FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Jacobs, JP O'Brien, SM Shahian, DM Edwards, FH Badhwar, V Dokholyan, RS Sanchez, JA Morales, DL Prager, RL Wright, CD Puskas, JD Gammie, JS Haan, CK George, KM Sheng, SB Peterson, ED Shewan, CM Han, JM Bongiorno, PA Yohe, C Williams, WG Mayer, JE Grover, FL AF Jacobs, Jeffrey P. O'Brien, Sean M. Shahian, David M. Edwards, Fred H. Badhwar, Vinay Dokholyan, Rachel S. Sanchez, Juan A. Morales, David L. Prager, Richard L. Wright, Cameron D. Puskas, John D. Gammie, James S. Haan, Constance K. George, Kristopher M. Sheng, Shubin Peterson, Eric D. Shewan, Cynthia M. Han, Jane M. Bongiorno, Phillip A. Yohe, Courtney Williams, William G. Mayer, John E. Grover, Frederick L. TI Successful linking of the Society of Thoracic Surgeons Database to Social Security data to examine the accuracy of Society of Thoracic Surgeons mortality data SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article; Proceedings Paper CT International Mesothelioma Interest Group Congress CY SEP 11-14, 2012 CL Boston, MA ID CORONARY-ARTERY-BYPASS; LONG-TERM SURVIVAL; CARDIAC-SURGERY; PUMP AB Objectives: The Society of Thoracic Surgeons Adult Cardiac Surgery Database has been linked to the Social Security Death Master File to verify "life status" and evaluate long-term surgical outcomes. The objective of this study is explore practical applications of the linkage of the Society of Thoracic Surgeons Adult Cardiac Surgery Database to Social Securtiy Death Master File, including the use of the Social Securtiy Death Master File to examine the accuracy of the Society of Thoracic Surgeons 30-day mortality data. Methods: On January 1, 2008, the Society of Thoracic Surgeons Adult Cardiac Surgery Database began collecting Social Security numbers in its new version 2.61. This study includes all Society of Thoracic Surgeons Adult Cardiac Surgery Database records for operations with nonmissing Social Security numbers between January 1, 2008, and December 31, 2010, inclusive. To match records between the Society of Thoracic Surgeons Adult Cardiac Surgery Database and the Social Security Death Master File, we used a combined probabilistic and deterministic matching rule with reported high sensitivity and nearly perfect specificity. Results: Between January 1, 2008, and December 31, 2010, the Society of Thoracic Surgeons Adult Cardiac Surgery Database collected data for 870,406 operations. Social Security numbers were available for 541,953 operations and unavailable for 328,453 operations. According to the Society of Thoracic Surgeons Adult Cardiac Surgery Database, the 30-day mortality rate was 17,757/541,953 = 3.3%. Linkage to the Social Security Death Master File identified 16,565 cases of suspected 30-day deaths (3.1%). Of these, 14,983 were recorded as 30-day deaths in the Society of Thoracic Surgeons database (relative sensitivity = 90.4%). Relative sensitivity was 98.8% (12,863/13,014) for suspected 30-day deaths occurring before discharge and 59.7% (2120/3551) for suspected 30-day deaths occurring after discharge. Conclusions: Linkage to the Social Security Death Master File confirms the accuracy of data describing "mortality within 30 days of surgery" in the Society of Thoracic Surgeons Adult Cardiac Surgery Database. The Society of Thoracic Surgeons and Social Security Death Master File link reveals that capture of 30-day deaths occurring before discharge is highly accurate, and that these in-hospital deaths represent the majority (79% [13,014/16,565]) of all 30-day deaths. Capture of the remaining 30-day deaths occurring after discharge is less complete and needs improvement. Efforts continue to encourage Society of Thoracic Surgeons Database participants to submit Social Security numbers to the Database, thereby enhancing accurate determination of 30-day life status. The Society of Thoracic Surgeons and Social Security Death Master File linkage can facilitate ongoing refinement of mortality reporting. (J Thorac Cardiovasc Surg 2013;145:976-83) C1 [Jacobs, Jeffrey P.] Univ S Florida, All Childrens Hosp, Johns Hopkins Childrens Heart Surg, St Petersburg, FL 33701 USA. [Jacobs, Jeffrey P.] All Childrens Hosp, Johns Hopkins Childrens Heart Surg, Tampa, FL USA. [Jacobs, Jeffrey P.] All Childrens Hosp, Johns Hopkins Childrens Heart Surg, Orlando, FL USA. [Jacobs, Jeffrey P.] Florida Hosp Children, St Petersburg, FL USA. [Jacobs, Jeffrey P.] Florida Hosp Children, Tampa, FL USA. [Jacobs, Jeffrey P.] Florida Hosp Children, Orlando, FL USA. [O'Brien, Sean M.; Dokholyan, Rachel S.; Sheng, Shubin; Peterson, Eric D.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Shahian, David M.; Wright, Cameron D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Edwards, Fred H.; Haan, Constance K.] Univ Florida, Coll Med Jacksonville, Shands Jacksonville, Jacksonville, FL USA. [Badhwar, Vinay] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Sanchez, Juan A.] Univ Connecticut, Ctr Hlth, Farmington, CT USA. [Morales, David L.] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Prager, Richard L.] Univ Michigan, Ann Arbor, MI 48109 USA. [Puskas, John D.] Emory Univ, Div Cardiothorac Surg, Atlanta, GA 30322 USA. [Gammie, James S.] Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. [George, Kristopher M.] Cardiac Surg Associates Florida, Orlando, FL USA. [Shewan, Cynthia M.; Han, Jane M.; Bongiorno, Phillip A.; Yohe, Courtney] Soc Thorac Surg, Chicago, IL USA. [Shewan, Cynthia M.; Han, Jane M.; Bongiorno, Phillip A.; Yohe, Courtney] Soc Thorac Surg, Washington, DC USA. [Williams, William G.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Mayer, John E.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA USA. [Grover, Frederick L.] Univ Colorado Denver, Sch Med, Aurora, CO USA. RP Jacobs, JP (reprint author), Univ S Florida, All Childrens Hosp, Ctr Heart, 625 6th Ave South,Suite 475, St Petersburg, FL 33701 USA. EM JeffJacobs@msn.com RI O'Brien, Sean/H-6268-2013; Sanchez, Juan/I-1936-2016 OI Sanchez, Juan/0000-0002-6789-3208 NR 21 TC 5 Z9 5 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 EI 1097-685X J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD APR PY 2013 VL 145 IS 4 BP 976 EP 983 DI 10.1016/j.jtcvs.2012.11.094 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 114PA UT WOS:000316753100015 PM 23497944 ER PT J AU Baruch, L Sherman, O AF Baruch, Lawrence Sherman, Olga TI Utilization of laboratory testing to optimize dabigatran dosing in 5 octogenarians: Focus on the 75-mg BID dose SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Meeting Abstract C1 [Baruch, Lawrence; Sherman, Olga] James J Peters VA Med Ctr, Bronx, NY USA. [Baruch, Lawrence] Mt Sinai Sch Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD APR PY 2013 VL 35 IS 3 SI SI BP 404 EP 405 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 115OQ UT WOS:000316822100032 ER PT J AU McDermott, S Oliveira, GR Wicky, S Oklu, R AF McDermott, Shaunagh Oliveira, George R. Wicky, Stephan Oklu, Rahmi TI Measurements of the Left Common Iliac Vein Diameter May Not Be Consistent over Time SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Letter C1 [McDermott, Shaunagh; Oliveira, George R.; Wicky, Stephan; Oklu, Rahmi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc Imaging & Intervent, Boston, MA 02114 USA. RP McDermott, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc Imaging & Intervent, 55 Fruit St,290A Gray Bigelow, Boston, MA 02114 USA. NR 2 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 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD APR PY 2013 VL 24 IS 4 BP 192 EP 193 DI 10.1016/j.jvir.2013.01.502 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 115QW UT WOS:000316828000025 PM 23522166 ER PT J AU Misra, S Lookstein, R Rundback, J Hirsch, AT Hiatt, WR Jaff, MR White, CR Conte, M Geraghty, P Patel, M Rosenfield, K AF Misra, Sanjay Lookstein, Robert Rundback, John Hirsch, Alan T. Hiatt, William R. Jaff, Michael R. White, Christopher R. Conte, Michael Geraghty, Patrick Patel, Manesh Rosenfield, Kenneth TI Proceedings from the Society of Interventional Radiology Research Consensus Panel on Critical Limb Ischemia SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID PERIPHERAL ARTERIAL-DISEASE; DRUG-ELUTING STENTS; THE-KNEE LESIONS; INFRAPOPLITEAL ARTERIES; DOUBLE-BLIND; OUTCOMES; THERAPY; RECANALIZATION; RUNOFF; CLAUDICATION C1 [Misra, Sanjay] Mayo Clin, Dept Radiol, Div Vasc & Intervent Radiol, Rochester, MN 55905 USA. [Lookstein, Robert] Mt Sinai Hosp, New York, NY 10029 USA. [Rundback, John] Holy Name Hosp, Cardiovasc Dis Intervent Inst, Teaneck, NJ USA. [Hirsch, Alan T.] Univ Minnesota, Sch Med, Lillehei Heart Inst, Vasc Med Program, Minneapolis, MN 55455 USA. Univ Minnesota, Sch Med, Div Cardiovasc, Minneapolis, MN 55455 USA. [Hiatt, William R.] Univ Colorado Denver, Sch Med, Div Cardiol, Aurora, CO USA. [Hiatt, William R.] Univ Colorado Denver, Sch Med, CPC Clin Res, Aurora, CO USA. [Jaff, Michael R.; Rosenfield, Kenneth] Massachusetts Gen Hosp, Vasc Med & Intervent Dept, Boston, MA 02114 USA. [White, Christopher R.] Ochsner Med Ctr, John Ochsner Heart & Vasc Inst, New Orleans, LA USA. [Conte, Michael] UCSF Heart & Vasc Ctr, San Francisco, CA USA. [Geraghty, Patrick] Washington Univ St Louis, Sch Med, St Louis, MO USA. [Patel, Manesh] Duke Univ Hlth Syst, Durham, NC USA. RP Misra, S (reprint author), Mayo Clin, Dept Radiol, Div Vasc & Intervent Radiol, 200 1st St SW, Rochester, MN 55905 USA. FU SIR Foundation; NIH [HL098967, HL109192, HL 88476]; Covidien/ev3; NHLBI/Washington University; SIRtex; Abbott; EKOS; Flexmedics; Aastrom; CeloNova; Abbott Vascular; Aastrom Biosciences; Sanofi-aventis Partnership; Cytokinetics; Viromed; AstraZeneca; DNAVEC; Pluristem; Takeda; ReNeuron; Tarix; Theravasc; NHBLI; Johnson and Johnson; Astra Zeneca; Baxter Healthcare; AHRQ; Cordis; Lutonix/Bard; Atrium; IDEV Technologies FX This meeting was funded by the SIR Foundation.; S.M. received funding from NIH (HL098967, HL109192, HL 88476). He is on the data safety monitoring board for Arteriocyte and Flexstent. R.L. is a consultant for Bayer Interventional, Cordis, and Boston Scientific. J.R. is a consultant for Covidien/ev3, Biotronik, St. Jude, EKOS, Simbionix, and CSI, is a speaker for Boston Scientific, Terumo, and Cook, and received research support from Covidien/ev3, NHLBI/Washington University, SIRtex, Abbott, EKOS, Flexmedics, Aastrom, and CeloNova. A.T H. received research grants from Abbott Vascular, Aastrom Biosciences, Sanofi-aventis Partnership, Cytokinetics, and Viromed, is on the advisory board of AstraZeneca and Merck, and is a consultant for Novartis, Pozen, Summit Doppler, and Shire HGT. W.R.H. received grant income for trials in peripheral artery disease structured as a contract between the sponsor and CPC Clinical Research (a nonprofit research center affiliated with the University of Colorado) from Aastrom, AstraZeneca, DNAVEC, Pluristem, Takeda, ReNeuron, Tarix and Theravasc. M.R.J. is a consultant for Abbott Vascular (noncompensated), Becker Venture Services Group, Bluegrass Vascular Therapies, Cordis Corporation (noncompensated), Covidien (noncompensated), Hansen Medical, Medtronic (noncompensated), Micell Incorporated, Primacea, Trivascular Inc., and Vortex, and has equity in Access Closure Inc., Embolitech Inc., Hotspur Inc., Icon Interventional Inc., I.C. Sciences Inc., Janacare Inc., Northwind Medical Inc., PQ Bypass Inc., Primacea, Sadra Medical, TMI/Trireme Inc., and Vascular Therapies Inc., is a board member of VIVA Physicians (not for profit), and is a 501(c) 3 Organization member (www.vivapvd com). C.J.W. is a consultant for Baxter Cellular Therapies and is a member of the PAD Guidelines Task Force (ACC/AHA). He is the CARE Steering committee chair (NCDR/ACC) and president of the Society of Cardiovascular Angiography and Interventions (SCAI). M.C. is on the advisory board of Aastrom Biosciences and Humacyte Inc P.G. is a scientific advisory board member of Bard/Lutonix and Bayer/Medrad He is an equity holder and has stock options with Pulse Therapeutics. M.P. has research grants with NHBLI, Johnson and Johnson, Astra Zeneca, Baxter Healthcare, and AHRQ and is a consultant and is on the advisory board of Bayer Healthcare, Baxter, Genzyme, Otsuka, and Cardiostem. K R. is a consultant for Abbott Vascular, Accelmed, Becker Ventures, Micell, Complete Conference Management, Vortex/AngioDynamics, Endospan, Medicines Company, Shockwave Medical, and VuMedi. He has equity in CardioMEMs, Contego, Endospan, Embolitech, Icon, JanaCare, Medical Simulation Corporation, Micell, Primacea, PQ Bypass, Shockwave Medical, and Vortex. He received research or fellowship support from Abbott Vascular, Cordis, Lutonix/Bard, Atrium, and IDEV Technologies. He is a board member of VIVA Physicians (www.vivapvd.com). NR 44 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD APR PY 2013 VL 24 IS 4 BP 451 EP 458 DI 10.1016/j.jvir.2012.10.028 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 115QW UT WOS:000316828000001 PM 23522155 ER PT J AU Gallagher, KA Tracci, MC Scovell, SD AF Gallagher, Katherine A. Tracci, Margaret Clarke Scovell, Sherry D. TI Vascular arteritides in women SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID GIANT-CELL ARTERITIS; OBLITERANS BUERGERS-DISEASE; RHEUMATOLOGY 1990 CRITERIA; ANCA-ASSOCIATED VASCULITIS; PLACEBO-CONTROLLED TRIAL; MEDIUM-VESSEL VASCULITIS; SPINAL-CORD STIMULATION; WEGENERS-GRANULOMATOSIS; THROMBOANGIITIS-OBLITERANS; FIBROMUSCULAR DYSPLASIA AB The vasculitides are multiple clinical disease states that are characterized by inflammation of the wall of blood vessels. They are typically classified by the size of the vessel that is affected. Some of the vasculitides are more commonly identified in women, such as the large-vessel vasculitides. In addition, the incidence of some of the medium and small-vessel vasculitides in women has increased during the past several decades. These inflammatory conditions specifically affecting women will be reviewed here. The implications that pregnancy may have on various vasculitides will also be highlighted. (J Vasc Surg 2013;57:27S-36S.) C1 [Gallagher, Katherine A.] Univ Michigan, Med Ctr, Div Vasc & Endovasc Surg, Ann Arbor, MI USA. [Tracci, Margaret Clarke] Univ Virginia Hlth Syst, Div Vasc & Endovasc Surg, Charlottesville, VA USA. [Scovell, Sherry D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc & Endovasc Surg, Boston, MA USA. RP Scovell, SD (reprint author), MGH North Shore Ctr Outpatient Care, 104 Endicott St,Ste 200, Danvers, MA 01923 USA. EM sscovell@partners.org NR 100 TC 1 Z9 1 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD APR PY 2013 VL 57 IS 4 SU S BP 27S EP 36S DI 10.1016/j.jvs.2012.10.119 PG 10 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 113KF UT WOS:000316665200005 PM 23522715 ER PT J AU Bachler, BC Humbert, M Palikuqi, B Siddappa, NB Lakhashe, SK Rasmussen, RA Ruprecht, RM AF Bachler, Barbara C. Humbert, Michael Palikuqi, Brisa Siddappa, Nagadenahalli B. Lakhashe, Samir K. Rasmussen, Robert A. Ruprecht, Ruth M. TI Novel Biopanning Strategy To Identify Epitopes Associated with Vaccine Protection SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-1 TAT PROTEIN; BIMODAL AIDS VACCINE; B-CELL EPITOPES; RHESUS MACAQUES; TYPE-1 TAT; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; CYNOMOLGUS MONKEYS; PEPTIDE LIBRARIES AB Identifying immune correlates of protection is important to develop vaccines against infectious diseases. We designed a novel, universally applicable strategy to profile the antibody (Ab) repertoire of protected vaccine recipients, using recombinant phages encoding random peptide libraries. The new approach, termed "protection-linked (PL) biopanning," probes the Ab paratopes of protected vaccinees versus those with vaccine failure. As proof of concept, we screened plasma samples from vaccinated rhesus macaques (RMs) that had completely resisted multiple mucosal challenges with R5-tropic simian-human immunodeficiency viruses (SHIVs). The animals had been immunized with a multicomponent vaccine (multimeric HIV-1 gp160, HIV-1 Tat, and SIV Gag-Pol particles). After PL biopanning, we analyzed the phagotopes selected for amino acid homologies; in addition to the expected Env mimotopes, one recurring motif reflected the neutralizing Ab epitope at the N terminus (NT) of HIV-1 Tat. Subsequent binding and functional assays indicated that anti-Tat NT Abs were present only in completely or partially protected RMs; peak viremia of the latter was inversely correlated with anti-Tat NT Ab titers. In contrast, highly viremic, unvaccinated controls did not develop detectable Abs against the same epitope. Based upon the protective effect observed in vivo, we suggest that Tat should be included in multicomponent HIV-1 vaccines. Our data highlight the power of the new PL-biopanning strategy to identify Ab responses with significant association to vaccine protection, regardless of the mechanism(s) or targets of the protective Abs. PL biopanning is also unbiased with regard to pathogens or disease model, making it a universal tool. C1 [Bachler, Barbara C.; Humbert, Michael; Palikuqi, Brisa; Siddappa, Nagadenahalli B.; Lakhashe, Samir K.; Rasmussen, Robert A.; Ruprecht, Ruth M.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Bachler, Barbara C.] Univ Vet Med Vienna, VetCore, Res Facil, Vienna, Austria. [Humbert, Michael; Siddappa, Nagadenahalli B.; Lakhashe, Samir K.; Rasmussen, Robert A.; Ruprecht, Ruth M.] Harvard Univ, Sch Med, Boston, MA USA. RP Ruprecht, RM (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM ruth_ruprecht@dfci.harvard.edu RI Lakhashe, Samir/F-1150-2014; OI Byrareddy, Siddappa /0000-0002-7423-1763 FU National Institutes of Health [P01 AI048240, R37 AI034266, R01 AI100703]; Harvard University [P30 AI060354] FX This work was supported by National Institutes of Health grants P01 AI048240, R37 AI034266, and R01 AI100703 to R.M.R. and Harvard University C.F.A.R grant P30 AI060354. NR 69 TC 19 Z9 19 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2013 VL 87 IS 8 BP 4403 EP 4416 DI 10.1128/JVI.02888-12 PG 14 WC Virology SC Virology GA 113MC UT WOS:000316671000026 PM 23388727 ER PT J AU Mallipattu, SK Liu, RJ Zhong, YF Chen, EY D'Agati, V Kaufman, L Ma'ayan, A Klotman, PE Chuang, PY He, JC AF Mallipattu, Sandeep K. Liu, Ruijie Zhong, Yifei Chen, Ed Y. D'Agati, Vivette Kaufman, Lewis Ma'ayan, Avi Klotman, Paul E. Chuang, Peter Y. He, John C. TI Expression of HIV transgene aggravates kidney injury in diabetic mice SO KIDNEY INTERNATIONAL LA English DT Article DE diabetic nephropathy; glomerulopathy; HIV ID ACQUIRED IMMUNODEFICIENCY SYNDROME; HIV-1-ASSOCIATED NEPHROPATHY; INFECTED PATIENTS; RENAL-DISEASE; MOUSE KIDNEY; GLOMERULOSCLEROSIS; GENES; PODOCYTES; PROTEIN; BIOPSY AB With the widespread use of combination antiretroviral agents, the incidence of HIV-associated nephropathy has decreased. Currently, HIV-infected patients live much longer and often suffer from comorbidities such as diabetes mellitus. Recent epidemiological studies suggest that concurrent HIV infection and diabetes mellitus may have a synergistic effect on the incidence of chronic kidney disease. To address this, we determined whether HIV-1 transgene expression accelerates diabetic kidney injury using a diabetic HIV-1 transgenic (Tg26) murine model. Diabetes was initially induced with low-dose streptozotocin in both Tg26 and wildtype mice on a C57BL/6 background, which is resistant to classic HIV-associated nephropathy. Although diabetic nephropathy is minimally observed on the C57BL/6 background, diabetic Tg26 mice exhibited a significant increase in glomerular injury compared with nondiabetic Tg26 mice and diabetic wild-type mice. Validation of microarray gene expression analysis from isolated glomeruli showed a significant upregulation of proinflammatory pathways in diabetic Tg26 mice. Thus, our study found that expression of HIV-1 genes aggravates diabetic kidney disease. Kidney International (2013) 83, 626-634; doi:10.1038/ki.2012.445; published online 16 January 2013 C1 [Mallipattu, Sandeep K.; Liu, Ruijie; Kaufman, Lewis; Chuang, Peter Y.; He, John C.] Mt Sinai Sch Med, Dept Med, Div Nephrol, New York, NY 10029 USA. [Liu, Ruijie; He, John C.] James J Peters VA Med Ctr, Renal Sect, New York, NY USA. [Zhong, Yifei] Shanghai Univ Tradit Chinese Med, Longhua Hosp, Dept Nephrol, Shanghai, Peoples R China. [Chen, Ed Y.; Ma'ayan, Avi; He, John C.] Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [D'Agati, Vivette] Columbia Univ, Dept Pathol, New York, NY USA. [Klotman, Paul E.] Baylor Coll Med, Houston, TX 77030 USA. RP He, JC (reprint author), Mt Sinai Sch Med, Dept Med Nephrol, 1 Gustave L Levy Pl,Box 1243, New York, NY 10029 USA. EM cijiang.he@mssm.edu RI Mallipattu , Sandeep/M-7009-2014 FU NIH/NIDDK [1R01DK078897-01, 2012CB517601, P01DK056492, 5K08DK082760, T32 DK07757-12, 1F32 DK094635-01] FX We thank Dr A Gharavi for use of the backcrossed Tg26 mice. This work was supported by funds from the NIH/NIDDK (1R01DK078897-01 and 973 fund 2012CB517601 to JCH, P01DK056492 to PEK and JCH, 5K08DK082760 to PYC, and T32 DK07757-12 and 1F32 DK094635-01 to SKM). NR 41 TC 19 Z9 19 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD APR PY 2013 VL 83 IS 4 BP 626 EP 634 DI 10.1038/ki.2012.445 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 117HY UT WOS:000316945400014 PM 23325078 ER PT J AU Bonawitz, SC Duvvuri, U AF Bonawitz, Steven C. Duvvuri, Umamaheswar TI Robotic-assisted FAMM flap for soft palate reconstruction SO LARYNGOSCOPE LA English DT Article DE FAMM flap; robotic; oropharyngeal ID ARTERY MUSCULOMUCOSAL FLAP; NECK-CANCER; SURGERY TORS; HEAD; DEFECTS AB Objectives/Hypothoses: TORS (Trans Oral Robotic Surgery) has been demonstrated to be an acceptable alternative to chemoradiation for the treatment of early stage malignant lesions of the oropharynx, with equivalent tumor control and enhanced functional outcomes. Surgical ablation of tumors of the oropharynx under conditions of limited access, however, creates the need to adapt the robotic platform to surgical reconstruction and to assess reconstructive outcomes. We present our experience with the Facial Artery Musculomucosal (FAMM) flap with robotic assistance for the reconstruction of defects of the soft palate. Methods: We reviewed the records of five patients who underwent combined robot-assisted resection of malignant lesions of the oropharynx with immediate reconstruction. The reconstructions included four ispilateral and one bilateral FAMM flaps. Patients were assessed for complications and functional results. Results: Successful closure of the defect was achieved in all five patients. There were no major complications; however, three patients developed minor wound dehiscence and two were revised at the time of planned subsequent lymphadenectomy. All five patients achieved a good functional outcome. Conclusions: The FAMM flap is reliable and easy to raise and transfer, with the surgical robot making it a good candidate for reconstruction of moderate-sized defects created by TORS applied to malignancies of the soft palate. Minor wound dehiscence is not infrequent, but reconstructive outcomes are nevertheless good. A unilateral FAMM flap will reach to the contralateral border of the uvula and is best limited to defects with a width of 2 cm or less. C1 [Bonawitz, Steven C.] Johns Hopkins Univ, Sch Med, Dept Plast & Reconstruct Surg, Baltimore, MD USA. [Duvvuri, Umamaheswar] Univ Pittsburgh, Med Ctr, Vet Affairs Pittsburgh Hlth Syst, Dept Otolaryngol,Eye & Ear Inst, Pittsburgh, PA 15213 USA. RP Duvvuri, U (reprint author), Univ Pittsburgh, Med Ctr, Dept Head & Neck Surg, Inst Eye & Ear, Suite 500,200 Lothrop St, Pittsburgh, PA 15213 USA. EM duvvuriu@upmc.edu NR 17 TC 7 Z9 7 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD APR PY 2013 VL 123 IS 4 BP 870 EP 874 DI 10.1002/lary.23578 PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 115KZ UT WOS:000316812400012 PM 23529879 ER PT J AU Kleiss, IJ Hohman, MH Quatela, OE Marres, HAM Hadlock, TA AF Kleiss, Ingrid J. Hohman, Marc H. Quatela, Olivia E. Marres, Henri A. M. Hadlock, Tessa A. TI Computer-Assisted Assessment of Ocular Synkinesis: A Comparison of Methods SO LARYNGOSCOPE LA English DT Article DE Facial nerve; facial paralysis; ocular synkinesis; assessment; objective; Facial Assessment by Computer Evaluation; Glasgow Facial Palsy Scale ID FACIAL-NERVE FUNCTION; GRADING SYSTEM; OBJECTIVE METHOD; MEASUREMENT TOOL; CONTROLLED-TRIAL; BOTULINUM-TOXIN; HOUSE-BRACKMANN; MOVEMENT; PARALYSIS; MOTION AB Objectives/Hypothesis: To define an objective, easy to perform, rapid method for the assessment of ocular synkinesis by employing both the Facial Assessment by Computer Evaluation software and a modification of the Glasgow Facial Palsy Scale. Study Design: Retrospective study. Methods: Fifty normal subjects and 50 patients with known ocular synkinesis were studied. Measurements of ocular synkinesis were made using the semiautomated Facial Assessment by Computer Evaluation software, and a modification of the automated Glasgow Facial Palsy program. Results: The mean resting vertical palpebral fissure width of a normal eye was 10.17 mm (standard deviation [SD], 1.63 mm), and the degree of eye closure during smile was on average 21.56% (SD, 13.38%). Synkinetic eyes had a statistically significantly smaller resting palpebral fissure width on average (8.99 mm; SD, 1.61 mm; P < .001, t test), and a statistically significantly greater degree of narrowing during smiling (32.65%; SD, 13.68%; P < .001, t test). Using a modified synkinesis-determining application of the Glasgow Facial Palsy Scale did not consistently correlate with the Facial Assessment by Computer Evaluation program or clinical observations of eye closure during smiling (R = 0.251, Pearson correlation) and puckering (R = 0.253, Pearson correlation). Conclusions: The Facial Assessment by Computer Evaluation program yields rapid, consistent, palpebral fissure width measurements, and when combined with a subjective self-assessment questionnaire yields a comprehensive measure of ocular synkinesis. Our modified application of the Glasgow Facial Palsy Scale did not appear to be a reliable method for quantitative ocular synkinesis assessment. C1 [Kleiss, Ingrid J.; Hohman, Marc H.; Quatela, Olivia E.; Hadlock, Tessa A.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kleiss, Ingrid J.; Marres, Henri A. M.] Radboud Univ Nijmegen, Med Ctr, Dept Otorhinolaryngol Head & Neck Surg, NL-6525 ED Nijmegen, Netherlands. RP Hadlock, TA (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM tessa_hadlock@meei.harvard.edu RI Marres, H.A.M./H-8071-2014 NR 28 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD APR PY 2013 VL 123 IS 4 BP 879 EP 883 DI 10.1002/lary.23778 PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 115KZ UT WOS:000316812400014 PM 23404714 ER PT J AU Dalal, SR Shekelle, PG Hempel, S Newberry, SJ Motala, A Shetty, KD AF Dalal, Siddhartha R. Shekelle, Paul G. Hempel, Susanne Newberry, Sydne J. Motala, Aneesa Shetty, Kanaka D. TI A Pilot Study Using Machine Learning and Domain Knowledge to Facilitate Comparative Effectiveness Review Updating SO MEDICAL DECISION MAKING LA English DT Review DE machine learning; comparative effectiveness reviews; text classification ID SYSTEMATIC REVIEWS; TEXT CATEGORIZATION; CONTROLLED-TRIAL; CONCEPT DRIFT; DOUBLE-BLIND; OSTEOPOROSIS; OLANZAPINE; REGRESSION; MODELS AB Background. Comparative effectiveness and systematic reviews require frequent and time-consuming updating. Results of earlier screening should be useful in reducing the effort needed to screen relevant articles. Methods. We collected 16,707 PubMed citation classification decisions from 2 comparative effectiveness reviews: interventions to prevent fractures in low bone density (LBD) and off-label uses of atypical antipsychotic drugs (AAP). We used previously written search strategies to guide extraction of a limited number of explanatory variables pertaining to the intervention, outcome, and study design. We empirically derived statistical models (based on a sparse generalized linear model with convex penalties [GLMnet] and a gradient boosting machine [GBM]) that predicted article relevance. We evaluated model sensitivity, positive predictive value (PPV), and screening workload reductions using 11,003 PubMed citations retrieved for the LBD and AAP updates. Results. GLMnet-based models performed slightly better than GBM-based models. When attempting to maximize sensitivity for all relevant articles, GLMnet-based models achieved high sensitivities (0.99 and 1.0 for AAP and LBD, respectively) while reducing projected screening by 55.4% and 63.2%. The GLMnet-based model yielded sensitivities of 0.921 and 0.905 and PPVs of 0.185 and 0.102 when predicting articles relevant to the AAP and LBD efficacy/effectiveness analyses, respectively (using a threshold of P >= 0.02). GLMnet performed better when identifying adverse effect relevant articles for the AAP review (sensitivity = 0.981) than for the LBD review (0.685). The system currently requires MEDLINE-indexed articles. Conclusions. We evaluated statistical classifiers that used previous classification decisions and explanatory variables derived from MEDLINE indexing terms to predict inclusion decisions. This pilot system reduced workload associated with screening 2 simulated comparative effectiveness review updates by more than 50% with minimal loss of relevant articles. C1 [Dalal, Siddhartha R.; Shekelle, Paul G.; Hempel, Susanne; Newberry, Sydne J.; Motala, Aneesa; Shetty, Kanaka D.] RAND Corp, Southern Calif Evidence Based Practice Ctr, Santa Monica, CA 90401 USA. [Shekelle, Paul G.] Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA USA. RP Dalal, SR (reprint author), RAND Corp, 1776 Main St, Santa Monica, CA 90401 USA. EM sdalal@rand.org FU RAND Corporation; Agency for Healthcare Research and Quality [290-2007-10062-I] FX Received 21 March 2012 from Southern California Evidence-based Practice Center, RAND Corporation, Santa Monica, CA (SRD, PGS, SH, SJN, AM, KDS); and the Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA (PGS). This work was largely produced under Agency for Healthcare Research and Quality Contract No. 290-2007-10062-I. The funding agreement ensured the authors' independence in designing the study, interpreting the data, and writing and publishing the report. This work was also funded by an internal grant from the RAND Corporation. The RAND Corporation played no role in the design or conduct of the study. Revision accepted for publication 29 May 2012. NR 40 TC 5 Z9 5 U1 1 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X J9 MED DECIS MAKING JI Med. Decis. Mak. PD APR PY 2013 VL 33 IS 3 SI SI BP 343 EP 355 DI 10.1177/0272989X12457243 PG 13 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 113RH UT WOS:000316685000006 PM 22961102 ER PT J AU Saleem, F Bouatra, S Guo, AC Psychogios, N Mandal, R Dunn, SM Ametaj, BN Wishart, DS AF Saleem, Fozia Bouatra, Souhaila Guo, An Chi Psychogios, Nikolaos Mandal, Rupasri Dunn, Suzanna M. Ametaj, Burim N. Wishart, David S. TI The Bovine Ruminal Fluid Metabolome SO METABOLOMICS LA English DT Article DE Rumen fluid; Bovine Metabolome; Metabolomics; Nuclear magnetic resonance; Mass spectrometry; ICP-MS ID QUANTITATIVE METABOLOMICS; H-1-NMR SPECTROSCOPY; RUMEN MICROORGANISMS; LINOLEIC-ACID; FATTY-ACIDS; DAIRY-COWS; NMR; DOMESTICATION; PERFORMANCE; MANAGEMENT AB The rumen is a unique organ that serves as the primary site for microbial fermentation of ingested plant material for domestic livestock such as cattle, sheep and goats. The chemical composition of ruminal fluid is thought to closely reflect the healthy/unhealthy interaction between rumen microflora and diet. Just as diet and feed quality is important for livestock production, rumen health is also critical to the growth and production of high quality milk and meat. Therefore a detailed understanding of the chemical composition of ruminal fluid and the influence of diet on its composition could help improve the efficiency and effectiveness of farming and veterinary practices. Consequently we have undertaken an effort to comprehensively characterize the bovine ruminal fluid metabolome. In doing so, we combined NMR spectroscopy, inductively coupled plasma mass-spectroscopy (ICP-MS), gas chromatography-mass spectrometry (GC-MS), direct flow injection (DFI) mass spectrometry and lipidomics with computer-aided literature mining to identify and quantify essentially all of the metabolites in bovine ruminal fluid that can be routinely detected (with today's technology). The use of multiple metabolomics platforms and technologies allowed us to substantially enhance the level of metabolome coverage while critically assessing the relative strengths and weaknesses of these techniques. Tables containing the set of 246 ruminal fluid metabolites or metabolite species, their concentrations, related literature reference and links to their known diet associations for the bovine rumen metabolome are freely available at http://www.rumendb.ca. C1 [Saleem, Fozia; Bouatra, Souhaila; Guo, An Chi; Mandal, Rupasri; Wishart, David S.] Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E8, Canada. [Psychogios, Nikolaos] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Dunn, Suzanna M.; Ametaj, Burim N.] Univ Alberta, Dept Agr Food & Nutr Sci, Edmonton, AB T6G 2E8, Canada. [Wishart, David S.] Univ Alberta, Dept Comp Sci, Edmonton, AB T6G 2E8, Canada. RP Wishart, DS (reprint author), Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E8, Canada. EM burim.ametaj@ualberta.ca; dwishart@ualberta.ca OI Psychogios, Nikolaos/0000-0002-2747-6012; Wishart, David S/0000-0002-3207-2434 FU Alberta Agricultural Research Institute (AARI; Edmonton, Alberta, Canada); Alberta Livestock and Meat Agency Ltd. (ALMA; Edmonton, Alberta, Canada); Genome Alberta (Calgary, Alberta, Canada); Natural Sciences and Engineering Research Council of Canada (NSERC; Ottawa, Ontario, Canada) FX Financial support for this work was provided by the Alberta Agricultural Research Institute (AARI; Edmonton, Alberta, Canada), the Alberta Livestock and Meat Agency Ltd. (ALMA; Edmonton, Alberta, Canada), Genome Alberta (Calgary, Alberta, Canada) and the Natural Sciences and Engineering Research Council of Canada (NSERC; Ottawa, Ontario, Canada). We also are grateful to the technical staff of Dairy Research and Technology Centre at the University of Alberta for their help in caring for and monitoring the cows used in this study. NR 45 TC 10 Z9 11 U1 10 U2 84 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1573-3882 J9 METABOLOMICS JI Metabolomics PD APR PY 2013 VL 9 IS 2 BP 360 EP 378 DI 10.1007/s11306-012-0458-9 PG 19 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 116WG UT WOS:000316913200009 ER PT J AU Ogino, S Lochhead, P Chan, AT Nishihara, R Cho, E Wolpin, BM Meyerhardt, JA Meissner, A Schernhammer, ES Fuchs, CS Giovannucci, E AF Ogino, Shuji Lochhead, Paul Chan, Andrew T. Nishihara, Reiko Cho, Eunyoung Wolpin, Brian M. Meyerhardt, Jeffrey A. Meissner, Alexander Schernhammer, Eva S. Fuchs, Charles S. Giovannucci, Edward TI Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease SO MODERN PATHOLOGY LA English DT Review DE CIMP; genetics; hypermethylation; molecular pathological epidemiology; omics; personalized therapy; unique tumor principle ID ISLAND METHYLATOR PHENOTYPE; COLORECTAL-CANCER RISK; BODY-MASS INDEX; FATTY-ACID SYNTHASE; III COLON-CANCER; MICROSATELLITE INSTABILITY STATUS; ONE-CARBON METABOLISM; POSTMENOPAUSAL HORMONE-THERAPY; GENOME-WIDE ASSOCIATION; POPULATION-BASED SAMPLE AB Epigenetics acts as an interface between environmental/exogenous factors, cellular responses, and pathological processes. Aberrant epigenetic signatures are a hallmark of complex multifactorial diseases (including neoplasms and malignancies such as leukemias, lymphomas, sarcomas, and breast, lung, prostate, liver, and colorectal cancers). Epigenetic signatures (DNA methylation, mRNA and microRNA expression, etc) may serve as biomarkers for risk stratification, early detection, and disease classification, as well as targets for therapy and chemoprevention. In particular, DNA methylation assays are widely applied to formalin-fixed, paraffin-embedded archival tissue specimens as clinical pathology tests. To better understand the interplay between etiological factors, cellular molecular characteristics, and disease evolution, the field of 'molecular pathological epidemiology (MPE)' has emerged as an interdisciplinary integration of 'molecular pathology' and 'epidemiology'. In contrast to traditional epidemiological research including genome-wide association studies (GWAS), MPE is founded on the unique disease principle, that is, each disease process results from unique profiles of exposomes, epigenomes, transcriptomes, proteomes, metabolomes, microbiomes, and interactomes in relation to the macroenvironment and tissue microenvironment. MPE may represent a logical evolution of GWAS, termed 'GWAS-MPE approach'. Although epigenome-wide association study attracts increasing attention, currently, it has a fundamental problem in that each cell within one individual has a unique, time-varying epigenome. Having a similar conceptual framework to systems biology, the holistic MPE approach enables us to link potential etiological factors to specific molecular pathology, and gain novel pathogenic insights on causality. The widespread application of epigenome (eg, methylome) analyses will enhance our understanding of disease heterogeneity, epigenotypes (CpG island methylator phenotype, LINE-1 (long interspersed nucleotide element-1; also called long interspersed nuclear element-1; long interspersed element-1; L1) hypomethylation, etc), and host-disease interactions. In this article, we illustrate increasing contribution of modern pathology to broader public health sciences, which attests pivotal roles of pathologists in the new integrated MPE science towards our ultimate goal of personalized medicine and prevention. Modern Pathology (2013) 26, 465-484; doi:10.1038/modpathol.2012.214; published online 11 January 2013 C1 [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Chan, Andrew T.; Cho, Eunyoung; Schernhammer, Eva S.; Fuchs, Charles S.; Giovannucci, Edward] Harvard Univ, Sch Med, Boston, MA USA. [Ogino, Shuji; Schernhammer, Eva S.; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ogino, Shuji; Lochhead, Paul; Nishihara, Reiko; Wolpin, Brian M.; Meyerhardt, Jeffrey A.; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Lochhead, Paul] Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.; Cho, Eunyoung; Schernhammer, Eva S.; Fuchs, Charles S.; Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Meissner, Alexander] Broad Inst MIT & Harvard Univ, Cambridge, MA USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Ogino, S (reprint author), Harvard Univ, Sch Publ Hlth, Brigham & Womens Hosp, Dept Epidemiol,Dept Pathol, 450 Brookline Ave,Room JF 215C, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu FU USA National Institute of Health (NIH) [R01 CA151993, R01 CA137178, R01 CA136950, R01 CA149222, P50 CA127003, R01 CA124908, P01 CA87969, 1UM1 CA167552] FX This work was supported by grants from USA National Institute of Health (NIH) (R01 CA151993 (to SO), R01 CA137178 (to ATC), R01 CA136950 (to EC), R01 CA149222 (to JAM), P50 CA127003 (to CSF), R01 CA124908 (to CSF), P01 CA87969 (to SE Hankinson), and 1UM1 CA167552 (to WC Willett)). PL is a Scottish Government Clinical Academic Fellow. ATC is a Damon Runyon Clinical Investigator. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. Funding agencies did not have any role in the decision to submit the manuscript for publication, or the writing of the manuscript. NR 381 TC 97 Z9 97 U1 2 U2 86 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD APR PY 2013 VL 26 IS 4 BP 465 EP 484 DI 10.1038/modpathol.2012.214 PG 20 WC Pathology SC Pathology GA 117GN UT WOS:000316941600001 PM 23307060 ER PT J AU Ryan, RJH Akin, C Castells, M Wills, M Selig, MK Nielsen, GP Ferry, JA Hornick, JL AF Ryan, Russell J. H. Akin, Cem Castells, Mariana Wills, Marcia Selig, Martin K. Nielsen, G. Petur Ferry, Judith A. Hornick, Jason L. TI Mast cell sarcoma: a rare and potentially under-recognized diagnostic entity with specific therapeutic implications SO MODERN PATHOLOGY LA English DT Article DE mast cell sarcoma; mastocytosis; urticaria pigmentosa; KIT mutation; imatinib ID MASTOCYTOSIS; IMATINIB; ADULTS AB Mast cell sarcoma is a rare, aggressive neoplasm composed of cytologically malignant mast cells presenting as a solitary mass. Previous descriptions of mast cell sarcoma have been limited to single case reports, and the pathologic features of this entity are not well known. Here, we report three new cases of mast cell sarcoma and review previously reported cases. Mast cell sarcoma has a characteristic morphology of medium-sized to large epithelioid cells, including bizarre multinucleated cells, and does not closely resemble either normal mast cells or the spindle cells of systemic mastocytosis. One of our three cases arose in a patient with a remote history of infantile cutaneous mastocytosis, an association also noted in one previous case report. None of our three cases were correctly diagnosed as mast cell neoplasms on initial pathological evaluation, suggesting that this entity may be under-recognized. Molecular testing of mast cell sarcoma has not thus far detected the imatinib-resistant KIT D816V mutation, suggesting that recognition of these cases may facilitate specific targeted therapy. Modern Pathology (2013) 26, 533-543; doi:10.1038/modpathol.2012.199; published online 30 November 2012 C1 [Ryan, Russell J. H.; Selig, Martin K.; Nielsen, G. Petur; Ferry, Judith A.] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Ryan, Russell J. H.; Selig, Martin K.; Nielsen, G. Petur; Ferry, Judith A.; Hornick, Jason L.] Harvard Univ, Sch Med, Boston, MA USA. [Akin, Cem; Castells, Mariana; Hornick, Jason L.] Harvard Univ, Sch Med, Mastocytosis Ctr, Boston, MA USA. [Akin, Cem; Castells, Mariana] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Wills, Marcia] Aurora Diagnost, Seacoast Pathol, Exeter, NH USA. [Hornick, Jason L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Ryan, RJH (reprint author), Massachusetts Gen Hosp, Pathol Serv, Warren Bldg 225,55 Fruit St, Boston, MA 02114 USA. EM rryan6@partners.org; jhornick@partners.org OI Akin, Cem/0000-0001-6301-4520 NR 22 TC 10 Z9 10 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD APR PY 2013 VL 26 IS 4 BP 533 EP 543 DI 10.1038/modpathol.2012.199 PG 11 WC Pathology SC Pathology GA 117GN UT WOS:000316941600007 PM 23196796 ER PT J AU He, J Shen, L Wan, M Taranova, O Wu, H Zhang, Y AF He, Jin Shen, Li Wan, Ma Taranova, Olena Wu, Hao Zhang, Yi TI Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of developmental genes SO NATURE CELL BIOLOGY LA English DT Article ID POLYCOMB REPRESSIVE COMPLEX-2; HISTONE H3; MOUSE DEVELOPMENT; INK4A/ARF LOCUS; TARGET GENES; HUMAN GENOME; CXXC DOMAIN; PLURIPOTENT; PROTEINS; METHYLATION AB Polycomb group (PcG) proteins play important roles in repressing lineage-specific genes and maintaining the undifferentiated state of mouse embryonic stem cells (mESCs). However, how PcG proteins are recruited to their target genes is largely unknown. Here, we show that the H3K36-specific histone demethylase Kdm2b is highly expressed in mESCs and regulated by the pluripotent factors Oct4 and Sox2 directly. Depletion of Kdm2b in mESCs causes de-repression of lineage-specific genes and induces early differentiation. The function of Kdm2b depends on its CxxC-ZF domain, which mediates its genome-wide binding to CpG islands (CGIs). Kdm2b interacts with the core components of polycomb repressive complex 1 (PRC1) and recruits the complex to the CGIs of early lineage-specific genes. Thus, our study not only reveals an Oct4-Sox2-Kdm2b-PRC1-CGI regulatory axis and its function in maintaining the undifferentiated state of mESCs, but also demonstrates a critical function of Kdm2b in recruiting PRC1 to the CGIs of lineage-specific genes to repress their expression. C1 [He, Jin; Shen, Li; Wan, Ma; Taranova, Olena; Wu, Hao; Zhang, Yi] Howard Hughes Med Inst, Boston, MA 02115 USA. [He, Jin; Shen, Li; Wan, Ma; Taranova, Olena; Wu, Hao; Zhang, Yi] Program Cellular & Mol Med, Boston, MA 02115 USA. [He, Jin; Shen, Li; Wan, Ma; Taranova, Olena; Wu, Hao; Zhang, Yi] Boston Childrens Hosp, Dept Pediat, Div Hematol Oncol, Boston, MA 02115 USA. [Zhang, Yi] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Zhang, Yi] Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Zhang, Y (reprint author), Howard Hughes Med Inst, WAB 149G,200 Longwood Ave, Boston, MA 02115 USA. EM yzhang@genetics.med.harvard.edu RI Wu, Hao/G-4145-2013 OI Wu, Hao/0000-0002-1256-6891 FU NIH [GM068804, U01DK089565] FX We thank R. Klose for the plasmid pGEM3z-601. This project was supported by NIH GM068804 and U01DK089565. Y.Z. is an investigator of the Howard Hughes Medical Institute. NR 59 TC 92 Z9 94 U1 1 U2 31 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD APR PY 2013 VL 15 IS 4 BP 373 EP + DI 10.1038/ncb2702 PG 22 WC Cell Biology SC Cell Biology GA 118DX UT WOS:000317004200008 PM 23502314 ER PT J AU Kokel, D Cheung, CYJ Mills, R Coutinho-Budd, J Huang, LY Setola, V Sprague, J Jin, S Jin, YN Huang, XP Bruni, G Woolf, CJ Roth, BL Hamblin, MR Zylka, MJ Milan, DJ Peterson, RT AF Kokel, David Cheung, Chung Yan J. Mills, Robert Coutinho-Budd, Jaeda Huang, Liyi Setola, Vincent Sprague, Jared Jin, Shan Jin, Youngnam N. Huang, Xi-Ping Bruni, Giancarlo Woolf, Clifford J. Roth, Bryan L. Hamblin, Michael R. Zylka, Mark J. Milan, David J. Peterson, Randall T. TI Photochemical activation of TRPA1 channels in neurons and animals SO NATURE CHEMICAL BIOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; ION CHANNELS; GLUTAMATE-RECEPTOR; REMOTE-CONTROL; COVALENT MODIFICATION; CAGED GLUTAMATE; OPTICAL CONTROL; ZEBRAFISH; LIGHT; PHOTOSTIMULATION AB Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild-type zebrafish and mice. To our surprise, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in nontransgenic animals, including humans. C1 [Kokel, David; Cheung, Chung Yan J.; Mills, Robert; Jin, Shan; Jin, Youngnam N.; Bruni, Giancarlo; Milan, David J.; Peterson, Randall T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Cardiovasc Res Ctr, Charlestown, MA USA. [Kokel, David; Cheung, Chung Yan J.; Mills, Robert; Jin, Shan; Jin, Youngnam N.; Bruni, Giancarlo; Milan, David J.; Peterson, Randall T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA USA. [Kokel, David; Cheung, Chung Yan J.; Jin, Shan; Jin, Youngnam N.; Bruni, Giancarlo; Peterson, Randall T.] Broad Inst, Cambridge, MA USA. [Coutinho-Budd, Jaeda; Zylka, Mark J.] Univ N Carolina, Ctr Neurosci, Chapel Hill, NC USA. [Zylka, Mark J.] Univ N Carolina, Dept Cell & Mol Physiol, Chapel Hill, NC USA. [Huang, Liyi; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Huang, Liyi; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Huang, Liyi] Guangxi Med Univ, Affiliated Coll & Hosp 1, Dept Infect Dis, Nanning, Peoples R China. [Setola, Vincent; Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA. [Setola, Vincent; Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina, Sch Med, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC USA. [Sprague, Jared; Woolf, Clifford J.] Harvard Univ, Sch Med, Dept Neurobiol, Childrens Hosp Boston, Boston, MA 02115 USA. [Sprague, Jared] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard Massachusetts Inst Technol Div Hlth Sci &, Cambridge, MA USA. RP Kokel, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Cardiovasc Res Ctr, Charlestown, MA USA. EM dkokel@cvrc.mgh.harvard.edu; peterson@cvrc.mgh.harvard.edu RI Roth, Bryan/F-3928-2010; OI Bruni, Giancarlo/0000-0003-2850-4633; kokel, david/0000-0002-1981-1511; Hamblin, Michael/0000-0001-6431-4605 FU US National Institutes of Health (NIH) [K01MH091449, MH086867, MH085205, P01 NS072040, R01 AI050875]; Charles and Ann Sanders Massachusetts General Hospital; Michael Hooker Chair; NIMH PDSP; National Institute of Neurological Disorders and Stroke (NINDS) [R01NS060725, R01NS067688]; NINDS [F31NS068038]; NIH [HL109004, DA026982] FX We thank K. Kwan and D. Corey (Harvard Medical School), T. Miyamoto and A. Patapoutian (Scripps Research Institute), and T. Numata and Y. Mori (Kyoto University) for human TrpA1 constructs. A. Schier, D. Prober and D. Robson (Harvard University) generously provided TrpA1 mutant zebrafish. We thank R. Gaudet, A. Vakkasglu, B. Shoichet, T. Dunn, M. Ahrens, F. Engert, R. Mazitschek and members of our research groups for helpful advice. This work was supported by US National Institutes of Health (NIH) grants K01MH091449 (D.K.), MH086867 and MH085205 (R.T.P.), P01 NS072040 (C.J.W.), R01 AI050875 (L.H. and M.R.H.); the Charles and Ann Sanders Massachusetts General Hospital Research Scholar award (R.T.P.); and the Michael Hooker Chair and the NIMH PDSP (B.L.R.). M.J.Z. was supported by grants from National Institute of Neurological Disorders and Stroke (NINDS; R01NS060725, R01NS067688), J.C.-B. was supported by a National Research Service Award training grant from NINDS (F31NS068038) and D.J.M. was supported by NIH grants HL109004 and DA026982. NR 45 TC 22 Z9 23 U1 1 U2 40 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD APR PY 2013 VL 9 IS 4 BP 257 EP 263 DI 10.1038/NCHEMBIO.1183 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 118LA UT WOS:000317025800016 PM 23396078 ER PT J AU Pharoah, PDP Tsai, YY Ramus, SJ Phelan, CM Goode, EL Lawrenson, K Buckley, M Fridley, BL Tyrer, JP Shen, H Weber, R Karevan, R Larson, MC Song, HL Tessier, DC Bacot, F Vincent, D Cunningham, JM Dennis, J Dicks, E Katja, KA Anton-Culver, H Antonenkova, N Armasu, SM Baglietto, L Bandera, EV Beckmann, MW Birrer, MJ Bloom, G Bogdanova, N Brenton, JD Brinton, LA Brooks-Wilson, A Brown, R Butzow, R Campbell, I Carney, ME Carvalho, RS Chang-Claude, J Chen, YA Chen, ZH Chow, WH Cicek, MS Coetzee, G Cook, LS Cramer, DW Cybulski, C Dansonka-Mieszkowska, A Despierre, E Doherty, JA Doerk, T du Bois, A Duerst, M Eccles, D Edwards, R Ekici, AB Fasching, PA Fenstermacher, D Flanagan, J Gao, YT Garcia-Closas, M Gentry-Maharaj, A Giles, G Gjyshi, A Gore, M Gronwald, J Guo, Q Halle, MK Harter, P Hein, A Heitz, F Hillemanns, P Hoatlin, M Hogdall, E Hogdall, CK Hosono, S Jakubowska, A Jensen, A Kalli, KR Karlan, BY Kelemen, LE Kiemeney, LA Kjaer, SK Konecny, GE Krakstad, C Kupryjanczyk, J Lambrechts, D Lambrechts, S Le, ND Lee, N Lee, J Leminen, A Lim, BK Lissowska, J Lubinski, J Lundvall, L Lurie, G Massuger, LFAG Matsuo, K McGuire, V McLaughlin, JR Menon, U Modugno, F Moysich, KB Nakanishi, T Narod, SA Ness, RB Nevanlinna, H Nickels, S Noushmehr, H Odunsi, K Olson, S Orlow, I Paul, J Pejovic, T Pelttari, LM Permuth-Wey, J Pike, MC Poole, EM Qu, XT Risch, HA Rodriguez-Rodriguez, L Rossing, MA Rudolph, A Runnebaum, I Rzepecka, IK Salvesen, HB Schwaab, I Severi, G Shen, H Shridhar, V Shu, XO Sieh, W Southey, MC Spellman, P Tajima, K Teo, SH Terry, KL Thompson, PJ Timorek, A Tworoger, SS van Altena, AM van den Berg, D Vergote, I Vierkant, RA Vitonis, AF Wang-Gohrke, S Wentzensen, N Whittemore, AS Wik, E Winterhoff, B Woo, YL Wu, AH Yang, HP Zheng, W Ziogas, A Zulkifli, F Goodman, MT Hall, P Easton, DF Pearce, CL Berchuck, A Chenevix-Trench, G Iversen, E Monteiro, ANA Gayther, SA Schildkraut, JM Sellers, TA AF Pharoah, Paul D. P. Tsai, Ya-Yu Ramus, Susan J. Phelan, Catherine M. Goode, Ellen L. Lawrenson, Kate Buckley, Melissa Fridley, Brooke L. Tyrer, Jonathan P. Shen, Howard Weber, Rachel Karevan, Rod Larson, Melissa C. Song, Honglin Tessier, Daniel C. Bacot, Francois Vincent, Daniel Cunningham, Julie M. Dennis, Joe Dicks, Ed Aben, Katja K. Anton-Culver, Hoda Antonenkova, Natalia Armasu, Sebastian M. Baglietto, Laura Bandera, Elisa V. Beckmann, Matthias W. Birrer, Michael J. Bloom, Greg Bogdanova, Natalia Brenton, James D. Brinton, Louise A. Brooks-Wilson, Angela Brown, Robert Butzow, Ralf Campbell, Ian Carney, Michael E. Carvalho, Renato S. Chang-Claude, Jenny Chen, Y. Anne Chen, Zhihua Chow, Wong-Ho Cicek, Mine S. Coetzee, Gerhard Cook, Linda S. Cramer, Daniel W. Cybulski, Cezary Dansonka-Mieszkowska, Agnieszka Despierre, Evelyn Doherty, Jennifer A. Doerk, Thilo du Bois, Andreas Duerst, Matthias Eccles, Diana Edwards, Robert Ekici, Arif B. Fasching, Peter A. Fenstermacher, David Flanagan, James Gao, Yu-Tang Garcia-Closas, Montserrat Gentry-Maharaj, Aleksandra Giles, Graham Gjyshi, Anxhela Gore, Martin Gronwald, Jacek Guo, Qi Halle, Mari K. Harter, Philipp Hein, Alexander Heitz, Florian Hillemanns, Peter Hoatlin, Maureen Hogdall, Estrid Hogdall, Claus K. Hosono, Satoyo Jakubowska, Anna Jensen, Allan Kalli, Kimberly R. Karlan, Beth Y. Kelemen, Linda E. Kiemeney, Lambertus A. Kjaer, Susanne Kruger Konecny, Gottfried E. Krakstad, Camilla Kupryjanczyk, Jolanta Lambrechts, Diether Lambrechts, Sandrina Le, Nhu D. Lee, Nathan Lee, Janet Leminen, Arto Lim, Boon Kiong Lissowska, Jolanta Lubinski, Jan Lundvall, Lene Lurie, Galina Massuger, Leon F. A. G. Matsuo, Keitaro McGuire, Valerie McLaughlin, John R. Menon, Usha Modugno, Francesmary Moysich, Kirsten B. Nakanishi, Toru Narod, Steven A. Ness, Roberta B. Nevanlinna, Heli Nickels, Stefan Noushmehr, Houtan Odunsi, Kunle Olson, Sara Orlow, Irene Paul, James Pejovic, Tanja Pelttari, Liisa M. Permuth-Wey, Jenny Pike, Malcolm C. Poole, Elizabeth M. Qu, Xiaotao Risch, Harvey A. Rodriguez-Rodriguez, Lorna Rossing, Mary Anne Rudolph, Anja Runnebaum, Ingo Rzepecka, Iwona K. Salvesen, Helga B. Schwaab, Ira Severi, Gianluca Shen, Hui Shridhar, Vijayalakshmi Shu, Xiao-Ou Sieh, Weiva Southey, Melissa C. Spellman, Paul Tajima, Kazuo Teo, Soo-Hwang Terry, Kathryn L. Thompson, Pamela J. Timorek, Agnieszka Tworoger, Shelley S. van Altena, Anne M. van den Berg, David Vergote, Ignace Vierkant, Robert A. Vitonis, Allison F. Wang-Gohrke, Shan Wentzensen, Nicolas Whittemore, Alice S. Wik, Elisabeth Winterhoff, Boris Woo, Yin Ling Wu, Anna H. Yang, Hannah P. Zheng, Wei Ziogas, Argyrios Zulkifli, Famida Goodman, Marc T. Hall, Per Easton, Douglas F. Pearce, Celeste L. Berchuck, Andrew Chenevix-Trench, Georgia Iversen, Edwin Monteiro, Alvaro N. A. Gayther, Simon A. Schildkraut, Joellen M. Sellers, Thomas A. CA Australian Canc Study Australian Ovarian Canc Study Grp TI GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; RISK; GENE; EXPRESSION; CARCINOMA; NEBULETTE; LEUKEMIA; CELLS; 19P13; MYC AB Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 x 10(-9)) and 10p12 (rs1243180, P = 1.8 x 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 x 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer. C1 [Pharoah, Paul D. P.; Tyrer, Jonathan P.; Song, Honglin; Dicks, Ed; Guo, Qi; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Pharoah, Paul D. P.; Dennis, Joe; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Tsai, Ya-Yu; Phelan, Catherine M.; Buckley, Melissa; Bloom, Greg; Chen, Y. Anne; Chen, Zhihua; Fenstermacher, David; Gjyshi, Anxhela; Permuth-Wey, Jenny; Qu, Xiaotao; Monteiro, Alvaro N. A.; Sellers, Thomas A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Div Populat Sci, Tampa, FL 33682 USA. [Ramus, Susan J.; Lawrenson, Kate; Shen, Howard; Karevan, Rod; Lee, Nathan; Lee, Janet; Pike, Malcolm C.; van den Berg, David; Wu, Anna H.; Pearce, Celeste L.; Gayther, Simon A.] Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Goode, Ellen L.; Fridley, Brooke L.; Cicek, Mine S.; Vierkant, Robert A.] Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN USA. [Weber, Rachel; Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Larson, Melissa C.; Armasu, Sebastian M.] