergency department visits (incidence rate ratio, 0.79 [95% CI, 0.64 to 0.98]; P = 0.029) but not hospitalizations (incidence rate ratio, 0.92 [CI, 0.75 to 1.11]; P = 0.37) up to 2 years after the survey compared with survey respondents who reported less-than-very good case manager performance on 1 or more questions on the survey. Limitations: Satisfaction data demonstrated substantial ceiling effects. Survey nonresponse may have introduced bias in the results. Conclusion: Patients' favorable perceptions of case managers are associated with higher overall satisfaction with care and may lower risk for future acute care use. C1 [Epstein, Andrew J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Li, Huilin] NYU, Langone Med Ctr, Dept Populat Hlth, New York, NY 10016 USA. [Graham, Jove] Geisinger Ctr Hlth Res, Danville, PA 17822 USA. [Maeng, Daniel D.] Geisinger Hlth Syst, Danville, PA 17822 USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Jubelt, LE (reprint author), NYU, Sch Med, Dept Populat Hlth, 1 Pk Ave,10th Floor, New York, NY 10016 USA. EM lindsay.jubelt@nyumc.org FU Robert Wood Johnson Foundation; U.S. Department of Veterans Affairs FX Robert Wood Johnson Foundation and the U.S. Department of Veterans Affairs. NR 36 TC 2 Z9 2 U1 1 U2 4 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 NOV 18 PY 2014 VL 161 IS 10 SU S BP S59 EP S65 DI 10.7326/M13-3007 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA CW3RR UT WOS:000364909900009 PM 25402405 ER PT J AU Kullgren, JT Dicks, TN Fu, XY Richardson, D Tzanis, GL Tobi, M Marcus, SC AF Kullgren, Jeffrey T. Dicks, Tanisha N. Fu, Xiaoying Richardson, Diane Tzanis, George L. Tobi, Martin Marcus, Steven C. TI Financial Incentives for Completion of Fecal Occult Blood Tests Among Veterans A 2-Stage, Pragmatic, Cluster, Randomized, Controlled Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID COLORECTAL-CANCER; LONGITUDINAL ADHERENCE; CLINICAL-TRIALS; WEIGHT-LOSS; INTERVENTION; DECISION; BEHAVIOR; QUALITY; IMPACT; COLON AB Background: Rates of patient completion of fecal occult blood tests (FOBTs) are often low. Objective: To examine whether financial incentives increase rates of FOBT completion. Design: A 2-stage, parallel-design, pragmatic, cluster, randomized, controlled trial with clustering by clinic day (ClinicalTrials.gov: NCT01516489). Setting: Primary care clinic of the Philadelphia Veterans Affairs Medical Center. Patients: 1549 patients who were prescribed an FOBT (unique samples of 713 patients for stage 1 and 836 patients for stage 2). Intervention: In stage 1, patients were assigned to usual care or receipt of $5, $10, or $20 for FOBT completion. In stage 2, different patients were assigned to usual care or receipt of $5, a 1 in 10 chance of $50, or entry into a $500 raffle for FOBT completion. Measurements: Primary outcome was FOBT completion within 30 days. Preplanned subgroup analyses examined 30-day FOBT completion by previous nonadherence to a prescribed FOBT. Results: In stage 1, none of the incentives increased rates of FOBT completion. In stage 2, a 1 in 10 chance of $50 increased FOBT completion compared with usual care (between-group difference, 19.6% [95% CI, 10.7% to 28.6%]; P < 0.001) but a $5 fixed payment and entry into a raffle for $500 did not. None of the incentives were more effective among patients who had previously been nonadherent to an FOBT than among patients who had previously completed an FOBT. Limitations: Single Veterans Affairs medical center setting, short follow-up, use of 3-sample rather than 1-sample immunochemical FOBTs, limited power to detect small effects of incentives, inability to evaluate cost-effectiveness. Conclusion: A 1 in 10 chance of receiving $50 was effective at increasing rates of FOBT completion, but 5 other tested incentives were not. C1 [Kullgren, Jeffrey T.] Vet Affairs Ann Arbor Healthcare Syst, Vet Affairs Ctr Clin Management Res, Ann Arbor, MI 48113 USA. Univ Michigan, Sch Med, Ann Arbor, MI USA. [Dicks, Tanisha N.; Fu, Xiaoying; Richardson, Diane; Tzanis, George L.; Tobi, Martin] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Marcus, Steven C.] Univ Penn, Sch Social Policy & Practice, Philadelphia, PA 19104 USA. RP Kullgren, JT (reprint author), Vet Affairs Ann Arbor Healthcare Syst, Vet Affairs Ctr Clin Management Res, POB 130170, Ann Arbor, MI 48113 USA. EM jkullgre@med.umich.edu FU Veterans Affairs Center for Health Equity Research and Promotion FX Veterans Affairs Center for Health Equity Research and Promotion. NR 44 TC 7 Z9 7 U1 1 U2 3 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 NOV 18 PY 2014 VL 161 IS 10 SU S BP S35 EP S43 DI 10.7326/M13-3015 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CW3RR UT WOS:000364909900006 PM 25402401 ER PT J AU Patel, MS Day, S Small, DS Howell, JT Lautenbach, GL Nierman, EH Volpp, KG AF Patel, Mitesh S. Day, Susan Small, Dylan S. Howell, John T., III Lautenbach, Gillian L. Nierman, Eliot H. Volpp, Kevin G. TI Using Default Options Within the Electronic Health Record to Increase the Prescribing of Generic-Equivalent Medications A Quasi-experimental Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CARE; PHYSICIANS; DECISIONS; ECONOMICS; PATTERNS; POWER AB Background: Low-value services, such as prescribing brand-name medications that have existing generic equivalents, contribute to unnecessary health care spending. Objective: To evaluate the association of an intervention by using the electronic health record with provider prescription of generic-equivalent medications. Design: Quasi-experimental study. Setting: General internal medicine (IM) (n = 2) and family medicine (FM) (n = 2) clinics at the University of Pennsylvania from June 2011 to September 2012. Participants: Attending physicians (IM, n = 38; FM, n = 17) and residents (IM, n = 166; FM, n = 34). Intervention: In January 2012, the default in the electronic health record was changed for IM providers from displaying brand and generic medications to displaying initially only generics, with the ability to opt out. Measurements: Monthly prescriptions of brand-name and generic-equivalent beta-blockers, statins, and proton-pump inhibitors. Results: During the preintervention period, FM providers had slightly higher rates of generic medication prescribing (range, 80.8% to 85.5%) than did IM providers (range, 75.4% to 79.6%), but both groups had similar trends. In the postintervention period relative to the preintervention period, IM providers had an increase in generic prescribing compared with FM providers for all 3 medications combined (5.4 percentage points [95% CI, 2.2 to 8.7 percentage points]; P < 0.001), beta-blockers (10.5 percentage points [CI, 5.8 to 15.2 percentage points]; P < 0.001), and statins (4.0 percentage points [CI, 0.4 to 7.6 percentage points]; P = 0.002). Results for proton-pump inhibitors (2.1 percentage points [CI, -3.7 to 8.0 percentage points]; P = 0.47) were not significant. Subset analyses revealed similar findings for attending physicians. Among residents, however, results were imprecise, with wide CIs. Limitation: Observational single-center evaluation, comparison groups that represented different specialties, and a small subset of medication classes studied. Conclusion: The use of default options was an effective method to increase the odds of prescribing generic medication equivalents for beta-blockers and statins. C1 [Patel, Mitesh S.; Day, Susan; Lautenbach, Gillian L.; Nierman, Eliot H.; Volpp, Kevin G.] Univ Penn, Perelman Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Small, Dylan S.] Univ Penn, Dept Stat, Wharton Sch, Philadelphia, PA 19104 USA. [Howell, John T., III] Univ Penn, Off Chief Med Informat Officer, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Patel, MS (reprint author), Univ Penn, Perelman Sch Med, Div Gen Internal Med, 423 Guardian Dr,12th Floor,Blockley Hall, Philadelphia, PA 19104 USA. EM mpatel@upenn.edu FU U.S. Department of Veterans Affairs; Robert Wood Johnson Foundation FX U.S. Department of Veterans Affairs and Robert Wood Johnson Foundation. NR 35 TC 11 Z9 11 U1 2 U2 6 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 NOV 18 PY 2014 VL 161 IS 10 SU S BP S44 EP S52 DI 10.7326/M13-3001 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA CW3RR UT WOS:000364909900007 PM 25402402 ER PT J AU Velardi, E Tsai, JJ Holland, AM Wertheimer, T Yu, VWC Zakrzewski, JL Tuckett, AZ Singer, NV West, ML Smith, OM Young, LF Kreines, FM Levy, ER Boyd, RL Scadden, DT Dudakov, JA van den Brink, MRM AF Velardi, Enrico Tsai, Jennifer J. Holland, Amanda M. Wertheimer, Tobias Yu, Vionnie W. C. Zakrzewski, Johannes L. Tuckett, Andrea Z. Singer, Natalie V. West, Mallory L. Smith, Odette M. Young, Lauren F. Kreines, Fabiana M. Levy, Emily R. Boyd, Richard L. Scadden, David T. Dudakov, Jarrod A. van den Brink, Marcel R. M. TI Sex steroid blockade enhances thymopoiesis by modulating Notch signaling SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID BONE-MARROW-TRANSPLANTATION; T-CELL DEVELOPMENT; DELTA-LIKE 4; IMMUNE RECONSTITUTION; THYMOCYTE DEVELOPMENT; LINEAGE COMMITMENT; EPITHELIAL-CELLS; THYMUS; DIFFERENTIATION; REGENERATION AB Paradoxical to its importance for generating a diverse T cell repertoire, thymic function progressively declines throughout life. This process has been at least partially attributed to the effects of sex steroids, and their removal promotes enhanced thymopoiesis and recovery from immune injury. We show that one mechanism by which sex steroids influence thymopoiesis is through direct inhibition in cortical thymic epithelial cells (cTECs) of Delta-like 4 (Dll4), a Notch ligand crucial for the commitment and differentiation of T cell progenitors in a dose-dependent manner. Consistent with this, sex steroid ablation (SSA) led to increased expression of Dll4 and its downstream targets. Importantly, SSA induced by luteinizing hormone-releasing hormone (LHRH) receptor antagonism bypassed the surge in sex steroids caused by LHRH agonists, the gold standard for clinical ablation of sex steroids, thereby facilitating increased Dll4 expression and more rapid promotion of thymopoiesis. Collectively, these findings not only reveal a novel mechanism underlying improved thymic regeneration upon SSA but also offer an improved clinical strategy for successfully boosting immune function. C1 [Velardi, Enrico; Tsai, Jennifer J.; Holland, Amanda M.; Wertheimer, Tobias; Zakrzewski, Johannes L.; Tuckett, Andrea Z.; Singer, Natalie V.; West, Mallory L.; Smith, Odette M.; Young, Lauren F.; Kreines, Fabiana M.; Levy, Emily R.; Dudakov, Jarrod A.; van den Brink, Marcel R. M.] Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10065 USA. [van den Brink, Marcel R. M.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Zakrzewski, Johannes L.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA. [Velardi, Enrico] Univ Perugia, Dept Clin & Expt Med, I-06122 Perugia, Italy. [Tsai, Jennifer J.; Holland, Amanda M.; van den Brink, Marcel R. M.] Weill Cornell Med Coll, Dept Immunol & Microbial Pathogenesis, New York, NY 10021 USA. [Holland, Amanda M.] Univ Birmingham, Sch Med, MRC Ctr Immune Regulat, Inst Biomed Res, Birmingham B15 2TT, W Midlands, England. [Wertheimer, Tobias] Univ Freiburg, Med Ctr, Dept Med, Div Hematol & Oncol, D-79106 Freiburg, Germany. [Yu, Vionnie W. C.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Yu, Vionnie W. C.; Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Yu, Vionnie W. C.; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Boyd, Richard L.; Dudakov, Jarrod A.] Monash Univ, Dept Anat & Dev Biol, Clayton, Vic 3800, Australia. RP Velardi, E (reprint author), Mem Sloan Kettering Canc Ctr, Program Immunol, New York, NY 10065 USA. EM velardie@mskcc.org; dudakovj@mskcc.org; vandenbm@mskcc.org OI Dudakov, Jarrod/0000-0001-6220-5632; VELARDI, ENRICO/0000-0001-8383-0453 FU National Institutes of Health [K99-CA176376, R01-HL069929, R01-AI100288, R01-AI080455, R01-AI101406, P01-CA023766]; NIAID [HHSN272200900059C]; Experimental Therapeutics Center of MSKCC; Lymphoma Foundation; Alex's Lemonade Stand; Geoffrey Beene Cancer Research Center at MSKCC; Susan and Peter Solomon Divisional Genomics Program; Australian National Health and Medical Research Council; American Society for Hematology Scholar Award; Italian Foundation for Cancer Research; Italian Society of Pharmacology; American Society of Bone Marrow Transplantation new investigator award; Cancer Research Institute; Boehringer Ingelheim Fonds MD fellowship; European Union [602587]; Associazione Italiana per la Ricerca sul Cancro FX This research was supported by National Institutes of Health award numbers K99-CA176376 (J.A. Dudakov), R01-HL069929 (M.R.M. van den Brink), R01-AI100288 (M. R. M. van den Brink), R01-AI080455 (M. R. M. van den Brink), R01-AI101406 (M. R. M. van den Brink), and P01-CA023766 (M. R. M. van den Brink), and NIAID Contract HHSN272200900059C (M. R. M. van den Brink). Support was also received from The Experimental Therapeutics Center of MSKCC funded by Mr. William H. Goodwin and Mrs. Alice Goodwin, The Lymphoma Foundation, Alex's Lemonade Stand, The Geoffrey Beene Cancer Research Center at MSKCC, and The Susan and Peter Solomon Divisional Genomics Program. J.A. Dudakov was supported by a fellowship from the Australian National Health and Medical Research Council and an American Society for Hematology Scholar Award. E. Velardi was supported by fellowships from the Italian Foundation for Cancer Research, the Italian Society of Pharmacology, and an American Society of Bone Marrow Transplantation new investigator award. J. J. Tsai was supported by the Tumor Immunology Predoctoral Fellowship Training Grant from the Cancer Research Institute. T. Wertheimer was supported by a Boehringer Ingelheim Fonds MD fellowship. This project has received funding from the European Union's Seventh Programme for research, technological development, and demonstration under grant agreement no. 602587. NR 38 TC 16 Z9 16 U1 0 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD NOV 17 PY 2014 VL 211 IS 12 BP 2341 EP 2349 DI 10.1084/jem.20131289 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AT9TL UT WOS:000345268800007 PM 25332287 ER PT J AU Anand, S Ebner, J Warren, CB Raam, MS Piliang, M Billings, SD Maytin, EV AF Anand, Sanjay Ebner, John Warren, Christine B. Raam, Manu S. Piliang, Melissa Billings, Steven D. Maytin, Edward V. TI C/EBP Transcription Factors in Human Squamous Cell Carcinoma: Selective Changes in Expression of Isoforms Correlate with the Neoplastic State SO PLOS ONE LA English DT Article ID BINDING-PROTEIN-BETA; MAMMARY EPITHELIAL-CELLS; BREAST-CANCER; TUMOR-SUPPRESSOR; GENE-EXPRESSION; IN-VIVO; PHOTODYNAMIC THERAPY; INHIBITORY PROTEIN; SKIN TUMORIGENESIS; DOWN-REGULATION AB The CCAAT/Enhancer Binding Proteins (C/EBPs) are a family of leucine-zipper transcription factors that regulate physiological processes such as energy metabolism, inflammation, cell cycle, and the development and differentiation of several tissues including skin. Recently, a role for C/EBPs in tumor cell proliferation and differentiation has been proposed, but the incomplete characterization in the literature of multiple translational isoforms of these proteins has made interpretation of these roles difficult. Therefore, we have carefully reexamined C/EBP isoform expression in human non-melanoma skin cancers. C/EBP alpha, C/EBP beta, and C/EBP delta were analyzed histologically in squamous cell carcinomas (SCC). The individual isoforms of C/EBP alpha and C/EBP beta were examined by immunofluorescent digital imaging, western blotting and DNA binding activity (electrophoretic mobility shift analysis). Expression of all C/EBP family proteins was decreased in SCC tumors. Suppression was greatest for C/EBP alpha, less for C/EBP beta, and least for C/EBP delta. Western analyses confirmed that C/EBP alpha p42 and p30 isoforms were decreased. For C/EBP beta, only the abundant full-length isoform (C/EBP beta-1, LAP*, 55 kD) was reduced, whereas the smaller isoforms, C/EBP beta-2 (LAP, 48 kD) and C/EBP beta-3 (LIP, 20 kD), which are predominantly nuclear, were significantly increased in well-and moderately-differentiated SCC (up to 14-fold for C/EBP beta-3). These elevations correlated with increases in PCNA, a marker of proliferation. Although C/EBP beta displayed increased post-translational modifications in SCC, phosphorylation of C/EBP beta-1 (Thr 235) was not altered. C/EBP-specific DNA binding activity in nuclear and whole-cell extracts of cultured cells and tumors was predominantly attributable to C/EBP beta. In summary, two short C/EBP beta isoforms, C/EBP beta-2 and C/EBP beta-3, represent strong candidate markers for epithelial skin malignancy, due to their preferential expression in carcinoma versus normal skin, and their strong correlation with tumor proliferation. C1 [Anand, Sanjay; Ebner, John; Warren, Christine B.; Piliang, Melissa; Billings, Steven D.; Maytin, Edward V.] Cleveland Clin, Dept Dermatol, Cleveland, OH 44106 USA. [Anand, Sanjay; Raam, Manu S.; Maytin, Edward V.] Cleveland Clin, Dept Biomed Engn, Cleveland, OH 44106 USA. [Piliang, Melissa; Billings, Steven D.] Cleveland Clin, Dept Anat Pathol, Cleveland, OH 44106 USA. [Maytin, Edward V.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA USA. RP Maytin, EV (reprint author), Cleveland Clin, Dept Dermatol, Cleveland, OH 44106 USA. EM maytine@ccf.org FU National Cancer Institute, of the National Institute of Health [PO1-CA84203] FX This study was funded by the National Cancer Institute, of the National Institute of Health, grant number PO1-CA84203. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 1 Z9 1 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 17 PY 2014 VL 9 IS 11 AR e112073 DI 10.1371/journal.pone.0112073 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT8BL UT WOS:000345158700027 PM 25402211 ER PT J AU Golnabi, AH Harris, RS Venegas, JG Winkler, T AF Golnabi, Amir H. Harris, R. Scott Venegas, Jose G. Winkler, Tilo TI Deep Inspiration and the Emergence of Ventilation Defects during Bronchoconstriction: A Computational Study SO PLOS ONE LA English DT Article ID AIRWAY SMOOTH-MUSCLE; HEALTHY-SUBJECTS; NONASTHMATIC SUBJECTS; METHACHOLINE; ASTHMA; LUNG; INFLATION; VOLUME; RESPONSIVENESS; HETEROGENEITY AB Deep inspirations (DIs) have a dilatory effect on airway smooth muscle (ASM) that helps to prevent or reduce more severe bronchoconstriction in healthy individuals. However, this bronchodilation appears to fail in some asthmatic patients or under certain conditions, and the reason is unclear. Additionally, quantitative effects of the frequency and magnitude of DIs on bronchodilation are not well understood. In the present study, we used a computational model of bronchoconstriction to study the effects of DI volumes, time intervals between intermittent DIs, relative speed of ASM constriction, and ASM activation on bronchoconstriction and the emergence of ventilation defects (VDefs). Our results showed a synergistic effect between the volume of DIs and the time intervals between them on bronchoconstriction and VDefs. There was a domain of conditions with sufficiently large volumes of DIs and short time intervals between them to prevent VDefs. Among conditions without VDefs, larger volumes of DIs resulted in greater airway dilation. Similarly, the time interval between DIs, during which the activated ASM re-constricts, affected the amplitude of periodic changes in airway radii. Both the relative speed of ASM constriction and ASM activation affected what volume of DIs and what time interval between them could prevent the emergence of VDefs. In conclusion, quantitative characteristics of DIs, such as their volume and time interval between them, affect bronchoconstriction and may contribute to difficulties in asthma. Better understanding of the quantitative aspects of DIs may result in novel or improved therapeutic approaches. C1 [Golnabi, Amir H.; Venegas, Jose G.; Winkler, Tilo] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Golnabi, Amir H.; Harris, R. Scott; Venegas, Jose G.; Winkler, Tilo] Harvard Univ, Sch Med, Boston, MA USA. [Harris, R. Scott] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. RP Winkler, T (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM twinkler@mgh.harvard.edu RI Winkler, Tilo/B-5337-2009 OI Winkler, Tilo/0000-0002-7276-5550 FU National Heart, Lung, and Blood Institute of the National Institutes of Health [R01HL087281] FX Research reported in this publication was supported by National Heart, Lung, and Blood Institute of the National Institutes of Health under award number R01HL087281. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 3 Z9 4 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 NOV 17 PY 2014 VL 9 IS 11 AR e112443 DI 10.1371/journal.pone.0112443 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT8BL UT WOS:000345158700044 PM 25402457 ER PT J AU Lee, BC Scadden, DT AF Lee, Byeong Chel Scadden, David T. TI From quiescence to senescence SO CELL CYCLE LA English DT Editorial Material ID P2Y(14) RECEPTOR; CHEMOTAXIS; EXPRESSION C1 [Lee, Byeong Chel] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. [Lee, Byeong Chel] Univ Pittsburgh, Sch Med, Dept Med, Div Hematol & Oncol, Pittsburgh, PA 15213 USA. [Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Scadden, David T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA USA. [Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Lee, BC (reprint author), Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. EM leeb4@upmc.edu; david_scadden@harvard.edu NR 7 TC 0 Z9 0 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD NOV 15 PY 2014 VL 13 IS 22 BP 3469 EP 3470 DI 10.4161/15384101.2014.980696 PG 2 WC Cell Biology SC Cell Biology GA AZ6KM UT WOS:000348328800003 PM 25493411 ER PT J AU Abedalthagafi, MS Merrill, PH Bi, WL Jones, RT Listewnik, ML Ramkissoon, SH Thorner, AR Dunn, IF Beroukhim, R Alexander, BM Brastianos, PK Francis, JM Folkerth, RD Ligon, KL Van Hummelen, P Ligon, AH Santagata, S AF Abedalthagafi, Malak S. Merrill, Parker H. Bi, Wenya Linda Jones, Robert T. Listewnik, Marc L. Ramkissoon, Shakti H. Thorner, Aaron R. Dunn, Ian F. Beroukhim, Rameen Alexander, Brian M. Brastianos, Priscilla K. Francis, Joshua M. Folkerth, Rebecca D. Ligon, Keith L. Van Hummelen, Paul Ligon, Azra H. Santagata, Sandro TI Angiomatous meningiomas have a distinct genetic profile with multiple chromosomal polysomies including polysomy of chromosome 5 SO ONCOTARGET LA English DT Article DE meningioma; angiomatous; polysomy; aCGH; molecular diagnostics; Next Generation Sequencing ID CIRCULAR BINARY SEGMENTATION; CENTRAL-NERVOUS-SYSTEM; DNA-SEQUENCING DATA; TUMOR-SUPPRESSOR; MUTATIONS; CANCER; ANEUPLOIDY; HEMANGIOBLASTOMAS; INACTIVATION; EPENDYMOMA AB Meningiomas are a diverse group of tumors with a broad spectrum of histologic features. There are over 12 variants of meningioma, whose genetic features are just beginning to be described. Angiomatous meningioma is a World Health Organization (WHO) meningioma variant with a predominance of blood vessels. They are uncommon and confirming the histopathologic classification can be challenging. Given a lack of biomarkers that define the angiomatous subtype and limited understanding of the genetic changes underlying its tumorigenesis, we compared the genomic characteristics of angiomatous meningioma to more common meningioma subtypes. While typical grade I meningiomas demonstrate monosomy of chromosome 22 or lack copy number aberrations, 13 of 14 cases of angiomatous meningioma demonstrated a distinct copy number profile - polysomies of at least one chromosome, but often of many, especially in chromosomes 5, 13, and 20. WHO grade II atypical meningiomas with angiomatous features have both polysomies and genetic aberrations characteristic of other atypical meningiomas. Sequencing of over 560 cancer-relevant genes in 16 cases of angiomatous meningioma showed that these tumors lack common mutations found in other variants of meningioma. Our study demonstrates that angiomatous meningiomas have distinct genomic features that may be clinically useful for their diagnosis. C1 [Abedalthagafi, Malak S.; Merrill, Parker H.; Jones, Robert T.; Ramkissoon, Shakti H.; Folkerth, Rebecca D.; Ligon, Keith L.; Santagata, Sandro] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol,Div Neuropathol, Boston, MA 02115 USA. [Bi, Wenya Linda; Dunn, Ian F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA 02115 USA. [Listewnik, Marc L.; Ligon, Azra H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Clin Cytogenet Lab,Ctr Adv Mol Diagnost,Dept Path, Boston, MA 02115 USA. [Thorner, Aaron R.; Beroukhim, Rameen; Brastianos, Priscilla K.; Francis, Joshua M.; Ligon, Keith L.; Van Hummelen, Paul] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Thorner, Aaron R.; Van Hummelen, Paul] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Beroukhim, Rameen; Brastianos, Priscilla K.; Francis, Joshua M.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Alexander, Brian M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. [Brastianos, Priscilla K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurooncol, Boston, MA USA. [Beroukhim, Rameen; Santagata, Sandro] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Santagata, S (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol,Div Neuropathol, Boston, MA 02115 USA. EM ssantagata@partners.org FU King Abdulaziz City for Science and Technology (KACST), Saudi Arabia [35-1041]; Brain Science Foundation; Jared Branfman Sunflowers for Life Fund for Pediatric Brain and Spinal Cancer Research FX We thank the staff of the Center for Cancer Genome Discovery (CCGD) at the Dana Farber Cancer Institute for DNA sequencing. We thank Dimity Zepf from the Center for Advanced Molecular Diagnostics at Brigham and Women's Hospital for sample processing. We thank Marian Slaney and Sebastian Valentin for assistance with histopathology and sample submission and Adrian M. Dubuc and Amaro Taylor-Weiner for valuable discussions and advice on genomic analysis. The work is supported by 35-1041 grant from King Abdulaziz City for Science and Technology (KACST), Saudi Arabia (M. A. A.), the Brain Science Foundation (S.S.) and the Jared Branfman Sunflowers for Life Fund for Pediatric Brain and Spinal Cancer Research (S.S.). NR 44 TC 10 Z9 10 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 15 PY 2014 VL 5 IS 21 BP 10596 EP 10606 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ2AL UT WOS:000348036900030 PM 25347344 ER PT J AU Prasad, R Katiyar, SK AF Prasad, Ram Katiyar, Santosh K. TI Down-regulation of miRNA-106b inhibits growth of melanoma cells by promoting G1-phase cell cycle arrest and reactivation of p21/WAF1/Cip1 protein SO ONCOTARGET LA English DT Article DE Melanoma; MicroRNA-106b; cell cycle; tumor xenograft growth; grape seed proanthocyanidins ID MICRORNAS; CANCER; EXPRESSION; MIR-106B; CARCINOMA; ACQUISITION; EXTRACTION; CLUSTER AB MiR-106b is overexpressed in various types of cancers and is associated with the regulation of the carcinogenic processes. Using RT-PCR, we have identified overexpression of miRNA-106b in various melanoma cell lines (A375, Hs294t, SK-el28, SK-Mel 119, Mel 1241, Mel 1011 and Mel 928) as compared to its expression in normal human epidermal melanocytes (NHEM). The overexpression of miR-106b in melanoma cells (A375, Hs294t) was associated with greater cell proliferation capacity than NHEM. Treatment of A375 and Hs294t cells with anti-miR-106b resulted in inhibition of cell proliferation as well as G1-phase arrest. We determined the effects of grape seed proanthocyanidins (GSPs) on the expression of miRNA-106b and its underlying molecular targets. Treatment of A375 and Hs294t cells with GSPs resulted in suppression of the levels of miRNA-106b, cytotoxicity, G1-phase arrest and reactivation of p21/WAF1/Cip1. Dietary GSPs significantly inhibited growth of A375 melanoma cell tumor xenografts in nude mice, which was associated with reduction in the levels of miRNA-106b, tumor cell proliferation and increases in the levels of p21/WAF1/Cip1 protein. These studies suggest that miRNA-106b plays a crucial role in melanoma growth and that GSPs act as an inhibitor of miR-106b thereby blocking melanoma growth in vitro and in vivo models. C1 [Prasad, Ram; Katiyar, Santosh K.] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Katiyar, SK (reprint author), Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. EM skatiyar@uab.edu FU National Institutes of Health [CA166883]; Veterans Administration Merit Review Award [1I01BX001410] FX The study is partially supported by the funds from the National Institutes of Health (CA166883, S.K.K.), and Veterans Administration Merit Review Award (1I01BX001410, S.K.K.). Normal human melanocytes were obtained from the UAB Skin Diseases Research Center (AR050948). The content of this manuscript does not necessarily reflect the views or policies of the funding agencies. NR 33 TC 19 Z9 19 U1 1 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 15 PY 2014 VL 5 IS 21 BP 10636 EP 10649 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ2AL UT WOS:000348036900033 PM 25361006 ER PT J AU Ringer, L Sirajuddin, P Tricoli, L Waye, S Choudhry, MU Parasido, E Sivakumar, A Heckler, M Naeem, A Abdelgawad, I Liu, XF Feldman, AS Lee, RJ Wu, CL Yenugonda, V Kallakury, B Dritschilo, A Lynch, J Schlegel, R Rodriguez, O Pestell, RG Avantaggiati, ML Albanese, C AF Ringer, Lymor Sirajuddin, Paul Tricoli, Lucas Waye, Sarah Choudhry, Muhammad Umer Parasido, Erika Sivakumar, Angiela Heckler, Mary Naeem, Aisha Abdelgawad, Iman Liu, Xuefeng Feldman, Adam S. Lee, Richard J. Wu, Chin-Lee Yenugonda, Venkata Kallakury, Bhaskar Dritschilo, Anatoly Lynch, John Schlegel, Richard Rodriguez, Olga Pestell, Richard G. Avantaggiati, Maria Laura Albanese, Chris TI The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells SO ONCOTARGET LA English DT Article DE p53; apoptosis; autophagy; primary cells; prostate ID MUTANT P53; REPROGRAMMED CELLS; EPITHELIAL-CELLS; CDK INHIBITOR; DISEASE; HOMEOSTASIS; PROGRESSION; ACTIVATION; CYCLIN-D1; VMY-1-103 AB The p53 tumor suppressor protein plays a crucial role in influencing cell fate decisions in response to cellular stress. As p53 elicits cell cycle arrest, senescence or apoptosis, the integrity of the p53 pathway is considered a key determinant of anti-tumor responses. p53 can also promote autophagy, however the role of p53-ependent autophagy in chemosensitivity is poorly understood. VMY-1-103 (VMY), a dansylated analog of purvalanol B, displays rapid and potent anti-tumor activities, however the pathways by which VMY works are not fully defined. Using established prostate cancer cell lines and novel conditionally reprogrammed cells (CRCs) derived from prostate cancer patients; we have defined the mechanisms of VMY-induced prostate cancer cell death. Herein, we show that the cytotoxic effects of VMY required a p53-dependent induction of autophagy, and that inhibition of autophagy abrogated VMY-induced cell death. Cancer cell lines harboring p53 missense mutations evaded VMY toxicity and treatment with a small molecule compound that restores p53 activity re-established VMY-induced cell death. The elucidation of the molecular mechanisms governing VMY-dependent cell death in cell lines, and importantly in CRCs, provides the rationale for clinical studies of VMY, alone or in combination with p53 reactivating compounds, in human prostate cancer. C1 [Ringer, Lymor; Sirajuddin, Paul; Tricoli, Lucas; Waye, Sarah; Choudhry, Muhammad Umer; Parasido, Erika; Sivakumar, Angiela; Heckler, Mary; Naeem, Aisha; Abdelgawad, Iman; Yenugonda, Venkata; Schlegel, Richard; Rodriguez, Olga; Avantaggiati, Maria Laura; Albanese, Chris] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Ringer, Lymor; Sirajuddin, Paul; Tricoli, Lucas; Waye, Sarah; Choudhry, Muhammad Umer; Parasido, Erika; Sivakumar, Angiela; Heckler, Mary; Naeem, Aisha; Abdelgawad, Iman; Yenugonda, Venkata; Schlegel, Richard; Rodriguez, Olga; Avantaggiati, Maria Laura; Albanese, Chris] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Liu, Xuefeng; Kallakury, Bhaskar; Schlegel, Richard; Albanese, Chris] Georgetown Univ, Med Ctr, Dept Pathol, Washington, DC 20007 USA. [Feldman, Adam S.; Lee, Richard J.; Wu, Chin-Lee] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dritschilo, Anatoly; Lynch, John] Georgetown Univ Hosp, Washington, DC 20007 USA. [Pestell, Richard G.] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Abdelgawad, Iman] Natl Canc Inst Egypt, Cairo, Egypt. RP Albanese, C (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. EM albanese@georgetown.edu FU NIH CTSA Pilot award FX Cell cycle analyses were performed in the Lombardi Cancer Center's Flow Cytometry Shared Resource and microscopy was performed in the Lombardi Cancer Center's Microscopy and Imaging Shared Resource. DOD -PC101946 (LR, CA), NIH R01 CA129003 (CA), DOD PCRP SIDA W81XWH-13-1-0327 (CA), an NIH CTSA Pilot award (CA), NIH P30 CA51008-18 and NIH CA009686. We thank Robert Clarke for the LC3-GFP vector, Todd Waldman for the p53shRNA and control lentivirus's and Milton Brown for supplying VMY-1-103. NR 50 TC 10 Z9 11 U1 1 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD NOV 15 PY 2014 VL 5 IS 21 BP 10678 EP 10691 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ2AL UT WOS:000348036900036 PM 25296977 ER PT J AU Farhat, MR Shapiro, BJ Sheppard, SK Colijn, C Murray, M AF Farhat, Maha R. Shapiro, B. Jesse Sheppard, Samuel K. Colijn, Caroline Murray, Megan TI A phylogeny-based sampling strategy and power calculator informs genome-wide associations study design for microbial pathogens SO GENOME MEDICINE LA English DT Article ID DRUG-RESISTANT TUBERCULOSIS; MYCOBACTERIUM-TUBERCULOSIS; PRINCIPAL-COMPONENTS; BACTERIAL GENOMES; RECOMBINATION; INFERENCE; SELECTION; MODEL; EVOLUTION; STRATIFICATION AB Whole genome sequencing is increasingly used to study phenotypic variation among infectious pathogens and to evaluate their relative transmissibility, virulence, and immunogenicity. To date, relatively little has been published how and how many pathogen strains should be selected for studies associating phenotype and genotype. There are specific challenges when identifying genetic associations in bacteria which often comprise highly structured populations. Here we consider general methodological questions related to sampling and analysis focusing on clonal to moderately recombining pathogens. We propose that a matched sampling scheme constitutes an efficient study design, and provide a power calculator based on phylogenetic convergence. We demonstrate this approach by applying it to genomic datasets for two microbial pathogens: Mycobacterium tuberculosis and Campylobacter species. C1 [Farhat, Maha R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pulm & Crit Care, Boston, MA 02114 USA. [Shapiro, B. Jesse] Univ Montreal, Dept Sci Biol, Montreal, PQ H3C 3J7, Canada. [Sheppard, Samuel K.] Swansea Univ, Coll Med, Inst Life Sci, Swansea SA2 8PP, W Glam, Wales. [Colijn, Caroline] Univ London Imperial Coll Sci Technol & Med, Dept Math, London, England. [Murray, Megan] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA 02115 USA. [Murray, Megan] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Farhat, MR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pulm & Crit Care, Boston, MA 02114 USA. EM mrfarhat@partners.org OI Farhat, Maha/0000-0002-3871-5760; Shapiro, B. Jesse/0000-0001-6819-8699; Sheppard, Samuel/0000-0001-6901-3203 FU Parker B. Francis Foundation; NIH [U19-AI109755, U19 A1-076217]; Canadian Institutes for Health Research; Natural Sciences and Engineering Research Council of Canada; Canada Research Chairs program; Engineering and Physical Sciences Research Council EPSRC [EP/K026003/1]; UK Biotechnology and Biological Sciences Research Council (BBSRC); Wellcome Trust; UK Medical Research Council (MRC) FX This work was funded by the Parker B. Francis Foundation (MF) and the NIH U19-AI109755 (MF and MM), NIH U19 A1-076217 (MM), the Canadian Institutes for Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Canada Research Chairs program (BJS), the Engineering and Physical Sciences Research Council EPSRC EP/K026003/1 (CC). SS is funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC), the Wellcome Trust, and the UK Medical Research Council (MRC) - under the Cloud Infrastructure for Microbial Bioinformatics (CLIMB) project. We thank Dr. Alkes Price, Harvard School of Public Health Department of Biostatistics, for his helpful feedback on the manuscript and methods. NR 56 TC 6 Z9 6 U1 1 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD NOV 15 PY 2014 VL 6 AR 101 DI 10.1186/s13073-014-0101-7 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA AY1JJ UT WOS:000347349400001 PM 25484920 ER PT J AU Woo, JM Jeon, HJ Kim, HJ Lee, KH Lee, CU Noh, JS Lee, CH Hong, JP AF Woo, Jong-Min Jeon, Hong Jin Kim, Hyo-Jin Lee, Kwang-Hun Lee, Chang Uk Noh, Jai Sung Lee, Chang Hwa Hong, Jin Pyo TI Excess cost of non-remission among outpatients with major depressive disorder SO INTERNATIONAL JOURNAL OF MENTAL HEALTH SYSTEMS LA English DT Article DE Major depressive disorder; HPQ; Lost productive time; Presenteeism; Remission ID WORK PRODUCTIVITY; HEALTH CONDITIONS; MENTAL-DISORDERS; PANIC DISORDER; PERFORMANCE; EMPLOYERS; ABSENCE; VALIDATION; DISABILITY; WORKFORCE AB Background: The purpose of this study was to assess the economic benefit of achieving remission among outpatients with major depressive disorder (MDD) who are currently employed in Korea. Methods: Cross-sectional observational study. A total of 337 outpatients with MDD with paid jobs were recruited from 14 psychiatric clinics in Korea and were then divided into three groups as follows: new visit group (n = 128), remitted group (n = 100) and non-remitted group (n = 109). The 17-item Hamilton Depression Rating Scale (HAM-D) was used to decide whether a patient should be assigned to the remitted or non-remitted group. Direct medical and non-medical costs were measured via interview with the subjects. The World Health Organization Health and Work Performance Questionnaire (HPQ) were applied in order to measure the lost productive time (LPT) and related productivity costs. Results: The three groups did not show a significant difference in direct medical cost. However, the difference between the remitted group and non-remitted group was statistically significant (25.49 +/- 52.99 vs. 44.79 +/- 126.55, chi(2) = 12.99, p = 0.0015). The remitted group demonstrated a significant improvement in productivity (particularly presenteeism) when compared with the new visit group (Z = -3.29, p = 0.001). Although the non-remitted group received treatment at psychiatric clinics similar to the remitted group, it lost 33 more working hours per month, which is compatible to $332 per month. Conclusion: These results suggest the economic importance of achieving remission in treating depression. C1 [Woo, Jong-Min] Inje Univ, Sch Med, Seoul Paik Hosp, Dept Psychiat, Seoul, South Korea. [Woo, Jong-Min] Inje Univ, Stress Res Inst, Seoul, South Korea. [Jeon, Hong Jin] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Psychiat,Depress Ctr, Seoul, South Korea. [Jeon, Hong Jin] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02115 USA. [Kim, Hyo-Jin] Pfizer Pharmaceut Korea Ltd, Market Access Div, OR EBM Team, Seoul, South Korea. [Lee, Kwang-Hun] Dongguk Univ, Coll Med, Dept Psychiat, Gyeongju, South Korea. [Lee, Chang Uk] Catholic Univ, Coll Med, Dept Psychiat, Seoul, South Korea. [Noh, Jai Sung] Ajou Univ, Sch Med, Dept Psychiat, Suwon 441749, South Korea. [Lee, Chang Hwa] Eulji Univ, Sch Med, Dept Psychiat, Taejon, South Korea. [Hong, Jin Pyo] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Psychiat, Seoul, South Korea. RP Hong, JP (reprint author), Univ Ulsan, Coll Med, Asan Med Ctr, Dept Psychiat, Seoul, South Korea. EM jphong@amc.seoul.kr NR 22 TC 0 Z9 0 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-4458 J9 INT J MENT HEALTH SY JI Int. J. Ment. Health Syst. PD NOV 15 PY 2014 VL 8 AR 42 DI 10.1186/1752-4458-8-42 PG 7 WC Psychiatry SC Psychiatry GA AX9AZ UT WOS:000347197800001 PM 25435902 ER PT J AU Abazeed, M Xu, C Adams, D Tamayo, P Loeffler, J Suh, J Meyerson, M Wong, K Hammerman, P AF Abazeed, M. Xu, C. Adams, D. Tamayo, P. Loeffler, J. Suh, J. Meyerson, M. Wong, K. Hammerman, P. TI NRF2 Is a Novel Oncogene and Biomarker of Therapeutic Resistance in Non-Small Cell Lung Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY OCT 30-NOV 01, 2014 CL Chicago, IL C1 [Abazeed, M.; Suh, J.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Xu, C.; Meyerson, M.; Wong, K.; Hammerman, P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Adams, D.; Tamayo, P.] Broad Inst, Cambridge, MA USA. [Loeffler, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 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. 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TI Safety and Clinical Activity of MK-3475 as Initial Therapy in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY OCT 30-NOV 01, 2014 CL Chicago, IL C1 [Balmanoukian, A. S.] Angeles Clin & Res Inst, Los Angeles, CA USA. [Rizvi, N. A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Garon, E. B.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Patnaik, A.; Papadopoulos, K. P.] South Texas Accelerated Res Therapeut, San Antonio, TX USA. [Gandhi, L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Leighl, N. B.] Princess Margaret Canc Ctr UHN, Toronto, ON, Canada. [Goldman, J. W.] Univ Calif Los Angeles, Santa Monica, CA USA. [Eder, J. P.] Yale Univ, New Haven, CT USA. [Johnson, E. A.] Mayo Clin Florida, Jacksonville, FL USA. [Blumenschein, G. 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Phys. PD NOV 15 PY 2014 VL 90 SU 5 MA 5 BP S3 EP S3 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW6ZG UT WOS:000346413500006 ER PT J AU Ferguson, BD Kanteti, RS Tan, Y Liu, R Gayed, MJ Vokes, EE Ferguson, MK Iafrate, AJ Gill, PS Salgia, R AF Ferguson, B. D. Kanteti, R. S. Tan, Y. Liu, R. Gayed, M. J. Vokes, E. E. Ferguson, M. K. Iafrate, A. J. Gill, P. S. Salgia, R. TI Novel EPHB4 Receptor Tyrosine Kinase Mutations and Kinomic Pathway Analysis in Lung Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY OCT 30-NOV 01, 2014 CL Chicago, IL C1 [Ferguson, B. D.; Kanteti, R. S.; Tan, Y.; Gayed, M. J.; Vokes, E. E.; Ferguson, M. K.; Salgia, R.] Univ Chicago, Chicago, IL 60637 USA. [Liu, R.; Gill, P. S.] Univ So Calif, Los Angeles, CA USA. [Iafrate, A. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. OI Ferguson, Benjamin/0000-0001-8358-3368 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2014 VL 90 SU 5 MA 277 BP S76 EP S76 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW6ZG UT WOS:000346413500170 ER PT J AU Gerber, DE Socinski, MA Neal, JW Wakelee, HA Shirai, K Sequist, LV Rosovsky, R Lilenbaum, R Bastos, BR Huang, C Johnson, ML Hasketh, PJ Subramaniam, DS Chai, F Kazakin, J Schwartz, BE Schiller, JH Brahmer, JR AF Gerber, D. E. Socinski, M. A. Neal, J. W. Wakelee, H. A. Shirai, K. Sequist, L. V. Rosovsky, R. Lilenbaum, R. Bastos, B. R. Huang, C. Johnson, M. L. Hasketh, P. J. Subramaniam, D. S. Chai, F. Kazakin, J. Schwartz, B. E. Schiller, J. H. Brahmer, J. R. TI Randomized Phase 2 Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Single-Agent Chemotherapy in Previously Treated KRAS Mutant Advanced Non-Small Cell Lung Cancer (NSCLC) SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY OCT 30-NOV 01, 2014 CL Chicago, IL C1 [Gerber, D. E.; Schiller, J. H.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Socinski, M. A.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Neal, J. W.; Wakelee, H. A.] Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. [Shirai, K.] Med Univ S Carolina, Charleston, SC 29425 USA. [Sequist, L. V.; Rosovsky, R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Lilenbaum, R.] Yale Canc Ctr, New Haven, CT USA. [Bastos, B. R.] Cleveland Clin Florida, Weston, FL USA. [Huang, C.] Univ Kansas, Ctr Canc, Westwood, KS USA. [Johnson, M. L.] Northwestern Univ, Chicago, IL 60611 USA. [Hasketh, P. J.] Lahey Hosp, Burlington, MA USA. [Hasketh, P. J.] Lahey Clin Fdn, Med Ctr, Burlington, MA 01805 USA. [Subramaniam, D. S.] Georgetown Univ Hosp, Washington, DC 20007 USA. [Chai, F.; Kazakin, J.; Schwartz, B. E.] ArQule Inc, Woburn, MA USA. [Brahmer, J. R.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2014 VL 90 SU 5 MA 174 BP S36 EP S36 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW6ZG UT WOS:000346413500076 ER PT J AU Gettinger, SN Horn, L Gandhi, L Spigel, DR Antonia, SJ Rizvi, NA Powderly, JD Heist, RS Carvajal, RD Jackman, DM Sequist, LV Smith, DC Leming, PD Topalian, SL Hodi, F Sznol, M Harbison, CT Kollia, GD Brahmer, JR AF Gettinger, S. N. Horn, L. Gandhi, L. Spigel, D. R. Antonia, S. J. Rizvi, N. A. Powderly, J. D. Heist, R. S. Carvajal, R. D. Jackman, D. M. Sequist, L. V. Smith, D. C. Leming, P. D. Topalian, S. L. Hodi, F. Sznol, M. Harbison, C. T. Kollia, G. D. Brahmer, J. R. TI Long-term Survival, Clinical Activity, and Safety of Nivolumab (Anti-PD-1; BMS-936558, ONO-4538) in Patients (Pts) With Advanced Non-Small Cell Lung Cancer (NSCLC) SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY OCT 30-NOV 01, 2014 CL Chicago, IL C1 [Gettinger, S. N.; Sznol, M.] Yale Canc Ctr, New Haven, CT USA. [Horn, L.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Gandhi, L.; Jackman, D. M.; Hodi, F.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Spigel, D. R.] Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN USA. [Antonia, S. J.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Rizvi, N. A.; Carvajal, R. 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PD NOV 15 PY 2014 VL 90 SU 5 MA 169 BP S33 EP S34 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW6ZG UT WOS:000346413500071 ER PT J AU Piotrowska, Z Niederst, MJ Mino-Kenudson, M Morales-Oyarvide, V Fulton, L Lockerman, E Howe, E Gainor, JF Fidias, P Heist, RS Shaw, AT Engelman, JA Sequist, LV AF Piotrowska, Z. Niederst, M. J. Mino-Kenudson, M. Morales-Oyarvide, V. Fulton, L. Lockerman, E. Howe, E. Gainor, J. F. Fidias, P. Heist, R. S. Shaw, A. T. Engelman, J. A. Sequist, L. V. TI Variation in Mechanisms of Acquired Resistance Among EGFR-Mutant NSCLC Patients With More Than 1 Postresistant Biopsy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY OCT 30-NOV 01, 2014 CL Chicago, IL C1 [Piotrowska, Z.; Niederst, M. J.; Mino-Kenudson, M.; Morales-Oyarvide, V.; Fulton, L.; Lockerman, E.; Howe, E.; Gainor, J. F.; Fidias, P.; Heist, R. S.; Shaw, A. T.; Engelman, J. A.; Sequist, L. V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 6 Z9 6 U1 0 U2 0 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 NOV 15 PY 2014 VL 90 SU 5 MA 11 BP S6 EP S7 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW6ZG UT WOS:000346413500012 ER PT J AU Sacher, AG Mach, S Messineo, M Jackman, DM Jaenne, PA Paweletz, CP Oxnard, GR AF Sacher, A. G. Mach, S. Messineo, M. Jackman, D. M. Jaenne, P. A. Paweletz, C. P. Oxnard, G. R. TI Noninvasive, Highly Specific Detection of T790M-Mediated Acquired Resistance in EGFR Mutant NSCLC Using a Novel Droplet Digital PCR (ddPCR)-Based Cell-free Plasma DNA (cfDNA) Assay SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY OCT 30-NOV 01, 2014 CL Chicago, IL C1 [Sacher, A. G.; Mach, S.; Jackman, D. M.; Jaenne, P. A.; Oxnard, G. R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sacher, A. G.] Univ Toronto, Toronto, ON, Canada. [Messineo, M.; Jaenne, P. A.; Paweletz, C. P.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA USA. RI Sacher, Adrian/I-8080-2016 OI Sacher, Adrian/0000-0001-7865-2701 NR 0 TC 0 Z9 0 U1 1 U2 8 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 NOV 15 PY 2014 VL 90 SU 5 MA 263 BP S71 EP S71 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW6ZG UT WOS:000346413500157 ER PT J AU Sequist, L Wu, Y Schuler, M O'Byrne, K Sebastian, M Popat, S Boyer, M Mok, T Yamamoto, N Hirsh, V Geater, SL Zhou, C Massey, D Zazulina, V Jones, H Yang, J AF Sequist, L. Wu, Y. Schuler, M. O'Byrne, K. Sebastian, M. Popat, S. Boyer, M. Mok, T. Yamamoto, N. Hirsh, V. Geater, S. L. Zhou, C. Massey, D. Zazulina, V. Jones, H. Yang, J. TI Overall Survival (OS) With Afatinib Versus Chemotherapy in Patients (Pts) With Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring Common (Del19/L858R) Epidermal Growth Factor Receptor Mutations (EGFR Mut): Results of LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6) SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY OCT 30-NOV 01, 2014 CL Chicago, IL C1 [Sequist, L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sequist, L.] Harvard Univ, Sch Med, Boston, MA USA. [Wu, Y.] Guangdong Gen Hosp, Guangdong Lung Canc Inst, Guangzhou, Guangdong, Peoples R China. [Wu, Y.] Guangdong Acad Med Sci, Guangzhou, Guangdong, Peoples R China. [Schuler, M.] Univ Duisburg Essen, Univ Hosp Essen, West German Canc Ctr, Essen, Germany. [O'Byrne, K.] St James Hosp, Dublin 8, Ireland. [Sebastian, M.] Goethe Univ Frankfurt, D-60054 Frankfurt, Germany. [Popat, S.] Royal Marsden Hosp, London SW3 6JJ, England. [Boyer, M.] Royal Prince Alfred Hosp, Camperdown, NSW 2050, Australia. [Mok, T.] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Yamamoto, N.] Wakayama Med Univ, Wakayama, Japan. [Hirsh, V.] McGill Univ, Montreal, PQ, Canada. [Geater, S. L.] Prince Songkla Univ, Hat Yai, Thailand. [Zhou, C.] Tongji Univ, Shanghai Pulm Hosp, Shanghai 200092, Peoples R China. [Massey, D.; Zazulina, V.; Jones, H.] Boehringer Ingelheim Ltd UK, Bracknell, Berks, England. [Yang, J.] Natl Taiwan Univ Hosp, Taipei, Taiwan. NR 0 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2014 VL 90 SU 5 MA 9 BP S5 EP S6 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW6ZG UT WOS:000346413500010 ER PT J AU Sequist, LV Gerber, DE Fidias, P Shaw, AT Temel, JS Heist, RS Gainor, JF Fulton, L Kennedy, EA Muzikansky, A Engelma, JA AF Sequist, L. V. Gerber, D. E. Fidias, P. Shaw, A. T. Temel, J. S. Heist, R. S. Gainor, J. F. Fulton, L. Kennedy, E. A. Muzikansky, A. Engelma, J. A. TI Acquired Resistance to Afatinib in EGFR- Mutant Lung Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY OCT 30-NOV 01, 2014 CL Chicago, IL C1 [Sequist, L. V.; Fidias, P.; Shaw, A. T.; Temel, J. S.; Heist, R. S.; Gainor, J. F.; Fulton, L.; Kennedy, E. A.; Muzikansky, A.; Engelma, J. A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gerber, D. E.] Univ Texas Southwestern, Dallas, TX USA. NR 0 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2014 VL 90 SU 5 MA 190 BP S43 EP S44 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW6ZG UT WOS:000346413500092 ER PT J AU Wu, Y Geater, SL Mok, T O'Byrne, KJ Schuler, MH Sequist, LV Yang, JC Massey, D O'Brien, D Zazulina, V AF Wu, Y. Geater, S. L. Mok, T. O'Byrne, K. J. Schuler, M. H. Sequist, L. V. Yang, J. C. Massey, D. O'Brien, D. Zazulina, V. TI Epidermal Growth Factor Receptor (EGFR)-Mediated Adverse Events (AEs) in Patients (pts) With EGFR-Mutation Positive (EGFR M plus ) Non-Small Cell Lung Cancer (NSCLC) Treated With Afatinib (A) SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Meeting Abstract CT Chicago Multidisciplinary Symposium in Thoracic Oncology CY OCT 30-NOV 01, 2014 CL Chicago, IL C1 [Wu, Y.] Guangdong Gen Hosp, Guangzhou, Guangdong, Peoples R China. [Geater, S. L.] Prince Songkla Univ, Hat Yai, Thailand. [Mok, T.] Chinese Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [O'Byrne, K. J.] Princess Alexandra Hosp, Brisbane, Qld 4102, Australia. [Schuler, M. H.] Univ Duisburg Essen, West German Canc Ctr, Essen, Germany. [Sequist, L. V.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Yang, J. C.] Natl Taiwan Univ Hosp, Taipei, Taiwan. [Massey, D.; Zazulina, V.] Boehringer Ingelheim Ltd, Bracknell, Berks, England. [O'Brien, D.] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2014 VL 90 SU 5 MA 184 BP S41 EP S41 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW6ZG UT WOS:000346413500086 ER PT J AU Schnedl, C Dobnig, H Quraishi, SA McNally, JD Amrein, K AF Schnedl, Christian Dobnig, Harald Quraishi, Sadeq A. McNally, J. Dayre Amrein, Karin TI Native and Active Vitamin D in Intensive Care: Who and How We Treat Is Crucially Important SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter C1 [Schnedl, Christian; Dobnig, Harald; Amrein, Karin] Med Univ Graz, Graz, Austria. [Quraishi, Sadeq A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [McNally, J. Dayre] Childrens Hosp Eastern Ontario, Ottawa, ON K1H 8L1, Canada. RP Schnedl, C (reprint author), Med Univ Graz, Graz, Austria. NR 6 TC 1 Z9 1 U1 0 U2 1 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 NOV 15 PY 2014 VL 190 IS 10 BP 1193 EP 1194 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AU5XM UT WOS:000345676900021 PM 25398112 ER PT J AU Froehner, S Reed, S Anderson, K Huang, P Percival, J AF Froehner, Stanley Reed, Sarah Anderson, Kendra Huang, Paul Percival, Justin TI Defective skeletal muscle nNOS-cGMP signaling as a therapeutic target in Duchenne muscular dystrophy SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract DE nNOS; Dystrophin; Sildenafil; PDE5; Muscle; Duchenne muscular dystrophy; nNOSbeta C1 [Froehner, Stanley; Reed, Sarah; Anderson, Kendra] Univ Washington, Seattle, WA 98195 USA. [Huang, Paul] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Percival, Justin] Univ Miami, Coral Gables, FL 33124 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD NOV 15 PY 2014 VL 42 MA 2022-1 BP 114 EP 114 DI 10.1016/j.niox.2014.09.047 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU7XZ UT WOS:000345812900054 ER PT J AU Robrecht, T Emmanuel, B Cauwels, A Decaluwe, K Geschka, S Tainsh, R Delanghe, J Hochepied, T De Cauwer, L Rogge, E Sips, P Karas, R Bloch, K Van De Voorde, J Stasch, JP Vuylsteke, M Brouckaert, P AF Robrecht, T. Emmanuel, Buys Cauwels, Anje Decaluwe, Kelly Geschka, Sandra Tainsh, Robert Delanghe, Joris Hochepied, Tino De Cauwer, Lode Rogge, Elke Sips, Patrick Karas, Richard Bloch, Kenneth Van De Voorde, Johan Stasch, Johannes-Peter Vuylsteke, Marnik Brouckaert, Peter TI Heme-deficient NO-unresponsive sGC knock-in mice: Novel aspects of NO sGC signaling in cardiovascular (patho)physiology SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract DE Soluble guanylate cyclase; Heme-independent sGC activators; Oxidative stress; Inflammatory shock C1 [Robrecht, T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 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 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD NOV 15 PY 2014 VL 42 MA 2022-2 BP 114 EP 114 DI 10.1016/j.niox.2014.09.048 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU7XZ UT WOS:000345812900055 ER PT J AU Babykutty, S Heishi, T Tsukada, K Huang, YH Kozin, S Conner, D Lin, QC Kucherlapati, R Jain, RK Fukumura, D AF Babykutty, Suboj Heishi, Takahiro Tsukada, Kosuke Huang, Yuhui Kozin, Sergey Conner, David Lin, Qingcong Kucherlapati, Raju Jain, Rakesh K. Fukumura, Dai TI Restoring perivascular nitric oxide gradients normalizes breast cancer vasculature SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract DE Nitric oxide; Tumor microenvironment; Vessel normalization C1 [Babykutty, Suboj; Heishi, Takahiro; Tsukada, Kosuke; Huang, Yuhui; Kozin, Sergey; Conner, David; Lin, Qingcong; Kucherlapati, Raju; Jain, Rakesh K.; Fukumura, Dai] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD NOV 15 PY 2014 VL 42 MA P103 BP 115 EP 115 DI 10.1016/j.niox.2014.09.051 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU7XZ UT WOS:000345812900058 ER PT J AU Dordea, A Vandenwijngaert, S Tainsh, R Nathan, D Raher, MJ Kirby, A Daly, CSM Brouckaert, P Schwartzman, M Bloch, KD Emmanuel, B AF Dordea, Ana Vandenwijngaert, Sara Tainsh, Robert Nathan, Daniel Raher, M. J. Kirby, Andrew Daly, C. Stevens Marc Brouckaert, Peter Schwartzman, Michal Bloch, Kenneth D. Emmanuel, Buys TI A role for 20-HETE in the development of gender- and strain-specific hypertension in soluble guanylate cyclase alpha1-deficient mice SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract DE NO signaling; 20-HETE; Strain- and gender-specific hypertension C1 [Dordea, Ana] Massachusetts Gen Hosp, Boston, MA 02114 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 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD NOV 15 PY 2014 VL 42 MA P119 BP 120 EP 121 DI 10.1016/j.niox.2014.09.066 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU7XZ UT WOS:000345812900073 ER PT J AU Yu, BL Han, L Leyton, P Bloch, K Zapol, W AF Yu, Binglan Han, Liu Leyton, Patricio Bloch, Kenneth Zapol, Warren TI Nitric oxide synthase 3 deficiency does not prevent the adverse effects of transfusing stored blood in murine hemorrhagic shock SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Meeting Abstract DE Nitric oxide; Hemorrhagic shock; Blood transfusion C1 [Yu, Binglan; Han, Liu; Leyton, Patricio; Bloch, Kenneth; Zapol, Warren] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 EI 1089-8611 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD NOV 15 PY 2014 VL 42 MA P214 BP 152 EP 152 DI 10.1016/j.niox.2014.09.154 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AU7XZ UT WOS:000345812900161 ER PT J AU Abreo, AP Glidden, D Painter, P Lea, J Herzog, CA Kutner, NG Johansen, KL AF Abreo, Adrian P. Glidden, David Painter, Patricia Lea, Janice Herzog, Charles A. Kutner, Nancy G. Johansen, Kirsten L. TI Association of physical function with predialysis blood pressure in patients on hemodialysis SO BMC NEPHROLOGY LA English DT Article DE Blood pressure; End-stage renal disease; Physical function ID STAGE RENAL-DISEASE; MORTALITY RISK; PERFORMANCE; DIALYSIS; HYPERTENSION; PREDICTION; DISABILITY; PATTERNS; OUTCOMES; ADULTS AB Background: New information from various clinical settings suggests that tight blood pressure control may not reduce mortality and may be associated with more side effects. Methods: We performed cross-sectional multivariable ordered logistic regression to examine the association between predialysis blood pressure and the short physical performance battery (SPPB) in a cohort of 749 prevalent hemodialysis patients in the San Francisco and Atlanta areas recruited from July 2009 to August 2011 to study the relationship between systolic blood pressure and objective measures of physical function. Mean blood pressure for three hemodialysis sessions was analyzed in the following categories: <110 mmHg, 110-129 mmHg (reference), 130-159 mmHg, and >= 160 mmHg. SPPB includes three components: timed repeated chair stands, timed 15-ft walk, and balance tests. SPPB was categorized into ordinal groups (<= 6, 7-9, 10-12) based on prior literature. Results: Patients with blood pressure 130-159 mmHg had lower odds (OR 0.57, 95% CI 0.35-0.93) of scoring in a lower SPPB category than those whose blood pressure was between 110 and 129 mmHg, while those with blood pressure >= 160 mmHg had 0.56 times odds (95% CI 0.33-0.94) of scoring in a lower category when compared with blood pressure 110-129 mmHg. When individual components were examined, blood pressure was significantly associated with chair stand (130-159 mmHg: OR 0.59, 95% CI 0.38-0.92) and gait speed (>= 160 mmHg: OR 0.59, 95% CI 0.35-0.98). Blood pressure >= 160 mmHg was not associated with substantially higher SPPB score compared with 130-159 mmHg. Conclusions: Patients with systolic blood pressure at or above 130 mmHg had better physical performance than patients with lower blood pressure in the normotensive range. The risk-benefit tradeoff of aggressive blood pressure control, particularly in low-functioning patients, should be reexamined. C1 [Abreo, Adrian P.] Univ Cincinnati, Coll Med, Dept Nephrol, Cincinnati, OH 45267 USA. [Glidden, David; Johansen, Kirsten L.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Painter, Patricia] Univ Utah, Dept Phys Therapy, Salt Lake City, UT USA. [Lea, Janice] Emory Univ, Div Nephrol, Atlanta, GA 30322 USA. [Herzog, Charles A.] Hennepin Cty Med Ctr, Div Cardiol, Minneapolis, MN 55415 USA. [Herzog, Charles A.] Univ Minnesota, Minneapolis, MN USA. [Herzog, Charles A.] US Renal Data Syst Cardiovasc Special Studies Ctr, Minneapolis, MN USA. [Kutner, Nancy G.; Johansen, Kirsten L.] US Renal Data Syst Rehabil Qual Life Special Stud, Atlanta, GA USA. [Johansen, Kirsten L.] San Francisco VA Med Ctr, Nephrol Sect, San Francisco, CA 94121 USA. [Johansen, Kirsten L.] US Renal Data Syst Nutr Special Studies Ctr, San Francisco, CA USA. [Johansen, Kirsten L.] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. [Johansen, Kirsten L.] Nephrol Sect, San Francisco, CA 94121 USA. RP Johansen, KL (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. EM kirsten.johansen@ucsf.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [N01-DK-7-0005, N01-DK-7-5004]; [K24DK085153] FX This work was supported through contracts N01-DK-7-0005 and N01-DK-7-5004 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and a K24DK085153 grant. The authors would like to thank Julie W. Doyle, MS for administrative support. NR 21 TC 1 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD NOV 15 PY 2014 VL 15 AR 177 DI 10.1186/1471-2369-15-177 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AU7RN UT WOS:000345797700001 PM 25399253 ER PT J AU Varenhorst, C Alstrom, U Braun, OO Storey, RF Mahaffey, KW Bertilsson, M Cannon, CP Scirica, BM Himmelmann, A James, SK Wallentin, L Held, C AF Varenhorst, Christoph Alstrom, Ulrica Braun, Oscar O. Storey, Robert F. Mahaffey, Kenneth W. Bertilsson, Maria Cannon, Christopher P. Scirica, Benjamin M. Himmelmann, Anders James, Stefan K. Wallentin, Lars Held, Claes TI Causes of mortality with ticagrelor compared with clopidogrel in acute coronary syndromes SO HEART LA English DT Article ID PLATO PLATELET INHIBITION; ARTERY-BYPASS SURGERY; PATIENT OUTCOMES TRIAL; RECEPTOR ANTAGONIST; ADENOSINE; AGGREGATION; EFFICACY; THERAPY; ASPIRIN; AZD6140 AB Objective To describe specific causes of death and evaluate whether bleeding events and infection contributed to mortality in all ticagrelor-treated and clopidogrel-treated patients with acute coronary syndromes. Methods In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor significantly reduced rates of vascular and total death compared with clopidogrel. In the 905 patients who died postenrolment in the PLATO trial (n=18 624), reviewers, blinded to study treatment, subclassified direct causes of death and evaluated whether infection or bleeding events contributed to fatal events. Results Among vascular deaths, there were significantly fewer sudden deaths (63 (0.7%) vs 98 (1.1%), p<0.01) but no significant difference in deaths caused by acute myocardial infarction (179 (1.9%) vs 194 (2.1%), p=0.43) or heart failure (31 (0.3%) vs 42 (0.5%), p=0.20) with ticagrelor compared with clopidogrel. For non-vascular deaths, there was no difference between treatments in deaths directly caused by infection. Although, patients treated with ticagrelor were at lower risk for death where infection was either a direct cause or contributed to death (51 (0.5%) vs 76 (0.8%), HR 0.67 (0.47 to 0.95), p<0.05) but not for bleeding (42 (0.5%) vs 42 (0.5%), HR 0.99 (0.65 to 1.53), p=0.98). Conclusions In this post hoc analysis, ticagrelor compared with clopidogrel reduced total and cardiovascular mortality, which appeared to be mainly mediated by a reduction in sudden death. Importantly, bleeding causing or contributing to death did not differ between treatments. C1 [Varenhorst, Christoph; James, Stefan K.; Wallentin, Lars; Held, Claes] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Varenhorst, Christoph; Bertilsson, Maria; James, Stefan K.; Wallentin, Lars; Held, Claes] Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden. [Alstrom, Ulrica] Uppsala Univ, Dept Cardiac & Thorac Anaesthesia & Surg, Uppsala, Sweden. [Braun, Oscar O.] Lund Univ, Dept Cardiol, Lund, Sweden. [Storey, Robert F.] Univ Sheffield, Dept Cardiovasc Sci, Sheffield, S Yorkshire, England. [Mahaffey, Kenneth W.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Cannon, Christopher P.; Scirica, Benjamin M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp, Boston, MA 02115 USA. [Himmelmann, Anders] AstraZeneca R&D, Molndal, Sweden. RP Varenhorst, C (reprint author), Uppsala Clin Res Ctr, Dag Hammarskjolds Vag 14B,Level 1,MTC Bldg,Sci Pk, S-75237 Uppsala, Sweden. EM christoph.varenhorst@ucr.uu.se OI Held, Claes/0000-0001-9402-7404; Varenhorst, Christoph/0000-0002-8378-3869 FU AstraZeneca FX The PLATO trial was funded by AstraZeneca. NR 23 TC 12 Z9 13 U1 0 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 EI 1468-201X J9 HEART JI Heart PD NOV 15 PY 2014 VL 100 IS 22 BP 1762 EP + DI 10.1136/heartjnl-2014-305619 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AU2LS UT WOS:000345450400007 PM 24957530 ER PT J AU Wey, HY Catana, C Hooker, JM Dougherty, DD Knudsen, GM Wang, DJJ Chonde, DB Rosen, BR Gollub, RL Kong, J AF Wey, Hsiao-Ying Catana, Ciprian Hooker, Jacob M. Dougherty, Darin D. Knudsen, Gitte M. Wang, Danny J. J. Chonde, Daniel B. Rosen, Bruce R. Gollub, Randy L. Kong, Jian TI Simultaneous fMRI-PET of the opioidergic pain system in human brain SO NEUROIMAGE LA English DT Article DE Simultaneous MRI/PET; Neurotransmission; Hemodynamic response; Opioid receptor; Pain ID RECEPTOR REGULATION; NUCLEUS-ACCUMBENS; HEAT PAIN; IN-VIVO; BINDING; ROBUST; REGISTRATION; ACTIVATION; IMAGES; NEUROTRANSMISSION AB MRI and PET provide complementary information for studying brain function. While the potential use of simultaneous MRI/PET for clinical diagnostic and disease staging has been demonstrated recently; the biological relevance of concurrent functional MRI-PET brain imaging to dissect neurochemically distinct components of the blood oxygenation level dependent (BOLD) fMRI signal has not yet been shown. We obtained sixteen fMRI-PET data sets from eight healthy volunteers. Each subject participated in randomized order in a pain scan and a control (nonpainful pressure) scan on the same day. Dynamic PET data were acquired with an opioid radioligand, [C-11] diprenorphine, to detect endogenous opioid releases in response to pain. BOLD fMRI data were collected at the same time to capture hemodynamic responses. In this simultaneous human fMRI-PET imaging study, we show co-localized responses in thalamus and striatum related to pain processing, while modality specific brain networks were also found. Co-localized fMRI and PET signal changes in the thalamus were positively correlated suggesting that pain-induced changes in opioid neurotransmission contribute a significant component of the fMRI signal change in this region. Simultaneous fMRI-PET provides unique opportunities allowing us to relate specific neurochemical events to functional hemodynamic activation and to investigate the impacts of neurotransmission on neurovascular coupling of the human brain in vivo. (c) 2014 Elsevier Inc. All rights reserved. C1 [Wey, Hsiao-Ying; Catana, Ciprian; Hooker, Jacob M.; Dougherty, Darin D.; Chonde, Daniel B.; Rosen, Bruce R.; Gollub, Randy L.; Kong, Jian] Harvard Univ, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Dept Radiol,Med Sch, Charlestown, MA 02129 USA. [Dougherty, Darin D.; Gollub, Randy L.; Kong, Jian] Harvard Univ, Dept Psychiat, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. [Knudsen, Gitte M.] Rigshosp, Ctr Integrated Mol Brain Imaging, Neurobiol Res Unit, Copenhagen, Denmark. [Knudsen, Gitte M.] Univ Copenhagen, DK-1168 Copenhagen, Denmark. [Wang, Danny J. J.] Univ Calif Los Angeles, Dept Neurol, Ahmanson Lovelace Brain Mapping Ctr, Los Angeles, CA 90095 USA. RP Wey, HY (reprint author), Harvard Univ, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Dept Radiol,Med Sch, 149 13th St, Charlestown, MA 02129 USA. EM wey@nmr.mgh.harvard.edu; kongj@nmr.mgh.harvard.edu RI Knudsen, Gitte/C-1368-2013; OI Knudsen, Gitte/0000-0003-1508-6866; Gollub, Randy L./0000-0002-9434-4044 FU NIDA [R03-AT218317]; NIH/NCCAM [R01-AT006364, R01-AT005280, P01-AT006663-01] FX The authors thank Patricia McCarthy, NP for her help on placing i.v. lines and monitoring subject condition during scans; Grae Arabasz and Shirley Hsu for their assistance with radiotracer administration; and Steve Carlin and Chris Moseley for radiotracer synthesis. We also thank Ms. Amanda Cook, Xiaoyan Chen, Rosa Spaeth, and Lisette Roman for the subject recruitment and assistance with the experiments. This work was supported by R03-AT218317 (NIDA), R01-AT006364 (NIH/NCCAM) to Jian Kong, R01-AT005280 (NIH/NCCAM) to Randy Gollub, and P01-AT006663-01 (NIH/NCCAM) to Bruce Rosen. NR 46 TC 12 Z9 16 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD NOV 15 PY 2014 VL 102 BP 275 EP 282 DI 10.1016/j.neuroimage.2014.07.058 PN 2 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU1PD UT WOS:000345391700004 PM 25107855 ER PT J AU Arbabshirani, MR Damaraju, E Phlypo, R Plis, S Allen, E Ma, S Mathalon, D Preda, A Vaidya, JG Adali, T Calhoun, VD AF Arbabshirani, Mohammad R. Damaraju, Eswar Phlypo, Ronald Plis, Sergey Allen, Elena Ma, Sai Mathalon, Daniel Preda, Adrian Vaidya, Jatin G. Adali, Tuelay Calhoun, Vince D. TI Impact of autocorrelation on functional connectivity SO NEUROIMAGE LA English DT Article DE Autocorrelation; Functional connectivity; Independent component analysis; Autoregressive process; Resting-state fMRI ID FMRI TIME-SERIES; RESTING-STATE DATA; NETWORK CONNECTIVITY; TEMPORAL AUTOCORRELATION; EMPIRICAL ANALYSES; NULL-HYPOTHESIS; HUMAN BRAIN; NOISE; MRI; SCHIZOPHRENIA AB Although the impact of serial correlation (autocorrelation) in residuals of general linear models for fMRI time-series has been studied extensively, the effect of autocorrelation on functional connectivity studies has been largely neglected until recently. Some recent studies based on results from economics have questioned the conventional estimation of functional connectivity and argue that not correcting for autocorrelation in fMRI time-series results in "spurious" correlation coefficients. In this paper, first we assess the effect of autocorrelation on Pearson correlation coefficient through theoretical approximation and simulation. Then we present this effect on real fMRI data. To our knowledge this is the first work comprehensively investigating the effect of autocorrelation on functional connectivity estimates. Our results show that although FC values are altered, even following correction for autocorrelation, results of hypothesis testing on FC values remain very similar to those before correction. In real data we show this is true for main effects and also for group difference testing between healthy controls and schizophrenia patients. We further discuss model order selection in the context of autoregressive processes, effects of frequency filtering and propose a preprocessing pipeline for connectivity studies. (c) 2014 Elsevier Inc. All rights reserved. C1 [Arbabshirani, Mohammad R.; Damaraju, Eswar; Plis, Sergey; Allen, Elena; Calhoun, Vince D.] Mind Res Network, Albuquerque, NM 87106 USA. [Arbabshirani, Mohammad R.; Calhoun, Vince D.] Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA. [Phlypo, Ronald; Ma, Sai; Adali, Tuelay] Univ Maryland, Dept CSEE, Baltimore, MD USA. [Allen, Elena] Univ Bergen, KG Jebsen Cener Res Neuropsychiat Disorders, N-5020 Bergen, Norway. [Allen, Elena] Univ Bergen, Dept Biol & Med Psychol, N-5020 Bergen, Norway. [Mathalon, Daniel] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Mathalon, Daniel] San Francisco VA Med Ctr, San Francisco, CA USA. [Preda, Adrian] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. [Vaidya, Jatin G.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. RP Arbabshirani, MR (reprint author), Mind Res Network, 1101 Yale Blvd NE, Albuquerque, NM 87106 USA. EM marbabshirani@mrn.org RI Preda, Adrian /K-8889-2013; OI Preda, Adrian /0000-0003-3373-2438; Plis, Sergey/0000-0003-0040-0365 FU NIH (NCRR) [U24-RR021992]; COBRE NIGMS [P20GM103472] FX We would like to acknowledge the efforts of all parties responsible for designing and implementing the experiment, collecting the data, and facilitating the brain imaging that made this study possible. Funding was provided by NIH for the FBIRN study (NCRR grant U24-RR021992) and COBRE NIGMS P20GM103472. NR 53 TC 10 Z9 10 U1 0 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD NOV 15 PY 2014 VL 102 BP 294 EP 308 DI 10.1016/j.neuroimage.2014.07.045 PN 2 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU1PD UT WOS:000345391700006 PM 25072392 ER PT J AU Schultz, AP Chhatwal, JP Huijbers, W Hedden, T van Dijk, KRA McLaren, DG Ward, AM Wigman, S Sperling, RA AF Schultz, Aaron P. Chhatwal, Jasmeer P. Huijbers, Willem Hedden, Trey van Dijk, Koene R. A. McLaren, Donald G. Ward, Andrew M. Wigman, Sarah Sperling, Reisa A. TI Template based rotation: A method for functional connectivity analysis with a priori templates SO NEUROIMAGE LA English DT Article ID RESTING-STATE FMRI; INDEPENDENT COMPONENT ANALYSIS; DEFAULT-MODE NETWORK; BRAIN NETWORKS; GLOBAL SIGNAL; REGRESSION; REPRODUCIBILITY; ARCHITECTURE; MRI AB Functional connectivity magnetic resonance imaging (fcMRI) is a powerful tool for understanding the network level organization of the brain in research settings and is increasingly being used to study large-scale neuronal network degeneration in clinical trial settings. Presently, a variety of techniques, including seed-based correlation analysis and group independent components analysis (with either dual regression or back projection) are commonly employed to compute functional connectivity metrics. In the present report, we introduce template based rotation, 1 a novel analytic approach optimized for use with a priori network parcellations, which may be particularly useful in clinical trial settings. Template based rotation was designed to leverage the stable spatial patterns of intrinsic connectivity derived from out-of-sample datasets by mapping data from novel sessions onto the previously defined a priori templates. We first demonstrate the feasibility of using previously defined a priori templates in connectivity analyses, and then compare the performance of template based rotation to seed based and dual regression methods by applying these analytic approaches to an fMRI dataset of normal young and elderly subjects. We observed that template based rotation and dual regression are approximately equivalent in detecting fcMRI differences between young and old subjects, demonstrating similar effect sizes for group differences and similar reliability metrics across 12 cortical networks. Both template based rotation and dual-regression demonstrated larger effect sizes and comparable reliabilities as compared to seed based correlation analysis, though all three methods yielded similar patterns of network differences. When performing inter-network and sub-network connectivity analyses, we observed that template based rotation offered greater flexibility, larger group differences, and more stable connectivity estimates as compared to dual regression and seed based analyses. This flexibility owes to the reduced spatial and temporal orthogonality constraints of template based rotation as compared to dual regression. These results suggest that template based rotation can provide a useful alternative to existing fcMRI analytic methods, particularly in clinical trial settings where predefined outcome measures and conserved network descriptions across groups are at a premium. (c) 2014 Elsevier Inc. All rights reserved. C1 [Schultz, Aaron P.; Chhatwal, Jasmeer P.; Huijbers, Willem; Hedden, Trey; McLaren, Donald G.; Ward, Andrew M.; Wigman, Sarah; Sperling, Reisa A.] Massachusetts Gen Hosp, Dept Neurol, Massachusetts Alzheimers Dis Res Ctr, Harvard Aging Brain Study, Boston, MA 02114 USA. [Chhatwal, Jasmeer P.; Huijbers, Willem; Ward, Andrew M.; Wigman, Sarah; Sperling, Reisa A.] Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, Boston, MA 02115 USA. [Sperling, Reisa A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Schultz, Aaron P.; Chhatwal, Jasmeer P.; Huijbers, Willem; Hedden, Trey; van Dijk, Koene R. A.; McLaren, Donald G.; Ward, Andrew M.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [van Dijk, Koene R. A.] Harvard Univ, Dept Psychol, Ctr Brain Sci, Cambridge, MA 02138 USA. [Hedden, Trey] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Schultz, AP (reprint author), Massachusetts Gen Hosp, Dept Neurol, Massachusetts Alzheimers Dis Res Ctr, Harvard Aging Brain Study, Boston, MA 02114 USA. EM aschultz@nmr.mgh.harvard.edu RI Van Dijk, Koene/G-3317-2012; OI Van Dijk, Koene/0000-0001-6137-4282; Ward, Andrew/0000-0001-6948-4814; McLaren, Donald/0000-0002-0566-4610 FU NIA [S10 RR022976, S10 RR019933, P01 AG036694, P50 AG005134, R01 AG027435, R01 AG034556, K24 AG035007, K01 AG040197]; NCRR [P41 RR14075]; BrightFocus Foundation; American Brain Foundation/American Academy of Neurology FX Data collection and investigator support for this project were provided by NIA S10 RR022976, S10 RR019933, P01 AG036694, P50 AG005134, R01 AG027435, R01 AG034556, K24 AG035007, and K01 AG040197. Data collection and imaging resources at the Martinos Center for Biomedical Imaging greatly benefit from the support of NCRR grant P41 RR14075. Additional investigator support was provided by a postdoctoral fellowship from the BrightFocus Foundation (JPC), and a Clinical Research Training Fellowship from the American Brain Foundation/American Academy of Neurology (JPC). We extend special thanks to Dr. Randy Buckner for sharing the Harvard GSP dataset of young subjects with us and for his insightful input on this project. We also thank all the collaborators and contributors to the Harvard Aging Brain Study (http://www.martinos.org/harvardagingbrain/Acknowledgements.html). Lastly, we are grateful to our research participants for their altruism and willingness to take part in our studies. NR 55 TC 12 Z9 12 U1 0 U2 1 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 NOV 15 PY 2014 VL 102 BP 620 EP 636 DI 10.1016/j.neuroimage.2014.08.022 PN 2 PG 17 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU1PD UT WOS:000345391700036 PM 25150630 ER PT J AU Gregory, MD Agam, Y Selvadurai, C Nagy, A Vangel, M Tucker, M Robertson, EM Stickgold, R Manoach, DS AF Gregory, Michael D. Agam, Yigal Selvadurai, Chindhuri Nagy, Amanda Vangel, Mark Tucker, Matthew Robertson, Edwin M. Stickgold, Robert Manoach, Dara S. TI Resting state connectivity immediately following learning correlates with subsequent sleep-dependent enhancement of motor task performance SO NEUROIMAGE LA English DT Article DE Sleep; Motor learning; Memory consolidation; Resting state; Functional connectivity MRI; Procedural memory ID MEMORY CONSOLIDATION; FUNCTIONAL CONNECTIVITY; HUMAN BRAIN; CORTEX; SEQUENCE; SPEECH; FMRI; RECONSOLIDATION; ACQUISITION; INVOLVEMENT AB There is ongoing debate concerning the functions of resting-state brain activity. Prior work demonstrates that memory encoding enhances subsequent resting-state functional connectivity within task-relevant networks and that these changes predict better recognition. Here, we used functional connectivity MRI (fcMRI) to examine whether task-induced changes in resting-state connectivity correlate with performance improvement after sleep. In two separate sessions, resting-state scans were acquired before and after participants performed a motor task. In one session participants trained on the motor sequence task (MST), a well-established probe of sleep-dependent memory consolidation, and were tested the next day, after a night of sleep. In the other session they performed a motor control task (MCT) that minimized learning. In an accompanying behavioral control study, participants trained on the MST and were tested after either a night of sleep or an equivalent interval of daytime wake. Both the fcMRI and the sleep control groups showed significant improvement of MST performance, while the wake control group did not. In the fcMRI group, increased connectivity in bilateral motor cortex following MST training correlated with this next-day improvement. This increased connectivity did not appear to reflect initial learning since it did not correlate with learning during training and was not greater after MST training than MCT performance. Instead, we hypothesize that this increased connectivity processed the new memories for sleep-dependent consolidation. Our findings demonstrate that physiological processes immediately after learning correlate with sleep-dependent performance improvement and suggest that the wakeful resting brain prepares memories of recent experiences for later consolidation during sleep. (c) 2014 Elsevier Inc. All rights reserved. C1 [Gregory, Michael D.; Robertson, Edwin M.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Tucker, Matthew; Stickgold, Robert] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA 02215 USA. [Gregory, Michael D.; Agam, Yigal; Vangel, Mark; Manoach, Dara S.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Gregory, Michael D.; Agam, Yigal; Tucker, Matthew; Robertson, Edwin M.; Stickgold, Robert; Manoach, Dara S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Agam, Yigal; Selvadurai, Chindhuri; Manoach, Dara S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Nagy, Amanda] Harvard Univ, Cambridge, MA 02138 USA. RP Manoach, DS (reprint author), Massachusetts Gen Hosp, 149 13th St,Room 1-111, Charlestown, MA 02129 USA. EM dara@nmr.mgh.harvard.edu FU National Alliance for Research on Schizophrenia and Depression; Milton Fund, Harvard University; National Institute for Mental Health [F32 MH088081, R01 MH48832]; MGH-ECOR Fund for Medical Discovery; National Institute of Neurological Disorders and Stroke [5T32NS51151-5]; Biogen IDEC, Clinical Fellowship in Multiple Sclerosis; National Center for Research Resources [P41RR14075] FX The authors are grateful to Susan Whitfield-Gabrieli, Randy Buckner, and Frank Guenther for consultation. Support provided by the National Alliance for Research on Schizophrenia and Depression (DSM); Milton Fund, Harvard University (ER, DSM); the National Institute for Mental Health, F32 MH088081 (YA) R01 MH48832 (RS); MGH-ECOR Fund for Medical Discovery (YA); the National Institute of Neurological Disorders and Stroke, 5T32NS51151-5 (MDG); Biogen IDEC, Clinical Fellowship in Multiple Sclerosis (MDG); and the National Center for Research Resources, P41RR14075. The authors declare no competing financial interests. NR 42 TC 2 Z9 3 U1 2 U2 24 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 NOV 15 PY 2014 VL 102 BP 666 EP 673 DI 10.1016/j.neuroimage.2014.08.044 PN 2 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU1PD UT WOS:000345391700040 PM 25173415 ER PT J AU Yucel, MA Evans, KC Selb, J Huppert, TJ Boas, DA Gagnon, L AF Yuecel, Meryem A. Evans, Karleyton C. Selb, Juliette Huppert, Theodore J. Boas, David A. Gagnon, Louis TI Validation of the hypercapnic calibrated fMRI method using DOT-fMRI fusion imaging SO NEUROIMAGE LA English DT Article DE BOLD calibration; Hypercapnia; fNIRS; CMRO2 ID CEREBRAL-BLOOD-FLOW; OXIDATIVE-METABOLISM; CARBON-DIOXIDE; BOLD SIGNAL; OXYGEN-CONSUMPTION; EVOKED BOLD; ACTIVATION; VOLUME; MOTOR; PERFUSION AB Calibrated functional magnetic resonance imaging (fMRI) is a widely used method to investigate brain function in terms of physiological quantities such as the cerebral metabolic rate of oxygen (CMRO2). The first and one of the most common methods of fMRI calibration is hypercapnic calibration. This is achieved via simultaneous measures of the blood-oxygenation-level dependent (BOLD) and the arterial spin labeling (ASL) signals during a functional task that evokes regional changes in CMRO2. A subsequent acquisition is then required during which the subject inhales carbon dioxide for short periods of time. A calibration constant, typically labeled M, is then estimated from the hypercapnic data and is subsequently used together with the BOLD-ASL recordings to compute evoked changes in CMRO2 during the functional task. The computation of M assumes a constant CMRO2 during the CO2 inhalation, an assumption that has been questioned since the origin of calibrated fMRI. In this study we used diffuse optical tomography (DOT) together with BOLD and ASL - an alternative calibration method that does not require any gas manipulation and therefore no constant CMRO2 assumption - to cross-validate the estimation of M obtained from a traditional hypercapnic calibration. We found a high correlation between the M values (R = 0.87, p < 0.01) estimated using these two approaches. The findings serve to validate the hypercapnic fMRI calibration technique and suggest that the inter-subject variability routinely obtained for M is reproducible with an alternative method and might therefore reflect inter-subject physiological variability. (C) 2014 Elsevier Inc. All rights reserved. C1 [Yuecel, Meryem A.; Selb, Juliette; Boas, David A.; Gagnon, Louis] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,MGH HST Athinoula A Martinos Ctr Biom, Charlestown, MA 02129 USA. [Evans, Karleyton C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Huppert, Theodore J.] Univ Pittsburgh, Dept Radiol & Bioengn, Pittsburgh, PA 15261 USA. RP Yucel, MA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,MGH HST Athinoula A Martinos Ctr Biom, 149,13th St, Charlestown, MA 02129 USA. EM mayucel@nmr.mgh.harvard.edu FU [P41-RR14075]; [R01-EB0000790]; [K23MH086619] FX We would like to thank Jean J Chen, Divya Bolar, Donald Mclaren and Elfar Adalsteinsson for helpful discussions regarding the analysis performed in this work. We also thank Richard Hoge, Frederic Lesage, Bruce Rosen and Claudine Gauthier for their guidance in initiating this project. We wish to also acknowledge Tian Yue, Allison Song and Jared Zimmerman for the technical assistance. Primary support for this work was P41-RR14075 and R01-EB0000790. This work was supported in part by K23MH086619 (KCE). NR 39 TC 4 Z9 4 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 NOV 15 PY 2014 VL 102 BP 729 EP 735 DI 10.1016/j.neuroimage.2014.08.052 PN 2 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU1PD UT WOS:000345391700046 PM 25196509 ER PT J AU Wheelock, MD Sreenivasan, KR Wood, KH Hoef, LWV Deshpande, G Knight, DC AF Wheelock, M. D. Sreenivasan, K. R. Wood, K. H. Hoef, L. W. Ver Deshpande, Gopikrishna Knight, D. C. TI Threat-related learning relies on distinct dorsal prefrontal cortex network connectivity SO NEUROIMAGE LA English DT Article DE Anxiety; Connectivity; Conditioning; Fear; fMRI ID GRANGER CAUSALITY ANALYSIS; ANTERIOR CINGULATE CORTEX; RESTING-STATE CONNECTIVITY; HUMAN AMYGDALA ACTIVITY; COGNITIVE CONTROL; CONDITIONED DIMINUTION; NEURAL MECHANISMS; ANXIETY DISORDER; FUNCTIONAL MRI; FEAR RESPONSES AB Conditioned changes in the emotional response to threat (e. g. aversive unconditioned stimulus; UCS) are mediated in part by the prefrontal cortex (PFC). Unpredictable threats elicit large emotional responses, while the response is diminished when the threat is predictable. A better understanding of how PFC connectivity to other brain regions varies with threat predictability would provide important insights into the neural processes that mediate conditioned diminution of the emotional response to threat. The present study examined brain connectivity during predictable and unpredictable threat exposure using a fear conditioning paradigm (previously published in Wood et al., 2012) in which unconditioned functional magnetic resonance imaging data were reanalyzed to assess effective connectivity. Granger causality analysis was performed using the time series data from 15 activated regions of interest after hemodynamic deconvolution, to determine regional effective connectivity. In addition, connectivity path weights were correlated with trait anxiety measures to assess the relationship between negative affect and brain connectivity. Results indicate the dorsomedial PFC (dmPFC) serves as a neural hub that influences activity in other brain regions when threats are unpredictable. In contrast, the dorsolateral PFC (dlPFC) serves as a neural hub that influences the activity of other brain regions when threats are predictable. These findings are consistent with the view that the dmPFC coordinates brain activity to take action, perhaps in a reactive manner, when an unpredicted threat is encountered, while the dlPFC coordinates brain regions to take action, in what may be a more proactive manner, to respond to predictable threats. Further, dlPFC connectivity to other brain regions (e. g. ventromedial PFC, amygdala, and insula) varied with negative affect (i.e. trait anxiety) when the UCS was predictable, suggesting that stronger connectivity may be required for emotion regulation in individuals with higher levels of negative affect. (C) 2014 Elsevier Inc. All rights reserved. C1 [Wheelock, M. D.; Wood, K. H.; Knight, D. C.] Univ Alabama Birmingham, Dept Psychol, Birmingham, AL 35233 USA. [Hoef, L. W. Ver] Univ Alabama Birmingham, Birmingham VA Med Ctr, Sch Med, Dept Neurol, Birmingham, AL 35233 USA. [Sreenivasan, K. R.; Deshpande, Gopikrishna] Auburn Univ, AU MRI Res Ctr, Dept Elect & Comp Engn, Auburn, AL 36849 USA. [Deshpande, Gopikrishna] Auburn Univ, Dept Psychol, Auburn, AL 36849 USA. RP Knight, DC (reprint author), Univ Alabama Birmingham, Dept Psychol, CIRC 235H,1720 2nd Ave S, Birmingham, AL 35233 USA. EM knightdc@uab.edu OI Deshpande, Gopikrishna/0000-0001-7471-5357 FU University of Alabama at Birmingham Faculty Development Grant Program; NIH [MH098348] FX This research was supported by the University of Alabama at Birmingham Faculty Development Grant Program and NIH grant MH098348 (D.C.K). NR 87 TC 13 Z9 13 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD NOV 15 PY 2014 VL 102 BP 904 EP 912 DI 10.1016/j.neuroimage.2014.08.005 PN 2 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AU1PD UT WOS:000345391700063 PM 25111474 ER PT J AU Kahraman, S Dirice, E De Jesus, DF Hu, J Kulkarni, RN AF Kahraman, Sevim Dirice, Ercument De Jesus, Dario F. Hu, Jiang Kulkarni, Rohit N. TI Maternal insulin resistance and transient hyperglycemia impact the metabolic and endocrine phenotypes of offspring SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE maternal insulin resistance; intrauterine environment; offspring metabolism; endocrine pancreas development; hyperinsulinemia ID GESTATIONAL DIABETES-MELLITUS; ISLET CELL-POPULATIONS; PLACENTAL HORMONES; GLUCAGON-SECRETION; WEIGHT-GAIN; RATS LEADS; C-PEPTIDE; GROWTH; PREGNANCY; FETAL AB Studies in both humans and rodents suggest that maternal diabetes leads to a higher risk of the fetus developing impaired glucose tolerance and obesity during adulthood. However, the impact of hyperinsulinemia in the mother on glucose homeostasis in the offspring has not been fully explored. We aimed to determine the consequences of maternal insulin resistance on offspring metabolism and endocrine pancreas development using the LIRKO mouse model, which exhibits sustained hyperinsulinemia and transient increase in blood glucose concentrations during pregnancy. We examined control offspring born to either LIRKO or control mothers on embryonic days 13.5, 15.5, and 17.5 and postpartum days 0, 4, and 10. Control offspring born to LIRKO mothers displayed low birth weights and subsequently rapidly gained weight, and their blood glucose and plasma insulin concentrations were higher than offspring born to control mothers in early postnatal life. In addition, concentrations of plasma leptin, glucagon, and active GLP-1 were higher in control pups from LIRKO mothers. Analyses of the endocrine pancreas revealed significantly reduced beta-cell area in control offspring of LIRKO mothers shortly after birth. beta-Cell proliferation and total islet number were also lower in control offspring of LIRKO mothers during early postnatal days. Together, these data indicate that maternal hyperinsulinemia and the transient hyperglycemia impair endocrine pancreas development in the control offspring and induce multiple metabolic alterations in early postnatal life. The relatively smaller beta-cell mass/area and beta-cell proliferation in these control offspring suggest cell-autonomous epigenetic mechanisms in the regulation of islet growth and development. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Kahraman, S (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. EM Rohit.Kulkarni@joslin.harvard.edu RI Dirice, Ercument/B-2825-2017; OI Kahraman, Sevim/0000-0002-2880-6589 FU National Institute of Diabetes and Digestive and Kidney Diseases [RO1-DK-67536, R01-DK-103215] FX R. N. Kulkarni acknowledges support from National Institute of Diabetes and Digestive and Kidney Diseases Grants RO1-DK-67536 and R01-DK-103215. NR 46 TC 4 Z9 4 U1 1 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD NOV 15 PY 2014 VL 307 IS 10 BP E906 EP E918 DI 10.1152/ajpendo.00210.2014 PG 13 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA AT9LP UT WOS:000345249200005 PM 25249504 ER PT J AU Badizadegan, K Thomas, AR Nagy, N Ndishabandi, D Miller, SA Alessandrini, A Belkind-Gerson, J Goldstein, AM AF Badizadegan, Kamran Thomas, Alyssa R. Nagy, Nandor Ndishabandi, Dorothy Miller, Sarah A. Alessandrini, Alessandro Belkind-Gerson, Jaime Goldstein, Allan M. TI Presence of intramucosal neuroglial cells in normal and aganglionic human colon SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE enteric nervous system; enteric glial cells; Hirschsprung disease ID ENTERIC NERVOUS-SYSTEM; HIRSCHSPRUNG-DISEASE; GLIAL-CELLS; CALRETININ IMMUNOHISTOCHEMISTRY; ABDOMINAL-PAIN; S-100 PROTEIN; GUT; BOWEL; EXPRESSION; DIAGNOSIS AB The enteric nervous system (ENS) is composed of neural crest-derived neurons (also known as ganglion cells) the cell bodies of which are located in the submucosal and myenteric plexuses of the intestinal wall. Intramucosal ganglion cells are known to exist but are rare and often considered ectopic. Also derived from the neural crest are enteric glial cells that populate the ganglia and the associated nerves, as well as the lamina propria of the intestinal mucosa. In Hirschsprung disease (HSCR), ganglion cells are absent from the distal gut because of a failure of neural crest-derived progenitor cells to complete their rostrocaudal migration during embryogenesis. The fate of intramucosal glial cells in human HSCR is essentially unknown. We demonstrate a network of intramucosal cells that exhibit dendritic morphology typical of neurons and glial cells. These dendritic cells are present throughout the human gut and express Tuj1, S100, glial fibrillary acidic protein, CD56, synaptophysin, and calretinin, consistent with mixed or overlapping neuroglial differentiation. The cells are present in aganglionic colon from patients with HSCR, but with an altered immunophenotype. Coexpression of Tuj1 and HNK1 in this cell population supports a neural crest origin. These findings extend and challenge the current understanding of ENS microanatomy and suggest the existence of an intramucosal population of neural crest-derived cells, present in HSCR, with overlapping immunophenotype of neurons and glia. Intramucosal neuroglial cells have not been previously recognized, and their presence in HSCR poses new questions about ENS development and the pathobiology of HSCR that merit further investigation. C1 [Badizadegan, Kamran] Nemours Childrens Hosp, Dept Pathol & Lab Med, Orlando, FL USA. [Thomas, Alyssa R.; Nagy, Nandor; Ndishabandi, Dorothy; Miller, Sarah A.; Alessandrini, Alessandro; Goldstein, Allan M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat Surg, Boston, MA USA. [Nagy, Nandor] Semmelweis Univ, Fac Med, Dept Human Morphol & Dev Biol, H-1085 Budapest, Hungary. [Belkind-Gerson, Jaime] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Pediat Gastroenterol, Boston, MA USA. RP Goldstein, AM (reprint author), Massachusetts Gen Hosp, Warren 1153, Boston, MA 02114 USA. EM agoldstein@partners.org NR 37 TC 5 Z9 5 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 EI 1522-1547 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD NOV 15 PY 2014 VL 307 IS 10 BP G1002 EP G1012 DI 10.1152/ajpgi.00164.2014 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA AT9YW UT WOS:000345281000006 PM 25214400 ER PT J AU Ishikawa, K Aguero, J Tilemann, L Ladage, D Hammoudi, N Kawase, Y Santos-Gallego, CG Fish, K Levine, RA Hajjar, RJ AF Ishikawa, Kiyotake Aguero, Jaume Tilemann, Lisa Ladage, Dennis Hammoudi, Nadjib Kawase, Yoshiaki Santos-Gallego, Carlos G. Fish, Kenneth Levine, Robert A. Hajjar, Roger J. TI Characterizing preclinical models of ischemic heart failure: differences between LAD and LCx infarctions SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE anterior; posterior; remodeling; torsion; sphericity ID CORONARY-ARTERY-DISEASE; MYOCARDIAL-INFARCTION; MITRAL REGURGITATION; PORCINE MODEL; ANIMAL-MODELS; SWINE; THERAPY; STRAIN; ECHOCARDIOGRAPHY; CARDIOMYOPATHY AB Large animal studies are an important step toward clinical translation of novel therapeutic approaches. We aimed to establish an ischemic heart failure (HF) model with a larger myocardial infarction (MI) relative to previous studies, and characterize the functional and structural features of this model. An MI was induced by occluding the proximal left anterior descending artery (LAD; n = 15) or the proximal left circumflex artery (LCx; n = 6) in Yorkshire pigs. Three pigs with sham procedures were also included. All pigs underwent hemodynamic and echocardiographic assessments before MI, at 1 mo, and 3 mo after MI. Analyses of left ventricular (LV) myocardial mechanics by means of strains and torsion were performed using speckle-tracking echocardiography and compared between the groups. The proximal LAD MI approach induced larger infarct sizes (14.2 +/- 3.2% vs. 10.6 +/- 1.9%, P = 0.03), depressed systolic function (LV ejection fraction; 39.8 +/- 7.5% vs. 54.1 +/- 4.6%, P < 0.001), and more LV remodeling (end-systolic volume index; 82 +/- 25 ml/m(2) vs. 51 +/- 18 ml/m(2), P = 0.02, LAD vs. LCx, respectively) compared with the LCx MI approach without compromising the survival rate. At the papillary muscle level, echocardiographic strain analysis revealed no differences in radial and circumferential strain between LAD and LCx MIs. However, in contrast with the LCx MI, the LAD MI resulted in significantly decreased longitudinal strain. The proximal LAD MI model induces more LV remodeling and depressed LV function relative to the LCx MI model. Location of MI significantly impacts the severity of HF, thus careful consideration is required when choosing an MI model for preclinical HF studies. C1 [Ishikawa, Kiyotake; Aguero, Jaume; Tilemann, Lisa; Ladage, Dennis; Hammoudi, Nadjib; Kawase, Yoshiaki; Santos-Gallego, Carlos G.; Fish, Kenneth; Hajjar, Roger J.] Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, New York, NY 10029 USA. [Levine, Robert A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Ishikawa, K (reprint author), Mt Sinai Sch Med, Cardiovasc Res Ctr, One Gustave L Levy Pl,Box 1030, New York, NY 10029 USA. EM kiyotake.ishikawa@mssm.edu RI ishikawa, kiyotake/I-6013-2015; Aguero, Jaume/I-8582-2016 OI Aguero, Jaume/0000-0001-7416-871X FU Leducq Foundation; National Heart, Lung, and Blood Institute [HHSN268201000045C, R01-HL-093183, HL-088434, HL-071763, HL-080498, HL-083156, P20-HL-100396]; Spanish Society of Cardiology (Ischemic Heart Disease section); Fundacion Alfonso Martin-Escudero; French Federation of Cardiology; German Research Foundation FX This work is supported by a grant from Leducq Foundation (to R. J. Hajjar) and by National Heart, Lung, and Blood Institute, as a Program of Excellence in Nanotechnology (PEN) Award, Contract No. HHSN268201000045C, and Grants R01-HL-093183, HL-088434, HL-071763, HL-080498, HL-083156, and P20-HL-100396 (to R. J. Hajjar). J. Aguero was supported by Spanish Society of Cardiology (Ischemic Heart Disease section) and Fundacion Alfonso Martin-Escudero. N. Hammoudi was supported by French Federation of Cardiology. D. Ladage was supported by the German Research Foundation. NR 37 TC 5 Z9 5 U1 0 U2 2 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 NOV 15 PY 2014 VL 307 IS 10 BP H1478 EP H1486 DI 10.1152/ajpheart.00797.2013 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA AT9LG UT WOS:000345248300012 PM 25217654 ER PT J AU Ban, J Aryee, DNT Fourtouna, A van der Ent, W Kauer, M Niedan, S Machado, I Rodriguez-Galindo, C Tirado, OM Schwentner, R Picci, P Flanagan, AM Berg, V Strauss, SJ Scotlandi, K Lawlor, ER Snaar-Jagalska, E Llombart-Bosch, A Kovar, H AF Ban, Jozef Aryee, Dave N. T. Fourtouna, Argyro van der Ent, Wietske Kauer, Max Niedan, Stephan Machado, Isidro Rodriguez-Galindo, Carlos Tirado, Oscar M. Schwentner, Raphaela Picci, Piero Flanagan, Adrienne M. Berg, Verena Strauss, Sandra J. Scotlandi, Katia Lawlor, Elizabeth R. Snaar-Jagalska, Ewa Llombart-Bosch, Antonio Kovar, Heinrich TI Suppression of Deacetylase SIRT1 Mediates Tumor-Suppressive NOTCH Response and Offers a Novel Treatment Option in Metastatic Ewing Sarcoma SO CANCER RESEARCH LA English DT Article ID DNA-DAMAGE; TRANSCRIPTIONAL ACTIVITY; PROTEIN STABILITY; REGULATES SIRT1; CELL-SURVIVAL; CANCER-CELLS; P53; PHOSPHORYLATION; ACETYLATION; ACTIVATION AB The developmental receptor NOTCH plays an important role in various human cancers as a consequence of oncogenic mutations. Here we describe a novel mechanism of NOTCH-induced tumor suppression involving modulation of the deacetylase SIRT1, providing a rationale for the use of SIRT1 inhibitors to treat cancers where this mechanism is inactivated because of SIRT1 overexpression. In Ewing sarcoma cells, NOTCH signaling is abrogated by the driver oncogene EWS-FLI1. Restoration of NOTCH signaling caused growth arrest due to activation of the NOTCH effector HEY1, directly suppressing SIRT1 and thereby activating p53. This mechanism of tumor suppression was validated in Ewing sarcoma cells, B-cell tumors, and human keratinocytes where NOTCH dysregulation has been implicated pathogenically. Notably, the SIRT1/2 inhibitor Tenovin-6 killed Ewing sarcoma cells in vitro and prohibited tumor growth and spread in an established xenograft model in zebrafish. Using immunohistochemistry to analyze primary tissue specimens, we found that high SIRT1 expression was associated with Ewing sarcoma metastasis and poor prognosis. Our findings suggest a mechanistic rationale for the use of SIRT1 inhibitors being developed to treat metastatic disease in patients with Ewing sarcoma. (C) 2014 AACR. C1 [Ban, Jozef; Aryee, Dave N. T.; Fourtouna, Argyro; Kauer, Max; Niedan, Stephan; Schwentner, Raphaela; Berg, Verena; Kovar, Heinrich] Childrens Canc Res Inst, A-1090 Vienna, Austria. [Aryee, Dave N. T.; Kovar, Heinrich] Med Univ Vienna, Dept Pediat, Vienna, Austria. [van der Ent, Wietske; Snaar-Jagalska, Ewa] Leiden Univ, Inst Biol, Leiden, Netherlands. [van der Ent, Wietske; Snaar-Jagalska, Ewa] Leiden Univ, Dept Pathol, Leiden, Netherlands. [Machado, Isidro; Llombart-Bosch, Antonio] Univ Med Sch, Dept Pathol, Valencia, Spain. [Rodriguez-Galindo, Carlos] Dana Farber Canc Inst, Boston, MA 02115 USA. [Tirado, Oscar M.] Hosp Llobregat, Inst Invest Biomed Bellvitge IDIBEL, Lab Oncol Mol, Barcelona, Spain. [Picci, Piero; Scotlandi, Katia] Rizzoli Inst, Lab Expt Oncol, Bologna, Italy. [Flanagan, Adrienne M.; Strauss, Sandra J.] UCL, Inst Canc, London, England. [Lawlor, Elizabeth R.] Univ Michigan, Translat Oncol Program, Dept Pediat, Ann Arbor, MI 48109 USA. [Lawlor, Elizabeth R.] Univ Michigan, Translat Oncol Program, Dept Pathol, Ann Arbor, MI 48109 USA. RP Kovar, H (reprint author), Childrens Canc Res Inst, Zimmermannplatz 10, A-1090 Vienna, Austria. EM heinrich.kovar@ccri.at RI Picci, Piero/J-5979-2016 OI Kovar, Heinrich/0000-0001-6873-9109; Picci, Piero/0000-0002-8519-4101 FU European Commission [259348]; Austrian Science Fund [P22328-B09, I1225-B19]; Fondo de Investigaciones Sanitarias-ISCIII-FEDER [CES12/021, PI110038]; National Institute for Health Research, University College London Hospitals Biomedical Research Centre; UCL Experimental Cancer Centre FX This study was supported by grants of the European Commission (FP7 grant 259348 "ASSET"), the Austrian Science Fund, grants P22328-B09 and I1225-B19 (ERA-NET "PROVABES"), and Fondo de Investigaciones Sanitarias-ISCIII-FEDER (CES12/021; PI110038). Support was provided to A.M. Flanagan and S.J. Strauss (UCL) by the National Institute for Health Research, University College London Hospitals Biomedical Research Centre, and the UCL Experimental Cancer Centre. NR 50 TC 13 Z9 13 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 NOV 15 PY 2014 VL 74 IS 22 BP 6578 EP 6588 DI 10.1158/0008-5472.CAN-14-1736 PG 11 WC Oncology SC Oncology GA AT7PR UT WOS:000345130500020 PM 25281719 ER PT J AU Cornaz-Buros, S Riggi, N DeVito, C Sarre, A Letovanec, I Provero, P Stamenkovic, I AF Cornaz-Buros, Sandrine Riggi, Nicolo DeVito, Claudio Sarre, Alexandre Letovanec, Igor Provero, Paolo Stamenkovic, Ivan TI Targeting Cancer Stem-like Cells as an Approach to Defeating Cellular Heterogeneity in Ewing Sarcoma SO CANCER RESEARCH LA English DT Article ID PLASTICITY; NETWORK AB Plasticity in cancer stem-like cells (CSC) may provide a key basis for cancer heterogeneity and therapeutic response. In this study, we assessed the effect of combining a drug that abrogates CSC properties with standard-of-care therapy in a Ewing sarcoma family tumor (ESFT). Emergence of CSC in this setting has been shown to arise from a defect in TARBP2-dependent microRNA maturation, which can be corrected by exposure to the fluoroquinolone enoxacin. In the present work, primary ESFT from four patients containing CD133(+) CSC subpopulations ranging from 3% to 17% of total tumor cells were subjected to treatment with enoxacin, doxorubicin, or both drugs. Primary ESFT CSC and bulk tumor cells displayed divergent responses to standard-of-care chemotherapy and enoxacin. Doxorubicin, which targets the tumor bulk, displayed toxicity toward primary adherent ESFT cells in culture but not to CSC-enriched ESFT spheres. Conversely, enoxacin, which enhances miRNA maturation by stimulating TARBP2 function, induced apoptosis but only in ESFT spheres. In combination, the two drugs markedly depleted CSCs and strongly reduced primary ESFTs in xenograft assays. Our results identify a potentially attractive therapeutic strategy for ESFT that combines mechanism-based targeting of CSC using a low-toxicity antibiotic with a standard-of-care cytotoxic drug, offering immediate applications for clinical evaluation. (C) 2014 AACR. C1 [Cornaz-Buros, Sandrine; Stamenkovic, Ivan] CHU Vaudois, Expt Pathol Serv, Lausanne, Switzerland. [Cornaz-Buros, Sandrine; Letovanec, Igor; Stamenkovic, Ivan] Univ Lausanne, Lausanne, Switzerland. [Riggi, Nicolo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [DeVito, Claudio] HUG, Dept Pathol, Geneva, Switzerland. [DeVito, Claudio] Univ Geneva, Geneva, Switzerland. [Sarre, Alexandre] Univ Lausanne, Mouse Cardiovasc Assessment Facil, Lausanne, Switzerland. [Letovanec, Igor] CHU Vaudois, Clin Pathol Serv, Lausanne, Switzerland. [Provero, Paolo] Ist Sci San Raffaele, Ctr Translat Genom & Bioinformat, I-20132 Milan, Italy. RP Stamenkovic, I (reprint author), Inst Pathol, 25 Rue Bugnon, CH-1011 Lausanne, Switzerland. EM Ivan.Stamenkovic@chuv.ch FU FNS [310030_150024, 32360-133894, P3SMP3_148408]; Oncosuisse [2766-02-2011]; ISREC Foundation Sarcoma Grant; Nuovo Soldati Foundation FX This study was supported by an FNS grant 310030_150024, Oncosuisse Grant 2766-02-2011, and ISREC Foundation Sarcoma Grant (I. Stamenkovic); FNS grant 32360-133894 (S. Cornaz-Buros); FNS grant P3SMP3_148408 and Nuovo Soldati Foundation grant (N. Riggi). NR 29 TC 3 Z9 3 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD NOV 15 PY 2014 VL 74 IS 22 BP 6610 EP 6622 DI 10.1158/0008-5472.CAN-14-1106 PG 13 WC Oncology SC Oncology GA AT7PR UT WOS:000345130500023 PM 25261238 ER PT J AU Gilbert, MR Armstrong, TS Pope, WB van den Bent, MJ Wen, PY AF Gilbert, Mark R. Armstrong, Terri S. Pope, Whitney B. van den Bent, Martin J. Wen, Patrick Y. TI Facing the Future of Brain Tumor Clinical Research SO CLINICAL CANCER RESEARCH LA English DT Article ID NEWLY-DIAGNOSED GLIOBLASTOMA; PHASE-II TRIAL; RECURRENT MALIGNANT GLIOMA; HIGH-GRADE GLIOMAS; SINGLE-AGENT BEVACIZUMAB; RANDOMIZED-TRIAL; ADJUVANT TEMOZOLOMIDE; RESPONSE ASSESSMENT; RADIATION-THERAPY; UNITED-STATES AB This edition of CCR Focus provides critical reviews of several important areas in the field, including the application of findings from genomic investigations of brain tumors to improve diagnosis, clinical trial design, and ultimately optimizing individual patient treatment. Another article is a critical review provided by experts in the field that discusses the recent clinical trials using angiogenesis inhibitors, possible explanations for the results, and how to move forward. There is a concise discussion of the application of immunotherapy to brain tumors by key investigators in this field, reflecting the potential opportunities as well as the disease-specific challenges. Finally, leading pediatric brain tumor investigators provide an overview of the field and insights about the recent seminal discoveries in two pediatric brain tumors, supporting the paradigm that laboratory investigations lead to more precise diagnosis, prognosis, and ultimately better treatment. Herein, an overview of the recent advances and challenges in the area of clinical and translational brain tumor research is provided to set the stage for the contributions that follow. (C) 2014 AACR. C1 [Gilbert, Mark R.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Armstrong, Terri S.] Univ Texas Houston, Hlth Sci Ctr, Sch Nursing, Houston, TX USA. [Pope, Whitney B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol, Los Angeles, CA 90095 USA. [van den Bent, Martin J.] Erasmus MC Canc Inst, Rotterdam, Netherlands. [Wen, Patrick Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Gilbert, MR (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, 1515 Holcombe Blvd,Box0100, Houston, TX 77030 USA. EM mrgilbert@mdanderson.org RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 FU Genentech; GlaxoSmithKline; Merck; AbbVie; Roche; Agios; Angiochem; AstraZeneca; Karyopharm Therapeutics; Novartis; Sanofi FX M. R. Gilbert reports receiving commercial research grants from Genentech, GlaxoSmithKline, and Merck, and is a consultant/advisory board member for AbbVie, Genentech, Heron Therapeutics, and Merck. T. S. Armstrong reports receiving a commercial research grant from Merck, other commercial research support from Genentech, and is a consultant/advisory board member for Roche. W. B. Pope is a consultant/advisory board member for Roche. M. J. van den Bent reports receiving commercial research grants from AbbVie and Roche; speakers bureau honoraria from Merck; and is a consultant/advisory board member for AbbVie, Amgen, CellDex Therapeutics, and Roche. P. Y. Wen reports receiving commercial research grants from Agios, Angiochem, AstraZeneca, Genentech, GlaxoSmithKline, Karyopharm Therapeutics, Novartis, and Sanofi; speakers bureau honoraria from Merck; and is a consultant/advisory board member for AbbVie, CellDex Therapeutics, Midatech, Novartis, Roche, Sigma-Tau Pharmaceuticals, and Vascular Biogenics. No other potential conflicts of interest were disclosed. NR 72 TC 2 Z9 2 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 NOV 15 PY 2014 VL 20 IS 22 BP 5591 EP 5600 DI 10.1158/1078-0432.CCR-14-0835 PG 10 WC Oncology SC Oncology GA AT7PT UT WOS:000345130800005 PM 25398842 ER PT J AU Batchelor, TT Reardon, DA de Groot, JF Wick, W Weller, M AF Batchelor, Tracy T. Reardon, David A. de Groot, John F. Wick, Wolfgang Weller, Michael TI Antiangiogenic Therapy for Glioblastoma: Current Status and Future Prospects SO CLINICAL CANCER RESEARCH LA English DT Article ID NEWLY-DIAGNOSED GLIOBLASTOMA; RECURRENT MALIGNANT GLIOMA; ANTI-VEGF THERAPY; POSITRON-EMISSION-TOMOGRAPHY; BEVACIZUMAB PLUS IRINOTECAN; STANDARD RADIATION-THERAPY; TYROSINE KINASE INHIBITOR; SINGLE-AGENT BEVACIZUMAB; BRAIN-TUMOR CONSORTIUM; III RANDOMIZED-TRIAL AB Glioblastoma is characterized by high expression levels of proangiogenic cytokines and microvascular proliferation, highlighting the potential value of treatments targeting angiogenesis. Antiangiogenic treatment likely achieves a beneficial impact through multiple mechanisms of action. Ultimately, however, alternative proangiogenic signal transduction pathways are activated, leading to the development of resistance, even in tumors that initially respond. The identification of biomarkers or imaging parameters to predict response and to herald resistance is of high priority. Despite promising phase II clinical trial results and patient benefit in terms of clinical improvement and longer progression-free survival, an overall survival benefit has not been demonstrated in four randomized phase III trials of bevacizumab or cilengitide in newly diagnosed glioblastoma or cediranib or enzastaurin in recurrent glioblastoma. However, future studies are warranted. Predictive markers may allow appropriate patient enrichment, combination with chemotherapy may ultimately prove successful in improving overall survival, and novel agents targeting multiple proangiogenic pathways may prove effective. (C)2014 AACR. C1 [Batchelor, Tracy T.] Massachusetts Gen Hosp, Stephen E & Catherine Pappas Ctr Neurooncol, Ctr Canc, Boston, MA 02114 USA. [Batchelor, Tracy T.; Reardon, David A.] Harvard Univ, Sch Med, Boston, MA USA. [Reardon, David A.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. [de Groot, John F.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Wick, Wolfgang] Univ Clin Heidelberg, Heidelberg, Germany. [Wick, Wolfgang] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany. [Weller, Michael] Univ Zurich Hosp, Dept Neurol, CH-8091 Zurich, Switzerland. [Weller, Michael] Univ Zurich Hosp, Brain Tumor Ctr, CH-8091 Zurich, Switzerland. RP Batchelor, TT (reprint author), Massachusetts Gen Hosp, Stephen E & Catherine Pappas Ctr Neurooncol, Yawkey 9E,55 Fruit St, Boston, MA 02114 USA. EM tbatchelor@mgh.harvard.edu FU NIH [P50CA165962, R01CA129371, K24CA125440, K12CA090354, R13CA124293] FX T.T. Batchelor was supported by the NCI of the NIH under award numbers P50CA165962, R01CA129371, K24CA125440, K12CA090354, and R13CA124293. NR 98 TC 25 Z9 25 U1 3 U2 12 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 NOV 15 PY 2014 VL 20 IS 22 BP 5612 EP 5619 DI 10.1158/1078-0432.CCR-14-0834 PG 8 WC Oncology SC Oncology GA AT7PT UT WOS:000345130800007 PM 25398844 ER PT J AU Katayama, R Friboulet, L Koike, S Lockerman, EL Khan, TM Gainor, JF Iafrate, AJ Takeuchi, K Taiji, M Okuno, Y Fujita, N Engelman, JA Shaw, AT AF Katayama, Ryohei Friboulet, Luc Koike, Sumie Lockerman, Elizabeth L. Khan, Tahsin M. Gainor, Justin F. Iafrate, A. John Takeuchi, Kengo Taiji, Makoto Okuno, Yasushi Fujita, Naoya Engelman, Jeffrey A. Shaw, Alice T. TI Two Novel ALK Mutations Mediate Acquired Resistance to the Next-Generation ALK Inhibitor Alectinib SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; ANAPLASTIC LYMPHOMA KINASE; EML4-ALK FUSION GENE; CRIZOTINIB RESISTANCE; IDENTIFICATION; NEUROBLASTOMA; CH5424802; SENSITIVITY; NVP-TAE684; CERITINIB AB Purpose: The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged non-small cell lung cancer (NSCLC). Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance. Experimental Design: We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure-activity relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE. Results: We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib. Conclusions: We have identified two novel ALK mutations arising after alectinib exposure that are sensitive to other next-generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs. (C) 2014 AACR. C1 [Katayama, Ryohei; Friboulet, Luc; Lockerman, Elizabeth L.; Khan, Tahsin M.; Gainor, Justin F.; Iafrate, A. John; Engelman, Jeffrey A.; Shaw, Alice T.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. [Katayama, Ryohei; Friboulet, Luc; Lockerman, Elizabeth L.; Gainor, Justin F.; Engelman, Jeffrey A.; Shaw, Alice T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Katayama, Ryohei; Koike, Sumie; Fujita, Naoya] Japanese Fdn Canc Res, Ctr Canc Chemotherapy, Tokyo 1358550, Japan. [Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Takeuchi, Kengo] Japanese Fdn Canc Res, Inst Canc, Pathol Project Mol Targets, Tokyo 1358550, Japan. [Taiji, Makoto] RIKEN Adv Inst Computat Sci 6F, Processor Res Team, Kobe, Hyogo, Japan. [Okuno, Yasushi] Kyoto Univ, Grad Sch Med, Kyoto, Japan. RP Fujita, N (reprint author), Japanese Fdn Canc Res, Ctr Canc Chemotherapy, Koto Ku, 3-8-31 Ariake, Tokyo 1358550, Japan. EM naoya.fujita@jfcr.or.jp; jengelman@mgh.harvard.edu; ashaw1@mgh.harvard.edu RI friboulet, luc/N-7276-2015 OI friboulet, luc/0000-0002-1129-4978 FU National Cancer Institute Lung SPORE [R01CA137008, R01CA140594]; JSPS KAKENHI [24300344, 22112008, 25710015]; [R01CA164273] FX The study was supported, in part, by R01CA137008, R01CA140594, National Cancer Institute Lung SPORE (to J.A. Engelman), R01CA164273 (to A.T. Shaw and J.A. Engelman) and JSPS KAKENHI grant number 24300344 and 22112008 (to N. Fujita) and 25710015 (to R. Katayama). NR 35 TC 69 Z9 70 U1 4 U2 20 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 NOV 15 PY 2014 VL 20 IS 22 BP 5686 EP 5696 DI 10.1158/1078-0432.CCR-14-1511 PG 11 WC Oncology SC Oncology GA AT7PT UT WOS:000345130800014 PM 25228534 ER PT J AU Garner, AP Gozgit, JM Anjum, R Vodala, S Schrock, A Zhou, TJ Serrano, C Eilers, G Zhu, MJ Ketzer, J Wardwell, S Ning, YY Song, Y Kohlmann, A Wang, F Clackson, T Heinrich, MC Fletcher, JA Bauer, S Rivera, VM AF Garner, Andrew P. Gozgit, Joseph M. Anjum, Rana Vodala, Sadanand Schrock, Alexa Zhou, Tianjun Serrano, Cesar Eilers, Grant Zhu, Meijun Ketzer, Julia Wardwell, Scott Ning, Yaoyu Song, Youngchul Kohlmann, Anna Wang, Frank Clackson, Tim Heinrich, Michael C. Fletcher, Jonathan A. Bauer, Sebastian Rivera, Victor M. TI Ponatinib Inhibits Polyclonal Drug-Resistant KIT Oncoproteins and Shows Therapeutic Potential in Heavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients SO CLINICAL CANCER RESEARCH LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; CHROMOSOME-POSITIVE LEUKEMIAS; C-KIT; IMATINIB RESISTANCE; MUTAGENESIS SCREEN; KINASE INHIBITOR; TYROSINE KINASE; MUTATIONS; SUNITINIB; EFFICACY AB Purpose: KIT is the major oncogenic driver of gastrointestinal stromal tumors (GIST). Imatinib, sunitinib, and regorafenib are approved therapies; however, efficacy is often limited by the acquisition of polyclonal secondary resistance mutations in KIT, with those located in the activation (A) loop (exons 17/18) being particularly problematic. Here, we explore the KIT-inhibitory activity of ponatinib in preclinical models and describe initial characterization of its activity in patients with GIST. Experimental Design: The cellular and in vivo activities of ponatinib, imatinib, sunitinib, and regorafenib against mutant KIT were evaluated using an accelerated mutagenesis assay and a panel of engineered and GIST-derived cell lines. The ponatinib-KIT costructure was also determined. The clinical activity of ponatinib was examined in three patients with GIST previously treated with all three FDA-approved agents. Results: In engineered and GIST-derived cell lines, ponatinib potently inhibited KIT exon 11 primary mutants and a range of secondary mutants, including those within the A-loop. Ponatinib also induced regression in engineered and GIST-derived tumor models containing these secondary mutations. In a mutagenesis screen, 40 nmol/L ponatinib was sufficient to suppress outgrowth of all secondary mutants except V654A, which was suppressed at 80 nmol/L. This inhibitory profile could be rationalized on the basis of structural analyses. Ponatinib (30 mg daily) displayed encouraging clinical activity in two of three patients with GIST. Conclusion: Ponatinib possesses potent activity against most major clinically relevant KIT mutants and has demonstrated preliminary evidence of activity in patients with refractory GIST. These data strongly support further evaluation of ponatinib in patients with GIST. Clin Cancer Res; 20(22); 5745-55. (C) 2014 AACR. C1 [Garner, Andrew P.; Gozgit, Joseph M.; Anjum, Rana; Vodala, Sadanand; Schrock, Alexa; Zhou, Tianjun; Wardwell, Scott; Ning, Yaoyu; Song, Youngchul; Kohlmann, Anna; Wang, Frank; Clackson, Tim; Rivera, Victor M.] ARIAD Pharmaceut Inc, Cambridge, MA 02139 USA. [Serrano, Cesar; Eilers, Grant; Zhu, Meijun; Fletcher, Jonathan A.] Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Sch Med, Boston, MA 02115 USA. [Ketzer, Julia; Bauer, Sebastian] Univ Duisburg Essen, West German Canc Ctr, Dept Med Oncol, Sarcoma Ctr, Essen, Germany. [Heinrich, Michael C.] Portland VA Med Ctr, Portland, OR USA. [Heinrich, Michael C.] OHSU Knight Canc Inst, Portland, OR USA. RP Rivera, VM (reprint author), ARIAD Pharmaceut Inc, Preclin & Translat Res, 26 Landsdowne St, Cambridge, MA 02139 USA. EM victor.rivera@ariad.com FU Deutsche Krebshilfe; U.S. NIH [1P50CA127003-07, 1P50CA168512-01]; Virginia and Daniel K. Ludwig Trust for Cancer Research; GIST Cancer Research Fund; Life Raft Group; ASCO Young Investigator Award; Spanish Society of Medical Oncology Translational Award; VA Merit Award from the Department of Veterans Affairs FX This work was supported by grants from Deutsche Krebshilfe (S.Bauer); the U.S. NIH, including 1P50CA127003-07 and 1P50CA168512-01 (J.A.Fletcher); the Virginia and Daniel K. Ludwig Trust for Cancer Research (J.A.Fletcher); the GIST Cancer Research Fund (M.C. Heinrich, J.A.Fletcher); the Life Raft Group (M.C.Heinrich, J.A.Fletcher, S.Bauer); an ASCO Young Investigator Award (C.Serrano); the Spanish Society of Medical Oncology Translational Award (C. Serrano); and a VA Merit Award Grant (M.C. Heinrich) from the Department of Veterans Affairs. NR 34 TC 14 Z9 16 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 NOV 15 PY 2014 VL 20 IS 22 BP 5745 EP 5755 DI 10.1158/1078-0432.CCR-14-1397 PG 11 WC Oncology SC Oncology GA AT7PT UT WOS:000345130800019 PM 25239608 ER PT J AU Kwon, MY Bao, PL Millin, R Tjan, BS AF Kwon, MiYoung Bao, Pinglei Millin, Rachel Tjan, Bosco S. TI Radial-tangential anisotropy of crowding in the early visual areas SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE anisotropy; crowding; fMRI; suppression; V1 ID OBJECT RECOGNITION; RECEPTIVE-FIELDS; CORTICAL MAGNIFICATION; SPATIAL INTERACTION; PERIPHERAL-VISION; VERNIER ACUITY; FUNCTIONAL MRI; CORTEX; PSYCHOPHYSICS; SUPPRESSION AB Crowding, the inability to recognize an individual object in clutter (Bouma H. Nature 226: 177-178, 1970), is considered a major impediment to object recognition in peripheral vision. Despite its significance, the cortical loci of crowding are not well understood. In particular, the role of the primary visual cortex (V1) remains unclear. Here we utilize a diagnostic feature of crowding to identify the earliest cortical locus of crowding. Controlling for other factors, radially arranged flankers induce more crowding than tangentially arranged ones (Toet A, Levi DM. Vision Res 32: 1349-1357, 1992). We used functional magnetic resonance imaging (fMRI) to measure the change in mean blood oxygenation level-dependent (BOLD) response due to the addition of a middle letter between a pair of radially or tangentially arranged flankers. Consistent with the previous finding that crowding is associated with a reduced BOLD response [Millin R, Arman AC, Chung ST, Tjan BS. Cereb Cortex (July 5, 2013). doi: 10.1093/cercor/bht159], we found that the BOLD signal evoked by the middle letter depended on the arrangement of the flankers: less BOLD response was associated with adding the middle letter between radially arranged flankers compared with adding it between tangentially arranged flankers. This anisotropy in BOLD response was present as early as V1 and remained significant in downstream areas. The effect was observed while subjects' attention was diverted away from the testing stimuli. Contrast detection threshold for the middle letter was unaffected by flanker arrangement, ruling out surround suppression of contrast response as a major factor in the observed BOLD anisotropy. Our findings support the view that V1 contributes to crowding. C1 [Tjan, Bosco S.] Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. [Bao, Pinglei; Millin, Rachel; Tjan, Bosco S.] Univ So Calif, Grad Program Neurosci, Los Angeles, CA USA. [Kwon, MiYoung] Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. [Kwon, MiYoung] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Tjan, BS (reprint author), South McClintock Ave,SGM 501, Los Angeles, CA 90089 USA. EM btjan@usc.edu FU National Eye Institute [R01 EY-017707] FX This work was supported by National Eye Institute Grant R01 EY-017707. NR 60 TC 5 Z9 6 U1 1 U2 14 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD NOV 15 PY 2014 VL 112 IS 10 BP 2413 EP 2422 DI 10.1152/jn.00476.2014 PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA AT9MQ UT WOS:000345251800006 PM 25122703 ER PT J AU Gandhi, PU Gaggin, HK Sheftel, AD Belcher, AM Weiner, RB Baggish, AL Motiwala, SR Liu, PP Januzzi, JL AF Gandhi, Parul U. Gaggin, Hanna K. Sheftel, Alex D. Belcher, Arianna M. Weiner, Rory B. Baggish, Aaron L. Motiwala, Shweta R. Liu, Peter P. Januzzi, James L., Jr. TI Prognostic Usefulness of Insulin-Like Growth Factor-Binding Protein 7 in Heart Failure With Reduced Ejection Fraction: A Novel Biomarker of Myocardial Diastolic Function? SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID NATRIURETIC PEPTIDE; THERAPY; DYSFUNCTION; PROTECT AB Insulin-like growth factor binding protein 7 (IGFBP7) is a biomarker that has recently been associated with heart failure and cardiac hypertrophy. The aim of this study was to examine IGFBP7 relative to echocardiographic abnormalities reflecting diastolic dysfunction. One hundred twenty-four patients with ambulatory heart failure with reduced ejection fraction and baseline detailed 2-dimensional echocardiograms were followed for a mean of 10 months. IGFBP7 was measured serially at each office visit; 108 patients underwent follow-up echocardiography. Echocardiographic parameters of diastolic function were compared at baseline and over time. IGFBP7 concentrations were not linked to left ventricular size or systolic function. In contrast, those with elevated baseline IGFBP7 concentrations were more likely to have abnormalities of parameters describing diastolic function, such as higher left atrial volume index, transmitral E/A ratio, E/E' ratio, and right ventricular systolic pressure. IGFBP7 was correlated with left atrial volume index (rho = 0.237, p = 0.008), transmitral E/A ratio (rho = 0.304, p = 0.001), E/E' ratio (rho = 0.257, p = 0.005), and right ventricular systolic pressure (rho = 0.316, p = 0.001). Furthermore, each was found to be independently predictive of IGFBP7 in adjusted analysis. In subjects with baseline and final echocardiograms, more time spent with elevated IGFBP7 concentrations " in serial measurement was associated with worsening diastolic function and increasing left atrial volume index or right ventricular systolic pressure. IGFBP7 concentrations were predictive of an increased risk for cardiovascular events independent of echocardiographic measures of diastolic function (p = 0.006). In conclusion, IGFBP7 is a novel prognostic biomarker for heart failure with reduced ejection fraction and shows significant links to the presence and severity of echocardiographic parameters of abnormal diastolic function. (C) 2014 Elsevier Inc. All rights reserved. C1 [Gandhi, Parul U.; Gaggin, Hanna K.; Belcher, Arianna M.; Weiner, Rory B.; Baggish, Aaron L.; Motiwala, Shweta R.; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Sheftel, Alex D.; Liu, Peter P.] Univ Ottawa, Inst Heart, Ottawa, ON, Canada. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. EM jjanuzzi@partners.org RI Sheftel, Alex/G-1043-2010 OI Sheftel, Alex/0000-0002-3126-5066 FU Roche Diagnostics; Dennis and Marilyn Barry Fellowship in Cardiology; Clark Fund for Cardiac Research Innovation; Roman W. DeSanctis Clinical Scholar Endowment FX This study was partially supported by Roche Diagnostics, which had no role in the analysis of data or preparation of this manuscript. Drs. Gandhi and Motiwala are supported by the Dennis and Marilyn Barry Fellowship in Cardiology. Dr. Gaggin is supported in part by the Clark Fund for Cardiac Research Innovation. Dr. Januzzi is supported in part by the Roman W. DeSanctis Clinical Scholar Endowment. NR 16 TC 8 Z9 8 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 NOV 15 PY 2014 VL 114 IS 10 BP 1543 EP 1549 DI 10.1016/j.amjcard.2014.08.018 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT3LY UT WOS:000344837500013 PM 25248814 ER PT J AU Duan, QN Wang, ZC Fernandez, NF Rouillard, AD Tan, CM Benes, CH Ma'ayan, A AF Duan, Qiaonan Wang, Zichen Fernandez, Nicolas F. Rouillard, Andrew D. Tan, Christopher M. Benes, Cyril H. Ma'ayan, Avi TI Drug/Cell-line Browser: interactive canvas visualization of cancer drug/cell-line viability assay datasets SO BIOINFORMATICS LA English DT Article ID DRUG-SENSITIVITY AB Recently, several high profile studies collected cell viability data from panels of cancer cell lines treated with many drugs applied at different concentrations. Such drug sensitivity data for cancer cell lines provide suggestive treatments for different types and subtypes of cancer. Visualization of these datasets can reveal patterns that may not be obvious by examining the data without such efforts. Here we introduce Drug/Cell-line Browser (DCB), an online interactive HTML5 data visualization tool for interacting with three of the recently published datasets of cancer cell lines/drug-viability studies. DCB uses clustering and canvas visualization of the drugs and the cell lines, as well as a bar graph that summarizes drug effectiveness for the tissue of origin or the cancer subtypes for single or multiple drugs. DCB can help in understanding drug response patterns and prioritizing drug/cancer cell line interactions by tissue of origin or cancer subtype. C1 [Duan, Qiaonan; Wang, Zichen; Fernandez, Nicolas F.; Rouillard, Andrew D.; Tan, Christopher M.; Ma'ayan, Avi] Icahn Sch Med Mt Sinai, Syst Biol Ctr New York, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [Benes, Cyril H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc,Ctr Canc Res, Charlestown, MA 02129 USA. RP Ma'ayan, A (reprint author), Icahn Sch Med Mt Sinai, Syst Biol Ctr New York, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. EM avi.maayan@mssm.edu OI Wang, Zichen/0000-0002-1415-1286 FU NIH [R01GM098316-01A1, R01DK088541-01A1, U54HG006097-02S1, U54CA189201] FX This work was supported in part by grants from the NIH: R01GM098316-01A1, R01DK088541-01A1, U54HG006097-02S1 and U54CA189201 to A.M. NR 7 TC 2 Z9 2 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD NOV 15 PY 2014 VL 30 IS 22 BP 3289 EP 3290 DI 10.1093/bioinformatics/btu526 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA AT2OQ UT WOS:000344774600027 PM 25100688 ER PT J AU Gonzalez, A Japuntich, S Keating, NL Wallace, R He, YL Streck, JM Park, ER AF Gonzalez, Adam Japuntich, Sandra Keating, Nancy L. Wallace, Robert He, Yulei Streck, Joanna M. Park, Elyse R. TI Pain Experiences Among a Population-Based Cohort of Current, Former, and Never Regular Smokers With Lung and Colorectal Cancer SO CANCER LA English DT Article DE smoking; pain; lung cancer; colorectal cancer ID CARE OUTCOMES RESEARCH; CIGARETTE-SMOKING; NICOTINE DEPENDENCE; RISK-FACTORS; TOBACCO USE; BACK-PAIN; NECK PAIN; PREVALENCE; DEPRESSION; CESSATION AB BACKGROUND Smoking and pain are prevalent and comorbid among patients with cancer. Limited work has compared pain experiences among current, former, and never (regular) smokers with lung and colorectal cancer. METHODS We studied pain experiences of patients with lung (n=2390) and colorectal (n=2993) cancer participating in the multi-regional Cancer Care Outcomes Research and Surveillance study. We examined reports of pain, pain treatment, pain severity, and pain-related interference within each cancer group by smoking status, adjusting for demographic, psychosocial, and cancer characteristics. RESULTS Among lung cancer patients, current smokers reported pain and receiving pain treatment more often than former smokers. Never smokers did not differ from current and former smokers on endorsement of pain; however, they reported pain treatment less often than their counterparts. Current smokers reported greater pain severity than former smokers after adjusting for other contributing factors; however, no differences were detected between current and never smokers. There were no differences in pain-related interference. Among colorectal cancer patients, current smokers reported pain and pain treatment more often than former and never smokers; however, the latter 2 groups did not differ. Current smokers also reported greater pain severity than never smokers after adjustments; however, no differences were detected between current and former smokers. An identical pattern of findings was observed for pain-related interference. CONCLUSIONS Many smokers with lung and colorectal cancer experience pain following a cancer diagnosis. Future work should assess if comprehensive smoking cessation treatments that address pain can reduce pain and facilitate smoking cessation among patients with cancer. (c) 2014 American Cancer Society. C1 [Gonzalez, Adam] SUNY Stony Brook, Dept Psychiat, Stony Brook, NY 11794 USA. [Japuntich, Sandra] VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Jamaica Plain, MA USA. [Keating, Nancy L.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. [Keating, Nancy L.; He, Yulei] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Wallace, Robert] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Streck, Joanna M.; Park, Elyse R.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Gonzalez, A (reprint author), SUNY Stony Brook, Putnam Hall, Stony Brook, NY 11794 USA. EM adam.gonzalez@stonybrookmedicine.edu FU National Cancer Institute (NCI) [U01CA093344]; NCI [U01CA093332]; NCI (Harvard Medical School/Northern California Cancer Center) [U01CA093324]; NCI (RAND/UCLA) [U01CA093348]; NCI (University of Alabama at Birmingham) [U01CA093329]; NCI (University of Iowa) [U01 CA093339]; NCI (University of North Carolina) [U01CA093326]; Department of Veterans Affairs [CRS 02-164]; ACS [Park MSRG 005-05-CPPB] FX This work of the Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium was supported by grants from the National Cancer Institute (NCI) to the Statistical Coordinating Center (U01CA093344) and the NCI-supported Primary Data Collection and Research Centers (Dana Farber Cancer Institute/Cancer Research Network U01CA093332, Harvard Medical School/Northern California Cancer Center U01CA093324, RAND/UCLA U01CA093348, University of Alabama at Birmingham U01CA093329, University of Iowa U01 CA093339, University of North Carolina U01CA093326), Department of Veterans Affairs grant to the Durham VA Medical Center CRS 02-164, and the ACS (Park MSRG 005-05-CPPB). NR 51 TC 5 Z9 5 U1 3 U2 6 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 NOV 15 PY 2014 VL 120 IS 22 BP 3554 EP 3561 DI 10.1002/cncr.28893 PG 8 WC Oncology SC Oncology GA AT0UT UT WOS:000344650900018 PM 25043285 ER PT J AU Kontoyiannis, DP Patterson, TF AF Kontoyiannis, Dimitrios P. Patterson, Thomas F. TI Diagnosis and Treatment of Invasive Fungal Infections in the Cancer Patient: Recent Progress and Ongoing Questions SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE cancer; Aspergillosis; candidiasis; treatment; diagnosis ID POLYMERASE-CHAIN-REACTION; HEMATOLOGICAL MALIGNANCIES; ANTIFUNGAL THERAPY; MOLD INFECTIONS; ASPERGILLOSIS; PULMONARY; GALACTOMANNAN; DISEASES; IDENTIFICATION; MUCORMYCOSIS AB In the last 5 years we have witnessed further developments in diagnosis and treatment of invasive fungal infections (IFIs) that complicate cancer chemotherapy. In this brief overview, we highlight some advancement, discuss future directions, and unmet needs in this complex area. C1 [Kontoyiannis, Dimitrios P.; Patterson, Thomas F.] Univ Texas MD Anderson Canc Ctr, Div Internal Med, Houston, TX 77030 USA. [Kontoyiannis, Dimitrios P.; Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Kontoyiannis, Dimitrios P.; Patterson, Thomas F.