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Tessier, Daniel C.; Bacot, Francois; Vincent, Daniel] McGill Univ, Ctr Technol, Montreal, PQ, Canada. [Tessier, Daniel C.; Bacot, Francois; Vincent, Daniel] McGill Univ, Montreal, PQ, Canada. [Tessier, Daniel C.; Bacot, Francois; Vincent, Daniel] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Cunningham, Julie M.; Shridhar, Vijayalakshmi] Mayo Clin, Dept Lab Med & Pathol, Div Anat Pathol, Rochester, MN USA. [Aben, Katja K.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & Hlth Technol Assessment, NL-6525 ED Nijmegen, Netherlands. [Aben, Katja K.; Kiemeney, Lambertus A.] Comprehens Canc Ctr Netherlands, Utrecht, Netherlands. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Dept Epidemiol, Ctr Canc Genet Res & Prevent, Irvine, CA 92717 USA. [Antonenkova, Natalia] NN Aleksandrov Byelorussian Inst Oncol & Med Radi, Minsk, Byelarus. 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[Chow, Wong-Ho] NCI, Div Canc Etiol & Genet, Bethesda, MD 20892 USA. [Coetzee, Gerhard; Noushmehr, Houtan] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Microbiol & Prevent Med, Los Angeles, CA 90033 USA. [Cook, Linda S.] Univ New Mexico, Dept Internal Med, Albuquerque, NM 87131 USA. [Cramer, Daniel W.; Terry, Kathryn L.; Vitonis, Allison F.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Cramer, Daniel W.; Terry, Kathryn L.; Vitonis, Allison F.] Harvard Univ, Sch Med, Boston, MA USA. [Cramer, Daniel W.; Poole, Elizabeth M.; Terry, Kathryn L.; Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Cybulski, Cezary; Gronwald, Jacek; Jakubowska, Anna; Lubinski, Jan] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Rzepecka, Iwona K.] Maria Sklodowska Curie Mem Canc Ctr, Dept Mol Pathol, Warsaw, Poland. [Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Rzepecka, Iwona K.] Inst Oncol, Warsaw, Poland. [Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace] Leuven Canc Inst, Dept Obstet & Gynaecol, Div Gynecol Oncol, Louvain, Belgium. [Doherty, Jennifer A.] Geisel Sch Med Dartmouth, Sect Biostat & Epidemiol, Lebanon, NH USA. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Dr Horst Schmidt Kliniken Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [du Bois, Andreas; Harter, Philipp; Heitz, Florian] Kliniken Essen Mitte Evang Huyssens Stiftung Knap, Dept Gynecol & Gynecol Oncol, Essen, Germany. [Duerst, Matthias; Runnebaum, Ingo] Jena Univ Hosp, Dept Gynecol, Jena, Germany. [Eccles, Diana] Univ Southampton, Fac Med, Southampton Univ Hosp, Southampton SO9 5NH, Hants, England. [Edwards, Robert; Modugno, Francesmary] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Edwards, Robert] Magee Womens Res Inst, Womens Canc Program, Pittsburgh, PA USA. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Fasching, Peter A.; Konecny, Gottfried E.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Garcia-Closas, Montserrat] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London, England. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Elizabeth Garrett Anderson Inst Womens Hlth, Gynaecol Canc Res Ctr, London, England. [Giles, Graham] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Gore, Martin] Royal Marsden Hosp, Gynecol Oncol Unit, London SW3 6JJ, England. [Halle, Mari K.; Krakstad, Camilla; Salvesen, Helga B.; Wik, Elisabeth] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway. 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[Kelemen, Linda E.] Alberta Hlth Serv Canc Care, Dept Populat Hlth Res, Calgary, AB, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Med Genet, Calgary, AB, Canada. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands. [Lambrechts, Diether] Katholieke Univ Leuven, Vesalius Res Ctr, Louvain, Belgium. [Le, Nhu D.] BC Canc Agcy, Canc Control Res, Vancouver, BC, Canada. [Lim, Boon Kiong; Woo, Yin Ling] Univ Malaya, Med Ctr, Dept Obstet & Gynaecol, Kuala Lumpur, Malaysia. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Massuger, Leon F. A. G.; van Altena, Anne M.] Radboud Univ Nijmegen, Med Ctr, Dept Gynaecol, NL-6525 ED Nijmegen, Netherlands. [McGuire, Valerie; Sieh, Weiva; Whittemore, Alice S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA 94305 USA. [McLaughlin, John R.] Univ Toronto, Fac Med, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. 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[Teo, Soo-Hwang; Zulkifli, Famida] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya, Malaysia. [Teo, Soo-Hwang; Zulkifli, Famida] Univ Malaya, Med Ctr, Kuala Lumpur, Malaysia. [Timorek, Agnieszka] Warsaw Med Univ, Fac Med 2, Dept Obstet Gynecol & Oncol, Warsaw, Poland. [Timorek, Agnieszka] Brodnowski Hosp, Dept Obstet & Gynaecol, Warsaw, Poland. [Wang-Gohrke, Shan] Univ Ulm, Dept Obstet & Gynaecol, D-89069 Ulm, Germany. [Winterhoff, Boris] Mayo Clin, Dept Obstet & Gynaecol, Rochester, MN USA. [Hall, Per] Karolinska Istitutet, Dept Epidemiol & Biostat, Stockholm, Sweden. [Berchuck, Andrew] Duke Univ, Med Ctr, Dept Obstet & Gynaecol, Durham, NC USA. [Chenevix-Trench, Georgia] Queensland Inst Med Res, Canc Div, Herston, Qld 4006, Australia. [Iversen, Edwin] Duke Univ, Dept Stat, Durham, NC USA. [Schildkraut, Joellen M.] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC USA. RP Pharoah, PDP (reprint author), Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. EM paul.pharoah@medschl.cam.ac.uk RI Hein, Alexander/F-6999-2010; Noushmehr, Houtan/C-9692-2013; Verdrengh, Evelien/H-4571-2012; Ekici, Arif/C-3971-2013; McLaughlin, John/E-4577-2013; Kiemeney, Lambertus/D-3357-2009; Tang, Macy/B-9798-2014; Dork, Thilo/J-8620-2012; Whittemore, Alice/F-9925-2014; Brooks-Wilson, Angela/E-9399-2012; Teo, Soo-hwang/H-2353-2014; Bandera, Elisa/M-4169-2014; Massuger, Leon/H-8072-2014; Jakubowska, Anna/O-8050-2014; campbell, Ian/F-6006-2011; Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Woo, Yin Ling/B-5198-2010; van Altena, Anne/B-9824-2016; Aben, Katja/G-9686-2016; Bowtell, David/H-1007-2016; Gronwald, Jacek/A-4576-2017; salvesen, Helga/C-1187-2017 OI Hein, Alexander/0000-0003-2601-3398; Noushmehr, Houtan/0000-0003-4051-8114; Kiemeney, Lambertus/0000-0002-2368-1326; Brooks-Wilson, Angela/0000-0003-1009-6408; Bandera, Elisa/0000-0002-8789-2755; Krakstad, Camilla/0000-0002-0174-8139; Giles, Graham/0000-0003-4946-9099; Matsuo, Keitaro/0000-0003-1761-6314; Rudolph, Anja/0000-0001-7520-2035; Brenton, James/0000-0002-5738-6683; Tworoger, Shelley/0000-0002-6986-7046; Kjaer, Susanne/0000-0002-8347-1398; Monteiro, Alvaro/0000-0002-8448-4801; Ramus, Susan/0000-0003-0005-7798; Lissowska, Jolanta/0000-0003-2695-5799; Dennis, Joe/0000-0003-4591-1214; Nevanlinna, Heli/0000-0002-0916-2976; Halle, Mari/0000-0002-2660-8271; Orlow, Irene/0000-0001-6234-6961; Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Woo, Yin Ling/0000-0003-1742-1066; Aben, Katja/0000-0002-0214-2147; Bowtell, David/0000-0001-9089-7525; Gronwald, Jacek/0000-0002-3643-2871; salvesen, Helga/0000-0002-4438-8831 FU European Commission's Seventh Framework Programme [223175, HEALTH-F22009-223175]; Ovarian Cancer Research Fund; Genetic Associations and Mechanisms in Oncology (GAME-ON); National Cancer Institute Cancer Post-GWAS Initiative [U19-CA148112]; Wellcome Trust [076113] FX We thank all the individuals who took part in this study and all the researchers, clinicians and technical and administrative staff who made possible the many studies contributing to this work (a full list is provided in the Supplementary Note). The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F22009-223175). The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were supported in part by the Genetic Associations and Mechanisms in Oncology (GAME-ON) and a National Cancer Institute Cancer Post-GWAS Initiative (U19-CA148112). Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium; funding for the project was provided by the Wellcome Trust under award 076113. A full list of the investigators who contributed to the generation of the data is available from the website (see URLs). The results published here are based in part on data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute; information about The Cancer Genome Atlas (TCGA) and the investigators and institutions who constitute the TCGA research network can be found on the website (see URLs). NR 31 TC 144 Z9 146 U1 3 U2 48 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2013 VL 45 IS 4 BP 362 EP 370 DI 10.1038/ng.2564 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600006 PM 23535730 ER PT J AU Bojesen, SE Pooley, KA Johnatty, SE Beesley, J Michailidou, K Tyrer, JP Edwards, SL Pickett, HA Shen, HC Smart, CE Hillman, KM Mai, PL Lawrenson, K Stutz, MD Lu, Y Karevan, R Woods, N Johnstonw, RL French, JD Chen, XQ Weischer, M Nielsen, SF Maranian, MJ Ghoussaini, M Ahmed, S Baynes, C Bolla, MK Wang, Q Dennis, J McGuffog, L Barrowdale, D Lee, A Healey, S Lush, M Tessier, DC Vincent, D Bacot, F Vergote, I Lambrechts, S Despierre, E Risch, HA Gonzaalez-Neira, A Rossing, MA Pita, G Doherty, JA Alvarez, N Larson, MC Fridley, BL Schoof, N Chang-Claude, J Cicek, MS Peto, J Kalli, KR Broeks, A Armasu, SM Schmidt, MK Braaf, LM Winterhoff, B Nevanlinna, H Konecny, GE Lambrechts, D Rogmann, L Guenel, P Teoman, A Milne, RL Garcia, JJ Cox, A Shridhar, V Burwinkel, B Marme, F Hein, R Sawyer, EJ Haiman, CA Wang-Gohrke, S Andrulis, IL 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JJ Bandera, EV Li, JM Olson, SH Humphreys, K Row, I Blomqvist, C Rodriguez-Rodriguez, L Aittomaki, K Salvesen, HB Muranen, TA Wik, E Brouwers, B Krakstad, C Wauters, E Halle, MK Wildiers, H Kiemeney, LA Mulot, C Aben, KK Laurent-Puig, P Altena, AM Truong, T Massuger, LFAG Benitez, J Pejovic, T Perez, JIA Hoatlin, M Zamora, MP Cook, LS Balasubramanian, SP Kelemen, LE Schneeweiss, A Le, ND Sohn, C Brooks-Wilson, A Tomlinson, I Kerin, MJ Miller, N Cybulski, C Henderson, BE Menkiszak, J Schumacher, F Wentzensen, N Le Marchand, L Yang, HP Mulligan, AM Glendon, G Engelholm, SA Knight, JA Hogdall, CK Apicella, C Gore, M Tsimiklis, H Song, HL Southey, MC Jager, A den Ouweland, AMW Brown, R Martens, JWM Flanagan, JM Kriege, M Paul, J Margolin, S Siddiqui, N Severi, G Whittemore, AS Baglietto, L McGuire, V Stegmaier, C Sieh, W Muller, H Arndt, V Labreche, F Gao, YT Goldberg, MS Yang, G Dumont, M McLaughlin, JR Hartmann, A Ekici, AB Beckmann, MW Phelan, CM Lux, MP Permuth-Wey, J Peissel, B Sellers, TA Ficarazzi, F Barile, M Ziogas, A Ashworth, A Gentry-Maharaj, A Jones, M Ramus, SJ Orr, N Menon, U Pearce, CL Bruning, T Pike, MC Ko, YD Lissowska, J Figueroa, J Kupryjanczyk, J Chanock, SJ Dansonka-Mieszkowska, A Jukkola-Vuorinen, A Rzepecka, IK Pylkas, K Bidzinski, M Kauppila, S Hollestelle, A Seynaeve, C Tollenaar, RAEM Durda, K Jaworska, K Hartikainen, JM Kosma, VM Kataja, V Antonenkova, NN Long, JR Shrubsole, M Deming-Halverson, S Lophatananon, A Siriwanarangsan, P Stewart-Brown, S Ditsch, N Lichtner, P Schmutzler, RK Ito, H Iwata, H Tajima, K Tseng, CC Stram, DO van den Berg, D Yip, CH Ikrarn, MK Teh, YC Cai, H Lu, W Signorello, LB Cai, QY Noh, DY Yoo, KY Miao, H Iau, PTC Teo, YY McKay, J Shapiro, C Ademuyiwa, F Fountzilas, G Hsiung, CN Yu, JC Hou, MF Healey, CS Luccarini, C Peock, S Stoppa-Lyonnet, D Peterlongo, P Rebbeck, TR Piedmonte, M Singer, CF Friedman, E Thomassen, M Offit, K Hansen, TVO Neuhausen, SL Szabo, CI Blanco, I Garber, J Narod, SA Weitzel, JN 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Cunningham, JM Slager, S Pankratz, VS Dicks, E Lakhani, SR Couch, FJ Hall, P Monteiro, ANA Gayther, SA Pharoah, PDP Reddel, RR Goode, EL Greene, MH Easton, DF Berchuck, A Antoniou, AC Chenevix-Trench, G Dunning, AM AF Bojesen, Stig E. Pooley, Karen A. Johnatty, Sharon E. Beesley, Jonathan Michailidou, Kyriaki Tyrer, Jonathan P. Edwards, Stacey L. Pickett, Hilda A. Shen, Howard C. Smart, Chanel E. Hillman, Kristine M. Mai, Phuong L. Lawrenson, Kate Stutz, Michael D. Lu, Yi Karevan, Rod Woods, Nicholas Johnstonw, Rebecca L. French, Juliet D. Chen, Xiaoqing Weischer, Maren Nielsen, Sune F. Maranian, Melanie J. Ghoussaini, Maya Ahmed, Shahana Baynes, Caroline Bolla, Manjeet K. Wang, Qin Dennis, Joe McGuffog, Lesley Barrowdale, Daniel Lee, Andrew Healey, Sue Lush, Michael Tessier, Daniel C. Vincent, Daniel Bacot, Francis Vergote, Ignace Lambrechts, Sandrina Despierre, Evelyn Risch, Harvey A. Gonzalez-Neira, Anna Rossing, Mary Anne Pita, Guillermo Doherty, Jennifer A. Alvarez, Nuria Larson, Melissa C. Fridley, Brooke L. Schoof, Nils Chang-Claude, Jenny Cicek, Mine S. Peto, Julian Kalli, Kimberly R. Broeks, Annegien Armasu, Sebastian M. Schmidt, Marjanka K. Braaf, Linde M. Winterhoff, Boris Nevanlinna, Heli Konecny, Gottfried E. Lambrechts, Diether Rogmann, Lisa Guenel, Pascal Teoman, Attila Milne, Roger L. Garcia, Joaquin J. Cox, Angela Shridhar, Vijayalakshmi Burwinkel, Barbara Marme, Frederik Hein, Rebecca Sawyer, Elinor J. Haiman, Christopher A. Wang-Gohrke, Shan Andrulis, Irene L. Moysich, Kirsten B. Hopper, John L. Odunsi, Kunle Lindblom, Annika Giles, Graham G. Brenner, Hermann Simard, Jacques Lurie, Galina Fasching, Peter A. Carney, Michael E. Radice, Paolo Wilkens, Lynne R. Swerdlow, Anthony Goodman, Marc T. Brauch, Hiltrud Garcia-Closas, Montserrat Hillemanns, Peter Winqvist, Robert Durst, Matthias Devilee, Peter Runnebaum, Ingo Jakubowska, Anna Lubinski, Jan Mannermaa, Arto Butzow, Ralf Bogdanova, Natalia V. Doerk, Thilo Pelttari, Liisa M. Zheng, Wei Leminen, Arto Anton-Culver, Hoda Bunker, Clareann H. Kristensen, Vessela Ness, Roberta B. Muir, Kenneth Edwards, Robert Meindl, Alfons Heitz, Florian Matsuo, Keitaro du Bois, Andreas Wu, Anna H. Harter, Philipp Teo, Soo-Hwang Schwaab, Ira Shu, Xiao-Ou Blot, William Hosono, Satoyo Kang, Daehee Nakanishi, Toru Hartman, Mikael Yatabe, Yasushi Hamann, Ute Karlan, Beth Y. Sangrajrang, Suleeporn Kjaer, Susanne Kruger Gaborieau, Valerie Jensen, Allan Eccles, Diana Hogdall, Estrid Shen, Chen-Yang Brown, Judith Woo, Yin Ling Shah, Mitul Azmi, Mat Adenan Noor Luben, Robert Omar, Siti Zawiah Czene, Kamila Vierkant, Robert A. Nordestgaard, Borge G. Flyger, Henrik Vachon, Celine Olson, Janet E. Wang, Xianshu Levine, Douglas A. Rudolph, Anja Weber, Rachel Palmieri Flesch-Janys, Dieter Iversen, Edwin Nickels, Stefan Schildkraut, Joellen M. Silva, Isabel Dos Santos Cramer, Daniel W. Gibson, Lorna Terry, Kathryn L. Fletcher, Olivia Vitonis, Allison F. van der Schoot, C. Ellen Poole, Elizabeth M. Hogervorst, Frans B. L. Tworoger, Shelley S. Liu, Jianjun Bandera, Elisa V. Li, Jingmei Olson, Sara H. 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Flanagan, James M. Kriege, Mieke Paul, James Margolin, Sara Siddiqui, Nadeem Severi, Gianluca Whittemore, Alice S. Baglietto, Laura McGuire, Valerie Stegmaier, Christa Sieh, Weiva Mueller, Heiko Arndt, Volker Labreche, France Gao, Yu-Tang Goldberg, Mark S. Yang, Gong Dumont, Martine McLaughlin, John R. Hartmann, Arndt Ekici, Arif B. Beckmann, Matthias W. Phelan, Catherine M. Lux, Michael P. Permuth-Wey, Jenny Peissel, Bernard Sellers, Thomas A. Ficarazzi, Filomena Barile, Monica Ziogas, Argyrios Ashworth, Alan Gentry-Maharaj, Aleksandra Jones, Michael Ramus, Susan J. Orr, Nick Menon, Usha Pearce, Celeste L. Bruening, Thomas Pike, Malcolm C. Ko, Yon-Dschun Lissowska, Jolanta Figueroa, Jonine Kupryjanczyk, Jolanta Chanock, Stephen J. Dansonka-Mieszkowska, Agnieszka Jukkola-Vuorinen, Arja Rzepecka, Iwona K. Pylkas, Katri Bidzinski, Mariusz Kauppila, Saila Hollestelle, Antoinette Seynaeve, Caroline Tollenaar, Rob A. E. M. Durda, Katarzyna Jaworska, Katarzyna Hartikainen, Jaana M. Kosma, Veli-Matti Kataja, Vesa Antonenkova, Natalia N. Long, Jirong Shrubsole, Martha Deming-Halverson, Sandra Lophatananon, Artitaya Siriwanarangsan, Pornthep Stewart-Brown, Sarah Ditsch, Nina Lichtner, Peter Schmutzler, Rita K. Ito, Hidemi Iwata, Hiroji Tajima, Kazuo Tseng, Chiu-Chen Stram, Daniel O. van den Berg, David Yip, Cheng Har Ikrarn, M. Kamran Teh, Yew-Ching Cai, Hui Lu, Wei Signorello, Lisa B. Cai, Qiuyin Noh, Dong-Young Yoo, Keun-Young Miao, Hui Iau, Philip Tsau-Choong Teo, Yik Ying McKay, James Shapiro, Charles Ademuyiwa, Foluso Fountzilas, George Hsiung, Chia-Ni Yu, Jyh-Cherng Hou, Ming-Feng Healey, Catherine S. Luccarini, Craig Peock, Susan Stoppa-Lyonnet, Dominique Peterlongo, Paolo Rebbeck, Timothy R. Piedmonte, Marion Singer, Christian F. Friedman, Eitan Thomassen, Mads Offit, Kenneth Hansen, Thomas V. O. Neuhausen, Susan L. Szabo, Csilla I. Blanco, Ignacio Garber, Judy Narod, Steven A. Weitzel, Jeffrey N. Montagna, Marco Olah, Edith Godwin, Andrew K. Yannoukakos, Drakoulis Goldgar, David E. Caldes, Trinidad Imyanitov, Evgeny N. Tihomirova, Laima Arun, Banu K. Campbell, Ian Mensenkamp, Arjen R. van Asperen, Christi J. van Roozendaa, Kees E. P. Meijers-Heijboer, Hanne Collee, J. Margriet Oosterwijk, Jan C. Hooning, Maartje J. Rookus, Matti A. van der Luijt, Rob B. Os, Theo A. Mvan Evans, D. Gareth Frost, Debra Fineberg, Elena Barwell, Julian Walker, Lisa Kennedy, M. John Platte, Radka Davidson, Rosemarie Ellis, Steve D. Cole, Trevor Bressac-de Paillerets, Brigitte Buecher, Bruno Damiola, Francesca Faivre, Laurence Frenay, Marc Sinilnikova, Olga M. Caron, Olivier Giraud, Sophie Mazoyer, Sylvie Bonadona, Valerie Caux-Moncoutier, Virginie Toloczko-Grabarek, Aleksandra Gronwald, Jacek Byrski, Tomasz Spurdle, Amanda B. Bonanni, Bernardo Zaffaroni, Daniela Giannini, Giuseppe Bernard, Loris Dolcetti, Riccardo Manoukian, Siranoush Arnold, Norbert Engel, Christoph Deissler, Helmut Rhiem, Kerstin Niederacher, Dieter Pendl, Hansjoerg Sutter, Christian Wappenschmidt, Barbara Borg, Ake Mein, Beatrice Rantala, Johanna Soller, Maria Nathanson, Katherine L. Domchek, Susan M. Rodriguez, Gustavo C. Salani, Ritu Kaulich, Daphne Gschwantler Tea, Muy-Kheng Paluch, Shani Shimon Laitman, Yael Skytte, Anne-Bine Kruse, Torben A. Jensen, Uffe Birk Robson, Mark Gerdes, Anne-Marie Ejlertsen, Bent Foretova, Lenka Savage, Sharon A. Lesterm, Jenny Soucy, Penny Kuchenbaecker, Karoline B. Olswold, Curtis Cunningham, Julie M. Slager, Susan Pankratz, Vernon S. Dicks, Ed Lakhani, Sunil R. Couch, Fergus J. Hall, Per Monteiro, Alvaro N. A. Gayther, Simon A. Pharoah, Paul D. P. Reddel, Roger R. Goode, Ellen L. Greene, Mark H. Easton, Douglas F. Berchuck, Andrew Antoniou, Antonis C. Chenevix-Trench, Georgia Dunning, Alison M. CA Australian Canc Study Australian Ovarian Canc Study Kathleen Cuningham Fdn Consortium Gene Environm Interactimi Breast Swedish Breast Canc Study SWE-BRCA Hereditary Breast Ovarian Canc Res Epidemiological Study BRCA1 Genetic Modifiers Canc Risk BRCA1 TI Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; REVERSE-TRANSCRIPTASE HTERT; SUSCEPTIBILITY LOCI; TERT-CLPTM1L LOCUS; GENETIC-VARIATION; COMMON VARIANTS; BUCCAL CELLS; FIBROBLASTS; CARCINOMA; METAANALYSIS AB TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant. 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[Cox, Angela; Balasubramanian, Sabapathy P.] Univ Sheffield, Dept Oncol, Canc Res UK Norkshire Canc Res Sheffield Canc Red, Sheffield, S Yorkshire, England. [Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany. [Burwinkel, Barbara] DKFZ, Mol Epidemiol Grp, Heidelberg, Germany. [Marme, Frederik; Schneeweiss, Andreas] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany. [Hein, Rebecca] Univ Cologne, Primarmed Versorgung PMV Res Grp, Dept Child & Adolescent Psychiat & Psychotherapy, D-50931 Cologne, Germany. [Sawyer, Elinor J.] Kings Coll London, Div Canc Studies, Natl Inst Hlth Res NIHR, Comprehens Biomed Res Ctr,Guys & St Thomas Natl H, London WC2R 2LS, England. [Wang-Gohrke, Shan; Deissler, Helmut] Univ Ulm, Dept Obstet & Gynaecol, Ulm, Germany. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Andrulis, Irene L.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ontario Canc Genet Network, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada. [Moysich, Kirsten B.; Odunsi, Kunle] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Hopper, John L.; Giles, Graham G.; Apicella, Carmel; Severi, Gianluca; Baglietto, Laura] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Brenner, Hermann; Mueller, Heiko; Arndt, Volker] DKFZ, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Simard, Jacques; Dumont, Martine; Soucy, Penny] CHU Quebec, Canc Genom Lab, Quebec City, PQ, Canada. [Simard, Jacques; Dumont, Martine; Soucy, Penny] Univ Laval, Quebec City, PQ, Canada. [Lurie, Galina; Carney, Michael E.; Wilkens, Lynne R.; Marchand, Loic Le] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Fasching, Peter A.; Beckmann, Matthias W.; Lux, Michael P.] Univ Breast Ctr Franconia Erlangen Univ Hosp, Dept Gynecol & Obstet, Erlangen, Germany. [Radice, Paolo; Peterlongo, Paolo] Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Fdn Ist Ricovero & Cura Carattere Sci IRCCS, I-20133 Milan, Italy. [Radice, Paolo; Ficarazzi, Filomena; Peterlongo, Paolo] Ist Fdn Italiana Ric Cancro Oncol Mol, Milan, Italy. [Swerdlow, Anthony; Jones, Michael] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Swerdlow, Anthony] Inst Canc Res, Div Breast Canc Res, Sutton, Surrey, England. [Goodman, Marc T.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Brauch, Hiltrud] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud] Univ Tubingen, Fac Med, Tubingen, Germany. [Garcia-Closas, Montserrat; Fletcher, Olivia; Ashworth, Alan; Orr, Nick] Inst Canc Res, Div Breast Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Hillemanns, Peter] Hannover Med Sch, Clin Obstet, Hannover, Germany. [Hillemanns, Peter] Hannover Med Sch, Clin Gynaecol, Hannover, Germany. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Lab Canc Genet & Tumor Biol, Dept Clin Genet, Oulu Univ Hosp, Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Durst, Matthias; Runnebaum, Ingo] Jena Univ Hosp, Dept Gynecol, Jena, Germany. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands. [Jakubowska, Anna; Lubinski, Jan; Durda, Katarzyna; Jaworska, Katarzyna; Toloczko-Grabarek, Aleksandra; Gronwald, Jacek; Byrski, Tomasz] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Mannermaa, Arto; Hartikainen, Jaana M.; Kosma, Veli-Matti] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Mannermaa, Arto; Hartikainen, Jaana M.; Kosma, Veli-Matti; Kataja, Vesa] Univ Eastern Finland, Canc Ctr Eastern Finland, Bioctr Kuopio, Sch Med,Inst Clin Med Pathol & Forens Med, Kuopio, Finland. [Butzow, Ralf] Univ Helsinki, Dept Pathol, Cent Hosp, Helsinki, Finland. [Bogdanova, Natalia V.; Doerk, Thilo] Hannover Med Sch, Dept Obstet & Gynaecol, Hannover, Germany. [Bogdanova, Natalia V.; Cai, Qiuyin] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany. [Zheng, Wei; Shu, Xiao-Ou; Blot, William; Yang, Gong; Long, Jirong; Shrubsole, Martha; Deming-Halverson, Sandra; Cai, Hui; Signorello, Lisa B.] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr,Vanderbilt Ingr, Nashville, TN 37212 USA. [Anton-Culver, Hoda] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Bunker, Clareann H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Kristensen, Vessela] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Kristensen, Vessela] Univ Oslo, Fac Med, Fac Div Ahus, Oslo, Norway. [Ness, Roberta B.] Univ Texas Sch Publ Hlth, Houston, TX USA. [Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Muir, Kenneth; Lophatananon, Artitaya] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Edwards, Robert] Magee Womens Hosp, Pittsburgh, PA USA. [Meindl, Alfons] Tech Univ Munich, Klinikum Rechts Isar, Div Tumor Genet, Dept Gynecol & Obstet, D-80290 Munich, Germany. [Heitz, Florian; du Bois, Andreas; Harter, Philipp] Dr Horst Schmidt Klin Wiesbaden, Dept Gynecol & Gynecol Oncol, Wiesbaden, Germany. [Heitz, Florian; du Bois, Andreas; Harter, Philipp] Kliniken Essen Mitte, Dept Gynecol & Gynecol Oncol, Essen, Germany. [Matsuo, Keitaro; Hosono, Satoyo; Ito, Hidemi; Tajima, Kazuo] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Nagoya, Aichi, Japan. [Teo, Soo-Hwang] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya, Malaysia. [Teo, Soo-Hwang; Yip, Cheng Har; Teh, Yew-Ching] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia. [Schwaab, Ira] Inst Humangenet Wiesbaden, Wiesbaden, Germany. [Blot, William; Signorello, Lisa B.] Int Epidemiol Inst, Rockville, MD USA. [Kang, Daehee; Noh, Dong-Young; Yoo, Keun-Young] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Nakanishi, Toru] Aichi Canc Ctr Cent Hosp, Dept Gynecol Oncol, Nagoya, Aichi, Japan. [Hartman, Mikael; Iau, Philip Tsau-Choong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Surg, Singapore 117595, Singapore. [Hartman, Mikael; Miao, Hui; Teo, Yik Ying] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Yatabe, Yasushi] Aichi Canc Ctr Cent Hosp, Dept Pathol & Mol Diagnost, Nagoya, Aichi, Japan. [Hamann, Ute] DKFZ, Heidelberg, Germany. [Karlan, Beth Y.; Lesterm, Jenny] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA. [Sangrajrang, Suleeporn] Natl Canc Inst, Div Res, Bangkok, Thailand. [Kjaer, Susanne Kruger; Jensen, Allan; Hogdall, Estrid] Danish Canc Soc Res Ctr, Copenhagen, Denmark. [Kjaer, Susanne Kruger; Hogdall, Claus K.] Rigshosp, Dept Obstet & Gynecol, Juliane Marie Ctr, DK-2100 Copenhagen, Denmark. [Gaborieau, Valerie; McKay, James] Int Agcy Res Canc, F-69372 Lyon, France. [Eccles, Diana] Univ Southampton, Fac Med, Southampton Univ Hosp, Southampton SO9 5NH, Hants, England. [Hogdall, Estrid] Univ Copenhagen, Herlev Hosp, Dept Pathol, Mol Unit, Copenhagen, Denmark. [Shen, Chen-Yang] China Med Univ, Coll Publ Hlth, Taichong, Taiwan. [Shen, Chen-Yang; Hsiung, Chia-Ni] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Woo, Yin Ling; Azmi, Mat Adenan Noor; Omar, Siti Zawiah] Univ Malaya, Fac Med, Med Ctr, Dept Obstet & Gynaecol, Kuala Lumpur, Malaysia. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Copenhagen, Denmark. [Vachon, Celine; Olson, Janet E.; Olswold, Curtis; Slager, Susan; Pankratz, Vernon S.; Couch, Fergus J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Levine, Douglas A.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Weber, Rachel Palmieri; Schildkraut, Joellen M.] Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Iversen, Edwin] Duke Univ, Dept Stat Sci, Durham, NC USA. [Iversen, Edwin; Schildkraut, Joellen M.] Duke Canc Inst, Canc Prevent Detect & Control Res Program, Durham, NC USA. [Cramer, Daniel W.; Terry, Kathryn L.; Vitonis, Allison F.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Boston, MA 02115 USA. [Cramer, Daniel W.; Terry, Kathryn L.; Vitonis, Allison F.] Harvard Univ, Sch Med, Boston, MA USA. [Cramer, Daniel W.; Terry, Kathryn L.; Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [van der Schoot, C. Ellen] Sanquin Res, Amsterdam, Netherlands. [Poole, Elizabeth M.; Tworoger, Shelley S.] Harvard Univ, Sch Med, Channing Div Network Med, Boston, MA USA. [Poole, Elizabeth M.; Tworoger, Shelley S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Hogervorst, Frans B. L.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Liu, Jianjun; Li, Jingmei] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Bandera, Elisa V.; Rodriguez-Rodriguez, Lorna] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. [Olson, Sara H.; Row, Irene; Pike, Malcolm C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Blomqvist, Carl] Univ Helsinki, Dept Oncol, Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Salvesen, Helga B.; Wik, Elisabeth; Krakstad, Camilla; Halle, Mari K.] Haukeland Hosp, Dept Gynecol & Obstet, N-5021 Bergen, Norway. [Salvesen, Helga B.; Wik, Elisabeth; Krakstad, Camilla; Halle, Mari K.] Univ Bergen, Dept Clin Med, Bergen, Norway. [Brouwers, Barbara] Katholieke Univ Leuven, Dept Oncol, Expt Oncol Lab, Louvain, Belgium. [Brouwers, Barbara; Wildiers, Hans] Katholieke Univ Leuven Hosp, Dept Gen Med Oncol, Louvain, Belgium. [Kiemeney, Lambertus A.; Aben, Katja K.] Comprehens Canc Ctr Netherlands, Utrecht, Netherlands. [Kiemeney, Lambertus A.; Aben, Katja K.] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & Hlth Technol Assessment, NL-6525 ED Nijmegen, Netherlands. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands. [Mulot, Claire; Laurent-Puig, Pierre] Univ Paris Sorbonne Cite, UMR S775, INSERM, Paris, France. [Altena, Anne Mvan; Massuger, Leon F. A. G.] Radboud Univ Nijmegen, Med Ctr, Dept Gynecol, NL-6525 ED Nijmegen, Netherlands. [Benitez, Javier] CNIO, Human Genet Grp, Madrid, Spain. [Benitez, Javier] Biomed Network Rare Dis CIBERER, Madrid, Spain. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Pejovic, Tanja] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Arias Perez, Jose Ignacio] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain. [Hoatlin, Maureen] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97201 USA. [Zamora, M. Pilar] Hosp Univ La Paz, Serv Oncol Med, Madrid, Spain. [Cook, Linda S.] Univ New Mexico, Div Epidemiol & Biostat, Albuquerque, NM 87131 USA. [Kelemen, Linda E.] Alberta Hlth Serv Canc Care, Dept Populat Hlth Res, Calgary, AB, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Med Genet, Calgary, AB, Canada. [Kelemen, Linda E.] Univ Calgary, Dept Oncol, Calgary, AB, Canada. [Le, Nhu D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Brooks-Wilson, Angela] British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada. [Brooks-Wilson, Angela] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada. [Tomlinson, Ian] Univ Oxford, Welcome Trust Ctr Human Genet, Oxford, England. [Tomlinson, Ian] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England. [Kerin, Michael J.; Miller, Nicola] Natl Univ Ireland Univ Coll Galway, Sch Med, Galway, Ireland. [Cybulski, Cezary] Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland. [Menkiszak, Janusz] Pomeranian Med Univ, Dept Surg Gynecol & Gynecol Oncol Adults & Adolsc, Szczecin, Poland. [Wentzensen, Nicolas; Yang, Hannah P.; Figueroa, Jonine; Chanock, Stephen J.] NCI, Div Canc Epidemiol, Bethesda, MD 20892 USA. [Mulligan, Anna Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Mulligan, Anna Marie] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada. [Glendon, Gord; McLaughlin, John R.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Engelholm, Svend Aage] Univ Copenhagen, Rigshosp, Dept Radiat Oncol, DK-2100 Copenhagen, Denmark. [Knight, Julia A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada. [Knight, Julia A.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada. [Gore, Martin] Royal Marsden Hosp, Gynecol Oncol Unit, London SW3 6JJ, England. [Tsimiklis, Helen; Southey, Melissa C.] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia. [Jager, Agnes; Martens, John W. M.; Kriege, Mieke; Hollestelle, Antoinette; Seynaeve, Caroline; Hooning, Maartje J.] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [den Ouweland, Ans M. Wvan; Collee, J. Margriet] Erasmus Univ, Med Ctr, Dept Clin Genet, Family Canc Clin, Rotterdam, Netherlands. [Brown, Robert; Flanagan, James M.] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, London, England. [Paul, James] Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland. [Margolin, Sara] Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden. [Siddiqui, Nadeem] Glasgow Royal Infirm, Dept Gynecol Oncol, Glasgow G4 0SF, Lanark, Scotland. [Whittemore, Alice S.; McGuire, Valerie; Sieh, Weiva] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Stegmaier, Christa] Saarland Canc Registry, Saarbrucken, Germany. [Labreche, France] Univ Montreal, Fac Med, Dept Environm & Occupat Hlth, Montreal, PQ H3C 3J7, Canada. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Goldberg, Mark S.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Goldberg, Mark S.] McGill Univ, Royal Victoria Hosp, Ctr Hlth, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada. [McLaughlin, John R.] Univ Toronto, Fac Med, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Hartmann, Arndt] Univ Erlangen Nurnberg, Inst Pathol, Univ Hosp Erlangen, Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Peissel, Bernard; Zaffaroni, Daniela; Manoukian, Siranoush] Fdn IRCCS INT, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Ficarazzi, Filomena; Bernard, Loris] Cogentech Canc Genet Test Lab, Milan, Italy. [Barile, Monica; Bonanni, Bernardo] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Ziogas, Argyrios] Univ Calif Irvine, Sch Med, Dept Epidemiol, Ctr Canc Genet Res & Prevent, Irvine, CA 92717 USA. [Gentry-Maharaj, Aleksandra; Menon, Usha] UCL, Gynaecol Canc Res Ctr, Elizabeth Garrett Anderson Inst Womens Hlth, London, England. [Bruening, Thomas] Ruhr Univ Bochum, Inst Prevent & Occupat Med, German Social Accid Insurance, Bochum, Germany. [Ko, Yon-Dschun] Johanniter Krankenhaus, Evangel Kliniken Bonn, Dept Internal Med, Bonn, Germany. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K.] Maria Sklodowska Curie Mem Canc Ctr, Dept Mol Pathol, Warsaw, Poland. [Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K.; Bidzinski, Mariusz] Inst Oncol, Warsaw, Poland. [Jukkola-Vuorinen, Arja] Univ Oulu, Oulu Univ Hosp, Dept Oncol, Oulu, Finland. [Bidzinski, Mariusz] Maria Sklodowska Curie Mem Canc Ctr, Dept Gynecol Oncol, Warsaw, Poland. [Kauppila, Saila] Univ Oulu, Dept Pathol, Oulu Univ Hosp, Oulu, Finland. [Tollenaar, Rob A. E. M.] Leiden Univ, Med Ctr, Dept Surg Oncol, Leiden, Netherlands. [Jaworska, Katarzyna] Warsaw Med Univ, Postgrad Sch Mol Med, Warsaw, Poland. [Antonenkova, Natalia N.] NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, Byelarus. [Siriwanarangsan, Pornthep] Minist Publ Hlth, Bangkok, Thailand. [Ditsch, Nina] Univ Munich, Dept Gynecol & Obstet, Munich, Germany. [Lichtner, Peter] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Schmutzler, Rita K.; Rhiem, Kerstin; Wappenschmidt, Barbara] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Dept Gynaecol & Obstet, Cologne, Germany. [Schmutzler, Rita K.; Rhiem, Kerstin; Wappenschmidt, Barbara] Univ Hosp Cologne, Ctr Mol Med Cologne CMMC, Cologne, Germany. [Iwata, Hiroji] Aichi Canc Ctr Hosp, Dept Breast Oncol, Nagoya, Aichi, Japan. [Ikrarn, M. Kamran] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Lu, Wei] Shanghai Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Shapiro, Charles] Ohio State Univ, Div Oncol, Wexner Med Ctr, Columbus, OH 43210 USA. [Ademuyiwa, Foluso] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Fountzilas, George] Aristotle Univ Thessaloniki, Sch Med, Dept Med Oncol, Papageorgiou Hosp, GR-54006 Thessaloniki, Greece. [Yu, Jyh-Cherng] Triserv Gen Hosp, Dept Surg, Taipei, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Ctr Canc, Kaohsiung, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Dept Surg, Kaohsiung, Taiwan. [Stoppa-Lyonnet, Dominique; Buecher, Bruno; Caux-Moncoutier, Virginie] Inst Curie, Dept Tumor Biol, Paris, France. [Stoppa-Lyonnet, Dominique] INSERM, Inst Curie, U830, Paris, France. [Stoppa-Lyonnet, Dominique] Univ Paris 05, Paris, France. [Rebbeck, Timothy R.; Nathanson, Katherine L.; Domchek, Susan M.] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Basser Res Ctr, Philadelphia, PA USA. [Rebbeck, Timothy R.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Piedmonte, Marion] Roswell Pk Canc Inst, Gynecol Oncol Grp Stat, Buffalo, NY 14263 USA. [Piedmonte, Marion] Roswell Pk Canc Inst, Ctr Data, Buffalo, NY 14263 USA. [Singer, Christian F.; Kaulich, Daphne Gschwantler; Tea, Muy-Kheng] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, Vienna, Austria. [Friedman, Eitan; Paluch, Shani Shimon; Laitman, Yael] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel. [Friedman, Eitan; Paluch, Shani Shimon; Laitman, Yael] Chaim Sheba Med Ctr, Inst Oncol, IL-52621 Tel Hashomer, Israel. [Thomassen, Mads; Kruse, Torben A.] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Offit, Kenneth; Robson, Mark] Mem Sloan Kettering Canc Ctr, Clin Genet Serv, New York, NY 10021 USA. [Hansen, Thomas V. O.] Rigshosp, Copenhagen Univ Hosp, Ctr Genom Med, DK-2100 Copenhagen, Denmark. [Neuhausen, Susan L.] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA USA. [Szabo, Csilla I.] Univ Delaware, Dept Biol Sci, Ctr Translat Canc Res, Newark, DE USA. [Blanco, Ignacio] Inst Invest Biomed Bellvitge Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Barcelona, Spain. [Garber, Judy] Dana Farber Canc Inst, Ctr Canc Genet & Prevent, Boston, MA 02115 USA. [Narod, Steven A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Clin Canc Genet, Duarte, CA USA. [Montagna, Marco] IRCCS, Ist Oncol Veneto IOV, Immunol & Mol Oncol Unit, Padua, Italy. [Olah, Edith] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Yannoukakos, Drakoulis] Aghia Paraskevi Attikis, Mol Diagnost Lab, Inst Radioisotopes & Radiodiagnost Prod, Natl Ctr Sci Res Demokritos, Athens, Greece. [Goldgar, David E.] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA. [Goldgar, David E.] Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT USA. [Caldes, Trinidad] Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [Imyanitov, Evgeny N.] NN Petrov Inst Oncol, St Petersburg, Russia. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA. [Arun, Banu K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Campbell, Ian] Peter MacCallum Canc Ctr, Victorian Breast Canc Res Consortium Canc Genet L, Melbourne, Vic, Australia. [Mensenkamp, Arjen R.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [van Asperen, Christi J.] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands. [van Roozendaa, Kees E. P.] Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [Meijers-Heijboer, Hanne] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Oosterwijk, Jan C.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [van der Luijt, Rob B.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Os, Theo A. Mvan] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [Evans, D. Gareth] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Barwell, Julian] Univ Hosp Leicester NHS Trust, Leicestershire Clin Genet Serv, Leicester, Leics, England. [Walker, Lisa] Churchill Hosp, Oxford Reg Genet Serv, Oxford OX3 7LJ, England. [Kennedy, M. John] Trinity Coll Dublin, Acad Unit Clin & Mol Oncol, Dublin, Ireland. [Kennedy, M. John] St James Hosp, Dublin 8, Ireland. [Davidson, Rosemarie] So Gen Hosp, Lab Med, Glasgow G51 4TF, Lanark, Scotland. [Cole, Trevor] Birmingham Womens Hosp Healthcare NHS Trust, West Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Bressac-de Paillerets, Brigitte] Fdn Jean Dausset, INSERM, U946, Paris, France. [Bressac-de Paillerets, Brigitte] Inst Cancerol Gustave Roussy, Serv Genet, Villejuif, France. [Damiola, Francesca; Sinilnikova, Olga M.; Mazoyer, Sylvie] Univ Lyon 1, INSERM, U1052, CNRS,UMR 5286,Ctr Rech Cancerol Lyon, F-69365 Lyon, France. [Faivre, Laurence] Univ Bourgogne, CHU Dijon, Ctr Genet, Dijon, France. [Faivre, Laurence] Ctr Georges Francois Leclerc, Dijon, France. [Frenay, Marc] Ctr Antoine Lacassagne, Nice, France. [Sinilnikova, Olga M.; Giraud, Sophie] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France. [Caron, Olivier] Inst Cancerol Gustave Roussy, Dept Med, Villejuif, France. [Bonadona, Valerie] Ctr Leon Berard, Unite Prevent & Epiderniol Genet, F-69373 Lyon, France. [Bonadona, Valerie] Univ Lyon 1, CNRS, UMR 5558, F-69365 Lyon, France. [Giannini, Giuseppe] Univ Roma La Sapienza, Dept Mol Med, Rome, Italy. Ist Europeo Oncol, Dept Expt Oncol, Milan, Italy. [Dolcetti, Riccardo] IRCCS, Ctr Riferimento Oncol, Canc Bioimmunotherapy Unit, Aviano, Italy. [Arnold, Norbert] Univ Hosp Schleswig Holstein, Dept Gynecol & Obstet, Kiel, Germany. [Arnold, Norbert] Univ Kiel, Kiel, Germany. [Engel, Christoph] Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany. [Niederacher, Dieter] Univ Dusseldorf, Univ Med Ctr, Dept Obstet & Gynecol, D-40225 Dusseldorf, Germany. [Pendl, Hansjoerg] Univ Kiel, Univ Hosp Schleswig Holstein, Inst Human Genet, Kiel, Germany. [Sutter, Christian] Heidelberg Univ, Inst Human Genet, Heidelberg, Germany. [Borg, Ake] Lund Univ, Dept Oncol, Lund, Sweden. [Mein, Beatrice] Umea Univ, Dept Radiat Sci, Umea, Sweden. [Rantala, Johanna] Karolinska Hosp, Dept Clin Genet, S-10401 Stockholm, Sweden. [Soller, Maria] Univ Lund Hosp, Univ & Reg Labs, Dept Clin Genet, S-22185 Lund, Sweden. [Nathanson, Katherine L.; Domchek, Susan M.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Rodriguez, Gustavo C.] Univ Chicago, North Shore Univ Hlth Syst, Div Gynecol Oncol, Evanston, IL USA. [Salani, Ritu] Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Skytte, Anne-Bine] Vejle Hosp, Dept Clin Genet, Vejle, Denmark. [Jensen, Uffe Birk] Aarhus Univ Hosp, Dept Clin Genet, DK-8000 Aarhus, Denmark. [Gerdes, Anne-Marie] Rigshosp, Copenhagen Univ Hosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark. [Ejlertsen, Bent] Rigshosp, Copenhagen Univ Hosp, Dept Oncol, DK-2100 Copenhagen, Denmark. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Lakhani, Sunil R.] Royal Brisbane & Womens Hosp, Pathol Queensland, Herston, Qld, Australia. [Berchuck, Andrew] Duke Univ, Med Ctr, Duke Canc Inst, Durham, NC USA. RP Bojesen, SE (reprint author), Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark. EM stig.egil.bojesen@regionh.dk; Georgia.Trench@qimr.edu.au; amd24@medschl.cam.ac.uk RI Spurdle, Amanda/A-4978-2011; Peissel, Bernard/E-8187-2017; Mensenkamp, A.R./L-4520-2015; laurent-puig, pierre/B-2226-2013; Savage, Sharon/B-9747-2015; Aben, Katja/G-9686-2016; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Edwards, Stacey/A-4980-2011; Menkiszak, Janusz/I-4036-2014; Johnatty, Sharon/R-8890-2016; Gronwald, Jacek/A-4576-2017; Brenner, Hermann/B-4627-2017; salvesen, Helga/C-1187-2017; manoukian, siranoush/E-7132-2017; Bandera, Elisa/M-4169-2014; Massuger, Leon/H-8072-2014; Jakubowska, Anna/O-8050-2014; Yip, Cheng-Har/B-1909-2010; campbell, Ian/F-6006-2011; Gonzalez-Neira, Anna/C-5791-2015; Fridley, Brooke/D-8315-2015; Garcia-Closas, Montserrat /F-3871-2015; montagna, marco/E-2225-2012; Woo, Yin Ling/B-5198-2010; Shrubsole, Martha/K-5052-2015; Hartikainen, Jaana/E-6256-2015; Dolcetti, Riccardo/O-3832-2015; Blanco, Ignacio/D-2565-2013; Salani, Ritu/E-4008-2011; Dork, Thilo/J-8620-2012; Ditsch, Nina/F-6267-2014; Whittemore, Alice/F-9925-2014; Oosterwijk, Jan C./G-5770-2011; Brooks-Wilson, Angela/E-9399-2012; Teo, Soo-hwang/H-2353-2014; Hartman, Mikael/B-4324-2011; Noh, Dong-Young/G-5531-2011; Bernard, Loris/K-5953-2014; Arnold, Norbert/E-3012-2010; BYRSKI, Tomasz/I-2844-2014; Giannini, Giuseppe/B-5672-2013; Verdrengh, Evelien/H-4571-2012; Kerin, Michael/D-6748-2013; Radice, Paolo/O-3119-2013; Reddel, Roger/A-6635-2014; Knight, Julia/A-6843-2012; Kiemeney, Lambertus/D-3357-2009; Andrulis, Irene/E-7267-2013; Smart, Chanel/C-9583-2011; Ekici, Arif/C-3971-2013; French, Juliet/A-4982-2011; Li, Jingmei/I-2904-2012; McLaughlin, John/E-4577-2013; Tang, Macy/B-9798-2014; OI Lissowska, Jolanta/0000-0003-2695-5799; Arias Perez, Jose Ignacio/0000-0003-4500-397X; Dennis, Joe/0000-0003-4591-1214; Luben, Robert/0000-0002-5088-6343; Nevanlinna, Heli/0000-0002-0916-2976; Cox, Angela/0000-0002-5138-1099; Halle, Mari/0000-0002-2660-8271; Yannoukakos, Drakoulis/0000-0001-7509-3510; Orlow, Irene/0000-0001-6234-6961; Dunning, Alison Margaret/0000-0001-6651-7166; Tworoger, Shelley/0000-0002-6986-7046; Devilee, Peter/0000-0002-8023-2009; Kjaer, Susanne/0000-0002-8347-1398; Monteiro, Alvaro/0000-0002-8448-4801; Ramus, Susan/0000-0003-0005-7798; Spurdle, Amanda/0000-0003-1337-7897; Barrowdale, Daniel/0000-0003-1661-3939; Peissel, Bernard/0000-0001-9233-3571; Hollestelle, Antoinette/0000-0003-1166-1966; Nathanson, Katherine/0000-0002-6740-0901; Rudolph, Anja/0000-0001-7520-2035; Lux, Michael Patrick/0000-0002-2781-2178; Robson, Mark/0000-0002-3109-1692; Czene, Kamila/0000-0002-3233-5695; laurent-puig, pierre/0000-0001-8475-5459; Savage, Sharon/0000-0001-6006-0740; Aben, Katja/0000-0002-0214-2147; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Johnatty, Sharon/0000-0002-7888-1966; Gronwald, Jacek/0000-0002-3643-2871; Brenner, Hermann/0000-0002-6129-1572; salvesen, Helga/0000-0002-4438-8831; manoukian, siranoush/0000-0002-6034-7562; Bandera, Elisa/0000-0002-8789-2755; Fridley, Brooke/0000-0001-7739-7956; Garcia-Closas, Montserrat /0000-0003-1033-2650; montagna, marco/0000-0002-4929-2150; Woo, Yin Ling/0000-0003-1742-1066; Shrubsole, Martha/0000-0002-5591-7575; Dolcetti, Riccardo/0000-0003-1625-9853; Blanco, Ignacio/0000-0002-7414-7481; Brooks-Wilson, Angela/0000-0003-1009-6408; Arnold, Norbert/0000-0003-4523-8808; Giannini, Giuseppe/0000-0003-0299-4056; Reddel, Roger/0000-0002-6302-6107; Kiemeney, Lambertus/0000-0002-2368-1326; Li, Jingmei/0000-0001-8587-7511; Krakstad, Camilla/0000-0002-0174-8139; ADEMUYIWA, FOLUSO/0000-0002-6766-2258; Ikram, Mohammad Kamran/0000-0003-0173-9571; Giles, Graham/0000-0003-4946-9099; Muranen, Taru/0000-0002-5895-1808; Skytte, Anne-Bine/0000-0002-0067-9557; Matsuo, Keitaro/0000-0003-1761-6314; Arndt, Volker/0000-0001-9320-8684; Evans, Gareth/0000-0002-8482-5784 FU European Commission's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; Cancer Research UK [C1287/A10118, C1287/Al2014]; European Union Cooperation in Science and Technology (COST) [BM0606]; Cancer Research UK; Canadian Institutes of Health Research (CIHR); Ministry of Economic Development, Innovation and Export Trade of Quebec [PSR-SIIRI-701]; Genetic Associations and Mechanisms in Oncology [U19-CA148112]; US National Institutes of Health [CAl28978]; National Cancer Institute (NCI) [CA116201]; US Department of Defense Ovarian Cancer Idea [W81XWH-10-1-0341]; Breast Cancer Research Foundation; Komen Foundation for the Cure; Wellcome Trust Case Control Consortium; Wellcome Trust [076113] FX We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. COGS is funded through a grant from the European Commission's Seventh Framework Programme (agreement 223175 HEALTH-F2-2009-223175). BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/Al2014). BCAC meetings have been funded by the European Union Cooperation in Science and Technology (COST) programme (BM0606). Telomere length measurement and analysis were funded by Cancer Research UK project grant C1287/A9540 and Chief Physician Johan Boserup and Lise Boserup's Fund. CIMBA data management and analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. OCAC is supported by a grant from the Ovarian Cancer Research Fund thanks to the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program (J.S. and D.E.) and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701; J.S., D.E. and P. Hall). Scientific development and funding of the OCAC portion of this project were supported by Genetic Associations and Mechanisms in Oncology (GAME-ON; U19-CA148112). CIMBA genotyping was supported by US National Institutes of Health (NIH) grant CAl28978, a National Cancer Institute (NCI) Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a US Department of Defense Ovarian Cancer Idea award (W81XWH-10-1-0341) and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. This study made use of data generated by The Wellcome Trust Case Control Consortium (funding was provided by Wellcome Trust award 076113) and the TCGA Pilot Project established by NCI and the National Human Genome Research Institute. NR 70 TC 211 Z9 216 U1 15 U2 171 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2013 VL 45 IS 4 BP 371 EP 384 DI 10.1038/ng.2566 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600007 PM 23535731 ER PT J AU Eeles, RA Al Olama, AA Benlloch, S Saunders, EJ Leongamornlert, DA Tymrakiewicz, M Ghoussaini, M Luccarini, C Dennis, J Jugurnauth-Little, S Dadaev, T Neal, DE Hamdy, FC Donovan, JL Muir, K Giles, GG Severi, G Wiklund, F Gronberg, H Haiman, CA Schumacher, F Henderson, BE Le Marchand, L Lindstrom, S Kraft, P Hunter, DJ Gapstur, S Chanock, SJ Berndt, SI Albanes, D Andriole, G Schleutker, J Weischer, M Canzian, F Riboli, E Key, TJ Travis, RC Campa, D Ingles, SA John, EM Hayes, RB Pharoah, PDP Pashayan, N Khaw, KT Stanford, JL Ostrander, EA Signorello, LB Thibodeau, SN Schaid, D Maier, C Vogel, W Kibel, AS Cybulski, C Lubhiski, J Cannon-Albright, L Brenner, H Park, JY Kaneva, R Batra, J Spurdle, AB Clements, JA Teixeira, MR Dicks, E Lee, A Dunning, AM Baynes, C Conroy, D Maranian, MJ Ahmed, S Govindasami, K Guy, M Wilkinson, RA Sawyer, EJ Morgan, A Dearnaley, DP Horwich, A Huddart, RA Khoo, VS Parker, CC Van As, NJ Woodhouse, CJ Thompson, A Dudderidge, T Ogden, C Cooper, CS Lophatananon, A Cox, A Southey, MC Hopper, JL English, DR Aly, M Adolfsson, J Xu, JF Zheng, SL Yeager, M Kaaks, R Diver, WR Gaudet, MM Stern, MC Corral, R Joshi, AD Shahabi, A Wahlfors, T Tammela, TLJ Auvinen, A Virtamo, J Klarskov, P Nordestgaard, BG Roder, MA Nielsen, SF Bojesen, SE Siddiq, A FitzGerald, LM Kolb, S Kwon, EM Karyadi, DM Blot, WJ Zheng, W Cai, QY McDonnell, SK Rinckleb, AE Drake, B Colditz, G Wokolorczyk, D Stephenson, RA Teerlink, C Muller, H Rothenbacher, D Sellers, TA Lin, HY Slavov, C Mitev, V Lose, F Srinivasan, S Maia, S Paulo, P Lange, E Cooney, KA Antoniou, AC Vincent, D Bacot, F Tessier, DC Kote-Jarai, Z Easton, DF AF Eeles, Rosalind A. Al Olama, Ali Amin Benlloch, Sara Saunders, Edward J. Leongamornlert, Daniel A. Tymrakiewicz, Malgorzata Ghoussaini, Maya Luccarini, Craig Dennis, Joe Jugurnauth-Little, Sarah Dadaev, Tokhir Neal, David E. Hamdy, Freddie C. Donovan, Jenny L. Muir, Ken Giles, Graham G. Severi, Gianluca Wiklund, Fredrik Gronberg, Henrik Haiman, Christopher A. Schumacher, Fredrick Henderson, Brian E. Le Marchand, Loic Lindstrom, Sara Kraft, Peter Hunter, David J. Gapstur, Susan Chanock, Stephen J. Berndt, Sonja I. Albanes, Demetrius Andriole, Gerald Schleutker, Johanna Weischer, Maren Canzian, Federico Riboli, Elio Key, Tim J. Travis, Ruth C. Campa, Daniele Ingles, Sue A. John, Esther M. Hayes, Richard B. Pharoah, Paul D. P. Pashayan, Nora Khaw, Kay-Tee Stanford, Janet L. Ostrander, Elaine A. Signorello, Lisa B. Thibodeau, Stephen N. Schaid, Dan Maier, Christiane Vogel, Walther Kibel, Adam S. Cybulski, Cezary Lubhiski, Jan Cannon-Albright, Lisa Brenner, Hermann Park, Jong Y. Kaneva, Radka Batra, Jyotsna Spurdle, Amanda B. Clements, Judith A. Teixeira, Manuel R. Dicks, Ed Lee, Andrew Dunning, Alison M. Baynes, Caroline Conroy, Don Maranian, Melanie J. Ahmed, Shahana Govindasami, Koveela Guy, Michelle Wilkinson, Rosemary A. Sawyer, Emma J. Morgan, Angela Dearnaley, David P. Horwich, Alan Huddart, Robert A. Khoo, Vincent S. Parker, Christopher C. Van As, Nicholas J. Woodhouse, Christopher J. Thompson, Alan Dudderidge, Tim Ogden, Chris Cooper, Colin S. Lophatananon, Artitaya Cox, Angela Southey, Melissa C. Hopper, John L. English, Dallas R. Aly, Markus Adolfsson, Jan Xu, Jiangfeng Zheng, Siqun L. Yeager, Meredith Kaaks, Rudolf Diver, W. Ryan Gaudet, Mia M. Stern, Mariana C. Corral, Roman Joshi, Amit D. Shahabi, Ahva Wahlfors, Tiina Tammela, Teuvo L. J. Auvinen, Anssi Virtamo, Jarmo Klarskov, Peter Nordestgaard, Borge G. Roder, M. Andreas Nielsen, Sune F. Bojesen, Stig E. Siddiq, Afshan FitzGerald, Liesel M. Kolb, Suzanne Kwon, Erika M. Karyadi, Danielle M. Blot, William J. Zheng, Wei Cai, Qiuyin McDonnell, Shannon K. Rinckleb, Antje E. Drake, Bettina Colditz, Graham Wokolorczyk, Dominika Stephenson, Robert A. Teerlink, Craig Muller, Heiko Rothenbacher, Dietrich Sellers, Thomas A. Lin, Hui-Yi Slavov, Chavdar Mitev, Vanio Lose, Felicity Srinivasan, Srilakshmi Maia, Sofia Paulo, Paula Lange, Ethan Cooney, Kathleen A. Antoniou, Antonis C. Vincent, Daniel Bacot, Francois Tessier, Daniel C. Kote-Jarai, Zsofia Easton, Douglas F. CA COGS-Canc Res UK GWAS-ELLIPSE Part Australian Prostate Canc UK Genetic Prostate Canc Study UK ProtecT Prostate Testing Canc PRACTICAL Prostate Canc Assoc Grp TI Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; VARIANTS; RISK; HOXB13; PREDISPOSITION; MUTATIONS; MEN AB Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom II lumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genomewide significance (P < 5 x 10(-8)). More than 70 prostate cancer susceptibility loci, explaining similar to 30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies. C1 [Eeles, Rosalind A.; Saunders, Edward J.; Leongamornlert, Daniel A.; Tymrakiewicz, Malgorzata; Jugurnauth-Little, Sarah; Dadaev, Tokhir; Govindasami, Koveela; Guy, Michelle; Wilkinson, Rosemary A.; Sawyer, Emma J.; Morgan, Angela; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Cooper, Colin S.; Kote-Jarai, Zsofia] Inst Canc Res, Sutton, Surrey, England. [Eeles, Rosalind A.; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Van As, Nicholas J.; Woodhouse, Christopher J.; Thompson, Alan; Dudderidge, Tim; Ogden, Chris] Royal Marsden Natl Hlth Serv NHS Fdn, London, England. [Eeles, Rosalind A.; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Van As, Nicholas J.; Woodhouse, Christopher J.; Thompson, Alan; Dudderidge, Tim; Ogden, Chris] Royal Marsden Natl Hlth Serv NHS Fdn, Sutton, Surrey, England. [Al Olama, Ali Amin; Benlloch, Sara; Ghoussaini, Maya; Luccarini, Craig; Dennis, Joe; Pharoah, Paul D. P.; Pashayan, Nora; Dicks, Ed; Lee, Andrew; Dunning, Alison M.; Baynes, Caroline; Conroy, Don; Maranian, Melanie J.; Ahmed, Shahana; Antoniou, Antonis C.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Neal, David E.] Univ Cambridge, Addenbrookes Hosp, Cambridge CB2 2QQ, England. [Neal, David E.] Canc Res UK Cambridge Res Inst, Li Ka Shing Ctr, Cambridge, England. [Hamdy, Freddie C.] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Hamdy, Freddie C.] Univ Oxford, John Radcliffe Hosp, Fac Med Sci, Oxford OX3 9DU, England. [Donovan, Jenny L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Muir, Ken; Lophatananon, Artitaya] Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Muir, Ken] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England. [Giles, Graham G.; Severi, Gianluca; English, Dallas R.] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic, Australia. [Giles, Graham G.; Severi, Gianluca; Hopper, John L.; English, Dallas R.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Wiklund, Fredrik; Gronberg, Henrik; Aly, Markus] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Haiman, Christopher A.; Schumacher, Fredrick; Henderson, Brian E.; Ingles, Sue A.; Stern, Mariana C.; Corral, Roman; Joshi, Amit D.; Shahabi, Ahva] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Lindstrom, Sara; Kraft, Peter; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Gapstur, Susan; Diver, W. Ryan; Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Chanock, Stephen J.; Berndt, Sonja I.; Yeager, Meredith] NCI, Div Canc Epidemiol & Genet, US Natl Inst Hlth NIH, Bethesda, MD 20892 USA. [Albanes, Demetrius] NCI, Nutr Epidemiol Branch, US NIH, Bethesda, MD 20892 USA. [Andriole, Gerald; Drake, Bettina; Colditz, Graham] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Schleutker, Johanna; Wahlfors, Tiina] Univ Tampere, Inst Biomed Technol BioMediTech, FIN-33101 Tampere, Finland. [Schleutker, Johanna; Wahlfors, Tiina] FimLab Labs, Tampere, Finland. [Schleutker, Johanna] Univ Turku, Dept Med Biochem & Genet, Turku, Finland. [Weischer, Maren; Nordestgaard, Borge G.; Nielsen, Sune F.; Bojesen, Stig E.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark. [Canzian, Federico; Campa, Daniele] German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Key, Tim J.; Travis, Ruth C.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA. [John, Esther M.] Stanford Univ, Sch Med, Div Epidemiol, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Hayes, Richard B.] NYU, Dept Environm Med, Langone Med Ctr, Div Epidemiol, New York, NY 10016 USA. [Khaw, Kay-Tee] Univ Cambridge, Clin Gerontol Unit, Cambridge, England. [Stanford, Janet L.; FitzGerald, Liesel M.; Kolb, Suzanne] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Ostrander, Elaine A.; Kwon, Erika M.; Karyadi, Danielle M.] NHGRI, US NIH, Bethesda, MD 20892 USA. [Signorello, Lisa B.; Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Signorello, Lisa B.; Blot, William J.; Zheng, Wei; Cai, Qiuyin] Vanderbilt Univ, Sch Med, Dept Med,Div Epidemiol, Vanderbilt Epidemiol Ctr,Vanderbilt Ingram Canc C, Nashville, TN 37212 USA. [Thibodeau, Stephen N.; McDonnell, Shannon K.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Schaid, Dan] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA. [Maier, Christiane; Rinckleb, Antje E.] Univ Hosp Ulm, Dept Urol, Ulm, Germany. [Maier, Christiane; Vogel, Walther; Rinckleb, Antje E.] Univ Hosp Ulm, Inst Human Genet, Ulm, Germany. [Kibel, Adam S.] Brigham & Womens Hosp, Div Urol Surg, Dana Farber Canc Inst, Boston, MA 02115 USA. [Cybulski, Cezary; Lubhiski, Jan; Wokolorczyk, Dominika] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Cannon-Albright, Lisa; Teerlink, Craig] Univ Utah, Sch Med, Dept Med, Div Genet Epidemiol, Salt Lake City, UT USA. [Cannon-Albright, Lisa; Stephenson, Robert A.] George E Wahlen Dept Vet Affairs Med Ctr, Salt Lake City, UT USA. [Brenner, Hermann; Muller, Heiko; Rothenbacher, Dietrich] DKFZ, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Park, Jong Y.; Sellers, Thomas A.; Lin, Hui-Yi] Univ S Florida, H Lee Moffitt Canc Ctr, Div Canc Prevent & Control, Tampa, FL 33682 USA. [Kaneva, Radka; Mitev, Vanio] Med Univ Sofia, Mol Med Ctr, Dept Med Chem & Biochem, Sofia, Bulgaria. [Batra, Jyotsna; Clements, Judith A.; Srinivasan, Srilakshmi] Queensland Univ Technol, Australian Prostate Canc Res Ctr, Queensland Inst Hlth & Biomed Innovat, Brisbane, Qld 4001, Australia. [Batra, Jyotsna; Clements, Judith A.; Srinivasan, Srilakshmi] Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld 4001, Australia. [Spurdle, Amanda B.; Lose, Felicity] Queensland Inst Med Res, Mol Canc Epidemiol Lab, Brisbane, Qld 4006, Australia. [Teixeira, Manuel R.; Maia, Sofia; Paulo, Paula] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal. [Teixeira, Manuel R.; Maia, Sofia; Paulo, Paula] Univ Porto, Abel Salazar Biomed Sci Inst ICBAS, P-4100 Oporto, Portugal. [Cooper, Colin S.] Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England. [Cox, Angela] Univ Sheffield, Canc Res UK Yorkshire Canc Res Sheffield Canc Res, Sheffield, S Yorkshire, England. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Parkville, Vic 3052, Australia. [Aly, Markus] Karolinska Inst, Danderyd Hosp, Div Urol, Dept Clin Sci, Stockholm, Sweden. [Adolfsson, Jan] Karolinska Inst, Reg Canc Ctr, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden. [Xu, Jiangfeng] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Zheng, Siqun L.] Wake Forest Univ Hlth Sci, Ctr Canc Genom, Genom Genotyping Lab, Winston Salem, NC USA. [Yeager, Meredith] NCI, Core Genotyping Facil, SAIC Frederick, US NIH, Gaithersburg, MD USA. [Kaaks, Rudolf] DKFZ, Div Canc Epidemiol, Heidelberg, Germany. [Tammela, Teuvo L. J.] Tampere Univ Hosp, Dept Urol, Tampere, Finland. [Tammela, Teuvo L. J.] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Auvinen, Anssi] Univ Tampere, Dept Epidemiol, Sch Hlth Sci, FIN-33101 Tampere, Finland. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Klarskov, Peter] Copenhagen Univ Hosp, Herlev Hosp, Dept Urol, Herlev, Denmark. [Roder, M. Andreas] Copenhagen Univ Hosp, Rigshosp, Dept Urol, Copenhagen, Denmark. [Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Stephenson, Robert A.] Huntsman Canc Inst, Salt Lake City, UT USA. [Slavov, Chavdar] Med Univ Sofia, Alexandrovska Univ Hosp, Dept Urol, Sofia, Bulgaria. [Lange, Ethan] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Cooney, Kathleen A.] Univ Michigan, Sch Med, Ctr Comprehens Canc, Div Hematol Oncol, Ann Arbor, MI USA. [Vincent, Daniel; Bacot, Francois; Tessier, Daniel C.] McGill Univ, Montreal, PQ, Canada. [Vincent, Daniel; Bacot, Francois; Tessier, Daniel C.] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. RP Eeles, RA (reprint author), Inst Canc Res, Sutton, Surrey, England. EM rosalind.eeles@icr.ac.uk RI Spurdle, Amanda/A-4978-2011; Batra, Jyotsna/B-4130-2011; Albanes, Demetrius/B-9749-2015; Paulo, Paula/F-1441-2016; Teixeira, Manuel/E-4885-2011; Campa, Daniele/K-1617-2016; Colditz, Graham/A-3963-2009; Brenner, Hermann/B-4627-2017; OI albright, lisa/0000-0003-2602-3668; Cox, Angela/0000-0002-5138-1099; Drake, Bettina/0000-0001-9340-5848; Dunning, Alison Margaret/0000-0001-6651-7166; Giles, Graham/0000-0003-4946-9099; Clements, Judith/0000-0001-6026-1964; English, Dallas/0000-0001-7828-8188; Ostrander, Elaine/0000-0001-6075-9738; Eeles, Rosalind/0000-0002-3698-6241; Lose, Felicity/0000-0001-8337-3547; Roder, Martin Andreas/0000-0002-0019-5333; Spurdle, Amanda/0000-0003-1337-7897; Adolfsson, Jan/0000-0003-2992-1869; Dennis, Joe/0000-0003-4591-1214; Teerlink, Craig/0000-0002-1992-2326; Neal, David/0000-0002-6033-5086; Leongamornlert, Daniel/0000-0002-3486-3168; Hayes, Richard/0000-0002-0918-661X; van As, Nicholas/0000-0001-6829-8788; Paulo, Paula/0000-0001-8387-2127; Teixeira, Manuel/0000-0002-4896-5982; Campa, Daniele/0000-0003-3220-9944; Colditz, Graham/0000-0002-7307-0291; Brenner, Hermann/0000-0002-6129-1572; Dadaev, Tokhir/0000-0002-8268-0438; Auvinen, Anssi/0000-0003-1125-4818; Saunders, Ed/0000-0003-4343-3570 FU Cancer Research UK [10118, 10124, 10588, 11174, 13065, 14136]; Intramural NIH HHS [Z99 CA999999, ZIA CP010195-06]; Medical Research Council [G0401527, G0900871, G1000143]; NCATS NIH HHS [TL1 TR000132]; NCI NIH HHS [P30 CA042014, P30 CA076292, R01 CA056678, R01 CA082664, R01 CA092447, R01 CA092579]; Prostate Cancer UK [G2011/36] NR 29 TC 228 Z9 229 U1 4 U2 61 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 APR PY 2013 VL 45 IS 4 BP 385 EP 391 DI 10.1038/ng.2560 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600008 PM 23535732 ER PT J AU Garcia-Closas, M Couch, FJ Lindstrom, S Michailidouo, K Schmidt, MK Brook, MN Orr, N Rhie, SK Riboli, E Feigelson, HS Le Marchand, L Buring, JE Eccles, D Miron, P Fasching, PA Brauch, H Chang-Claude, J Carpenter, J Godwin, AK Nevanlinna, H Giles, GG Cox, A Hopper, JL Bolla, MK Wang, Q Dennis, J Dicks, E Howat, WJ Schoof, N Bojesen, SE Lambrechts, D Broeks, A Andrulis, IL Guenel, P Burwinkel, B Sawyer, EJ Hollestelle, A Fletcher, O Winqvist, R Brenner, H Mannermaa, A Hamann, U Meindl, A Lindblom, A Zheng, W Devillee, P Goldberg, MS Lubinski, J Kristensen, V Swerdlow, A Anton-Culver, H Doerk, T Muir, K Matsuo, K Wu, AH Radice, P Teo, SH Shu, XO Blot, W Kang, D Hartman, M Sangrajrang, S Shen, CY Southey, MC Park, DJ Hammet, F Stone, J Van't Veer, LJ Rutgers, EJ Lophatananon, A Stewart-Brown, S Siriwanarangsan, P Peto, J Schrauder, MG Ekici, AB Beckmann, MW Silva, ID Johnson, N Warren, H Tomlins, I Kerin, MJ Miller, N Marme, F Schneeweiss, A Sohn, C Truong, T Laurent-Puig, P Kerbrat, P Nordestgaard, BG Nielsen, SF Flyger, H Milne, RL Perez, JIA Menendez, P Muller, H Arndt, V Stegmaier, C Lichtner, P Lochmann, M Justenhoven, C Ko, YD Muranen, TA Aittomaki, K Blomqvist, C Greco, D Heikkinen, T Ito, H Iwata, H Yatabe, Y Antonenkova, NN Margolin, S Kataja, V Kosma, VM Hartikainen, JM Balleine, R Tseng, CC Van den Berg, D Stram, DO Neven, P Dieudonne, AS Leunen, K Rudolph, A Nickels, S Flesch-Janys, D Peterlongo, P Peissel, B Bernard, L Olson, JE Wang, XS Stevens, K Severi, G Baglietto, L McLean, C Coetzee, GA Feng, Y Henderson, BE Schumacher, F Bogdanova, NV Labreche, F Dumont, M Yip, CH Taib, NAM Cheng, CY Shrubsole, M Long, JR Pylkas, K Jukkola-Vuorinen, A Kauppila, S Knight, JA Glendon, G Mulligan, AM Tollenaar, RAEM Seynaeve, CM Kriege, M Hooning, MJ van den Ouweland, AMW van Deurzen, CHM Lu, W Gao, YT Cai, H Balasubramanian, SP Cross, SS Reed, MWR Signorello, L Cai, QY Shah, M Miao, H Chan, CW Chia, KS Jakubowska, A Jaworska, K Durda, K Hsiung, CN Wu, P Yu, JC Ashworth, A Jones, M Tessier, DC Gonzalez-Neira, A Pita, G Alonso, MR Vincent, D Bacot, F Ambrosone, CB Bandera, EV John, EM Chen, GK Hu, JJ Rodriguez-Gil, JL Bernstein, L Press, MF Ziegler, RG Millikan, RM Deming-Halverson, SL Nyante, S Ingles, SA Waisfisz, Q Tsimiklis, H Makalic, E Schmidt, D Bui, M Gibson, L Muller-Myhsok, B Schmutzler, RK Hein, R Dahmen, N Beckmann, L Aaltonen, K Czene, K Irwanto, A Liu, JJ Turnbull, C Rahman, N Meijers-Heijboer, H Uitterlinden, AG Rivadeneira, F Olswold, C Slager, S Pilarski, R Ademuyiwa, F Konstantopoulou, I Martin, NG Montgomery, GW Slamon, DJ Rauh, C Lux, MP Jud, SM Bruning, T Weaver, J Harma, P Pathak, H Tapper, W Gerty, S Durcan, L Trichopoulos, D Tumino, R Peeters, PH Kaaks, R Campa, D Canzian, F Weiderpass, E Johansson, M Khaw, KT Travis, R Clavel-Chapelon, F Kolonel, LN Chen, C Beck, A Hankinson, SE Berg, CD Hoover, RN Lissowska, J Figueroa, JD Chasman, DI Gaudet, MM Diver, WR Willett, WC Hunter, DJ Simard, J Benitez, J Dunning, AM Sherman, ME Chenevix-Trench, G Chanock, SJ Hall, P Pharoah, PDP Vachon, C Easton, DF Haiman, CA Kraft, P AF Garcia-Closas, Montserrat Couch, Fergus J. Lindstrom, Sara Michailidouo, Kyriaki Schmidt, Marjanka K. Brook, Mark N. Orr, Nick Rhie, Suhn Kyong Riboli, Elio Feigelson, Heather S. Le Marchand, Loic Buring, Julie E. Eccles, Diana Miron, Penelope Fasching, Peter A. Brauch, Hiltrud Chang-Claude, Jenny Carpenter, Jane Godwin, Andrew K. Nevanlinna, Heli Giles, Graham G. Cox, Angela Hopper, John L. Bolla, Manjeet K. Wang, Qin Dennis, Joe Dicks, Ed Howat, Will J. Schoof, Nils Bojesen, Stig E. Lambrechts, Diether Broeks, Annegien Andrulis, Irene L. Guenel, Pascal Burwinkel, Barbara Sawyer, Elinor J. Hollestelle, Antoinette Fletcher, Olivia Winqvist, Robert Brenner, Hermann Mannermaa, Arto Hamann, Ute Meindl, Alfons Lindblom, Annika Zheng, Wei Devillee, Peter Goldberg, Mark S. Lubinski, Jan Kristensen, Vessela Swerdlow, Anthony Anton-Culver, Hoda Doerk, Thilo Muir, Kenneth Matsuo, Keitaro Wu, Anna H. Radice, Paolo Teo, Soo Hwang Shu, Xiao-Ou Blot, William Kang, Daehee Hartman, Mikael Sangrajrang, Suleeporn Shen, Chen-Yang Southey, Melissa C. Park, Daniel J. Hammet, Fleur Stone, Jennifer Van't Veer, Laura J. Rutgers, Emiel J. Lophatananon, Artitaya Stewart-Brown, Sarah Siriwanarangsan, Pornthep Peto, Julian Schrauder, Michael G. Ekici, Arif B. Beckmann, Matthias W. Silva, Isabel dos Santos Johnson, Nichola Warren, Helen Tomlins, Ian Kerin, Michael J. Miller, Nicola Marme, Federick Schneeweiss, Andreas Sohn, Christof Therese Truong Laurent-Puig, Pierre Kerbrat, Pierre Nordestgaard, Borge G. Nielsen, Sune F. Flyger, Henrik Milne, Roger L. Arias Perez, Jose Ignacio Menendez, Primitiva Mueller, Heiko Arndt, Volker Stegmaier, Christa Lichtner, Peter Lochmann, Magdalena Justenhoven, Christina Ko, Yon-Dschun Muranen, Taru A. Aittomaki, Kristiina Blomqvist, Carl Greco, Dario Heikkinen, Tuomas Ito, Hidemi Iwata, Hiroji Yatabe, Yasushi Antonenkova, Natalia N. Margolin, Sara Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Balleine, Rosemary Tseng, Chiu-Chen Van den Berg, David Stram, Daniel O. Neven, Patrick Dieudonne, Anne-Sophie Leunen, Karin Rudolph, Anja Nickels, Stefan Flesch-Janys, Dieter Peterlongo, Paolo Peissel, Bernard Bernard, Loris Olson, Janet E. Wang, Xianshu Stevens, Kristen Severi, Gianluca Baglietto, Laura McLean, Catriona Coetzee, Gerhard A. Feng, Ye Henderson, Brian E. Schumacher, Fredrick Bogdanova, Natalia V. Labreche, France Dumont, Martine Yip, Cheng Har Taib, Nur Aishah Mohd Cheng, Ching-Yu Shrubsole, Martha Long, Jirong Pylkas, Katri Jukkola-Vuorinen, Arja Kauppila, Saila Knight, Julia A. Glendon, Gord Mulligan, Anna Marie Tollenaar, Robertus A. E. M. Seynaeve, Caroline M. Kriege, Mieke Hooning, Maartje J. van den Ouweland, Ans M. W. van Deurzen, Carolien H. M. Lu, Wei Gao, Yu-Tang Cai, Hui Balasubramanian, Sabapathy P. Cross, Simon S. Reed, Malcolm W. R. Signorello, Lisa Cai, Qiuyin Shah, Mitul Miao, Hui Chan, Ching Wan Chia, Kee Seng Jakubowska, Anna Jaworska, Katarzyna Durda, Katarzyna Hsiung, Chia-Ni Wu, Peiei Yu, Jyh-Cherng Ashworth, Alan Jones, Michael Tessier, Daniel C. Gonzalez-Neira, Anna Pita, Guillermo Alonso, M. Rosario Vincent, Daniel Bacot, Francois Ambrosone, Christine B. Bandera, Elisa V. John, Esther M. Chen, Gary K. Hu, Jennifer J. Rodriguez-Gil, Jorge L. Bernstein, Leslie Press, Michael F. Ziegler, Regina G. Millikan, Robert M. Deming-Halverson, Sandra L. Nyante, Sarah Ingles, Sue A. Waisfisz, Quinten Tsimiklis, Helen Makalic, Enes Schmidt, Daniel Bui, Minh Gibson, Lorna Mueller-Myhsok, Bertram Schmutzler, Rita K. Hein, Rebecca Dahmen, Norbert Beckmann, Lars Aaltonen, Kirsimari Czene, Kamila Irwanto, Astrid Liu, Jianjun Turnbull, Clare Rahman, Nazneen Meijers-Heijboer, Hanne Uitterlinden, Andre G. Rivadeneira, Fernando Olswold, Curtis Slager, Susan Pilarski, Robert Ademuyiwa, Foluso Konstantopoulou, Irene Martin, Nicholas G. Montgomery, Grant W. Slamon, Dennis J. Rauh, Claudia Lux, Michael P. Jud, Sebastian M. Bruning, Thomas Weaver, JoEllen Harma, Priyanka Pathak, Harsh Tapper, Will Gerty, Sue Durcan, Lorraine Trichopoulos, Dimitrios Tumino, Rosario Peeters, Petra H. Kaaks, Rudolf Campa, Daniele Canzian, Federico Weiderpass, Elisabete Johansson, Mattias Khaw, Kay-Tee Travis, Ruth Clavel-Chapelon, Francoise Kolonel, Laurence N. Chen, Constance Beck, Andy Hankinson, Susan E. Berg, Christine D. Hoover, Robert N. Lissowska, Jolanta Figueroa, Jonine D. Chasman, Daniel I. Gaudet, Mia M. Diver, W. Ryan Willett, Walter C. Hunter, David J. Simard, Jacques Benitez, Javier Dunning, Alison M. Sherman, Mark E. Chenevix-Trench, Georgia Chanock, Stephen J. Hall, Per Pharoah, Paul D. P. Vachon, Celine Easton, Douglas F. Haiman, Christopher A. Kraft, Peter CA Gene ENvironm Interaction Breast KConFab Investigators Familial Breast Canc Study FBCS Australian Breast Canc Tissue Bank TI Genome-wide association studies identify four ER negative-specific breast cancer risk loci SO NATURE GENETICS LA English DT Article ID BODY-MASS INDEX; COMMON VARIANT; SUSCEPTIBILITY; EXPRESSION; ESTROGEN; GENE AB Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a metaanalysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P= 2.1 x 10(-12) and LGR6, P = 1.4 x 10(-8)), 2p24.1 (P = 4.6 x 10(-8)) and 16q12.2 (FTO, P = 4.0 x 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P> 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers. C1 [Garcia-Closas, Montserrat; Brook, Mark N.; Swerdlow, Anthony; Jones, Michael; Turnbull, Clare; Rahman, Nazneen] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Garcia-Closas, Montserrat; Orr, Nick; Fletcher, Olivia; Johnson, Nichola; Ashworth, Alan] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Couch, Fergus J.; Olson, Janet E.; Wang, Xianshu; Stevens, Kristen; Olswold, Curtis; Slager, Susan; Vachon, Celine] Mayo Clin, Coll Med, Rochester, MN USA. [Lindstrom, Sara; Trichopoulos, Dimitrios; Chen, Constance; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Michailidouo, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Dicks, Ed; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Schmidt, Marjanka K.; Broeks, Annegien; Van't Veer, Laura J.; Rutgers, Emiel J.] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands. [Rhie, Suhn Kyong; Wu, Anna H.; Tseng, Chiu-Chen; Van den Berg, David; Stram, Daniel O.; Coetzee, Gerhard A.; Feng, Ye; Henderson, Brian E.; Schumacher, Fredrick; Chen, Gary K.; Ingles, Sue A.; Haiman, Christopher A.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Feigelson, Heather S.] Kaiser Permanente, Inst Hlth Res, Denver, CO USA. [Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Buring, Julie E.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Eccles, Diana; Tapper, Will; Gerty, Sue; Durcan, Lorraine] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. [Miron, Penelope] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Fasching, Peter A.; Schrauder, Michael G.; Beckmann, Matthias W.; Rauh, Claudia; Lux, Michael P.; Jud, Sebastian M.] Univ Breast Ctr Franconia, Dept Gynecol & Obstet, Univ Hosp Erlangen, Erlangen, Germany. [Fasching, Peter A.; Slamon, Dennis J.] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Brauch, Hiltrud; Justenhoven, Christina] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany. [Brauch, Hiltrud; Justenhoven, Christina] Univ Tubingen, Tubingen, Germany. [Chang-Claude, Jenny; Rudolph, Anja; Nickels, Stefan; Hein, Rebecca; Kaaks, Rudolf; Campa, Daniele; Canzian, Federico] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Carpenter, Jane] Univ Sydney, Westmead Millennium Inst, Australian Breast Canc Tissue Bank, Westmead, NSW 2145, Australia. [Godwin, Andrew K.; Pathak, Harsh] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. 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[Schoof, Nils; Czene, Kamila; Weiderpass, Elisabete; Hall, Per] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.] Univ Copenhagen, Dept Clin Biochem, Herlev Hosp, Copenhagen Gen Populat Study,Copenhagen Univ Hosp, Copenhagen, Denmark. [Lambrechts, Diether] VIB, VRC, Louvain, Belgium. [Lambrechts, Diether] Katholieke Univ Leuven, Dept Oncol, Louvain, Belgium. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Ontario Canc Genet Network, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada. [Guenel, Pascal; Therese Truong; Clavel-Chapelon, Francoise] Univ Paris Sud, UMRS 1018, Villejuif, France. [Guenel, Pascal; Therese Truong; Clavel-Chapelon, Francoise] Environm Epidemiol Canc, INSERM, Natl Inst Hlth & Med Res, CESP Ctr Res Epidemiol & Populat Hlth, Villejuif, France. 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[Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.] Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland. [Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Bioctr Kuopio, Canc Ctr Eastern Finland, Kuopio, Finland. [Hamann, Ute] DKFZ, Heidelberg, Germany. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol Tumor Genet, Clin Gynaecol & Obstet, D-80290 Munich, Germany. [Meindl, Alfons; Lochmann, Magdalena] Tech Univ Munich, Div Gynaecol & Obstet, D-80290 Munich, Germany. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Zheng, Wei; Shu, Xiao-Ou; Blot, William; Shrubsole, Martha; Long, Jirong; Cai, Hui; Signorello, Lisa; Deming-Halverson, Sandra L.] Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Epidemiol Ctr,Vanderbilt Ingr, Nashville, TN 37212 USA. [Devillee, Peter] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Devillee, Peter; van Deurzen, Carolien H. 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[Cross, Simon S.] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield, S Yorkshire, England. [Shah, Mitul; Dunning, Alison M.; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Chan, Ching Wan] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore. [Wu, Peiei] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan. [Yu, Jyh-Cherng] Triserv Gen Hosp, Dept Surg, Taipei, Taiwan. [Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois] McGill Univ, Montreal, PQ, Canada. [Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois] Genome Quebec Innovat Ctr, Montreal, PQ, Canada. [Gonzalez-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Benitez, Javier] CNIO, Human Canc Genet Programme, Human Genotyping Unit CEGEN, Madrid, Spain. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Bandera, Elisa V.] Canc Inst New Jersey, New Brunswick, NJ USA. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol,Stanford Canc Inst, Stanford, CA 94305 USA. [Hu, Jennifer J.; Rodriguez-Gil, Jorge L.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Hu, Jennifer J.; Rodriguez-Gil, Jorge L.] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Bernstein, Leslie] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Press, Michael F.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Ziegler, Regina G.; Hoover, Robert N.; Figueroa, Jonine D.; Sherman, Mark E.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. [Millikan, Robert M.; Nyante, Sarah] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Waisfisz, Quinten; Meijers-Heijboer, Hanne] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Sect Oncogenet, Amsterdam, Netherlands. [Tsimiklis, Helen] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, Stat Genet Res Grp, D-80804 Munich, Germany. [Schmutzler, Rita K.] Univ Hosp, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Hosp, Ctr Integrated Oncol, Cologne, Germany. [Hein, Rebecca] Univ Cologne, Dept Child & Adolescent Psychiat & Psychotherapy, PMV Primarmed Versorgung Res Grp, D-50931 Cologne, Germany. [Dahmen, Norbert] Johannes Gutenberg Univ Mainz, Dept Psychiat, Mainz, Germany. [Beckmann, Lars] Inst Qual & Efficiency Hlth Care IQWiG, Cologne, Germany. [Irwanto, Astrid; Liu, Jianjun] Genome Inst Singapore, Human Genet Div, Singapore, Singapore. [Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med & Epidemiol, Rotterdam, Netherlands. [Pilarski, Robert] Ohio State Univ, Dept Internal Med, James Comprehens Canc Ctr, Columbus, OH 43210 USA. [Ademuyiwa, Foluso] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Konstantopoulou, Irene] Natl Ctr Sci Res Demokritos, Inst Radioisotopes & Radiodiagnost Prod IRRP, Mol Diagnost Lab, Athens, Greece. [Martin, Nicholas G.; Montgomery, Grant W.] Queensland Inst Med Res, QIMR GWAS Collect, Brisbane, Qld 4006, Australia. [Slamon, Dennis J.] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90024 USA. [Bruning, Thomas] Inst Prevent & Occupat Med German Social Accident, Bochum, Germany. [Weaver, JoEllen] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Harma, Priyanka] Univ Kansas, Med Ctr, Dept Internal Med, Div Hematol & Oncol, Kansas City, KS USA. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens, Greece. [Tumino, Rosario] Civile MPArezzo Hosp, Canc Registry, Histopathol Unit, Ragusa, Italy. [Peeters, Petra H.] Univ Med Ctr Utrecht, Julius Ctr, Utrecht, Netherlands. [Weiderpass, Elisabete] Univ Tromso, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Folkhalsan Res Canc Ctr, Helsinki, Finland. [Weiderpass, Elisabete] Canc Registry Norway, Oslo, Norway. [Johansson, Mattias] World Hlth Org, Int Agcy Res Canc, Genet Epidemiol Grp, Lyon, France. [Khaw, Kay-Tee] Univ Cambridge, Clin Gerontol Unit, Cambridge, England. [Travis, Ruth] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Beck, Andy] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Beck, Andy] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Hankinson, Susan E.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Hankinson, Susan E.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Berg, Christine D.] NCI, Div Canc Prevent, Bethesda, MD 20892 USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Gaudet, Mia M.; Diver, W. Ryan] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Benitez, Javier] CNIO, Human Genet Grp, Madrid, Spain. [Benitez, Javier] Ctr Invest Red Enfermedades Raras CIBERER, Madrid, Spain. [Chenevix-Trench, Georgia] Queensland Inst Med Res, Dept Genet, Brisbane, Qld 4006, Australia. RP Garcia-Closas, M (reprint author), Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. EM montse.garciaclosas@icr.ac.uk RI Brenner, Hermann/B-4627-2017; Peissel, Bernard/E-8187-2017; Bandera, Elisa/M-4169-2014; Jakubowska, Anna/O-8050-2014; Yip, Cheng-Har/B-1909-2010; Gonzalez-Neira, Anna/C-5791-2015; Garcia-Closas, Montserrat /F-3871-2015; Pilarski, Robert/E-3871-2011; Shrubsole, Martha/K-5052-2015; Hartikainen, Jaana/E-6256-2015; Montgomery, Grant/B-7148-2008; laurent-puig, pierre/B-2226-2013; Bruning, Thomas/G-8120-2015; Campa, Daniele/K-1617-2016; Weiderpass, Elisabete/M-4029-2016; Bernard, Loris/K-5953-2014; Verdrengh, Evelien/H-4571-2012; Andrulis, Irene/E-7267-2013; Ekici, Arif/C-3971-2013; Kerin, Michael/D-6748-2013; Cheng, Ching-Yu/K-7017-2013; Radice, Paolo/O-3119-2013; Knight, Julia/A-6843-2012; Dork, Thilo/J-8620-2012; Clavel-Chapelon, Francoise/G-6733-2014; Teo, Soo-hwang/H-2353-2014; Hartman, Mikael/B-4324-2011; Berg , Christine/K-1047-2014 OI Muranen, Taru/0000-0002-5895-1808; Matsuo, Keitaro/0000-0003-1761-6314; Arndt, Volker/0000-0001-9320-8684; Martin, Nicholas/0000-0003-4069-8020; Dennis, Joe/0000-0003-4591-1214; Dunning, Alison Margaret/0000-0001-6651-7166; Brook, Mark/0000-0002-8969-2378; Rivadeneira, Fernando/0000-0001-9435-9441; Nevanlinna, Heli/0000-0002-0916-2976; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Bui, Minh/0000-0002-9099-6870; Park, Daniel/0000-0002-6354-0931; ADEMUYIWA, FOLUSO/0000-0002-6766-2258; Giles, Graham/0000-0003-4946-9099; Brenner, Hermann/0000-0002-6129-1572; Peissel, Bernard/0000-0001-9233-3571; Hollestelle, Antoinette/0000-0003-1166-1966; Konstantopoulou, Irene/0000-0002-0470-0309; Rudolph, Anja/0000-0001-7520-2035; Greco, Dario/0000-0001-9195-9003; Lux, Michael Patrick/0000-0002-2781-2178; Czene, Kamila/0000-0002-3233-5695; Cross, Simon/0000-0003-2044-1754; Lissowska, Jolanta/0000-0003-2695-5799; Arias Perez, Jose Ignacio/0000-0003-4500-397X; Bandera, Elisa/0000-0002-8789-2755; Garcia-Closas, Montserrat /0000-0003-1033-2650; Shrubsole, Martha/0000-0002-5591-7575; Montgomery, Grant/0000-0002-4140-8139; laurent-puig, pierre/0000-0001-8475-5459; Bruning, Thomas/0000-0001-9560-5464; Campa, Daniele/0000-0003-3220-9944; Weiderpass, Elisabete/0000-0003-2237-0128; Cheng, Ching-Yu/0000-0003-0655-885X; FU Cancer Research UK [C1287/A10118, C1287/Al2014]; European Community's Seventh Framework Programme [223175, HEALTH-F2-2009-223175]; European Union European Cooperation in Science and Technology (COST) [BM0606]; US National Cancer Institute [U01-CA98233, U01-CA98710, U01CA98216, U01-CA98758]; Intramural Research Program of the US National Institutes of Health (NIH)/National Cancer Institute, Division of Cancer Epidemiology and Genetics; Mayo Clinic Breast Cancer Study (MCBCS); US NIH [CA122340, CA116201]; Komen Foundation; European Union [HEALTH-F2-2009223175]; Breast Cancer Research Foundation; Canadian Institutes of Health Research (CIHR); Ministry of Economic Development, Innovation and Export Trade of Quebec [PSR-SIIRI701]; US NIH Cancer Post-Cancer GWAS initiative [U19 CA 148065-01] FX The authors wish to thank all the individuals who took part in these studies and all the researchers, clinicians and administrative staff who have enabled this work to be carried out. We are very grateful to Illumina, in particular J. Stone, S. McBean, J. Hadlington, A. Mustafa and K. Cook, for their help with designing the array. BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/Al2014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of BCAC have been funded by the European Union European Cooperation in Science and Technology (COST) programme (BM0606). BPC3 is funded by US National Cancer Institute cooperative agreements U01-CA98233, U01-CA98710, U01CA98216 and U01-CA98758 and the Intramural Research Program of the US National Institutes of Health (NIH)/National Cancer Institute, Division of Cancer Epidemiology and Genetics. TNBCC is supported by Mayo Clinic Breast Cancer Study (MCBCS) (US NIH grants CAl22340 and a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201)), grants from the Komen Foundation for the Cure and the Breast Cancer Research Foundation. Genotyping on the iCOGS array was funded by the European Union (HEALTH-F2-2009223175), Cancer Research UK (C1287/A10710), US NIH grant CAl22340, the Komen Foundation for the Cure, the Breast Cancer Research Foundation, the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program (J. Simiard and D.E.) and Ministry of Economic Development, Innovation and Export Trade of Quebec grant PSR-SIIRI701 (J. Simiard, D.E. and P.H.). J. Simiard holds the Canada Research Chair in Oncogenetics. Combination of the GWAS data was supported in part by US NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065-01 (DRIVE, part of the GAME-ON initiative) and Breakthrough Breast Cancer Research. NR 17 TC 174 Z9 177 U1 9 U2 98 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2013 VL 45 IS 4 BP 392 EP 398 DI 10.1038/ng.2561 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600009 PM 23535733 ER PT J AU Codd, V Nelson, CP Albrecht, E Mangino, M Deelen, J Buxton, JL Hottenga, JJ Fischer, K Esko, T Surakka, I Broer, L Nyholt, DR Leach, IM Salo, P Hagg, S Matthews, MK Palmen, J Norata, GD O'Reilly, PF Saleheen, D Amin, N Balmforth, AJ Beekman, M de Boer, RA Bohringer, S Braund, PS Burton, PR de Craen, AJM Denniff, M Dong, YB Douroudis, K Dubinina, E Eriksson, JG Garlaschelli, K Guo, DH Hartikainen, AL Henders, AK Houwing-Duistermaat, JJ Kananen, L Karssen, LC Kettunen, J Klopp, N Lagou, V van Leeuwen, EM Madden, PA Magi, R Magnusson, PKE Mannisto, S McCarthy, MI Medland, SE Mihailov, E Montgomery, GW Oostra, B Palotie, A Peters, A Pollard, H Pouta, A Prokopenko, I Ripatti, S Salomaa, V Suchiman, HED Valdes, AM Verweij, N Vinuela, A Wang, XL Wichmann, HE Widen, E Willemsen, G Wright, MJ Xia, K Xiao, XJ van Veldhuisen, DJ Catapano, AL Tobin, MD Hall, AS Blakemore, AIF van Gilst, WH Zhu, HD Erdmann, J Reilly, MP Kathiresan, S Schunkert, H Talmud, PJ Pedersen, NL Perola, M Ouwehand, W Kaprio, J Martin, NG van Duijn, CM Hovatta, I Gieger, C Metspalu, A Boomsma, DI Jarvelin, MR Slagboom, PE Thompson, JR Spector, TD van der Harst, P Samani, NJ AF Codd, Veryan Nelson, Christopher P. Albrecht, Eva Mangino, Massimo Deelen, Joris Buxton, Jessica L. Hottenga, Jouke Jan Fischer, Krista Esko, Tonu Surakka, Ida Broer, Linda Nyholt, Dale R. Leach, Irene Mateo Salo, Perttu Hagg, Sara Matthews, Mary K. Palmen, Jutta Norata, Giuseppe D. O'Reilly, Paul F. Saleheen, Danish Amin, Najaf Balmforth, Anthony J. Beekman, Marian de Boer, Rudolf A. Bohringer, Stefan Braund, Peter S. Burton, Paul R. de Craen, Anton J. M. Denniff, Matthew Dong, Yanbin Douroudis, Konstantinos Dubinina, Elena Eriksson, Johan G. Garlaschelli, Katia Guo, Dehuang Hartikainen, Anna-Liisa Henders, Anjali K. Houwing-Duistermaat, Jeanine J. Kananen, Laura Karssen, Lennart C. Kettunen, Johannes Klopp, Norman Lagou, Vasiliki van Leeuwen, Elisabeth M. Madden, Pamela A. Maegi, Reedik Magnusson, Patrik K. E. Mannisto, Satu McCarthy, Mark I. Medland, Sarah E. Mihailov, Evelin Montgomery, Grant W. Oostra, Ben A. Palotie, Aarno Peters, Annette Pollard, Helen Pouta, Anneli Prokopenko, Inga Ripatti, Samuli Salomaa, Veikko Suchiman, H. Eka D. Valdes, Ana M. Verweij, Niek Vinuela, Ana Wang, Xiaoling Wichmann, H-Erich Widen, Elisabeth Willemsen, Gonneke Wright, Margaret J. Xia, Kai Xiao, Xiangjun van Veldhuisen, Dirk J. Catapano, Alberico L. Tobin, Martin D. Hall, Alistair S. Blakemore, Alexandra I. F. van Gilst, Wiek H. Zhu, Haidong Erdmann, Jeanette Reilly, Muredach P. Kathiresan, Sekar Schunkert, Heribert Talmud, Philippa J. Pedersen, Nancy L. Perola, Markus Ouwehand, Willem Kaprio, Jaakko Martin, Nicholas G. van Duijn, Cornelia M. Hovatta, Iris Gieger, Christian Metspalu, Andres Boomsma, Dorret I. Jarvelin, Marjo-Riitta Slagboom, P. Eline Thompson, John R. Spector, Tim D. van der Harst, Pim Samani, Nilesh J. CA CARDIoGRAM Consortium TI Identification of seven loci affecting mean telomere length and their association with disease SO NATURE GENETICS LA English DT Article ID CORONARY-ARTERY-DISEASE; CARDIOVASCULAR-DISEASE; RISK; CANCER; ATHEROSCLEROSIS; SUSCEPTIBILITY; FIBROBLASTS; DYSFUNCTION; VARIANTS; STRESS AB Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 x 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases. C1 [Codd, Veryan; Nelson, Christopher P.; Matthews, Mary K.; Braund, Peter S.; Denniff, Matthew; Dubinina, Elena; Pollard, Helen; van der Harst, Pim; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Codd, Veryan; Nelson, Christopher P.; Samani, Nilesh J.] Glenfield Gen Hosp, Natl Inst Hlth Res, Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England. [Albrecht, Eva; Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Mangino, Massimo; Valdes, Ana M.; Vinuela, Ana; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Deelen, Joris; Beekman, Marian; Suchiman, H. Eka D.; Slagboom, P. Eline] Leiden Univ, Med Ctr, Sect Mol Epidemiol, Leiden, Netherlands. [Deelen, Joris; Broer, Linda; Beekman, Marian; Houwing-Duistermaat, Jeanine J.; van Duijn, Cornelia M.; Slagboom, P. Eline] Leiden Univ, Med Ctr, Netherlands Consortium Hlth Aging, Leiden, Netherlands. [Buxton, Jessica L.; Blakemore, Alexandra I. F.] Univ London Imperial Coll Sci Technol & Med, Sect Invest Med, London, England. [Hottenga, Jouke Jan; Willemsen, Gonneke; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Fischer, Krista; Esko, Tonu; Douroudis, Konstantinos; Maegi, Reedik; Mihailov, Evelin; Perola, Markus; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Surakka, Ida; Kettunen, Johannes; Ripatti, Samuli; Widen, Elisabeth; Perola, Markus; Kaprio, Jaakko] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland. [Surakka, Ida; Salo, Perttu; Eriksson, Johan G.; Kettunen, Johannes; Mannisto, Satu; Ripatti, Samuli; Salomaa, Veikko; Perola, Markus] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Publ Hlth Genom Unit, Helsinki, Finland. [Broer, Linda; Amin, Najaf; Karssen, Lennart C.; van Leeuwen, Elisabeth M.; Oostra, Ben A.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Broer, Linda; van Duijn, Cornelia M.] Ctr Med Syst Biol, Leiden, Netherlands. [Nyholt, Dale R.; Henders, Anjali K.; Medland, Sarah E.; Montgomery, Grant W.; Wright, Margaret J.; Martin, Nicholas G.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Leach, Irene Mateo; de Boer, Rudolf A.; Verweij, Niek; van Veldhuisen, Dirk J.; van Gilst, Wiek H.; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Hagg, Sara; Magnusson, Patrik K. E.; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Palmen, Jutta; Talmud, Philippa J.] UCL, Inst Cardiovasc Sci, London, England. [Norata, Giuseppe D.; Catapano, Alberico L.] Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy. [Norata, Giuseppe D.; Garlaschelli, Katia] Bassini Hosp, Ctr Soc Italiana Studio Aterosclerosi, Cinisello Balsamo, Italy. [Norata, Giuseppe D.] Queen Mary Univ, Barts & London Sch Med & Dent, Blizard Inst, London, England. [O'Reilly, Paul F.; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England. [O'Reilly, Paul F.; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Fac Med, MRC, Hlth Protect Agcy Ctr Environm & Hlth, London, England. [Saleheen, Danish] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Saleheen, Danish] Ctr Noncommunicable Dis, Karachi, Pakistan. [Balmforth, Anthony J.; Hall, Alistair S.] Univ Leeds, Sch Med, Div Epidemiol, Leeds Inst Genet Hlth & Therapeut, Leeds LS2 9JT, W Yorkshire, England. [Bohringer, Stefan; Houwing-Duistermaat, Jeanine J.] Leiden Univ, Med Ctr, Sect Med Stat, Leiden, Netherlands. [Burton, Paul R.; Tobin, Martin D.; Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [de Craen, Anton J. M.] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [Dong, Yanbin; Guo, Dehuang; Wang, Xiaoling; Zhu, Haidong] Georgia Hlth Sci Univ, Georgia Prevent Inst, Augusta, GA USA. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Hartikainen, Anna-Liisa; Pouta, Anneli] Univ Oulu, Inst Clin Med Obstet & Gynecol, Oulu, Finland. [Kananen, Laura; Hovatta, Iris] Univ Helsinki, Biomedicum Helsinki, Res Programs Unit, Helsinki, Finland. [Kananen, Laura; Hovatta, Iris] Univ Helsinki, Dept Med Genet, Haartman Inst, Helsinki, Finland. [Klopp, Norman; Peters, Annette] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Klopp, Norman] Hannover Med Sch, Hanover Unified Biobank, Hannover, NH, Germany. [Lagou, Vasiliki; McCarthy, Mark I.; Prokopenko, Inga] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Madden, Pamela A.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [McCarthy, Mark I.] Churchill Hosp, Oxford Natl Inst Hlth Res Biomed Res Ctr, Oxford OX3 7LJ, England. [Palotie, Aarno; Ripatti, Samuli; Ouwehand, Willem] Wellcome Trust Sanger Inst, Hinxton, England. [Palotie, Aarno] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Palotie, Aarno] Helsinki Univ Hosp, Helsinki, Finland. [Peters, Annette] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Peters, Annette] Munich Heart Alliance, Munich, Germany. [Pouta, Anneli] Natl Inst Hlth & Welf, Oulu, Finland. [Wichmann, H-Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Wichmann, H-Erich] Univ Munich, Chair Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-80539 Munich, Germany. [Xia, Kai] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Xiao, Xiangjun] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Catapano, Alberico L.] Inst Ricovero & Cura Carattere Sci Multimed, Milan, Italy. [Erdmann, Jeanette; Schunkert, Heribert] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Reilly, Muredach P.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar] Broad Inst Massachusetts Inst Technol & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Ouwehand, Willem] Univ Cambridge, Dept Hematol, Cambridge, England. [Ouwehand, Willem] Natl Hlth Serv Blood & Transplant, Cambridge, England. [Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland. [Kaprio, Jaakko; Hovatta, Iris] Natl Inst Hlth & Welf, Dept Mental Hlth & Subst Abuse Serv, Helsinki, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Lifecourse & Serv, Oulu, Finland. [van der Harst, Pim] Univ Groningen, Univ Med Ctr, Dept Genet, Groningen, Netherlands. RP Samani, NJ (reprint author), Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. EM njs@le.ac.uk RI Peters, Annette/A-6117-2011; Burton, Paul/H-7527-2016; mangino, massimo/F-5134-2011; Slagboom, P. Eline/R-4790-2016; Verweij, Niek/A-4499-2017; Magnusson, Patrik/C-4458-2017; Suchiman, H. Eka D./F-5024-2017; Nyholt, Dale/C-8384-2013; Buxton, Jessica/I-4033-2014; Hovatta, Iiris/D-6871-2012; Medland, Sarah/C-7630-2013; Ripatti, Samuli/H-9446-2014; Montgomery, Grant/B-7148-2008; Prokopenko, Inga/H-3241-2014; Wright, Margaret/A-4560-2016; Vinuela, Ana/J-9326-2012; Lagou, Vasiliki/N-8451-2013; Xia, Kai/B-7214-2014; van Veldhuisen, Dirk Jan/E-8967-2014; Erdmann, Jeanette/P-7513-2014; OI mangino, massimo/0000-0002-2167-7470; Slagboom, P. Eline/0000-0002-2875-4723; Suchiman, H. Eka D./0000-0002-7168-5516; Magi, Reedik/0000-0002-2964-6011; Deelen, Joris/0000-0003-4483-3701; Vinuela, Ana/0000-0003-3771-8537; Talmud, Philippa/0000-0002-5560-1933; Beekman, Marian/0000-0003-0585-6206; Buxton, Jessica/0000-0002-0918-9335; Hovatta, Iiris/0000-0002-5990-7892; Medland, Sarah/0000-0003-1382-380X; Ripatti, Samuli/0000-0002-0504-1202; Montgomery, Grant/0000-0002-4140-8139; Prokopenko, Inga/0000-0003-1624-7457; Wright, Margaret/0000-0001-7133-4970; Ouwehand, Willem/0000-0002-7744-1790; Kaprio, Jaakko/0000-0002-3716-2455; Karssen, Lennart C./0000-0002-1959-342X; Martin, Nicholas/0000-0003-4069-8020; Esko, Tonu/0000-0003-1982-6569; Erdmann, Jeanette/0000-0002-4486-6231; Norata, Giuseppe Danilo/0000-0002-6081-1257; Mannisto, Satu/0000-0002-8668-3046; Gieger, Christian/0000-0001-6986-9554; Verweij, Niek/0000-0002-4303-7685; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Eriksson, Johan/0000-0002-2516-2060; Catapano, Alberico Luigi/0000-0002-7593-2094 FU European Union Framework 7 ENGAGE Project [HEALTH-F4-2007-201413] FX This study was undertaken under the framework of European Union Framework 7 ENGAGE Project (HEALTH-F4-2007-201413). NR 39 TC 222 Z9 226 U1 6 U2 62 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2013 VL 45 IS 4 BP 422 EP 427 DI 10.1038/ng.2528 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600013 PM 23535734 ER PT J AU Fritsche, LG Chen, W Schu, M Yaspan, BL Yu, Y Thorleifsson, G Zack, DJ Arakawa, S Cipriani, V Ripke, S Igo, RP Buitendijk, GHS Sim, XL Weeks, DE Guymer, RH Merriam, JE Francis, PJ Hannum, G Agarwal, A Armbrecht, AM Audo, I Aung, T Barile, GR Benchaboune, M Bird, AC Bishop, PN Branham, KE Brooks, M Brucker, AJ Cade, WH Cain, MS Campochiaroll, PA Chan, CC Cheng, CY Chew, EY Chin, KA Chowers, I Clayton, DG Cojocaru, R Conley, YP Cornes, BK Daly, MJ Dhillon, B Edwards, A Evangelou, E Fagemess, J Ferreyra, HA Friedman, JS Geirsdottir, A George, RJ Gieger, C Gupta, N Hagstrom, SA Harding, SP Haritoglou, C Heckenlively, JR Hoz, FG Hughes, G Ioannidis, JPA Ishibashi, T Joseph, P Jun, G Kamatani, Y Katsanis, N Keilhauer, CN Khan, JC Kim, IK Kiyohara, Y Klein, BEK Klein, R Kovach, JL Kozak, I Lee, CJ Lee, KE Lichtner, P Lotery, AJ Meitinger, T Mitchell, P Mohand-Said, S Moore, AT Morgan, DJ Margaux, AM Myers, CE Naj, AC Nakamura, Y Okada, Y Orlin, A Ortube, MC Othman, MI Pappas, C Park, KH Pauer, GJT Peachey, NS Poch, O Priya, RR Reynolds, R Richardson, AJ Ripp, R Rudolph, G Ryu, E Sahel, JA Schaumberg, DA Scholl, HPN Schwartz, SG Scott, WK Shahid, H Sigurdsson, H Silvestri, G Sivakumaran, TA Smith, RT Sobrin, L Souied, EH Stambolian, DE Stefansson, H Sturgill-Short, GM Takahashi, A Tosakulwong, N Truitt, BJ Tsironi, EE Uitterlinden, AG van Duijn, CM Vijaya, L Vingerling, JR Vithana, EN Webster, AR Wichmann, HE Winkler, TW Wong, TY Wright, AF Zelenika, D Zhang, M Zhao, L Zhang, K Klein, ML Hageman, GS Lathrop, GM Stefansson, K Allikmets, R Baird, PN Gorin, MB Wang, JJ Klaver, CCW Seddon, JM Pericak-Vance, MA Iyengar, SK Yates, JRW Swaroop, A Weber, BHF Kubo, M DeAngelis, MM Leveillard, T Thorsteinsdottir, U Haines, JL Farrer, LA Heid, IM Abecasis, GR AF Fritsche, Lars G. Chen, Wei Schu, Matthew Yaspan, Brian L. Yu, Yi Thorleifsson, Gudmar Zack, Donald J. Arakawa, Satoshi Cipriani, Valentina Ripke, Stephan Igo, Robert P., Jr. Buitendijk, Gabrielle H. S. Sim, Xueling Weeks, Daniel E. Guymer, Robyn H. Merriam, Joanna E. Francis, Peter J. Hannum, Gregory Agarwal, Anita Armbrecht, Ana Maria Audo, Isabelle Aung, Tin Barile, Gaetano R. Benchaboune, Mustapha Bird, Alan C. Bishop, Paul N. Branham, Kari E. Brooks, Matthew Brucker, Alexander J. Cade, William H. Cain, Melinda S. Campochiaroll, Peter A. Chan, Chi-Chao Cheng, Ching-Yu Chew, Emily Y. Chin, Kimberly A. Chowers, Itay Clayton, David G. Cojocaru, Radu Conley, Yvette P. Cornes, Belinda K. Daly, Mark J. Dhillon, Baljean Edwards, Albert Evangelou, Evangelos Fagemess, Jesen Ferreyra, Henry A. Friedman, James S. Geirsdottir, Asbjorg George, Ronnie J. Gieger, Christian Gupta, Neel Hagstrom, Stephanie A. Harding, Simon P. Haritoglou, Christos Heckenlively, John R. Hoz, Frank G. Hughes, Guy Ioannidis, John P. A. Ishibashi, Tatsuro Joseph, Peronne Jun, Gyungah Kamatani, Yoichiro Katsanis, Nicholas Keilhauer, Claudia N. Khan, Jane C. Kim, Ivana K. Kiyohara, Yutaka Klein, Barbara E. K. Klein, Ronald Kovach, Jaclyn L. Kozak, Igor Lee, Clara J. Lee, Kristine E. Lichtner, Peter Lotery, Andrew J. Meitinger, Thomas Mitchell, Paul Mohand-Saied, Saddek Moore, Anthony T. Morgan, Denise J. Morrison, Margaux A. Myers, Chelsea E. Naj, Adam C. Nakamura, Yusuke Okada, Yukinori Orlin, Anton Ortube, M. Carolina Othman, Mohammad I. Pappas, Chris Park, Kyu Hyung Pauer, Gayle J. T. Peachey, Neal S. Poch, Olivier Priya, Rinki Ratna Reynolds, Robyn Richardson, Andrea J. Ripp, Raymond Rudolph, Guenther Ryu, Euijung Sahel, Jose-Alain Schaumberg, Debra A. Scholl, Hendrik P. N. Schwartz, Stephen G. Scott, William K. Shahid, Humma Sigurdsson, Haraldur Silvestri, Giuliana Sivakumaran, Theru A. Smith, R. Theodore Sobrin, Lucia Souied, Eric H. Stambolian, Dwight E. Stefansson, Hreinn Sturgill-Short, Gwen M. Takahashi, Atsushi Tosakulwong, Nirubol Truitt, Barbara J. Tsironi, Evangelia E. Uitterlinden, Andre G. van Duijn, Cornelia M. Vijaya, Lingam Vingerling, Johannes R. Vithana, Eranga N. Webster, Andrew R. Wichmann, H-Erich Winkler, Thomas W. Wong, Tien Y. Wright, Alan F. Zelenika, Diana Zhang, Ming Zhao, Ling Zhang, Kang Klein, Michael L. Hageman, Gregory S. Lathrop, G. Mark Stefansson, Kari Allikmets, Rando Baird, Paul N. Gorin, Michael B. Wang, Jie Jin Klaver, Caroline C. W. Seddon, Johanna M. Pericak-Vance, Margaret A. Iyengar, Sudha K. Yates, John R. W. Swaroop, Anand Weber, Bernhard H. F. Kubo, Michiaki DeAngelis, Margaret M. Leveillard, Thierry Thorsteinsdottir, Unnur Haines, Jonathan L. Farrer, Lindsay A. Heid, Iris M. Abecasis, Goncalo R. CA AMD Gene Consortium TI Seven new loci associated with age-related macular degeneration SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COMPLEMENT FACTOR-H; GENOTYPE IMPUTATION; APOLIPOPROTEIN-E; INFLUENCES RISK; SUSCEPTIBILITY; GENE; VARIANTS; DISEASES; CFH AB Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 x 10(-8) These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 x 10-8 for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD. C1 [Fritsche, Lars G.; Weber, Bernhard H. F.] Univ Regensburg, Inst Human Genet, D-93053 Regensburg, Germany. [Fritsche, Lars G.; Chen, Wei; Sim, Xueling; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Chen, Wei] Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med,Med Ctr, Div Pediat Pulm Med Allergy & Immunol,Dept Pediat, Pittsburgh, PA USA. [Schu, Matthew; Jun, Gyungah; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med, Sect Biomed Genet, Boston, MA 02118 USA. [Schu, Matthew; Jun, Gyungah; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Med, Sect Biomed Genet, Boston, MA USA. [Yaspan, Brian L.; Haines, Jonathan L.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Yaspan, Brian L.; Haines, Jonathan L.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Nashville, TN 37232 USA. [Yu, Yi; Chin, Kimberly A.; Reynolds, Robyn; Seddon, Johanna M.] Tufts Med Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA USA. [Thorleifsson, Gudmar; Stefansson, Hreinn] deCODE Genet, Reykjavik, Iceland. [Zack, Donald J.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. [Zack, Donald J.; Sahel, Jose-Alain; Leveillard, Thierry] Univ Paris 06, Dept Genet, Inst Vis, UMRS 968, Paris, France. [Zack, Donald J.; Campochiaroll, Peter A.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dept Neurosci, Baltimore, MD 21205 USA. [Zack, Donald J.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Inst Genet Med, Baltimore, MD 21205 USA. [Arakawa, Satoshi; Kubo, Michiaki] RIKEN, CGM, Res Grp Genotyping, Lab Genotyping Dev, Yokohama, Kanagawa, Japan. [Cipriani, Valentina; Bird, Alan C.; Moore, Anthony T.; Webster, Andrew R.; Yates, John R. W.] Moorfields Eye Hosp, London, England. [Cipriani, Valentina; Bird, Alan C.; Moore, Anthony T.; Sahel, Jose-Alain; Webster, Andrew R.; Yates, John R. W.] UCL, Inst Ophthalmol, London, England. [Ripke, Stephan; Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ripke, Stephan] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Igo, Robert P., Jr.; Joseph, Peronne; Truitt, Barbara J.; Iyengar, Sudha K.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Buitendijk, Gabrielle H. S.; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Vingerling, Johannes R.; Klaver, Caroline C. W.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Buitendijk, Gabrielle H. S.; Vingerling, Johannes R.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Sim, Xueling] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore. [Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Weeks, Daniel E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Guymer, Robyn H.; Cain, Melinda S.; Richardson, Andrea J.; Wong, Tien Y.; Baird, Paul N.; Wang, Jie Jin] Univ Melbourne, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia, East Melbourne, Vic, Australia. [Merriam, Joanna E.; Barile, Gaetano R.; Smith, R. Theodore; Allikmets, Rando] Columbia Univ, Dept Ophthalmol, New York, NY 10027 USA. [Francis, Peter J.; Klein, Michael L.] Oregon Hlth & Sci Univ, Casey Eye Inst, Macular Degenerat Ctr, Portland, OR 97201 USA. [Hannum, Gregory] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Agarwal, Anita] Vanderbilt Univ, Med Ctr, Vanderbilt Eye Inst, Nashville, TN USA. [Agarwal, Anita] Vanderbilt Univ, Sch Med, Dept Ophthalmol & Visual Sci, Nashville, TN 37212 USA. 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[Bishop, Paul N.] Cent Manchester Univ Hosp Natl Hlth Serv NHS Fdn, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Branham, Kari E.; Heckenlively, John R.; Othman, Mohammad I.; Swaroop, Anand] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Brooks, Matthew; Cojocaru, Radu; Friedman, James S.; Gupta, Neel; Priya, Rinki Ratna; Swaroop, Anand] NEI, Neurobiol Neurodegenerabon & Repair Lab N NNRL, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Brucker, Alexander J.] Penn Presbyterian Med Ctr, Scheie Eye Inst, Philadelphia, PA USA. [Cade, William H.; Naj, Adam C.; Scott, William K.; Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA. [Cade, William H.; Naj, Adam C.; Scott, William K.; Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn Dept Human Genet, Miami, FL 33136 USA. [Campochiaroll, Peter A.; Scholl, Hendrik P. N.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dept Ophthalmol, Baltimore, MD 21205 USA. [Chan, Chi-Chao] NEI, Immunopathol Sect, Immunol Lab, US Natl Inst Hlth, Bethesda, MD USA. [Cheng, Ching-Yu] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. [Cheng, Ching-Yu] Duke Natl Univ Singapore Grad Med Sch, Off Clin Sci, Ctr Quantitat Med, Singapore, Singapore. [Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Chowers, Itay] Hadassah Hebrew Univ Med Ctr, Dept Ophthalmol, Jerusalem, Israel. [Clayton, David G.; Khan, Jane C.; Shahid, Humma; Yates, John R. W.] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge, England. [Conley, Yvette P.] Univ Pittsburgh, Sch Nursing, Dept Hlth Promot & Dev, Pittsburgh, PA 15261 USA. [Edwards, Albert] Univ Oregon, Inst Mol Biol, Eugene, OR 97403 USA. [Evangelou, Evangelos] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Fagemess, Jesen] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Fagemess, Jesen; Lee, Clara J.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Ferreyra, Henry A.; Hughes, Guy; Kozak, Igor; Lee, Clara J.; Zhang, Ming; Zhao, Ling; Zhang, Kang] Univ Calif San Diego, Dept Ophthalmol, La Jolla, CA 92093 USA. [Ferreyra, Henry A.; Hughes, Guy; Kozak, Igor; Lee, Clara J.; Zhang, Ming; Zhao, Ling; Zhang, Kang] Univ Calif San Diego, Shiley Eye Ctr, La Jolla, CA 92093 USA. [Geirsdottir, Asbjorg; Sigurdsson, Haraldur] Natl Univ Hosp Reykjavik, Dept Ophthalmol, Reykjavik, Iceland. [George, Ronnie J.; Vijaya, Lingam] Vis Res Fdn, Glaucoma Project, Madras, Tamil Nadu, India. [Gieger, Christian; Heid, Iris M.] Deutsch Forschungszentrum Gesundheit & Umwelt, Helmholtz Zentrum Manchen, Inst Genet Epidemiol, Neuherberg, Germany. [Hagstrom, Stephanie A.; Pauer, Gayle J. T.; Peachey, Neal S.] Cleveland Clin Fdn, Cole Eye Inst, Cleveland, OH 44195 USA. [Harding, Simon P.] Univ Liverpool, Dept Eye & Vis Sci, Inst Ageing & Chron Dis, Liverpool L69 3BX, Merseyside, England. [Haritoglou, Christos; Rudolph, Guenther] Univ Munich, Augenklin, D-80539 Munich, Germany. [Hoz, Frank G.; Scholl, Hendrik P. N.] Univ Bonn, Dept Ophthalmol, Bonn, Germany. [Hughes, Guy; Zhang, Ming; Zhao, Ling; Zhang, Kang] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Ioannidis, John P. A.] Stanford Univ, Dept Med, Sch Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Dept Stat, Sch Humanities & Sci, Stanford, CA 94305 USA. [Ishibashi, Tatsuro] Kyushu Univ, Grad Sch Med Sci, Dept Ophthalmol, Fukuoka, Japan. [Jun, Gyungah; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Jun, Gyungah; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Ophthalmol, Boston, MA 02118 USA. [Jun, Gyungah; Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Jun, Gyungah; Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kamatani, Yoichiro; Lathrop, G. Mark] Ctr Etud Polymorphisme Humain CEPH, Fdn Jean Dausset, Paris, France. [Katsanis, Nicholas] Duke Univ, Ctr Human Dis Modeling, Durham, NC USA. [Katsanis, Nicholas] Duke Univ, Dept Cell Biol, Durham, NC USA. [Katsanis, Nicholas] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Keilhauer, Claudia N.] Univ Wurzburg, Dept Ophthalmol, D-97070 Wurzburg, Germany. [Khan, Jane C.] Royal Perth Hosp, Dept Ophthalmol, Perth, WA, Australia. [Khan, Jane C.] Univ Western Australia, Ctr Ophthalmol & Visual Sci, Perth, WA 6009, Australia. [Kim, Ivana K.; Schaumberg, Debra A.; Sobrin, Lucia] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Kim, Ivana K.; Sobrin, Lucia] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Kiyohara, Yutaka; Thorsteinsdottir, Unnur] Kyushu Univ, Grad Sch Med Sci, Dept Environm Med, Fukuoka, Japan. [Klein, Barbara E. K.; Klein, Ronald; Lee, Kristine E.; Myers, Chelsea E.] Univ Wisconsin, Sch Med, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Klein, Barbara E. K.; Klein, Ronald; Lee, Kristine E.; Myers, Chelsea E.] Univ Wisconsin, Sch Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Kovach, Jaclyn L.; Schwartz, Stephen G.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Lichtner, Peter; Meitinger, Thomas] Deutsch Forschungszentrum Gesundheit & Umwelt, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Lotery, Andrew J.] Univ Southampton, Fac Med Clin & Expt Sci, Southampton, Hants, England. [Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany. [Mitchell, Paul; Wang, Jie Jin] Univ Sydney, Dept Ophthalmol, Ctr Vis Res, Sydney, NSW 2006, Australia. [Mitchell, Paul; Wang, Jie Jin] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Mohand-Saied, Saddek] Univ Paris 06, Dept Therapeut, Inst Vis, UMRS 968, Paris, France. [Morgan, Denise J.; Morrison, Margaux A.; Stefansson, Kari; DeAngelis, Margaret M.] Univ Utah, Dept Ophthalmol & Visual Sci, John A Moran Eye Ctr, Salt Lake City, UT USA. [Nakamura, Yusuke] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Mol Med, Tokyo, Japan. [Okada, Yukinori; Takahashi, Atsushi] RIKEN, Lab Stat Anal, Yokohama, Kanagawa, Japan. [Orlin, Anton] Weill Cornell Med Coll, Dept Ophthalmol, New York, NY USA. [Ortube, M. Carolina; Gorin, Michael B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Ortube, M. Carolina; Gorin, Michael B.] Jules Stein Eye Inst, Los Angeles, CA 90024 USA. [Pappas, Chris; Hageman, Gregory S.] Univ Utah, Moran Ctr Translat Med, John A Moran Eye Ctr, Salt Lake City, UT USA. [Park, Kyu Hyung] Seoul Natl Univ, Bundang Hosp, Dept Ophthalmol, Kyeounggi, South Korea. [Peachey, Neal S.; Sturgill-Short, Gwen M.] Louis Stokes Vet Affairs Med Ctr, Res Serv, Cleveland, OH USA. [Poch, Olivier; Ripp, Raymond] IGBMC, Lab Integrat Bioinformat & Genom, Illkirch Graffenstaden, France. [Ryu, Euijung; Tosakulwong, Nirubol] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Sahel, Jose-Alain] Fdn Ophtalmol Adolphe Rothschild, Paris, France. [Sahel, Jose-Alain] Acad Sci Inst France, Paris, France. [Schaumberg, Debra A.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Shahid, Humma] Addenbrookes Hosp, Dept Ophthalmol, Cambridge, England. [Sigurdsson, Haraldur; Stefansson, Kari; Thorsteinsdottir, Unnur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Silvestri, Giuliana] Queens Univ Belfast, Ctr Vis & Vasc Sci, Belfast, Antrim, North Ireland. [Sivakumaran, Theru A.] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH USA. [Smith, R. Theodore] Columbia Univ, Dept Biomed Engn, New York, NY USA. [Souied, Eric H.] Univ Paris Est, Hop Henri Mondor, Ctr Rech Clin Ophthalmol, Hop Intercommunal Creteil, Creteil, France. [Stambolian, Dwight E.] Univ Penn, Dept Ophthalmol & Genet, Philadelphia, PA 19104 USA. [Tsironi, Evangelia E.] Univ Thessaly, Sch Med, Dept Ophthalmol, Larisa, Greece. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Wichmann, H-Erich] Deutsch Forschungszentrum Gesundheit & Umwelt, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany. [Gorin, Michael B.] Univ Munich, Inst Med Informat, Munich, Germany. [Wichmann, H-Erich; Gorin, Michael B.] Univ Munich, Klinikum Grosshadern, D-80539 Munich, Germany. [Kubo, Michiaki] Univ Munich, Inst Biometry, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Inst Epidemiol, Munich, Germany. [Winkler, Thomas W.; Heid, Iris M.] Univ Regensburg, Dept Epidemiol & Prevent Med, D-93053 Regensburg, Germany. [Wright, Alan F.] Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh, Midlothian, Scotland. [Zelenika, Diana; Lathrop, G. Mark] Ctr Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France. [Zhang, Ming; Zhang, Kang] Sichuan Univ, West China Hosp, Mol Med Res Ctr, Chengdu 610064, Peoples R China. [Zhang, Ming; Zhang, Kang] Sichuan Univ, West China Hosp, Dept Ophthalmol, Chengdu 610064, Peoples R China. [Allikmets, Rando] Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA. [Gorin, Michael B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. [Seddon, Johanna M.] Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA. [Iyengar, Sudha K.] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. [Iyengar, Sudha K.] Case Western Reserve Univ, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA. [Iyengar, Sudha K.] Case Western Reserve Univ, Ctr Clin Invest, Cleveland, OH 44106 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Neurol, Boston, MA USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Abecasis, GR (reprint author), Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. EM jonathan@chgr.mc.vanderbilt.edu; farrer@bu.edu; iris.heid@klinik.uni-regensburg.de; goncalo@umich.edu RI Kubo, Michiaki/N-7947-2015; Abecasis, Goncalo/B-7840-2010; Sahel, Jose-Alain/F-3172-2017; Cipriani, Valentina/A-8549-2012; Cheng, Ching-Yu/K-7017-2013; Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Zhao, Ling/D-9005-2015; DeAngelis, e/J-7863-2015; Meitinger, Thomas/O-1318-2015; Klaver, Caroline/A-2013-2016; Kamatani, Yoichiro/N-5513-2015; OI Farrer, Lindsay/0000-0001-5533-4225; george, ronnie/0000-0001-7368-0252; Baird, Paul/0000-0002-1305-3502; Zack, Don/0000-0002-7966-1973; Abecasis, Goncalo/0000-0003-1509-1825; Harding, Simon/0000-0003-4676-1158; Swaroop, Anand/0000-0002-1975-1141; Gieger, Christian/0000-0001-6986-9554; Stefansson, Hreinn/0000-0002-9331-6666; Klein, Ronald/0000-0002-4428-6237; Bishop, Paul/0000-0001-7937-7932; Cipriani, Valentina/0000-0002-0839-9955; Cheng, Ching-Yu/0000-0003-0655-885X; Wang, Jie Jin/0000-0001-9491-4898; Jun, Gyungah/0000-0002-3230-8697; Evangelou, Evangelos/0000-0002-5488-2999; smith, theodore/0000-0002-1693-943X; Weeks, Daniel/0000-0001-9410-7228; Katsanis, Nicholas/0000-0002-2480-0171 FU Medical Research Council [G0000067, MC_U127584475, MR/K006584/1]; NEI NIH HHS [P30 EY014800, R01 EY013435, R01 EY022005]; NHGRI NIH HHS [R01 HG007022] NR 51 TC 281 Z9 282 U1 14 U2 108 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2013 VL 45 IS 4 BP 433 EP 439 DI 10.1038/ng.2578 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 115VS UT WOS:000316840600015 PM 23455636 ER PT J AU Pillai, S AF Pillai, Shiv TI Love the one you're with: the HIV, B cell and T-FH cell triangle SO NATURE MEDICINE LA English DT Editorial Material ID FOLLICULAR HELPER-CELLS; INFECTION AB Many HIV-infected people show impaired humoral immune responses, but it is unclear why. A new view into this conundrum may be provided with the recent discovery of altered interactions between follicular helper T (T-FH) cells and germinal center B cells from HIV-infected individuals. This leads to inadequate T-FH cell help for germinal center B cells and decreased B cell antibody responses (pages 494-499). C1 Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. RP Pillai, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. EM pillai@helix.mgh.harvard.edu NR 9 TC 4 Z9 4 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD APR PY 2013 VL 19 IS 4 BP 401 EP 402 DI 10.1038/nm.3141 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 119PF UT WOS:000317109100017 PM 23558623 ER PT J AU Cubas, RA Mudd, JC Savoye, AL Perreau, M van Grevenynghe, J Metcalf, T Connick, E Meditz, A Freeman, GJ Abesada-Terk, G Jacobson, JM Brooks, AD Crotty, S Estes, JD Pantaleo, G Lederman, MM Haddad, EK AF Cubas, Rafael A. Mudd, Joseph C. Savoye, Anne-Laure Perreau, Matthieu van Grevenynghe, Julien Metcalf, Talibah Connick, Elizabeth Meditz, Amie Freeman, Gordon J. Abesada-Terk, Guillermo, Jr. Jacobson, Jeffrey M. Brooks, Ari D. Crotty, Shane Estes, Jacob D. Pantaleo, Giuseppe Lederman, Michael M. Haddad, Elias K. TI Inadequate T follicular cell help impairs B cell immunity during HIV infection SO NATURE MEDICINE LA English DT Article ID ACTIVE-ANTIRETROVIRAL-THERAPY; HUMORAL IMMUNITY; VIRAL-INFECTION; SIV INFECTION; LYMPH-NODES; C-MAF; MEMORY; RESPONSES; INDIVIDUALS; ANTIBODIES AB The majority of HIV-infected individuals fail to produce protective antibodies and have diminished responses to new immunizations(1-3). We report here that even though there is an expansion of follicular helper T (T-FH) cells in HIV-infected individuals, the cells are unable to provide adequate B cell help. We found a higher frequency of programmed cell death ligand 1 (PD-L1)(+) germinal center B cells from lymph nodes of HIV-infected individuals suggesting a potential role for PD-1-PD-L1 interaction in regulating T-FH cell function. In fact, we show that engagement of PD-1 on T-FH cells leads to a reduction in cell proliferation, activation, inducible T-cell co-stimulator (ICOS) expression and interleukin-21 (IL-21) cytokine secretion. Blocking PD-1 signaling enhances HIV-specific immunoglobulin production in vitro. We further show that at least part of this defect involves IL-21, as addition of this cytokine rescues antibody responses and plasma cell generation in vitro. Our results suggest that deregulation of T-FH cell-mediated B cell help diminishes B cell responses during HIV infection and may be related to PD-1 triggering on T-FH cells. These results demonstrate a role for T-FH cell impairment in HIV pathogenesis and suggest that enhancing their function could have a major impact on the outcome and control of HIV infection, preventing future infections and improving immune responses to vaccinations. C1 [Cubas, Rafael A.; van Grevenynghe, Julien; Metcalf, Talibah; Haddad, Elias K.] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL 34987 USA. [Mudd, Joseph C.; Lederman, Michael M.] Case Western Reserve Univ, Div Infect Dis, Ctr AIDS Res, Univ Hosp,Case Med Ctr, Cleveland, OH 44106 USA. [Savoye, Anne-Laure; Perreau, Matthieu; Pantaleo, Giuseppe] Univ Lausanne, Lausanne Univ Hosp, Swiss Vaccine Res Inst, Div Immunol & Allergy, Lausanne, Switzerland. [Connick, Elizabeth; Meditz, Amie] Univ Colorado Denver, Div Infect Dis, Denver, CO USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Abesada-Terk, Guillermo, Jr.] Martin Mem Hlth Syst, Robert & Carol Weissman Canc Ctr, Stuart, FL USA. [Jacobson, Jeffrey M.] Drexel Univ, Coll Med, Div Infect Dis & HIV Med, Philadelphia, PA 19104 USA. [Brooks, Ari D.] Drexel Univ, Coll Med, Dept Surg, Philadelphia, PA 19104 USA. [Crotty, Shane] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA USA. [Crotty, Shane] Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA USA. [Estes, Jacob D.] SAIC Frederick Inc, AIDS & Canc Virus Program, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Haddad, EK (reprint author), Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL 34987 USA. EM ehaddad@vgtifl.org RI Pantaleo, Giuseppe/K-6163-2016; Perreau, Matthieu/D-6309-2017 FU US National Institutes of Health (NIH) [HHSN272201100017C, NIH-1P01 AI080192, U19AI082630, 2P01 AI056299, R01 AI096966]; Case Western Reserve University Center for AIDS Research [AI 36219]; Cleveland Immunopathogenesis Consortium [AI 76174] FX We thank W. Ryzner, R. Bordi and D. Brown for sample collection. We also thank K. Kusser and Y. Shi from the Flow Cytometry Core at Vaccine & Gene Therapy Institute Florida for their help with sorting all the samples. We are grateful to R. Debernardo (Case Western Reserve University and University Hospitals Case Medical Center) for obtaining the HIV-uninfected lymph nodes and to B. Rodriguez for his help with the infected lymph node samples. This study was supported in part by US National Institutes of Health (NIH) contract HHSN272201100017C, NIH-1P01 AI080192, U19AI082630, 2P01 AI056299 and R01 AI096966. This work was also supported by the Case Western Reserve University Center for AIDS Research (AI 36219) and by the Cleveland Immunopathogenesis Consortium (AI 76174). NR 40 TC 138 Z9 144 U1 2 U2 29 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD APR PY 2013 VL 19 IS 4 BP 494 EP + DI 10.1038/nm.3109 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 119PF UT WOS:000317109100036 PM 23475201 ER PT J AU Kennedy, PJ Feng, J Robison, AJ Maze, I Badimon, A Mouzon, E Chaudhury, D Damez-Werno, DM Haggarty, SJ Han, MH Bassel-Duby, R Olson, EN Nestler, EJ AF Kennedy, Pamela J. Feng, Jian Robison, A. J. Maze, Ian Badimon, Ana Mouzon, Ezekiell Chaudhury, Dipesh Damez-Werno, Diane M. Haggarty, Stephen J. Han, Ming-Hu Bassel-Duby, Rhonda Olson, Eric N. Nestler, Eric J. TI Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation SO NATURE NEUROSCIENCE LA English DT Article ID NUCLEUS-ACCUMBENS; BEHAVIORAL SENSITIZATION; DEACETYLASE INHIBITORS; LOCOMOTOR SENSITIZATION; SYNAPTIC PLASTICITY; MEMORY FORMATION; DELTA-FOSB; AMPHETAMINE; EXPRESSION; MICE AB Induction of histone acetylation in the nucleus accumbens (NAc), a key brain reward region, promotes cocaine-induced alterations in gene expression. Histone deacetylases (HDACs) tightly regulate the acetylation of histone tails, but little is known about the functional specificity of different HDAC isoforms in the development and maintenance of cocaine-induced plasticity, and previous studies of HDAC inhibitors report conflicting effects on cocaine-elicited behavioral adaptations. Here we demonstrate that specific and prolonged blockade of HDAC1 in NAc of mice increased global levels of histone acetylation, but also induced repressive histone methylation and antagonized cocaine-induced changes in behavior, an effect mediated in part through a chromatin-mediated suppression of GABA(A) receptor subunit expression and inhibitory tone on NAc neurons. Our findings suggest a new mechanism by which prolonged and selective HDAC inhibition can alter behavioral and molecular adaptations to cocaine and inform the development of therapeutics for cocaine addiction. C1 [Kennedy, Pamela J.; Feng, Jian; Robison, A. J.; Badimon, Ana; Mouzon, Ezekiell; Damez-Werno, Diane M.; Nestler, Eric J.] Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY USA. [Kennedy, Pamela J.; Feng, Jian; Robison, A. J.; Badimon, Ana; Mouzon, Ezekiell; Damez-Werno, Diane M.; Nestler, Eric J.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY USA. [Maze, Ian] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10021 USA. [Chaudhury, Dipesh; Han, Ming-Hu] Mt Sinai Sch Med, Friedman Brain Inst, Dept Pharmacol & Syst Therapeut, New York, NY USA. [Haggarty, Stephen J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Dept Neurol, Boston, MA USA. [Bassel-Duby, Rhonda; Olson, Eric N.] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. RP Nestler, EJ (reprint author), Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, New York, NY USA. EM eric.nestler@mssm.edu OI Maze, Ian/0000-0003-1490-7781; Robison, Alfred/0000-0002-4150-9570; Haggarty, Stephen J./0000-0002-7872-168X FU US National Institute on Drug Abuse; US National Institute of Mental Health; Canadian Institutes for Health Research [MFE 90086] FX The authors would like to thank R. Neve (Massachusetts Institute of Technology) for viral vectors and M. Baxter for statistical expertise. This work was supported by grants from the US National Institute on Drug Abuse and National Institute of Mental Health (E.J.N.) and the Canadian Institutes for Health Research (P.J.K.; MFE 90086). NR 45 TC 62 Z9 64 U1 1 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD APR PY 2013 VL 16 IS 4 BP 434 EP U95 DI 10.1038/nn.3354 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 114EM UT WOS:000316723700013 PM 23475113 ER PT J AU Gellhorn, AC Katz, JN Suri, P AF Gellhorn, Alfred C. Katz, Jeffrey N. Suri, Pradeep TI Osteoarthritis of the spine: the facet joints SO NATURE REVIEWS RHEUMATOLOGY LA English DT Review ID LOW-BACK-PAIN; BONE-MARROW LESIONS; LUMBAR ZYGAPOPHYSEAL JOINTS; COMMUNITY-BASED POPULATION; CERVICAL-SPINE; DISC DEGENERATION; LONGITUDINAL ASSESSMENT; KNEE OSTEOARTHRITIS; CLINICAL-FEATURES; PREVALENCE AB Osteoarthritis (OA) of the spine involves the facet joints, which are located in the posterior aspect of the vertebral column and, in humans, are the only true synovial joints between adjacent spinal levels. Facet joint osteoarthritis (FJ OA) is widely prevalent in older adults, and is thought to be a common cause of back and neck pain. The prevalence of facet-mediated pain in clinical populations increases with increasing age, suggesting that FJ OA might have a particularly important role in older adults with spinal pain. Nevertheless, to date FJ OA has received far less study than other important OA phenotypes such as knee OA, and other features of spine pathoanatomy such as degenerative disc disease. This Review presents the current state of knowledge of FJ OA, including relevant anatomy, biomechanics, epidemiology, and clinical manifestations. We present the view that the modern concept of FJ OA is consonant with the concept of OA as a failure of the whole joint, and not simply of facet joint cartilage. Gellhorn, A. C. et al. Nat. Rev. Rheumatol. 9, 216-224 (2013); published online 13 November 2012; doi:10.1038/nrrheum.2012.199 C1 [Gellhorn, Alfred C.] Univ Washington, Dept Rehabil Med, Med Ctr, Seattle, WA 98105 USA. [Katz, Jeffrey N.] Harvard Univ, Dept Orthoped Surg, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Suri, Pradeep] VA Puget Sound Healthcare Syst, Div Rehabil Care Serv, Seattle, WA 98108 USA. RP Suri, P (reprint author), VA Puget Sound Healthcare Syst, Div Rehabil Care Serv, 1660 S Columbian Way, Seattle, WA 98108 USA. EM pradeep.suri@va.gov FU NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases [P60 AR 47782] FX J. N. Katz's work is supported in part by a grant (P60 AR 47782) from the NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases. NR 97 TC 34 Z9 36 U1 5 U2 42 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4790 J9 NAT REV RHEUMATOL JI Nat. Rev. Rheumatol. PD APR PY 2013 VL 9 IS 4 BP 216 EP 224 DI 10.1038/nrrheum.2012.199 PG 9 WC Rheumatology SC Rheumatology GA 117KR UT WOS:000316952600005 PM 23147891 ER PT J AU Kittner, SJ Singhal, AB AF Kittner, Steven J. Singhal, Aneesh B. TI Premature atherosclerosis A major contributor to early-onset ischemic stroke SO NEUROLOGY LA English DT Editorial Material ID YOUNG-ADULTS; REGISTRY C1 [Kittner, Steven J.] Baltimore Vet Adm Med Ctr, Dept Neurol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Singhal, Aneesh B.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Kittner, SJ (reprint author), Baltimore Vet Adm Med Ctr, Dept Neurol, Baltimore, MD 21201 USA. EM SKittner@som.umaryland.edu FU NINDS NIH HHS [U01 NS069208-01] NR 15 TC 7 Z9 9 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR PY 2013 VL 80 IS 14 BP 1272 EP 1273 DI 10.1212/WNL.0b013e31828ab3a4 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 118AW UT WOS:000316995800006 PM 23468547 ER PT J AU Hedden, T Oh, H Younger, AP Patel, TA AF Hedden, Trey Oh, Hwamee Younger, Alayna P. Patel, Tanu A. TI Meta-analysis of amyloid-cognition relations in cognitively normal older adults SO NEUROLOGY LA English DT Review ID PRECLINICAL ALZHEIMERS-DISEASE; WHITE-MATTER; A-BETA; EXECUTIVE FUNCTION; IN-VIVO; DECLINE; BURDEN; IMPAIRMENT; DEMENTIA; MEMORY AB Objective: We conducted a meta-analysis of relationships between amyloid burden and cognition in cognitively normal, older adult humans. Methods: Methods of assessing amyloid burden included were CSF or plasma assays, histopathology, and PET ligands. Cognitive domains examined were episodic memory, executive function, working memory, processing speed, visuospatial function, semantic memory, and global cognition. Sixty-four studies representing 7,140 subjects met selection criteria, with 3,495 subjects from 34 studies representing independent cohorts. Weighted effect sizes were obtained for each study. Primary analyses were conducted limiting to independent cohort studies using only the most common assessment method (Pittsburgh compound B). Exploratory analyses included all assessment methods. Results: Episodic memory (r = 0.12) had a significant relationship to amyloid burden. Executive function and global cognition did not have significant relationships to amyloid in the primary analysis of Pittsburgh compound B (r = 0.05 and r = 0.08, respectively), but did when including all assessment methods (r = 0.08 and r = 0.09, respectively). The domains of working memory, processing speed, visuospatial function, and semantic memory did not have significant relationships to amyloid. Differences in the method of amyloid assessment, study design (longitudinal vs cross-sectional), or inclusion of control variables (age, etc.) had little influence. Conclusions: Based on this meta-analytic survey of the literature, increased amyloid burden has small but nontrivial associations with specific domains of cognitive performance in individuals who are currently cognitively normal. These associations may be useful for identifying preclinical Alzheimer disease or developing clinical outcome measures. Neurology (R) 2013;80:1341-1348 C1 [Hedden, Trey; Younger, Alayna P.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Hedden, Trey] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Younger, Alayna P.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Oh, Hwamee; Patel, Tanu A.] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. RP Hedden, T (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM hedden@nmr.mgh.harvard.edu FU National Institute on Aging [P01 AG036694, R01 AG034556, R01 AG034570, K01 AG040197]; Alzheimer's Association; Center for Functional Neuroimaging Technologies [RR14075]; Biomedical Technology Program of the National Center for Research Resources, NIH; NIH [P01 AG036694, R01 AG034556, R01 AG034570, K01 AG040197] FX This work was supported in part by the National Institute on Aging (grant numbers P01 AG036694, R01 AG034556, R01 AG034570, and K01 AG040197); and by the Alzheimer's Association. This research was performed in part at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies (grant number P41 RR14075), a P41 Regional Resource supported by the Biomedical Technology Program of the National Center for Research Resources, NIH.; T. Hedden received funding from NIH grants K01 AG040197, P01 AG036694, and R01 AG034556. H. Oh received funding from the Alzheimer's Association and NIH grant R01 AG034570. A. P. Younger has received funding from NIH grants P01 AG036694 and R01 AG034556. T. A. Patel reports no disclosures. Go to Neurology.org for full disclosures. NR 51 TC 65 Z9 65 U1 1 U2 25 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR PY 2013 VL 80 IS 14 BP 1341 EP 1348 DI 10.1212/WNL.0b013e31828ab35d PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 118AW UT WOS:000316995800019 PM 23547267 ER PT J AU Gonda, DD Akers, JC Kim, R Kalkanis, SN Hochberg, FH Chen, CC Carter, BS AF Gonda, David D. Akers, Johnny C. Kim, Ryan Kalkanis, Steven N. Hochberg, Fred H. Chen, Clark C. Carter, Bob S. TI Neuro-oncologic Applications of Exosomes, Microvesicles, and Other Nano-Sized Extracellular Particles SO NEUROSURGERY LA English DT Review DE Biomarkers; Extracellular vesicles; Exosomes; Microvesicles ID TUMOR-DERIVED MICROVESICLES; CANCER-CELL-LINES; GLIOBLASTOMA-MULTIFORME; PILOCYTIC ASTROCYTOMAS; INTERCELLULAR TRANSFER; T-CELLS; PROGNOSTIC-SIGNIFICANCE; BEARING MICROVESICLES; TRANSFERRIN RECEPTOR; SHEEP RETICULOCYTES AB The discovery that tumor-derived proteins and nucleic acids can be detected in nano-sized vesicles in the plasma and cerebrospinal fluid of patients afflicted with brain tumors has expanded opportunities for biomarker and therapeutic discovery. Through delivery of their contents to surrounding cells, exosomes, microvesicles, and other nano-sized extracellular vesicles secreted by tumors modulate their environment to promote tumor growth and survival. In this review, we discuss the biological processes mediated by these extracellular vesicles and their applications in terms of brain tumor diagnosis, monitoring, and therapy. We review the normal physiology of these extracellular vesicles, their pertinence to tumor biology, and directions for research in this field. C1 [Gonda, David D.; Kim, Ryan; Chen, Clark C.; Carter, Bob S.] Univ Calif San Diego, Dept Neurosurg, San Diego, CA 92103 USA. [Gonda, David D.; Akers, Johnny C.; Kim, Ryan; Chen, Clark C.; Carter, Bob S.] Univ Calif San Diego, Ctr Theoret & Appl Neurooncol, San Diego, CA 92103 USA. [Kalkanis, Steven N.] Henry Ford Hlth Syst, Dept Neurosurg, Detroit, MI USA. [Hochberg, Fred H.] Massachusetts Gen Hosp, Pappas Ctr, Boston, MA 02114 USA. RP Chen, CC (reprint author), 3855 Hlth Sci Dr,0987, La Jolla, CA 92093 USA. EM clarkchen@ucsd.edu FU Exosome Diagnostic; ABC2 foundation FX Dr Carter reports receiving consulting fees and grant support from Exosome Diagnostic and ABC2 foundation. The other authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article. NR 102 TC 13 Z9 13 U1 1 U2 33 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD APR PY 2013 VL 72 IS 4 BP 501 EP 510 DI 10.1227/NEU.0b013e3182846e63 PG 10 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 113KU UT WOS:000316667000018 PM 23277376 ER PT J AU Nagler, RH Viswanath, K AF Nagler, Rebekah H. Viswanath, Kasisomayajula TI Implementation and Research Priorities for FCTC Articles 13 and 16: Tobacco Advertising, Promotion, and Sponsorship and Sales to and by Minors SO NICOTINE & TOBACCO RESEARCH LA English DT Review ID YOUTH SMOKING PREVENTION; SURVEY GYTS DATA; POINT-OF-SALE; FRAMEWORK-CONVENTION; UNITED-STATES; YOUNG-ADULTS; CONTROL POLICY; LATIN-AMERICA; CIGARETTE ADS; CIVIL-SOCIETY AB Introduction: Article 13 of the Framework Convention on Tobacco Control (FCTC) calls for a comprehensive ban on tobacco advertising, promotion, and sponsorship (TAPS), and Article 16 calls for prohibition of tobacco sales to and by minors. Although these mandates are based on sound science, many countries have found provision implementation to be rife with challenges. Objective: This paper reviews the history of tobacco marketing and minor access restrictions in high-, middle-, and low-income countries, identifying past challenges and successes. We consider current challenges to FCTC implementation, how these barriers can be addressed, and what research is necessary to support such efforts. Specifically, we identify implementation and research priorities for FCTC Articles 13 and 16. Discussion: Although a solid evidence base underpins the FCTC's call for TAPS bans and minor access restrictions, we know substantially less about how best to implement these restrictions. Drawing on the regulatory experiences of high-, middle-, and low-income countries, we discern several implementation and research priorities, which are organized into 4 categories: policy enactment and enforcement, human capital expertise, the effects of FCTC marketing and youth access policies, and knowledge exchange and transfer among signatories. Future research should provide detailed case studies on implementation successes and failures, as well as insights into how knowledge of successful restrictions can be translated into tobacco control policy and practice and shared among different stakeholders. Conclusion: Tobacco marketing surveillance, sales-to-minors compliance checks, enforcement and evaluation of restriction policies, and capacity building and knowledge transfer are likely to prove central to effective implementation. C1 [Nagler, Rebekah H.; Viswanath, Kasisomayajula] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Nagler, Rebekah H.; Viswanath, Kasisomayajula] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02215 USA. [Viswanath, Kasisomayajula] Dana Farber Canc Inst, McGraw Patterson Ctr Populat Sci, Boston, MA 02215 USA. RP Nagler, RH (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 450 Brookline Ave,LW 601, Boston, MA 02215 USA. EM rebekah_nagler@dfci.harvard.edu FU Tobacco Disparities Research Network; National Cancer Institute; American Legacy Foundation; Harvard School of Public Health's Lung Cancer Disparities Center [3 P50-CA148596]; Dana-Farber/Harvard Cancer Center [P30-CA006516]; National Cancer Institute by the Harvard Education Program in Cancer Prevention and Control [5 R25-CA057711] FX This work was supported by the Tobacco Disparities Research Network (jointly funded by the National Cancer Institute and American Legacy Foundation), the Harvard School of Public Health's Lung Cancer Disparities Center (3 P50-CA148596), and the Dana-Farber/Harvard Cancer Center (P30-CA006516). Funding support for RHN was also provided through the National Cancer Institute by the Harvard Education Program in Cancer Prevention and Control (5 R25-CA057711). NR 107 TC 14 Z9 14 U1 3 U2 22 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD APR PY 2013 VL 15 IS 4 BP 832 EP 846 DI 10.1093/ntr/nts331 PG 15 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 114XQ UT WOS:000316776700008 PM 23291641 ER PT J AU Bradford, LS Boruta, DM AF Bradford, Leslie S. Boruta, David M. TI Laparoendoscopic Single-Site Surgery in Gynecology: A Review of the Literature, Tools, and Techniques SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Article ID ASSISTED VAGINAL HYSTERECTOMY; PORT LAPAROSCOPIC SURGERY; PERIOPERATIVE OUTCOMES; INITIAL-EXPERIENCE; ENDOMETRIAL CANCER; SURGICAL OUTCOMES; LEARNING-CURVE; LESS; SALPINGECTOMY; PREGNANCY AB Recent decades have witnessed a tremendous shift from laparotomy to laparoscopy as the surgical approach of choice in gynecology. Completion of increasingly complicated procedures has been facilitated by technical advances in instrumentation. Lately, increasing attention has been paid to reducing both the number and size of laparoscopic incisions, with the ultimate goal being the absence of any visible scar. Laparoendoscopic single-site surgery (LESS), or single-incision laparoscopy, describes the use of 1 small skin incision to complete laparoscopic surgical procedures where traditionally multiple incisions were created. In addition to examining the developing literature related to LESS in gynecology, the aims of this review were to describe the technical challenges encountered during performance of LESS and to provide practical solutions for instrumentation and surgical techniques that allow them to be overcome. Target Audience: Obstetricians and gynecologists, family physicians Learning Objectives: After completing this CME activity, physicians should be better able to identify potential benefits of LESS, and implement practical solutions for instrumentation and surgical techniques to overcome technical challenges faced during LESS. C1 [Bradford, Leslie S.] Massachusetts Gen Hosp, Div Gynecol Oncol, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Boruta, David M.] Harvard Univ, Sch Med, Boston, MA USA. RP Boruta, DM (reprint author), Massachusetts Gen Hosp, Yawkey Ctr, Suite 9E,55 Fruit St, Boston, MA 02114 USA. EM dboruta@partners.org NR 46 TC 5 Z9 6 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD APR PY 2013 VL 68 IS 4 BP 295 EP 304 DI 10.1097/OGX.0b013e318286f673 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 117JB UT WOS:000316948300019 PM 23943039 ER PT J AU Barroilhet, L Van Hanegem, L Bernstein, M Feldman, S AF Barroilhet, Lisa Van Hanegem, Lennie Bernstein, Marilyn Feldman, Sarah TI Potential Effects of Updated Pap Test Screening Guidelines and Adenocarcinoma In Situ of the Cervix SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; PAPANICOLAOU SMEAR SENSITIVITY; ATYPICAL GLANDULAR CELLS; UTERINE CERVIX; HUMAN-PAPILLOMAVIRUS; YOUNGER WOMEN; UNITED-STATES; POPULATION; CANCER; PREVENTION AB OBJECTIVE: To review cases of adenocarcinoma in situ (AIS) at our institution to examine how updated guidelines affect the timing of diagnosis. METHODS: We identified patients with AIS diagnosed between 1998 and 2010 using the International Classification of Diseases, 9th Revision, Clinical Modification, code 233.1. Diagnosis was confirmed by pathology review. We abstracted demographic data, dysplasia history, and modalities utilized for diagnosis and treatment. RESULTS: We identified 242 patients who met selection criteria. Two hundred eight (86%) had Pap test abnormalities at presentation. One hundred thirty-seven out of 208 (66%) patients with abnormal Pap test results had a squamous, rather than glandular, abnormality. The mean time from abnormal Pap test to diagnosis of AIS was 29 months in patients older than 30 years and was 21 months in patients 30 years or younger. In patients younger than 21 years, 16 out of 17 had abnormal screening Pap test results showing squamous lesions. Their subsequent treatment for squamous dysplasia ultimately led to the diagnosis of AIS. CONCLUSION: Updated screening guidelines may prevent the expeditious diagnosis of AIS in females younger than 21 years and those aged 21-29 years, many of whom had normal Pap test results within 3 years of diagnosis. (Obstet Gynecol 2013;121:759-64) DOI: http://10.1097/AOG.0b013e3182887cad C1 Univ Wisconsin, Madison, WI USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. RP Barroilhet, L (reprint author), UW Hosp, H4-658 CSC,600 Highland Ave, Madison, WI 53792 USA. EM barroilhet@wisc.edu NR 27 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2013 VL 121 IS 4 BP 759 EP 764 DI 10.1097/AOG.0b013e3182887cad PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 112RJ UT WOS:000316610000010 PM 23635675 ER PT J AU Murji, A Patel, VI Leyland, N Choi, M AF Murji, Ally Patel, Virendra I. Leyland, Nicholas Choi, Matthew TI Single-Incision Laparoscopy in Gynecologic Surgery A Systematic Review and Meta-analysis SO OBSTETRICS AND GYNECOLOGY LA English DT Review ID ASSISTED VAGINAL HYSTERECTOMY; RANDOMIZED-CONTROLLED-TRIAL; SITE SURGERY; CONVENTIONAL LAPAROSCOPY; PERIOPERATIVE OUTCOMES; SURGICAL OUTCOMES; PORT LAPAROSCOPY; ADNEXAL DISEASE; SALPINGECTOMY; PREGNANCY AB OBJECTIVE: To evaluate surgical outcomes for gynecologic surgery performed by single-incision laparoscopy compared with conventional multi-incision laparoscopy. DATA SOURCES: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and clinicaltrials.gov through August 2012. We also screened reference lists of retrieved articles and manually searched abstracts from conference proceedings. METHODS OF STUDY SELECTION: We included randomized control trials (RCTs) and high-quality observational studies that compared outcomes for single-incision laparoscopy and conventional laparoscopy for gynecologic surgery in patients. Included studies met predefined quality criteria and reported, at minimum, on complications, conversions, and operative time. TABULATION, INTEGRATION, RESULTS: Six RCTs and 15 observational studies met inclusion criteria, with a total of 2,085 patients (899 single-incision laparoscopies and 1,186 conventional laparoscopies). In the pooled analysis, there was no significant difference in the risk of total complications between single-incision laparoscopy and conventional laparoscopy groups (relative risk 1.01, 95% confidence interval [CI] 0.72-1.40; P=.97, random effects model). The meta-analysis was powered to detect a 5% difference in complications (power=0.8, alpha=0.05). Mean operative time for adnexal surgery performed by single-incision laparoscopy was 6.97 minutes longer than conventional laparoscopy (95% CI 0.16-13.77; P=.045; I-2=47.2; random effects based on three RCTs). There was no significant difference in mean operative time for hysterectomy procedures performed by single-incision laparoscopy (8.29 minutes, 95% CI -5.85 to 22.43; P=.251; I-2=83.6; random effects based on three RCTs). Clinical outcomes of postoperative pain, change in hemoglobin, length of hospital stay, and scar cosmesis could not be pooled because of paucity of data and lack of uniform reporting. CONCLUSION: There was no difference in the risk of complications between single-incision laparoscopy and conventional laparoscopy approaches in gynecologic surgery. Studies with imprecise effect sizes suggest that single-incision laparoscopy may have longer operative time for adnexal surgery, but not for hysterectomy. Effects on other surgical outcomes remain uncertain. (Obstet Gynecol 2013;121:819-28) DOI: http://10.1097/AOG.0b013e318288828c C1 McMaster Univ, Dept Obstet & Gynecol, Hamilton, ON, Canada. McMaster Univ, Dept Surg, Hamilton, ON L8S 4L8, Canada. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Murji, A (reprint author), Hamilton Hlth Sci, 1280 Main St West HSC 2F39, Hamilton, ON L8S 4K1, Canada. EM ally.murji@gmail.com RI Murji, Ally/C-1442-2016 NR 31 TC 14 Z9 14 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2013 VL 121 IS 4 BP 819 EP 828 DI 10.1097/AOG.0b013e318288828c PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 112RJ UT WOS:000316610000018 PM 23635683 ER PT J AU Li, Q Yang, XH Xu, F Sharma, C Wang, HX Knoblich, K Rabinovitz, I Granter, SR Hemler, ME AF Li, Q. Yang, X. H. Xu, F. Sharma, C. Wang, H-X Knoblich, K. Rabinovitz, I. Granter, S. R. Hemler, M. E. TI Tetraspanin CD151 plays a key role in skin squamous cell carcinoma SO ONCOGENE LA English DT Article DE tetraspanin CD151; skin squamous cell carcinoma; chemical carcinogenesis; integrin alpha 6 beta 4; STAT3; PKC alpha ID TRANSMEMBRANE 4 SUPERFAMILY; KERATINOCYTE STEM-CELLS; ALPHA-6-BETA-4 INTEGRIN; IN-VIVO; BETA-4 INTEGRIN; MICE LACKING; ALPHA-3-BETA-1 INTEGRIN; MALIGNANT PROGRESSION; PROSTATE-CANCER; TYROSINE KINASE AB Here we provide the first evidence that tetraspanin CD151 can support de novo carcinogenesis. During two-stage mouse skin chemical carcinogenesis, CD151 reduces tumor lag time and increases incidence, multiplicity, size and progression to malignant squamous cell carcinoma (SCC), while supporting both cell survival during tumor initiation and cell proliferation during the promotion phase. In human skin SCC, CD151 expression is selectively elevated compared with other skin cancer types. CD151 support of keratinocyte survival and proliferation may depend on activation of transcription factor STAT3 (signal transducers and activators of transcription), a regulator of cell proliferation and apoptosis. CD151 also supports protein kinase C (PKC)alpha-alpha 6 beta 4 integrin association and PKC-dependent beta 4 S1424 phosphorylation, while regulating alpha 6 beta 4 distribution. CD151-PKC alpha effects on integrin beta 4 phosphorylation and subcellular localization are consistent with epithelial disruption to a less polarized, more invasive state. CD151 ablation, while minimally affecting normal cell and normal mouse functions, markedly sensitized mouse skin and epidermoid cells to chemicals/drugs including 7,12-dimethylbenz[alpha]anthracene (mutagen) and camptothecin (topoisomerase inhibitor), as well as to agents targeting epidermal growth factor receptor, PKC, Jak2/Tyk2 and STAT3. Hence, CD151 'co-targeting' may be therapeutically beneficial. These findings not only support CD151 as a potential tumor target, but also should apply to other cancers utilizing CD151/laminin-binding integrin complexes. Oncogene (2013) 32, 1772-1783; doi: 10.1038/onc.2012.205; published online 23 July 2012 C1 [Li, Q.; Xu, F.; Sharma, C.; Wang, H-X; Knoblich, K.; Hemler, M. E.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Li, Q.; Xu, F.; Sharma, C.; Wang, H-X; Knoblich, K.; Rabinovitz, I.; Hemler, M. E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Yang, X. H.] Univ Kentucky, Dept Mol & Biomed Pharmacol, Lexington, KY USA. [Rabinovitz, I.] Beth Israel Deaconess Med Ctr, Div Canc Biol & Angiogenesis, Dept Pathol, Boston, MA 02215 USA. [Granter, S. R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Hemler, ME (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Room D1430,44 Binney St, Boston, MA 02115 USA. EM martin_hemler@dfci.harvard.edu RI Knoblich, Konstantin/B-5980-2009; Li, Qinglin/K-2570-2015 OI Knoblich, Konstantin/0000-0002-5646-837X; Li, Qinglin/0000-0002-4125-1944 FU NIH [CA42368]; SG Komen Career Catalyst Award FX We thank Dr R Bronson for assistance with mouse histopathology, Dr Julie Aldridge for assistance with statistical analyses, and Drs David Frank, Sarah Walker and coworkers for nifuroxazide, ST3-01, assistance with STAT3 functional assay and helpful discussions. This work was supported by NIH grant CA42368 (to MEH), and a SG Komen Career Catalyst Award (to XHY). NR 77 TC 23 Z9 24 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD APR PY 2013 VL 32 IS 14 BP 1772 EP 1783 DI 10.1038/onc.2012.205 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 118RQ UT WOS:000317043900004 PM 22824799 ER PT J AU Martins, F de Oliveira, MA Wang, Q Sonis, S Gallottini, M George, S Treister, N AF Martins, Fabiana de Oliveira, Marcio Augusto Wang, Qian Sonis, Stephen Gallottini, Marina George, Suzanne Treister, Nathaniel TI A review of oral toxicity associated with mTOR inhibitor therapy in cancer patients SO ORAL ONCOLOGY LA English DT Review DE mTOR inhibitors; Stomatitis; Mucositis; Cancer; Toxicities ID ADVANCED SOLID TUMORS; RENAL-CELL CARCINOMA; PHASE-II TRIAL; REFRACTORY HEMATOLOGIC MALIGNANCIES; EVERY 2 WEEKS; MAMMALIAN TARGET; TEMSIROLIMUS CCI-779; RAPAMYCIN INHIBITOR; DEFOROLIMUS AP23573; BREAST-CANCER AB Aphthous-like stomatitis has been identified as one of the most common dose-limiting toxicities associated with mTOR inhibitor therapy in cancer patients. The objective of this study was to summarize the cumulative oral toxicities associated with mTOR inhibitors in published oncology trials with respect to dose, schedule, and need for dose modifications. A review of all oncology-related clinical trials of mTOR inhibitors was conducted and standardized data was abstracted from each study. 44 studies were included in the analysis with a total of 2822 patients treated with temsirolimus (19 studies), everolimus (20 studies), and ridaforolimus (five studies) for a wide range of malignancies. At least one adverse event (AE) occurred in 74.4% of patients. Mucositis was the most frequent AE overall (73.4%), the third most frequent severe AE (20.7%), accounting for 27.3% dose reductions and 13.1% of discontinuations, and the most frequent dose limiting toxicity (52.5%). Mucositis typically occurred during the first cycle of therapy and was graded as mild to moderate in approximately 90% of the patients; severe mucositis generally occurred at higher doses. There were no clear differences in mucositis among the three agents and in most cases lesions resolved spontaneously. Oral mucositis is a frequent complication of mTOR inhibitor therapy and a significant cause of dose reductions and discontinuations in oncology trials. Prevention and management strategies should be investigated to improve tolerability and better permit effective long-term regimens. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Martins, Fabiana; de Oliveira, Marcio Augusto; Gallottini, Marina] Univ Sao Paulo, Dept Oral Pathol, Sch Dent, Sao Paulo, Brazil. [Wang, Qian] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Sonis, Stephen; Treister, Nathaniel] Dana Farber Brigham & Womens Canc Ctr, Div Oral Med & Dent, Boston, MA USA. [Sonis, Stephen; Treister, Nathaniel] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [George, Suzanne] Dana Farber Canc Inst, Dept Med Oncol, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. RP Treister, N (reprint author), Brigham & Womens Hosp, Div Oral Med & Dent, 1620 Tremont St,Suite BC 3-028, Boston, MA 02120 USA. EM ntreister@partners.org RI gallottini, marina/B-8893-2011 OI gallottini, marina/0000-0001-6071-5110 NR 55 TC 38 Z9 41 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD APR PY 2013 VL 49 IS 4 BP 293 EP 298 DI 10.1016/j.oraloncology.2012.11.008 PG 6 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 114JL UT WOS:000316736800006 PM 23312237 ER PT J AU Kang, WS Shim, BS Lee, KS AF Kang, Woo Seok Shim, Byoung Soo Lee, Kwang-Sun TI Audiologic Performance After Cochlear Implantation in Children With X-Linked Deafness: Comparison With Deaf Children With a Normal Inner Ear Structure SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Cochlear implantation; Incomplete partition type III; Inner ear anomaly; X-linked deformity ID CLASSIFICATION; MUTATIONS; SURGERY AB Objective: To compare audiologic performances of cochlear implantation (CI) in children with X-linked deafness with those of CI in age-and sex-matched children with normal cochleae. Patients: We identified 4 patients with X-linked deafness and selected 10 age-and sex-matched deaf patients with normal cochleae between April 1999 and April 2012. Main Outcome Measures: Auditory brainstem responses, Categories of Auditory Performance (CAP), and Meaningful Auditory Integration Scale (MAIS). Results: The ages of patients with X-linked deafness at the time of implantation ranged between 1.3 and 13.6 years, with a mean age of 5.3 years. All patients were male subjects and showed severe-to-profound hearing loss. Patient 1 lacked ABR in both ears. Patients 2, 3, and 4 showed ABR in the contralateral ear, at 70, 70, and 90 dB nHL, respectively. All 4 patients had bilateral X-linked cochlear anomaly and experienced cerebrospinal fluid (CSF) gushers. Straight electrodes were used in Patients 1 and 3, with perimodiolar electrodes used in the others. Patients 2 and 3, who were about the same age, had CAP scores of 6 or more at 18 months after activation of the implant despite the use of different electrode arrays. There were no statistically significant differences in MAIS and CAP scores between each patient with X-linked deafness and the control group. Conclusion: The audiologic performances of patient with Xlinked deafness after CI are comparable to those of patients with normal inner ear structure after CI. C1 [Kang, Woo Seok] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Kang, Woo Seok] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Shim, Byoung Soo; Lee, Kwang-Sun] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Otolaryngol, Seoul 138736, South Korea. RP Lee, KS (reprint author), Univ Ulsan, Coll Med, Asan Med Ctr, Dept Otolaryngol, 388-1 Pungnap 2Dong, Seoul 138736, South Korea. EM kslee2@amc.seoul.kr NR 22 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD APR PY 2013 VL 34 IS 3 BP 544 EP 548 DI 10.1097/MAO.0b013e3182839864 PG 5 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 110NZ UT WOS:000316452300033 PM 23470556 ER PT J AU Morasco, BJ Lovejoy, TI Lu, M Turk, DC Lewis, L Dobscha, SK AF Morasco, Benjamin J. Lovejoy, Travis I. Lu, Mary Turk, Dennis C. Lewis, Lynsey Dobscha, Steven K. TI The relationship between PTSD and chronic pain: Mediating role of coping strategies and depression SO PAIN LA English DT Article DE Chronic pain; Chronic pain coping inventory; Coping strategies; Mediation; Posttraumatic stress disorder; Quality of life ID POSTTRAUMATIC-STRESS-DISORDER; COMORBID CHRONIC PAIN; MUTUAL MAINTENANCE; FIT INDEXES; BACK-PAIN; VETERANS; SYMPTOMS; INVENTORY; BELIEFS; MODELS AB People with chronic pain and comorbid posttraumatic stress disorder (PTSD) report more severe pain and poorer quality of life than those with chronic pain alone. This study evaluated the extent to which associations between PTSD and chronic pain interference and severity are mediated by pain-related coping strategies and depressive symptoms. Veterans with chronic pain were divided into 2 groups, those with (n = 65) and those without (n = 136) concurrent PTSD. All participants completed measures of pain severity, interference, emotional functioning, and coping strategies. Those with current PTSD reported significantly greater pain severity and pain interference, had more symptoms of depression, and were more likely to meet diagnostic criteria for a current alcohol or substance use disorder (all p-values <.01). Participants with PTSD reported more use of several coping strategies, including guarding, resting, relaxation, exercise/stretching, and coping self-statements. Illness-focused pain coping (i.e., guarding, resting, and asking for assistance) and depressive symptoms jointly mediated the relationship between PTSD and both pain interference (total indirect effect = 0.194, p < .001) and pain severity (total indirect effect = 0.153, p = .004). Illness-focused pain coping also evidenced specific mediating effects, independent of depression. In summary, specific pain coping strategies and depressive symptoms partially mediated the relationship between PTSD and both pain interference and severity. Future research should examine whether changes in types of coping strategies after targeted treatments predict improvements in pain-related function for chronic pain patients with concurrent PTSD. Published by Elsevier B.V. on behalf of International Association for the Study of Pain. C1 [Morasco, Benjamin J.; Lovejoy, Travis I.; Lu, Mary; Dobscha, Steven K.] Portland VA Med Ctr, Mental Hlth & Clin Neurosci Div, Portland, OR USA. [Morasco, Benjamin J.; Lu, Mary; Lewis, Lynsey; Dobscha, Steven K.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Morasco, Benjamin J.; Lu, Mary; Dobscha, Steven K.] Portland VA Med Ctr, Portland Ctr Study Chron Comorbid Med & Psychiat, Portland, OR USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. RP Morasco, BJ (reprint author), Portland VA Med Ctr R&D99, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM benjamin.morasco@va.gov FU National Institute on Drug Abuse [K23DA023467]; Endo; Johnson Johnson; Philips Respironics; National Institutes of Health; Eli Lilly; Empi; Pfizer; SK Life Science FX This study was supported in part by award K23DA023467 from the National Institute on Drug Abuse to Dr. Morasco. The work was supported with resources and the use of facilities at the Portland VA Medical Center. During the past 12 months, Dr. Turk has received research support from Endo, Johnson & Johnson, Philips Respironics, and the National Institutes of Health, and consulting fees from Eli Lilly, Empi, Johnson & Johnson, Pfizer, Philips Respironics, and SK Life Science. He is also a Special Government Employee of the US Food and Drug Administration. No other author reports having any potential conflict of interest with this study. The authors appreciate the assistance of Susan Gritzner, Renee Cavanagh, and Aysha Crain with data collection, and Jonathan Duckart, MPS, for extracting data from the electronic medical record. NR 55 TC 14 Z9 14 U1 3 U2 34 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD APR PY 2013 VL 154 IS 4 BP 609 EP 616 DI 10.1016/j.pain.2013.01.001 PG 8 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 113HW UT WOS:000316658200013 PM 23398939 ER PT J AU To, THM Agar, M Shelby-James, T Abernethy, AP Doogue, M Rowett, D Ko, D Currow, DC AF To, Timothy H. M. Agar, Meera Shelby-James, Tania Abernethy, Amy P. Doogue, Matthew Rowett, Debra Ko, Danielle Currow, David C. TI Off-label prescribing in palliative care - a cross-sectional national survey of Palliative Medicine doctors SO PALLIATIVE MEDICINE LA English DT Article DE Off-label prescribing; palliative care; drug regulation; physician knowledge; iatrogenic harm ID ADVERSE DRUG-REACTIONS; RANDOMIZED CONTROLLED-TRIALS; TIME-LIMITED TRIALS; PEDIATRIC WARDS; CANCER-PATIENTS; THE-LITERATURE; PRESCRIPTIONS; MEDICATION; ONCOLOGY; LICENSE AB Background: Regulatory bodies including the European Medicines Agency register medications (formulation, route of administration) for specific clinical indications. Once registered, prescription is at clinicians' discretion. Off-label use is beyond the registered use. While off-label prescribing may, at times, be appropriate, efficacy and toxicity data are often lacking. Aim: The aim of this study was to document off-label use policies (including disclosure and consent) in Australian palliative care units and current practices by palliative care clinicians. Design: A national, cross-sectional survey was conducted online following an invitation letter. The survey asked clinicians their most frequent off-label medication/indication dyads and unit policies. Dyads were classified into unregistered, off-label and on-label, and for the latter, whether medications were nationally subsidised. Setting/participants: All Australian palliative medicine Fellows and advanced trainees. Results: Overall, 105 clinicians responded (53% response rate). The majority did not have policies on off-label medications, and documented consent rarely. In all, 236 medication/indication dyads for 36 medications were noted: 45 dyads (19%) were for two unregistered medications, 118 dyads (50%) were for 26 off-label medications and 73 dyads (31%) were for 12 on-label medications. Conclusions: Off-label prescribing with its clinical, legal and ethical implications is common yet poorly recognised by clinicians. A distinction needs to be made between where quality evidence exists but registration has not been updated by the pharmaceutical sponsor and the evidence has not been generated. Further research is required to quantify any iatrogenic harm from off-label prescribing in palliative care. C1 [To, Timothy H. M.; Agar, Meera; Abernethy, Amy P.; Currow, David C.] Flinders Univ S Australia, Discipline Serv, Adelaide, SA 5001, Australia. [To, Timothy H. M.; Agar, Meera; Abernethy, Amy P.; Currow, David C.] Flinders Univ S Australia, Palliat Serv, Adelaide, SA 5001, Australia. [To, Timothy H. M.; Agar, Meera; Abernethy, Amy P.; Currow, David C.] Flinders Univ S Australia, Support Serv, Adelaide, SA 5001, Australia. [To, Timothy H. M.] Southern Adelaide Palliat Serv, Adelaide, SA, Australia. [To, Timothy H. M.] Repatriat Gen Hosp, Dept Rehabil & Aged Care, Adelaide, SA, Australia. [Agar, Meera] Braeside Hosp, Prairiewood, NSW, Australia. [Shelby-James, Tania] Flinders Univ S Australia, Flinders Prevent Promot & Primary Hlth Care, Adelaide, SA 5001, Australia. [Abernethy, Amy P.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Doogue, Matthew] Flinders Med Ctr, Dept Clin Pharmacol, Adelaide, SA, Australia. [Doogue, Matthew] Flinders Univ S Australia, Discipline Clin Pharmacol, Adelaide, SA 5001, Australia. [Rowett, Debra] Repatriat Gen Hosp, Drug & Therapeut Informat Serv, Adelaide, SA, Australia. [Ko, Danielle] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP To, THM (reprint author), Repatriat Gen Hosp, Dept Rehabil & Aged Care, Daw Pk, SA 5041, Australia. EM timothy.to@health.sa.gov.au OI To, Timothy/0000-0003-0025-6543; Doogue, Matt/0000-0002-2525-6307; Currow, David/0000-0003-1988-1250 NR 67 TC 4 Z9 4 U1 0 U2 9 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-2163 J9 PALLIATIVE MED JI Palliat. Med. PD APR PY 2013 VL 27 IS 4 BP 320 EP 328 DI 10.1177/0269216312464263 PG 9 WC Health Care Sciences & Services; Public, Environmental & Occupational Health; Medicine, General & Internal SC Health Care Sciences & Services; Public, Environmental & Occupational Health; General & Internal Medicine GA 114PB UT WOS:000316753200005 PM 23128901 ER PT J AU Shaikh, F Nathan, PC Hale, J Uleryk, E Frazier, L AF Shaikh, Furqan Nathan, Paul C. Hale, Juliet Uleryk, Elizabeth Frazier, Lindsay TI Is There a Role for Carboplatin in the Treatment of Malignant Germ Cell Tumors? A Systematic Review of Adult and Pediatric Trials SO PEDIATRIC BLOOD & CANCER LA English DT Article DE chemotherapy; germ cell tumors; late effects ID SINGLE-AGENT CARBOPLATIN; GOOD-RISK PATIENTS; TESTICULAR CANCER; RANDOMIZED-TRIAL; COMBINATION CHEMOTHERAPY; CISPLATIN OTOTOXICITY; METASTATIC SEMINOMA; PROGNOSTIC-FACTORS; DOSE CISPLATIN; ETOPOSIDE AB Background. While cisplatin is considered superior to carboplatin for the treatment of malignant germ cell tumors (MGCTs) in adults, pediatric oncology collaborative groups still remain concerned about the late effects of cisplatin in children. Methods. We performed a literature search to identify randomized controlled trials (RCTs) that used carboplatin for MGCTs in adults. Since no RCTs were available in children, we identified cohort studies of pediatric MGCTs treated with carboplatin. We compared the adult and pediatric studies in terms of characteristics, doses of chemotherapy, and outcomes. Results. Of 2,131 publications retrieved, five RCTs in adults (1,340 patients) and four cohort studies in children (219 patients) met criteria for inclusion. All adult RCTs evaluated carboplatin versus cisplatin regimens in men with good-prognosis metastatic MGCTs. Carboplatin regimens had a higher risk of events (RR 2.51, P < 0.001) and of deaths (RR 2.21, P < 0.001) than cisplatin regimens. Across all five RCTs, 497/654 (76%) of adults who received carboplatin remained event-free. Compared to the adult trials, three pediatric studies used carboplatin at a higher dose, frequency, and number of cycles. Across these three studies, 158/179 (88%) of children remained event-free. Conclusions. Cisplatin is superior to carboplatin at the studied doses for the treatment of adult metastatic MGCTs. However, we observe that carboplatin is associated with good outcomes for children with MGCT when used at the higher doses. We hypothesize that a risk-adapted approach utilizing both platinum agents may achieve the optimal balance between cure and late effects. Pediatr Blood Cancer 2013;60:587-592. (C) 2012 Wiley Periodicals, Inc. C1 [Shaikh, Furqan; Nathan, Paul C.] Hosp Sick Children, Div Paediat Haematol Oncol, Toronto, ON M5G 1X8, Canada. [Hale, Juliet] Royal Victoria Infirm, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Uleryk, Elizabeth] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Frazier, Lindsay] Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. RP Shaikh, F (reprint author), Hosp Sick Children, Div Paediat Haematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM furqan.shaikh@sickkids.ca OI Uleryk, Elizabeth/0000-0002-8989-5597 FU Pediatric Oncology Group of Ontario (POGO) Research Unit FX Grant sponsor: Pediatric Oncology Group of Ontario (POGO) Research Unit. NR 29 TC 4 Z9 4 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD APR PY 2013 VL 60 IS 4 BP 587 EP 592 DI 10.1002/pbc.24288 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 108KI UT WOS:000316291400012 PM 22976789 ER PT J AU Thibert, RL Larson, AM Hsieh, DT Raby, AR Thiele, EA AF Thibert, Ronald L. Larson, Anna M. Hsieh, David T. Raby, Annabel R. Thiele, Elizabeth A. TI Neurologic Manifestations of Angelman Syndrome SO PEDIATRIC NEUROLOGY LA English DT Review ID HAPPY PUPPET SYNDROME; EEG PATTERNS; MOLECULAR DIAGNOSIS; CLINICAL-FEATURES; EPILEPSY; SLEEP; DELETION; INDIVIDUALS; CHILDREN; BEHAVIOR AB Angelman syndrome is a neurogenetic disorder characterized by the loss or reduction of the ubiquitin-protein ligase E3A enzyme. Angelman syndrome results from a deletion or mutation of the maternally inherited 15q11.2-13.1 region, paternal uniparental disomy of chromosome 15, or an imprinting error. Epilepsy is common and may present with multiple seizure types, including nonconvulsive status epilepticus. Seizures are often intractable and typically require broad-spectrum antiepileptic medications. Dietary therapy has also proved successful in Angelman syndrome. Electroencephalographic patterns include notched 8 and rhythmic theta activity and epileptiform discharges. Sleep disorders are also common, often characterized by abnormal sleep-wake cycles. Movement disorders are nearly universal in Angelman syndrome, most frequently presenting with ataxia and tremor. Neurocognitive impairment is always present to varying degrees, and expressive speech is typically severely affected. Individuals with Angelman syndrome often manifest psychiatric comorbidities including hyperactivity, anxiety, and challenging behaviors such as aggression and self-injury. We focus on a comprehensive whole-child approach to the diagnosis and long-term clinical care of individuals with Angelman syndrome. (C) 2013 Elsevier Inc. All rights reserved. C1 [Thiele, Elizabeth A.] Massachusetts Gen Hosp, Dept Neurol, Pediat Epilepsy Program, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Angelman Syndrome Clin, Boston, MA 02114 USA. RP Thiele, EA (reprint author), Massachusetts Gen Hosp, Dept Neurol, Pediat Epilepsy Program, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM ethiele@partners.org NR 92 TC 38 Z9 39 U1 4 U2 30 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD APR PY 2013 VL 48 IS 4 BP 271 EP 279 DI 10.1016/j.pediatrneurol.2012.09.015 PG 9 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 114XZ UT WOS:000316777600002 PM 23498559 ER PT J AU Nan, HM Giovannucci, EL Wu, KN Selhub, J Paul, L Rosner, B Fuchs, CS Cho, E AF Nan, Hongmei Giovannucci, Edward L. Wu, Kana Selhub, Jacob Paul, Ligi Rosner, Bernard Fuchs, Charles S. Cho, Eunyoung TI Pre-Diagnostic Leukocyte Genomic DNA Methylation and the Risk of Colorectal Cancer in Women SO PLOS ONE LA English DT Article ID METHYLENETETRAHYDROFOLATE-REDUCTASE GENE; ONE-CARBON METABOLISM; FOLATE STATUS; LIQUID-CHROMATOGRAPHY; COMMON MUTATION; BREAST-CANCER; HYPOMETHYLATION; ADENOMA; CARCINOGENESIS; POLYMORPHISM AB Background: Abnormal one-carbon metabolism may lead to general genomic (global) hypomethylation, which may predispose an individual to the development of colorectal neoplasia. Methods: We evaluated the association between pre-diagnostic leukocyte genomic DNA methylation level and the risk of colorectal cancer in a nested case-control study of 358 colorectal cancer cases and 661 matched controls within the all-female cohort of the Nurses' Health Study (NHS). Among control subjects, we further examined major plasma components in the one-carbon metabolism pathway in relation to genomic DNA methylation level. Liquid chromatography/tandem mass spectrometry was used to examine leukocyte genomic DNA methylation level. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) using logistic regression. Results: Overall genomic DNA methylation level was not associated with the risk of colorectal cancer (p for trend, 0.45). Compared with women in the lowest quintile of methylation, the multivariate OR of colorectal cancer risk was 1.32 (95% CI, 0.82-2.13) for those in the highest quintile. We did not find significant associations between major plasma components of one-carbon metabolism or risk factors for colorectal cancer and genomic DNA methylation level (all p for trend >0.05). Also, neither one-carbon metabolism-related plasma components nor well-known risk factors for colorectal cancer modified the association between genomic DNA methylation level and the risk of colorectal cancer (all p for interaction >0.05). Conclusions: We found no evidence that hypomethylation of leukocyte genomic DNA increases risk of colorectal cancer among women. Additional studies are needed to investigate the association between pre-diagnostic genomic DNA methylation level and colorectal cancer risk among diverse populations. C1 [Nan, Hongmei] Univ Maryland, Sch Med, Div Canc Epidemiol, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Nan, Hongmei; Giovannucci, Edward L.; Rosner, Bernard; Fuchs, Charles S.; Cho, Eunyoung] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Nan, Hongmei; Giovannucci, Edward L.; Rosner, Bernard; Fuchs, Charles S.; Cho, Eunyoung] Harvard Univ, Sch Med, Boston, MA USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Giovannucci, Edward L.; Wu, Kana] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Selhub, Jacob; Paul, Ligi] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Rosner, Bernard] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Cho, E (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. EM eunyoung.cho@channing.harvard.edu FU United States National Institutes of Health [CA136950, CA55075] FX This work was supported by research grants CA136950 and CA55075 from the United States National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 6 Z9 7 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 1 PY 2013 VL 8 IS 4 AR e59455 DI 10.1371/journal.pone.0059455 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 117CY UT WOS:000316930900017 PM 23560049 ER PT J AU Smucny, J Rojas, DC Eichman, LC Tregellas, JR AF Smucny, Jason Rojas, Donald C. Eichman, Lindsay C. Tregellas, Jason R. TI Neural Effects of Auditory Distraction on Visual Attention in Schizophrenia SO PLOS ONE LA English DT Article ID FUSIFORM FACE AREA; DORSOLATERAL PREFRONTAL CORTEX; WORD FORM AREA; BOTTOM-UP; HEMODYNAMIC-RESPONSE; NEURONAL MECHANISMS; NEGATIVE SYMPTOMS; ODDBALL TASK; FMRI; MEMORY AB Sensory flooding, particularly during auditory stimulation, is a common problem for patients with schizophrenia. The functional consequences of this impairment during cross-modal attention tasks, however, are unclear. The purpose of this study was to examine how auditory distraction differentially affects task-associated response during visual attention in patients and healthy controls. To that end, 21 outpatients with schizophrenia and 23 healthy comparison subjects performed a visual attention task in the presence or absence of distracting, environmentally relevant "urban'' noise while undergoing functional magnetic resonance imaging at 3T. The task had two conditions (difficult and easy); task-related neural activity was defined as difficult - easy. During task performance, a significant distraction (noise or silence) by group (patient or control) interaction was observed in the left dorsolateral prefrontal cortex, right hippocampus, left temporoparietal junction, and right fusiform gyrus, with patients showing relative hypoactivation during noise compared to controls. In patients, the ability to recruit the dorsolateral prefrontal cortex during the task in noise was negatively correlated with the effect of noise on reaction time. Clinically, the ability to recruit the fusiform gyrus during the task in noise was negatively correlated with SANS affective flattening score, and hippocampal recruitment during the task in noise was positively correlated with global functioning. In conclusion, schizophrenia may be associated with abnormalities in neural response during visual attention tasks in the presence of cross-modal noise distraction. These response differences may predict global functioning in the illness, and may serve as a biomarker for therapeutic development. C1 [Smucny, Jason; Rojas, Donald C.; Tregellas, Jason R.] Univ Colorado, Neurosci Program, Aurora, CO 80045 USA. [Smucny, Jason; Rojas, Donald C.; Eichman, Lindsay C.; Tregellas, Jason R.] Univ Colorado, Dept Psychiat, Aurora, CO USA. [Rojas, Donald C.; Eichman, Lindsay C.; Tregellas, Jason R.] Denver VA Med Ctr, Res Serv, Denver, CO USA. RP Tregellas, JR (reprint author), Univ Colorado, Neurosci Program, Anschutz Med Campus, Aurora, CO 80045 USA. EM Jason.Tregellas@ucdenver.edu RI Tregellas, Jason/J-3637-2015; OI Rojas, Don/0000-0001-6560-9616; Smucny, Jason/0000-0001-5656-7987 FU National Institute of Mental Health [MH-061412]; NIMH [MH-086383]; Brain & Behavior Research Foundation; United States Department of Veterans Affairs; Blowitz-Ridgeway Foundation FX Funding came from National Institute of Mental Health Grant MH-061412 (http://www.nimh.nih.gov/index.shtml); NIMH Grant MH-086383; National Alliance for Research on Schizophrenia and Depression, now Brain & Behavior Research Foundation (No Grant Number) (bbrfoundation.org); United States Department of Veterans Affairs (No Grant Number) (www.va.gov); and Blowitz-Ridgeway Foundation (No Grant Number) (http://www.blowitzridgeway.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 3 Z9 3 U1 3 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 1 PY 2013 VL 8 IS 4 AR e60606 DI 10.1371/journal.pone.0060606 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 117CY UT WOS:000316930900071 PM 23560100 ER PT J AU Albert, RK Connett, J Bailey, WC Casaburi, R Cooper, JAD Criner, GJ Curtis, JL Dransfield, MT Han, MK Lazarus, SC Make, B Marchetti, N Martinez, FJ Madinger, NE Mcevoy, C Niewoehner, DE Porsasz, J Price, CS Reilly, J Scanlon, PD Sciurba, FC Scharf, SM Washko, GR Woodruff, PG Anthonisen, NR AF Albert, R. K. Connett, J. Bailey, W. C. Casaburi, R. Cooper, J. A. D., Jr. Criner, G. J. Curtis, J. L. Dransfield, M. T. Han, M. K. Lazarus, S. C. Make, B. Marchetti, N. Martinez, F. J. Madinger, N. E. Mcevoy, C. Niewoehner, D. E. Porsasz, J. Price, C. S. Reilly, J. Scanlon, P. D. Sciurba, F. C. Scharf, S. M. Washko, G. R. Woodruff, P. G. Anthonisen, N. R. CA COPD Clinical Res Network TI LONG-TERM AZITHROMYCIN DECREASES COPD EXACERBATIONS SO RESPIROLOGY LA English DT Meeting Abstract C1 [Albert, R. K.; Price, C. S.] Denver Hlth, Med Serv, Denver, CO USA. [Albert, R. K.; Price, C. S.] Univ Colorado Denver, Dept Med, Denver, CO USA. [Connett, J.] Univ Minnesota, Div Biostat, Sch Publ Hlth, Minneapolis, MN 55455 USA. [Bailey, W. C.] Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Dept Med, Birmingham, AL USA. [Casaburi, R.; Porsasz, J.] Harbor UCLA Med Ctr, Dept Med, Div Resp & Crit Care Physiol & Med, Torrance, CA 90509 USA. [Cooper, J. A. D., Jr.; Dransfield, M. T.] Birmingham VA Med Ctr, Pulm Sect, Birmingham, AL USA. [Criner, G. J.; Marchetti, N.] Temple Univ, Div Pulm & Crit Care Med, Dept Med, Philadelphia, PA 19122 USA. [Curtis, J. L.; Martinez, F. J.] Ann Arbor VA Med Ctr, Div Pulm & Crit Care Med, Ann Arbor, MI USA. [Han, M. K.] Univ Michigan, Dept Med, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA. [Lazarus, S. C.; Woodruff, P. G.] Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA USA. [Lazarus, S. C.; Woodruff, P. G.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Make, B.] Natl Jewish Hlth, Div Pulm Med, Denver, CO USA. [Madinger, N. E.] Univ Colorado Denver, Dept Med, Div Infect Dis, Denver, CO USA. [Mcevoy, C.] HealthPartners Res Fdn, Pulm Crit Care & Sleep Dept, St Paul, MN USA. [Niewoehner, D. E.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Niewoehner, D. E.] Minneapolis Vet Affairs VA Med Ctr, Med Serv, Div Pulm Med, Minneapolis, MN USA. [Reilly, J.; Washko, G. R.] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Scanlon, P. D.] Mayo Clin, Div Pulm & Crit Care Med, Rochester, MN USA. [Sciurba, F. C.] Univ Pittsburgh, Div Pulm & Crit Care Med, Dept Med, Pittsburgh, PA 15260 USA. [Scharf, S. M.] Univ Maryland, Dept Med, Div Pulm & Crit Care, Baltimore, MD 21201 USA. [Anthonisen, N. R.] Resp Hosp, Winnipeg, MB, Canada. 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 1323-7799 J9 RESPIROLOGY JI Respirology PD APR PY 2013 VL 18 SU 1 SI SI BP 5 EP 5 PG 1 WC Respiratory System SC Respiratory System GA 114RO UT WOS:000316760200011 ER PT J AU Malhotra, A Younes, M Kuna, ST Benca, R Kushida, CA Walsh, J Hanlon, A Staley, B Pack, AI Pien, GW AF Malhotra, Atul Younes, Magdy Kuna, Samuel T. Benca, Ruth Kushida, Clete A. Walsh, James Hanlon, Alexandra Staley, Bethany Pack, Allan I. Pien, Grace W. TI Performance of an Automated Polysomnography Scoring System Versus Computer-Assisted Manual Scoring SO SLEEP LA English DT Article DE apnea-hypopnea index; lung; polysomnography; reliability; scoring; sleep ID SLEEP CLASSIFICATION; SIESTA DATABASE; SOMNOLYZER 24X7; VARIABILITY; RELIABILITY; RECORDINGS; ADULTS; DISORDERS; AGREEMENT; INSOMNIA AB Study Objectives: Manual scoring of polysomnograms (PSG) is labor intensive and has considerable variance between scorers. Automation of scoring could reduce cost and improve reproducibility. The purpose of this study was to compare a new automated scoring system (YST-Limited, Winnipeg, Canada) with computer-assisted manual scoring. Design: Technical assessment. Setting: Five academic medical centers. Participants: N/A. Interventions: N/A. Measurements and Results: Seventy PSG files were selected at University of Pennsylvania (Penn) and distributed to five US academic sleep centers. Two blinded technologists from each center scored each file. Automatic scoring was performed at Penn by a YST Limited technician using a laptop containing the software. Variables examined were sleep stages, arousals, and apnea-hypopnea index (AHI) using three methods of identifying hypopneas. Automatic scores were not edited and were compared to the average scores of the 10 technologists. Intraclass correlation coefficient (ICC) was obtained for the 70 pairs and compared to across-sites ICCs for manually scored results. ICCs for automatic versus manual scoring were > 0.8 for total sleep time, stage N2, and nonrapid eye movement arousals and > 0.9 for AHI scored by primary and secondary American Academy of Sleep Medicine criteria. ICCs for other variables were not as high but were comparable to the across-site ICCs for manually scored results. Conclusion: The automatic system yielded results that were similar to those obtained by experienced technologists. Very good ICCs were obtained for many primary PSG outcome measures. This automated scoring software, particularly if supplemented with manual editing, may increase laboratory efficiency and standardize PSG scoring results within and across sleep centers. C1 [Malhotra, Atul] Harvard Univ, Dept Med, Boston, MA 02115 USA. [Younes, Magdy] Univ Manitoba, Dept Med, Winnipeg, MB, Canada. [Kuna, Samuel T.; Hanlon, Alexandra; Staley, Bethany; Pack, Allan I.; Pien, Grace W.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Kuna, Samuel T.; Hanlon, Alexandra; Staley, Bethany; Pack, Allan I.; Pien, Grace W.] Univ Penn, Ctr Sleep & Circadian Neurobiol, Philadelphia, PA 19104 USA. [Kuna, Samuel T.] Philadelphia VA Med Ctr, Dept Med, Philadelphia, PA USA. [Benca, Ruth] Univ Wisconsin, Dept Med, Madison, WI USA. [Kushida, Clete A.] Stanford Univ, Dept Psychiat, Palo Alto, CA 94304 USA. [Walsh, James] St Lukes Hosp, Sleep Med & Res Ctr, Chesterfield, MO USA. RP Malhotra, A (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. EM amalhotra1@partners.org FU NIH [R01 HL085695]; Academic Alliance for Sleep Research (Philips-Respironics Foundation); Philips Respironics Foundation; Philips Respironics; SHC; SGS; Apnex Medical; Pfizer; Apnicure; Merck; Sanofi-Aventis; NovoNordisk; Vanda; Ventus; ResMed; Pacific Medico; Cephalon; Ventus Medical; Jazz Pharmaceuticals; Apnex; Philips-Respironics FX Scorers at the University of Pennsylvania: Haideliza Soto-Calderon, Mary Jones-Parker, RPSGT; scorers at Harvard University: Mary MacDonald, RPSGT, Pam DeYoung, RPSGT; scorers at the University of Wisconsin at Madison: Jennifer Noe, RPSGT, Rebecca Weise, RPSGT; scorers at Stanford University: Martin Ukockis, RPSGT; scorers at St. Luke's Hospital: Hilary Simon, RPSGT, Laura Rahubka, RPSGT. Eileen O'Leary, RPSGT coordinated activity at Stanford University and assisted in data export at the sites using Alice software. Sources of support: NIH R01 HL085695; Academic Alliance for Sleep Research (Philips-Respironics Foundation); This study was funded in part by the Philips Respironics Foundation. Dr. Malhotra had previously received (prior to May 2012) consulting and/or research income from Philips Respironics, SHC, SGS, Apnex Medical, Pfizer and Apnicure. Dr. Kuna receives grant support from Philips-Respironics. Dr. Benca has received consulting income from Merck and Sanofi-Aventis. Dr. Walsh has received research support from Apnex, NovoNordisk, Merck, Phillips-Respironics, Vanda, and Ventus. Dr. Younes is the owner of YRT a research and development company. Dr. Kushida receives research support from ResMed, Pacific Medico, Merck, Cephalon, Ventus Medical, and Jazz Pharmaceuticals. He receives royalties from Philips-Respironics. The other authors have indicated no financial conflicts of interest. NR 26 TC 20 Z9 20 U1 2 U2 14 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD APR 1 PY 2013 VL 36 IS 4 BP 573 EP 582 DI 10.5665/sleep.2548 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 117FN UT WOS:000316939000017 PM 23565003 ER PT J AU Kuna, ST Benca, R Kushida, CA Walsh, J Younes, M Staley, B Hanlon, A Pack, AI Pien, GW Malhotra, A AF Kuna, Samuel T. Benca, Ruth Kushida, Clete A. Walsh, James Younes, Magdy Staley, Bethany Hanlon, Alexandra Pack, Allan I. Pien, Grace W. Malhotra, Atul TI Agreement in Computer-Assisted Manual Scoring of Polysomnograms across Sleep Centers SO SLEEP LA English DT Article DE Apnea-hypopnea index; polysomnography; reliability; scoring ID APNEA-HYPOPNEA INDEX; VARIABILITY; RELIABILITY; AROUSAL; RECOMMENDATIONS; RECORDINGS; DISORDERS; IMPACT AB Study Objectives: To determine intersite agreement in respiratory event scoring of polysomnograms (PSGs) using different hypopnea definitions. Design: Technical assessment. Setting: Five academic medical centers. Participants: N/A. Interventions: N/A. Measurements and Results: Seventy good-quality PSGs performed in middle-aged women were manually scored by two experienced technologists at each of the five sleep centers using the particular laboratory's own software system. Studies were scored once by each scorer using American Academy of Sleep Medicine (AASM) standards for scoring sleep stages, arousals, and apneas. Hypopneas were then scored using three different AASM criteria: recommended, alternate, and research (Chicago). Means of each PSG variable for the scorers at each site were used to calculate an across-site intraclass correlation coefficient (ICC). Average AHI across the 10 scorers was 7.4 +/- 12.3 (standard deviation) events/h using recommended criteria (ICC 0.984; 95% confidence interval [CI] 0.977-0.990), 12.1 +/- 13.3 events/h using alternate criteria (ICC 0.947; 95% CI 0.889-0.972), and 15.1 +/- 13.9 events/h with Chicago criteria (ICC 0.800; 95% CI 0.768-0.828). ICC across sites was 0.870 (95% CI = 0.847-0.889) for total sleep time, 0.861 (95% CI 0.837-0.881) for number of obstructive apneas and 0.683 (95% CI 0.640-0.722) for number of central apneas. ICCs across sites for hypopneas were very good using recommended criteria (ICC 0.843; 95% CI 0.820-0.870) but decreased when alternate criteria (ICC 0.728; 95% CI 0.689-0.763) and Chicago criteria (ICC 0.535; 95% CI 0.485-0.583) were used. Conclusion: Experienced scorers at different laboratories have very good agreement in hypopnea and AHI results when good-quality PSGs are scored using AASM-recommended criteria. Substantial degradation of reliability was observed for alternative definitions of hypopneas, particularly that proposed for research. C1 [Kuna, Samuel T.; Staley, Bethany; Hanlon, Alexandra; Pack, Allan I.; Pien, Grace W.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Kuna, Samuel T.; Staley, Bethany; Hanlon, Alexandra; Pack, Allan I.; Pien, Grace W.] Univ Penn, Ctr Sleep & Circadian Neurobiol, Philadelphia, PA 19104 USA. [Kuna, Samuel T.] Philadelphia VA Med Ctr, Dept Med, Philadelphia, PA 19104 USA. [Benca, Ruth] Univ Wisconsin, Dept Med, Madison, WI USA. [Kushida, Clete A.] Stanford Univ, Dept Psychiat, Palo Alto, CA 94304 USA. [Walsh, James] St Lukes Hosp, Sleep Med & Res Ctr, Chesterfield, MO USA. [Younes, Magdy] Univ Manitoba, Dept Med, Winnipeg, MB, Canada. [Malhotra, Atul] Harvard Univ, Dept Med, Boston, MA 02115 USA. RP Kuna, ST (reprint author), Philadelphia VA Med Ctr, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM skuna@mail.med.upenn.edu FU NIH [R01 HL085695, 1PO1-1HL094307]; Academic Alliance for Sleep Research (Philips-Respironics Foundation); Philips-Respironics; Merck; Sanofi-Aventis; Philips Respironics; SHC; SGS; Apnex Medical; Pfizer; Apnicure; ResMed; Pacific Medico; Cephalon; Ventus Medical; Jazz Pharmaceuticals; Apnex; NovoNordisk; Vanda; Ventus FX Scorers at the University of Pennsylvania: Haideliza Soto-Calderon, Mary Jones-Parker, RPSGT; scorers at Harvard University: Mary MacDonald, RPSGT, Pam DeYoung, RPSGT; scorers at the University of Wisconsin at Madison: Jennifer Noe, RPSGT, Rebecca Weise, RPSGT; scorers at Stanford University: Martin Ukockis, RPSGT, Julianne Blythe; scorers at St. Luke's Hospital: Hilary Field, RPSGT, Laura Rahubka, RPSGT. Eileen O'Leary, RPSGT coordinated activity at Stanford University and assisted in data export at the sites using Alice software. Sources of support: NIH R01 HL085695; NIH 1PO1-1HL094307; Academic Alliance for Sleep Research (Philips-Respironics Foundation).; This was not an industry supported study. Dr. Kuna receives grant support from Philips-Respironics. Dr. Benca has received consulting income from Merck and Sanofi-Aventis. Dr. Malhotra had previously received (prior to May 2012) consulting and/or research income from Philips Respironics, SHC, SGS, Apnex Medical, Pfizer and Apnicure. Dr. Kushida receives research support from ResMed, Pacific Medico, Merck, Cephalon, Ventus Medical, and Jazz Pharmaceuticals. He receives royalties from Philips-Respironics. Dr. Younes is the owner of YRT a research and development company. Dr. Walsh has received research support from Apnex, NovoNordisk, Merck, Phillips-Respironics, Vanda, and Ventus. The other authors have indicated no financial conflicts of interest. NR 25 TC 20 Z9 20 U1 1 U2 3 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD APR 1 PY 2013 VL 36 IS 4 BP 583 EP 589 DI 10.5665/sleep.2550 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 117FN UT WOS:000316939000018 PM 23565004 ER PT J AU Passias, PG Wang, SL Zhao, D Wang, SB Kozanek, M Wang, C AF Passias, Peter G. Wang, Shenglin Zhao, Deng Wang, Shaobai Kozanek, Michal Wang, Chao TI The Reversibility of Swan Neck Deformity in Chronic Atlantoaxial Dislocations SO SPINE LA English DT Article DE swan neck; cervical spine; alignment; atlantoaxial dislocation; kyphosis ID LOWER CERVICAL-SPINE; RHEUMATOID-ARTHRITIS; OCCIPITOCERVICAL FUSION; FOLLOW-UP; ALIGNMENT; ANGLE AB Study Design. Prospective case series and radiographical analysis. Objective. This study aimed to characterize the changes in subaxial alignment after surgical correction of occipitoaxial kyphosis, establish normal parameters, and report on clinical outcomes in a population of patients with chronic atlantoaxial dislocation patients presenting with swan neck deformities. Summary of Background Data. Swan neck deformity of the cervical spine is a term used to describe the simultaneous development of both abnormal kyphosis and hyperlordosis malalignments. Currently, there are no published series that discuss their outcomes after treatment and, more specifically, the subsequent changes that occur in the subaxial spine after the correction of the primary deformity in cases of chronic hyperkyphosis at the occipitoaxial segment. Methods. This was a prospective clinical and radiographical study in a population of patients with chronic atlantoaxial dislocation presenting with swan neck deformities. C0-C2 and C2-C7 angles were measured using plain radiographs pre- and postsurgery. The relationship between the alignment of the occipitoaxial joint and the subaxial cervical spine was evaluated. Japanese Orthopaedic Society scores were used to assess functional outcomes. Results. C0-C2 improved from a mean of -14.4 degrees (SD, 9.5 degrees) preoperatively to a mean of 7.8 degrees (SD, 1.0 degrees) postoperatively (P = 0.02). C2-C7 changed from a mean of 43 degrees (SD, 2.8 degrees) to a mean of 18.6 degrees (SD, 11.2 degrees) postoperatively (P = 0.02). A significant correlation was detected between the changes that occurred in the upper and lower cervical alignments (R-2 = 0.133; P < 0.01). Clinically, the Japanese Orthopaedic Society preoperative scores improved significantly to postoperative (P < 0.01). Conclusion. This study reports the novel auto-correction of subaxial abnormalities after treatment of the primary upper cervical deformity and delineates the relationship between these 2 occurrences, thus demonstrating the reversibility of such complex abnormalities. Furthermore, the clinical outcomes after surgical treatment of swan neck deformities secondary to atlantoaxial dislocation are favorable and associated with a low complication rate. C1 [Passias, Peter G.] NYU, Hosp Joint Dis, Sch Med, Div Spinal Surg,Med Ctr, New York, NY 10003 USA. [Wang, Shenglin; Zhao, Deng; Wang, Chao] Peking Univ, Dept Orthopaed, Hosp 3, Beijing 100191, Peoples R China. [Wang, Shaobai; Kozanek, Michal] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, Boston, MA USA. RP Wang, C (reprint author), Peking Univ, Dept Orthopaed, Hosp 3, 49 North Garden St, Beijing 100191, Peoples R China. EM wangchaoo@ynet.com NR 19 TC 5 Z9 7 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD APR 1 PY 2013 VL 38 IS 7 BP E379 EP E385 DI 10.1097/BRS.0b013e31828625e4 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 117FW UT WOS:000316939900001 PM 23324935 ER PT J AU Janzen, DM Cheng, DH Schafenacker, AM Paik, DY Goldstein, AS Witte, ON Jaroszewicz, A Pellegrini, M Memarzadeh, S AF Janzen, Deanna M. Cheng, Donghui Schafenacker, Amanda M. Paik, Daniel Y. Goldstein, Andrew S. Witte, Owen N. Jaroszewicz, Artur Pellegrini, Matteo Memarzadeh, Sanaz TI Estrogen and progesterone together expand murine endometrial epithelial progenitor cells SO STEM CELLS LA English DT Article DE Endometrial epithelial progenitors; Progesterone; Estrogen; Paracrine signaling ID LABEL-RETAINING CELLS; LARGE GENE LISTS; STEM-CELLS; PROSTATE-CANCER; SELF-RENEWAL; POSTMENOPAUSAL WOMEN; UTERINE EPITHELIUM; MOUSE ENDOMETRIUM; COLON-CARCINOMA; CD44 ISOFORMS AB Synchronous with massive shifts in reproductive hormones, the uterus and its lining the endometrium expand to accommodate a growing fetus during pregnancy. In the absence of an embryo the endometrium, composed of epithelium and stroma, undergoes numerous hormonally regulated cycles of breakdown and regeneration. The hormonally mediated regenerative capacity of the endometrium suggests that signals that govern the growth of endometrial progenitors must be regulated by estrogen and progesterone. Here, we report an antigenic profile for isolation of mouse endometrial epithelial progenitors. These cells are EpCAM+CD44+ITGA6hiThy1PECAM1PTPRCTer119, comprise a minor subpopulation of total endometrial epithelia and possess a gene expression profile that is unique and different from other cells of the endometrium. The epithelial progenitors of the endometrium could regenerate in vivo, undergo multilineage differentiation and proliferate. We show that the number of endometrial epithelial progenitors is regulated by reproductive hormones. Coadministration of estrogen and progesterone dramatically expanded the endometrial epithelial progenitor cell pool. This effect was not observed when estrogen or progesterone was administered alone. Despite the remarkable sensitivity to hormonal signals, endometrial epithelial progenitors do not express estrogen or progesterone receptors. Therefore, their hormonal regulation must be mediated through paracrine signals resulting from binding of steroid hormones to the progenitor cell niche. Discovery of signaling defects in endometrial epithelial progenitors or their niche can lead to development of better therapies in diseases of the endometrium. STEM CELLS 2013;31:808822 C1 [Janzen, Deanna M.; Schafenacker, Amanda M.; Paik, Daniel Y.; Memarzadeh, Sanaz] Univ Calif Los Angeles, Dept Obstet & Gynecol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Goldstein, Andrew S.; Witte, Owen N.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Goldstein, Andrew S.] Univ Calif Los Angeles, Dept Urol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Cheng, Donghui; Witte, Owen N.] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90024 USA. [Goldstein, Andrew S.; Witte, Owen N.; Pellegrini, Matteo; Memarzadeh, Sanaz] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90024 USA. [Witte, Owen N.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90024 USA. [Jaroszewicz, Artur; Pellegrini, Matteo] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90024 USA. [Memarzadeh, Sanaz] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. RP Memarzadeh, S (reprint author), Univ Calif Los Angeles, Dept Obstet & Gynecol, David Geffen Sch Med, Los Angeles, CA 90024 USA. EM smemarzadeh@mednet.ucla.edu OI Goldstein, Andrew/0000-0003-0434-9149 FU VA CDA-2 Career Development Award; Mary Kay Foundation Award; PCF Young Investigators Award; STOP Cancer Award; Broad Stem Cell Research Center, Research Award; U54 CA 143,931 award; Kimmel Translational Scholar Award; Joe and Ali Torre-Prostate Cancer Foundation Young Investigator Award FX SM is supported by a VA CDA-2 Career Development Award, a gift from the Scholars in Translational Medicine Program, Mary Kay Foundation Award, PCF Young Investigators Award, STOP Cancer Award, the Broad Stem Cell Research Center, Research Award, the U54 CA 143,931 award and a Kimmel Translational Scholar Award. ASG is supported by the Joe and Ali Torre-Prostate Cancer Foundation Young Investigator Award. ONW is a Howard Hughes Medical Institute investigator. NR 84 TC 10 Z9 10 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 EI 1549-4918 J9 STEM CELLS JI Stem Cells PD APR PY 2013 VL 31 IS 4 BP 808 EP 822 DI 10.1002/stem.1337 PG 15 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 112WG UT WOS:000316624300018 PM 23341289 ER PT J AU Rajamani, K Kennedy, KF Ruggiero, NJ Rosenfield, K Spertus, J Chaturvedi, S AF Rajamani, Kumar Kennedy, Kevin F. Ruggiero, Nicholas J. Rosenfield, Kenneth Spertus, John Chaturvedi, Seemant TI Outcomes of Carotid Endarterectomy in the Elderly Report From the National Cardiovascular Data Registry SO STROKE LA English DT Article; Proceedings Paper CT International Stroke Conference CY JAN 31-FEB 03, 2012 CL New Orleans, LA DE Carotid Artery Revascularization and Endarterectomy registry; carotid endarterectomy; National Cardiovascular Data Registry; elderly patients ID MORTALITY; AGE AB Background and Purpose-Benchmark trials of carotid endarterectomy often did not include elderly patients, and the results may not be easily extrapolated to the general population. Using the Carotid Artery Revascularization and Endarterectomy registry, we sought to determine real-world outcomes of carotid endarterectomy in the elderly. Methods-This was a retrospective cohort study of patients aged >70 years. We compared outcomes stratified by age among symptomatic and asymptomatic patients. Results-There were 4149 patients who underwent carotid endarterectomy; 1376 (33.1%) were symptomatic. Overall mortality rate was 0.5%. The primary outcome of in-hospital death, stroke, and myocardial infarction showed a significant trend and was highest in the age >85 years group (5.6%). Among symptomatic patients, mortality and the primary outcome were not statistically different between those aged >75 years and those aged 70 to 74 years. Among asymptomatic elderly patients, mortality rate was significantly higher in age group >75 years compared with <75 years (0.7% vs 0.0%); however, the combined outcome of stroke, death, and myocardial infarction was not statistically different. Conclusions-Elderly patients >85 years of age were at increased risk for death or perioperative complications of stroke, death, and myocardial infarction compared with those who were relatively younger. More elderly patients underwent carotid endarterectomy for asymptomatic carotid stenosis and had higher mortality than the younger counterparts, underlining need for caution in subjecting them to the procedure. (Stroke. 2013;44:1172-1174.) C1 [Rajamani, Kumar; Chaturvedi, Seemant] Wayne State Univ, Sch Med, Detroit, MI USA. [Kennedy, Kevin F.; Spertus, John] Univ Missouri, Mid Amer Heart Inst, Kansas City, MO 64110 USA. [Ruggiero, Nicholas J.] Thomas Jefferson Univ, Jefferson Med Coll, Jefferson Heart Inst, Philadelphia, PA 19107 USA. [Rosenfield, Kenneth] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rajamani, K (reprint author), 8C UHC,4201 St Antoine, Detroit, MI 48201 USA. EM krajaman@med.wayne.edu FU American College of Cardiology Foundation's National Cardiovascular Data Registry (NCDR); American College of Cardiology Foundation FX The study was supported by American College of Cardiology Foundation's National Cardiovascular Data Registry (NCDR). Views expressed are those of the author(s) and do not necessarily represent the official views of the NCDR or its associated professional societies. Dr Spertus has a contract from American College of Cardiology Foundation to analyze the Carotid Artery Revascularization and Endarterectomy registry. Dr Chaturvedi is a consultant for Abbot Vascular and Thornhill Research. Dr Ruggiero is consultant for St. Jude and Boston Scientific. NR 7 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD APR PY 2013 VL 44 IS 4 BP 1172 EP 1174 DI 10.1161/STROKEAHA.111.000513 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 113NE UT WOS:000316673900052 PM 23422084 ER PT J AU Abbott, AL Adelman, MA Alexandrov, AV Barber, PA Barnett, HJM Beard, J Bell, P Bjorck, M Blacker, D Bonati, LH Brown, MM Buckley, CJ Cambria, RP Castaldo, JE Comerota, AJ Connolly, ES Dalman, RL Davies, AH Eckstein, HH Faruqi, R Feasby, TE Fraedrich, G Gloviczki, P Hankey, GJ Harbaugh, RE Heldenberg, E Hennerici, MG Hill, MD Kleinig, TJ Mikhailidis, DP Moore, WS Naylor, R Nicolaides, A Paraskevas, KI Pelz, DM Prichard, JW Purdie, G Ricco, JB Ringleb, PA Riles, T Rothwell, PM Sandercock, P Sillesen, H Spence, JD Spinelli, F Sturm, J Tan, A Thapar, A Veith, FJ Wijeratne, T Zhou, W AF Abbott, Anne L. Adelman, Mark A. Alexandrov, Andrei V. Barber, P. Alan Barnett, Henry J. M. Beard, Jonathan Bell, Peter Bjorck, Martin Blacker, David Bonati, Leo H. Brown, Martin M. Buckley, Clifford J. Cambria, Richard P. Castaldo, John E. Comerota, Anthony J. Connolly, E. Sander, Jr. Dalman, Ronald L. Davies, Alun H. Eckstein, Hans-Henning Faruqi, Rishad Feasby, Thomas E. Fraedrich, Gustav Gloviczki, Peter Hankey, Graeme J. Harbaugh, Robert E. Heldenberg, Eitan Hennerici, Michael G. Hill, Michael D. Kleinig, Timothy J. Mikhailidis, Dimitri P. Moore, Wesley S. Naylor, Ross Nicolaides, Andrew Paraskevas, Kosmas I. Pelz, David M. Prichard, James W. Purdie, Grant Ricco, Jean-Baptiste Ringleb, Peter A. Riles, Thomas Rothwell, Peter M. Sandercock, Peter Sillesen, Henrik Spence, J. David Spinelli, Francesco Sturm, Jonathon Tan, Aaron Thapar, Ankur Veith, Frank J. Wijeratne, Tissa Zhou, Wei TI Why Calls for More Routine Carotid Stenting Are Currently Inappropriate An International, Multispecialty, Expert Review and Position Statement SO STROKE LA English DT Article; Proceedings Paper CT International Stroke Conference CY JAN 31-FEB 03, 2012 CL New Orleans, LA DE carotid angioplasty/stenting; carotid endarterectomy; carotid stenosis; health policy; stroke prevention ID ARTERY STENOSIS; UNITED-STATES; REVASCULARIZATION ENDARTERECTOMY; COST-EFFECTIVENESS; MEDICAID SERVICES; CLINICAL-TRIALS; RISK; STROKE; GUIDELINES; PROFESSIONALS C1 [Abbott, Anne L.] Monash Univ, Alfred Ctr, Sch Publ Hlth & Prevent Med, Melbourne, Vic 3004, Australia. [Abbott, Anne L.] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Abbott, Anne L.] Florey Inst Neurosci & Mental Hlth, Melbourne, Vic, Australia. [Adelman, Mark A.] NYU, Langone Med Ctr, Div Vasc & Endovasc Surg, New York, NY USA. [Alexandrov, Andrei V.] Univ Alabama Hosp & Clin, Comprehens Stroke Ctr, Birmingham, AL USA. [Barber, P. Alan] Univ Auckland, Dept Med, Ctr Brain Res, Auckland, New Zealand. [Barnett, Henry J. M.] Univ Western Ontario, Div Neurol, London, ON, Canada. [Beard, Jonathan] No Gen Hosp, Sheffield Vasc Inst, Sheffield S5 7AU, S Yorkshire, England. [Bell, Peter] Univ Leicester, Univ Leicester Hosp, Leicester, Leics, England. [Bjorck, Martin] Uppsala Univ, Dept Surg Sci, Uppsala, Sweden. [Blacker, David] Sir Charles Gairdner Hosp, Dept Neurol, Perth, WA, Australia. [Bonati, Leo H.] Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland. [Bonati, Leo H.] Univ Basel Hosp, Stroke Unit, CH-4031 Basel, Switzerland. [Brown, Martin M.] Natl Hosp, UCL Inst Neurol, London WC1N 3BG, England. [Buckley, Clifford J.] Cent Texas Vet Hlth Care Syst, Scott & White Hlth Care Syst, Texas A&M Hlth Sci Ctr, Coll Med, Temple, TX USA. [Cambria, Richard P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc & Endovasc Surg, Boston, MA USA. [Castaldo, John E.] Lehigh Valley Hlth Network, USF Coll Med, Div Neurol, Allentown, PA USA. [Comerota, Anthony J.] Toledo Hosp, Jobst Vasc Inst, Toledo, OH USA. [Connolly, E. Sander, Jr.] Columbia Univ, Dept Neurol Surg, New York, NY USA. [Dalman, Ronald L.] Stanford Univ, Div Vasc Surg, Stanford, CA 94305 USA. [Dalman, Ronald L.] Stanford Univ, Div Cardiovasc Hlth Qual & Outcomes, Stanford, CA 94305 USA. [Davies, Alun H.] Charing Cross Hosp, Imperial Coll Sch Med, Dept Surg & Canc, Acad Sect Vasc Surg, London, England. [Eckstein, Hans-Henning] Univ Munich, Klinikum Rechts Isar Tech, Vasc Ctr, Dept Vasc & Endovasc Surg, Munich, Germany. [Faruqi, Rishad] Stanford Univ, Stanford, CA 94305 USA. [Faruqi, Rishad] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Faruqi, Rishad] Kaiser Permanente Med Ctr, Dept Vasc & Endovasc Surg, Santa Clara, CA USA. [Feasby, Thomas E.] Univ Calgary, Fac Med, Dept Clin Neurosci, Calgary, AB, Canada. [Fraedrich, Gustav] Med Univ Innsbruck, Dept Vasc Surg, A-6020 Innsbruck, Austria. [Gloviczki, Peter] Mayo Clin, Div Vasc & Endovasc Surg, Rochester, MN USA. [Hankey, Graeme J.] Univ Western Australia, Royal Perth Hosp, Dept Neurol, Perth, WA 6009, Australia. [Harbaugh, Robert E.] Penn State Univ, Penn State Inst Neurosci, Hershey, PA USA. [Heldenberg, Eitan] Assaf Harofeh Med Ctr, Dept Vasc Surg, IL-70300 Zerifin, Israel. [Heldenberg, Eitan] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Hennerici, Michael G.] UMM, Univ Med Mannheim, Neurol Univ Klin, Mannheim, Germany. [Hennerici, Michael G.] Heidelberg Univ, Mannheim, Germany. [Hill, Michael D.] Univ Calgary, Dept Clin Neurosci, Hotchkiss Brain Inst, Calgary, AB, Canada. [Kleinig, Timothy J.] Royal Adelaide Hosp, Dept Neurol, Adelaide, SA 5000, Australia. [Kleinig, Timothy J.] Lyell McEwin Hosp, Adelaide, SA, Australia. [Kleinig, Timothy J.] Univ Adelaide, Dept Med, Adelaide, SA 5001, Australia. [Mikhailidis, Dimitri P.] UCL, Sch Med, Dept Clin Biochem, Vasc Dis Prevent Clin, London W1N 8AA, England. [Moore, Wesley S.] Univ Calif Los Angeles, Div Vasc Surg, Los Angeles, CA USA. [Naylor, Ross] Univ Leicester, Leicester Royal Infirm, Div Cardiovasc Sci, Vasc Surg Grp, Leicester, Leics, England. [Nicolaides, Andrew] Univ London Imperial Coll Sci Technol & Med, Dept Vasc Surg, Vasc Noninvas Diagnost Ctr, London, England. [Paraskevas, Kosmas I.] Red Cross Hosp, Athens, Greece. [Pelz, David M.; Spence, J. David] Univ Western Ontario, London, ON, Canada. [Prichard, James W.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. [Purdie, Grant] Queen Elizabeth Hosp, Dept Neurol, Adelaide, SA, Australia. [Ricco, Jean-Baptiste] Univ Poitiers, Vasc Surg Serv, Poitiers, France. [Ringleb, Peter A.] Univ Heidelberg Hosp, Dept Neurol, Heidelberg, Germany. [Riles, Thomas] NYU, Sch Med, Div Vasc Surg, New York, NY USA. [Rothwell, Peter M.] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England. [Sandercock, Peter] Univ Edinburgh, Western Gen Hosp, Div Clin Neurosci, Edinburgh, Midlothian, Scotland. [Sillesen, Henrik] Univ Copenhagen, Rigshosp, Dept Vasc Surg, DK-2100 Copenhagen, Denmark. [Spence, J. David] Robarts Res Inst, Stroke Prevent & Atherosclerosis Res Ctr, London, ON N6A 5C1, Canada. [Spinelli, Francesco] Univ Messina, Dept Cardiovasc & Thorac Sci, Messina, Italy. [Sturm, Jonathon] Univ Newcastle, Gosford Hosp, Dept Neurol, Callaghan, NSW 2308, Australia. [Sturm, Jonathon] Univ Newcastle, Wyong Hosp, Callaghan, NSW 2308, Australia. Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, Acad Sect Vasc Surg, London, England. [Veith, Frank J.] Univ Hlth Sci, F Edward Hebert Sch Med, Case Western Reserve Univ,Div Vasc Surg, Lerner Sch Med,Cleveland Clin,NYU,Sch Med, New York, NY USA. [Wijeratne, Tissa] Univ Melbourne, Western Clin Sch, Western Hosp, Dept Neurol, Melbourne, Vic, Australia. [Zhou, Wei] Stanford Univ, Palo Alto VA Hlth Care Syst, Stanford, CA 94305 USA. RP Abbott, AL (reprint author), Alfred Ctr, Sch Publ Hlth & Prevent Med, 99 Commercial Rd, Melbourne, Vic 3004, Australia. EM Anne.L.Abbott@gmail.com RI Abbott, Anne/G-6604-2013; Spence, J. David/K-6396-2013; Hankey, Graeme /H-4968-2014; Bonati, Leo/G-4058-2012; Barber, Philip/C-7108-2016; OI Barber, P Alan/0000-0003-2469-9023; Hill, Michael/0000-0002-6269-1543; Adelman, Mark/0000-0001-9276-6131; Spence, J. David/0000-0001-7478-1098; Hankey, Graeme /0000-0002-6044-7328; Bonati, Leo/0000-0003-1163-8133; Spinelli, Francesco/0000-0001-6527-1993; Sandercock, Peter/0000-0001-8484-0135; Alexandrov, Andrei V/0000-0001-8871-1023; Eckstein, Hans-Henning/0000-0002-0743-1642; Ringleb, Peter/0000-0002-5473-8671 FU Australian National Health and Medical Research Council Fellowship [472700]; Victorian Government's OIS Program; Boehringer Ingelheim; Carotid Revascularization Endarterectomy versus Stenting Trial (CREST); Stroke Association; Merck; Novartis; Boehringer-Ingelheim; Canadian Institutes of Health Research; Heart and Stroke Foundation of Canada (Ontario); National Institutes of Health; Royal College of Surgeons of England; National Institute of Health/National Institute of Neurological Disorders and Stroke FX Anne Abbott's time on this project was partially supported by an Australian National Health and Medical Research Council Fellowship (ID: 472700) and supported in part by the Victorian Government's OIS Program.; Henry Barnett was PI of the North American Symptomatic Carotid Endarterectomy Trial (NASCET). Jonathan Beard is on the Steering Committee of the International Carotid Stenting Study (ICSS). David Blacker has received sponsorship to scientific meetings from Boehringer Ingelheim. He has previously been a member of the advisory board for NovoNorsdisk (regarding Factor VII) and receives funding for involvement in the Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) Study. Leo Bonati is a member of the ICSS Study Group, a member of the Steering Committee of the European Carotid Surgery Trial 2 (ECST-2) and the coordinating member of the Steering Committee of the Carotid Stenting Trialists Collaboration (CSTC). Prof Martin Brown is the Chief Investigator of the Carotid and Vertebral Transluminal Angioplasty Study (CAVATAS), ICSS, and the ECST-2. Richard Cambria is co-PI for a future transcervical carotid stenting/flow reversal trial (ROADSTER). Anthony Comerota received research funding for the Jobst Vascular Institute to participate in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Ronald Dalman previously served as site PI for the Abbott Industries Protected Carotid Artery Stenting in Patients at High Risk for Carotid Endarterectomy (PROTECT) trial for California and is a co-holder of a provisional patent for a carotid distal protection device. Alun Davies receives funding from the Stroke Association on the evaluation of carotid plaque. Hans-Henning Eckstein is co-PI of the Stent-Supported Percutaneous Angioplasty of the Carotid Artery versus Endarterectomy (SPACE-2) Study. He was a member of the Steering Committee of the SPACE-1 Study. Gustav Fraedrich is member of the steering committee of the Carotid Stenting Trialists Collaboration (CSTC) and member of the steering committee of the SPACE-2-Study. He was a member of the Writing Committee of the SPACE-1 Study. Graeme Hankey was a member of the ECST Collaborative Group and the NASCET Collaborators. Michael Hennerici founded the European Stroke Conference: http://www.eurostroke.eu. He is a principal investigator, coordinator, and board member for several international clinical trials including the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events Trial (CAPRIE), Aspirin and Clopidogrel Compared With Clopidogrel Alone After Recent Ischemic Stroke or Transient Ischemic Attack in High-Risk Patients Trial (MATCH), Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trial (SPARCL), SPACE-1, and SPACE 2. Dimitri Mikhailidis has given talks and attended conferences sponsored by Merck, Sharp and Dohme, Genzyme, and Abbott Industries. Wesley Moore is a co-PI for the CREST and member of the CREST Executive Committee. Peter A. Ringleb is the Clinical coordinator of SPACE-1, a member of the steering committee of SPACE-2 and a member of the guideline-committee of the German Neurological Society, German Stroke Society, and European Stroke Organization. Peter Rothwell is on the Data Monitoring Committee of the SPACE-2 trial. He is Chair of the End point Adjudication Committee of the Asymptomatic Carotid Artery Surgery Trial-2 (ACST-2). He is on the Steering Committee of the ECST-2 and the General Anesthetic versus Local Anesthetic (GALA) for Carotid Surgery Trial. Peter Sandercock is the independent chair of the MRC/NIHR ACST-2 Trial. J.; David Spence has received lecture fees or consulting fees from Merck, Novartis and Boehringer-Ingelheim and sponsorship to scientific meetings from Boehringer-Ingelheim. He obtains research funding from the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada (Ontario), and the National Institutes of Health. Ankur Thapar receives research funding from the Royal College of Surgeons of England. Wei Zhou receives research funding from the National Institute of Health/National Institute of Neurological Disorders and Stroke for evaluating outcomes of carotid interventions. The other authors have no conflicts to report. NR 46 TC 20 Z9 21 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD APR PY 2013 VL 44 IS 4 BP 1186 EP 1190 DI 10.1161/STROKEAHA.111.000261 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 113NE UT WOS:000316673900056 PM 23512977 ER PT J AU Goldberg, SB Willers, H Heist, RS AF Goldberg, Sarah B. Willers, Henning Heist, Rebecca S. TI Multidisciplinary Management of Small Cell Lung Cancer SO SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Small cell lung cancer; Multidisciplinary management; Surgical resection; Cranial irradiation ID PHASE-III TRIAL; PROPHYLACTIC CRANIAL IRRADIATION; COUNCIL COMPARATIVE TRIAL; THORACIC RADIOTHERAPY; SURGICAL RESECTION; RADIATION-THERAPY; FOLLOW-UP; CHEMOTHERAPY; CARCINOMA; CISPLATIN AB Multidisciplinary Management of Small Cell Lung Cancer Sarah B. Goldberg, Henning Willers, and Rebecca S. Heist The standard treatment of limited-stage small cell lung cancer (SCLC) is concurrent cisplatin and etoposide with thoracic radiation therapy, whereas treatment of extensive-stage disease is typically chemotherapy alone with a platinum compound plus etoposide. Surgical resection of early disease is generally reserved for patients with small, node-negative disease. Prophylactic cranial irradiation reduces the development of brain metastases and prolongs survival in patients with both limited-stage and extensive-stage disease who have responded to chemotherapy. Further understanding of the molecular underpinnings of SOLO is necessary to develop better treatment options and improve outcomes for patients. C1 [Goldberg, Sarah B.] Yale Canc Ctr, Dept Hematol Oncol, New Haven, CT 06520 USA. [Willers, Henning] Massachusetts Gen Hosp, Ctr Canc, Dept Radiat Oncol, Clark Ctr Radiat Oncol, Boston, MA 02114 USA. [Heist, Rebecca S.] Massachusetts Gen Hosp, Ctr Canc, Dept Hematol Oncol, Boston, MA 02114 USA. RP Heist, RS (reprint author), Massachusetts Gen Hosp, Ctr Canc, Dept Hematol Oncol, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. EM rheist@partners.org NR 52 TC 5 Z9 6 U1 1 U2 14 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1055-3207 EI 1558-5042 J9 SURG ONCOL CLIN N AM JI Surg. Oncol. Clin. N. Am. PD APR PY 2013 VL 22 IS 2 BP 329 EP + DI 10.1016/j.soc.2012.12.002 PG 16 WC Oncology; Surgery SC Oncology; Surgery GA 117SN UT WOS:000316973500011 PM 23453338 ER PT J AU Ma, RS Latif, R Davies, TF AF Ma, Risheng Latif, Rauf Davies, Terry F. TI Thyroid Follicle Formation and Thyroglobulin Expression in Multipotent Endodermal Stem Cells SO THYROID LA English DT Article ID SYNERGISTICALLY ACTIVATE; GENE-EXPRESSION; TRANSCRIPTION; DIFFERENTIATION; MOUSE; PAX8; PRESERVATION; ORGANOIDS AB Objective: The aim of this study was to assess the impact of transcriptional induction on thyroid follicular cell (TFC) differentiation from endodermally matured embryonic stem (ES) cells. The thyroid transcription factors-NKx2 homeobox 1 (NKx2-1, formerly called TTF-1) and Paired box gene 8 (Pax8)-are known to associate biochemically and synergistically in the activation of thyroid functional genes including the sodium/iodide symporter (NIS), thyrotropin (TSH) receptor (TSHR), thyroglobulin (Tg), and thyroid peroxidase (TPO) genes. In this study, we investigated the ability of ectopically expressed Pax8 and NKx2-1 to further the induction and differentiation of murine ES cells into potential TFCs. Methods: ES cells were stably transfected with either the Pax8 gene, the NKx2-1 gene, or both genes to study the induction of NIS, TSHR, Tg, and TPO genes as assessed using both quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and protein expression. The derived cells were cultured with or without the presence of activin A to allow their differentiation into multipotent endodermal cells. Results: The four thyroid-specific genes NIS, TSHR, Tg, and TPO were all significantly activated by expressing both transcription factors within the same ES cell. In contrast, significant but much lower transcriptional activity of the TSHR, Tg, and TPO genes was detected in cells expressing just NKx2-1, and only the NIS and TSHR genes responded to Pax8 alone. No Tg protein expression could be detected prior to their development into endodermal derivatives. However, after further differentiation of postembryoid body ES cells with activin A and TSH into endodermal cell lines, those cells with dual transfection of Pax8 and NKx2-1 demonstrated greatly enhanced expression of the NIS, TSHR, Tg, and TPO genes to such a degree that it was similar to that found in control thyroid cells. Furthermore, these same cells formed three-dimensional neofollicles in vitro and expressed Tg protein, but these phenomena were absent from lines expressing only Pax8 or NKx2-1. Conclusion: These findings provide further evidence that co-expression of Pax8 and NKx2-1 in murine ES cells may induce the differentiation of thyroid-specific gene expression within endodermally differentiated ES cells and commit them to form three-dimensional neofollicular structures. C1 [Ma, Risheng; Latif, Rauf; Davies, Terry F.] Icahn Sch Med Mt Sinai, Dept Med, Thyroid Res Unit, New York, NY USA. [Ma, Risheng; Latif, Rauf; Davies, Terry F.] James J Peters VA Med Ctr, Dept Med, New York, NY USA. RP Ma, RS (reprint author), VA Med Ctr, Room 2F-27,130 West Kingsbridge Rd, New York, NY 10468 USA. EM risheng.ma@mssm.edu OI latif, rauf/0000-0002-4226-3728 FU National Institutes of Health [DK080459, DK069713, DK052464]; VA Merit Review Program FX This work was supported in part by DK080459, DK069713, and DK052464 from the National Institutes of Health and the VA Merit Review Program. NR 14 TC 15 Z9 16 U1 1 U2 13 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD APR PY 2013 VL 23 IS 4 BP 385 EP 391 DI 10.1089/thy.2012.0644 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 115FT UT WOS:000316798700003 PM 23360087 ER PT J AU Anderson, RT Linnehan, JE Tongbram, V Keating, K Wirth, LJ AF Anderson, Roger T. Linnehan, John E. Tongbram, Vanita Keating, Karen Wirth, Lori J. TI Clinical, Safety, and Economic Evidence in Radioactive Iodine-Refractory Differentiated Thyroid Cancer: A Systematic Literature Review SO THYROID LA English DT Review ID PHASE-II TRIAL; DISTANT METASTASES; CARCINOMA; SORAFENIB; THERAPY; DOXORUBICIN; MANAGEMENT; PAPILLARY; TOXICITY; EFFICACY AB Background: Thyroid cancer is the most common endocrine malignancy, with differentiated thyroid cancer (DTC) comprising similar to 93% of all thyroid cancers. While most cases of DTC are curable with the use of surgery and radioactive iodine (RAI) ablation of the remaining thyroid remnant, prognosis is dire and treatment options limited when DTC becomes RAI-refractory (RAI-R). Standard cytotoxic chemotherapy has limited efficacy, making enrollment in clinical trials of novel targeted therapies the preferred treatment approach. Thus, we conducted a comprehensive systematic review of the clinical trial scientific literature with a focus on efficacy, safety, and economics to identify all potential treatment options that have been or are currently being evaluated for the treatment of RAI-R DTC. Methods: Embase.com (including Medline), Medline In-Process and other nonindexed citations, the Cochrane Libraries, ClinicalTrials.gov, and relevant recent conference proceedings were searched using predefined search criteria. Important inclusion criteria included English language, randomized controlled studies or interventional single-arm studies only, and studies of drug therapies only. Search results were screened utilizing the discretion of multiple researchers, and key data were abstracted. Results: Forty-five unique trials (16 full-text, 4 conference abstracts, and 25 ClinicalTrials.gov entries) were included in the clinical review. No studies that met criteria for inclusion in the economic review were identified. Among 20 trials with results available, all were Phase II and only one was randomized. The most commonly studied drugs were tyrosine kinase inhibitors (TKIs); other drugs included celecoxib, doxorubicin with interferon alpha-2b, rosiglitazone, selumetinib (AZD6244), thalidomide, VEGF trap, and vorinostat. Overall, efficacy and safety profiles were specific to treatment regimen, with objective response rates (ORR) ranging from 0% on gefitinib, rosiglitazone, VEGF trap, and vorinostat to 50% on lenvatinib, a TKI. Conclusions: Limited clinical research and no economic research has been conducted in RAI-R DTC. Certain treatments, notably TKIs, have shown promise in Phase II trials, and two Phase III randomized placebo-controlled trials are ongoing. New research on the economic and humanistic burden of RAI-R DTC must be paired with the clinical evidence currently in development to examine the existing burden and future promise in treating patients with RAI-R DTC. C1 [Anderson, Roger T.] Penn State Univ, Penn State Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. [Linnehan, John E.] Oxford Outcomes, Dept Hlth Econ, Bethesda, MD USA. [Tongbram, Vanita] Oxford Outcomes, Dept Hlth Econ, Morristown, NJ USA. [Keating, Karen] Bayer Healthcare Pharmaceut, Dept Global Hlth Econ Outcomes Reimbursement & Ma, Montville, NJ USA. [Wirth, Lori J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Oncol, Boston, MA USA. RP Linnehan, JE (reprint author), Oxford Outcomes, 7315 Wisconsin Ave,Suite 250W, Bethesda, MD 20814 USA. EM john.linnehan@comcast.net FU Bayer Healthcare Pharmaceuticals FX This project was funded by Bayer Healthcare Pharmaceuticals. J.E.L. and V.T. were paid consultants to Bayer Healthcare Pharmaceuticals for this project. R.A. reports no compensation for the role of authorship of this manuscript; he serves as a paid consultant to Bayer Pharma AG relating to patient-reported outcomes assessments. L.J.W. reports no compensation for the role of authorship of this manuscript; she serves as a paid consultant to Bayer Pharma AG and Exelexis. K.K. is an employee of Bayer Healthcare Pharmaceuticals. NR 45 TC 23 Z9 25 U1 0 U2 12 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD APR PY 2013 VL 23 IS 4 BP 392 EP 407 DI 10.1089/thy.2012.0520 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 115FT UT WOS:000316798700004 PM 23294230 ER PT J AU Murphy, AM Rabkin, SD AF Murphy, Andrea M. Rabkin, Samuel D. TI Current status of gene therapy for brain tumors SO TRANSLATIONAL RESEARCH LA English DT Review ID MESENCHYMAL STEM-CELLS; HERPES-SIMPLEX-VIRUS; HIGH-GRADE GLIOMA; LONG-TERM SURVIVAL; COMPETENT RETROVIRUS VECTORS; RECURRENT MALIGNANT GLIOMAS; GUTLESS ADENOVIRUS VECTORS; HUMAN GLIOBLASTOMA CELLS; MEASLES-VIRUS; ONCOLYTIC ADENOVIRUS AB Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults, with current treatments having limited impact on disease progression. Therefore the development of alternative treatment options is greatly needed. Gene therapy is a treatment strategy that relies on the delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes, and has been applied to GBM with increasing promise. We have included selectively replication-competent oncolytic viruses within this strategy, although the virus acts directly as a complex biologic anti-tumor agent rather than as a classic gene delivery vehicle. GBM is a good candidate for gene therapy because tumors remain locally within the brain and only rarely metastasize to other tissues; the majority of cells in the brain are post-mitotic, which allows for specific targeting of dividing tumor cells; and tumors can often be accessed neurosurgically for administration of therapy. Delivery vehicles used for brain tumors include nonreplicating viral vectors, normal adult stem/progenitor cells, and oncolytic viruses. The therapeutic transgenes or viruses are typically cytotoxic or express prodrug activating suicide genes to kill glioma cells, immunostimulatory to induce or amplify anti-tumor immune responses, and/or modify the tumor microenvironment such as blocking angiogenesis. This review describes current preclinical and clinical gene therapy strategies for the treatment of glioma. (Translational Research 2013;161:339-354) C1 [Rabkin, Samuel D.] Massachusetts Gen Hosp, Dept Neurosurg, Mol Neurosurg Lab, Brain Tumor Res Ctr, Boston, MA 02114 USA. [Rabkin, Samuel D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Rabkin, SD (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Mol Neurosurg Lab, Brain Tumor Res Ctr, 185 Cambridge St,CPZN-3800, Boston, MA 02114 USA. EM rabkin@helix.mgh.harvard.edu RI Waha, Andreas/J-2950-2014; OI rabkin, samuel/0000-0003-2344-2795 FU National Institutes of Health (National Cancer Institute); National Institutes of Health (National Institute of Neurologic Disorders and Stroke); Department of Defense; American Brain Tumor Association FX The authors thank past and current members of the laboratory for contributing to our research, which has been supported by grants from the National Institutes of Health (National Cancer Institute, National Institute of Neurologic Disorders and Stroke), Department of Defense, and the American Brain Tumor Association. NR 181 TC 26 Z9 28 U1 3 U2 44 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1931-5244 J9 TRANSL RES JI Transl. Res. PD APR PY 2013 VL 161 IS 4 BP 339 EP 354 DI 10.1016/j.trsl.2012.11.003 PG 16 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA 115UM UT WOS:000316837400013 PM 23246627 ER PT J AU Van Nieuwenhove, L Buscher, P Balharbi, F Humbert, M Guisez, Y Lejon, V AF Van Nieuwenhove, Liesbeth Buescher, Philippe Balharbi, Fatima Humbert, Michael Guisez, Yves Lejon, Veerle TI A LiTat 1.5 variant surface glycoprotein-derived peptide with diagnostic potential for Trypanosoma brucei gambiense SO TROPICAL MEDICINE & INTERNATIONAL HEALTH LA English DT Article DE diagnosis; sensitivity; specificity; sleeping sickness; Trypanosoma brucei gambiense; variant surface glycoprotein AB Objective To evaluate the accuracy of a peptide, corresponding to the variant surface glycoprotein (VSG) LiTat 1.5 amino acid (AA) sequence 268281 and identified through alignment of monoclonal antibody selected mimotopes, for diagnosis of Trypanosoma brucei gambiense sleeping sickness. Methods A synthetic biotinylated peptide (peptide 1.5/268281), native VSG LiTat 1.3 and VSG LiTat 1.5 were tested in an indirect ELISA with 102 sera from patients with HAT and 102 endemic HAT-negative controls. Results The area under the curve (AUC) of peptide 1.5/268281 was 0.954 (95% confidence interval 0.9180.980), indicating diagnostic potential. The areas under the curve of VSG LiTat 1.3 and LiTat 1.5 were 1.000 (0.9821.000) and 0.997 (0.9731.000), respectively, and significantly higher than the AUC of peptide 1.5/268281. On a model of VSG LiTat 1.5, peptide 1.5/268281 was mapped near the top of the VSG. Conclusions A biotinylated peptide corresponding to AA 268281 of VSG LiTat 1.5 may replace the native VSG in serodiagnostic tests, but the diagnostic accuracy is lower than for the full-length native VSG LiTat 1.3 and VSG LiTat 1.5. Objectif Evaluer la precision diagnostique d'un peptide correspondant a une variante de la sequence des acides amines 268 a 281 de la glycoproteine de surface LiTat 1.5 et identifie grace a l'alignement des mimotopes selectionnes des anticorps monoclonaux, pour le diagnostic de la maladie du sommeil due a Trypanosoma brucei gambiense. Methodes Un peptide synthetique biotinyle (peptide 1.5/268-281) et les proteines de surface natives LiTat 1.3 et LiTat 1.5 ont ete testes dans une reaction ELISA indirecte sur 102 echantillons de serum provenant de patients atteints de THA et 102 controles negatifs de zone endemique. Resultats L'aire sous la courbe (AUC) du peptide 1.5/268-281 etait de 0.954 (IC95%: 0.918 a 0.980), ce qui indique un potentiel diagnostique. Les aires sous la courbe de LiTat 1.3 et LiTat 1.5 etaient de 1000 (0.982 a 1000) et 0.997 (0.973 a 1000), respectivement, et nettement superieures a l'AUC du peptide 1.5/268-281. Sur un modele de LiTat 1.5, le peptide 1.5/268-281 a ete cartographie pres du sommet de la glycoproteine de surface. Conclusions Un peptide biotinyle correspondant a la sequence des acides amines 268 a 281 de LiTat 1.5 pourrait remplacer la glycoproteine de surface native dans les tests de serodiagnostic, mais la precision du diagnostic est plus faible qu'avec l'entierete des glycoproteines de surfaces natives LiTat 1.3 et LiTat 1.5. Objetivo Evaluar la precision diagnostica de un peptido correspondiente a la secuencia de aminoacidos 268281 de la glicoproteina variante de superficie (VSG) LiTat 1.5, identificados mediante un alineamiento de una seleccion de mimotopes de anticuerpos monoclonales, para el diagnostico de la enfermedad del sueno por Trypanosoma brucei gambiense (HAT). Metodos Utilizando un ELISA indirecto, se probaron el peptido sintetico biotinilado (peptido 1.5/268-281), la VSG nativa LiTat 1.3 y la VSG LiTat 1.5, con 102 sueros de pacientes con HAT y 102 controles negativos endemicos. Resultados El area bajo la curva (ABC) del peptido 1.5/268-281 era de 0.954 (IC 95% 0.9180.980), indicando su potencial diagnostico. Las ABC de VSG LiTat 1.3 y LiTat 1.5 eran 1.000 (0.982-1.000) y 0.997 (0.9731.000) respectivamente, y significativamente mayor que el ABC del peptido 1.5/268-281. En un modelo del VSG LiTat 1.5, el peptido 1.5/268-281 se mapeo cerca de la parte superior del VSG. Conclusiones Un peptido biotinilado, que corresponde al AA 268281 del VSG LiTat 1. 