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Kontoyiannis, DP (reprint author), Univ Texas MD Anderson Canc Ctr, Div Internal Med, 1400 Pressler St,FCT 12-5069,Unit 1463, Houston, TX 77030 USA. EM dkontoyi@mdanderson.org FU National Institute of Health; Agency for Healthcare Research and Quality (AHRQ) [R13 HS021599] FX Funding for this conference was made possible [in part] by the National Institute of Health and by grant (R13 HS021599) from the Agency for Healthcare Research and Quality (AHRQ). NR 37 TC 4 Z9 4 U1 0 U2 4 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 NOV 15 PY 2014 VL 59 SU 5 BP S356 EP S359 DI 10.1093/cid/ciu591 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0TQ UT WOS:000344648100006 PM 25352631 ER PT J AU Kuiper, JJW Van Setten, J Ripke, S Van 'T Slot, R Mulder, F Missotten, T Baarsma, GS Francioli, LC Pulit, SL De Kovel, CGF Ten Dam-Van Loon, N Den Hollander, AI Veld, PHIH Hoyng, CB Cordero-Coma, M Martin, J Llorenc, V Arya, B Thomas, D Bakker, SC Ophoff, RA Rothova, A De Bakker, PIW Mutis, T Koeleman, BPC AF Kuiper, Jonas J. W. Van Setten, Jessica Ripke, Stephan Van 'T Slot, Ruben Mulder, Flip Missotten, Tom Baarsma, G. Seerp Francioli, Laurent C. Pulit, Sara L. De Kovel, Carolien G. F. Ten Dam-Van Loon, Ninette Den Hollander, Anneke I. Veld, Paulien Huis In Het Hoyng, Carel B. Cordero-Coma, Miguel Martin, Javier Llorenc, Victor Arya, Bharti Thomas, Dhanes Bakker, Steven C. Ophoff, Roel A. Rothova, Aniki De Bakker, Paul I. W. Mutis, Tuna Koeleman, Bobby P. C. TI A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy SO HUMAN MOLECULAR GENETICS LA English DT Article ID CROHNS-DISEASE SUSCEPTIBILITY; ANKYLOSING-SPONDYLITIS; ENDOPLASMIC-RETICULUM; RHEUMATOID-ARTHRITIS; HUMAN HEIGHT; RISK LOCI; RETINOCHOROIDOPATHY; AUTOPHAGY; MULTIPLE; VARIANTS AB Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC association (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 x 10(-74)). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093; OR = 2.3, 95% CI 1.7-3.1, for the T allele, P = 8.6 x 10(-8)) and at 14q32.31 in the TECPR2 gene (rs150571175; OR = 6.1, 95% CI 3.2-11.7, for the Aallele, P = 3.2 x 10(-8)). The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 x 10(-9)). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum. C1 [Kuiper, Jonas J. W.; Ten Dam-Van Loon, Ninette; Rothova, Aniki] Rudolf Magnus Inst Neurosci, Dept Ophthalmol, NL-3508 TA Utrecht, Netherlands. [Kuiper, Jonas J. W.; Mutis, Tuna] Rudolf Magnus Inst Neurosci, Dept Clin Chem & Hematol, NL-3508 TA Utrecht, Netherlands. [Van Setten, Jessica; Van 'T Slot, Ruben; Mulder, Flip; Francioli, Laurent C.; Pulit, Sara L.; De Kovel, Carolien G. F.; De Bakker, Paul I. W.; Koeleman, Bobby P. C.] Rudolf Magnus Inst Neurosci, Dept Med Genet, NL-3508 TA Utrecht, Netherlands. [Bakker, Steven C.; Ophoff, Roel A.] Rudolf Magnus Inst Neurosci, Dept Psychiat, NL-3508 TA Utrecht, Netherlands. [De Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Epidemiol, Utrecht, Netherlands. [Ripke, Stephan] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Ripke, Stephan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Missotten, Tom; Baarsma, G. Seerp] Rotterdam Eye Hosp, Rotterdam, Netherlands. [Den Hollander, Anneke I.; Veld, Paulien Huis In Het; Hoyng, Carel B.] Radboud Univ Nijmegen, Med Ctr, Dept Ophthalmol, NL-6525 ED Nijmegen, Netherlands. [Den Hollander, Anneke I.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Cordero-Coma, Miguel] Hosp Univ Leon, Unidad Uveitis, Serv Oftalmol, Leon, Spain. [Martin, Javier] CSIC, IPBLN, Granada, Spain. [Llorenc, Victor] Hosp Clin Barcelona, Inst Clin Oftalmol ICOF, Barcelona, Spain. [Arya, Bharti] Moorfields Eye Hosp NHS Fdn Trust, London, England. [Ophoff, Roel A.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Ophoff, Roel A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Rothova, Aniki] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. RP Koeleman, BPC (reprint author), Lundlaan 6, NL-3584 CG Utrecht, Netherlands. EM B.P.C.Koeleman@umcutrecht.nl RI de Bakker, Paul/B-8730-2009; Hoyng, C.B./H-8050-2014; Hollander, Anneke/N-4911-2014; Martin, Javier/B-8141-2008; OI de Bakker, Paul/0000-0001-7735-7858; de Kovel, Carolien/0000-0002-7818-1396 FU NIH/NIMH [MH090553]; Netherlands Organization for Scientific Research (N.W.O.) [016.126.354] FX Genotyping of Dutch control sample was supported by NIH/NIMH MH090553 to R.A.O. P.I.W.d.B. is a recipient of a VIDI Award from the Netherlands Organization for Scientific Research (N.W.O. project number 016.126.354). NR 54 TC 20 Z9 20 U1 0 U2 8 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 NOV 15 PY 2014 VL 23 IS 22 BP 6081 EP 6087 DI 10.1093/hmg/ddu307 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AT1CY UT WOS:000344671900020 PM 24957906 ER PT J AU Mell, LK Zietman, AL AF Mell, Loren K. Zietman, Anthony L. TI Introducing Prospective Manuscript Review to Address Publication Bias SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID CLINICAL-RESEARCH; VICE-VERSA; METAANALYSIS; DECISIONS; TRIALS; TESTS C1 [Mell, Loren K.] Univ Calif San Diego, Dept Radiat Med & Appl Sci, La Jolla, CA 92093 USA. [Zietman, Anthony L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Mell, LK (reprint author), Dept Radiat Med & Appl Sci, 3855 Hlth Sci Dr,MC0843, La Jolla, CA 92093 USA. EM lmell@ucsd.edu NR 20 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2014 VL 90 IS 4 BP 729 EP 732 DI 10.1016/j.ijrobp.2014.07.052 PG 4 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AT2AY UT WOS:000344734300003 PM 25585776 ER PT J AU Warren, LEG Punglia, RS Wong, JS Bellon, JR AF Warren, Laura E. G. Punglia, Rinaa S. Wong, Julia S. Bellon, Jennifer R. TI Management of the Regional Lymph Nodes Following Breast-Conservation Therapy for Early-Stage Breast Cancer: An Evolving Paradigm SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID EORTC TRIAL 22922/10925; INTERNAL MAMMARY NODES; NO AXILLARY DISSECTION; ACOSOG Z0011 TRIAL; RADIATION-THERAPY; RANDOMIZED-TRIAL; QUALITY-ASSURANCE; CLINICAL-PRACTICE; AMERICAN-COLLEGE; TOTAL MASTECTOMY AB Radiation therapy to the breast following breast conservation surgery has been the standard of care since randomized trials demonstrated equivalent survival compared to mastectomy and improved local control and survival compared to breast conservation surgery alone. Recent controversies regarding adjuvant radiation therapy have included the potential role of additional radiation to the regional lymph nodes. This review summarizes the evolution of regional nodal management focusing on 2 topics: first, the changing paradigm with regard to surgical evaluation of the axilla; second, the role for regional lymph node irradiation and optimal design of treatment fields. Contemporary data reaffirm prior studies showing that complete axillary dissection may not provide additional benefit relative to sentinel lymph node biopsy in select patient populations. Preliminary data also suggest that directed nodal radiation therapy to the supraclavicular and internal mammary lymph nodes may prove beneficial; publication of several studies are awaited to confirm these results and to help define subgroups with the greatest likelihood of benefit. (C) 2014 Elsevier Inc. C1 [Warren, Laura E. G.] Harvard Radiat Oncol Program, Boston, MA USA. [Punglia, Rinaa S.; Wong, Julia S.; Bellon, Jennifer R.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Punglia, Rinaa S.; Wong, Julia S.; Bellon, Jennifer R.] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Bellon, JR (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM jbellon@lroc.harvard.edu NR 44 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2014 VL 90 IS 4 BP 772 EP 777 DI 10.1016/j.ijrobp.2014.07.006 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AT2AY UT WOS:000344734300010 PM 25585780 ER PT J AU Mouw, KW Sethi, RV Yeap, BY MacDonald, SM Chen, YLE Tarbell, NJ Yock, TI Munzenrider, JE Adams, J Grabowski, E Mukai, S Shih, HA AF Mouw, Kent W. Sethi, Roshan V. Yeap, Beow Y. MacDonald, Shannon M. Chen, Yen-Lin E. Tarbell, Nancy J. Yock, Torunn I. Munzenrider, John E. Adams, Judith Grabowski, Eric Mukai, Shizuo Shih, Helen A. TI Proton Radiation Therapy for the Treatment of Retinoblastoma SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID EXTERNAL-BEAM RADIOTHERAPY; LONG-TERM SURVIVORS; SARCOMA; RISK AB Purpose: To investigate long-term disease and toxicity outcomes for pediatric retinoblastoma patients treated with proton radiation therapy (PRT). Methods and Materials: This is a retrospective analysis of 49 retinoblastoma patients (60 eyes) treated with PRT between 1986 and 2012. Results: The majority (84%) of patients had bilateral disease, and nearly half (45%) had received prior chemotherapy. At a median follow-up of 8 years (range, 1-24 years), no patients died of retinoblastoma or developed metastatic disease. The post-PRT enucleation rate was low (18%), especially in patients with early-stage disease (11% for patients with International Classification for Intraocular Retinoblastoma [ ICIR] stage A-B disease vs 23% for patients with ICIR stage C-D disease). PostPRT ophthalmologic follow-up was available for 61% of the preserved eyes (30 of 49): 14 of 30 eyes (47%) had 20/40 visual acuity or better, 7 of 30 (23%) had moderate visual acuity (20/40-20/600), and 9 of 30 (30%) had little or no useful vision (worse than 20/600). Twelve of 60 treated eyes (20%) experienced a post-PRT event requiring intervention, with cataracts the most common (4 eyes). No patients developed an infield second malignancy. Conclusions: Long-term follow-up of retinoblastoma patients treated with PRT demonstrates that PRT can achieve high local control rates, even in advanced cases, and many patients retain useful vision in the treated eye. Treatment-related ocular side effects were uncommon, and no radiation-associated malignancies were observed. (C) 2014 Elsevier Inc. C1 [Mouw, Kent W.] Harvard Radiat Oncol Program, Boston, MA USA. [Mouw, Kent W.; Sethi, Roshan V.; Yeap, Beow Y.; MacDonald, Shannon M.; Chen, Yen-Lin E.; Tarbell, Nancy J.; Yock, Torunn I.; Munzenrider, John E.; Adams, Judith; Shih, Helen A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Grabowski, Eric] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Mukai, Shizuo] Massachusetts Eye & Ear Infirm, Retina Serv, Dept Ophthalmol, Boston, MA 02114 USA. RP Shih, HA (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. EM hshih@partners.org FU NCI NIH HHS [K12 CA090354, P01 CA021239, P50 CA127003] NR 21 TC 7 Z9 7 U1 0 U2 5 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 NOV 15 PY 2014 VL 90 IS 4 BP 863 EP 869 DI 10.1016/j.ijrobp.2014.07.031 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AT2AY UT WOS:000344734300022 PM 25227498 ER PT J AU Shusharina, N Sharp, GC Choi, NC AF Shusharina, Nadya Sharp, Gregory C. Choi, Noah C. TI Correlation of F-18-FDG PET Avid Volumes on Pre-Radiation Therapy and Post-Radiation Therapy FDG PET Scans in Recurrent Lung Cancer Reply SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Letter C1 [Shusharina, Nadya; Sharp, Gregory C.; Choi, Noah C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02163 USA. RP Shusharina, N (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02163 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 15 PY 2014 VL 90 IS 4 BP 969 EP 970 DI 10.1016/j.ijrobp.2014.07.010 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AT2AY UT WOS:000344734300038 PM 25585791 ER PT J AU Li, JZ Gandhi, RT AF Li, Jonathan Z. Gandhi, Rajesh T. TI The Sooner, the Better: More Evidence That Early Antiretroviral Therapy Lowers Viral Reservoirs in HIV-Infected Infants SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material DE HIV reservoir; perinatal infection; antiretroviral therapy ID CD4(+) T-CELLS; IMMUNODEFICIENCY-VIRUS TYPE-1; CHILDREN; ACTIVATION; ESTABLISHMENT; PERSISTENCE; CESSATION; VIREMIA; SIZE; GUT C1 [Li, Jonathan Z.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Li, Jonathan Z.; Gandhi, Rajesh T.] Harvard Univ, Sch Med, Boston, MA USA. [Gandhi, Rajesh T.] Ragon Inst MGH MIT & Harvard, Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. RP Gandhi, RT (reprint author), Massachusetts Gen Hosp, GRJ 504,55 Fruit St, Boston, MA 02114 USA. EM rgandhi@partners.org FU NIAID NIH HHS [5P30AI060354-08] NR 34 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 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 15 PY 2014 VL 210 IS 10 BP 1519 EP 1522 DI 10.1093/infdis/jiu298 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0EY UT WOS:000344611200001 PM 24850791 ER PT J AU Sandler, NG Zhang, XY Bosch, RJ Funderburg, NT Choi, AI Robinson, JK Fine, DM Coombs, RW Jacobson, JM Landay, AL Douek, DC Tressler, R Read, SW Wilson, CC Deeks, SG Lederman, MM Gandhi, RT AF Sandler, Netanya G. Zhang, Xinyan Bosch, Ronald J. Funderburg, Nicholas T. Choi, Andrew I. Robinson, Janet K. Fine, Derek M. Coombs, Robert W. Jacobson, Jeffrey M. Landay, Alan L. Douek, Daniel C. Tressler, Randall Read, Sarah W. Wilson, Cara C. Deeks, Steven G. Lederman, Michael M. Gandhi, Rajesh T. CA AIDS Clinical Trials Grp A5296 TI Sevelamer Does Not Decrease Lipopolysaccharide or Soluble CD14 Levels But Decreases Soluble Tissue Factor, Low-Density Lipoprotein (LDL) Cholesterol, and Oxidized LDL Cholesterol Levels in Individuals With Untreated HIV Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; sevelamer; microbial translocation; LPS; sCD14; soluble tissue factor; LDL; oxLDL ID HEMODIALYSIS-PATIENTS; MORTALITY AB Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)-infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits. C1 [Sandler, Netanya G.; Douek, Daniel C.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Tressler, Randall; Read, Sarah W.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Fine, Derek M.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Sandler, Netanya G.] Univ Texas Med Branch, Dept Internal Med, Galveston, TX 77555 USA. [Zhang, Xinyan; Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Ctr Biostatist AIDS Res, Boston, MA 02115 USA. [Gandhi, Rajesh T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Funderburg, Nicholas T.; Robinson, Janet K.; Lederman, Michael M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Deeks, Steven G.] San Francisco Gen Hosp, Dept Med, San Francisco, CA USA. [Coombs, Robert W.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Coombs, Robert W.] Univ Washington, Dept Med, Seattle, WA USA. [Jacobson, Jeffrey M.] Drexel Univ, Coll Med, Div Infect Dis & HIV Med, Philadelphia, PA 19104 USA. [Landay, Alan L.] Rush Univ, Med Ctr, Dept Immunol & Microbiol, Chicago, IL 60612 USA. [Wilson, Cara C.] Univ Colorado, Dept Internal Med, Aurora, CO USA. RP Sandler, NG (reprint author), Univ Texas Med Branch, Dept Internal Med, Div Infect Dis, 301 Univ Blvd,Rte 0435, Galveston, TX 77555 USA. EM neutay@utmb.edu RI Funderburg, Nicholas/L-8022-2013; OI Utay, Netanya/0000-0002-6407-8670 FU National Institutes of Health [U01 AI-68636, AI-68634, 2UM1AI069452-08, AI069501, UM1-A1069424, UM1-AI069534-08, 2UM1AI069412-08]; National Institutes of Health. [AI069471, 2UMIAI069511-08, UM1 AI069424, 5UO1 AI069502-07, A1-069513, 2UM1A I069432, UL1 TR001082, AI069477, UM1AI069495, UL1TR000124, 5-P30-AI-045008-15, UL1 RR024160, UM1-AI068636, P30-AI027757, AI-076174] FX This work was supported by the National Institutes of Health (grant U01 AI-68636 to the ACTG, grants to the Statistical and Data Analysis Center [AI-68634] and participating clinical trials units [2UM1AI069452-08 to Alabama Therapeutics, AI069501 to Case Western Reserve University, UM1-A1069424 to Harbor-UCLA, UM1-AI069534-08 to the Hospital of the University of Pennsylvania, 2UM1AI069412-08 to Massachusetts General Hospital, AI069471 to Northwestern University, 2UMIAI069511-08 to Trillium Health, UM1 AI069424 to the UCLA CARE Center, 5UO1 AI069502-07 to the University of California-San Francisco, A1-069513 to the University of Cincinnati, 2UM1A I069432 and UL1 TR001082 to University of Colorado Health, AI069477 to the University of Miami, 2UMIAI069511-08 to the University of Rochester, and UM1AI069495 to Washington University)], grant UL1TR000124 to the UCLA Clinical and Translational Science Institute, grants to the Center for AIDS Research at the Hospital of the University of Pennsylvania [5-P30-AI-045008-15] and affiliated clinical research centers [UL1 RR024160 to Trillium Health and UL1 RR024160 to the University of Rochester], grants UM1-AI068636 and P30-AI027757 to R. W. C., and grant AI-076174 to the Cleveland Immunopathogenesis Consortium). NR 15 TC 24 Z9 24 U1 0 U2 5 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 NOV 15 PY 2014 VL 210 IS 10 BP 1549 EP 1554 DI 10.1093/infdis/jiu305 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0EY UT WOS:000344611200006 PM 24864123 ER PT J AU Miura, K Sahara, H Sekijima, M Kawai, A Waki, S Nishimura, H Setoyama, K Clayman, ES Shimizu, A Yamada, K AF Miura, Kohei Sahara, Hisashi Sekijima, Mitsuhiro Kawai, Akihiro Waki, Shiori Nishimura, Hiroaki Setoyama, Kentaro Clayman, Eric S. Shimizu, Akira Yamada, Kazuhiko TI Protective Effect of Neutralization of the Extracellular High-Mobility Group Box 1 on Renal Ischemia-Reperfusion Injury in Miniature Swine SO TRANSPLANTATION LA English DT Article DE High-mobility group box-1; CLAWN miniature swine; Ischemia-reperfusion injury ID CHRONIC ALLOGRAFT NEPHROPATHY; ISCHEMIA/REPERFUSION INJURY; CHROMATIN PROTEIN; HMGB1; INFLAMMATION; FAILURE; KIDNEY; CELLS; PROLIFERATION; REJECTION AB Background Strategies that reduce ischemia-reperfusion injury (IRI) have the potential to expand the numbers of available organs for transplantation. Recent reports in rodent models have demonstrated that high-mobility group box 1 (HMGB1) acts as an alarm in initiating the inflammatory response resulting from ischemic injury. The aim of this study was to evaluate the cytoprotective effects of anti-HMGB1 antibodies on renal IRI in preclinical large animals. Methods One hundred twenty minutes of warm and 60 min of cold renal ischemia were induced in 8 CLAWN miniature swine. Three of eight animals received intravenous anti-HMGB1 antibody at 1 mg/kg just before the reperfusion of renal blood flow. Renal function was assessed by serum creatinine and renal biopsy. Serum levels of interleukin (IL)-1, IL-6, and HMGB1 were measured. Results The concentration of HMGB1 increased as early as 30 min after reperfusion and before the elevation of IL-1 and IL-6. Serum creatinine levels were markedly elevated, peaking at a median of 5 days (peak creatinine levels: 11.61.6 mg/dL) and recovering by day 14. Anti-HMGB1 antibody injection dramatically decreased renal damage as well as serum levels of HMGB1 associated with IRI. Renal function returned to near normal by day 9, and peak creatinine levels were markedly lower (7.4 +/- 0.2 mg/dL), and biopsies possessed fewer pathologic changes when compared to the control group. Conclusion In this study, we demonstrated the beneficial effects of perioperative administration of anti-HMGB1 antibody in reducing renal IRI in a clinically relevant, large animal model. C1 [Miura, Kohei; Sahara, Hisashi; Sekijima, Mitsuhiro; Kawai, Akihiro; Waki, Shiori; Nishimura, Hiroaki; Setoyama, Kentaro; Shimizu, Akira; Yamada, Kazuhiko] Kagoshima Univ, Ctr Adv Biomed Sci & Swine Res, Div Organ Replacement & Xenotransplantat Surg, Kagoshima 8908520, Japan. [Clayman, Eric S.; Shimizu, Akira; Yamada, Kazuhiko] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. RP Yamada, K (reprint author), Kagoshima Univ, Ctr Adv Biomed Sci & Swine Res, 8-35-1 Sakuragaoka, Kagoshima 8908520, Japan. EM kyyamada@m2.kufm.kagoshima-u.ac.jp FU Kagoshima University FX This research was supported by a Grant-in-Aid for Scientific Research (B) (H.S.) and the Kagoshima University Research Awards (K.Y.). NR 33 TC 4 Z9 4 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD NOV 15 PY 2014 VL 98 IS 9 BP 937 EP 943 DI 10.1097/TP.0000000000000358 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AT2OL UT WOS:000344774000006 PM 25136847 ER PT J AU Yeh, RW Drachman, DE AF Yeh, Robert W. Drachman, Douglas E. TI Culprit Only, Multivessel, or Staged Multivessel Intervention in STEMI: New Insights or Insurmountable Methodologic Obstacles? SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material ID PERCUTANEOUS CORONARY INTERVENTION; MYOCARDIAL-INFARCTION; TRIAL C1 [Yeh, Robert W.; Drachman, Douglas E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. RP Yeh, RW (reprint author), Massachusetts Gen Hosp, Div Cardiol, GRB800,55 Fruit St, Boston, MA 02114 USA. EM ryeh@partners.org NR 6 TC 2 Z9 2 U1 0 U2 0 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 NOV 15 PY 2014 VL 84 IS 6 BP 923 EP 924 DI 10.1002/ccd.25673 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AS6JI UT WOS:000344369500014 PM 25352189 ER PT J AU Toleva, O Westerhout, CM Senaratne, MPJ Bode, C Lindroos, M Sulimov, VA Montalescot, G Newby, LK Giugliano, RP Van de Werf, F Armstrong, PW AF Toleva, Olga Westerhout, Cynthia M. Senaratne, Manohara P. J. Bode, Christoph Lindroos, Magnus Sulimov, Vitaly A. Montalescot, Gilles Newby, L. Kristin Giugliano, Robert P. Van de Werf, Frans Armstrong, Paul W. TI Practice Patterns and Clinical Outcomes Among Non-ST-Segment Elevation Acute Coronary Syndrome (NSTE-ACS) Patients Presenting to Primary and Tertiary Hospitals: Insights from the EARLY Glycoprotein IIb/IIIa Inhibition in NSTE-ACS (EARLY-ACS) Trial SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE acute coronary syndrome; bleeding; mortality; revascularization; transfer; practice patterns ID ASSOCIATION TASK-FORCE; MYOCARDIAL-INFARCTION; PRACTICE GUIDELINES; AMERICAN-COLLEGE; MANAGEMENT; INTERVENTION; EPTIFIBATIDE; STRATEGIES; UPDATE AB ObjectivesWe evaluated patients at tertiary [both percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) capable] and primary hospitals in the EARLY-ACS trial. BackgroundEarly invasive management is recommended for high-risk non-ST-segment elevation acute coronary syndromes. MethodsWe evaluated outcomes in 9,204 patients presenting to: tertiary sites, primary sites with transfer to tertiary sites (transferred) and those who remained at primary sites (non-transfer). ResultsThere were 348 tertiary (n=7,455 patients) and 89 primary hospitals [n=1,749 patients (729 transferred; 1,020 non-transfer)]. Significant delays occurred in time from symptom onset to angiography (49 hr), PCI (53h), and CABG (178 hr) for transferred patients (P<0.001). Non-transfer patients had less 30-day death/myocardial infarction [9.4% vs. 11.7% (tertiary); adjusted odds ratio (OR): 0.78 (0.62-0.97), P=0.026]; transferred (14.0%) and tertiary patients were similar [adjusted OR: 1.23 (0.98-1.53), P=0.074]. Non-transfer patients had lower 1-year mortality [4.3% vs. 6.3% (tertiary); adjusted hazard ratio (HR): 0.64 (0.47-0.87), P=0.005]: there was no difference between transferred and tertiary patients [5.2% vs. 6.3%; adjusted HR: 0.80 (0.58-1.12), P=0.202]. Despite similar rates of catheterization, GUSTO severe/moderate bleeding within 120 hr was less in non-transfer [3.1% vs. 6.7% (tertiary); adjusted OR: 0.47 (0.32-0.68), P<0.001], whereas transferred (6.1%) and tertiary patients were similar [adjusted OR: 0.94 (0.68-1.30), P=0.693]. There was no difference in non-CABG bleeding. ConclusionsTimely angiography and revascularization were often not achieved in transferred patients. Non-transferred patients presenting to primary sites had the lowest event rates and the best long-term survival. (c) 2014 Wiley Periodicals, Inc. C1 [Toleva, Olga; Westerhout, Cynthia M.; Armstrong, Paul W.] Univ Alberta, Canadian VIGOUR Ctr, Edmonton, AB T6G 2E1, Canada. [Senaratne, Manohara P. J.] Grey Nuns Hosp, Coronary Care Unit, Edmonton, AB, Canada. [Bode, Christoph] Univ Freiburg Klinikum, Freiburg, Germany. [Lindroos, Magnus] Jorvi Univ Hosp, Dept Invas Cardiol, Espoo, Finland. [Sulimov, Vitaly A.] First Moscow State Med Univ, Moscow, Russia. [Montalescot, Gilles] CHU Pitie Salpetriere, Paris, France. [Newby, L. Kristin] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Giugliano, Robert P.] Brigham & Womens Hosp RPG, Thrombolysis Myocardial Infarct TIMI Study Grp, Boston, MA USA. [Van de Werf, Frans] Univ Ziekenhuis Gasthuisberg, Dept Cardiol, Leuven, Belgium. RP Armstrong, PW (reprint author), Univ Alberta, Canadian VIGOUR Ctr, 2-132 Li Ka Shing Ctr Hlth Res Innovat, Edmonton, AB T6G 2E1, Canada. EM paul.armstrong@ualberta.ca OI Van de Werf, Frans/0000-0001-9479-7767 NR 11 TC 0 Z9 0 U1 0 U2 3 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 NOV 15 PY 2014 VL 84 IS 6 BP 934 EP 942 DI 10.1002/ccd.25590 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AS6JI UT WOS:000344369500017 PM 24976083 ER PT J AU Song, MY Chan, AT Fuchs, CS Ogino, S Hu, FB Mozaffarian, D Ma, J Willett, WC Giovannucci, EL Wu, KN AF Song, Mingyang Chan, Andrew T. Fuchs, Charles S. Ogino, Shuji Hu, Frank B. Mozaffarian, Dariush Ma, Jing Willett, Walter C. Giovannucci, Edward L. Wu, Kana TI Dietary intake of fish, omega-3 and omega-6 fatty acids and risk of colorectal cancer: A prospective study in U.S. men and women SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE fish; omega-3 polyunsaturated fatty acid; omega-6 polyunsaturated fatty acid; colorectal cancer ID FOOD FREQUENCY QUESTIONNAIRE; FAMILIAL ADENOMATOUS POLYPOSIS; PROSPECTIVE COHORT; MEAT CONSUMPTION; COLON-CANCER; PROXIMAL COLON; RECTAL-CANCER; MARINE N-3; FOLLOW-UP; HEALTH AB The association between fish, -3 and -6 polyunsaturated fatty acid (PUFA) intake and risk of colorectal cancer (CRC) remains inconclusive. Recent prospective studies suggest that the relationship may vary by gender, subsite and duration of follow-up. We followed 123,529 US adults (76,386 women and 47,143 men) without a history of cancer at baseline for 24 to 26 years. Fish and PUFA intake was assessed at baseline and updated every 4 years by using a validated food-frequency questionnaire. We found no overall association between fish, -3 and -6 PUFA intake and CRC risk with hazard ratio (HR) of 1.03 [95% confidence interval (CI): 0.89-1.20] comparing marine -3 intake of 0.30 g/d versus <0.15 g/d among women and 1.05 (95% CI: 0.85-1.30) comparing intake of 0.41 g/d versus <0.16 g/d among men. However, fish and marine -3 PUFA intake appeared to be positively associated with risk of distal colon cancer in both men and women and inversely with risk of rectal cancer in men. In an analysis based on a limited number of cases, marine -3 PUFA intake assessed 12-16 years before diagnosis tended to be inversely associated with CRC risk in men (HR: 0.76; 95% CI: 0.52-1.10). In conclusion, although no overall association between fish, -3 or -6 PUFA intake was observed with CRC risk, marine -3 PUFA may be differentially associated with risk of distal colon and rectal cancers and a long latency may be needed for its protection against CRC in men. C1 [Song, Mingyang; Hu, Frank B.; Willett, Walter C.; Giovannucci, Edward L.; Wu, Kana] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Song, Mingyang; Ogino, Shuji; Hu, Frank B.; Mozaffarian, Dariush; Ma, Jing; Willett, Walter C.; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chan, Andrew T.; Fuchs, Charles S.; Ogino, Shuji; Hu, Frank B.; Mozaffarian, Dariush; Ma, Jing; Willett, Walter C.; Giovannucci, Edward L.] Brigham & Womens Hosp, Med Network, Channing Div, Boston, MA 02115 USA. [Chan, Andrew T.; Fuchs, Charles S.; Ogino, Shuji; Hu, Frank B.; Mozaffarian, Dariush; Ma, Jing; Willett, Walter C.; Giovannucci, Edward L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Chan, Andrew T.; Fuchs, Charles S.; Ogino, Shuji; Hu, Frank B.; Mozaffarian, Dariush; Ma, Jing; Willett, Walter C.; Giovannucci, Edward L.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Mozaffarian, Dariush] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. RP Giovannucci, EL (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 655 Huntington Ave, Boston, MA 02115 USA. EM egiovann@hsph.harvard.edu; kana.wu@channing.harvard.edu RI Song, Mingyang/M-6701-2013 OI Song, Mingyang/0000-0002-1324-0316 FU National Institutes of Health [P01 CA87969, R01 CA49449, UM1 CA167552, P01 CA 55075, 1U54CA155626]; Entertainment Industry Foundation's National Colorectal Cancer Research Alliance (NCCRA) FX Grant sponsor: National Institutes of Health; Grant numbers: P01 CA87969, R01 CA49449, UM1 CA167552, P01 CA 55075, 1U54CA155626; Grant sponsor: Entertainment Industry Foundation's National Colorectal Cancer Research Alliance (NCCRA) NR 57 TC 18 Z9 19 U1 0 U2 50 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD NOV 15 PY 2014 VL 135 IS 10 BP 2413 EP 2423 DI 10.1002/ijc.28878 PG 11 WC Oncology SC Oncology GA AP3OB UT WOS:000341984500021 PM 24706410 ER PT J AU Sax, PE Sypek, A Berkowitz, BK Morris, BL Losina, E Paltiel, AD Kelly, KA Seage, GR Walensky, RP Weinstein, MC Eron, J Freedberg, KA AF Sax, Paul E. Sypek, Alexis Berkowitz, Bethany K. Morris, Bethany L. Losina, Elena Paltiel, A. David Kelly, Kathleen A. Seage, George R., III Walensky, Rochelle P. Weinstein, Milton C. Eron, Joseph Freedberg, Kenneth A. TI HIV Cure Strategies: How Good Must They Be to Improve on Current Antiretroviral Therapy? SO PLOS ONE LA English DT Article ID QUALITY-OF-LIFE; COST-EFFECTIVENESS; UNITED-STATES; HEPATITIS-C; INFECTION; VACCINE; TRANSPLANTATION; POPULATION; VORINOSTAT; LYMPHOMA AB Background: We examined efficacy, toxicity, relapse, cost, and quality-of-life thresholds of hypothetical HIV cure interventions that would make them cost-effective compared to life-long antiretroviral therapy (ART). Methods: We used a computer simulation model to assess three HIV cure strategies: Gene Therapy, Chemotherapy, and Stem Cell Transplantation (SCT), each compared to ART. Efficacy and cost parameters were varied widely in sensitivity analysis. Outcomes included quality-adjusted life expectancy, lifetime cost, and cost-effectiveness in dollars/quality-adjusted life year ($/QALY) gained. Strategies were deemed cost-effective with incremental cost-effectiveness ratios <$100,000/QALY. Results: For patients on ART, discounted quality-adjusted life expectancy was 16.4 years and lifetime costs were $591,400. Gene Therapy was cost-effective with efficacy of 10%, relapse rate 0.5%/month, and cost $54,000. Chemotherapy was cost-effective with efficacy of 88%, relapse rate 0.5%/month, and cost $12,400/month for 24 months. At $150,000/procedure, SCT was cost-effective with efficacy of 79% and relapse rate 0.5%/month. Moderate efficacy increases and cost reductions made Gene Therapy cost-saving, but substantial efficacy/cost changes were needed to make Chemotherapy or SCT cost-saving. Conclusions: Depending on efficacy, relapse rate, and cost, cure strategies could be cost-effective compared to current ART and potentially cost-saving. These results may help provide performance targets for developing cure strategies for HIV. C1 [Sax, Paul E.; Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Sax, Paul E.; Losina, Elena; Walensky, Rochelle P.; Freedberg, Kenneth A.] Harvard Univ, Ctr AIDS Res, Boston, MA 02115 USA. [Seage, George R., III; Weinstein, Milton C.; Freedberg, Kenneth A.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Sypek, Alexis; Berkowitz, Bethany K.; Morris, Bethany L.; Losina, Elena; Kelly, Kathleen A.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Sypek, Alexis; Berkowitz, Bethany K.; Morris, Bethany L.; Losina, Elena; Kelly, Kathleen A.; Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Dept Med, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Paltiel, A. David] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Eron, Joseph] Univ N Carolina, Sch Med, Div Infect Dis, Chapel Hill, NC USA. RP Sax, PE (reprint author), Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. EM psax@partners.org FU National Institute of Allergy and Infectious Diseases [R37 AI042006, AI051966, R01 AI093269, U01 AI 069472, U01 AI068636, UM1 AI 069423] FX This research was funded by the National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov/Pages/default.aspx): R37 AI042006 (PS, AS, BB, BM, EL, ADP, KK, RW, MW, KF), AI051966 (GS), R01 AI093269 (RW, KF, ADP, MW), U01 AI 069472 (PS, EL, KF, RQ, ADP, AS, BB, BM, KK) (Partners/Harvard AIDS Clinical Trials Unit), U01 AI068636 (PS, EL, KF, RQ, ADP, AS, BB, BM, KK) (Central AIDS Clinical Trials Group), and UM1 AI 069423 (JE) (UNC Global Clinical Trials Unit). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 11 Z9 11 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 NOV 14 PY 2014 VL 9 IS 11 AR e113031 DI 10.1371/journal.pone.0113031 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AU4DF UT WOS:000345558500125 PM 25397616 ER PT J AU Lu, L Zheng, L Si, Y Luo, WY Dujardin, G Kwan, T Potochick, NR Thompson, SR Schneider, DA King, PH AF Lu, Liang Zheng, Lei Si, Ying Luo, Wenyi Dujardin, Gwendal Kwan, Thaddaeus Potochick, Nicholas R. Thompson, Sunnie R. Schneider, David A. King, Peter H. TI Hu Antigen R (HuR) Is a Positive Regulator of the RNA-binding Proteins TDP-43 and FUS/TLS IMPLICATIONS FOR AMYOTROPHIC LATERAL SCLEROSIS SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Amyotrophic Lateral Sclerosis (ALS) (Lou Gehrig Disease); Astrocyte; Neuron; RNA Processing; RNA Splicing; 3 Untranslated Region ID NUCLEAR FACTOR TDP-43; MESSENGER-RNA; MOTOR-NEURONS; TRANSLATIONAL CONTROL; STRESS GRANULES; RICH ELEMENTS; WIDE ANALYSIS; UP-REGULATION; CFTR EXON-9; STABILITY AB Background: RNA processing abnormalities have been linked to amyotrophic lateral sclerosis (ALS). Results: HuR promotes the expression of the ALS-associated TDP-43 and FUS/TLS RNA-binding proteins. Conclusion: Through its regulation of TDP-43 and FUS/TLS, HuR potentially impacts a wide range of molecular and cellular phenotypes. Significance: A network of proteins exists to maintain RNA processing, and ALS-associated abnormalities may stem from disruption of this network. Posttranscriptional gene regulation is governed by a network of RNA-binding proteins (RBPs) that interact with regulatory elements in the mRNA to modulate multiple molecular processes, including splicing, RNA transport, RNA stability, and translation. Mounting evidence indicates that there is a hierarchy within this network whereby certain RBPs cross-regulate other RBPs to coordinate gene expression. HuR, an RNA-binding protein we linked previously to aberrant VEGF mRNA metabolism in models of SOD1-associated amyotrophic lateral sclerosis, has been identified as being high up in this hierarchy, serving as a regulator of RNA regulators. Here we investigated the role of HuR in regulating two RBPs, TDP-43 and FUS/TLS, that have been linked genetically to amyotrophic lateral sclerosis. We found that HuR promotes the expression of both RBPs in primary astrocytes and U251 cells under normal and stressed (hypoxic) conditions. For TDP-43, we found that HuR binds to the 3 untranslated region (UTR) and regulates its expression through translational efficiency rather than RNA stability. With HuR knockdown, there was a shift of TDP-43 and FUS mRNAs away from polysomes, consistent with translational silencing. The TDP-43 splicing function was attenuated upon HuR knockdown and could be rescued by ectopic TDP-43 lacking the 3 UTR regulatory elements. Finally, conditioned medium from astrocytes in which HuR or TDP-43 was knocked down produced significant motor neuron and cortical neuron toxicity in vitro. These findings indicate that HuR regulates TDP-43 and FUS/TLS expression and that loss of HuR-mediated RNA processing in astrocytes can alter the molecular and cellular landscape to produce a toxic phenotype. C1 [Lu, Liang; Zheng, Lei; Si, Ying; Luo, Wenyi; Kwan, Thaddaeus; King, Peter H.] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL 35294 USA. [Lu, Liang; King, Peter H.] Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA. [King, Peter H.] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL 35294 USA. [Potochick, Nicholas R.; Thompson, Sunnie R.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Schneider, David A.] Univ Alabama Birmingham, Dept Biochem & Mol Genet, Birmingham, AL 35294 USA. [Lu, Liang; King, Peter H.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. [Dujardin, Gwendal] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Buenos Aires, DF, Argentina. RP Lu, L (reprint author), Sparks Ctr, Dept Neurol, Suite 260,1720 7th Ave S, Birmingham, AL 35233 USA. EM luliang@uab.edu; pking@uab.edu RI Dujardin, Gwendal/K-7464-2015; OI Dujardin, Gwendal/0000-0003-4320-6351; Schneider, David/0000-0003-0635-5091 FU NINDS, National Intitutes of Health [NS064133, R21NS081743, R21NS085497, NS057664]; Department of Veterans Affairs FX This work was supported, in whole or in part, by NINDS, National Intitutes of Health Grants NS064133, R21NS081743, and R21NS085497 (to P. H. K.) and NS057664 (to L. L.). This work was also supported by a Merit Review award from the Department of Veterans Affairs (to P. H. K.). NR 70 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD NOV 14 PY 2014 VL 289 IS 46 BP 31792 EP 31804 DI 10.1074/jbc.M114.573246 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AU0LP UT WOS:000345314700011 PM 25239623 ER PT J AU Hsu, C Lemon, JM Wong, ES Carson-Cheng, E Perkins, M Nordstrom, MS Liu, CF Sprague, C Bryson, CL AF Hsu, Clarissa Lemon, Jaclyn M. Wong, Edwin S. Carson-Cheng, Elizabeth Perkins, Mark Nordstrom, Margaret S. Liu, Chuan-Fen Sprague, Carol Bryson, Christopher L. TI Factors affecting medication adherence: patient perspectives from five veterans affairs facilities SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Diabetes; Medication adherence; Chronic disease management; Patient self-management; Delivery of care; Veterans; Health systems research; Pharmacy services research; Patient-oriented research ID TYPE-2 DIABETES-MELLITUS; SELF-MANAGEMENT; BARRIERS; CARE; OUTCOMES; NONADHERENCE; PERCEPTIONS; PREDICTORS; GUIDELINE; PROGRAM AB Background: In the United States, more than 25 million people have diabetes. Medication adherence is known to be important for disease control. However, factors that consistently predict medication adherence are unclear and the literature lacks patient perspectives on how health care systems affect adherence to oral hypoglycemic agents (OHAs). This study explored facilitators and barriers to OHA adherence by obtaining the perspectives of Veterans Affairs (VA) patients with OHA prescriptions. Methods: A total of 45 patients participated in 12 focus groups that explored a wide range of issues that might affect medication adherence. Participants were patients at clinics in Seattle, Washington; San Antonio, Texas; Portland, Oregon; Salem, Oregon, and Warrenton, Oregon. Results: Key system-level facilitators of OHA adherence included good overall pharmacy service and several specific mechanisms for ordering and delivering medications (automated phone refill service, Web-based prescription ordering), as well as providing pillboxes and printed lists of current medications to patients. Barriers mirrored many of the facilitators. Poor pharmacy service quality and difficulty coordinating multiple prescriptions emerged as key barriers. Conclusions: VA patient focus groups provided insights on how care delivery systems can encourage diabetes medication adherence by minimizing the barriers and enhancing the facilitators at both the patient and system levels. Major system-level factors that facilitated adherence were overall pharmacy service quality, availability of multiple systems for reordering medications, having a person to call when questions arose, counseling about the importance of adherence and providing tools such as pillboxes and updated medication lists. C1 [Hsu, Clarissa; Carson-Cheng, Elizabeth] Ctr Community Hlth & Evaluat, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Lemon, Jaclyn M.; Wong, Edwin S.; Perkins, Mark; Nordstrom, Margaret S.; Liu, Chuan-Fen; Bryson, Christopher L.] VA Puget Sound Hlth Care Syst, Northwest Ctr Outcomes Res Older Adults, Seattle, WA 98108 USA. [Bryson, Christopher L.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Hsu, Clarissa; Wong, Edwin S.; Liu, Chuan-Fen] Univ Washington, Sch Publ Hlth & Community Med, Dept Hlth Serv, Seattle, WA 98195 USA. [Sprague, Carol] Portland VA Med Ctr, Portland, OR 97239 USA. [Sprague, Carol] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. RP Hsu, C (reprint author), Ctr Community Hlth & Evaluat, Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM hsu.c@ghc.org FU Investigator Initiated Research Award from the Department of Veterans Affairs, Health Services Research and Development [IIR 07-068-2]; VA Health Services Research and Development Postdoctoral Fellowship [TPP 61-024]; VA Career Development Award [03-177] FX This research was supported by an Investigator Initiated Research Award (IIR 07-068-2, PI: Bryson) from the Department of Veterans Affairs, Health Services Research and Development. Dr. Wong is supported by VA Health Services Research and Development Postdoctoral Fellowship TPP 61-024. Dr. Bryson was supported by VA Career Development Award 03-177. NR 39 TC 5 Z9 5 U1 2 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD NOV 13 PY 2014 VL 14 AR 533 DI 10.1186/s12913-014-0533-1 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AZ7ST UT WOS:000348418800001 PM 25391694 ER PT J AU Stewart, MH Gutierrez-Martinez, P Beerman, I Garrison, B Gallagher, EJ LeRoith, D Rossi, DJ AF Stewart, Morag H. Gutierrez-Martinez, Paula Beerman, Isabel Garrison, Brian Gallagher, Emily J. LeRoith, Derek Rossi, Derrick J. TI Growth hormone receptor signaling is dispensable for HSC function and aging SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; I GENE-EXPRESSION; AGE; GH; 5-FLUOROURACIL; DECLINE; CYCLE; MICE AB Growth hormone receptor (Ghr) signaling is important in a wide variety of cellular processes including aging; however, the role of Ghr signaling in hematopoietic stem cell (HSC) biology remains unexplored. Within the hematopoietic system, Ghr is expressed in a highly HSC-specific manner and is significantly upregulated during aging. Exposure of young and old HSCs to recombinant growth hormone ex vivo led to diminished short-term reconstitution and restored B-cell output from old HSCs. Hematopoietic-specific genetic deletion of Ghr neither impacted steady-state hematopoiesis nor serial transplantation potential. Repeat challenge with 5-fluorouracil showed that Ghr was dispensable for HSC activation and homeostatic recovery in vivo and, after challenge, Ghr-deficient HSCs functioned normally through serial transplantation. Although exogenous Gh induces age-dependent HSC effects, these results indicate that Ghr signaling appears largely dispensable for HSC function and aging. C1 [Stewart, Morag H.; Gutierrez-Martinez, Paula; Beerman, Isabel; Garrison, Brian; Rossi, Derrick J.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Stewart, Morag H.; Gutierrez-Martinez, Paula; Beerman, Isabel; Garrison, Brian; Rossi, Derrick J.] Harvard Univ, Dept Stem Cell & Regenerat Med, Cambridge, MA 02138 USA. [Gallagher, Emily J.; LeRoith, Derek] Mt Sinai Sch Med, Dept Med, Div Med Endocrinol Diabet & Bone Dis, New York, NY USA. RP Rossi, DJ (reprint author), Boston Childrens Hosp, 200 Longwood Ave,Warren Alpert Bldg,Room WAB 149e, Boston, MA 02115 USA. EM derrick.rossi@childrens.harvard.edu FU National Institutes of Health (National Institute of Aging) [R00AG029760]; National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases) [UO1DK072473-01]; Leona M. and Harry B. Helmsley Charitable Trust; New York Stem Cell Foundation; Harvard Stem Cell Institute FX This work was supported by grants from the National Institutes of Health (National Institute of Aging; R00AG029760) (D.J.R.), (National Institute of Diabetes and Digestive and Kidney Diseases; UO1DK072473-01) (D.J.R.), the Leona M. and Harry B. Helmsley Charitable Trust (D.J.R.), the New York Stem Cell Foundation (D.J.R.), and the Harvard Stem Cell Institute (D.J.R.). NR 26 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD NOV 13 PY 2014 VL 124 IS 20 BP 3076 EP 3080 DI 10.1182/blood-2014-05-575308 PG 5 WC Hematology SC Hematology GA AY3CR UT WOS:000347462700011 PM 25274507 ER PT J AU Rashid, NU Sperling, AS Bolli, N Wedge, DC Van Loo, P Tai, YT Shammas, MA Fulciniti, M Samur, MK Richardson, PG Magrangeas, F Minvielle, S Futreal, PA Anderson, KC Avet-Loiseau, H Campbell, PJ Parmigiani, G Munshi, NC AF Rashid, Naim U. Sperling, Adam S. Bolli, Niccolo Wedge, David C. Van Loo, Peter Tai, Yu-Tzu Shammas, Masood A. Fulciniti, Mariateresa Samur, Mehmet K. Richardson, Paul G. Magrangeas, Florence Minvielle, Stephane Futreal, P. Andrew Anderson, Kenneth C. Avet-Loiseau, Herve Campbell, Peter J. Parmigiani, Giovanni Munshi, Nikhil C. TI Differential and limited expression of mutant alleles in multiple myeloma SO BLOOD LA English DT Article ID INTRACLONAL HETEROGENEITY; RNA-SEQ; CANCER; GENOME; EVOLUTION; LEUKEMIA; BREAST AB Recent work has delineated mutational profiles in multiple myeloma and reported a median of 52 mutations per patient, as well as a set of commonly mutated genes across multiple patients. In this study, we have used deep sequencing of RNA from a subset of these patients to evaluate the proportion of expressed mutations. We find that the majority of previously identified mutations occur within genes with very low or no detectable expression. On average, 27%( range, 11% to 47%) of mutated alleles are found to be expressed, and among mutated genes that are expressed, there often is allele-specific expression where either the mutant or wild-type allele is suppressed. Even in the absence of an overall change in gene expression, the presence of differential allelic expression within malignant cells highlights the important contribution of RNA-sequencing in identifying clinically significant mutational changes relevant to our understanding of myeloma biology and also for therapeutic applications. C1 [Rashid, Naim U.; Sperling, Adam S.; Tai, Yu-Tzu; Shammas, Masood A.; Fulciniti, Mariateresa; Samur, Mehmet K.; Richardson, Paul G.; Anderson, Kenneth C.; Munshi, Nikhil C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr,Dept Med Oncol, Boston, MA 02115 USA. [Rashid, Naim U.; Samur, Mehmet K.; Parmigiani, Giovanni] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Rashid, Naim U.; Samur, Mehmet K.; Parmigiani, Giovanni] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Bolli, Niccolo; Wedge, David C.; Van Loo, Peter; Campbell, Peter J.] Wellcome Trust Sanger Inst, Canc Genome Project, Dept Canc Genet & Gen, Hinxton, England. [Bolli, Niccolo; Campbell, Peter J.] Univ Cambridge, Dept Haematol, Cambridge Inst Med Res, Cambridge, England. [Van Loo, Peter] Vlaams Inst Biotechnol, Dept Human Genet, Leuven, Belgium. [Van Loo, Peter] Univ Leuven, Leuven, Belgium. [Shammas, Masood A.; Munshi, Nikhil C.] Boston Vet Adm Healthcare Syst, Dept Hematol Oncol, West Roxbury, MA USA. [Magrangeas, Florence; Minvielle, Stephane] Univ Nantes, Dept Hematol, Ctr Rech Canc, Nantes Angers Unit Mixte Rech INSERM 892,Ctr Natl, Nantes, France. [Futreal, P. Andrew] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Avet-Loiseau, Herve] Ctr Hosp Univ Rangueil, Unite Genom Myelome, Toulouse, France. [Avet-Loiseau, Herve] Ctr Rech Canc Toulouse, INSERM, U1037, Toulouse, France. RP Munshi, NC (reprint author), Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England. EM pc8@sanger.ac.uk RI Magrangeas, Florence/L-3080-2015; Minvielle, Stephane/K-8251-2015; Bolli, Niccolo/D-4057-2011; OI Bolli, Niccolo/0000-0002-1018-5139; Van Loo, Peter/0000-0003-0292-1949; Wedge, David/0000-0002-7572-3196 FU National Institutes of Health, National Cancer Institute [PO1-155258, RO1-124929, P50-100007, PO1-78378, RCA125711C]; Wellcome Trust [077012/Z/05/Z]; Wellcome Trust Senior Clinical Research Fellowship; Lady Tata Memorial Trust FX This study was supported by National Institutes of Health, National Cancer Institute grants PO1-155258 (N.C.M., P.J.C., K.C.A., G.P., H.A.L., and S.M.), RO1-124929 (N.C.M.), P50-100007 (K.C.A. and N.C.M.), PO1-78378 (K.C.A. and N.C.M.), RCA125711C (M.A.S.), and a Wellcome Trust grant 077012/Z/05/Z. P.V.L. is a postdoctoral researcher of the Research Foundation-Flanders. P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship. K.C.A. is an American Cancer Society Clinical Research Professor. N.B. is a European Hematology Association fellow and was supported by a grant from the Lady Tata Memorial Trust. The authors thank Yaoyou Wang and Renee Rubio at the Center for Cancer Computational Biology for assistance with sequencing and analysis. NR 25 TC 14 Z9 14 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD NOV 13 PY 2014 VL 124 IS 20 BP 3110 EP 3117 DI 10.1182/blood-2014-04-569327 PG 8 WC Hematology SC Hematology GA AY3CR UT WOS:000347462700015 PM 25237203 ER PT J AU McKeown, MR Shaw, DL Fu, H Liu, S Xu, X Marineau, JJ Huang, YB Zhang, XF Buckley, DL Kadam, A Zhang, ZJ Blacklow, SC Qi, J Zhang, W Bradner, JE AF McKeown, Michael R. Shaw, Daniel L. Fu, Harry Liu, Shuai Xu, Xiang Marineau, Jason J. Huang, Yibo Zhang, Xiaofeng Buckley, Dennis L. Kadam, Asha Zhang, Zijuan Blacklow, Stephen C. Qi, Jun Zhang, Wei Bradner, James E. TI Biased Multicomponent Reactions to Develop Novel Bromodomain Inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID C-MYC; COUPLING REACTIONS; BET BROMODOMAINS; TRANSCRIPTION; CHROMATIN; BRD4; OPTIMIZATION; ACTIVATION; DISCOVERY; LEUKEMIA AB BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions, we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a Kd of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was cocrystallized with BRD4, yielding a 1.56 angstrom resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors. C1 [McKeown, Michael R.; Shaw, Daniel L.; Marineau, Jason J.; Kadam, Asha; Qi, Jun; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Fu, Harry; Liu, Shuai; Huang, Yibo; Zhang, Xiaofeng; Kadam, Asha; Zhang, Zijuan; Zhang, Wei] Univ Massachusetts, Dept Chem, Boston, MA 02125 USA. [Xu, Xiang; Blacklow, Stephen C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Xu, Xiang] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Bradner, James E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Bradner, JE (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM wei2.zhang@umb.edu; james_bradner@dfci.harvard.edu OI Shaw, Daniel/0000-0003-0021-8109 FU National Institutes of Health [CA156732]; NIH [HD076508]; Damon Runyon Cancer Research Foundation [DRG-2196-14]; The William Lawrence and Blanche Hughes Foundation FX We acknowledge undergraduate students Yuan Xia and Shiva Dastjerdi for their assistance. The work in this study was supported by National Institutes of Health U54 grant CA156732 (J.E.B. and W.Z.), NIH U01 grant HD076508 (J.E.B.), the Damon Runyon Cancer Research Foundation (J.E.B.), and The William Lawrence and Blanche Hughes Foundation (J.E.B.). D.L.B. is a Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2196-14). NR 47 TC 23 Z9 23 U1 5 U2 28 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 NOV 13 PY 2014 VL 57 IS 21 BP 9019 EP 9027 DI 10.1021/jm501120z PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AT5IP UT WOS:000344977400024 PM 25314271 ER PT J AU Kil, KE Poutiainen, P Zhang, ZD Zhu, AJ Choi, JK Jokivarsi, K Brownell, AL AF Kil, Kun-Eek Poutiainen, Pekka Zhang, Zhaoda Zhu, Aijun Choi, Ji-Kyung Jokivarsi, Kimmo Brownell, Anna-Liisa TI Radiosynthesis and Evaluation of an F-18-Labeled Positron Emission Tomography (PET) Radioligand for Metabotropic Glutamate Receptor Subtype 4 (mGlu(4)) SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID GROUP-III; MEDIATED MODULATION; PARKINSONS-DISEASE; LOCALIZATION; PHARMACOLOGY; RADIOTRACER; DISCOVERY; MGLUR4; SERIES; RAT AB Four 4-phthalimide derivatives of N-(3-chlorophenyl)-2-picolinamide were synthesized as potential ligands for the PET imaging of mGlu4 in the brain. Of these compounds, N-(3-chloro-4-(4-fluoro-1,3-dioxoisoindolin-2-yl)phenyl)-2-picolinamide (3, KALB001) exhibited improved binding affinity (IC50 = 5.1 nM) compared with ML128 (1) and was subsequently labeled with F-18. When finally formulated in 0.1 M citrate buffer (pH 4) with 10% ethanol, the specific activity of [F-18]3 at the end of synthesis (EOS) was 233.5 +/- 177.8 GBq/mu mol (n = 4). The radiochemical yield of [F-18]3 was 16.4 +/- 4.8% (n = 4), and the purity was over 98%. In vivo imaging studies in a monkey showed that the radiotracer quickly penetrated the brain with the highest accumulation in the brain areas known to express mGlu4. Despite some unfavorable radiotracer properties like fast washout in rodent studies, [F-18]3 is the first F-18-labeled mGlu4 radioligand, which can be further modified to improve pharmacokinetics and brain penetrability for future human studies. C1 [Kil, Kun-Eek; Poutiainen, Pekka; Zhang, Zhaoda; Zhu, Aijun; Choi, Ji-Kyung; Jokivarsi, Kimmo; Brownell, Anna-Liisa] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Brownell, AL (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM abrownell@partners.org FU Orion Farmos Research Foundation; Kuopio University Foundation; NIMH PDSP program [HHSN-271-2008-00025-C]; [1S10RR029495-01]; [1S10RR026666-01]; [1S10RR023452-01]; [NIBIB-R01EB012864]; [NIMH-R01MH91684] FX The authors thank the technical staff of the PET/MRI and radiochemistry facilities at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital for the operation of cyclotron and synthesis modules. We thank Drs. Tanabe and Nakanishi's laboratory (Osaka Bioscience Institute, Osaka, Japan) for providing the vector of mGlu4 from the rat as a gift. The authors acknowledge the following supporting instrument grants: Grants 1S10RR029495-01, 1S10RR026666-01, and 1S10RR023452-01. Financial support for PP from The Orion Farmos Research Foundation and Kuopio University Foundation is gratefully acknowledged. Finally, we also appreciate the generous help from the NIMH PDSP program (Contract HHSN-271-2008-00025-C) led by Dr. Bryan L. Roth, M.D., Ph.D., at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, U.S. Grants NIBIB-R01EB012864 and NIMH-R01MH91684 to A.-L.B. supported this work. NR 27 TC 3 Z9 3 U1 0 U2 14 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 NOV 13 PY 2014 VL 57 IS 21 BP 9130 EP 9138 DI 10.1021/jm501245b PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AT5IP UT WOS:000344977400032 PM 25330258 ER PT J AU De Rubeis, S He, X Goldberg, AP Poultney, CS Samocha, K Cicek, AE Kou, Y Liu, L Fromer, M Walker, S Singh, T Klei, L Kosmicki, J Fu, SC Aleksic, B Biscaldi, M Bolton, PF Brownfeld, JM Cai, JL Campbell, NG Carracedo, A Chahrour, MH Chiocchetti, AG Coon, H Crawford, EL Crooks, L Curran, SR Dawson, G Duketis, E Fernandez, BA Gallagher, L Geller, E Guter, SJ Hill, RS Ionita-Laza, I Gonzalez, PJ Kilpinen, H Klauck, SM Kolevzon, A Lee, I Lei, J Lehtimaki, T Lin, CF Ma'ayan, A Marshall, CR McInnes, AL Neale, B Owen, MJ Ozaki, N Parellada, M Parr, JR Purcell, S Puura, K Rajagopalan, D Rehnstrom, K Reichenberg, A Sabo, A Sachse, M Sanders, SJ Schafer, C Schulte-Ruther, M Skuse, D Stevens, C Szatmari, P Tammimies, K Valladares, O Voran, A Wang, LS Weiss, LA Willsey, AJ Yu, TW Yuen, RKC Cook, EH Freitag, CM Gill, M Hultman, CM Lehner, T Palotie, A Schellenberg, GD Skiar, P State, MW Sutcliffe, JS Walsh, CA Scherer, SW Zwick, ME Barrett, JC Cutler, DJ Roeder, K Devlin, B Daly, MJ Buxbaum, JD AF De Rubeis, Silvia He, Xin Goldberg, Arthur P. Poultney, Christopher S. Samocha, Kaitlin Cicek, A. Ercument Kou, Yan Liu, Li Fromer, Menachem Walker, Susan Singh, Tarjinder Klei, Lambertus Kosmicki, Jack Fu, Shih-Chen Aleksic, Branko Biscaldi, Monica Bolton, Patrick F. Brownfeld, Jessica M. Cai, Jinlu Campbell, Nicholas G. Carracedo, Angel Chahrour, Maria H. Chiocchetti, Andreas G. Coon, Hilary Crawford, Emily L. Crooks, Lucy Curran, Sarah R. Dawson, Geraldine Duketis, Eftichia Fernandez, Bridget A. Gallagher, Louise Geller, Evan Guter, Stephen J. Hill, R. Sean Ionita-Laza, Iuliana Gonzalez, Patricia Jimenez Kilpinen, Helena Klauck, Sabine M. Kolevzon, Alexander Lee, Irene Lei, Jing Lehtimaeki, Terho Lin, Chiao-Feng Ma'ayan, Avi Marshall, Christian R. McInnes, Alison L. Neale, Benjamin Owen, Michael J. Ozaki, Norio Parellada, Mara Parr, Jeremy R. Purcell, Shaun Puura, Kaija Rajagopalan, Deepthi Rehnstrom, Karola Reichenberg, Abraham Sabo, Aniko Sachse, Michael Sanders, Stephan J. Schafer, Chad Schulte-Ruether, Martin Skuse, David Stevens, Christine Szatmari, Peter Tammimies, Kristiina Valladares, Otto Voran, Annette Wang, Li-San Weiss, Lauren A. Willsey, A. Jeremy Yu, Timothy W. Yuen, Ryan K. C. Cook, Edwin H. Freitag, Christine M. Gill, Michael Hultman, Christina M. Lehner, Thomas Palotie, Aarno Schellenberg, Gerard D. Skiar, Pamela State, Matthew W. Sutcliffe, James S. Walsh, Christopher A. Scherer, Stephen W. Zwick, Michael E. Barrett, Jeffrey C. Cutler, David J. Roeder, Kathryn Devlin, Bernie Daly, Mark J. Buxbaum, Joseph D. CA DDD Study Homozygosity Mapping Collaborative UK10K Consortium Autism Sequencing Consortium TI Synaptic, transcriptional and chromatin genes disrupted in autism SO NATURE LA English DT Article ID DE-NOVO MUTATIONS; COPY-NUMBER VARIATION; SPECTRUM DISORDERS; NEURODEVELOPMENTAL DISORDERS; FRAMEWORK; NETWORK; RISK; SCHIZOPHRENIA; EXPRESSION; DISCOVERY AB The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones. C1 [De Rubeis, Silvia; Goldberg, Arthur P.; Poultney, Christopher S.; Kou, Yan; Fu, Shih-Chen; Brownfeld, Jessica M.; Cai, Jinlu; Kolevzon, Alexander; Reichenberg, Abraham; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA. [De Rubeis, Silvia; Goldberg, Arthur P.; Poultney, Christopher S.; Kou, Yan; Fromer, Menachem; Fu, Shih-Chen; Brownfeld, Jessica M.; Cai, Jinlu; Kolevzon, Alexander; Purcell, Shaun; Reichenberg, Abraham; Skiar, Pamela; Buxbaum, Joseph D.] Mt Sinai Med Ctr, Dept Psychiat, New York, NY 10029 USA. [He, Xin; Cicek, A. Ercument; Roeder, Kathryn] Carnegie Mellon Univ, Ray & Stephanie Lane Ctr Computat Biol, Pittsburgh, PA 15213 USA. [Goldberg, Arthur P.; Fromer, Menachem; Skiar, Pamela; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Samocha, Kaitlin; Fromer, Menachem; Kosmicki, Jack; Palotie, Aarno] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Liu, Li; Lei, Jing; Schafer, Chad; Roeder, Kathryn] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA. [Walker, Susan; Marshall, Christian R.; Rajagopalan, Deepthi; Tammimies, Kristiina; Yuen, Ryan K. C.; Scherer, Stephen W.] Hosp Sick Children, Ctr Appl Genom, Program Genet & Genome Biol, Toronto, ON M5G 0A4, Canada. [Singh, Tarjinder; Crooks, Lucy; Rehnstrom, Karola; Barrett, Jeffrey C.] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Klei, Lambertus; Devlin, Bernie] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Aleksic, Branko; Ozaki, Norio; UK10K Consortium] Nagoya Univ, Sch Med, Dept Psychiat, Nagoya, Aichi 4668550, Japan. [Biscaldi, Monica] Univ Med Ctr Freiburg, Dept Child & Adolescent Psychiat Psychotherapy &, D-79106 Freiburg, Germany. [Biscaldi, Monica] Ctr Mental Disorders, D-79106 Freiburg, Germany. [Bolton, Patrick F.; Curran, Sarah R.] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Child Psychiat, London SE5 8AF, England. [Bolton, Patrick F.; Curran, Sarah R.] Kings Coll London, Inst Psychiat Psychol & Neurosci, SGDP Ctr, London SE5 8AF, England. [Campbell, Nicholas G.; Crawford, Emily L.; Sutcliffe, James S.] Vanderbilt Univ, Sch Med, Vanderbilt Brain Inst, Nashville, TN 37212 USA. [Campbell, Nicholas G.; Crawford, Emily L.; Sutcliffe, James S.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37232 USA. [Carracedo, Angel] Univ Santiago de Compostela, CIBERER, Genom Med Grp, Santiago De Compostela 15706, Spain. [Carracedo, Angel] Galician Fdn Genom Med SERGAS, Santiago De Compostela 15706, Spain. [Carracedo, Angel] King Abdulaziz Univ, Ctr Excellence Genom Med Res, Jeddah 21589, Saudi Arabia. [Chahrour, Maria H.; Hill, R. Sean; Yu, Timothy W.; Walsh, Christopher A.; Daly, Mark J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Chahrour, Maria H.; Hill, R. Sean; Yu, Timothy W.; Walsh, Christopher A.] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA. [Chiocchetti, Andreas G.; Duketis, Eftichia; Sachse, Michael; Freitag, Christine M.] Goethe Univ Frankfurt, Dept Child & Adolescent Psychiat Psychosomat & Ps, D-60528 Frankfurt, Germany. [Coon, Hilary] Univ Utah, Dept Internal Med, Salt Lake City, UT 84132 USA. [Coon, Hilary] Univ Utah, Dept Psychiat, Salt Lake City, UT 84108 USA. [Dawson, Geraldine] Duke Univ, Duke Inst Brain Sci, Durham, NC 27708 USA. [Fernandez, Bridget A.] Mem Univ Newfoundland, Disciplines Genet & Med, St John, NF A1B 3V6, Canada. [Gallagher, Louise; Gill, Michael] Trin Coll Dublin, Sch Med, Dept Psychiat, Dublin 8, Ireland. [Geller, Evan; Lin, Chiao-Feng; Valladares, Otto; Wang, Li-San; Schellenberg, Gerard D.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Guter, Stephen J.; Cook, Edwin H.] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60608 USA. [Ionita-Laza, Iuliana] Columbia Univ, Dept Biostat, New York, NY 10032 USA. [Gonzalez, Patricia Jimenez] Hosp Nacl de Ninos Dr Saenz Herrera, CCSS, Child Dev & Behav Unit, San Jose, Costa Rica. [Kilpinen, Helena] European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England. [Klauck, Sabine M.] German Canc Res Ctr, Div Mol Genome Anal, D-69120 Heidelberg, Germany. [Kolevzon, Alexander] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. [Lee, Irene; Skuse, David] UCL, Inst Child Hlth, London WC1N 1EH, England. [Lehtimaeki, Terho] Fimlab Labs, Dept Clin Chem, SF-33100 Tampere, Finland. [Ma'ayan, Avi] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [McInnes, Alison L.] Kaiser Permanente, Dept Psychiat, San Francisco, CA 94118 USA. [Neale, Benjamin; Stevens, Christine; Daly, Mark J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Owen, Michael J.] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF24 4HQ, S Glam, Wales. [Owen, Michael J.] Cardiff Univ, Neurosci & Mental Hlth Res Inst, Cardiff CF24 4HQ, S Glam, Wales. [Parellada, Mara] Univ Complutense, Hosp Gen Univ Gregorio Maranon, Child & Adolescent Psychiat Dept, IiSGM,CIBERSAM, E-28040 Madrid, Spain. [Parr, Jeremy R.] Newcastle Univ, Sch Neurosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Puura, Kaija] Tampere Univ, Dept Child Psychiat, Tampere 33521, Finland. [Puura, Kaija] Tampere Univ Hosp, Tampere 33521, Finland. [Reichenberg, Abraham] Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA. [Sabo, Aniko] Baylor Coll Med, Dept Human Mol Genet, Houston, TX 77030 USA. [Sanders, Stephan J.; Weiss, Lauren A.; Willsey, A. Jeremy; State, Matthew W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Schulte-Ruether, Martin] Univ Hosp RWTH Aachen, JARA Brain Translat Med, Translat Brain Med Psychiat & Neurol, Dept Child & Adolescent Psychiat Psychosomat Psyc, D-52056 Aachen, Germany. [Skuse, David] Great Ormond St Hosp Sick Children, Natl Hlth Serv Fdn Trust, Dept Child & Adolescent Mental Hlth, London WC1N 3JH, England. [Szatmari, Peter] McMaster Univ, Dept Psychiat & Behav Neurosci, Offord Ctr Child Studies, Hamilton, ON L8S 4K1, Canada. [Voran, Annette] Saarland Univ Hosp, Dept Child & Adolescent Psychiat, D-66424 Homburg, Germany. [Hultman, Christina M.] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Lehner, Thomas] NIMH, NIH, Bethesda, MD 20892 USA. [Palotie, Aarno] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Palotie, Aarno] Univ Helsinki, Inst Mol Med Finland, FI-00014 Helsinki, Finland. [Palotie, Aarno] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Skiar, Pamela; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Scherer, Stephen W.] Univ Toronto, McLaughlin Ctr, Toronto, ON M5S 1A1, Canada. [Zwick, Michael E.; Cutler, David J.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 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 mjdaly@broadinstitute.org; joseph.buxbaum@mssm.edu RI Scherer, Stephen /B-3785-2013; Yuen, Ryan/J-4876-2012; Ozaki, Norio/M-8908-2014; Sutcliffe, James/C-1348-2012; Liu, Li/G-1897-2015; Aleksic, Branko/G-1540-2011; Breen, Gerome/A-5540-2010; Collier, David/D-1649-2011; Schulte-Ruther, Martin /F-4784-2013; De Rubeis, Silvia/E-9852-2013; OI De Rubeis, Silvia/0000-0001-9383-6883; Tammimies, Kristiina/0000-0002-8324-4697; Gill, Michael/0000-0003-0206-5337; Carracedo, Angel/0000-0003-1085-8986; Chahrour, Maria/0000-0002-3174-1480; Buxbaum, Joseph/0000-0001-8898-8313; Geller, Evan/0000-0002-8035-8736; Anney, Richard/0000-0002-6083-407X; Sanders, Stephan/0000-0001-9112-5148; Yu, Timothy/0000-0003-2988-7701; Gallagher, Louise/0000-0001-9462-2836; Scherer, Stephen /0000-0002-8326-1999; Yuen, Ryan/0000-0001-7273-4968; Ozaki, Norio/0000-0002-7360-4898; Sutcliffe, James/0000-0001-5200-6007; Aleksic, Branko/0000-0001-8982-4580; Breen, Gerome/0000-0003-2053-1792; Collier, David/0000-0003-4087-1559; Schulte-Ruther, Martin /0000-0002-7198-9923; Kilpinen-Barrett, Leena Helena/0000-0001-6692-6154 FU National Institutes of Health (NIH) [U01MH100233, U01MH100209, U01MH100229, U01MH100239]; NIH grants [R01MH089208, U54 HG003067]; NIH [R01 MH089482, R37 MH057881, R01 MH061009, UL1TR000445, P50 HD055751, MH089482, NIH RO1 MH083565, RC2MH089952, NIMH MH095034, MH077139, 5UL1 RR024975, P30 HD15052]; Charles and Ann Schlaifer Memorial Fund; UK National Institute for Health Research (NIHR) Senior Investigator award; NIHR Biomedical Research Centre in Mental Health at the South London&Maudsley Hospital; Maria Jose Jove Foundation; Strategic Action from Health Carlos III Institute (FEDER) [FIS PI13/01136]; [HICF-1009-003]; [WT098051]; [WT091310] FX This work was supported by National Institutes of Health (NIH) grants U01MH100233, U01MH100209, U01MH100229 and U01MH100239 to the Autism Sequencing Consortium. Sequencing at Broad Institute was supported by NIH grants R01MH089208 (M.J.D.) and new sequencing by U54 HG003067 (S. Gabriel, E. Lander). Other funding includes NIH R01 MH089482, R37 MH057881 (B. D. and K. R.), R01 MH061009 (J.S.S.), UL1TR000445 (NCAT to VUMC); P50 HD055751 (E. H. C.); MH089482 (J.S.S.), NIH RO1 MH083565 and RC2MH089952 (C. A. W.), NIMH MH095034 (P. S), MH077139 (P.F. Sullivan); 5UL1 RR024975 and P30 HD15052. The DDD Study is funded by HICF-1009-003 and WT098051. UK10K is funded by WT091310. We also acknowledge The National Children's Research Foundation, Our Lady's Children's Hospital, Crumlin; The Meath Foundation; AMNCH, Tallaght; The Health Research Board, Ireland and Autism Speaks, U. S. A. C. A. W. is an Investigator of the Howard Hughes Medical Institute. S.D.R., A.P.G., C.S.P., Y.K. and S.-C.F. are Seaver fellows, supported by the Seaver foundation. A. P. G. is also supported by the Charles and Ann Schlaifer Memorial Fund. P. F. B. is supported by a UK National Institute for Health Research (NIHR) Senior Investigator award and the NIHR Biomedical Research Centre in Mental Health at the South London&Maudsley Hospital. A. C. is supported by Maria Jose Jove Foundation and the grant FIS PI13/01136 of the Strategic Action from Health Carlos III Institute (FEDER). This work was supported in part through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. We acknowledge the assistance of D. Hall and his team at National Database for Autism Research. We thank Jian Feng for providing a list of targets of both RBFOX1 and H3K4me3. We thank M. Potter for data coordination; K. Moore and J. Reichert for technical assistance; and, S. Lindsay for helping with molecular validation. We acknowledge the clinicians and organizations that contributed to samples used in this study. Finally, we are grateful to the many families whose participation made this study possible. NR 47 TC 348 Z9 350 U1 27 U2 103 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 NOV 13 PY 2014 VL 515 IS 7526 BP 209 EP U119 DI 10.1038/nature13772 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT0MZ UT WOS:000344631400038 PM 25363760 ER PT J AU Choi, SH Kim, YH Hebisch, M Sliwinski, C Lee, S D'Avanzo, C Chen, HC Hooli, B Asselin, C Muffat, J Klee, JB Zhang, C Wainger, BJ Peitz, M Kovacs, DM Woolf, CJ Wagner, SL Tanzi, RE Kim, DY AF Choi, Se Hoon Kim, Young Hye Hebisch, Matthias Sliwinski, Christopher Lee, Seungkyu D'Avanzo, Carla Chen, Hechao Hooli, Basavaraj Asselin, Caroline Muffat, Julien Klee, Justin B. Zhang, Can Wainger, Brian J. Peitz, Michael Kovacs, Dora M. Woolf, Clifford J. Wagner, Steven L. Tanzi, Rudolph E. Kim, Doo Yeon TI A three-dimensional human neural cell culture model of Alzheimer's disease SO NATURE LA English DT Article ID TRANSGENIC MOUSE MODELS; PLURIPOTENT STEM-CELLS; AMYLOID HYPOTHESIS; A-BETA; TAU; RESPONSIVENESS; PATHOLOGY; NEURONS; IPSCS AB Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-beta plaques and neurofibrillary tangles(1). The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-beta peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau(2,3). However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer's disease (FAD) mutations exhibit amyloid-beta-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer's disease, including distinct neurofibrillary tangle pathology(4,5). Human neurons derived from Alzheimer's disease patients have shown elevated levels of toxic amyloid-beta species and phosphorylated tau but did not demonstrate amyloid-beta plaquesor neurofibrillary tangles(6-11). Here we report that FAD mutations in beta-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-beta, including amyloid-beta plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloidb beta generation with beta- or gamma-secretase inhibitors not only decreased amyloid-beta pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-beta-mediated tau phosphorylation. We have successfully recapitulated amyloid-beta and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer's disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders. C1 [Choi, Se Hoon; Kim, Young Hye; Hebisch, Matthias; Sliwinski, Christopher; D'Avanzo, Carla; Chen, Hechao; Hooli, Basavaraj; Asselin, Caroline; Klee, Justin B.; Zhang, Can; Kovacs, Dora M.; Tanzi, Rudolph E.; Kim, Doo Yeon] Harvard Univ, Massachusetts Gen Hosp, MassGeneral Inst Neurodegenerat Dis, Genet & Aging Res Unit,Med Sch, Charlestown, MA 02129 USA. [Kim, Young Hye] Korea Basic Sci Inst, Div Mass Spectrometry Res, Cheongju 363883, Chungbuk, South Korea. [Hebisch, Matthias; Peitz, Michael] Univ Bonn, Life & Brain Ctr, Inst Reconstruct Neurobiol, D-53127 Bonn, Germany. [Hebisch, Matthias; Peitz, Michael] Hertie Fdn, D-53127 Bonn, Germany. [Lee, Seungkyu; Wainger, Brian J.; Woolf, Clifford J.] Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Lee, Seungkyu; Wainger, Brian J.; Woolf, Clifford J.] Harvard Stem Cell Inst, Boston, MA 02115 USA. [Muffat, Julien] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Wagner, Steven L.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. RP Kim, DY (reprint author), Harvard Univ, Massachusetts Gen Hosp, MassGeneral Inst Neurodegenerat Dis, Genet & Aging Res Unit,Med Sch, Charlestown, MA 02129 USA. EM tanzi@helix.mgh.harvard.edu; dkim@helix.mgh.harvard.edu OI Muffat, Julien/0000-0003-1889-7023 FU Cure Alzheimer's fund; national Institute of Health grants [5P01AG15379, 5R37MH060009]; NIH/NINDS [P30NS04776]; IBDG Grant [DK43351]; BADERC Award [DK57521] FX This work was supported by the grants from the Cure Alzheimer's fund (D.Y.K., S.H.C. and R.E.T.) and national Institute of Health grants 5P01AG15379 (R.E.T.) and 5R37MH060009 (R.E.T.). We thank T. L. Spires, M. Polydoro and S. Wegmann for revising the manuscript, and M. L. McKee for the electron microscopy assistance. We also appreciate B. T. Hyman, O. Berezovska, J. Hardy and P. Davies for providing cDNAs and antibodies. We acknowledge Ragon Institute's Imaging Core facility (part of the Harvard CFAR Immunology Core), Massachusetts General Hospital (MGH) Viral Vector Core (supported by NIH/NINDS P30NS04776), MGH Microscopy Core of the Center for Systems Biology for immunoelectron microscopy (partially supported by an IBDG Grant DK43351 and a BADERC Award DK57521), MGH Confocal Microscope Core and MGH Pathology Core for technical and instrument support. NR 30 TC 151 Z9 154 U1 32 U2 203 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 NOV 13 PY 2014 VL 515 IS 7526 BP 274 EP U293 DI 10.1038/nature13800 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT0MZ UT WOS:000344631400052 PM 25307057 ER PT J AU Long, GV Stroyakovskiy, D Gogas, H Levchenko, E de Braud, F Larkin, J Garbe, C Jouary, T Hauschild, A Grob, JJ Sileni, VC Lebbe, C Mandala, M Millward, M Arance, A Bondarenko, I Haanen, JBAG Hansson, J Utikal, J Ferraresi, V Kovalenko, N Mohr, P Probachai, V Schadendorf, D Nathan, P Robert, C Ribas, A DeMarini, DJ Irani, JG Casey, M Ouellet, D Martin, AM Le, N Patel, K Flaherty, K AF Long, G. V. Stroyakovskiy, D. Gogas, H. Levchenko, E. de Braud, F. Larkin, J. Garbe, C. Jouary, T. Hauschild, A. Grob, J. J. Sileni, V. Chiarion Lebbe, C. Mandala, M. Millward, M. Arance, A. Bondarenko, I. Haanen, J. B. A. G. Hansson, J. Utikal, J. Ferraresi, V. Kovalenko, N. Mohr, P. Probachai, V. Schadendorf, D. Nathan, P. Robert, C. Ribas, A. DeMarini, D. J. Irani, J. G. Casey, M. Ouellet, D. Martin, A. -M. Le, N. Patel, K. Flaherty, K. TI Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID METASTATIC MELANOMA; RAF INHIBITORS; ACQUIRED-RESISTANCE; IMPROVED SURVIVAL; SOLID TUMORS; DABRAFENIB; MUTATIONS; TRIAL; VEMURAFENIB; PROGRESSION AB BACKGROUND Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations. METHODS In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted. RESULTS The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P = 0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P = 0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P = 0.02). However, a specified efficacy-stopping boundary (two-sided P = 0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group. CONCLUSIONS A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations. C1 [Long, G. V.] Univ Sydney, Melanoma Inst Australia, Mater Hosp, Sydney, NSW 2006, Australia. [Millward, M.] Sir Charles Gairdner Hosp, Perth, WA, Australia. [Stroyakovskiy, D.] Moscow City Oncol Hosp 62, Moscow, Russia. [Levchenko, E.] Petrov Res Inst Oncol, St Petersburg, Russia. [Kovalenko, N.] Volograd Reg Oncol Dispensary 3, Volzhsky, Russia. [Gogas, H.] Univ Athens, GR-10679 Athens, Greece. [de Braud, F.] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Sileni, V. Chiarion] Veneto Oncol Inst IRCCS, Padua, Italy. [Mandala, M.] Papa Giovanni XXIII Hosp, Bergamo, Italy. [Ferraresi, V.] Regina Elena Inst Canc Res, Rome, Italy. [Larkin, J.] Royal Marsden NHS Fdn Trust, London, England. [Nathan, P.] Mt Vernon Canc Ctr, Northwood, Middx, England. [Garbe, C.] Univ Tubingen, Tubingen, Germany. [Hauschild, A.] Univ Hosp Schleswig Holstein, Kiel, Germany. [Utikal, J.] Heidelberg Univ, German Canc Res Ctr DKFZ, Mannheim, Germany. [Utikal, J.] Heidelberg Univ, Univ Med Ctr Mannheim, Mannheim, Germany. [Utikal, J.] Heidelberg Univ, German Canc Res Ctr DKFZ, Heidelberg, Germany. [Utikal, J.] Heidelberg Univ, Univ Med Ctr Mannheim, Heidelberg, Germany. [Mohr, P.] Elbe Kliniken Stade Buxtehude, Buxtehude, Germany. [Stroyakovskiy, D.] Univ Hosp Essen, Essen, Germany. [Jouary, T.] Hop Francois Mitterrand, Pau, France. [Grob, J. J.] Hop Enfants La Timone, Marseille, France. [Lebbe, C.] Hop St Louis, Paris, France. [Robert, C.] Inst Gustave Roussy, Villejuif, France. [Arance, A.] Hosp Clin Barcelona, Barcelona, Spain. [Bondarenko, I.] Dnipropetrovsk Med Acad, Clin Hosp 4, Dnepropetrovsk, Ukraine. [Probachai, V.] Dnipropetrovsk State Council, Dnipropetrovsk Clin Oncol Ctr, Dnepropetrovsk, Ukraine. [Haanen, J. B. A. G.] Netherlands Canc Inst, Amsterdam, Netherlands. [Hansson, J.] Karolinska Inst, Stockholm, Sweden. [Ribas, A.] Univ Calif Los Angeles, Los Angeles, CA USA. [DeMarini, D. J.; Irani, J. G.; Casey, M.; Martin, A. -M.; Le, N.; Patel, K.] GlaxoSmithKline, Collegeville, PA USA. [Ouellet, D.] GlaxoSmithKline, Res Triangle Pk, NC USA. [Flaherty, K.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Long, GV (reprint author), Univ Sydney, Melanoma Inst Australia, 40 Rocklands Rd, Sydney, NSW 2060, Australia. EM georgina.long@sydney.edu.au RI de Braud, Filippo/B-9997-2017; OI de Braud, Filippo/0000-0003-0103-730X; Utikal, Jochen/0000-0001-5316-0241; Bondarenko, Igor/0000-0002-7071-2471 FU GlaxoSmithKline FX Supported by GlaxoSmithKline. NR 30 TC 347 Z9 352 U1 8 U2 32 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 NOV 13 PY 2014 VL 371 IS 20 BP 1877 EP 1888 DI 10.1056/NEJMoa1406037 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AT1RB UT WOS:000344709800005 PM 25265492 ER PT J AU Wakeman, SE Ghoshhajra, BB Dudzinski, DM Wilens, T Slavin, PL AF Wakeman, Sarah E. Ghoshhajra, Brian B. Dudzinski, David M. Wilens, Timothy Slavin, Peter L. TI Case 35-2014: A 31-Year-Old Woman with Fevers, Chest Pain, and a History of HCV Infection and Substance-Use Disorder SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MEDICAL ADVICE; RHEUMATIC MANIFESTATIONS; DRUG-USERS; ABUSERS; ENDOCARDITIS; ASSOCIATION; METHADONE; CRITERIA; ADDICTS; DEATH C1 [Wakeman, Sarah E.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Ghoshhajra, Brian B.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Dudzinski, David M.] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. [Wilens, Timothy] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Slavin, Peter L.] Massachusetts Gen Hosp, Dept Adm, Boston, MA 02114 USA. [Wakeman, Sarah E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Ghoshhajra, Brian B.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Dudzinski, David M.] Harvard Univ, Sch Med, Dept Cardiol, Boston, MA USA. [Wilens, Timothy] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Slavin, Peter L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Wakeman, SE (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. FU Siemens Healthcare; Sanofi; AdvantageHealthCare; Pfizer; Euthymics/Neurovance; Theravance; Tris; Guilford Press; U.S. National Football League (ERM Associates); U.S. Minor/Major League Baseball; Bay Cove Human Services (Clinical Services) FX Dr. Ghoshhajra reports receiving lecture fees from Siemens Healthcare; Dr. Dudzinski, consulting fees from Sanofi and AdvantageHealthCare; and Dr. Wilens, grant support from Pfizer and consulting fees from Euthymics/Neurovance, Theravance, Tris, Guilford Press, U.S. National Football League (ERM Associates), U.S. Minor/Major League Baseball, and Bay Cove Human Services (Clinical Services). No other potential conflict of interest relevant to this article was reported. NR 27 TC 1 Z9 1 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 NOV 13 PY 2014 VL 371 IS 20 BP 1918 EP 1926 DI 10.1056/NEJMcpc1407131 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AT1RB UT WOS:000344709800011 PM 25390743 ER PT J AU Zukotynski, K Yap, JT Giobbie-Hurder, A Weber, J Gonzalez, R Gajewski, TF O'Day, S Kim, K Hodi, FS Van den Abbeele, AD AF Zukotynski, Katherine Yap, Jeffrey T. Giobbie-Hurder, Anita Weber, Jeffrey Gonzalez, Rene Gajewski, Thomas F. O'Day, Steven Kim, Kevin Hodi, F. Stephen Van den Abbeele, Annick D. TI Metabolic response by FDG-PET to imatinib correlates with exon 11 KIT mutation and predicts outcome in patients with mucosal melanoma SO CANCER IMAGING LA English DT Article DE Melanoma; KIT mutation; F-18-FDG-PET/CT; Imatinib ID GASTROINTESTINAL STROMAL TUMORS; POSITRON-EMISSION-TOMOGRAPHY; MALIGNANT-MELANOMA; METASTATIC MELANOMA; CUTANEOUS MELANOMA; C-KIT; MEDICAL PROGRESS; MESYLATE; MANAGEMENT; THERAPY AB Background: In patients with metastatic melanoma and KIT amplifications and/or mutations, therapy with imatinib mesylate may prolong survival. F-18-labeled 2-fluoro-2-deoxy-D-glucose (F-18-FDG) PET/CT may be used to assess metabolic response. We investigated associations of metabolic response, mutational status, progression-free survival and overall survival in this population. Methods: Baseline and 4-week follow-up F-18-FDG-PET/CT were evaluated in 17 patients with metastatic melanoma and KIT amplifications and/or mutations treated with imatinib in a multicenter phase II clinical trial. The maximum standardized uptake values (SUVmax) were measured in up to 10 lesions on each scan. Metabolic response was classified using modified EORTC criteria. Each patient had a diagnostic CT or MR at baseline, after 6 weeks of therapy and then at intervals of 2 months and anatomic response was classified using RECIST 1.0. Median follow-up was 9.8 months. Results: Partial metabolic response (PMR), stable metabolic disease (SMD) and progressive metabolic disease (PMD) was seen in 5 (29%), 5 (29%), and 7 (41%) patients respectively. Five patients (29%) had a KIT mutation in exon 11, four of whom (80%) had PMR while 1 (20%) had SMD. Twelve patients (71%) did not have a KIT mutation in exon 11, and only 1 (8%) had PMR, 4 (33%) had SMD and 7 (58%) had PMD. There was agreement of metabolic and anatomic classification in 12 of 17 patients (71%). Four of 17 patients (24%) had PR on both metabolic and anatomic imaging and all had a KIT mutation in exon 11. Survival of patients with PMD was lower than with SMD or PMR. Conclusions: Metabolic response by F-18-FDG-PET/CT is associated with mutational status in metastatic melanoma patients treated with imatinib. F-18-FDG-PET/CT may be a predictor of outcome, although a larger study is needed to verify this. C1 [Zukotynski, Katherine] Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Zukotynski, Katherine; Van den Abbeele, Annick D.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Yap, Jeffrey T.] Univ Utah, Huntsman Canc Inst, Dept Radiol, Salt Lake City, UT 84112 USA. [Giobbie-Hurder, Anita; Hodi, F. Stephen; Van den Abbeele, Annick D.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Weber, Jeffrey] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Gonzalez, Rene] Univ Colorado, Ctr Canc, Aurora, CO 80045 USA. [Gajewski, Thomas F.] Univ Chicago, Chicago, IL 60637 USA. [O'Day, Steven] Beverly Hills Canc Ctr, Beverly Hills, CA 90211 USA. [Kim, Kevin] Calif Pacific Med Ctr, San Francisco, CA 94114 USA. RP Weber, J (reprint author), Univ Utah, Huntsman Canc Inst, Dept Radiol, 2000 Circle Hope Dr, Salt Lake City, UT 84112 USA. EM jeffrey.yap@hci.utah.edu FU Novartis; Pfizer; Bristol-Myers Squibb; Roche/Genentech; Eisai; Merck; Incyte FX The following authors have received research funding from the companies listed: F. Stephen Hodi, Novartis, Pfizer; Rene Gonzalez, Novartis; Thomas F. Gajewski, Bristol-Myers Squibb, Roche/Genentech, Eisai, Merck, Incyte; Steven J. O'Day, Novartis; Kevin B. Kim, Novartis; Jeffrey T. Yap, Novartis; Annick D. Van den Abbeele, Novartis. NR 45 TC 2 Z9 2 U1 1 U2 3 PU E-MED PI LONDON PA PO BOX 29761, LONDON, NW3 7ZS, ENGLAND SN 1470-7330 EI 1740-5025 J9 CANCER IMAGING JI Cancer Imaging PD NOV 12 PY 2014 VL 14 AR 30 DI 10.1186/s40644-014-0030-0 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA CE8NB UT WOS:000352098300001 PM 25609545 ER PT J AU Do, S Karl, WC Singh, S Kalra, M Brady, T Shin, E Pien, H AF Do, Synho Karl, William Clem Singh, Sarabjeet Kalra, Mannudeep Brady, Tom Shin, Ellie Pien, Homer TI High Fidelity System Modeling for High Quality Image Reconstruction in Clinical CT SO PLOS ONE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; POINT-SOURCE MEASUREMENTS; BEAM COMPUTED-TOMOGRAPHY; FLYING FOCAL SPOT; LOW-DOSE CT; ITERATIVE RECONSTRUCTION; PEDIATRIC CT; HELICAL CT; RADIATION; REDUCTION AB Today, while many researchers focus on the improvement of the regularization term in IR algorithms, they pay less concern to the improvement of the fidelity term. In this paper, we hypothesize that improving the fidelity term will further improve IR image quality in low-dose scanning, which typically causes more noise. The purpose of this paper is to systematically test and examine the role of high-fidelity system models using raw data in the performance of iterative image reconstruction approach minimizing energy functional. We first isolated the fidelity term and analyzed the importance of using focal spot area modeling, flying focal spot location modeling, and active detector area modeling as opposed to just flying focal spot motion. We then compared images using different permutations of all three factors. Next, we tested the ability of the fidelity terms to retain signals upon application of the regularization term with all three factors. We then compared the differences between images generated by the proposed method and Filtered-Back-Projection. Lastly, we compared images of low-dose in vivo data using Filtered-Back-Projection, Iterative Reconstruction in Image Space, and the proposed method using raw data. The initial comparison of difference maps of images constructed showed that the focal spot area model and the active detector area model also have significant impacts on the quality of images produced. Upon application of the regularization term, images generated using all three factors were able to substantially decrease model mismatch error, artifacts, and noise. When the images generated by the proposed method were tested, conspicuity greatly increased, noise standard deviation decreased by 90% in homogeneous regions, and resolution also greatly improved. In conclusion, the improvement of the fidelity term to model clinical scanners is essential to generating higher quality images in low-dose imaging. C1 [Do, Synho; Singh, Sarabjeet; Kalra, Mannudeep; Brady, Tom; Shin, Ellie; Pien, Homer] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Do, Synho; Singh, Sarabjeet; Kalra, Mannudeep; Brady, Tom; Shin, Ellie; Pien, Homer] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Karl, William Clem] Boston Univ, Dept Elect & Comp Engn, Boston, MA 02215 USA. RP Do, S (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM sdo@mgh.harvard.edu NR 56 TC 1 Z9 1 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 12 PY 2014 VL 9 IS 11 AR e111625 DI 10.1371/journal.pone.0111625 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CA8CP UT WOS:000349144400027 PM 25390888 ER PT J AU Axel, L Wedeen, VJ Ennis, DB AF Axel, Leon Wedeen, Van J. Ennis, Daniel B. TI Probing dynamic myocardial microstructure with cardiac magnetic resonance diffusion tensor imaging SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Editorial Material DE Cardiovascular magnetic resonance; Diffusion tensor imaging; Heart; Sheetlets; Strain; Hypertrophic cardiomyopathy ID CANINE LEFT-VENTRICLE; HYPERTROPHIC CARDIOMYOPATHY; IN-VIVO; FIBER-ORIENTATION; HISTOLOGICAL VALIDATION; LAMINAR ARCHITECTURE; CONFOCAL MICROSCOPY; SPIN ECHOES; MRI; HEART AB This article is an invited editorial comment on the paper entitled "In vivo cardiovascular magnetic resonance diffusion tensor imaging shows evidence of abnormal myocardial laminar orientations and mobility in hypertrophic cardiomyopathy" by Ferreira et al., and published as Journal of Cardiovascular Magnetic Resonance 2014; 16:87. C1 [Axel, Leon] NYU, Sch Med, Dept Radiol, New York, NY USA. [Axel, Leon] NYU, Sch Med, Dept Med, New York, NY USA. [Wedeen, Van J.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Ennis, Daniel B.] Univ Calif Los Angeles, Dept Radiol Sci, Los Angeles, CA 90024 USA. RP Axel, L (reprint author), NYU, Sch Med, Dept Radiol, New York, NY USA. EM Leon.Axel@nyumc.org OI Axel, Leon/0000-0003-0608-4690 NR 32 TC 10 Z9 10 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 EI 1532-429X J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD NOV 12 PY 2014 VL 16 AR 89 DI 10.1186/s12968-014-0089-6 PG 7 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA CA0MW UT WOS:000348612700001 PM 25388937 ER PT J AU Lakhashe, SK Byrareddy, SN Zhou, MK Bachler, BC Hemashettar, G Hu, SL Villinger, F Else, JG Stock, S Lee, SJ Vargas-Inchaustegui, DA Cofano, EB Robert-Guroff, M Johnson, WE Polonis, VR Forthal, DN Loret, EP Rasmussen, RA Ruprecht, RM AF Lakhashe, Samir K. Byrareddy, Siddappa N. Zhou, Mingkui Bachler, Barbara C. Hemashettar, Girish Hu, Shiu-Lok Villinger, Francois Else, James G. Stock, Shannon Lee, Sandra J. Vargas-Inchaustegui, Diego A. Cofano, Egidio Brocca Robert-Guroff, Marjorie Johnson, Welkin E. Polonis, Victoria R. Forthal, Donald N. Loret, Erwann P. Rasmussen, Robert A. Ruprecht, Ruth M. TI Multimodality vaccination against clade C SHIV: Partial protection against mucosal challenges with a heterologous tier 2 virus SO VACCINE LA English DT Article DE HIV vaccine; SHIV-C; Heterologous tier 2 virus; Rhesus monkey; Cellular immunity; ADCC ID SIMIAN IMMUNODEFICIENCY VIRUS; OVERLAPPING SYNTHETIC PEPTIDES; HIGHLY PATHOGENIC SIV; RHESUS MACAQUES; NEUTRALIZING ANTIBODIES; REPLICATION-COMPETENT; MOLECULAR CLONES; HIV-1 INFECTION; TAT VARIANTS; EFFICACY AB We sought to test whether vaccine-induced immune responses could protect rhesus macaques (RMs) against upfront heterologous challenges with an R5 simian-human immunodeficiency virus, SHIV-2873Nip. This SHIV strain exhibits many properties of transmitted HIV-1, such as tier 2 phenotype (relatively difficult to neutralize), exclusive CCR5 tropism, and gradual disease progression in infected RMs. Since no human AIDS vaccine recipient is likely to encounter an HIV-1 strain that exactly matches the immunogens, we immunized the RMs with recombinant Env proteins heterologous to the challenge virus. For induction of immune responses against Gag, Tat, and Nef, we explored a strategy of immunization with overlapping synthetic peptides (OSP). The immune responses against Gag and Tat were finally boosted with recombinant proteins. The vaccinees and a group of ten control animals were given five low-dose intrarectal (i.r.) challenges with SHIV-2873 Nip. All controls and seven out of eight vaccinees became systemically infected; there was no significant difference in viremia levels of vaccinees vs. controls. Prevention of viremia was observed in one vaccinee which showed strong boosting of virus-specific cellular immunity during virus exposures. The protected animal showed no challenge virus-specific neutralizing antibodies in the TZM-bl or A3R5 cell-based assays and had low-level ADCC activity after the virus exposures. Microarray data strongly supported a role for cellular immunity in the protected animal. Our study represents a case of protection against heterologous tier 2 SHIV-C by vaccine-induced, virus-specific cellular immune responses. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Lakhashe, Samir K.; Zhou, Mingkui; Ruprecht, Ruth M.] Texas Biomed Res Inst, San Antonio, TX 78245 USA. [Ruprecht, Ruth M.] Southwest Natl Primate Res Ctr, San Antonio, TX USA. [Lakhashe, Samir K.; Byrareddy, Siddappa N.; Zhou, Mingkui; Bachler, Barbara C.; Hemashettar, Girish; Stock, Shannon; Lee, Sandra J.; Rasmussen, Robert A.; Ruprecht, Ruth M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lakhashe, Samir K.; Byrareddy, Siddappa N.; Zhou, Mingkui; Lee, Sandra J.; Rasmussen, Robert A.; Ruprecht, Ruth M.] Harvard Univ, Sch Med, Boston, MA USA. [Hu, Shiu-Lok] Univ Washington, Seattle, WA 98195 USA. [Byrareddy, Siddappa N.; Villinger, Francois; Else, James G.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Villinger, Francois; Else, James G.] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Vargas-Inchaustegui, Diego A.; Cofano, Egidio Brocca; Robert-Guroff, Marjorie] NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. [Johnson, Welkin E.] Boston Coll, Dept Biol, Chestnut Hill, MA 02167 USA. [Polonis, Victoria R.] Walter Reed Army Inst Res, Mil HIV Res Program, Silver Spring, MD USA. [Forthal, Donald N.] Univ Calif Irvine, Irvine Sch Med, Dept Med, Div Infect Dis, Irvine, CA USA. [Loret, Erwann P.] Aix Marseille Univ, CNRS, Fac Pharm, ETRAV Lab, F-13385 Marseille 5, France. RP Ruprecht, RM (reprint author), Texas Biomed Res Inst, POB 760549, San Antonio, TX 78245 USA. EM rruprecht@txbiomed.org FU NIH [R01 AI100703, P01 AI048240, AI095092]; Intramural Research Program of the NIH, National Cancer Institute; Office of Research Infrastructure Programs [OD P51 OD011132, OD P51 OD011133]; NCRR [P51 RR13986] FX We thank Stephanie Ehnert, Chris Souder and Kalpana Patel from the YNPRC for assistance with the primate studies. We acknowledge ABL, Inc. for the production of the clade C gp145 protein. This work was supported by NIH grants R01 AI100703 to RMR and P01 AI048240 to RMR, SLH, RAR and JLE. This project was also funded in part by the Intramural Research Program of the NIH, National Cancer Institute and by the Office of Research Infrastructure Programs/OD P51 OD011132 to the YNPRC and OD P51 OD011133 (previously NCRR grant P51 RR13986) to the Southwest National Primate Research Center. The work conducted by WEJ was supported by NIH grant AI095092. NR 64 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD NOV 12 PY 2014 VL 32 IS 48 BP 6527 EP 6536 DI 10.1016/j.vaccine.2014.08.065 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AU2SY UT WOS:000345469000032 PM 25245933 ER PT J AU Irazoqui, JE AF Irazoqui, Javier E. TI DAF-tly Depart Stinky Situations with elegans SO CELL HOST & MICROBE LA English DT Editorial Material ID CAENORHABDITIS-ELEGANS; BEHAVIOR AB During acute infection our behavior tends to change. Despite how common sickness behavior is, its molecular basis is not well understood. In a study published in Cell, Kim and colleagues (Meisel et al., 2014) implicate bacterial secondary metabolites as triggers of neural TGF-beta signaling, which results in behavioral change during infection. C1 Harvard Univ, Ctr Study Inflammatory Bowel Dis, Massachusetts Gen Hosp, Lab Comparat Immunol,Med Sch, Boston, MA 02114 USA. RP Irazoqui, JE (reprint author), Harvard Univ, Ctr Study Inflammatory Bowel Dis, Massachusetts Gen Hosp, Lab Comparat Immunol,Med Sch, Boston, MA 02114 USA. EM jirazoqui@mgh.harvard.edu OI Irazoqui, Javier/0000-0001-6553-1329 FU NIGMS NIH HHS [R01 GM101056] NR 12 TC 0 Z9 0 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD NOV 12 PY 2014 VL 16 IS 5 BP 553 EP 555 DI 10.1016/j.chom.2014.10.017 PG 3 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AT7NG UT WOS:000345123900003 PM 25525785 ER PT J AU Fribourgh, JL Nguyen, HC Matreyek, KA Alvarez, FJD Summers, BJ Dewdney, TG Aiken, C Zhang, PJ Engelman, A Xiong, Y AF Fribourgh, Jennifer L. Nguyen, Henry C. Matreyek, Kenneth A. Alvarez, Frances Joan D. Summers, Brady J. Dewdney, Tamaria G. Aiken, Christopher Zhang, Peijun Engelman, Alan Xiong, Yong TI Structural Insight into HIV-1 Restriction by MxB SO CELL HOST & MICROBE LA English DT Article ID DYNAMIN-LIKE MXA; LA-CROSSE VIRUS; NUCLEAR IMPORT; PROTEIN; GTPASE; OLIGOMERIZATION; INHIBITOR; INFECTION; SYSTEM; DOMAIN AB The myxovirus resistance (Mx) proteins are interferon-induced dynamin GTPases that can inhibit a variety of viruses. Recently, MxB, but not MxA, was shown to restrict HIV-1 by an unknown mechanism that likely occurs in close proximity to the host cell nucleus and involves the viral capsid. Here, we present the crystal structure of MxB and reveal determinants involved in HIV-1 restriction. MxB adopts an extended antiparallel dimer and dimerization, but not higher-ordered oligomerization, is critical for restriction. Although MxB is structurally similar to MxA, the orientation of individual domains differs between MxA and MxB, and their antiviral functions rely on separate determinants, indicating distinct mechanisms for virus inhibition. Additionally, MxB directly binds the HIV-1 capsid, and this interaction depends on dimerization and the N terminus of MxB as well as the assembled capsid lattice. These insights establish a framework for understanding the mechanism by which MxB restricts HIV-1. C1 [Fribourgh, Jennifer L.; Nguyen, Henry C.; Summers, Brady J.; Xiong, Yong] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. [Matreyek, Kenneth A.; Dewdney, Tamaria G.; Engelman, Alan] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Alvarez, Frances Joan D.; Zhang, Peijun] Univ Pittsburgh, Dept Biol Struct, Sch Med, Pittsburgh, PA 15260 USA. [Aiken, Christopher] Vanderbilt Univ, Sch Med, Dept Pathol Microbiol & Immunol, Nashville, TN 37232 USA. RP Engelman, A (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. EM alan_engelman@dfci.harvard.edu; yong.xiong@yale.edu OI Matreyek, Kenneth/0000-0001-9149-551X FU NIH [AI052014, GM082251]; Pittsburgh Center for HIV Protein Interactions FX We thank Q. Zhao for technical assistance and discussions. We also thank the staff at the Advanced Photon Source beamline 24-ID and the National Synchrotron Light Source beamlines X25. This work was funded in part by NIH grants AI052014 (to A.E.) and GM082251 (to A.E., C.A., and P.Z.) and a Collaboration Development Pilot Program award from the Pittsburgh Center for HIV Protein Interactions (to Y.X.). NR 46 TC 19 Z9 19 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD NOV 12 PY 2014 VL 16 IS 5 BP 627 EP 638 DI 10.1016/j.chom.2014.09.021 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AT7NG UT WOS:000345123900013 PM 25312384 ER PT J AU Satterlee, JS Basanta-Sanchez, M Blanco, S Li, JB Meyer, K Pollock, J Sadri-Vakili, G Rybak-Wolf, A AF Satterlee, John S. Basanta-Sanchez, Maria Blanco, Sandra Li, Jin Billy Meyer, Kate Pollock, Jonathan Sadri-Vakili, Ghazaleh Rybak-Wolf, Agnieszka TI Novel RNA Modifications in the Nervous System: Form and Function SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG NONCODING RNAS; RECESSIVE INTELLECTUAL DISABILITY; METHYLTRANSFERASE MISU NSUN2; NUCLEUS-ACCUMBENS CORE; OBESITY-RELATED GENE; AMPA RECEPTORS; COCAINE-SEEKING; MESSENGER-RNA; SYNAPTIC PLASTICITY; OXIDATIVE STRESS AB Modified RNA molecules have recently been shown to regulate nervous system functions. This mini-review and associated mini-symposium provide an overview of the types and known functions of novel modified RNAs in the nervous system, including covalently modified RNAs, edited RNAs, and circular RNAs. We discuss basic molecular mechanisms involving RNA modifications as well as the impact of modified RNAs and their regulation on neuronal processes and disorders, including neural fate specification, intellectual disability, neurodegeneration, dopamine neuron function, and substance use disorders. C1 [Satterlee, John S.; Pollock, Jonathan] NIDA, Bethesda, MD 20892 USA. [Basanta-Sanchez, Maria] SUNY Albany, RNA Inst, Albany, NY 12222 USA. [Blanco, Sandra] Univ Cambridge, Wellcome Trust, MRC, Stem Cell Inst, Cambridge CB2 1QR, England. [Li, Jin Billy] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Meyer, Kate] Cornell Univ, Dept Pharmacol, Weill Med Coll, New York, NY 10065 USA. [Sadri-Vakili, Ghazaleh] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Boston, MA 02129 USA. [Rybak-Wolf, Agnieszka] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. RP Satterlee, JS (reprint author), NIDA, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM satterleej@nida.nih.gov RI Blanco, Sandra/B-2070-2017 OI Blanco, Sandra/0000-0001-7352-9392 FU NIGMS NIH HHS [R01 GM102484]; NIMH NIH HHS [K99 MH104712] NR 142 TC 7 Z9 8 U1 2 U2 18 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD NOV 12 PY 2014 VL 34 IS 46 BP 15170 EP 15177 DI 10.1523/JNEUROSCI.3236-14.2014 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AT9AU UT WOS:000345220900006 PM 25392485 ER PT J AU Shin, HK Oka, F Kim, JH Atochin, D Huang, PL Ayata, C AF Shin, Hwa Kyoung Oka, Fumiaki Kim, Ji Hyun Atochin, Dmitriy Huang, Paul L. Ayata, Cenk TI Endothelial Dysfunction Abrogates the Efficacy of Normobaric Hyperoxia in Stroke SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cerebral blood flow; focal cerebral ischemia; laser speckle imaging; multispectral reflectance imaging; optical imaging; viability threshold ID FOCAL CEREBRAL-ISCHEMIA; NITRIC-OXIDE SYNTHASE; APOE-DEFICIENT MICE; TISSUE-PLASMINOGEN ACTIVATOR; LASER SPECKLE FLOWMETRY; HIGH-FAT DIET; OXYGEN-THERAPY; HYPERBARIC-OXYGEN; BLOOD-FLOW; ARTERY OCCLUSION AB Hyperoxia has been uniformly efficacious in experimental focal cerebral ischemia. However, pilot clinical trials have showed mixed results slowing its translation in patient care. To explain the discordance between experimental and clinical outcomes, we tested the impact of endothelial dysfunction, exceedingly common in stroke patients but under-represented in experimental studies, on the neuroprotective efficacy of normobaric hyperoxia. We used hyperlipidemic apolipoprotein E knock-out and endothelial nitric oxide synthase knock-out mice as models of endothelial dysfunction, and examined the effects of normobaric hyperoxia on tissue perfusion and oxygenation using high-resolution combined laser speckle and multispectral reflectance imaging during distal middle cerebral artery occlusion. In normal wild-type mice, normobaric hyperoxia rapidly and significantly improved tissue perfusion and oxygenation, suppressed peri-infarct depolarizations, reduced infarct volumes, and improved neurological function. In contrast, normobaric hyperoxia worsened perfusion in ischemic brain and failed to reduce infarct volumes or improve neurological function in mice with endothelial dysfunction. These data suggest that the beneficial effects of hyperoxia on ischemic tissue oxygenation, perfusion, and outcome are critically dependent on endothelial nitric oxide synthase function. Therefore, vascular risk factors associated with endothelial dysfunction may predict normobaric hyperoxia nonresponders in ischemic stroke. These data may have implications for myocardial and systemic circulation as well. C1 [Shin, Hwa Kyoung; Oka, Fumiaki; Ayata, Cenk] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurovasc Res Lab,Dept Radiol, Charlestown, MA 02129 USA. [Shin, Hwa Kyoung; Kim, Ji Hyun] Pusan Natl Univ, Sch Korean Med, Div Meridian & Struct Med, Yangsan 626870, Gyeongnam, South Korea. [Atochin, Dmitriy; Huang, Paul L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Atochin, Dmitriy; Huang, Paul L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA 02129 USA. [Ayata, Cenk] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke Serv, Charlestown, MA 02129 USA. [Ayata, Cenk] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurosci Intens Care Unit,Dept Neurol, Charlestown, MA 02129 USA. RP Ayata, C (reprint author), Massachusetts Gen Hosp, Dept Radiol, Neurovasc Res Lab, 149 13th St,Room 6408, Charlestown, MA 02129 USA. EM cayata@partners.org RI Atochin, Dmitriy/Q-3150-2016 FU National Research Foundation of Korea (NRF) - Korea government (MSIP) [2014R1A5A2009936]; National Institutes of Health [NS061505, NS055104]; Fondation Leducq; Neuroendovascular Research Fund from the Andrew David Heitman Foundation; Ellison Foundation FX This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2014R1A5A2009936), the National Institutes of Health (NS061505 and NS055104), Fondation Leducq, Neuroendovascular Research Fund from the Andrew David Heitman Foundation, and The Ellison Foundation. NR 63 TC 5 Z9 5 U1 1 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD NOV 12 PY 2014 VL 34 IS 46 BP 15200 EP 15207 DI 10.1523/JNEUROSCI.1110-14.2014 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AT9AU UT WOS:000345220900010 PM 25392489 ER PT J AU Rajendran, L Bali, J Barr, MM Court, FA Kramer-Albers, EM Picou, F Raposo, G van der Vos, KE van Nie, G Wang, J Breakefield, XO AF Rajendran, Lawrence Bali, Jitin Barr, Maureen M. Court, Felipe A. Kramer-Albers, Eva-Maria Picou, Frederic Raposo, Graca van der Vos, Kristan E. van Nie, Guillaume Wang, Juan Breakefield, Xandra O. TI Emerging Roles of Extracellular Vesicles in the Nervous System SO JOURNAL OF NEUROSCIENCE LA English DT Article ID FUNCTIONAL AMYLOID FORMATION; ALZHEIMERS-DISEASE; TERMINAL FRAGMENT; ENDOCYTIC PATHWAY; IMMUNE-RESPONSES; SCHWANN-CELL; EXOSOMES; PROTEIN; RNA; TRANSPORT AB Information exchange executed by extracellular vesicles, including exosomes, is a newly described form of intercellular communication important in the development and physiology of neural systems. These vesicles can be released from cells, are packed with information including signaling proteins and both coding and regulatory RNAs, and can be taken up by target cells, thereby facilitating the transfer of multilevel information. Recent studies demonstrate their critical role in physiological processes, including nerve regeneration, synaptic function, and behavior. These vesicles also have a sinister role in the propagation of toxic amyloid proteins in neurodegenerative conditions, including prion diseases and Alzheimer's and Parkinson's diseases, in inducing neuroinflammation by exchange of information between the neurons and glia, as well as in aiding tumor progression in the brain by subversion of normal cells. This article provides a summary of topics covered in a symposium and is not meant to be a comprehensive review of the subject. C1 [Rajendran, Lawrence; Bali, Jitin] Univ Zurich, Div Psychiat Res, CH-8006 Zurich, Switzerland. [Rajendran, Lawrence; Bali, Jitin] Univ Zurich, Grad Sch, Zurich Neurosci Ctr, CH-8006 Zurich, Switzerland. [Rajendran, Lawrence; Bali, Jitin] Univ Zurich, CH-8006 Zurich, Switzerland. [Barr, Maureen M.] Rutgers State Univ, Dept Genet, Inst Human Genet, Piscataway, NJ 08854 USA. [Court, Felipe A.; Picou, Frederic] Pontificia Univ Catolica Chile, Fac Biol, Millenium Nucl Regenerat Biol, Santiago, Chile. [Court, Felipe A.] Neurounion Biomed Fdn, Santiago, Chile. [Kramer-Albers, Eva-Maria] Johannes Gutenberg Univ Mainz, Dept Mol Cell Biol, D-55122 Mainz, Germany. [Kramer-Albers, Eva-Maria] Johannes Gutenberg Univ Mainz, Focus Programme Translat Neurosci, D-55122 Mainz, Germany. [Raposo, Graca; van Nie, Guillaume] Inst Curie, Ctr Rech, F-75248 Paris, France. [Raposo, Graca; van Nie, Guillaume] CNRS, Unite Mixte Rech 144, F-75248 Paris, France. [van der Vos, Kristan E.] Netherlands Canc Inst, Div Mol Carcinogenesis, Amsterdam, Netherlands. [Breakefield, Xandra O.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Breakefield, Xandra O.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Breakefield, Xandra O.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02114 USA. RP Breakefield, XO (reprint author), Massachusetts Gen Hosp East, Mol Neurogenet Unit, 13th St,Bldg 149, Charlestown, MA 02129 USA. EM Rajendran@bli.uzh.ch; breakefield@hms.harvard.edu RI Court, Felipe/C-5911-2015; OI van Niel, Guillaume/0000-0002-8651-9705 FU Velux Foundation Professorship Grant; Swiss National Science Foundation Grant [SNF-CR3313-153039]; SCOPES Grant [IZ73Z0_152496]; Novartis Foundation Grant; Bangerter Stiftung; Synapsis Foundation; National Institutes of Health Grants [R01DK059418, R01DK074746]; Fondo Nacional de Desarrollo Cientifico y Tecnologico [1110987, 3130527]; Millennium Nucleus [RC-120003]; Ring Initiative [ACT1109]; Deutsche Forschungsgemeinschaft research Grants [KR 3668/1-1]; DFG [SPP1757, KR-3668/2-1]; Dutch Scientific Organisation (NWO-Rubicon); Amyloidosis Foundation; Fondation pour la Recherche Medicale; National Institutes of Health/National Cancer Institute Grants through the National Institutes of Health Common Fund, the Office of Strategic Coordination/Office of the National Institutes of Health Director [P01 CA069246, CA141150, U19 CA179563] FX L. R. was supported by the Velux Foundation Professorship Grant, the interdisciplinary Swiss National Science Foundation Grant SNF-CR3313-153039, the SCOPES Grant IZ73Z0_152496, the Novartis Foundation Grant, Bangerter Stiftung, and the Synapsis Foundation. M. M. B. and J.W. were supported by National Institutes of Health Grants R01DK059418 and R01DK074746. F. A. C. and F. P. were supported by Grants from Fondo Nacional de Desarrollo Cientifico y Tecnologico Grants 1110987 and 3130527, Millennium Nucleus RC-120003, and Ring Initiative ACT1109. E.-M. K.-A. was supported by Deutsche Forschungsgemeinschaft research Grants KR 3668/1-1 and DFG SPP1757 (KR-3668/2-1). K.E.v.d.V. was supported by the Dutch Scientific Organisation (NWO-Rubicon). G.v.N. and G. R. were supported by Research Grants from the Amyloidosis Foundation and the Fondation pour la Recherche Medicale. X.O.B. was supported by National Institutes of Health/National Cancer Institute Grants P01 CA069246, CA141150, and U19 CA179563 through the National Institutes of Health Common Fund, the Office of Strategic Coordination/Office of the National Institutes of Health Director. We thank Ms. Suzanne McDavitt for skilled editorial assistance. NR 69 TC 48 Z9 49 U1 3 U2 36 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD NOV 12 PY 2014 VL 34 IS 46 BP 15482 EP 15489 DI 10.1523/JNEUROSCI.3258-14.2014 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AT9AU UT WOS:000345220900036 PM 25392515 ER PT J AU Mayer, EA Knight, R Mazmanian, SK Cryan, JF Tillisch, K AF Mayer, Emeran A. Knight, Rob Mazmanian, Sarkis K. Cryan, John F. Tillisch, Kirsten TI Gut Microbes and the Brain: Paradigm Shift in Neuroscience SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ANXIETY-LIKE BEHAVIOR; PROBIOTIC BIFIDOBACTERIUM-INFANTIS; IRRITABLE-BOWEL-SYNDROME; LACTOBACILLUS-HELVETICUS; MICE; AXIS; DISORDERS; STRESS; DISEASE; RATS AB The discovery of the size and complexity of the human microbiome has resulted in an ongoing reevaluation of many concepts of health and disease, including diseases affecting the CNS. A growing body of preclinical literature has demonstrated bidirectional signaling between the brain and the gut microbiome, involving multiple neurocrine and endocrine signaling mechanisms. While psychological and physical stressors can affect the composition and metabolic activity of the gut microbiota, experimental changes to the gut microbiome can affect emotional behavior and related brain systems. These findings have resulted in speculation that alterations in the gut microbiome may play a pathophysiological role in human brain diseases, including autism spectrum disorder, anxiety, depression, and chronic pain. Ongoing large-scale population-based studies of the gut microbiome and brain imaging studies looking at the effect of gut microbiome modulation on brain responses to emotion-related stimuli are seeking to validate these speculations. This article is a summary of emerging topics covered in a symposium and is not meant to be a comprehensive review of the subject. C1 [Mayer, Emeran A.; Tillisch, Kirsten] Univ Calif Los Angeles, David Geffen Sch Med, Oppenheimer Ctr Neurobiol Stress, Dept Med, Los Angeles, CA 90095 USA. [Mayer, Emeran A.; Tillisch, Kirsten] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA. [Mayer, Emeran A.; Tillisch, Kirsten] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biobehav Sci, Div Digest Dis, Los Angeles, CA 90095 USA. [Knight, Rob] Univ Colorado, Howard Hughes Med Inst, Boulder, CO 80309 USA. [Knight, Rob] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Knight, Rob] Univ Colorado, Dept Comp Sci, Boulder, CO 80309 USA. [Knight, Rob] Univ Colorado, BioFrontiers Inst, Boulder, CO 80309 USA. [Mazmanian, Sarkis K.] CALTECH, Dept Biol & Biol Engn, Pasadena, CA 91125 USA. [Cryan, John F.] Natl Univ Ireland Univ Coll Cork, Dept Anat & Neurosci, Cork, Ireland. [Cryan, John F.] Natl Univ Ireland Univ Coll Cork, Alimentary Pharmabiot Ctr, Cork, Ireland. [Tillisch, Kirsten] Vet Adm Greater Los Angeles Healthcare Syst, Div Integrat Med, Dept Med, Los Angeles, CA 90073 USA. RP Mayer, EA (reprint author), Univ Calif Los Angeles, CHS 42-210,MC737818,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM emayer@ucla.edu RI Knight, Rob/D-1299-2010; OI Cryan, John/0000-0001-5887-2723 FU National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Grant [R01 DK048351, P30 DK041301]; National Institutes of Health/National Institute of Mental Health Grant [R01 MH100556]; Simons Foundation SFARI Program; Howard Hughes Medical Institute; Autism Speaks FX This work was supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK048351 to E. A. M., Grant P30 DK041301, National Institutes of Health/National Institute of Mental Health Grant R01 MH100556 to S. K. M., Autism Speaks to S. K. M., Simons Foundation SFARI Program to S. K. M., and Howard Hughes Medical Institute to R. K. NR 74 TC 105 Z9 108 U1 42 U2 258 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD NOV 12 PY 2014 VL 34 IS 46 BP 15490 EP 15496 DI 10.1523/JNEUROSCI.3299-14.2014 PG 7 WC Neurosciences SC Neurosciences & Neurology GA AT9AU UT WOS:000345220900037 PM 25392516 ER PT J AU Frenette, M Hatamimoslehabadi, M Bellinger-Buckley, S Laoui, S La, J Bag, S Mallidi, S Hasan, T Bouma, B Yeleswarapu, C Rochford, J AF Frenette, Mathieu Hatamimoslehabadi, Maryam Bellinger-Buckley, Stephanie Laoui, Samir La, Jeffrey Bag, Seema Mallidi, Srivalleesha Hasan, Tayyaba Bouma, Brett Yeleswarapu, Chandra Rochford, Jonathan TI Shining Light on the Dark Side of Imaging: Excited State Absorption Enhancement of a Bis-styryl BODIPY Photoacoustic Contrast Agent SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID TRANSIENT ABSORPTION; IN-VIVO; BIOMEDICAL APPLICATIONS; INDOCYANINE GREEN; MICROSCOPY; NANOPARTICLES; TOMOGRAPHY; THERAPY AB A first approach toward understanding the targeted design of molecular photoacoustic contrast agents (MPACs) is presented. Optical and photoacoustic Z-scan spectroscopy was used to identify how nonlinear (excited-state) absorption contributes to enhancing the photoacoustic emission of the curcuminBF(2) and bis-styryl (MeOPh)(2)BODIPY dyes relative to Cy3. C1 [Frenette, Mathieu; Bellinger-Buckley, Stephanie; Bag, Seema; Rochford, Jonathan] Univ Massachusetts, Dept Chem, Boston, MA 02125 USA. [Hatamimoslehabadi, Maryam; Laoui, Samir; La, Jeffrey; Yeleswarapu, Chandra] Univ Massachusetts, Dept Phys, Boston, MA 02125 USA. [Mallidi, Srivalleesha; Hasan, Tayyaba; Bouma, Brett] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Yeleswarapu, C (reprint author), Univ Massachusetts, Dept Phys, 100 Morrissey Blvd, Boston, MA 02125 USA. EM Chandra.Yelleswarapu@umb.edu; Jonathan.Rochford@umb.edu RI Yelleswarapu, Chandra/C-4392-2011 FU UMass Boston; Dana-Farber/Harvard Cancer Center [U54CA156734]; NIH [F32CA165881, 5R01CA156177, S10OD012326] FX The authors thank UMass Boston and Dana-Farber/Harvard Cancer Center Grant number U54CA156734 for financial support. The authors would also like to acknowledge support by NIH grants F32CA165881 (to S.M.), 5R01CA156177 (to T.H.), and S10OD012326 (to T.H.). NR 32 TC 16 Z9 16 U1 6 U2 64 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD NOV 12 PY 2014 VL 136 IS 45 BP 15853 EP 15856 DI 10.1021/ja508600x PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA AT4JQ UT WOS:000344906100012 PM 25329769 ER PT J AU Obermeyer, Z Makar, M Abujaber, S Dominici, F Block, S Cutler, DM AF Obermeyer, Ziad Makar, Maggie Abujaber, Samer Dominici, Francesca Block, Susan Cutler, David M. TI Association Between the Medicare Hospice Benefit and Health Care Utilization and Costs for Patients With Poor-Prognosis Cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID OF-LIFE CARE; NEAR-DEATH; END; CHEMOTHERAPY; CLAIMS; BENEFICIARIES; ADJUSTMENT; INTENSITY; BREAST; PLACE AB IMPORTANCE More patients with cancer use hospice currently than ever before, but there are indications that care intensity outside of hospice is increasing, and length of hospice stay decreasing. Uncertainties regarding how hospice affects health care utilization and costs have hampered efforts to promote it. OBJECTIVE To compare utilization and costs of health care for patients with poor-prognosis cancers enrolled in hospice vs similar patients without hospice care. DESIGN, SETTING, AND PARTICIPANTS Matched cohort study of patients in hospice and nonhospice care using a nationally representative 20% sample of Medicare fee-for-service beneficiaries who died in 2011. Patients with poor-prognosis cancers (eg, brain, pancreatic, metastatic malignancies) enrolled in hospice before death were matched to similar patients who died without hospice care. EXPOSURES Period between hospice enrollment and death for hospice beneficiaries, and the equivalent period of nonhospice care before death for matched nonhospice patients. MAIN OUTCOMES AND MEASURES Health care utilization including hospitalizations and procedures, place of death, cost trajectories before and after hospice start, and cumulative costs, all during the last year of life. RESULTS Among 86 851 patients with poor-prognosis cancers, median time from first poor-prognosis diagnosis to death was 13 months (interquartile range [IQR], 3-34), and 51 924 (60%) entered hospice before death. Matching yielded a cohort balanced on age, sex, region, time from poor-prognosis diagnosis to death, and baseline care utilization, with 18 165 patients in the hospice group and 18 165 in the nonhospice group. [GRAPHICS] After matching, 11% of nonhospice and 1% of hospice beneficiaries who had cancer-directed therapy after exposure were excluded. Median hospice duration was 11 days. Nonhospice beneficiaries had significantly greater health care utilization, largely for acute conditions not directly related to cancer and higher overall costs. CONCLUSIONS AND RELEVANCE In this sample of Medicare fee-for-service beneficiaries with poor-prognosis cancer, those receiving hospice care vs not (control), had significantly lower rates of hospitalization, intensive care unit admission, and invasive procedures at the end of life, along with significantly lower total costs during the last year of life. C1 [Obermeyer, Ziad] Harvard Univ, Sch Med, Dept Emergency Med, Boston, MA USA. [Obermeyer, Ziad] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Obermeyer, Ziad; Makar, Maggie; Abujaber, Samer] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Obermeyer, Ziad; Block, Susan] Brigham & Womens Hosp, Ariadne Labs, Boston, MA 02115 USA. [Obermeyer, Ziad; Block, Susan] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Dominici, Francesca] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Block, Susan] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Block, Susan] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Block, Susan] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Cutler, David M.] Harvard Univ, Dept Econ, Cambridge, MA 02138 USA. [Cutler, David M.] Natl Bur Econ Res, Cambridge, MA 02138 USA. RP Obermeyer, Z (reprint author), Brigham & Womens Hosp, Dept Emergency Med, Neville House,75 Francis St, Boston, MA 02115 USA. EM zobermeyer@partners.org OI , /0000-0002-1224-4657 FU National Institutes of Health [DP5 OD012161]; National Cancer Institute [P01 CA134294]; Agency for Healthcare Research and Quality [K18 HS021991] FX This work was supported by National Institutes of Health grant DP5 OD012161 (Dr Obermeyer), National Cancer Institute grant P01 CA134294 (Dr Dominici), and Agency for Healthcare Research and Quality grant K18 HS021991 (Dr Dominici). NR 25 TC 61 Z9 61 U1 7 U2 13 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 NOV 12 PY 2014 VL 312 IS 18 BP 1888 EP 1896 DI 10.1001/jama.2014.14950 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AS8ZE UT WOS:000344532600018 PM 25387186 ER PT J AU Jaff, MR AF Jaff, Michael R. TI Why Patients Know More About Cars Than Peripheral Artery Disease SO CIRCULATION LA English DT Editorial Material DE Editorials; peripheral vascular diseases ID LESIONS; STENTS C1 [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jaff, Michael R.] Harvard Univ, Sch Med, Boston, MA USA. RP Jaff, MR (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Warren 905, Boston, MA 02114 USA. EM mjaff@partners.org NR 12 TC 5 Z9 5 U1 0 U2 0 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 NOV 11 PY 2014 VL 130 IS 20 BP 1778 EP 1779 DI 10.1161/CIRCULATIONAHA.114.012872 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AT4TZ UT WOS:000344936700009 PM 25239437 ER PT J AU Ehdaie, A Rubin, SA AF Ehdaie, Ashkan Rubin, Stanley A. TI Letter by Ehdaie and Rubin Regarding Article, "Long-Term Arrhythmia-Free Survival in Patients With Severe Left Ventricular Dysfunction and No Inducible Ventricular Tachycardia After Myocardial Infarction" SO CIRCULATION LA English DT Letter ID RECOVERY C1 [Ehdaie, Ashkan] VA Greater Los Angeles Healthcare Syst, Cedars Sinai Heart Inst, Dept Cardiol, Los Angeles, CA 90073 USA. [Rubin, Stanley A.] UCLA Sch Med, Dept Cardiol, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Ehdaie, A (reprint author), VA Greater Los Angeles Healthcare Syst, Cedars Sinai Heart Inst, Dept Cardiol, Los Angeles, CA 90073 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD NOV 11 PY 2014 VL 130 IS 20 BP E177 EP E177 DI 10.1161/CIRCULATIONAHA.114.009059 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AT4TZ UT WOS:000344936700003 PM 25385942 ER PT J AU Legrand, M De Berardinis, B Gaggin, HK Magrini, L Belcher, A Zancla, B Femia, A Simon, M Motiwala, S Sambhare, R Di Somma, S Mebazaa, A Vaidya, VS Januzzi, JL AF Legrand, Matthieu De Berardinis, Benedetta Gaggin, Hanna K. Magrini, Laura Belcher, Arianna Zancla, Benedetta Femia, Alexandra Simon, Mandy Motiwala, Shweta Sambhare, Rasika Di Somma, Salvatore Mebazaa, Alexandre Vaidya, Vishal S. Januzzi, James L., Jr. CA Global Res Acute Conditions Team G TI Evidence of Uncoupling between Renal Dysfunction and Injury in Cardiorenal Syndrome: Insights from the BIONICS Study SO PLOS ONE LA English DT Article ID GELATINASE-ASSOCIATED LIPOCALIN; ACUTE KIDNEY INJURY; DECOMPENSATED HEART-FAILURE; CARDIAC-FAILURE; NGAL; BIOMARKERS AB Objective: The objective of the study was to assess urinary biomarkers of renal injury for their individual or collective ability to predict Worsening renal function (WRF) in patients with acutely decompensated heart failure (ADHF). Methods: In a prospective, blinded international study, 87 emergency department (ED) patients with ADHF were evaluated with biomarkers of cardiac stretch (B type natriuretic peptide [BNP] and its amino terminal equivalent [NT-proBNP], ST2), biomarkers of renal function (creatinine, estimated glomerular filtration rate [eGFR]) and biomarkers of renal injury (plasma neutrophil gelatinase associated lipocalin [pNGAL], urine kidney injury molecule-1 [KIM-1], urine N-acetyl-beta-D-glucosaminidase [NAG], urine Cystatin C, urine fibrinogen). The primary endpoint was WRF. Results: 26% developed WRF; baseline characteristics of subjects who developed WRF were generally comparable to those who did not. Biomarkers of renal function and urine biomarkers of renal injury were not correlated, while urine biomarkers of renal injury correlated between each other. Biomarker concentrations were similar between patients with and without WRF except for baseline BNP. Although plasma NGAL was associated with the combined endpoint, none of the biomarker showed predictive accuracy for WRF. Conclusions: In ED patients with ADHF, urine biomarkers of renal injury did not predict WRF. Our data suggest that a weak association exists between renal dysfunction and renal injury in this setting. C1 [Legrand, Matthieu; Mebazaa, Alexandre] Grp Hosp St Louis Lariboisiere, AP HP, Dept Anesthesiol, F-75475 Paris, France. [Legrand, Matthieu; Mebazaa, Alexandre] Grp Hosp St Louis Lariboisiere, AP HP, Burn Unit, F-75475 Paris, France. [Legrand, Matthieu; Mebazaa, Alexandre] Univ Paris Diderot, Paris, France. [Legrand, Matthieu; Femia, Alexandra; Mebazaa, Alexandre] INSERM, U942, F-75475 Paris, France. [De Berardinis, Benedetta; Magrini, Laura; Zancla, Benedetta; Di Somma, Salvatore] Univ Roma La Sapienza, StAndrea Hosp, Dept Med Surg Sci & Translat Med, I-00185 Rome, Italy. [Gaggin, Hanna K.; Belcher, Arianna; Simon, Mandy; Motiwala, Shweta; Januzzi, James L., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Sambhare, Rasika; Vaidya, Vishal S.] Harvard Univ, Sch Med, Boston, MA USA. [Sambhare, Rasika; Vaidya, Vishal S.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Legrand, M (reprint author), Grp Hosp St Louis Lariboisiere, AP HP, Dept Anesthesiol, F-75475 Paris, France. EM matthieu.m.legrand@gmail.com FU Astute; bioporto; BRAHMS; Roche Diagnostics; Siemens; Critical Diagnostics; BG Medicine; Singulex; Thermo Fisher FX The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Legrand consulted for Alere (lecture fees) and received support for research from Astute, bioporto and BRAHMS. Dr. Mebazaa served as board member for Critical Diagnostics, The Medicine Company, Cardiorentis, and Bayer and lectured for Alere, Bayer, Edwards Life Sciences, The Medicines Company, Novartis, Orion, Servier, Thermofisher, and Vifor Pharma. Dr. Januzzi received support for participation in review activities from Radiometer. His institution received grant support from Roche Diagnostics, Siemens, Critical Diagnostics, BG Medicine, Singulex, and Thermo Fisher. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. NR 25 TC 13 Z9 13 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD NOV 11 PY 2014 VL 9 IS 11 AR e112313 DI 10.1371/journal.pone.0112313 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT9MC UT WOS:000345250400054 PM 25386851 ER PT J AU Unternaehrer, JJ Zhao, R Kim, K Cesana, M Powers, JT Ratanasirintrawoot, S Onder, T Shibue, T Weinberg, RA Daley, GQ AF Unternaehrer, Juli J. Zhao, Rui Kim, Kitai Cesana, Marcella Powers, John T. Ratanasirintrawoot, Sutheera Onder, Tamer Shibue, Tsukasa Weinberg, Robert A. Daley, George Q. TI The Epithelial-Mesenchymal Transition Factor SNAIL Paradoxically Enhances Reprogramming SO STEM CELL REPORTS LA English DT Article ID PLURIPOTENT STEM-CELLS; HUMAN SOMATIC-CELLS; DEFINED FACTORS; EXPRESSION; MICRORNAS; CANCER; DIFFERENTIATION; GENERATION; MOUSE; LET-7 AB Reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs) entails a mesenchymal to epithelial transition (MET). While attempting to dissect the mechanism of MET during reprogramming, we observed that knockdown (KD) of the epithelial-to-mesenchymal transition (EMT) factor SNAI1 (SNAIL) paradoxically reduced, while overexpression enhanced, reprogramming efficiency in human cells and in mouse cells, depending on strain. We observed nuclear localization of SNAI1 at an early stage of fibroblast reprogramming and using mouse fibroblasts expressing a knockin SNAI1-YFP reporter found cells expressing SNAI1 reprogrammed at higher efficiency. We further demonstrated that SNAI1 binds the let-7 promoter, which may play a role in reduced expression of let-7 microRNAs, enforced expression of which, early in the reprogramming process, compromises efficiency. Our data reveal an unexpected role for the EMT factor SNAI1 in reprogramming somatic cells to pluripotency. C1 [Unternaehrer, Juli J.; Zhao, Rui; Kim, Kitai; Cesana, Marcella; Powers, John T.; Ratanasirintrawoot, Sutheera; Onder, Tamer; Daley, George Q.] Harvard Univ, Howard Hughes Med Inst, Childrens Hosp Boston,Stem Cell Transplantat Prog, Manton Ctr Orphan Dis Res,Div Pediat Hematol Onco, Cambridge, MA 02138 USA. [Unternaehrer, Juli J.; Zhao, Rui; Kim, Kitai; Cesana, Marcella; Powers, John T.; Ratanasirintrawoot, Sutheera; Onder, Tamer; Daley, George Q.] Dana Farber Canc Inst, Boston, MA USA. [Unternaehrer, Juli J.; Zhao, Rui; Kim, Kitai; Cesana, Marcella; Powers, John T.; Ratanasirintrawoot, Sutheera; Onder, Tamer; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Cambridge, MA 02138 USA. [Unternaehrer, Juli J.; Zhao, Rui; Kim, Kitai; Cesana, Marcella; Powers, John T.; Ratanasirintrawoot, Sutheera; Onder, Tamer; Daley, George Q.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Shibue, Tsukasa; Weinberg, Robert A.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Shibue, Tsukasa; Weinberg, Robert A.] MIT, Ludwig Ctr Mol Oncol, Cambridge, MA 02139 USA. [Weinberg, Robert A.] MIT, Dept Biol, Cambridge, MA 02139 USA. RP Unternaehrer, JJ (reprint author), Loma Linda Univ, Div Biochem, 11085 Campus St, Loma Linda, CA 92354 USA. EM junternaehrer@llu.edu RI Onder, Tamer /H-3330-2013 OI Onder, Tamer /0000-0002-2372-9158 FU Boston Children's Hospital Stem Cell Program; NIH [R01-GM107536, NIH-T32-HL07623-23] FX We are grateful to Patrick Cahan, Francesca Casano, and M. Willy Lensch for insightful discussion of the manuscript; Ronald Mathieu for FACS sorting; Yuko Fujiwara and Minh Nguyen for blastocyst injection; and Kitwa Ng and Kerrianne Cunniff Schlosser for expert technical assistance. G.Q.D. is a member of the scientific advisory board of iPierian and Verastem. The work was supported by private funds of the Boston Children's Hospital Stem Cell Program and by NIH R01-GM107536. J.J.U. was supported by NIH-T32-HL07623-23. NR 32 TC 18 Z9 18 U1 3 U2 12 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 NOV 11 PY 2014 VL 3 IS 5 BP 691 EP 698 DI 10.1016/j.stemcr.2014.09.008 PG 8 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AT7LP UT WOS:000345118600001 PM 25316190 ER PT J AU Lee, D Sykes, SM Kalaitzidis, D Lane, AA Kfoury, Y Raaijmakers, MHGP Wang, YH Armstrong, SA Scadden, DT AF Lee, Dongjun Sykes, Stephen M. Kalaitzidis, Demetrios Lane, Andrew A. Kfoury, Youmna Raaijmakers, Marc H. G. P. Wang, Ying-Hua Armstrong, Scott A. Scadden, David T. TI Transmembrane Inhibitor of RICTOR/mTORC2 in Hematopoietic Progenitors SO STEM CELL REPORTS LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; RICTOR-MTOR COMPLEX; STEM-CELLS; ACTIVATION; PTEN; PHOSPHORYLATION; KINASE; GROWTH; RAPTOR; MICE AB Central to cellular proliferative, survival, and metabolic responses is the serine/threonine kinase mTOR, which is activated in many human cancers. mTOR is present in distinct complexes that are either modulated by AKT (mTORC1) or are upstream and regulatory of it (mTORC2). Governance of mTORC2 activity is poorly understood. Here, we report a transmembrane molecule in hematopoietic progenitor cells that physically interacts with and inhibits RICTOR, an essential component of mTORC2. Upstream of mTORC2 (UT2) negatively regulates mTORC2 enzymatic activity, reducing AKT(S473), PKC alpha, and NDRG1 phosphorylation and increasing FOXO transcriptional activity in an mTORC2-dependent manner. Modulating UT2 levels altered animal survival in a T cell acute lymphoid leukemia T-ALL) model that is known to be mTORC2 sensitive. These studies identify an inhibitory component upstream of mTORC2 in hematopoietic cells that can reduce mortality from NOTCH-induced T-ALL. A transmembrane inhibitor of mTORC2 may provide an attractive target to affect this critical cell regulatory pathway. C1 [Lee, Dongjun; Sykes, Stephen M.; Kalaitzidis, Demetrios; Lane, Andrew A.; Kfoury, Youmna; Wang, Ying-Hua; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Lee, Dongjun; Sykes, Stephen M.; Kalaitzidis, Demetrios; Lane, Andrew A.; Kfoury, Youmna; Wang, Ying-Hua; Scadden, David T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Lee, Dongjun; Sykes, Stephen M.; Kalaitzidis, Demetrios; Lane, Andrew A.; Kfoury, Youmna; Wang, Ying-Hua; Scadden, David T.] Harvard Univ, Sch Med, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Lee, Dongjun; Sykes, Stephen M.; Kalaitzidis, Demetrios; Lane, Andrew A.; Kfoury, Youmna; Wang, Ying-Hua; Scadden, David T.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Lane, Andrew A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Raaijmakers, Marc H. G. P.] Erasmus Univ, Med Ctr, Dept Hematol, NL-3015 GE Rotterdam, Netherlands. [Raaijmakers, Marc H. G. P.] Erasmus Univ, Med Ctr, Erasmus Stem Cell Inst, NL-3015 GE Rotterdam, Netherlands. [Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA. RP Scadden, DT (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. EM david_scadden@harvard.edu OI lee, dongjun/0000-0001-6828-401X FU NIH NHLBI [U01HL100402, HL97794, HLO44851]; Ellison Medical Foundation; NIH NIDDK [K01DK092300]; MGH Fund for Medical Discovery fellowship; ISEH; Dubai Foundation; MGH/HSCI CRM flow-cytometry core FX We thank Joseph Avruch, David Sabatini, Sean Morrison, and Alex Soukas for advice and helpful comments. This work was supported by NIH NHLBI U01HL100402, HL97794, and HLO44851; the Ellison Medical Foundation (D.L., M.R., and D.S.), NIH NIDDK K01DK092300 (D.K.), an MGH Fund for Medical Discovery fellowship (D.L.); the ISEH (S.S.); the Dubai Foundation (Y.K.); and the MGH/HSCI CRM flow-cytometry core (L. Prickett, K. FolzDonahue, and M. Weglarz). NR 31 TC 4 Z9 4 U1 1 U2 2 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 NOV 11 PY 2014 VL 3 IS 5 BP 832 EP 840 DI 10.1016/j.stemcr.2014.08.011 PG 9 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AT7LP UT WOS:000345118600013 PM 25418727 ER PT J AU Chen, HH Welling, M Bloch, DB Munoz, J Mientjes, E Chen, X Tramp, C Wu, J Yabuuchi, A Chou, YF Buecker, C Krainer, A Willemsen, R Heck, AJ Geijsen, N AF Chen, Hsu-Hsin Welling, Maaike Bloch, Donald B. Munoz, Javier Mientjes, Edwin Chen, Xinjie Tramp, Cody Wu, Jie Yabuuchi, Akiko Chou, Yu-Fen Buecker, Christa Krainer, Adrian Willemsen, Rob Heck, Albert J. Geijsen, Niels TI DAZL Limits Pluripotency, Differentiation, and Apoptosis in Developing Primordial Germ Cells SO STEM CELL REPORTS LA English DT Article ID EMBRYONIC STEM-CELLS; MESSENGER-RNA; TRANSCRIPTIONAL REGULATION; BINDING PROTEINS; GENE ENCODES; WEB-SERVER; IN-VITRO; ES CELLS; MOUSE; TRANSLATION AB The scarcity of primordial germ cells (PGCs) in the developing mammalian embryo hampers robust biochemical analysis of the processes that underlie early germ cell formation. Here, we demonstrate that DAZL, a germ cell-specific RNA binding protein, is a robust PGC marker during in vitro germ cell development. Using Dazl-GFP reporter ESCs, we demonstrate that DAZL plays a central role in a large mRNA/protein interactive network that blocks the translation of core pluripotency factors, including Sox2 and Sall4, as well as of Suz12, a polycomb family member required for differentiation of pluripotent cells. Thus, DAZL limits both pluripotency and somatic differentiation in nascent PGCs. In addition, we observed that DAZL associates with mRNAs of key Caspases and similarly inhibits their translation. This elegant fail-safe mechanism ensures that, whereas loss of DAZL results in prolonged expression of pluripotency factors, teratoma formation is avoided due to the concomitant activation of the apoptotic cascade. C1 [Chen, Hsu-Hsin; Tramp, Cody; Chou, Yu-Fen] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Welling, Maaike; Buecker, Christa; Geijsen, Niels] Hubrecht Inst, NL-3584 CT Utrecht, Netherlands. [Welling, Maaike; Buecker, Christa; Geijsen, Niels] Univ Med Ctr, NL-3584 CT Utrecht, Netherlands. [Bloch, Donald B.] Ctr Immunol & Inflammatory Dis, Dept Rheumatol, Department Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Munoz, Javier; Heck, Albert J.] Univ Utrecht, Bijvoet Ctr Biomol Res, NL-3584 CH Utrecht, Netherlands. [Munoz, Javier; Heck, Albert J.] Univ Utrecht, Utrecht Inst Pharmaceut Sci, NL-3584 CH Utrecht, Netherlands. [Munoz, Javier; Heck, Albert J.] Univ Utrecht, Netherlands Prote Ctr, NL-3584 CH Utrecht, Netherlands. [Mientjes, Edwin; Willemsen, Rob] Erasmus MC, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands. [Chen, Xinjie] Guangzhou Med Univ, Affiliated Hosp 3, Key Lab Major Obstetr Dis Guangdong Prov, Guangzhou 510150, Guangdong, Peoples R China. [Wu, Jie; Krainer, Adrian] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Yabuuchi, Akiko] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Yabuuchi, Akiko] Dana Farber Canc Inst, Boston, MA 02115 USA. [Geijsen, Niels] Univ Utrecht, Fac Vet Med, Dept Compan Anim, NL-3584 CM Utrecht, Netherlands. RP Geijsen, N (reprint author), Hubrecht Inst, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. EM n.geijsen@hubrecht.eu RI Munoz, Javier/I-4891-2012; OI Munoz, Javier/0000-0003-3288-3496; Buecker, Christa/0000-0003-3055-2642; Wu, Jie/0000-0002-0989-8115 FU NIH [5-R01HD048769-05]; Netherlands Organization for Scientific Research (NWO) [91796323]; Postdoctoral Studies Abroad, National Science Council, Taiwan; NIRM FX The authors thank Drs. Jinzhong Qin, Rui Zhao, Hongmei Mou, Daniela S. Krause, Andre Catic, and Laurence Daheron for discussions and sharing of reagents, Laura Prickett-Rice, Kat Folz-Donohue, and Meredith Weglarz at HSCI Flow Cytometry core for FACS sorting, Stefan van der Elst and Kelly L. Shea for technical support, and Dr. Chih-Hao Li for MATLAB programming. We also thank Drs. Howard Cooke and David Page for providing the Dazl knockout mice. This work was funded by NIH grant 5-R01HD048769-05 and the Netherlands Organization for Scientific Research (NWO, Project 91796323). H.-H.C. was supported in part by Fellowship for Postdoctoral Studies Abroad, National Science Council, Taiwan. M.W. was supported by NIRM. NR 44 TC 11 Z9 11 U1 0 U2 15 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 NOV 11 PY 2014 VL 3 IS 5 BP 892 EP 904 DI 10.1016/j.stemcr.2014.09.003 PG 13 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AT7LP UT WOS:000345118600017 PM 25418731 ER PT J AU Levine, RA Schwammenthal, E Song, JK AF Levine, Robert A. Schwammenthal, Ehud Song, Jae-Kwan TI Diastolic Leading to Systolic Anterior Motion New Technology Reveals Physiology SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE cardiomyopathy; echocardiography; heart ventricles; hypertrophic; mitral valve; papillary muscles ID HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY; OUTFLOW TRACT OBSTRUCTION; CARDIOVASCULAR MAGNETIC-RESONANCE; MITRAL-VALVE ABNORMALITIES; ALCOHOL SEPTAL ABLATION; SUBAORTIC OBSTRUCTION; FLUID-MECHANICS; BLOOD-FLOW; MYECTOMY; REGURGITATION C1 [Levine, Robert A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA USA. [Schwammenthal, Ehud] Tel Aviv Univ, Chaim Sheba Med Ctr, Inst Heart, IL-69978 Tel Aviv, Israel. [Song, Jae-Kwan] Univ Ulsan, Cardiac Imaging Ctr, Asan Med Ctr, Inst Heart,Coll Med, Seoul, South Korea. RP Levine, RA (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Yawkey 5068,55 Fruit St, Boston, MA 02114 USA. EM rlevine@partners.org FU NHLBI NIH HHS [R01 HL109506, R01 HL72265, K24 HL067434, R01 HL038176, R01 HL072265] NR 40 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD NOV 11 PY 2014 VL 64 IS 19 BP 1996 EP 1999 DI 10.1016/j.jacc.2014.09.010 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT0HI UT WOS:000344617200004 PM 25440094 ER EF