5, podria reemplazar las pruebas serodiagnosticas basadas en la VSG nativa, pero la precision diagnostica es menor que para la VSG LiTat 1.3 nativa de tamano completo y la VSG LiTat 1.5. C1 [Van Nieuwenhove, Liesbeth; Buescher, Philippe; Balharbi, Fatima; Lejon, Veerle] Inst Trop Med, Dept Biomed Sci, B-2000 Antwerp, Belgium. [Humbert, Michael] Dana Farber Canc Inst, Boston, MA 02115 USA. [Humbert, Michael] Harvard Univ, Sch Med, Boston, MA USA. [Guisez, Yves] Univ Antwerp, Dept Biol, B-2020 Antwerp, Belgium. RP Lejon, V (reprint author), Inst Trop Med, Natl Str 155, B-2000 Antwerp, Belgium. EM vlejon@itg.be RI Buscher, Philippe/B-9956-2012; OI Buscher, Philippe/0000-0002-1926-7472; Lejon, Veerle/0000-0002-6795-0962 FU Belgian Directorate General for Development Cooperation; Research Foundation of Flanders; FWO FX We are grateful to Nicolas Bebronne and Annelies Ceusters for technical assistance. The project was funded by the Belgian Directorate General for Development Cooperation and the Research Foundation of Flanders. Liesbeth Van Nieuwenhove was supported by a PhD scholarship of the FWO. Development of the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, was supported by the NIH. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 0 TC 4 Z9 4 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1360-2276 J9 TROP MED INT HEALTH JI Trop. Med. Int. Health PD APR PY 2013 VL 18 IS 4 BP 461 EP 465 DI 10.1111/tmi.12058 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 112XF UT WOS:000316627200011 PM 23289521 ER PT J AU Sealock, RJ Kramer, JR Verstovsek, G Richardson, P Rugge, M Parente, P Vela, M El-Serag, HB AF Sealock, R. J. Kramer, J. R. Verstovsek, G. Richardson, P. Rugge, M. Parente, P. Vela, M. El-Serag, H. B. TI The prevalence of oesophageal eosinophilia and eosinophilic oesophagitis: a prospective study in unselected patients presenting to endoscopy SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID CONSENSUS RECOMMENDATIONS; BARRETTS-ESOPHAGUS; ADULTS; POPULATION; DYSPHAGIA; CHILDREN AB Background Oesophageal eosinophilia (EE) is encountered in clinical practice as oesophageal biopsies are being obtained in patients with GI symptoms other than classical symptoms of eosinophilic oesophagitis (EoE). The prevalence, determinants and clinical relevance of EE identified irrespective of symptoms are unclear. Aim To determine the prevalence and risk factors of EE with or without EoE in a nonselected group of patients undergoing endoscopy and in primary care patients. Methods A cross-sectional study in a single VA centre in which we obtained at least one oesophageal biopsy from patients presenting to elective endoscopy, as well as a sample of patients eligible for screening colonoscopy recruited from primary care clinics. EE was defined by >15 eosinophils in a single HPF; and EoE was defined as definite, probable or none depending on the presence of EE, acid-suppressive therapy and oesophageal symptoms. Results EE was identified in 33 of 1357 patients (2.4%, 95% CI: 1.73.4); of whom 9 had definite EoE (0.66%, 95% CI: 0.231.10), 17 had probable EoE (1.25%), and the only 7 patients had EE without EoE. The prevalence of EE was 2.3% among patients undergoing elective endoscopy and 0.1% among patients eligible for screening colonoscopy. Seasonal allergies (adjusted OR: 2.78; 95% CI: 1.266.11) and oesophageal strictures (4.50; 0.9022.40) were associated with EE. Conclusions The prevalence of EE was 2.3% among unselected patients presenting to endoscopy most of whom have EoE. EE was present in 0.1% in primary care patients none of whom had EoE. C1 [Sealock, R. J.; El-Serag, H. B.] Michael E DeBakey VA Med Ctr, Gastroenterol Sect, Houston, TX USA. [Sealock, R. J.; Vela, M.; El-Serag, H. B.] Baylor Coll Med, Dept Med, Gastroenterol Sect, Houston, TX 77030 USA. [Kramer, J. R.; Richardson, P.; El-Serag, H. B.] Michael E DeBakey VA Med Ctr, Houston VA Hlth Serv, Res & Dev Ctr Excellence, Houston, TX USA. [Kramer, J. R.; Richardson, P.] Baylor Coll Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Verstovsek, G.] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. [Rugge, M.] Univ Padua, Dept Med DIMED, Surg Pathol & Cytopathol Unit, Padua, Italy. [Parente, P.] Casa Sollievo della Sofferenza, Dept Pathol, San Giovanni Rotondo, Italy. RP El-Serag, HB (reprint author), VA Med Ctr, 152,2002 Holcombe Blvd, Houston, TX 77030 USA. EM hasheme@bcm.tmc.edu RI Rugge, Massimo/K-7525-2016 FU National Institutes of Health (NIH) [NCI R01 116845]; Houston VA HSR&D Center of Excellence [HFP90-020]; Texas Digestive Disease Center NIH [DK58338]; NIDDK [K24-04-107] FX This work is funded in part by National Institutes of Health (NIH) grant NCI R01 116845, the Houston VA HSR&D Center of Excellence (HFP90-020), and the Texas Digestive Disease Center NIH DK58338. Dr El-Serag is also supported by NIDDK K24-04-107. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs, the US government, the NIH or Baylor College of Medicine. The NIH had no role in the design and conduct of the study; the collection, management, analysis and interpretation of the data; or the preparation, review or approval of the manuscript. NR 23 TC 9 Z9 9 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD APR PY 2013 VL 37 IS 8 BP 825 EP 832 DI 10.1111/apt.12268 PG 8 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 108WC UT WOS:000316325900008 PM 23441936 ER PT J AU Wang, JL Wilbur, DC AF Wang, Jessica L. Wilbur, David C. TI Negative Biopsy Specimens in the Setting of High A Priori Probability of Disease Is It Time to Reconsider Quality Assurance Routines in a Time of New Diagnostic Capabilities? SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Editorial Material ID CERVICAL PATHOLOGY; AMERICAN SOCIETY; COLPOSCOPY; DYSPLASIA; LESIONS C1 [Wang, Jessica L.; Wilbur, David C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Tames Homer Wright Lab Pathol, Boston, MA 02115 USA. RP Wang, JL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Tames Homer Wright Lab Pathol, Boston, MA 02115 USA. NR 9 TC 0 Z9 0 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 APR PY 2013 VL 139 IS 4 BP 418 EP 420 DI 10.1309/AJCPU0UA5GYHXXIZ PG 3 WC Pathology SC Pathology GA 109LF UT WOS:000316369300002 PM 23525610 ER PT J AU Kim, SS Okechukwu, CA Buxton, OM Dennerlein, JT Boden, LI Hashimoto, DM Sorensen, G AF Kim, Seung-Sup Okechukwu, Cassandra A. Buxton, Orfeu M. Dennerlein, Jack T. Boden, Leslie I. Hashimoto, Dean M. Sorensen, Glorian TI Association between work-family conflict and musculoskeletal pain among hospital patient care workers SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE workfamily conflict; musculoskeletal symptoms; low back pain; hospital worker ID NATIONAL COMORBIDITY SURVEY; LIFE CONFLICT; SICKNESS ABSENCE; RISK-FACTORS; DEPRESSIVE SYMPTOMS; REGISTERED NURSES; MENTAL-HEALTH; JOB DEMAND; QUESTIONNAIRE; SWITZERLAND AB Background A growing body of evidence suggests that workfamily conflict is an important risk factor for workers' health and well-being. The goal of this study is to examine association between workfamily conflict and musculoskeletal pain among hospital patient care workers. Methods We analyzed a cross-sectional survey of 1,119 hospital patient care workers in 105 units in two urban, academic hospitals. Workfamily conflict was measured by 5-item WorkFamily Conflict Scale questionnaire. Multilevel logistic regression was applied to examine associations between workfamily conflict and self-reported musculoskeletal pain in the past 3 months, adjusting for covariates including work-related psychosocial factors and physical work factors. Results In fully adjusted models, high workfamily conflict was strongly associated with neck or shoulder pain (OR: 2.34, 95% CI: 1.643.34), arm pain (OR: 2.79, 95% CI: 1.644.75), lower extremity pain (OR: 2.20, 95% CI: 1.543.15) and any musculoskeletal pain (OR: 2.45, 95% CI: 1.563.85), and a number of body areas in pain (OR: 2.47, 95% CI: 1.823.36) in the past 3 months. The association with low back pain was attenuated and became non-significant after adjusting for covariates. Conclusions Given the consistent associations between workfamily conflict and self-reported musculoskeletal pains, the results suggest that workfamily conflict could be an important domain for health promotion and workplace policy development among hospital patient care workers. Am. J. Ind. Med. 56:488495, 2013. (c) 2012 Wiley Periodicals, Inc. C1 [Kim, Seung-Sup] Washington Univ, Dept Environm & Occupat Hlth, Sch Publ Hlth & Hlth Serv, Washington, DC 20037 USA. [Okechukwu, Cassandra A.; Sorensen, Glorian] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Buxton, Orfeu M.; Hashimoto, Dean M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Buxton, Orfeu M.; Hashimoto, Dean M.] Harvard Univ, Sch Med, Boston, MA USA. [Dennerlein, Jack T.; Hashimoto, Dean M.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Boden, Leslie I.] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Hashimoto, Dean M.] Partners HealthCare Syst, Occupat Hlth Serv, Boston, MA USA. [Sorensen, Glorian] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Kim, SS (reprint author), Washington Univ, Dept Environm & Occupat Hlth, Sch Publ Hlth & Hlth Serv, 2300 Eye St NW, Washington, DC 20037 USA. EM sskim@gwu.edu OI Boden, Leslie/0000-0002-9779-207X; Dennerlein, Jack/0000-0001-7703-643X FU National Institute for Occupational Safety and Health [U19 OH008861]; National Heart, Lung and Blood Institute [R01HL107240] FX Contract grant sponsor: National Institute for Occupational Safety and Health; Contract grant number: U19 OH008861.; Contract grant sponsor: National Heart, Lung and Blood Institute; Contract grant number: R01HL107240. NR 43 TC 12 Z9 12 U1 1 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD APR PY 2013 VL 56 IS 4 BP 488 EP 495 DI 10.1002/ajim.22120 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 108UD UT WOS:000316320800010 PM 23019044 ER PT J AU Ballard-Barbash, R Siddiqi, SM Berrigan, DA Ross, SA Nebeling, LC Dowling, EC AF Ballard-Barbash, Rachel Siddiqi, Sameer M. Berrigan, David A. Ross, Sharon A. Nebeling, Linda C. Dowling, Emily C. TI Trends in Research on Energy Balance Supported by the National Cancer Institute SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID PHYSICAL-ACTIVITY; OBESITY RESEARCH; SURVIVORS; RECOMMENDATIONS; INTERVENTIONS; METAANALYSIS; PREVENTION; OUTCOMES; BURDEN; HEALTH AB Over the past decade, the body of research linking energy balance to the incidence, development, progression, and treatment of cancer has grown substantially. No prior NIH portfolio analyses have focused on energy balance within one institute. This portfolio analysis describes the growth of National Cancer Institute (NCI) grant research on energy balance-related conditions and behaviors from 2004 to 2010 following the release of an NCI research priority statement in 2003 on energy balance and cancer-related research. Energy balance grants from fiscal years (FY) 2004 to 2010 were identified using multiple search terms and analyzed between calendar years 2008 and 2010. Study characteristics related to cancer site, design, population, and energy balance area (physical activity, diet, and weight) were abstracted. From FY2004 to FY2010, the NCI awarded 269 energy balance-relevant grants totaling $518 million. In FY2010, 4.2% of NCI's total research project grants budget was allocated to energy balance research, compared to 2.1% in FY2004. The NCI more than doubled support for investigator-initiated research project grants (R01) and increased support for cooperative agreement (U01, U54) and exploratory research (R21) grants. In the portfolio, research examining energy balance areas in combination accounted for 41.6%, and observational and interventional studies were equally represented (38.3% and 37.2%, respectively). Breast cancer was the most commonly studied cancer. Inclusion of minorities rose, and funding specific to cancer survivors more than doubled. From FY2004 to FY2010, NCI's investment in energy balance and related health behavior research showed growth in funding and diversity of mechanisms, topics, and disciplines growth that reflects new directions in this field. (Am J Prey Med 2013;44(4):416-423) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Ballard-Barbash, Rachel; Siddiqi, Sameer M.; Berrigan, David A.] NCI, Appl Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Nebeling, Linda C.] NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Ross, Sharon A.] NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Dowling, Emily C.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. RP Ballard-Barbash, R (reprint author), NCI, Div Canc Control & Populat Sci, EPN 4005,6130 Executive Blvd MSC 7344, Bethesda, MD 20892 USA. EM barbashr@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 28 TC 6 Z9 6 U1 0 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2013 VL 44 IS 4 BP 416 EP 423 DI 10.1016/j.amepre.2012.11.033 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 111GM UT WOS:000316509800014 PM 23498109 ER PT J AU Berris, T Gupta, R Rehani, MM AF Berris, Theocharis Gupta, Rajiv Rehani, Madan M. TI Radiation Dose From Cone-Beam CT in Neuroradiology Applications SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE cone-beam CT; neuroradiology; patient safety; radiation dose; radiation safety; staff safety ID IMAGE-GUIDED RADIOTHERAPY; COMPUTED-TOMOGRAPHY; PRINCIPLES; GUIDANCE; QUALITY; SYSTEM; HEAD; NECK; RADIOLOGY; EXPOSURE AB OBJECTIVE. In view of increasing concern about radiation dose, this article aims to provide a summary of radiation doses in neuroradiologic applications of cone-beam CT. CONCLUSION. The conventional wisdom that cone-beam CT incurs a much lower radiation dose than MDCT may not be uniformly true, especially in intraoperative use if operators are tempted to overuse the 3D imaging capabilities. The emerging nature of cone-beam CT warrants extra caution to avoid overexposure of patients. C1 [Berris, Theocharis; Rehani, Madan M.] IAEA, Radiat Protect Patients Unit, Vienna Int Ctr, A-1400 Vienna, Austria. [Gupta, Rajiv] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neuroradiol, Boston, MA USA. RP Rehani, MM (reprint author), IAEA, Radiat Protect Patients Unit, Vienna Int Ctr, POB 200, A-1400 Vienna, Austria. EM madan.rehani@gmail.com NR 36 TC 2 Z9 2 U1 5 U2 6 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD APR PY 2013 VL 200 IS 4 BP 755 EP 761 DI 10.2214/AJR.12.10177 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 112VK UT WOS:000316622100021 PM 23521443 ER PT J AU Covarrubias, DA O'Connor, OJ McDermott, S Arellano, RS AF Covarrubias, Diego Antonio O'Connor, Owen J. McDermott, Shaunagh Arellano, Ronald S. TI Radiologic Percutaneous Gastrostomy: Review of Potential Complications and Approach to Managing the Unexpected Outcome SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE feeding tubes; management of procedure complications; percutaneous gastrostomy ID INTERVENTIONAL RADIOLOGY; NONVASCULAR INTERVENTIONS; MANAGEMENT; GASTROJEJUNOSTOMY; GUIDELINES; GASTROPEXY; SOCIETY; ACCESS; TUBE AB OBJECTIVE. Radiologic percutaneous gastrostomy tube placement is a widely accepted method of enteral access for patients requiring long-term nutritional support for a variety of conditions. Although the safety of this procedure is well documented, complications do occur. The purpose of this article is to review the major and minor complications associated with gastrostomy tube placement and to present appropriate and effective management strategies. CONCLUSION. Familiarity with the potential complications, techniques for their prevention, and strategies for treatment will help practicing interventional radiologists successfully manage all possible outcomes. C1 [Covarrubias, Diego Antonio] Kaiser Permanente West Los Angeles Med Ctr, Dept Intervent Radiol, Diagnost Imaging Serv, Los Angeles, CA 90034 USA. [O'Connor, Owen J.] Cork Univ Hosp, Dept Radiol, Cork, Ireland. [McDermott, Shaunagh; Arellano, Ronald S.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp,Div Abdominal Imaging & In, Boston, MA 02115 USA. RP Covarrubias, DA (reprint author), Kaiser Permanente West Los Angeles Med Ctr, Dept Intervent Radiol, Diagnost Imaging Serv, 6041 Cadillac Ave, Los Angeles, CA 90034 USA. EM diego.a.covarrubias@kp.org NR 21 TC 13 Z9 13 U1 0 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD APR PY 2013 VL 200 IS 4 BP 921 EP 931 DI 10.2214/AJR.11.7804 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 112VK UT WOS:000316622100049 PM 23521471 ER PT J AU Kraeft, JJ Uppot, RN Heffess, AM AF Kraeft, Jessica J. Uppot, Raul N. Heffess, Alejandro M. TI Imaging Findings in Eating Disorders SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE anorexia; bulimia; eating disorders; radiology ID OF-THE-LITERATURE; ACUTE GASTRIC DILATATION; TRABECULAR STRUCTURE-ANALYSIS; PANEL VOLUME CT; ANOREXIA-NERVOSA; PELVIC ULTRASONOGRAPHY; SWALLOWED TOOTHBRUSH; RECTAL PROLAPSE; BULIMIA-NERVOSA; ABDOMINAL-PAIN AB OBJECTIVE. Eating disorders, such as anorexia nervosa and bulimia nervosa, are often undiagnosed but potentially treatable illnesses that, if not identified, can lead to morbidity and death. Often, because of embarrassment or social stigma, patients do not readily admit to these disorders when interviewed by caregivers. Imaging findings can suggest the presence of an eating disorder; understanding these findings allows the radiologist to contribute to the diagnosis of these insidious conditions and alert the referring caregiver. Current concepts in eating disorders and their multimodality imaging findings in several organ systems will be reviewed. CONCLUSION. After reviewing this article, the radiologist will understand the imaging findings in eating disorders. This knowledge will empower the radiologist to raise the question of a patient's eating disorder, a condition that may be unsuspected by the referring caregiver and could otherwise remain undiagnosed. C1 [Kraeft, Jessica J.; Heffess, Alejandro M.] Mt Auburn Hosp, Dept Radiol, Cambridge, MA 02138 USA. [Uppot, Raul N.] Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. RP Kraeft, JJ (reprint author), Mt Auburn Hosp, Dept Radiol, 330 Mt Auburn St, Cambridge, MA 02138 USA. EM jkraeft@mah.harvard.edu NR 50 TC 3 Z9 3 U1 0 U2 17 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD APR PY 2013 VL 200 IS 4 BP W328 EP W335 DI 10.2214/AJR.12.9641 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 112VK UT WOS:000316622100001 PM 23521475 ER PT J AU Li, SP Sheng, JH Hu, JK Yu, WH Kishikawa, H Hu, MFG Shima, K Wu, D Xu, ZP Xin, W Sims, KB Landers, JE Brown, RH Hu, GF AF Li, Shuping Sheng, Jinghao Hu, Jamie K. Yu, Wenhao Kishikawa, Hiroko Hu, Miaofen G. Shima, Kaori Wu, David Xu, Zhengping Xin, Winnie Sims, Katherine B. Landers, John E. Brown, Robert H., Jr. Hu, Guo-fu TI Ribonuclease 4 protects neuron degeneration by promoting angiogenesis, neurogenesis, and neuronal survival under stress SO ANGIOGENESIS LA English DT Article DE Ribonuclease 4; Angiogenin; Angiogenesis; Neurogenesis; Neuroprotection; Amyotrophic lateral sclerosis (ALS) ID AMYOTROPHIC-LATERAL-SCLEROSIS; EOSINOPHIL CATIONIC PROTEIN; EMBRYONAL CARCINOMA-CELLS; TISSUE-SPECIFIC EXPRESSION; SITE-DIRECTED MUTAGENESIS; TRANSFER-RNA; ENDOTHELIAL-CELLS; PANCREATIC RIBONUCLEASE; A SUPERFAMILY; STEM-CELLS AB Altered RNA processing is an underlying mechanism of amyotrophic lateral sclerosis (ALS). Missense mutations in a number of genes involved in RNA function and metabolisms are associated with ALS. Among these genes is angiogenin (ANG), the fifth member of the vertebrate-specific, secreted ribonuclease superfamily. ANG is an angiogenic ribonuclease, and both its angiogenic and ribonucleolytic activities are important for motor neuron health. Ribonuclease 4 (RNASE4), the fourth member of this superfamily, shares the same promoters with ANG and is co-expressed with ANG. However, the biological role of RNASE4 is unknown. To determine whether RNASE4 is involved in ALS pathogenesis, we sequenced the coding region of RNASE4 in ALS and control subjects and characterized the angiogenic, neurogenic, and neuroprotective activities of RNASE4 protein. We identified an allelic association of SNP rs3748338 with ALS and demonstrated that RNASE4 protein is able to induce angiogenesis in in vitro, ex vivo, and in vivo assays. RNASE4 also induces neural differentiation of P19 mouse embryonal carcinoma cells and mouse embryonic stem cells. Moreover, RNASE4 not only stimulates the formation of neurofilaments from mouse embryonic cortical neurons, but also protects hypothermia-induced degeneration. Importantly, systemic treatment with RNASE4 protein slowed weight loss and enhanced neuromuscular function of SOD1 (G93A) mice. C1 [Li, Shuping; Sheng, Jinghao; Hu, Jamie K.; Yu, Wenhao; Kishikawa, Hiroko; Hu, Miaofen G.; Hu, Guo-fu] Tufts Med Ctr, Mol Oncol Res Inst, Boston, MA 02111 USA. [Li, Shuping] Zhejiang Univ, Sch Med, Affiliated Hosp 1, State Key Lab Diag & Treatment Infect Dis, Hangzhou 310003, Zhejiang, Peoples R China. [Sheng, Jinghao; Xu, Zhengping] Zhejiang Univ, Sch Med, Inst Environm Med, Hangzhou 310003, Zhejiang, Peoples R China. [Shima, Kaori] Kagoshima Univ, Grad Sch Med & Dent Sci, Div Oral Pathol, Kagoshima 890, Japan. [Wu, David] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Xin, Winnie; Sims, Katherine B.] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. [Landers, John E.; Brown, Robert H., Jr.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. RP Hu, GF (reprint author), Tufts Med Ctr, Mol Oncol Res Inst, 800 Washington St,Box 5069, Boston, MA 02111 USA. EM guo-fu.hu@tufts.edu FU National Institute of Health [R01 NS 065237]; NIH; ALS Therapy Alliance; Harvard University Technology Development Accelerator Fund; National Institute for Neurological Disease and Stroke; Angel Fund; ALS Association FX This work was supported by National Institute of Health grant R01 NS 065237 (to GFH). GFH receives fund from NIH, ALS Therapy Alliance, and Harvard University Technology Development Accelerator Fund, Massachusetts Alzheimer Disease Research Center, and Tufts University CTSI program. RHB receives support from the National Institute for Neurological Disease and Stroke, the Angel Fund, the ALS Association, Project ALS, P2ALS. Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Foundation, and the ALS Therapy Alliance. We thank Robert Shapiro (Harvard Medical School) for helpful discussions on biochemical characterization of RNASE4, Helene F. Rosenberg (NIH/NIAID) for providing mouse Rnase4 expression plasmid, Jan Hofsteenge (Friedrich Miescher Institute, Switzerland) for providing pig RNASE4 expression plasmid. NR 68 TC 9 Z9 12 U1 5 U2 16 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0969-6970 J9 ANGIOGENESIS JI Angiogenesis PD APR PY 2013 VL 16 IS 2 BP 387 EP 404 DI 10.1007/s10456-012-9322-9 PG 18 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 107FC UT WOS:000316199200009 PM 23143660 ER PT J AU Jacoby, GA Hooper, DC AF Jacoby, George A. Hooper, David C. TI Phylogenetic Analysis of Chromosomally Determined Qnr and Related Proteins SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID QUINOLONE-RESISTANCE DETERMINANT; PENTAPEPTIDE REPEAT PROTEINS; STENOTROPHOMONAS-MALTOPHILIA; INTRINSIC RESISTANCE; TRANSFERABLE PLASMID; VIBRIO-SPLENDIDUS; ESCHERICHIA-COLI; GENE; EXPRESSION; SMQNR AB qnr genes were discovered on plasmids by their ability to reduce quinolone susceptibility, but homologs can be found in the genomes of at least 92 Gram-negative, Gram-positive, and strictly anaerobic bacterial species. The related pentapeptide repeat protein-encoding mfpA gene is present in the genome of at least 19 species of Mycobacterium and 10 other Actinobacteria species. The native function of these genes is not yet known. C1 [Jacoby, George A.] Lahey Clin Fdn, Burlington, MA USA. [Hooper, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Jacoby, GA (reprint author), Lahey Clin Fdn, Burlington, MA USA. EM george.a.jacoby@lahey.org FU National Institutes of Health, U.S. Public Health Service [R01 AI057576] FX This work was supported by grant R01 AI057576 (to D.C.H. and G.A.J.) from the National Institutes of Health, U.S. Public Health Service. NR 46 TC 12 Z9 14 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD APR PY 2013 VL 57 IS 4 BP 1930 EP 1934 DI 10.1128/AAC.02080-12 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 106CN UT WOS:000316119100052 PM 23318805 ER PT J AU Tanpowpong, P Broder-Fingert, S Katz, AJ Camargo, CA AF Tanpowpong, Pornthep Broder-Fingert, Sarabeth Katz, Aubrey J. Camargo, Carlos A., Jr. TI Characteristics of children with positive coeliac serology and normal villous morphology: potential coeliac disease SO APMIS LA English DT Article DE Duodenum; biopsy; serology; gluten ID SMALL-INTESTINAL MUCOSA; AT-RISK GROUPS; INTRAEPITHELIAL LYMPHOCYTOSIS; GLUTEN; TRANSGLUTAMINASE; PREVALENCE; ANTIBODIES; DUODENOSIS; DIAGNOSIS; SPECTRUM AB Positive coeliac serology with normal villous morphology (NVM) indicates potential coeliac disease (CD). Few studies have compared characteristics of NVM vs villous atrophy in patients with positive serology. Our aim was to determine the independent clinical predictors of NVM in children with positive CD serology. We performed a structured medical record review of patients aged 119years who presented for an initial CD evaluation between 2000 and 2010 at a large teaching hospital. Data collection included demographics, medical history, prior history of gluten avoidance, CD-specific serology, oesophagogastroduodenoscopy and histopathology. Predictors of NVM (vs Marsh III) were determined using multivariable logistic regression. Among 320 patients with positive serology, we identified 62 patients (19%, 95% CI 1524) with NVM (i.e. potential CD). Younger children may have been more likely to exhibit NVM (p=0.06). Three significant predictors of NVM were prior gluten avoidance (OR 4.17, 95% CI 1.0217.13), positive tissue transglutaminase antibody but <100U/mL (OR 14.75, 95% CI 3.3365.30), and absence of gross duodenal abnormalities (OR 3.48, 95% CI 1.518.03). Among children with positive CD serology, prior gluten avoidance predicts NVM. Future studies are warranted on the impact of gluten intake and CD testing in children without prior established CD diagnosis. C1 [Tanpowpong, Pornthep; Broder-Fingert, Sarabeth; Katz, Aubrey J.] Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp Children, Boston, MA 02115 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Camargo, CA (reprint author), Massachusetts Gen Hosp, 326 Cambridge St,Suite 410, Boston, MA 02114 USA. EM ccamargo@partners.org OI Broder-Fingert, Sarabeth/0000-0002-0932-4461 NR 25 TC 3 Z9 3 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0903-4641 J9 APMIS JI APMIS PD APR PY 2013 VL 121 IS 4 BP 266 EP 271 DI 10.1111/j.1600-0463.2012.02966.x PG 6 WC Immunology; Microbiology; Pathology SC Immunology; Microbiology; Pathology GA 114RZ UT WOS:000316761400002 PM 23030455 ER PT J AU Therkelsen, KE Pedley, A Speliotes, EK Massaro, JM Murabito, J Hoffmann, U Fox, CS AF Therkelsen, Kate E. Pedley, Alison Speliotes, Elizabeth K. Massaro, Joseph M. Murabito, Joanne Hoffmann, Udo Fox, Caroline S. TI Intramuscular Fat and Associations With Metabolic Risk Factors in the Framingham Heart Study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE epidemiology; intramuscular fat; metabolism; obesity ID INDUCED INSULIN-RESISTANCE; VISCERAL ADIPOSE-TISSUE; MUSCLE LIPID-CONTENT; SKELETAL-MUSCLE; COMPUTED-TOMOGRAPHY; CARDIOVASCULAR-DISEASE; HUMAN OBESITY; ACCUMULATION; CHOLESTEROL; SENSITIVITY AB Objective-Intramuscular fat accumulates between muscle fibers or within muscle cells. We investigated the association of intramuscular fat with other ectopic fat deposits and metabolic risk factors. Approach and Results-Participants (n=2945; 50.2% women; mean age 50.8 years) from the Framingham Heart Study underwent multidetector computed tomography scanning of the abdomen. Regions of interest were placed on the left and right paraspinous muscle, and the muscle attenuation (MA) in Hounsfield units was averaged. We examined the association between MA and metabolic risk factors in multivariable models, and additionally adjusted for body mass index (BMI) and visceral adipose tissue (VAT) in separate models. MA was associated with dysglycemia, dyslipidemia, and hypertension in both sexes. In women, per standard deviation decrease in MA, there was a 1.34 (95% confidence interval, 1.10-1.64) increase in the odds of diabetes mellitus, a 1.40 (95% confidence interval, 1.22-1.61) increase in the odds of high triglycerides, and a 1.29 (95% confidence interval, 1.12-1.48) increase in the odds of hypertension. However, none of these associations persisted after adjustment for BMI or VAT. In men, we observed similar patterns for most risk factors. The exception was metabolic syndrome, which retained association in women even after adjustment for BMI and VAT, and low high density lipoprotein and high triglycerides in men, whose associations also persisted after adjustment for BMI and VAT. Conclusions-MA was associated with metabolic risk factors, but most of these associations were lost after adjustment for BMI or VAT. However, a unique association remained for metabolic syndrome in women and lipids in men. (Arterioscler Thromb Vasc Biol. 2013;33:863-870.) C1 [Therkelsen, Kate E.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Therkelsen, Kate E.; Pedley, Alison; Murabito, Joanne; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Speliotes, Elizabeth K.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Speliotes, Elizabeth K.] Univ Michigan, Sch Med, Dept Computat Med & Bioinformat, Ann Arbor, MI USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Murabito, Joanne] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. RP Fox, CS (reprint author), 73 Mt Wayte Ave Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Murabito, Joanne/0000-0002-0192-7516; Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute [N01-HC-25195]; [K23 DK080145-01] FX The Framingham Heart Study of the National Heart, Lung, and Blood Institute is supported by contract N01-HC-25195. Additionally, Dr Speliotes is supported through K23 DK080145-01. NR 35 TC 20 Z9 20 U1 0 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD APR PY 2013 VL 33 IS 4 BP 863 EP U541 DI 10.1161/ATVBAHA.112.301009 PG 19 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 105ZE UT WOS:000316110400029 PM 23349188 ER PT J AU Evens, AM Hong, FX Gordon, LI Fisher, RI Bartlett, NL Connors, JM Gascoyne, RD Wagner, H Gospodarowicz, M Cheson, BD Stiff, PJ Advani, R Miller, TP Hoppe, RT Kahl, BS Horning, SJ AF Evens, Andrew M. Hong, Fangxin Gordon, Leo I. Fisher, Richard I. Bartlett, Nancy L. Connors, Joseph M. Gascoyne, Randy D. Wagner, Henry Gospodarowicz, Mary Cheson, Bruce D. Stiff, Patrick J. Advani, Ranjana Miller, Thomas P. Hoppe, Richard T. Kahl, Brad S. Horning, Sandra J. TI The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496 SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE Hodgkin lymphoma; elderly; treatment-related toxicity; bleomycin lung toxicity ID EPSTEIN-BARR-VIRUS; LONG-TERM SURVIVAL; ELDERLY-PATIENTS; DISEASE PATIENTS; POPULATION; CHEMOTHERAPY; TOXICITY; INTENSITY; PROGNOSIS; OUTCOMES AB There is a lack of contemporary prospective data examining the adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) and Stanford V (SV; doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisone) regimens in older Hodgkin lymphoma (HL) patients. Forty-four advanced-stage, older HL patients (aged60years) were treated on the randomized study, E2496. Toxicities were mostly similar between chemotherapy regimens, although 24% of older patients developed bleomycin lung toxicity (BLT), which occurred mainly with ABVD (91%). Further, the BLT-related mortality rate was 18%. The overall treatment-related mortality for older HL patients was 9% vs. 0 center dot 3% for patients aged <60years (P<0 center dot 001). Among older patients, there were no survival differences between ABVD and SV. According to age, outcomes were significantly inferior for older versus younger patients (5-year failure-free survival: 48% vs. 74%, respectively, P=0 center dot 002; 5-year overall survival: 58% and 90%, respectively, P<0 center dot 0001), although time-to-progression (TTP) was not significantly different (5-year TTP: 68% vs. 78%, respectively, P=0 center dot 37). Furthermore, considering progression and death without progression as competing risks, the risk of progression was not different between older and younger HL patients (5years: 30% and 23%, respectively, P=0 center dot 30); however, the incidence of death without progression was significantly increased for older HL patients (22% vs. 9%, respectively, P<0 center dot 0001). Altogether, the marked HL age-dependent survival differences appeared attributable primarily to non-HL events. C1 [Evens, Andrew M.] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. [Hong, Fangxin] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hong, Fangxin] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Gordon, Leo I.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Fisher, Richard I.] Univ Rochester, Rochester, NY USA. [Bartlett, Nancy L.] Washington Univ, St Louis, MO USA. [Connors, Joseph M.; Gascoyne, Randy D.] BC Canc Agcy Ctr Lymphoid Canc, Vancouver, BC, Canada. [Wagner, Henry] Penn State Canc Inst, Hershey, PA USA. [Gospodarowicz, Mary] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Cheson, Bruce D.] Georgetown Univ Hosp, Washington, DC 20007 USA. [Stiff, Patrick J.] Loyola Univ, Chicago, IL 60611 USA. [Advani, Ranjana; Hoppe, Richard T.] Univ Arizona, Tucson, AZ USA. [Miller, Thomas P.] Stanford Univ, Palo Alto, CA 94304 USA. [Kahl, Brad S.] Univ Wisconsin, Madison, WI USA. [Horning, Sandra J.] Genentech Inc, San Francisco, CA 94080 USA. RP Evens, AM (reprint author), Univ Massachusetts, Sch Med, Div Hematol Oncol, 55 Lake Ave North, Worcester, MA 01655 USA. EM andrew.evens@umassmed.edu OI Gordon, Leo/0000-0003-1666-7064 FU Public Health Service Grant from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services [CA21115, CA23318, CA66636, CA17145, CA77440, CA11083, CA32102, CA46441, CA46282, CA38926, CA77202, CA21076, CA31946, CA13650] FX E2496 was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, M.D., Chair) and supported in part by Public Health Service Grants CA21115, CA23318, CA66636, CA17145, CA77440, CA11083, CA32102, CA46441, CA46282, CA38926, CA77202, CA21076, CA31946, CA13650 and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. This study was listed on clinicaltrials.gov as NCT00003389. NR 29 TC 29 Z9 30 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD APR PY 2013 VL 161 IS 1 BP 76 EP 86 DI 10.1111/bjh.12222 PG 11 WC Hematology SC Hematology GA 108YW UT WOS:000316333300009 PM 23356491 ER PT J AU Etchin, J Sanda, T Mansour, MR Kentsis, A Montero, J Le, BT Christie, AL McCauley, D Rodig, SJ Kauffman, M Shacham, S Stone, R Letai, A Kung, AL Look, AT AF Etchin, Julia Sanda, Takaomi Mansour, Marc R. Kentsis, Alex Montero, Joan Le, Bonnie T. Christie, Amanda L. McCauley, Dilara Rodig, Scott J. Kauffman, Michael Shacham, Sharon Stone, Richard Letai, Anthony Kung, Andrew L. Look, A. Thomas TI KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE Acute leukaemia; all; aml; new drugs for leukaemia; new drugs for lymphoma ID NUCLEOCYTOPLASMIC TRANSPORT; IN-VIVO; CANCER; EXPRESSION; SIGNALS; RESTORATION; RESISTANCE; MUTATIONS; PROGNOSIS; PROTEINS AB This study explored the anti-leukaemic efficacy of novel irreversible inhibitors of the major nuclear export receptor, chromosome region maintenance 1 (CRM1, also termed XPO1). We found that these novel CRM1 antagonists, termed SINE (Selective Inhibitors of Nuclear Export), induced rapid apoptosis at low nanomolar concentrations in a panel of 14 human T-cell acute lymphoblastic leukaemia (T-ALL) cell lines representing different molecular subtypes of the disease. To assess in vivo anti-leukaemia cell activity, we engrafted immunodeficient mice intravenously with the human T-ALL MOLT-4 cells, which harbour activating mutations of NOTCH1 and NRAS as well as loss of function of the CDKN2A, PTEN and TP53 tumour suppressors and express a high level of oncogenic transcription factor TAL1. Importantly, we examined the in vivo anti-leukaemic efficacy of the clinical SINE compound KPT-330 against T-ALL and acute myeloid leukaemia (AML) cells. These studies demonstrated striking in vivo activity of KPT-330 against T-ALL and AML cells, with little toxicity to normal murine haematopoietic cells. Taken together, our results show that SINE CRM1 antagonists represent promising first-in-class' drugs with a novel mechanism of action and wide therapeutic index, and imply that drugs of this class show promise for the targeted therapy of T-ALL and AML. C1 [Etchin, Julia; Sanda, Takaomi; Mansour, Marc R.; Kentsis, Alex; Le, Bonnie T.; Christie, Amanda L.; Rodig, Scott J.; Kung, Andrew L.; Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Etchin, Julia; Sanda, Takaomi; Mansour, Marc R.; Kentsis, Alex; Le, Bonnie T.; Christie, Amanda L.; Rodig, Scott J.; Kung, Andrew L.; Look, A. Thomas] Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp Boston, Boston, MA USA. [Montero, Joan; Stone, Richard; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Montero, Joan; Stone, Richard; Letai, Anthony] Harvard Univ, Sch Med, Boston, MA USA. [McCauley, Dilara; Kauffman, Michael; Shacham, Sharon] Karyopharm Therapeut, Natick, MA USA. RP Look, AT (reprint author), Dana Farber Canc Inst, Mayer Bldg,Rm 630,450 Brookline Ave, Boston, MA 02215 USA. EM thomas_look@dfci.harvard.edu OI Kentsis, Alex/0000-0002-8063-9191; Kung, Andrew/0000-0002-9091-488X FU William Lawrence and Hughes Blanche Foundation; Karyopharm Therapeutics Incorporated; Alex's Lemonade Stand; Leukemia and Lymphoma Society; National Cancer Institute [1K99CA157951]; Children's Leukemia Research Association; Japan Society for the Promotion of Science; Kay Kendall Leukaemia Fund, UK; [NIH-K08CA160660] FX The research was supported by William Lawrence and Hughes Blanche Foundation (J.E. and T. S.), Karyopharm Therapeutics Incorporated, Alex's Lemonade Stand (J.E.), the Leukemia and Lymphoma Society Translational grant (A. T. L.), National Cancer Institute (1K99CA157951; T. S.), the Children's Leukemia Research Association (T.S.) and the Japan Society for the Promotion of Science (T.S.), the Kay Kendall Leukaemia Fund, UK (M.R.M.), and NIH-K08CA160660 (A.K.). NR 42 TC 72 Z9 72 U1 2 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD APR PY 2013 VL 161 IS 1 BP 117 EP 127 DI 10.1111/bjh.12231 PG 11 WC Hematology SC Hematology GA 108YW UT WOS:000316333300013 PM 23373539 ER PT J AU Englander, M Chen, TC Paschalis, EI Miller, JW Kim, IK AF Englander, Miriam Chen, Teresa C. Paschalis, Eleftherios I. Miller, Joan W. Kim, Ivana K. TI Intravitreal injections at the Massachusetts Eye and Ear Infirmary: analysis of treatment indications and postinjection endophthalmitis rates SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID TRIAMCINOLONE ACETONIDE INJECTION; GROWTH-FACTOR THERAPY; MACULAR DEGENERATION; NONINFECTIOUS ENDOPHTHALMITIS; RANIBIZUMAB; SAFETY; ANTIBIOTICS; AGENTS; TRIAL; RISK AB Aim To report the incidence rate of acute postoperative endophthalmitis secondary to therapeutic intravitreal injections. Methods A retrospective review of all consecutive eyes after intravitreal injections was performed at the Massachusetts Eye and Ear Infirmary, Boston, from 1 January 2007 to 31 December 2011. Results During the 5-year study interval, 10 208 intravitreal injections were performed. The overall incidence rate of endophthalmitis was 0.029% per injection (3 of 10 208 injections). In the three cases, in our series, the endophthalmitis occurred at an average of seven injections, which lies within the SD of the mean number of injections received by each eye in this study, suggesting approximately equal probability of infection for each eye after receiving multiple, sequential injections. Bacterial cultures and Gram stain revealed coagulase-negative Staphylococcus species (n=1), moderate bacteria with negative culture (n=1) and moderate Staphylococcus epidermidis (n=1). All cases were successfully treated using either intravitreal antibiotics and steroids or pars plana vitrectomy. Best-corrected visual acuity reduction was not clinically significant at the last visit (>7 months for all cases). Conclusions Acute endophthalmitis is a rare potential complication after intravitreal injection. Further studies are required to elucidate the best prophylactic and aseptic techniques to prevent this rare complication. C1 [Englander, Miriam; Chen, Teresa C.; Paschalis, Eleftherios I.; Miller, Joan W.; Kim, Ivana K.] Harvard Univ, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. RP Englander, M (reprint author), Harvard Univ, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02114 USA. EM englander.miri@gmail.com OI Paschalis, Eleftherios/0000-0002-4544-4452 NR 25 TC 14 Z9 15 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 EI 1468-2079 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD APR PY 2013 VL 97 IS 4 BP 460 EP 465 DI 10.1136/bjophthalmol-2012-302435 PG 6 WC Ophthalmology SC Ophthalmology GA 107ZM UT WOS:000316259900018 PM 23390167 ER PT J AU Suhler, EB Lowder, CY Goldstein, DA Giles, T Lauer, AK Kurz, PA Pasadhika, S Lee, ST de Saint Sardos, A Butler, NJ Tessler, HH Smith, JR Rosenbaum, JT AF Suhler, Eric B. Lowder, Careen Y. Goldstein, Debra A. Giles, Tracy Lauer, Andreas K. Kurz, Paul A. Pasadhika, Sirichai Lee, Shelly T. de Saint Sardos, Alexandre Butler, Nicholas J. Tessler, Howard H. Smith, Justine R. Rosenbaum, James T. TI Adalimumab therapy for refractory uveitis: results of a multicentre, open-label, prospective trial SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; ANTERIOR UVEITIS; INFLIXIMAB THERAPY; PREVALENCE; CHILDHOOD; EFFICACY; DISEASES AB Objective Tumour necrosis factor (TNF) blockers have been demonstrated to be effective in the treatment of systemic and ocular inflammatory diseases. We conducted a prospective, multicentre, open-label Phase II clinical trial to assess the effectiveness and safety of adalimumab, a fully human anti-TNF monoclonal antibody, in treating refractory uveitis. Methods Subjects with non-infectious uveitis refractory to corticosteroids and at least one other immunosuppressive medication were enrolled. Treatment outcome was ascertained by a composite endpoint comprised of visual acuity, intraocular inflammation, ability to taper immunosuppressives, and posterior segment imaging. Clinical response was defined by improvement in at least one parameter, worsening in none, and well controlled intraocular inflammation. Week 10 responders were permitted to continue receiving adalimumab for the study duration of 50 weeks. Results Twenty-one of 31 patients (68%) were characterised as clinical responders at 10 weeks, of whom 12 patients (39%) exhibited durable response after 50 weeks. The most common reason for study termination was primary or secondary inefficacy. No patients experienced treatment-limiting toxicity clearly related to study therapy. Conclusions Adalimumab was safe and effective in 68% of refractory uveitis patients 10 weeks after study enrolment, and maintained in 39% after 1 year. Ongoing study is required to determine the place of adalimumab and other TNF blockers in the treatment of uveitis. C1 [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Suhler, Eric B.; Giles, Tracy; Lauer, Andreas K.; Kurz, Paul A.; Pasadhika, Sirichai; Lee, Shelly T.; de Saint Sardos, Alexandre; Butler, Nicholas J.; Smith, Justine R.; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Casey Eye Inst, Portland, OR 97239 USA. [Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA. [Lowder, Careen Y.] Cleveland Clin, Cole Eye Inst, Cleveland, OH 44106 USA. [Goldstein, Debra A.; Tessler, Howard H.] Univ Illinois, Dept Ophthalmol, Chicago, IL 60680 USA. [Tessler, Howard H.] Northwestern Univ, Dept Ophthalmol, Chicago, IL 60611 USA. [Smith, Justine R.; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Depatment Cell Biol, Portland, OR 97239 USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97239 USA. [Rosenbaum, James T.] Devers Eye Inst, Portland, OR USA. RP Suhler, EB (reprint author), Oregon Hlth & Sci Univ, Dept Ophthalmol, Casey Eye Inst, 3375 SW Terwilliger Blvd, Portland, OR 97239 USA. EM suhlere@ohsu.edu FU Abbott (Chicago, IL) [HUM05-029]; Department of Veterans' Affairs; Research to Prevent Blindness; University of Illinois-Chicago; Rosenfeld Family Trust; William and Mary Bauman Foundation; William C Kuzell Foundation; Abbott; Bristol-Myers-Squibb; EyeGate; Genentech; LuxBio; Novartis FX This work was supported by Abbott (Chicago, IL) protocol number HUM05-029. Research support was provided by the Department of Veterans' Affairs (EBS), Research to Prevent Blindness (unrestricted grant to Casey Eye Institute and University of Illinois-Chicago, Senior Scholar Award to JTR), the Rosenfeld Family Trust (JTR), the William and Mary Bauman Foundation, and the William C Kuzell Foundation. Dr Suhler has served as a paid consultant to LuxBio. Dr Rosenbaum has served as a paid consultant to Amgen, LuxBio, Xoma, Centocor, Genentech, Pfizer and Abbott. Dr Suhler, Dr Rosenbaum and Ms Giles have received research support from Abbott, Bristol-Myers-Squibb, EyeGate, Genentech, LuxBio and Novartis. Dr Goldstein has served as a paid consultant to Bausch and Lomb, Allergan, GSK, Santen, LuxBio, and serves on an IDMC for Abbott. Dr Lowder serves on an advisory board for Allergan. Authorship is based on (1) substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published. NR 30 TC 28 Z9 29 U1 0 U2 6 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 EI 1468-2079 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD APR PY 2013 VL 97 IS 4 BP 481 EP 486 DI 10.1136/bjophthalmol-2012-302292 PG 6 WC Ophthalmology SC Ophthalmology GA 107ZM UT WOS:000316259900022 PM 23376607 ER PT J AU Nagler, EM Viswanath, K Ebbeling, CB Stoddard, AM Sorensen, G AF Nagler, Eve M. Viswanath, K. Ebbeling, Cara B. Stoddard, Anne M. Sorensen, Glorian TI Correlates of fruit and vegetable consumption among construction laborers and motor freight workers SO CANCER CAUSES & CONTROL LA English DT Article DE Fruit and vegetable consumption; Blue-collar workers; Work-related health factors; Intervention development; Cancer prevention ID CANCER PREVENTION; PHYSICAL-ACTIVITY; TRUCK DRIVERS; UNITED-STATES; FOOD CHOICES; SOCIAL-CONTEXT; LORRY DRIVERS; HEART-DISEASE; TOBACCO USE; RISK AB The aim of this study was to compare and contrast correlates of fruit and vegetable consumption in two blue-collar populations: construction laborers and motor freight workers. Cross-sectional data were collected from two groups of male workers: (1) construction laborers (n = 1,013; response rate = 44 %) randomly selected from a national sample, as part of a diet and smoking cessation study; and (2) motor freight workers (n = 542; response rate = 78 %) employed in eight trucking terminals, as part of a tobacco cessation and weight management study. Data were analyzed using linear regression modeling methods. For both groups, higher income and believing it was important to eat right because of work were positively associated with fruit and vegetable consumption; conversely, being white was associated with lower intake. Construction laborers who reported eating junk food due to workplace stress and fatigue had lower fruit and vegetable intake. For motor freight workers, perceiving fast food to be the only choice at work and lack of time to eat right were associated with lower consumption. Comparing occupational groups illustrates how work experiences may be related to fruit and vegetable consumption in different ways as well as facilitates the development of interventions that can be used across groups. C1 [Nagler, Eve M.; Viswanath, K.; Sorensen, Glorian] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Viswanath, K.; Sorensen, Glorian] Harvard Univ, Dept Soc Human Dev & Hlth, Sch Publ Hlth, Boston, MA 02115 USA. [Ebbeling, Cara B.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Stoddard, Anne M.] New England Res Inst, Watertown, MA 02472 USA. RP Nagler, EM (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 450 Brookline Ave,LW722, Boston, MA 02115 USA. EM eve_nagler@dfci.harvard.edu FU Centers for Disease Control and Prevention [5 R01 DP000099-03]; National Institutes of Health [2 R25 CA057713-06, R01 CA 84387-04, 5 K05 CA108663-05] FX The authors wish to thank the members of the Laborers' International Union, the Laborers' Health and Safety Fund of North America, the International Brotherhood of Teamsters, and the Motor Freight Carriers Association for their support of and contributions to this study. The authors also wish to thank the numerous investigators and staff members who contributed to this study, including Elizabeth Barbeau, Josh Gagne, Elizabeth Harden, Kerry Kokkinogenis, Ruth Lederman, Lesley Pereira, Laura Shulman, and Lorraine Wallace. This work was supported by the Centers for Disease Control and Prevention [grant number 5 R01 DP000099-03 to G. S.], and National Institutes of Health [grant number 2 R25 CA057713-06 to G. S., R01 CA 84387-04 to G. S. and 5 K05 CA108663-05 to G.S.]. NR 53 TC 6 Z9 6 U1 1 U2 14 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD APR PY 2013 VL 24 IS 4 BP 637 EP 647 DI 10.1007/s10552-012-9998-6 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 109FX UT WOS:000316352900003 PM 22729935 ER PT J AU Patterson, RE Colditz, GA Hu, FB Schmitz, KH Ahima, RS Brownson, RC Carson, KR Chavarro, JE Chodosh, LA Gehlert, S Gill, J Glanz, K Haire-Joshu, D Herbst, KL Hoehner, CM Hovmand, PS Irwin, ML Jacobs, LA James, AS Jones, LW Kerr, J Kibel, AS King, IB Ligibel, JA Meyerhardt, JA Natarajan, L Neuhouser, ML Olefsky, JM Proctor, EK Redline, S Rock, CL Rosner, B Sarwer, DB Schwartz, JS Sears, DD Sesso, HD Stampfer, MJ Subramanian, SV Taveras, EM Tchou, J Thompson, B Troxel, AB Wessling-Resnick, M Wolin, KY Thornquist, MD AF Patterson, Ruth E. Colditz, Graham A. Hu, Frank B. Schmitz, Kathryn H. Ahima, Rexford S. Brownson, Ross C. Carson, Kenneth R. Chavarro, Jorge E. Chodosh, Lewis A. Gehlert, Sarah Gill, Jeff Glanz, Karen Haire-Joshu, Debra Herbst, Karen Louise Hoehner, Christine M. Hovmand, Peter S. Irwin, Melinda L. Jacobs, Linda A. James, Aimee S. Jones, Lee W. Kerr, Jacqueline Kibel, Adam S. King, Irena B. Ligibel, Jennifer A. Meyerhardt, Jeffrey A. Natarajan, Loki Neuhouser, Marian L. Olefsky, Jerrold M. Proctor, Enola K. Redline, Susan Rock, Cheryl L. Rosner, Bernard Sarwer, David B. Schwartz, J. Sanford Sears, Dorothy D. Sesso, Howard D. Stampfer, Meir J. Subramanian, S. V. Taveras, Elsie M. Tchou, Julia Thompson, Beti Troxel, Andrea B. Wessling-Resnick, Marianne Wolin, Kathleen Y. Thornquist, Mark D. TI The 2011-2016 Transdisciplinary Research on Energetics and Cancer (TREC) Initiative: Rationale and Design SO CANCER CAUSES & CONTROL LA English DT Article DE Energetics; Obesity; Diet; Physical activity; Cancer; Transdisciplinary ID PHYSICAL-ACTIVITY; EPIDEMIOLOGIC EVIDENCE; TEAM SCIENCE; CONTROLLED-TRIAL; CLINICAL-TRIAL; EXERCISE; OBESITY; WOMEN; RISK; BREAST AB Recognition of the complex, multidimensional relationship between excess adiposity and cancer control outcomes has motivated the scientific community to seek new research models and paradigms. The National Cancer Institute developed an innovative concept to establish a center grant mechanism in nutrition, energetics, and physical activity, referred to as the Transdisciplinary Research on Energetics and Cancer (TREC) Initiative. This paper gives an overview of the 2011-2016 TREC Collaborative Network and the 15 research projects being conducted at the centers. Four academic institutions were awarded TREC center grants in 2011: Harvard University, University of California San Diego, University of Pennsylvania, and Washington University in St. Louis. The Fred Hutchinson Cancer Research Center is the Coordination Center. The TREC research portfolio includes three animal studies, three cohort studies, four randomized clinical trials, one cross-sectional study, and two modeling studies. Disciplines represented by TREC investigators include basic science, endocrinology, epidemiology, biostatistics, behavior, medicine, nutrition, physical activity, genetics, engineering, health economics, and computer science. Approximately 41,000 participants will be involved in these studies, including children, healthy adults, and breast and prostate cancer survivors. Outcomes include biomarkers of cancer risk, changes in weight and physical activity, persistent adverse treatment effects (e.g., lymphedema, urinary and sexual function), and breast and prostate cancer mortality. The NIH Science of Team Science group will evaluate the value added by this collaborative science. However, the most important outcome will be whether this transdisciplinary initiative improves the health of Americans at risk of cancer as well as cancer survivors. C1 [Patterson, Ruth E.; Herbst, Karen Louise; Kerr, Jacqueline; Natarajan, Loki; Olefsky, Jerrold M.; Rock, Cheryl L.; Sears, Dorothy D.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Colditz, Graham A.; Brownson, Ross C.; Carson, Kenneth R.; Gehlert, Sarah; Gill, Jeff; Haire-Joshu, Debra; Hoehner, Christine M.; Hovmand, Peter S.; James, Aimee S.; Proctor, Enola K.; Wolin, Kathleen Y.] Washington Univ, St Louis, MO USA. [Hu, Frank B.; Chavarro, Jorge E.; Kibel, Adam S.; Stampfer, Meir J.; Subramanian, S. V.; Wessling-Resnick, Marianne] Harvard Univ, Boston, MA 02115 USA. [Schmitz, Kathryn H.; Ahima, Rexford S.; Chodosh, Lewis A.; Glanz, Karen; Jacobs, Linda A.; Sarwer, David B.; Schwartz, J. Sanford; Tchou, Julia; Troxel, Andrea B.] Univ Penn, Philadelphia, PA 19104 USA. [Irwin, Melinda L.] Yale Univ, New Haven, CT USA. [Jones, Lee W.] Duke Canc Inst, Durham, NC USA. [King, Irena B.] Univ New Mexico, Albuquerque, NM 87131 USA. [Ligibel, Jennifer A.; Meyerhardt, Jeffrey A.] Dana Farber Canc Inst, Boston, MA USA. [Neuhouser, Marian L.; Thompson, Beti; Thornquist, Mark D.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Redline, Susan; Sesso, Howard D.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Rosner, Bernard] Channing Labs, Boston, MA USA. [Taveras, Elsie M.] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. RP Thornquist, MD (reprint author), Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. EM mthornqu@fhcrc.org RI Colditz, Graham/A-3963-2009; OI Colditz, Graham/0000-0002-7307-0291; James, Aimee/0000-0002-1411-9307; Troxel, Andrea/0000-0002-1393-3075 FU National Cancer Institute Centers for Transdisciplinary Research on Energetics and Cancer (TREC) [U01 CA116850, U54 CA155626, U54 CA155435, U54 CA155850, U54 CA155496]; NCI as part of the TREC Initiative FX This work was supported by the National Cancer Institute Centers for Transdisciplinary Research on Energetics and Cancer (TREC) (U01 CA116850, U54 CA155626, U54 CA155435, U54 CA155850, U54 CA155496). All authors were funded by the NCI as part of the TREC Initiative. The opinions or assertions contained herein are the private ones of the authors and are not considered as official or reflecting the views of the National Institutes of Health. Thanks are expressed to all the co-principal investigators, investigators, and co-investigators who are contributing to the study, and also to key staff at each site: TREC Coordination Center: Carolyn C. Ehret and Gina Widell. Harvard University: Vanessa Boulanger, Nancy Campbell, Amy Lane, Laura Shockro, Miranda West, and Devin Wigler. University of California, San Diego: Lisa A. Cadmus-Bertram, Lesley G. Ellies, Shirley W. Flatt, Suneeta Godbole, Simon J. Marshall, Jessica L. Oratowski Coleman, Bilge Pakiz, Brinda K. Rana, and Nicholas J. Webster. University of Pennsylvania: Renata Alford, Justin Brown, Laura DiGiovanni, Rebecca Dilks, Deborah Dole, Margaret Evangelista, Anagha Kumar, Venetia Lambert, Monica Laudermilk, and Zi Zhang. Washington University in St. Louis: Victoria Anwuri, Casey Fagin, Robert Grubb III, Jennifer Haslag-Minoff, Timothy Hower, Christine Marx, Qiang Wang, and Jessica Wu. Finally, the TREC Initiative is thankful to all the study participants whose involvement is critical to curing cancer! NR 39 TC 17 Z9 17 U1 2 U2 28 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD APR PY 2013 VL 24 IS 4 BP 695 EP 704 DI 10.1007/s10552-013-0150-z PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 109FX UT WOS:000316352900008 PM 23378138 ER PT J AU Je, Y Lee, JE Ma, J Zhang, XH Cho, E Rosner, B Selhub, J Fuchs, CS Meyerhardt, J Giovannucci, E AF Je, Youjin Lee, Jung Eun Ma, Jing Zhang, Xuehong Cho, Eunyoung Rosner, Bernard Selhub, Jacob Fuchs, Charles S. Meyerhardt, Jeffrey Giovannucci, Edward TI Prediagnostic plasma vitamin B6 (pyridoxal 5 '-phosphate) and survival in patients with colorectal cancer SO CANCER CAUSES & CONTROL LA English DT Article DE Vitamin B6; Pyridoxal 5 ' phosphate (PLP); Colorectal cancer; Mortality; Survival; Prospective study ID NATIONAL DEATH INDEX; THYMIDYLATE SYNTHASE; COLON TUMORIGENESIS; CELL-PROLIFERATION; REGRESSION-MODELS; NURSES HEALTH; RISK; FOLATE; INHIBITION; ASSAY AB Higher plasma pyridoxal 5'-phosphate (PLP) levels are associated with a decreased incidence of colorectal cancer, but the influence of plasma PLP on survival of patients with colorectal cancer is unknown. We prospectively examined whether prediagnostic plasma PLP levels are associated with mortality among colorectal cancer patients. We included 472 incident cases of colorectal cancer identified in the Nurses' Health Study, the Health Professionals Follow-up Study, and the Physicians' Health Study from 1984 to 2002. The patients provided blood samples two or more years before cancer diagnosis. Stratified Cox proportional hazards models were used to calculate hazard ratios (HR) with 95 % confidence intervals (CI) adjusted for other risk factors for cancer survival. Higher plasma PLP levels were not associated with a significant reduction in colorectal cancer-specific (169 deaths) or overall mortality (259 deaths). Compared with patients who had less than 45 pmol/ml of plasma PLP (median: 33.6 pmol/ml), those who had 110 pmol/ml or higher levels (median: 158.8 pmol/ml) had multivariable HRs of 0.85 (95 % CI 0.50-1.45, p trend = 0.37) and 0.87 (95 % CI 0.56-1.35, p trend = 0.24) for colorectal cancer-specific and overall mortality. Higher plasma PLP levels, however, seemed to be associated with better survival among patients who had lower circulating 25-hydroxyvitamin D-3 levels (< 26.5 ng/ml) (p interaction a parts per thousand currency sign.005). Higher prediagnostic plasma PLP levels were not associated with an improvement on colorectal cancer survival overall. Further research is needed to clarify the influence of vitamin B6 on colorectal cancer progression and survival. C1 [Je, Youjin] Kyung Hee Univ, Dept Food & Nutr, Seoul, South Korea. [Lee, Jung Eun] Sookmyung Womens Univ, Dept Food & Nutr, Seoul, South Korea. [Ma, Jing; Zhang, Xuehong; Cho, Eunyoung; Rosner, Bernard; Fuchs, Charles S.; Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Selhub, Jacob] Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer US Dept Agr, Boston, MA 02111 USA. [Fuchs, Charles S.; Meyerhardt, Jeffrey] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA 02115 USA. RP Giovannucci, E (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. EM edward.giovannucci@channing.harvard.edu OI Lee, Jung Eun/0000-0003-1141-878X FU American Institute of Cancer Research; NIH [CA87969, CA55075] FX We are indebted to the participants and staffs in the Nurses' Health Study, Health Professionals Follow-up Study, and Physicians' Health Study for their dedication and commitment. This work was supported by a grant from American Institute of Cancer Research and the NIH grants CA87969 and CA55075. NR 45 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD APR PY 2013 VL 24 IS 4 BP 719 EP 729 DI 10.1007/s10552-013-0152-x PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 109FX UT WOS:000316352900010 PM 23340905 ER PT J AU Sorensen, G Allen, JD Adamkiewicz, G Yang, M Tamers, SL Stoddard, AM AF Sorensen, Glorian Allen, Jennifer D. Adamkiewicz, Gary Yang, May Tamers, Sara L. Stoddard, Anne M. TI Intention to quit smoking and concerns about household environmental risks: findings from the Health in Common Study in low-income housing SO CANCER CAUSES & CONTROL LA English DT Article DE Smoking; Tobacco use; Household hazards; Environmental toxins; Low income ID INNER-CITY CHILDREN; TRANSTHEORETICAL MODEL; SOCIOECONOMIC-STATUS; CANCER PREVENTION; PUBLIC-HEALTH; UNITED-STATES; DISPARITIES; PERCEPTION; ADULTS; VULNERABILITY AB To assess the association between intention to quit smoking and perceptions of household environmental risks among racially/ethnically diverse residents of low-income housing. Baseline data were collected from 2007 to 2009 for the Health in Common Study, which assessed social and physical determinants of cancer risk-related behaviors among residents of 20 low-income housing developments in the Greater Boston metropolitan area. Participants were surveyed about their tobacco use and concerns about household exposures. Household environmental inspections were also conducted to identify conditions associated with increased risk of exposure to indoor environmental agents, including pesticides, mold, and cleaning products. Intention to quit smoking was associated with a greater degree of concern about exposures in the home, yet not with the actual presence of household hazards, as identified by home inspections and survey findings. An ecological approach targeting multiple levels of influence may help to highlight the importance of both quitting tobacco and reducing potential household environmental exposures as part of comprehensive efforts to promote individual and household health. C1 [Sorensen, Glorian; Allen, Jennifer D.; Tamers, Sara L.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Sorensen, Glorian; Tamers, Sara L.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Allen, Jennifer D.] Harvard Univ, Sch Med, Boston, MA USA. [Adamkiewicz, Gary] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Yang, May; Stoddard, Anne M.] New England Res Inst, Watertown, MA 02172 USA. RP Sorensen, G (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. EM glorian_sorensen@dfci.harvard.edu RI Allen, Jennifer/M-2113-2015 FU National Cancer Institute [R01 CA111310-01A1, K05 CA108663-05] FX This research was supported by the National Cancer Institute, (grant numbers R01 CA111310-01A1; K05 CA108663-05). The authors would like to thank the 20 low-income housing sites that participated in this research, and the assistance from the Cambridge, Somerville, and Chelsea Public Housing Authorities. The authors also acknowledge the administrative and field staff at the Harvard School of Public Health and Dana-Farber Cancer Institute, and the study participants for their contributions to this project. They also thank Marty Alvarez-Reeves, Linnea Benson-Whelan, Caitlin Caspi, Amy Harley, Ruth Lederman, Samuel Lipson, Carol Lowenstein, Reginald Tucker-Seeley, Brianna Wadler and Lorraine Wallace for their contributions to the overall study design and implementation. The authors declare they have no competing financial interests. NR 43 TC 5 Z9 5 U1 2 U2 19 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD APR PY 2013 VL 24 IS 4 BP 805 EP 811 DI 10.1007/s10552-013-0149-5 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 109FX UT WOS:000316352900019 PM 23334887 ER PT J AU Torii, M Hackett, TA Rakic, P Levitt, P Polley, DB AF Torii, Masaaki Hackett, Troy A. Rakic, Pasko Levitt, Pat Polley, Daniel B. TI EphA Signaling Impacts Development of Topographic Connectivity in Auditory Corticofugal Systems SO CEREBRAL CORTEX LA English DT Article DE axon guidance; corticofugal; Eph; feedback; top-down ID MEDIAL GENICULATE-BODY; VESICULAR GLUTAMATE TRANSPORTERS; STIMULUS-SPECIFIC ADAPTATION; BRAIN-STEM; EPHRIN-AS; IMMUNOCYTOCHEMICAL LOCALIZATION; CORTICOTHALAMIC CONNECTIONS; STRUCTURED ACTIVITY; FUNCTIONAL MAPS; GENE-EXPRESSION AB Auditory stimulus representations are dynamically maintained by ascending and descending projections linking the auditory cortex (Actx), medial geniculate body (MGB), and inferior colliculus. Although the extent and topographic specificity of descending auditory corticofugal projections can equal or surpass that of ascending corticopetal projections, little is known about the molecular mechanisms that guide their development. Here, we used in utero gene electroporation to examine the role of EphA receptor signaling in the development of corticothalamic (CT) and corticocollicular connections. Early in postnatal development, CT axons were restricted to a deep dorsal zone (DDZ) within the MGB that expressed low levels of the ephrin-A ligand. By hearing onset, CT axons had innervated surrounding regions of MGB in control-electroporated mice but remained fixed within the DDZ in mice overexpressing EphA7. In vivo neurophysiological recordings demonstrated a corresponding reduction in spontaneous firing rate, but no changes in sound-evoked responsiveness within MGB regions deprived of CT innervation. Structural and functional CT disruption occurred without gross alterations in thalamocortical connectivity. These data demonstrate a potential role for EphA/ephrin-A signaling in the initial guidance of corticofugal axons and suggest that "genetic rewiring" may represent a useful functional tool to alter cortical feedback without silencing Actx. C1 [Torii, Masaaki; Rakic, Pasko] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06510 USA. [Torii, Masaaki; Rakic, Pasko] Yale Univ, Sch Med, Kavli Inst Neurosci, New Haven, CT 06510 USA. [Torii, Masaaki; Levitt, Pat] Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Los Angeles, CA 90089 USA. [Torii, Masaaki; Levitt, Pat] Univ So Calif, Keck Sch Med, Dept Cell & Neurobiol, Los Angeles, CA 90089 USA. [Hackett, Troy A.] Vanderbilt Univ, Vanderbilt Kennedy Ctr Res Human Dev, Sch Med, Dept Hearing & Speech Sci, Nashville, TN 37232 USA. [Polley, Daniel B.] Harvard Univ, Sch Med, Eaton Peabody Lab, Massachusetts Eye & Ear Infirm,Dept Otol & Laryng, Boston, MA 02114 USA. RP Torii, M (reprint author), Yale Univ, Sch Med, Dept Neurobiol, Kavli Inst Neurosci, 333 Cedar St SHM C316, New Haven, CT 06510 USA. EM masaaki.torii@yale.edu FU National Institutes of Health [DC009488, DC009836, DC04318, NS014841, DA022785]; NARSAD; Kavli Institute for Neuroscience at Yale FX National Institutes of Health (grant DC009488 and DC009836 to D. B. P., DC04318 to T. A. H., NS014841 to P. R., and DA022785 to P. L.); NARSAD Young Investigator Award (to M. T.); and Kavli Institute for Neuroscience at Yale (to M.T. and P.R.). NR 75 TC 11 Z9 11 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD APR PY 2013 VL 23 IS 4 BP 775 EP 785 DI 10.1093/cercor/bhs066 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 108EY UT WOS:000316275800003 PM 22490549 ER PT J AU Napadow, V Sheehan, JD Kim, J LaCount, LT Park, K Kaptchuk, TJ Rosen, BR Kuo, B AF Napadow, Vitaly Sheehan, James D. Kim, Jieun LaCount, Lauren T. Park, Kyungmo Kaptchuk, Ted J. Rosen, Bruce R. Kuo, Braden TI The Brain Circuitry Underlying the Temporal Evolution of Nausea in Humans SO CEREBRAL CORTEX LA English DT Article DE brain-gut interactions; interoception; motion sickness; neuroimaging ID MOTION SICKNESS; INTEROCEPTIVE AWARENESS; CORTEX; STIMULATION; EXPRESSION; PATHWAYS; SALIENCE; SYSTEM; MODEL; FMRI AB Nausea is a universal human experience. It evolves slowly over time, and brain mechanisms underlying this evolution are not well understood. Our functional magnetic resonance imaging (fMRI) approach evaluated brain activity contributing to and arising from increasing motion sickness. Subjects rated transitions to increasing nausea, produced by visually induced vection within the fMRI environment. We evaluated parametrically increasing brain activity 1) precipitating increasing nausea and 2) following transition to stronger nausea. All subjects demonstrated visual stimulus-associated activation (P < 0.01) in primary and extrastriate visual cortices. In subjects experiencing motion sickness, increasing phasic activity preceding nausea was found in amygdala, putamen, and dorsal pons/locus ceruleus. Increasing sustained response following increased nausea was found in a broader network including insular, anterior cingulate, orbitofrontal, somatosensory and prefrontal cortices. Moreover, sustained anterior insula activation to strong nausea was correlated with midcingulate activation (r = 0.87), suggesting a closer linkage between these specific regions within the brain circuitry subserving nausea perception. Thus, while phasic activation in fear conditioning and noradrenergic brainstem regions precipitates transition to strong nausea, sustained activation following this transition occurs in a broader interoceptive, limbic, somatosensory, and cognitive network, reflecting the multiple dimensions of this aversive commonly occurring symptom. C1 [Napadow, Vitaly; Kim, Jieun; LaCount, Lauren T.; Rosen, Bruce R.] Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Napadow, Vitaly; Kim, Jieun; LaCount, Lauren T.; Rosen, Bruce R.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. [Sheehan, James D.; Kuo, Braden] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastroenterol Unit, Boston, MA USA. [Park, Kyungmo] Kyung Hee Univ, Dept Biomed Engn, Yongin, South Korea. [Kaptchuk, Ted J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Napadow, V (reprint author), Martinos Ctr Biomed Imaging, 149 13th St 2301, Charlestown, MA 02129 USA. EM vitaly@nmr.mgh.harvard.edu FU National Institutes of Health [K01-AT002166, R01-AT004714, P01-AT002048, F05-AT003770, K23-DK069614, K24-AT004095]; National Center for Research Resources [P41RR14075, CRC 1 UL1 RR025758]; Mental Illness and Neuroscience Discovery (MIND) Institute; International Foundation of Functional Gastrointestinal Disorders; Information Technology Advancement, Korea [IITA-2008-(C1090-0801-0002)] FX This work was supported by the National Institutes of Health (grant numbers K01-AT002166 and R01-AT004714 to V.N., P01-AT002048 to B. R. R., F05-AT003770 to K. P., K23-DK069614 to B. K., K24-AT004095 to T. K.); the National Center for Research Resources (P41RR14075; CRC 1 UL1 RR025758, Harvard Clinical and Translational Science Center); Mental Illness and Neuroscience Discovery (MIND) Institute; the International Foundation of Functional Gastrointestinal Disorders; and Information Technology Advancement, Korea (grant number IITA-2008-(C1090-0801-0002) to K. P.). The content is solely the responsibility of the authors and does not necessarily represent the official views of our sponsors. NR 53 TC 47 Z9 48 U1 3 U2 22 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD APR PY 2013 VL 23 IS 4 BP 806 EP 813 DI 10.1093/cercor/bhs073 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 108EY UT WOS:000316275800006 PM 22473843 ER PT J AU Rosen, GD Azoulay, NG Griffin, EG Newbury, A Koganti, L Fujisaki, N Takahashi, E Grant, PE Truong, DT Fitch, RH Lu, L Williams, RW AF Rosen, G. D. Azoulay, N. G. Griffin, E. G. Newbury, A. Koganti, L. Fujisaki, N. Takahashi, E. Grant, P. E. Truong, D. T. Fitch, R. H. Lu, L. Williams, R. W. TI Bilateral Subcortical Heterotopia with Partial Callosal Agenesis in a Mouse Mutant SO CEREBRAL CORTEX LA English DT Article DE diffusion spectrum imaging; neuronal migration; rapid auditory discrimination; recombinant inbred; stereology ID NEURONAL MIGRATION DISORDERS; INDUCED CEREBROCORTICAL MICROGYRIA; AUDITORY PROCESSING DEFICITS; X-LINKED MALFORMATIONS; CEREBRAL-CORTEX; NODULAR HETEROTOPIA; CORPUS-CALLOSUM; CORTICAL MALFORMATION; BAND HETEROTOPIA; AUTOIMMUNE MICE AB Cognition and behavior depend on the precise placement and interconnection of complex ensembles of neurons in cerebral cortex. Mutations that disrupt migration of immature neurons from the ventricular zone to the cortical plate have provided major insight into mechanisms of brain development and disease. We have discovered a new and highly penetrant spontaneous mutation that leads to large nodular bilateral subcortical heterotopias with partial callosal agenesis. The mutant phenotype was first detected in a colony of fully inbred BXD29 mice already known to harbor a mutation in Tlr4. Neurons confined to the heterotopias are mainly born in midgestation to late gestation and would normally have migrated into layers 2-4 of overlying neocortex. Callosal cross-sectional area and fiber number are reduced up to 50% compared with coisogenic wildtype BXD29 substrain controls. Mutants have a pronounced and highly selective defect in rapid auditory processing. The segregation pattern of the mutant phenotype is most consistent with a two-locus autosomal recessive model, and selective genotyping definitively rules out the Tlr4 mutation as a cause. The discovery of a novel mutation with strong pleiotropic anatomical and behavioral effects provides an important new resource for dissecting molecular mechanisms and functional consequences of errors of neuronal migration. C1 [Rosen, G. D.; Azoulay, N. G.; Griffin, E. G.; Newbury, A.; Koganti, L.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Fujisaki, N.; Takahashi, E.; Grant, P. E.] Harvard Univ, Sch Med, Dept Radiol, Charlestown, MA 02129 USA. [Fujisaki, N.; Takahashi, E.; Grant, P. E.] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Takahashi, E.; Grant, P. E.] Harvard Univ, Div Newborn Med, Childrens Hosp Boston, Dept Med,Med Sch, Boston, MA 02115 USA. [Takahashi, E.; Grant, P. E.] Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA 02115 USA. [Grant, P. E.] Childrens Hosp, Dept Radiol, Boston, MA 02115 USA. [Grant, P. E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Truong, D. T.; Fitch, R. H.] Univ Connecticut, Dept Psychol, Storrs, CT 06269 USA. [Lu, L.; Williams, R. W.] Univ Tennessee, Hlth Sci Ctr, Dept Anat & Neurobiol, Ctr Integrat & Translat Genom, Memphis, TN 38163 USA. RP Rosen, GD (reprint author), Beth Israel Deaconess Med Ctr, Dept Neurol, E CLS 643,330 Brookline Ave, Boston, MA 02215 USA. EM grosen@bidmc.harvard.edu OI Azoulay, Norman/0000-0003-1453-4882; Rosen, Glenn/0000-0001-8281-5446; Williams, Robert/0000-0001-8924-4447 FU National Institute on Drug Abuse; National Institute of Mental Health [P20 DA021131]; National Institute of Neurological Diseases and Stroke [R01 NS052397-01A2]; National Eye Institute [R01EY021200]; National Center for Research Resources [1S10RR023401, 1S10RR019307, 1S10RR023043]; National Institutes of Health FX The National Institute on Drug Abuse and the National Institute of Mental Health (grant number P20 DA021131); the National Institute of Neurological Diseases and Stroke (grant number R01 NS052397-01A2); the National Eye Institute (grant number R01EY021200), and Shared Instrumentation Grants from the National Center for Research Resources (grant numbers 1S10RR023401, 1S10RR019307, and 1S10RR023043), which are all at the National Institutes of Health. NR 74 TC 10 Z9 11 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD APR PY 2013 VL 23 IS 4 BP 859 EP 872 DI 10.1093/cercor/bhs080 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 108EY UT WOS:000316275800011 PM 22455839 ER PT J AU de Villiers, TJ Gass, MLS Haines, CJ Hall, JE Lobo, RA Pierroz, DD Rees, M AF de Villiers, T. J. Gass, M. L. S. Haines, C. J. Hall, J. E. Lobo, R. A. Pierroz, D. D. Rees, M. TI Global Consensus Statement on Menopausal Hormone Therapy SO CLIMACTERIC LA English DT Editorial Material AB The following Consensus Statement is endorsed by The American Society for Reproductive Medicine, The Asia Pacific Menopause Federation, The Endocrine Society, The European Menopause and Andropause Society, The International Menopause Society, The International Osteoporosis Foundation and The North American Menopause Society. C1 [de Villiers, T. J.] Univ Stellenbosch, MediClin Panorama, Cape Town, South Africa. [de Villiers, T. J.] Univ Stellenbosch, Dept Obstet & Gynecol, Cape Town, South Africa. [Gass, M. L. S.] Case Western Reserve Univ, Sch Med, Dept Surg, Cleveland Clin,Lerner Coll Med, Cleveland, OH 44106 USA. [Haines, C. J.] Chinese Univ Hong Kong, Dept Obstet & Gynecol, Prince Wales Hosp, Shatin, Hong Kong, Peoples R China. [Hall, J. E.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hall, J. E.] Harvard Univ, Sch Med, Boston, MA USA. [Lobo, R. A.] Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. [Pierroz, D. D.] Univ Geneva, CH-1211 Geneva 4, Switzerland. [Rees, M.] Univ Oxford, Oxford OX1 2JD, England. RP de Villiers, TJ (reprint author), MediClin Panorama, ZA-7500 Parow, South Africa. OI Hall, Janet/0000-0003-4644-3061 NR 0 TC 79 Z9 89 U1 0 U2 11 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1369-7137 J9 CLIMACTERIC JI Climacteric PD APR PY 2013 VL 16 IS 2 BP 203 EP 204 DI 10.3109/13697137.2013.771520 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 107BY UT WOS:000316190900002 PM 23488524 ER PT J AU Goldstein, AM Hofstra, RMW Burns, AJ AF Goldstein, A. M. Hofstra, R. M. W. Burns, A. J. TI Building a brain in the gut: development of the enteric nervous system SO CLINICAL GENETICS LA English DT Review DE enteric nervous system; Hirschsprung disease; enteric neuropathies; neural crest cells; RET ID NEURAL CREST CELLS; ENDOTHELIN-B RECEPTOR; WAARDENBURG-HIRSCHSPRUNG-DISEASE; MICE LACKING GDNF; SMAD INTERACTING PROTEIN-1; GENOME-WIDE ASSOCIATION; HOMEOBOX GENE PHOX2B; RET PROTOONCOGENE; TYROSINE KINASE; IN-VITRO AB The enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, is an essential component of the gut neuromusculature and controls many aspects of gut function, including coordinated muscular peristalsis. The ENS is entirely derived from neural crest cells (NCC) which undergo a number of key processes, including extensive migration into and along the gut, proliferation, and differentiation into enteric neurons and glia, during embryogenesis and fetal life. These mechanisms are under the molecular control of numerous signaling pathways, transcription factors, neurotrophic factors and extracellular matrix components. Failure in these processes and consequent abnormal ENS development can result in so-called enteric neuropathies, arguably the best characterized of which is the congenital disorder Hirschsprung disease (HSCR), or aganglionic megacolon. This review focuses on the molecular and genetic factors regulating ENS development from NCC, the clinical genetics of HSCR and its associated syndromes, and recent advances aimed at improving our understanding and treatment of enteric neuropathies. C1 [Goldstein, A. M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat Surg, Boston, MA USA. [Hofstra, R. M. W.; Burns, A. J.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Burns, A. J.] UCL Inst Child Hlth, Neural Dev Unit, London WC1N 1EH, England. [Burns, A. J.] UCL Inst Child Hlth, Gastroenterol Unit, London WC1N 1EH, England. RP Burns, AJ (reprint author), UCL Inst Child Hlth, Neural Dev Unit, 30 Guilford St, London WC1N 1EH, England. EM alan.burns@ucl.ac.uk RI Burns, Alan/C-4988-2008; OI Hofstra, Robert/0000-0001-7498-3829 FU NIH [R01DK080914] FX A. M. G. is supported by NIH R01DK080914. NR 114 TC 44 Z9 47 U1 3 U2 58 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD APR PY 2013 VL 83 IS 4 BP 307 EP 316 DI 10.1111/cge.12054 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 107OD UT WOS:000316226600002 PM 23167617 ER PT J AU Mitsuma, SF Mansour, MK Dekker, JP Kim, J Rahman, MZ Tweed-Kent, A Schuetz, P AF Mitsuma, S. F. Mansour, M. K. Dekker, J. P. Kim, J. Rahman, M. Z. Tweed-Kent, A. Schuetz, P. TI Promising New Assays and Technologies for the Diagnosis and Management of Infectious Diseases SO CLINICAL INFECTIOUS DISEASES LA English DT Review DE procalcitonin; gene expression profiling; mass spectrometry; MALDI-TOF MS; sepsis ID DESORPTION IONIZATION-TIME; FLIGHT MASS-SPECTROMETRY; STAPHYLOCOCCUS-AUREUS; DIRECT IDENTIFICATION; ANTIBIOTIC-THERAPY; DNA APTAMERS; HUMAN SEPSIS; RNA APTAMER; PROCALCITONIN; BACTERIA AB In the first decade of the 21st century, we have seen the completion of the human genome project and marked progress in the human microbiome project. The vast amount of data generated from these efforts combined with advances in molecular and biomedical technologies have led to the development of a multitude of assays and technologies that may be useful in the diagnosis and management of infectious diseases. Here, we identify several new assays and technologies that have recently come into clinical use or have potential for clinical use in the near future. The scope of this review is broad and includes topics such as the serum marker procalcitonin, gene expression profiling, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and nucleic acid aptamers. Principles that underlie each assay or technology, their clinical applications, and potential strengths and limitations are addressed. C1 [Mitsuma, S. F.; Mansour, M. K.; Rahman, M. Z.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Dekker, J. P.; Kim, J.] Massachusetts Gen Hosp, Dept Clin Pathol, Boston, MA 02114 USA. [Tweed-Kent, A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Schuetz, P.] Univ Basel, Kantonsspital Aarau, Dept Internal Med, CH-4003 Basel, Switzerland. RP Schuetz, P (reprint author), Kantonsspital, Med Univ Dept, Tellstr, CH-5001 Aarau, Switzerland. EM schuetzph@gmail.com FU NIAID NIH [T32-AI007061-35]; BRAHMS; bioMerieux FX M. K. M. is supported by NIAID NIH T32-AI007061-35.; P. S. has received support from BRAHMS and bioMerieux: to attend meetings and has fulfilled speaking engagements. All other authors report no potential conflicts. NR 49 TC 23 Z9 24 U1 4 U2 82 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 1 PY 2013 VL 56 IS 7 BP 996 EP 1002 DI 10.1093/cid/cis1014 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 106TG UT WOS:000316167000015 PM 23223587 ER PT J AU Chen, WT Yuan, RY Chiang, SC Sheu, JJ Yu, JM Tseng, IJ Yang, SK Chang, HH Hu, CJ AF Chen, Wei-Ta Yuan, Rey-Yue Chiang, Shu-Chiung Sheu, Jau-Jiuan Yu, Jia-Ming Tseng, Ing-Jy Yang, Szu-Kuan Chang, Hsiu-Hui Hu, Chaur-Jong TI OnabotulinumtoxinA Improves Tactile and Mechanical Pain Perception in Painful Diabetic Polyneuropathy SO CLINICAL JOURNAL OF PAIN LA English DT Article DE onabotulinumtoxinA (BoNT/A); diabetes mellitus; neuropathic pain; pain threshold; tactile threshold; quantitative sensory testing (QST) ID TOXIN TYPE-A; LONGITUDINAL DATA-ANALYSIS; NEUROPATHIC PAIN; BOTULINUM-TOXIN; PERIPHERAL NEUROPATHY; THRESHOLDS; FIBERS AB Objectives: Diabetic neuropathic pain may be relieved by onabotulinumtoxinA (BoNT/A). However, whether BoNT/A changes sensory perception in neuropathic patients remains unknown. This study used a double-blind crossover design to explore the possible effect of BoNT/A on sensory perception. Methods: Eighteen patients with painful diabetic polyneuropathy underwent 2 consecutive 12-week periods of treatment either in the sequence of saline (control) and then BoNT/A (SB cohort, n=9) or BoNT/A followed by saline (BS cohort, n=9). Sensory perception was assessed according to the tactile threshold [TT, logarithmized force (g) of von Frey filaments] and mechanical pain threshold [PT, logarithmized weight (g) of weighted syringes], both being averages from 4 individual measurements of bilateral medial and lateral feet obtained at baseline (before injections) and at weeks 1, 4, 8, and 12 after treatment. Results: In either the SB or the BS cohort, there was a decrease in the TT and the PT after treatment with BoNT/A but not with saline. In the analysis merging both cohorts (n=18), BoNT/A resulted in a significant decrease in TT and PT at weeks 1, 4, 8, and 12 (all Ps<0.05 vs. saline). The longitudinal effect of BoNT/A on TT and PT remained significant when baseline values, treatment sequences, and periods were controlled using generalized estimating equations. Discussion: BoNT/A may improve tactile and mechanical pain perception in painful diabetic polyneuropathy. The beneficial effects of BoNT/A deserves further study to elucidate the exact mechanism and potential for preventing insensate injuries. C1 [Chen, Wei-Ta] Natl Yang Ming Univ, Neurol Inst, Taipei 112, Taiwan. [Chiang, Shu-Chiung] Natl Yang Ming Univ, Taichung Vet Gen Hosp, Informat Management Off, Taipei 112, Taiwan. [Chen, Wei-Ta] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan. [Chen, Wei-Ta; Yuan, Rey-Yue; Sheu, Jau-Jiuan; Yu, Jia-Ming; Hu, Chaur-Jong] Taipei Med Univ & Hosp, Dept Neurol, Taipei, Taiwan. [Tseng, Ing-Jy] Taipei Med Univ & Hosp, Coll Nursing, Taipei, Taiwan. [Chang, Hsiu-Hui] Chungyu Inst Technol, Dept Int Trade, Keelung, Taiwan. [Yang, Szu-Kuan] Chang Bing Show Chwan Mem Hosp, Dept Neurol, Changhua, Taiwan. [Hu, Chaur-Jong] Taipei Med Univ, Shuang Ho Hosp, Dept Neurol, New Taipei City 235, Taiwan. [Chen, Wei-Ta] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Hu, CJ (reprint author), Taipei Med Univ, Shuang Ho Hosp, Dept Neurol, 291 Jhongjheng Rd, New Taipei City 235, Taiwan. EM chaurjongh@tmu.edu.tw FU National Science Council (Taiwan) [NSC-95-2314-B-075-121, NSC 96-2314-B-075 -073 -MY3, NSC 97-2314-B-038-010-MY2]; Taipei Veterans General Hospital [V99C1-124]; Taipei Medical University [94TMU-WFH-217] FX Supported by the National Science Council (Taiwan; NSC-95-2314-B-075-121 and NSC 96-2314-B-075 -073 -MY3 to W-T. C., NSC 97-2314-B-038-010-MY2 to C-J. H.), Taipei Veterans General Hospital (V99C1-124 to W-T. C.), Taipei Medical University (94TMU-WFH-217 to C-J. H.). Allergan Asia Ltd. (Taipei, Taiwan) provided BOTOX (onabotulinumtoxinA). The authors declare no conflict of interest. NR 31 TC 7 Z9 7 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-8047 J9 CLIN J PAIN JI Clin. J. Pain PD APR PY 2013 VL 29 IS 4 BP 305 EP 310 DI 10.1097/AJP.0b013e318255c132 PG 6 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 104ML UT WOS:000315997400004 PM 23462284 ER PT J AU Mendoza, PR Jakobiec, FA Yoon, MK AF Mendoza, Pia R. Jakobiec, Frederick A. Yoon, Michael K. TI Keratinous Cyst of the Palpebral Conjunctiva: New Observations SO CORNEA LA English DT Article DE palpebral conjunctiva; eyelid; keratin; cyst ID HYPERPLASIA AB Purpose: To describe an acquired keratinizing cyst of the palpebral conjunctiva. Methods: Observational case report with clinical and histopathologic correlations. Results: A 41-year-old man presented with diffuse mild left upper eyelid swelling, eye pain, and redness in the absence of a nodule. Eversion of the eyelid revealed a whitish-gray, well-demarcated, superficial 4 x 4 mm lesion on the medial portion of the palpebral surface accompanied by a large epithelial erosion in the superior aspect of the cornea. The lesion was excised completely, sparing the tarsus. The site of excision healed completely after 1 week with no recurrence during 6 months of follow-up. Histopathologically, the lesion consisted of a round, eosinophilic, compact, acellular mass of keratin. The cyst's epithelial covering was a mixture of mostly flattened but occasionally polygonal basaloid epithelial cells, sometimes with foci of parakeratosis and pigmentation. There was no apparent keratohyalin granular layer (trichilemmal rather than epidermoid keratinization). Conclusions: The pathogenesis of this peculiar lesion is hypothesized to involve a pseudogland of Henle that developed trichilemmal keratinization. It represents another easily overlooked cause of corneal epithelial erosion. C1 [Mendoza, Pia R.; Jakobiec, Frederick A.] Harvard Univ, Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Boston, MA 02114 USA. [Mendoza, Pia R.; Jakobiec, Frederick A.; Yoon, Michael K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Yoon, Michael K.] Harvard Univ, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Suite 321,243 Charles St, Boston, MA 02114 USA. EM fred_jakobiec@meei.harvard.edu NR 12 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 J9 CORNEA JI Cornea PD APR PY 2013 VL 32 IS 4 BP 513 EP 516 DI 10.1097/ICO.0b013e31827932f3 PG 4 WC Ophthalmology SC Ophthalmology GA 104NC UT WOS:000315999500036 PM 23238396 ER PT J AU Eisenstat, SA Ulman, K Siegel, AL Carlson, K AF Eisenstat, Stephanie A. Ulman, Kathleen Siegel, Allison L. Carlson, Karen TI Diabetes Group Visits: Integrated Medical Care and Behavioral Support to Improve Diabetes Care and Outcomes from a Primary Care Perspective SO CURRENT DIABETES REPORTS LA English DT Article DE Diabetes; Group visits; Shared medical appointments; Self-management; Behavioral change; Medical care; Behavioral support ID QUALITY-OF-LIFE; SELF-MANAGEMENT EDUCATION; HEALTH MAINTENANCE ORGANIZATION; INSURED PATIENT POPULATION; CONTROLLED CLINICAL-TRIAL; RANDOMIZED-TRIAL; OLDER-ADULTS; DEPRESSIVE SYMPTOMS; COMORBID DEPRESSION; GROUP-PSYCHOTHERAPY AB Of the many innovations in health care delivery proposed in the context of health reform for those with chronic diseases such as diabetes, the group visit model is relatively easy to implement and is effective for improving health outcomes and patient and provider satisfaction, with a neutral to positive effect on health care costs. This article describes the evolution of group visits for those with diabetes, the theory underlying group visits for patients with chronic medical conditions, and the existing evidence for the effectiveness of this model. It also addresses implementation of groups in practice, with an emphasis on the practical aspects of program implementation, integration of behavioral expertise into medical groups, individualization in various practice settings, and reimbursement issues. C1 [Eisenstat, Stephanie A.; Ulman, Kathleen; Carlson, Karen] Harvard Univ, Sch Med, Boston, MA USA. [Siegel, Allison L.] John D Stoeckle Ctr Primary Care Innovat, Boston, MA 02114 USA. RP Eisenstat, SA (reprint author), Massachusetts Gen Hosp, Shared Med Care Program, Womens Hlth Associates, 55 Fruit St, Boston, MA 02114 USA. EM saeisenstat@partners.org; kulman@partners.org; Asiegel1@partners.org; kcarlson@partners.org NR 128 TC 8 Z9 8 U1 6 U2 23 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD APR PY 2013 VL 13 IS 2 BP 177 EP 187 DI 10.1007/s11892-012-0349-5 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 105KZ UT WOS:000316069500003 PM 23207990 ER PT J AU Lorincz, IS Lawson, BCT Long, JA AF Lorincz, Ilona S. Lawson, Brittany C. T. Long, Judith A. TI Provider and Patient Directed Financial Incentives to Improve Care and Outcomes for Patients with Diabetes SO CURRENT DIABETES REPORTS LA English DT Article DE Diabetes mellitus; Reimbursement; Incentives; Pay for performance; Economics; Behavioral ID PAY-FOR-PERFORMANCE; WEIGHT-LOSS; BARIATRIC SURGERY; RANDOMIZED-TRIAL; MEDICAL THERAPY; UNITED-KINGDOM; QUALITY; MANAGEMENT; IMPACT; ENGLAND AB Incentive programs directed at both providers and patients have become increasingly widespread. Pay-for-performance (P4P) where providers receive financial incentives to carry out specific care or improve clinical outcomes has been widely implemented. The existing literature indicates they probably spur initial gains which then level off or partially revert if incentives are withdrawn. The literature also indicates that process measures are easier to influence through P4P programs but that intermediate outcomes such as glucose, blood pressure, and cholesterol control are harder to influence, and the long-term impact of P4P programs on health is largely unknown. Programs directed at patients show greater promise as a means to influence patient behavior and intermediate outcomes such as weight loss; however, the evidence for long-term effects are lacking. In combination, both patient and provider incentives are potentially powerful tools but whether they are cost-effective has yet to be determined. C1 [Lorincz, Ilona S.] Univ Penn, Perelman Sch Med, Dept Med, Div Endocrine, Philadelphia, PA 19104 USA. [Lawson, Brittany C. T.; Long, Judith A.] Univ Penn, Perelman Sch Med, Dept Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Long, Judith A.] Philadelphia VA Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Long, Judith A.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Long, JA (reprint author), Univ Penn, Perelman Sch Med, Dept Med, Div Gen Internal Med, 1021 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM Ilona.Lorincz@uphs.upenn.edu; blaws@mail.med.upenn.edu; jalong@mail.med.upenn.edu FU NIDDK FX I.S. Lorincz: none; B.C.T. Lawson: none; J.A. Long: has received grant support from NIDDK. NR 45 TC 3 Z9 3 U1 1 U2 15 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD APR PY 2013 VL 13 IS 2 BP 188 EP 195 DI 10.1007/s11892-012-0353-9 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 105KZ UT WOS:000316069500004 PM 23225214 ER PT J AU Lacroix, M Kina, E Hivert, MF AF Lacroix, Marilyn Kina, Eralda Hivert, Marie-France TI Maternal/Fetal Determinants of Insulin Resistance in Women During Pregnancy and in Offspring Over Life SO CURRENT DIABETES REPORTS LA English DT Article DE Insulin resistance; Pregnancy; Early origin; Maternal metabolism; Fetal determinants; Programming; Epigenetics; Offspring ID GESTATIONAL DIABETES-MELLITUS; NECROSIS-FACTOR-ALPHA; BETA-CELL FUNCTION; BODY-MASS INDEX; GLUCOSE-TOLERANCE; INDIAN CHILDREN; SKELETAL-MUSCLE; METABOLIC SYNDROME; DNA METHYLATION; NORMAL-WEIGHT AB Insulin resistance is a component of the pathophysiology of both type 2 diabetes and gestational diabetes mellitus (GDM), but is also characteristic of normal glycemic physiology during pregnancy. In recent years, many studies have tried to understand determinants of insulin resistance in normal pregnancy and GDM, revealing that the placenta is capable of secreting many cytokines and hormones, classically considered as adipokines. More specifically, it appears that leptin and TNF alpha could be implicated in gestational insulin resistance and GDM pathophysiology. In addition, the maternal metabolic milieu was also identified as a key determinant of later insulin resistance in offspring, a phenomenon often described as 'fetal programming'. This article reviews the established risk factors and the more novel suspected biomarkers involved in maternal insulin resistance during pregnancy as well as the maternal and early life determinants of insulin resistance in offspring later in their life. We are also highlighting recent reports of the potential mechanisms involved in 'programming' of insulin resistance such as epigenetic modulation. C1 [Lacroix, Marilyn; Kina, Eralda; Hivert, Marie-France] Univ Sherbrooke, Dept Med, Sherbrooke, PQ J1K 2R1, Canada. [Hivert, Marie-France] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Hivert, MF (reprint author), Univ Sherbrooke, Dept Med, 3001,12E Ave Nord, Sherbrooke, PQ J1K 2R1, Canada. EM marie-france.hivert@usherbrooke.ca NR 64 TC 14 Z9 16 U1 0 U2 27 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD APR PY 2013 VL 13 IS 2 BP 238 EP 244 DI 10.1007/s11892-012-0360-x PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 105KZ UT WOS:000316069500010 PM 23307191 ER PT J AU Braun, JM Sathyanarayana, S Hauser, R AF Braun, Joseph M. Sathyanarayana, Sheela Hauser, Russ TI Phthalate exposure and children's health SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE children; endocrine disruption; epidemiology; phthalates ID IN-UTERO EXPOSURE; BODY TOPICAL APPLICATION; PERSONAL CARE PRODUCTS; SCHOOL-AGE-CHILDREN; NEW-YORK-CITY; URINARY CONCENTRATIONS; PRENATAL EXPOSURE; BISPHENOL-A; DIETHYLHEXYL PHTHALATE; DI(2-ETHYLHEXYL)PHTHALATE DEHP AB Purpose of review Phthalates are multifunctional chemicals used in personal care products, medications, and plastics. We reviewed the epidemiological literature examining the relationship between early life phthalate exposure and pediatric health outcomes. Recent findings Five studies from Asia, Europe, and the United States suggest that childhood exposure to di-2-ethylhexyl phthalate (DEHP) and butylbenzyl phthalate (BBzP) may increase the risk of allergic diseases including asthma and eczema. Six studies from four different prospective cohorts report that gestational BBzP, DEHP, di-butyl phthalate (DBP), and di-ethyl phthalate (DEP) exposures are associated with alterations in infant/toddler physical development as well as parent-reported externalizing, internalizing, and autistic-like child behavior. However, there are inconsistencies related to the specific phthalates and behavioral domains. Two small studies report shorter anogenital distance among male infants with higher gestational phthalate exposure. Summary Several epidemiological studies suggest fetal and childhood exposure to some phthalates may perturb normal development, with several studies consistently reporting increased risk of allergic diseases with DEHP and BBzP exposure. Although anticipatory guidance is not evidence-based at this time, providers can counsel concerned patients to reduce phthalate exposures in order to protect the developing fetus and child from potential adverse health outcomes. C1 [Braun, Joseph M.] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Sathyanarayana, Sheela] Univ Washington, Dept Pediat, Seattle Childrens Res Inst, Seattle, WA 98195 USA. [Hauser, Russ] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Fertil Ctr, Dept Obstet & Gynecol,Div Reprod Endocrinol & Inf, Boston, MA USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Braun, JM (reprint author), Brown Univ, Dept Epidemiol, Box G-S121-2, Providence, RI 02912 USA. EM joseph_braun_1@brown.edu RI Braun, Joseph/H-8649-2014 FU NIEHS [K99 ES020346, R01 ES021357, R01 ES009718] FX J.M.B. was supported by NIEHS grants K99 ES020346 and R01 ES021357. R. H. is supported by NIEHS grant R01 ES009718. NR 75 TC 70 Z9 73 U1 8 U2 113 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8703 J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD APR PY 2013 VL 25 IS 2 BP 247 EP 254 DI 10.1097/MOP.0b013e32835e1eb6 PG 8 WC Pediatrics SC Pediatrics GA 105YV UT WOS:000316109500015 PM 23429708 ER PT J AU Preer, G Sorrentino, D Ryznar, E Newton, AW AF Preer, Genevieve Sorrentino, Deborah Ryznar, Elizabeth Newton, Alice W. TI Child maltreatment: promising approaches and new directions SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE abusive head trauma; child abuse; child maltreatment; child sexual abuse; neglect; shaken baby syndrome ID ABUSIVE HEAD TRAUMA; UNITED-STATES; SEXUAL-ABUSE; PREVENTION; RISK; INJURIES; HOME; PRESENTATIONS; PREVALENCE; DISORDERS AB Purpose of review This review summarizes the key articles in the field of child maltreatment, addressing abusive head trauma, physical abuse, sexual abuse, and global issues surrounding maltreatment. This topic is salient for both general pediatricians as well as specialists. Recent findings Many articles this year focus on the importance of making an accurate diagnosis when considering child maltreatment, whether in the form of physical or sexual abuse. There is also a focus on understanding the epidemiology of abuse, as some data show a decrease in numbers, which is felt by many in the field to be a misleading impression. Summary An appreciation of the scope of Child Abuse Pediatrics requires an understanding of physical abuse, sexual abuse, and neglect. The authors summarize notable advances in our understanding of these key areas in a review of the year's best literature. C1 [Preer, Genevieve] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. [Preer, Genevieve] Boston Med Ctr, Dept Pediat, Div Family & Child Advocacy, Boston, MA USA. [Sorrentino, Deborah; Newton, Alice W.] Childrens Hosp, Child Protect Program, Boston, MA 02115 USA. [Ryznar, Elizabeth] Harvard Univ, Sch Med, Boston, MA USA. [Newton, Alice W.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Newton, Alice W.] Massachusetts Gen Hosp, Child Protect Program, Boston, MA 02114 USA. RP Newton, AW (reprint author), Childrens Hosp, Child Protect Program, 300 Longwood Ave, Boston, MA 02115 USA. EM Alice.Newton@childrens.harvard.edu OI Preer, Genevieve/0000-0001-8264-3541; Ryznar, Elizabeth/0000-0002-2922-7677 NR 37 TC 0 Z9 0 U1 1 U2 26 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8703 J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD APR PY 2013 VL 25 IS 2 BP 268 EP 274 DI 10.1097/MOP.0b013e32835eb347 PG 7 WC Pediatrics SC Pediatrics GA 105YV UT WOS:000316109500018 PM 23429709 ER PT J AU Hansen, HM Stasko, KD AF Hansen, H. M. Stasko, K. D. TI BRIDGING THE GAP: PROVIDING A WEB-BASED FORUM FOR EDUCATION AND COMMUNICATION IN A CHALLENGING WORKPLACE ENVIRONMENT SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Hansen, H. M.; Stasko, K. D.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD APR PY 2013 VL 15 IS 4 SU S MA 82 BP S26 EP S26 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 111QL UT WOS:000316535700081 ER PT J AU Liney, DJ AF Liney, D. J. TI COLLECTING HIGH QUALITY CORD BLOOD UNITS: THE CONTRAST BETWEEN MD AND DEDICATED COLLECTION SPECIALIST COLLECTIONS SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Liney, D. J.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD APR PY 2013 VL 15 IS 4 SU S MA 97 BP S30 EP S30 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 111QL UT WOS:000316535700096 ER PT J AU Sturtevant, OJ Jacobsen, ED Lehman, LE Ritz, J O'Rourke, S Kelley, MA Liney, D Urbina, M AF Sturtevant, O. J. Jacobsen, E. D. Lehman, L. E. Ritz, J. O'Rourke, S. Kelley, M. A. Liney, D. Urbina, M. TI AN ON-GOING QUALITY IMPROVEMENT PROJECT TO LOWER THE RATE OF BACTERIAL CONTAMINATION IN HIPC -MARROW PRODUCTS SO CYTOTHERAPY LA English DT Meeting Abstract C1 [Sturtevant, O. J.; Jacobsen, E. D.; Ritz, J.; O'Rourke, S.; Kelley, M. A.; Liney, D.; Urbina, M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lehman, L. E.] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD APR PY 2013 VL 15 IS 4 SU S MA 95 BP S29 EP S29 PG 1 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 111QL UT WOS:000316535700094 ER PT J AU Wolpert, HA Atakov-Castillo, A Smith, SA Steil, GM AF Wolpert, Howard A. Atakov-Castillo, Astrid Smith, Stephanie A. Steil, Garry M. TI Dietary Fat Acutely Increases Glucose Concentrations and Insulin Requirements in Patients With Type 1 Diabetes Implications for carbohydrate-based bolus dose calculation and intensive diabetes management SO DIABETES CARE LA English DT Article ID ARTIFICIAL PANCREAS; SENSITIVITY; HUMANS; RESISTANCE; ACIDS; MEAL; COMPLICATIONS; HYPERGLYCEMIA; SECRETION; DELIVERY AB OBJECTIVE-Current guidelines for intensive treatment of type 1 diabetes base the mealtime insulin bolus calculation exclusively on carbohydrate counting. There is strong evidence that free fatty acids impair insulin sensitivity. We hypothesized that patients with type 1 diabetes would require more insulin coverage for higher-fat meals than lower-fat meals with identical carbohydrate content. RESEARCH DESIGN AND METHODS-We used a crossover design comparing two 18-h periods of closed-loop glucose control after high-fat (HF) dinner compared with low-fat (LF) dinner. Each dinner had identical carbohydrate and protein content, but different fat content (60 vs. 10 g). RESULTS-Seven patients with type 1 diabetes (age, 55 +/- 12 years; A1C 7.2 +/- 0.8%) successfully completed the protocol. HF dinner required more insulin than LF dinner (12.6 +/- 1.9 units vs. 9.0 +/- 1.3 units; P = 0.01) and, despite the additional insulin, caused more hyperglycemia (area under the curve >120 mg/dL = 16,967 +/- 2,778 vs. 8,350 +/- 1,907 mg/dL.min; P < 0001). Carbohydrate-to-insulin ratio for HF dinner was significantly lower (9 +/- 2 vs. 13 +/- 3 g/unit; P = 0.01). There were marked interindividual differences in the effect of dietary fat on insulin requirements (percent increase significantly correlated with daily insulin requirement; R-2 = 0.64; P = 0.03). CONCLUSIONS-This evidence that dietary fat increases glucose levels and insulin requirements highlights the limitations of the current carbohydrate-based approach to bolus dose calculation. These findings point to the need for alternative insulin dosing algorithms for higher-fat meals and suggest that dietary fat intake is an important nutritional consideration for glycemic control in individuals with type 1 diabetes. Diabetes Care 36:810-816, 2013 C1 [Wolpert, Howard A.; Atakov-Castillo, Astrid; Smith, Stephanie A.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Wolpert, Howard A.; Steil, Garry M.] Harvard Univ, Sch Med, Boston, MA USA. [Steil, Garry M.] Childrens Hosp, Boston, MA 02115 USA. RP Wolpert, HA (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. EM howard.wolpert@joslin.harvard.edu FU Scripps Foundation; Juvenile Diabetes Research Foundation [1-2011-581, UL1 RR025758]; Harvard Clinical and Translational Science Center; National Center for Research Resources FX This project was supported by the Scripps Foundation, Juvenile Diabetes Research Foundation grants 1-2011-581 and UL1 RR025758, the Harvard Clinical and Translational Science Center, and the National Center for Research Resources. Abbott Diabetes Care and Animas Corporation provided devices for this study. No other potential conflicts of interest relevant to this article were reported. NR 34 TC 39 Z9 39 U1 0 U2 12 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD APR PY 2013 VL 36 IS 4 BP 810 EP 816 DI 10.2337/dc12-0092 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 110RG UT WOS:000316462400023 PM 23193216 ER PT J AU Gonzalez, JS Schneider, HE Wexler, DJ Psaros, C Delahanty, LM Cagliero, E Safren, SA AF Gonzalez, Jeffrey S. Schneider, Havah E. Wexler, Deborah J. Psaros, Christina Delahanty, Linda M. Cagliero, Enrico Safren, Steven A. TI Validity of Medication Adherence Self-Reports in Adults With Type 2 Diabetes SO DIABETES CARE LA English DT Article ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; DSM-IV; DEPRESSION; NONADHERENCE; METAANALYSIS; MORTALITY; THERAPY; RECALL; SCALE; ASSOCIATION AB OBJECTIVE-To assess the validity of self-report measures of diabetes medication adherence and evaluate the effect of depression on the validity of these reports. RESEARCH DESIGN AND METHODS-Adults with type 2 diabetes, treated with oral medications, completed a set of medication adherence self-reports that varied response scales and time frames, were administered structured clinical interviews for depression, and provided blood samples for HbA(1c) as part of a screening for an intervention study. A subsample of participants with HbA(1c) >= 7.0% and clinically significant depression received Medication Event Monitoring System (MEMS) bottle caps to record adherence. Analyses examined relationships between adherence measures and HbA(1c) and, in the subsample, MEMS. Moderated linear regression evaluated whether depression severity modified relationships with HbA(1c). RESULTS-Participant (n = 170, 57% men, 81% white, mean HbA(1c) 8.3% [SD, 1.7]) adherence self-reports were significantly (r = -0.18 to -0.28; P < 0.03) associated with lower HbA(1c). In the subsample (n = 88), all self-reports were significantly (r = 0.35 to 0.55; P <= 0.001) associated with MEMS-measured adherence. Depression significantly moderated the relationship between three of six self-reports and HbA(1c); at high levels of depression, associations with HbA(1c) became nonsignificant. CONCLUSIONS-Results support the validity of easily administered self-reports for diabetes medication adherence. One-month, percentage-based ratings of adherence had the strongest associations with MEMS and HbA(1c); those requiring the report of missed doses had weaker associations. One-week self-ratings and measures that require respondents to record the number of missed doses appear to be vulnerable to bias from depression severity. Diabetes Care 36: 831-837, 2013 C1 [Gonzalez, Jeffrey S.; Schneider, Havah E.] Yeshiva Univ, Ferkauf Grad Sch Psychol, Bronx, NY 10033 USA. [Gonzalez, Jeffrey S.] Albert Einstein Coll Med, Diabet Res Ctr, Bronx, NY 10467 USA. [Wexler, Deborah J.; Delahanty, Linda M.; Cagliero, Enrico] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Diabet,Dept Med, Boston, MA USA. [Psaros, Christina; Safren, Steven A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Gonzalez, JS (reprint author), Yeshiva Univ, Ferkauf Grad Sch Psychol, Bronx, NY 10033 USA. EM jeffrey.gonzalez@einstein.yu.edu FU National Institute of Mental Health (NIMH) [R01-MH-078571]; LifeScan, Inc.; Harvard Catalyst/Harvard Clinical and Translational Science Center by National Institutes of Health (NIH) [1 UL1-RR-025758-03]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK-020541, DK-080228-05] FX This project was supported by National Institute of Mental Health (NIMH) Grant R01-MH-078571; Principal Investigator: S. A. S. Additional support came from the Investigator-Initiated Study Program of LifeScan, Inc., in the form of donated glucometers and glucose test strips, and the Harvard Catalyst/Harvard Clinical and Translational Science Center by National Institutes of Health (NIH) Grant 1 UL1-RR-025758-03, for a portion of nurse and dietician study visits. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH/NIMH, LifeScan, or the Harvard Catalyst. J.S.G. was partially supported by Grant DK-020541 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). D. W. was supported by NIDDK Grant DK-080228-05. NR 36 TC 29 Z9 31 U1 4 U2 15 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD APR PY 2013 VL 36 IS 4 BP 831 EP 837 DI 10.2337/dc12-0410 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 110RG UT WOS:000316462400026 PM 23204245 ER PT J AU Pisprasert, V Ingram, KH Lopez-Davila, MF Munoz, AJ Garvey, WT AF Pisprasert, Veeradej Ingram, Katherine H. Lopez-Davila, Maria F. Munoz, A. Julian Garvey, W. Timothy TI Limitations in the Use of Indices Using Glucose and Insulin Levels to Predict Insulin Sensitivity Impact of race and gender and superiority of the indices derived from oral glucose tolerance test in African Americans SO DIABETES CARE LA English DT Article ID BETA-CELL FUNCTION; HOMEOSTASIS MODEL ASSESSMENT; NON-HISPANIC WHITES; CLAMP TECHNIQUE; RESISTANCE ATHEROSCLEROSIS; CHECK INDEX; IN-VIVO; SECRETION; BLACK; CLEARANCE AB OBJECTIVE-To examine the utility of commonly used insulin sensitivity indices in nondiabetic European Americans (EAs) and African Americans (AAs). RESEARCH DESIGN AND METHODS-Two-hundred forty nondiabetic participants were studied. Euglycemic-hyperinsulinemic clamp was the gold standard approach to assess glucose disposal rates (GDR) normalized by lean body mass. The homeostatic model assessment for insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) were calculated from fasting plasma glucose and insulin (FIL). Oral glucose tolerance test (OGTT) was performed to determine Matsuda index, the simple index assessing insulin sensitivity (SI(is)OGTT), Avignon index, and Stomvoll index. Relationships among these indices with GDR were analyzed by multiple regression. RESULTS-GDR values were similar in EA and AA subgroups; even so, AA exhibited higher FIL and were insulin-resistant compared with EA, as assessed by HOMA-IR, QUICKI, Matsuda index, SIisOGTT, Avignon index, and Stumvoll index. In the overall study population, GDR was significantly correlated with all studied insulin sensitivity indices (/r/ = 0.381-0.513); however, these indices were not superior to FIL in predicting GDR. Race and gender affected the strength of this relationship. In AA males, FIL and HOMA-IR were not correlated with GDR. In contrast, Matsuda index and SI(is)OGTT were significantly correlated with GDR in AA males, and Matsuda index was superior to HOMA-IR and QUICKI in AAs overall. CONCLUSIONS-Insulin sensitivity indices based on glucose and insulin levels should be used cautiously as measures of peripheral insulin sensitivity when comparing mixed gender and mixed race populations. Matsuda index and SI(is)OGTT are reliable in studies that include AA males. Diabetes Care 36:845-853, 2013 C1 [Pisprasert, Veeradej; Lopez-Davila, Maria F.; Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Ingram, Katherine H.] Kennesaw State Univ, Dept Exercise Sci & Sport Management, Kennesaw, GA USA. [Munoz, A. Julian] Univ S Carolina, Sch Med, Div Endocrinol, Columbia, SC USA. [Garvey, W. Timothy] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Pisprasert, V (reprint author), Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. EM veeradej@uab.edu FU National Institutes of Health [DK-083562, DK-038764]; Merit Review program of the U.S. Department of Veterans Affairs; UAB Diabetes Research and Training Center [P60-DK079626] FX This work was supported from grants from the National Institutes of Health (DK-083562 and DK-038764 to W.T.G.) and by the Merit Review program of the U.S. Department of Veterans Affairs (W.T.G.).; The authors are grateful to Dr. Barbara Gower (Department of Nutrition Sciences, University of Alabama at Birmingham) and Dr. Mark Beasley (Department of Biostatistics, University of Alabama at Birmingham) for insightful discussions regarding these data. The authors thank the support of the research core facilities of the UAB Diabetes Research and Training Center (P60-DK079626) and their research volunteers. NR 40 TC 85 Z9 85 U1 0 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD APR PY 2013 VL 36 IS 4 BP 845 EP 853 DI 10.2337/dc12-0840 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 110RG UT WOS:000316462400028 PM 23223406 ER PT J AU Foo, JP Aronis, KN Chamberland, JP Paruthi, J Moon, HS Mantzoros, CS AF Foo, Joo-Pin Aronis, Konstantinos N. Chamberland, John P. Paruthi, Jason Moon, Hyun-Seuk Mantzoros, Christos S. TI Fibroblast Growth Factor 21 Levels in Young Healthy Females Display Day and Night Variations and Are Increased in Response to Short-Term Energy Deprivation Through a Leptin-Independent Pathway SO DIABETES CARE LA English DT Article ID METHIONYL HUMAN LEPTIN; FREE FATTY-ACIDS; ANOREXIA-NERVOSA; PPAR-ALPHA; HYPOTHALAMIC AMENORRHEA; INSULIN SENSITIVITY; METABOLIC REGULATOR; CIRCADIAN-RHYTHM; FGF21; OBESITY AB OBJECTIVE-Fibroblast growth factor (FGF)-21 is an endocrine factor with potent metabolic effects. Its day-night patterns of secretion and/or its physiological response to energy deprivation and relationship to free fatty acids (FFAs) and/or leptin remain to be fully elucidated. We aim to elucidate day-night pattern of FGF-21 levels and its relationship to FFA, to assess whether energy deprivation alters its circulating patterns, and to examine whether leptin may mediate these changes. RESEARCH DESIGN AND METHODS-Six healthy lean females were studied for 72 h in a cross-over interventional study under three different conditions: on isocaloric diet and in a fasting state with administration of either placebo or metreleptin in physiological replacement doses. Blood samples were obtained hourly from 8: 00 A. M. on day 4 until 8: 00 A. M. on day 5. RESULTS-FGF-21 exhibited day-night variation pattern during the isocaloric fed state. Fasting significantly increased FGF-21 levels (P < 0.01) via a leptin-independent pathway. Day-night variation pattern in the fed state was lost on fasting. Leptin replacement in the hypoleptinemic state restored approximate entropy of FGF-21 time series but did not alter circulating levels. FGF-21 levels were closely cross-correlated with FFA levels in all three states. CONCLUSIONS-A day-night variation in the levels of FGF-21 exists in young lean females in the fed state. Energy deprivation increases FGF-21 levels via a leptin-independent pathway. The interaction between FGF-21 and starvation-induced lipolysis, as indicated by its close cross-correlations with FFA in both fed state and energy deprivation, needs to be studied further. Diabetes Care 36:935-942, 2013 C1 [Foo, Joo-Pin; Aronis, Konstantinos N.; Chamberland, John P.; Paruthi, Jason; Moon, Hyun-Seuk; Mantzoros, Christos S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Sch Med, Boston, MA 02215 USA. [Aronis, Konstantinos N.; Chamberland, John P.; Mantzoros, Christos S.] Harvard Univ, Endocrinol Sect, Boston VA Healthcare Syst, Sch Med, Boston, MA 02115 USA. RP Mantzoros, CS (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Sch Med, Boston, MA 02215 USA. EM cmantzor@bidmc.harvard.edu RI Aronis, Konstantinos/F-3586-2012; Moon, Hyun-Seuk/G-8576-2015; OI Aronis, Konstantinos/0000-0001-7189-8434; Moon, Hyun-Seuk/0000-0002-5216-2090; Chamberland, John/0000-0002-7862-1371 FU National Institute of Diabetes and Digestive and Kidney Diseases [58785, 79929, 81913]; Clinical Science Research and Development Service of the VA Office of Research and Development [1I01CX000422-01A1]; National Institutes of Health National Center for Research Resources grant [M01-RR-01032] FX This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases grants 58785, 79929, and 81913. The project described was also supported by Award Number 1I01CX000422-01A1 from the Clinical Science Research and Development Service of the VA Office of Research and Development. Funding was also received from the National Institutes of Health National Center for Research Resources grant M01-RR-01032 (Harvard Clinical and Translational Science Center). Amylin Pharmaceuticals, Inc. supplied metreleptin for this study but had no role in the study design, conduct of the study, collection, management, analysis, and interpretation of the data, or the preparation, review, or approval of the manuscript. No other potential conflicts of interest relevant to this article were reported. NR 39 TC 6 Z9 7 U1 0 U2 7 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 APR PY 2013 VL 36 IS 4 BP 935 EP 942 DI 10.2337/dc12-0497 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 110RG UT WOS:000316462400041 PM 23193213 ER PT J AU Cummings, DE Cohen, RV AF Cummings, David E. Cohen, Ricardo V. TI Response to Comment on: Cohen et al. Effects of Gastric Bypass Surgery in Patients With Type 2 Diabetes and Only Mild Obesity. Diabetes Care 2012;35:1420-1428 SO DIABETES CARE LA English DT Letter ID BARIATRIC SURGERY; MEDICAL THERAPY C1 [Cummings, David E.] Univ Washington, Sch Med, Diabet & Obes Ctr Excellence, Seattle, WA 98195 USA. [Cummings, David E.] Univ Washington, Sch Med, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Cohen, Ricardo V.] Oswaldo Cruz Hosp, Ctr Excellence Bariatr & Metab Surg, Sao Paulo, Brazil. [Cohen, Ricardo V.] Marcia Maria Braido Hosp, Sao Paulo, Brazil. RP Cummings, DE (reprint author), Univ Washington, Sch Med, Diabet & Obes Ctr Excellence, Seattle, WA 98195 USA. EM davidec@u.washington.edu NR 6 TC 1 Z9 1 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD APR PY 2013 VL 36 IS 4 BP E59 EP E59 DI 10.2337/dc12-2243 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 110RG UT WOS:000316462400012 PM 23520383 ER PT J AU Nowak, N Skupien, J Cyganek, K Matejko, B Malecki, MT AF Nowak, N. Skupien, J. Cyganek, K. Matejko, B. Malecki, M. T. TI 1,5-Anhydroglucitol as a marker of maternal glycaemic control and predictor of neonatal birthweight in pregnancies complicated by type 1 diabetes mellitus SO DIABETOLOGIA LA English DT Article DE 1,5-Anhydroglucitol; Birthweight; Haemoglobin A(1c); HbA(1c); Pregnancy; Type 1 diabetes mellitus ID GLUCOSE-LEVELS; WOMEN; MACROSOMIA AB Most pregnant women with type 1 diabetes mellitus achieve HbA(1c) targets; however, macrosomia remains prevalent and better pregnancy glycaemic markers are therefore needed. 1,5-Anhydroglucitol (1,5-AG) is a short-term marker of glycaemia, reflecting a period of 1 to 2 weeks. Its excretion rate depends on the renal glucose threshold and thus it is unclear whether it may be used in pregnant type 1 diabetes women. We evaluated 1,5-AG as a glycaemic marker and birthweight predictor in pregnant women with type 1 diabetes, and compared its performance with HbA(1c). 1,5-AG and HbA(1c) were measured in 82 pregnant women with type 1 diabetes. In addition, 58 continuous glucose monitoring system (CGMS) records were available. Macrosomia was defined as birthweight > 90th centile. The data were analysed with Pearson's correlations, and linear and logistic regression models. Receiver operating characteristic (ROC) analysis was used to evaluate third trimester 1,5-AG as a predictor of macrosomia. Unlike HbA(1c), 1,5-AG strongly correlated with CGMS indices: the AUC above 7.8 mmol/l (r = -0.66; p < 0.001), average maximum glucose (r = -0.58; p < 0.001) and mean glucose (r = -0.54; p < 0.001). In the third trimester, 1,5-AG was the strongest predictor of macrosomia, with ROC AUC 0.81 (95% CI 0.70, 0.89). In contrast, HbA(1c) in the third trimester had a ROC AUC of 0.69 (95% CI 0.58, 0.81). The best discrimination was achieved when both markers were used jointly, yielding a ROC AUC of 0.84 (95% CI 0.76, 0.93). In pregnant women with type 1 diabetes, 1,5-AG is a better glycaemic marker than HbA(1c), as assessed by CGMS. A decreased third trimester 1,5-AG level, either singly or with HbA(1c), is a strong predictor of macrosomia. C1 [Nowak, N.; Skupien, J.; Matejko, B.; Malecki, M. T.] Jagiellonian Univ, Coll Med, Dept Metab Dis, PL-31501 Krakow, Poland. [Skupien, J.] Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02215 USA. [Cyganek, K.; Malecki, M. T.] Univ Hosp, Dept Metab Dis, Krakow, Poland. RP Malecki, MT (reprint author), Jagiellonian Univ, Coll Med, Dept Metab Dis, 15 Kopernika St, PL-31501 Krakow, Poland. EM maciej.malecki@uj.edu.pl FU Polish Ministry of Science [N N407 414436] FX This work was supported by the Polish Ministry of Science Grant No. N N407 414436 NR 11 TC 8 Z9 8 U1 0 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD APR PY 2013 VL 56 IS 4 BP 709 EP 713 DI 10.1007/s00125-013-2830-3 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 105MX UT WOS:000316076300004 PM 23377619 ER PT J AU Goldfine, AB Conlin, PR Halperin, F Koska, J Permana, P Schwenke, D Shoelson, SE Reaven, PD AF Goldfine, A. B. Conlin, P. R. Halperin, F. Koska, J. Permana, P. Schwenke, D. Shoelson, S. E. Reaven, P. D. TI A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance SO DIABETOLOGIA LA English DT Article DE Adipose tissue; Cardiovascular risk factors; Endothelial function; Impaired glucose tolerance; Inflammation; Insulin resistance; Salicylates ID SODIUM-SALICYLATE; DIABETES-MELLITUS; IKK-BETA; ACETYLSALICYLIC-ACID; KAPPA-B; ASPIRIN; INFLAMMATION; HEALTHY; IDENTIFICATION; INDIVIDUALS AB Chronic sub-acute inflammation contributes to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease. High doses of salicylate reduce inflammation, glucose and triacylglycerols, and may improve insulin sensitivity, suggesting therapeutic potential in impaired fasting glucose and/or impaired glucose tolerance. This trial aimed to evaluate the effect of salsalate vs placebo on insulin resistance and glycaemia in impaired fasting glucose and/or impaired glucose tolerance. We conducted a 12 week, two-centre, randomised, placebo-controlled study to evaluate the effect of salsalate (up to 4 g/day) vs placebo on systemic glucose disposal. Secondary objectives included treatment effects on glycaemia, inflammation and cardiovascular risk factors. Seventy-eight participants with impaired fasting glucose and/or impaired glucose tolerance from two VA healthcare systems were enrolled. Randomisation assignment was provided by the coordinating center directly to site pharmacists, and participants and research staff were blinded to treatment assignment. Seventy-one individuals were randomised to placebo (n = 36) or salsalate (n = 35). Glucose disposal did not change in either group (salsalate 1% [95% CI -39%, 56%]; placebo 6% [95% CI -20%, 61%], p = 0.3 for placebo vs salsalate). Fasting glucose was reduced by 6% during the study by salsalate (p = 0.006) but did not change with placebo. Declines in glucose were accompanied by declines in fasting C-peptide with salsalate. Insulin clearance was reduced with salsalate. In the salsalate group, triacylglycerol levels were lower by 25% (p = 0.01) and adiponectin increased by 53% (p = 0.02) at the end of the study. Blood pressure, endothelial function and other inflammation markers did not differ between groups. Adipose tissue nuclear factor kappa B (NF-kappa B) activity declined in the salsalate group compared with placebo (-16% vs 42%, p = 0.005), but was not correlated with metabolic improvements. The frequency of tinnitus was low but tended to be higher with salsalate therapy (n = 4 vs n = 2). In summary, salsalate therapy was well tolerated, lowered fasting glucose, increased adiponectin and reduced adipose tissue NF-kappa B activity. These changes were not related to changes in peripheral insulin sensitivity, suggesting additional mechanisms for metabolic improvement. ClinicalTrials.gov NCT00330733 Office of Research and Development, Medical Research Service, Department of Veterans Affairs and NIH K24 DK63214. C1 [Goldfine, A. B.; Halperin, F.; Shoelson, S. E.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Med, Boston, MA 02115 USA. [Conlin, P. R.] Brigham & Womens Hosp, Boston VA Hlth Care Syst, Dept Med, Boston, MA 02115 USA. [Koska, J.; Permana, P.; Schwenke, D.] Phoenix VA Hlth Care Syst, Res Dept, Phoenix, AZ USA. [Reaven, P. D.] Phoenix VA Hlth Care Syst, Dept Med, Phoenix, AZ USA. [Reaven, P. D.] Univ Arizona, Dept Med, Phoenix, AZ USA. RP Reaven, PD (reprint author), Phoenix VA Hlth Care Syst, Dept Med, Phoenix, AZ USA. EM Peter.Reaven@va.gov FU Office of Research and Development, Medical Research Service, Department of Veterans Affairs; NIH [K24 DK63214] FX This material is based upon work supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs and NIH K24 DK63214. The contents do not represent the views of the Department of Veterans Affairs or the US Government. NR 42 TC 40 Z9 42 U1 1 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD APR PY 2013 VL 56 IS 4 BP 714 EP 723 DI 10.1007/s00125-012-2819-3 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 105MX UT WOS:000316076300005 PM 23370525 ER PT J AU Rountree, AM Reed, BJ Cummings, BP Jung, SR Stanhope, KL Graham, JL Griffen, SC Hull, RL Havel, PJ Sweet, IR AF Rountree, A. M. Reed, B. J. Cummings, B. P. Jung, S. -R. Stanhope, K. L. Graham, J. L. Griffen, S. C. Hull, R. L. Havel, P. J. Sweet, I. R. TI Loss of coupling between calcium influx, energy consumption and insulin secretion associated with development of hyperglycaemia in the UCD-T2DM rat model of type 2 diabetes SO DIABETOLOGIA LA English DT Article DE Calcium; Hyperglycaemia; Insulin secretion; Islets; Oxygen consumption ID PANCREATIC BETA-CELLS; PYRUVATE-CARBOXYLASE; ENDOPLASMIC-RETICULUM; OXYGEN-CONSUMPTION; B-CELLS; GLUCOSE; ISLETS; CHANNELS; RELEASE; MITOCHONDRIA AB Previous studies on isolated islets have demonstrated tight coupling between calcium (Ca2+) influx and oxygen consumption rate (OCR) that is correlated with insulin secretion rate (ISR). To explain these observations, we have proposed a mechanism whereby the activation of a highly energetic process (Ca2+/metabolic coupling process [CMCP]) by Ca2+ mediates the stimulation of ISR. The aim of the study was to test whether impairment of the CMCP could play a role in the development of type 2 diabetes. Glucose- and Ca2+-mediated changes in OCR and ISR in isolated islets were compared with the time course of changes of plasma insulin concentrations observed during the progression to hyperglycaemia in a rat model of type-2 diabetes (the University of California at Davis type 2 diabetes mellitus [UCD-T2DM] rat). Islets were isolated from UCD-T2DM rats before, 1 week, and 3 weeks after the onset of hyperglycaemia. Glucose stimulation of cytosolic Ca2+ and OCR was similar for islets harvested before and 1 week after the onset of hyperglycaemia. In contrast, a loss of decrement in islet OCR and ISR in response to Ca2+ channel blockade coincided with decreased fasting plasma insulin concentrations observed in rats 3 weeks after the onset of hyperglycaemia. These results suggest that phenotypic impairment of diabetic islets in the UCD-T2DM rat is downstream of Ca2+ influx and involves unregulated stimulation of the CMCP. The continuously elevated levels of CMCP induced by chronic hyperglycaemia in these islets may mediate the loss of islet function. C1 [Rountree, A. M.; Reed, B. J.; Jung, S. -R.; Sweet, I. R.] Univ Washington, Diabet & Obes Ctr Excellence, Seattle, WA 98109 USA. [Cummings, B. P.; Stanhope, K. L.; Graham, J. L.; Havel, P. J.] Univ Calif Davis, Dept Mol Biosci, Sch Vet Med, Davis, CA 95616 USA. [Cummings, B. P.; Stanhope, K. L.; Graham, J. L.; Havel, P. J.] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. [Griffen, S. C.] Bristol Myers Squibb Co, Princeton, NJ USA. [Hull, R. L.] VA Puget Sound Hlth Care Syst, Dept Med, Seattle, WA USA. [Hull, R. L.] Univ Washington, Seattle, WA 98109 USA. RP Sweet, IR (reprint author), Univ Washington, Diabet & Obes Ctr Excellence, 850 Republican St, Seattle, WA 98109 USA. EM isweet@u.washington.edu OI Hull, Rebecca/0000-0001-9690-4087 FU Merck Investigator Initiated Sponsored Program [33171]; National Institutes of Health [DK17047, DK063986, R01 HL075675, R01 HL091333, AT002599, AT002993, AT003645]; Washington State Life Sciences Discovery Fund; American Diabetes Association FX This research was funded by grants from Merck Investigator Initiated Sponsored Program (No. 33171), the National Institutes of Health (DK17047 and DK063986) and the Washington State Life Sciences Discovery Fund. P. J. Havel's laboratory also receives, or received, support during the time the experiments were conducted from NIH grants R01 HL075675, R01 HL091333, AT002599, AT002993, AT003645 and the American Diabetes Association. NR 35 TC 5 Z9 5 U1 0 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD APR PY 2013 VL 56 IS 4 BP 803 EP 813 DI 10.1007/s00125-012-2808-6 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 105MX UT WOS:000316076300014 PM 23404441 ER PT J AU Tyler, JA Fox, JP Desai, MM Perry, WB Glasgow, SC AF Tyler, Joshua A. Fox, Justin P. Desai, Mayur M. Perry, W. Brian Glasgow, Sean C. TI Outcomes and Costs Associated With Robotic Colectomy in the Minimally Invasive Era SO DISEASES OF THE COLON & RECTUM LA English DT Article DE Robotic surgery; Colectomy; Laparoscopic colectomy; Colon cancer ID SHORT-TERM OUTCOMES; MRC CLASICC TRIAL; COLON-CANCER; RANDOMIZED-TRIAL; ASSISTED SURGERY AB BACKGROUND: Robotic-assisted surgery has become increasingly common; however, it is unclear if its use for colectomy improves in-hospital outcomes compared with the laparoscopic approach. OBJECTIVE: The aim of the study is to compare in-hospital outcomes and costs between patients undergoing robotic or laparoscopic colectomy. DESIGN: This study is a retrospective review of the 2008 to 2009 Nationwide Inpatient Sample. SETTINGS, PATIENTS, INTERVENTIONS: All adult patients who underwent an elective robotic or laparoscopic colectomy in hospitals performing both procedures (N = 2583 representing an estimated 12,732 procedures) were included. MAIN OUTCOME MEASURES: Outcomes included intraoperative and postoperative complications, length of stay, and direct costs of care. Regression models were used to compare these outcomes between procedural approaches while controlling for baseline differences in patient characteristics. RESULTS: Overall, 6.1% of patients underwent a robotic procedure. Factors associated with robotic-assisted colectomy included younger age, benign diagnoses, and treatment at a lower-volume center. Patients undergoing robotic and laparoscopic procedures experienced similar rates of intraoperative (3.0% vs 3.3%; adjusted OR = 0.88 (0.35-2.22)) and postoperative (21.7% vs 21.6%; adjusted OR = 0.84 (0.54-1.30)) complications, as well as risk-adjusted average lengths of stay (5.4 vs 5.5 days, p = 0.66). However, robotic-assisted colectomy resulted in significantly higher costs of care ($19,231 vs $ 15,807, p < 0.001). Although the overall postoperative morbidity rate was similar between groups, the individual complications experienced by each group were different. LIMITATIONS: A limitation of this study is the potential miscoding of robotic cases in administrative data. CONCLUSIONS: Robotic-assisted colectomy significantly increases the costs of care without providing clear reductions in overall morbidity or length of stay. As the use of robotic technology in colon surgery continues to evolve, critical appraisal of the benefits offered in comparison with the resources consumed is required. C1 [Tyler, Joshua A.; Glasgow, Sean C.] San Antonio Mil Med Ctr, Dept Surg, San Antonio, TX USA. [Fox, Justin P.; Desai, Mayur M.] Yale Univ, Sch Med, Robert Wood Johnson Fdn, Clin Scholars Program, New Haven, CT USA. [Desai, Mayur M.] Yale Univ, Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA. [Perry, W. Brian] South Texas Vet Hlth Care Syst, Dept Gen Surg, San Antonio, TX USA. RP Tyler, JA (reprint author), San Antonio Mil Med Ctr, Dept Gen Surg, 3851 Roger Brooke Dr, Ft Sam Houston, TX 78234 USA. EM Joshua.Tyler.1@us.af.mil FU Robert Wood Johnson Foundation FX Drs Fox and Desai are involved with the Clinical Scholars Program, which is supported by the Robert Wood Johnson Foundation. NR 25 TC 27 Z9 28 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0012-3706 J9 DIS COLON RECTUM JI Dis. Colon Rectum PD APR PY 2013 VL 56 IS 4 BP 458 EP 466 DI 10.1097/DCR.0b013e31827085ec PG 9 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 106ZB UT WOS:000316183200467 PM 23478613 ER PT J AU Wicksell, RK Kemani, M Jensen, K Kosek, E Kadetoff, D Sorjonen, K Ingvar, M Olsson, GL AF Wicksell, R. K. Kemani, M. Jensen, K. Kosek, E. Kadetoff, D. Sorjonen, K. Ingvar, M. Olsson, G. L. TI Acceptance and commitment therapy for fibromyalgia: A randomized controlled trial SO EUROPEAN JOURNAL OF PAIN LA English DT Article ID COGNITIVE-BEHAVIORAL THERAPY; MAJOR DEPRESSIVE DISORDER; PAIN DISABILITY INDEX; HEALTH SURVEY SF-36; VALUES-BASED ACTION; LOW-BACK-PAIN; PSYCHOLOGICAL INTERVENTIONS; IMPACT QUESTIONNAIRE; MUSCULOSKELETAL PAIN; GENERAL-POPULATION AB Background Fibromyalgia (FM) is characterized by widespread pain and co-morbid symptoms such as fatigue and depression. For FM, medical treatments alone appear insufficient. Recent meta-analyses point to the utility of cognitive behaviour therapy (CBT), but effects are moderate. Within the continuous development of CBT, the empirical support for acceptance and commitment therapy (ACT) has increased rapidly. ACT focuses on improving functioning by increasing the patient's ability to act in accordance with personal values also in the presence of pain and distress (i.e., psychological flexibility). However, no study has yet explored the utility of ACT in FM. Objectives To evaluate the efficacy of ACT for FM and the role of psychological inflexibility as a mediator of improvement. Methods In this randomized controlled trial, ACT was evaluated in comparison to a waiting list control condition. Forty women diagnosed with FM participated in the study. Assessments were made pre- and post-treatment and at 3 months of follow-up. The ACT intervention consisted of 12 weekly group sessions. Results Significant differences in favour of ACT were seen in pain-related functioning, FM impact, mental health-related quality of life, self-efficacy, depression, anxiety and psychological inflexibility. Changes in psychological inflexibility during the course of treatment were found to mediate pre- to follow-up improvements in outcome variables. Conclusions The results correspond with previous studies on ACT for chronic pain and suggest the utility of ACT for FM as well as the role of psychological inflexibility as a mediator of improvement. C1 [Wicksell, R. K.; Kemani, M.; Olsson, G. L.] Karolinska Univ Hosp, Behav Med Pain Treatment Serv, Stockholm, Sweden. [Wicksell, R. K.; Kemani, M.; Kosek, E.; Kadetoff, D.; Sorjonen, K.; Ingvar, M.] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Olsson, G. L.] Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. [Jensen, K.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Jensen, K.] Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Kosek, E.; Kadetoff, D.; Ingvar, M.] Karolinska Inst, Osher Ctr Integrat Med, Stockholm, Sweden. RP Wicksell, RK (reprint author), Karolinska Univ Hosp, Behav Med Pain Treatment Serv, Stockholm, Sweden. EM rikard.wicksell@karolinska.se OI Jensen, Karin/0000-0003-2521-3160; Ingvar, Martin/0000-0002-9041-5714 FU Swedish Research Council [K2009-53X-21070-01-3]; Stockholm County Council; Swedish Rheumatism Association FX One author (E. K.) received support from the Swedish Research Council, Project No. K2009-53X-21070-01-3, the Stockholm County Council, and the Swedish Rheumatism Association. NR 65 TC 36 Z9 37 U1 15 U2 81 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1090-3801 EI 1532-2149 J9 EUR J PAIN JI Eur. J. Pain PD APR PY 2013 VL 17 IS 4 BP 599 EP 611 DI 10.1002/j.1532-2149.2012.00224.x PG 13 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 108HT UT WOS:000316284100015 PM 23090719 ER PT J AU Su, DA Shukla, AK Chen, BW Kim, JS Nakayasu, E Qu, Y Aryal, U Weitz, K Clauss, TRW Monroe, ME Camp, DG Bigelow, DJ Smith, RD Kulkarni, RN Qian, WJ AF Su, Dian Shukla, Anil K. Chen, Baowei Kim, Jong-Seo Nakayasu, Ernesto Qu, Yi Aryal, Uma Weitz, Karl Clauss, Therese R. W. Monroe, Matthew E. Camp, David G., II Bigelow, Diana J. Smith, Richard D. Kulkarni, Rohit N. Qian, Wei-Jun TI Quantitative site-specific reactivity profiling of S-nitrosylation in mouse skeletal muscle using cysteinyl peptide enrichment coupled with mass spectrometry SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE S-nitrosylation; Redox regulation; Chemical enrichment; Mouse muscle; Proteomics; LC-MS/MS; Free radicals ID BIOTIN-SWITCH ASSAY; COMPLEX PROTEIN MIXTURES; RETICULUM CA-ATPASE; LARGE GENE LISTS; NITRIC-OXIDE; POSTTRANSLATIONAL MODIFICATION; NITROSATED PROTEINS; SIGNAL-TRANSDUCTION; RYANODINE RECEPTOR; INSULIN-RECEPTOR AB S-nitrosylation, the formation of S-nitrosothiol (SNO), is an important reversible thiol oxidation event that has been increasingly recognized for its role in cell signaling. Although many proteins susceptible to S-nitrosylation have been reported, site-specific identification of physiologically relevant SNO modifications remains an analytical challenge because of the low abundance and labile nature of this modification. Herein we present further improvement and optimization of the recently reported resin-assisted cysteinyl peptide enrichment protocol for SNO identification and its application to mouse skeletal muscle to identify specific cysteine sites sensitive to S-nitrosylation by a quantitative reactivity profiling strategy. Our results indicate that the protein- and peptide-level enrichment protocols provide comparable specificity and coverage of SNO-peptide identifications. S-nitrosylation reactivity profiling was performed by quantitatively comparing the site-specific SNO modification levels in samples treated with S-nitrosoglutathione, an NO donor, at two different concentrations (i.e., 10 and 100 mu M). The reactivity profiling experiments led to the identification of 488 SNO-modified sites from 197 proteins with specificity of similar to 95% at the unique peptide level, i.e., similar to 95% of enriched peptides contain cysteine residues as the originally SNO-modified sites. Among these sites, 281 from 145 proteins were considered more sensitive to S-nitrosylation based on the ratios of observed SNO levels between the two treatments. These SNO-sensitive sites are more likely to be physiologically relevant. Many of the SNO-sensitive proteins are localized in mitochondria, contractile fiber, and actin cytoskeleton, suggesting the susceptibility of these subcellular compartments to redox regulation. Moreover, these observed SNO-sensitive proteins are primarily involved in metabolic pathways, including the tricarboxylic acid cycle, glycolysis/gluconeogenesis, glutathione metabolism, and fatty acid metabolism, suggesting the importance of redox regulation in muscle metabolism and insulin action. (C) 2012 Elsevier Inc. All rights reserved. C1 [Su, Dian; Shukla, Anil K.; Chen, Baowei; Kim, Jong-Seo; Nakayasu, Ernesto; Qu, Yi; Aryal, Uma; Weitz, Karl; Clauss, Therese R. W.; Monroe, Matthew E.; Camp, David G., II; Bigelow, Diana J.; Smith, Richard D.; Qian, Wei-Jun] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Qian, WJ (reprint author), Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. EM Weijun.qian@pnnl.gov RI Smith, Richard/J-3664-2012 OI Smith, Richard/0000-0002-2381-2349 FU NIH [DP2OD006668, R01 DK074795, P41 RR018522, P41 GM103493]; DOE [DE-AC05-76RLO-1830] FX Portions of this work were supported by the NIH Director's New Innovator Award Program DP2OD006668, a DOE Early Career Research Award, and NIH Grants R01 DK074795, P41 RR018522, and P41 GM103493. Experimental work was performed in the Environmental Molecular Science Laboratory, a DOE/BER national scientific user facility at PNNL in Richland, Washington. PNNL is operated by Battelle for the DOE under Contract DE-AC05-76RLO-1830. NR 79 TC 20 Z9 20 U1 0 U2 36 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD APR PY 2013 VL 57 BP 68 EP 78 DI 10.1016/j.freeradbiomed.2012.12.010 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 105AC UT WOS:000316037000008 PM 23277143 ER PT J AU Rosenberg, DE Huang, DL Simonovich, SD Belza, B AF Rosenberg, Dori E. Huang, Deborah L. Simonovich, Shannon D. Belza, Basia TI Outdoor Built Environment Barriers and Facilitators to Activity among Midlife and Older Adults with Mobility Disabilities SO GERONTOLOGIST LA English DT Article DE Ambulation; Neighborhood; Physical function; Walkability; Physical activity; Disability ID PHYSICAL-ACTIVITY; NEIGHBORHOOD ENVIRONMENT; QUALITATIVE RESEARCH; METROPOLITAN-AREAS; PEOPLE; HEALTH; WALKABILITY; VALIDATION; FRAMEWORK; ACCESS AB Purpose: To gain better understanding of how the built environment impacts neighborhood-based physical activity among midlife and older adults with mobility disabilities. Design and methods: We conducted in-depth interviews with 35 adults over age 50, which used an assistive device and lived in King County, Washington, U.S. In addition, participants wore Global Positioning Systems (GPS) devices for 3 days prior to the interview. The GPS maps were used as prompts during the interviews. Open coding of the 35 interviews using latent content analysis resulted in key themes and subthemes that achieved consensus between coders. Two investigators independently coded the text of each interview. Results: Participants were on average of 67 years of age (range: 5086) and predominantly used canes (57%), walkers (57%), or wheelchairs (46%). Key themes pertained to curb ramp availability and condition, sidewalk availability and condition, hills, aesthetics, lighting, ramp availability, weather, presence and features of crosswalks, availability of resting places and shelter on streets, paved or smooth walking paths, safety, and traffic on roads. Implications: A variety of built environment barriers and facilitators to neighborhood-based activity exist for midlife and older adults with mobility disabilities. Preparing our neighborhood environments for an aging population that uses assistive devices will be important to foster independence and health. C1 [Rosenberg, Dori E.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Huang, Deborah L.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr S 182, Seattle, WA USA. [Simonovich, Shannon D.; Belza, Basia] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. [Belza, Basia] Univ Washington, Hlth Promot Res Ctr, Seattle, WA 98195 USA. RP Rosenberg, DE (reprint author), Grp Hlth Res Inst, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM rosenberg.d@ghc.org FU NCCDPHP CDC HHS [U48-DP001911] NR 38 TC 39 Z9 39 U1 6 U2 70 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD APR PY 2013 VL 53 IS 2 BP 268 EP 279 DI 10.1093/geront/gns119 PG 12 WC Gerontology SC Geriatrics & Gerontology GA 106MR UT WOS:000316148600009 PM 23010096 ER PT J AU Pischke, CR Galarce, EM Nagler, E Aghi, M Sorensen, G Gupta, PC Pednekar, MS Sinha, DN Viswanath, K AF Pischke, Claudia R. Galarce, Ezequiel M. Nagler, Eve Aghi, Mira Sorensen, Glorian Gupta, Prakash C. Pednekar, Mangesh S. Sinha, Dhirendra N. Viswanath, K. TI Message formats and their influence on perceived risks of tobacco use: a pilot formative research project in India SO HEALTH EDUCATION RESEARCH LA English DT Article ID FEAR APPEALS; HEALTH; SMOKING; PSYCHOLOGY; BEHAVIORS AB In India, tobacco kills 900 000 people every year though the burden of tobacco is faced disproportionately in poorer states such as Bihar. Teachers may be a particularly influential group in setting norms around tobacco use in the Indian context. However, tobacco use among teachers remains high and perceptions of tobacco-related health risks are unexplored. To qualitatively explore perceptions about tobacco use among teachers in Bihar and to examine how risk information may be communicated through a variety of message formats, 12 messages on tobacco health risks varying in formats were tested in focus groups with teachers from Bihar. Participants stated that teachers were already aware of tobacco-related health risks. To further increase awareness of these risks, the inclusion of evidence-based facts in messages was recommended. Communicating risk information using negative emotions had a great appeal to teachers and was deemed most effective for increasing risk perception. Messages using narratives of teachers' personal accounts of quitting tobacco were deemed effective for increasing knowledge about the benefits of quitting. To conclude, messages using evidence-based information, possibly with negative emotions, testimonials with role models and those messages emphasizing self-efficacy in the format of narratives appear to appeal to teachers in Bihar. C1 [Pischke, Claudia R.] BIPS Inst Epidemiol & Prevent Res, D-28359 Bremen, Germany. [Galarce, Ezequiel M.; Nagler, Eve; Sorensen, Glorian; Viswanath, K.] Harvard Univ, Sch Publ Hlth, Ctr Community Based Res, Dana Farber Canc Inst, Boston, MA 02115 USA. [Aghi, Mira; Gupta, Prakash C.; Pednekar, Mangesh S.] Healis Sekhsaria Inst Publ Hlth, Bombay 400614, Maharashtra, India. [Sinha, Dhirendra N.] Sch Prevent Oncol, Patna 800001, Bihar, India. RP Pischke, CR (reprint author), BIPS Inst Epidemiol & Prevent Res, Achterstr 30, D-28359 Bremen, Germany. EM pischke@bips.uni-bremen.de FU NCI NIH HHS [2R25 CA057713-06, 5K05 CA108663-05, 5R01CA120958-02, K05 CA108663] NR 24 TC 3 Z9 3 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1153 J9 HEALTH EDUC RES JI Health Educ. Res. PD APR PY 2013 VL 28 IS 2 BP 326 EP 338 DI 10.1093/her/cys112 PG 13 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 108DY UT WOS:000316273100012 PM 23221589 ER PT J AU McCauley, MP Blake, KD Meissner, HI Viswanath, K AF McCauley, M. P. Blake, K. D. Meissner, H. I. Viswanath, K. TI The social group influences of US health journalists and their impact on the newsmaking process SO HEALTH EDUCATION RESEARCH LA English DT Article ID NATIONAL-SURVEY; MEDIA COVERAGE; CANCER CONTROL; NEWS MEDIA; DISPARITIES; WOMEN; REPORTERS; SCIENCE; CARE; OPPORTUNITIES AB The news media play a vital role in disseminating health information, yet little is known about the social characteristics of health journalists or the impact they have on the newsmaking process. This study examines how the social group influences of US health journalists impact two important aspects of news production-'media agenda-setting' and 'framing'. Using data from a national survey of health and medical science journalists, the authors conducted multivariable logistic regression analyses to study the links between the gender, age and race/ethnicity of respondents, and the ways in which they utilized news sources, other resources, news priorities and story angles. Female respondents were more likely than males to say that educating people to make informed decisions and disseminating new, accurate information are important priorities. Female and minority journalists were more likely than white males to use a variety of sources, and to say it is important to develop the health and scientific literacy of audiences and influence public health behaviors. The gender and race/ethnicity of journalists play an important role in the production of health news. Health educators can foster improved coverage by learning more about the life experiences of health journalists and developing better working relationships with them. C1 [McCauley, M. P.; Viswanath, K.] Harvard Univ, Dept Soc Human Dev & Hlth, Sch Publ Hlth, Boston, MA 02215 USA. [McCauley, M. P.; Viswanath, K.] Dana Farber Canc Inst, McGraw Patterson Ctr Populat Sci, Boston, MA 02215 USA. [Blake, K. D.] NCI, Hlth Commun & Informat Res Branch, NIH, Bethesda, MD 20892 USA. [Meissner, H. I.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. RP McCauley, MP (reprint author), Harvard Univ, Dept Soc Human Dev & Hlth, Sch Publ Hlth, Boston, MA 02215 USA. EM michael_mccauley@dfci.harvard.edu RI McCauley, Michael/C-3642-2014 OI McCauley, Michael/0000-0003-3851-1765 FU NCI NIH HHS [R25 CA057713] NR 70 TC 7 Z9 7 U1 4 U2 26 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1153 J9 HEALTH EDUC RES JI Health Educ. Res. PD APR PY 2013 VL 28 IS 2 BP 339 EP 351 DI 10.1093/her/cys086 PG 13 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 108DY UT WOS:000316273100013 PM 22907539 ER PT J AU Navathe, AS Silber, JH Small, DS Rosen, AK Romano, PS Even-Shoshan, O Wang, YL Zhu, JS Halenar, MJ Volpp, KG AF Navathe, Amol S. Silber, Jeffrey H. Small, Dylan S. Rosen, Amy K. Romano, Patrick S. Even-Shoshan, Orit Wang, Yanli Zhu, Jingsan Halenar, Michael J. Volpp, Kevin G. TI Teaching Hospital Financial Status and Patient Outcomes Following ACGME Duty Hour Reform SO HEALTH SERVICES RESEARCH LA English DT Article DE Resident duty hour reform; quality of care; hospital financial health; patient outcomes; health policy ID QUALITY-OF-CARE; RESIDENTS WORK HOURS; ADMINISTRATIVE DATA; MEDICARE BENEFICIARIES; COMORBIDITY MEASURES; COST IMPLICATIONS; SAFETY; MORTALITY; STAY; REIMBURSEMENT AB Objective To examine whether hospital financial health was associated with differential changes in outcomes after implementation of 2003 ACGME duty hour regulations. Data Sources/Study Setting Observational study of 3,614,174 Medicare patients admitted to 869 teaching hospitals from July 1, 2000 to June 30, 2005. Study Design Interrupted time series analysis using logistic regression to adjust for patient comorbidities, secular trends, and hospital site. Outcomes included 30-day mortality, AHRQ Patient Safety Indicators (PSIs), failure-to-rescue (FTR) rates, and prolonged length of stay (PLOS). Principal Findings All eight analyses measuring the impact of duty hour reform on mortality by hospital financial health quartile, in postreform year 1 (Post 1) or year 2 (Post 2) versus the prereform period, were insignificant: Post 1 OR range 1.001.02 and Post 2 OR range 0.991.02. For PSIs, all six tests showed clinically insignificant effect sizes. The FTR rate analysis demonstrated nonsignificance in both postreform years (OR 1.00 for both). The PLOS outcomes varied significantly only for the combined surgical sample in Post 2, but this effect was very small, OR 1.03 (95% CI 1.02, 1.04). Conclusions The impact of 2003 ACGME duty hour reform on patient outcomes did not differ by hospital financial health. This finding is somewhat reassuring, given additional financial pressure on teaching hospitals from 2011 duty hour regulations. C1 [Navathe, Amol S.; Silber, Jeffrey H.; Small, Dylan S.; Even-Shoshan, Orit; Volpp, Kevin G.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Navathe, Amol S.; Zhu, Jingsan; Halenar, Michael J.; Volpp, Kevin G.] Univ Penn, Dept Med, Sch Med, Philadelphia, PA 19104 USA. [Navathe, Amol S.; Silber, Jeffrey H.; Volpp, Kevin G.] Univ Penn, Wharton Sch, Dept Hlth Care Management & Econ, Philadelphia, PA 19104 USA. [Navathe, Amol S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Silber, Jeffrey H.; Even-Shoshan, Orit; Wang, Yanli] Childrens Hosp Philadelphia, Ctr Outcomes Res, Philadelphia, PA 19104 USA. [Silber, Jeffrey H.] Univ Penn, Dept Pediat, Sch Med, Philadelphia, PA 19104 USA. [Silber, Jeffrey H.] Univ Penn, Dept Anesthesiol & Crit Care, Sch Med, Philadelphia, PA 19104 USA. [Small, Dylan S.] Univ Penn, Wharton Sch, Dept Stat, Philadelphia, PA 19104 USA. [Rosen, Amy K.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Rosen, Amy K.] Vet Adm Hosp, Ctr Org Leadership & Management Res, Boston, MA USA. [Romano, Patrick S.] Univ Calif Davis, Div Gen Med, Sch Med, Sacramento, CA 95817 USA. [Romano, Patrick S.] Univ Calif Davis, Ctr Healthcare Policy & Res, Sch Med, Sacramento, CA 95817 USA. [Halenar, Michael J.; Volpp, Kevin G.] Vet Adm Hosp, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Navathe, AS (reprint author), Univ Penn, Leonard Davis Inst Hlth Econ, 3641 Locust Walk,Room 202, Philadelphia, PA 19104 USA. EM amol@wharton.upenn.edu RI Romano, Patrick/N-4225-2014 OI Romano, Patrick/0000-0001-6749-3979 FU National Heart, Lung, and Blood Institute (NHLBI) [R01 HL082637] FX This study was supported by grant R01 HL082637 from the National Heart, Lung, and Blood Institute (NHLBI), "Impact of Resident Work Hour Rules on Errors and Quality." NR 48 TC 4 Z9 4 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 J9 HEALTH SERV RES JI Health Serv. Res. PD APR PY 2013 VL 48 IS 2 BP 476 EP 498 DI 10.1111/j.1475-6773.2012.01453.x PN 1 PG 23 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 106CW UT WOS:000316120200008 PM 22862427 ER PT J AU Ghaffarzadegan, N Epstein, AJ Martin, EG AF Ghaffarzadegan, Navid Epstein, Andrew J. Martin, Erika G. TI Practice Variation, Bias, and Experiential Learning in Cesarean Delivery: A Data-Based System Dynamics Approach SO HEALTH SERVICES RESEARCH LA English DT Article DE Cesarean delivery; practice variation; experiential learning; simulation; system dynamics ID IDENTIFY INDICATIONS; DECISION-MAKING; HEALTH; MODEL; FEEDBACK; OUTCOMES; AGREEMENT; PHYSICIAN; SELECTION; SERVICES AB Objectives To simulate physician-driven dynamics of delivery mode decisions (scheduled cesarean delivery [CD] vs. vaginal delivery [VD] vs. unplanned CD after labor), and to evaluate a behavioral theory of how experiential learning leads to emerging bias toward more CD and practice variation across obstetricians. Data Sources/Study Setting Hospital discharge data on deliveries performed by 300 randomly selected obstetricians in Florida who finished obstetrics residency and started practice after 1991. Study Design We develop a system dynamics simulation model of obstetricians' delivery mode decision based on the literature of experiential learning. We calibrate the model and investigate the extent to which the model replicates the data. Principal Findings Our learning-based simulation model replicates the empirical data, showing that physicians are more likely to schedule CD as they practice longer. Variation in CD rates is related to the way that physicians learn from outcomes of past decisions and accumulate experience. Conclusions The repetitive nature of medical decision making, learning from past practice, and accumulating experience can account for increases in CD decisions and practice variation across physicians. Policies aimed at improving medical decision making should account for providers' feedback-based learning mechanisms. C1 [Ghaffarzadegan, Navid] MIT, Engn Syst Div, Cambridge, MA 02139 USA. [Epstein, Andrew J.] Univ Penn, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Epstein, Andrew J.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Martin, Erika G.] SUNY Albany, Rockefeller Coll Publ Affairs & Policy, Albany, NY 12222 USA. [Martin, Erika G.] SUNY Albany, Nelson A Rockefeller Inst Govt, Albany, NY 12222 USA. RP Ghaffarzadegan, N (reprint author), MIT, Engn Syst Div, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM navidg@mit.edu NR 52 TC 6 Z9 6 U1 1 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 J9 HEALTH SERV RES JI Health Serv. Res. PD APR PY 2013 VL 48 IS 2 BP 713 EP 734 DI 10.1111/1475-6773.12040 PN 2 PG 22 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 106CZ UT WOS:000316120600004 PM 23398502 ER PT J AU Lindrooth, RC Konetzka, RT Navathe, AS Zhu, JS Chen, W Volpp, K AF Lindrooth, Richard C. Konetzka, R. Tamara Navathe, Amol S. Zhu, Jingsan Chen, Wei Volpp, Kevin TI The Impact of Profitability of Hospital Admissions on Mortality SO HEALTH SERVICES RESEARCH LA English DT Article DE Hospital quality; medicare reimbursement; hospital finances ID ACUTE MYOCARDIAL-INFARCTION; PROSPECTIVE PAYMENT; HEALTH-CARE; QUALITY INFORMATION; COMPETITION; REIMBURSEMENT; MEDICARE; OUTCOMES; INCENTIVES; NONPROFIT AB Background Fiscal constraints faced by Medicare are leading to policies designed to reduce expenditures. Evidence of the effect of reduced reimbursement on the mortality of Medicare patients discharged from all major hospital service lines is limited. Methods We modeled risk-adjusted 30-day mortality of patients discharged from 21 hospital service lines as a function of service line profitability, service line time trends, and hospital service line and year-fixed effects. We simulated the effect of alternative revenue-neutral reimbursement policies on mortality. Our sample included all Medicare discharges from PPS-eligible hospitals (1997, 2001, and 2005). Results The results reveal a statistically significant inverse relationship between changes in profitability and mortality. A $0.19 average reduction in profit per $1.00 of costs led to a 0.0100.020 percentage-point increase in mortality rates (p<.001). Mortality in newly unprofitable service lines is significantly more sensitive to reduced payment generosity than in service lines that remain profitable. Policy simulations that target service line inequities in payment generosity result in lower mortality rates, roughly 70013,000 fewer deaths nationally. Conclusions The policy simulations raise questions about the trade-offs implicit in universal reductions in reimbursement. The effect of reduced payment generosity on mortality could be mitigated by targeting highly profitable services only for lower reimbursement. C1 [Lindrooth, Richard C.] Univ Colorado, Colorado Sch Publ Hlth, Aurora, CO 80045 USA. [Konetzka, R. Tamara] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Navathe, Amol S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Zhu, Jingsan; Chen, Wei] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Volpp, Kevin] Univ Penn, Perelman Sch Med, Leonard Davis Inst, Philadelphia VA Med Ctr,Ctr Hlth Incent & Behav E, Philadelphia, PA 19104 USA. [Volpp, Kevin] Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. RP Lindrooth, RC (reprint author), Univ Colorado, Colorado Sch Publ Hlth, Anschutz Med Campus,13001 E 17th Pl,Campus Box B1, Aurora, CO 80045 USA. EM richard.lindrooth@ucdenver.edu OI Lindrooth, Richard/0000-0001-9538-9749 FU Robert Wood Johnson Foundation's Health Care Financing and Organization Initiative; Agency for Healthcare Research and Quality FX Joint Acknowledgment/Disclosure Statement: We thank Robert Wood Johnson Foundation's Health Care Financing and Organization Initiative and the Agency for Healthcare Research and Quality for funding this research. We also thank Jeff Stensland for helpful comments on a previous draft of this manuscript. NR 34 TC 7 Z9 7 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0017-9124 J9 HEALTH SERV RES JI Health Serv. Res. PD APR PY 2013 VL 48 IS 2 BP 792 EP 809 DI 10.1111/1475-6773.12026 PN 2 PG 18 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 106CZ UT WOS:000316120600008 PM 23346946 ER PT J AU Focks, JJ Brouwer, MA van Oijen, MGH Lanas, A Bhatt, DL Verheugt, FWA AF Focks, Jeroen Jaspers Brouwer, Marc A. van Oijen, Martijn G. H. Lanas, Angel Bhatt, Deepak L. Verheugt, Freek W. A. TI Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review SO HEART LA English DT Review ID PERCUTANEOUS CORONARY INTERVENTION; DUAL-ANTIPLATELET THERAPY; ACUTE MYOCARDIAL-INFARCTION; EXPERT CONSENSUS DOCUMENTS; FOUNDATION TASK-FORCE; STENT IMPLANTATION; CARDIOVASCULAR OUTCOMES; GASTROINTESTINAL RISKS; HEALTHY-SUBJECTS; CONTROLLED-TRIAL AB Background Clopidogrel as an adjunct to aspirin has improved outcomes after acute coronary syndromes, but laboratory studies suggest a reduced antiplatelet effect when proton pump inhibitors (PPIs) are co-administered. Despite corroborating data from retrospective studies, new clinical data fuel the controversy on this issue. Purpose Systematic review of the impact of the addition of PPIs to clopidogrel on platelet function and cardiovascular outcome. Data sources PubMed, Web-of-Science, Cochrane Database and reference lists of related articles. Study selection Published articles on controlled studies addressing the addition of PPIs to clopidogrel. Platelet function studies describe patients as well as healthy volunteers. Clinical studies concern patients using clopidogrel for acute coronary syndromes or because of stent implantation for stable coronary disease. Data extraction Two investigators independently reviewed the identified articles for eligibility, and one author extracted the data. Data synthesis In 70% (7/10) of the laboratory studies examining healthy volunteers on clopidogrel, addition of PPIs resulted in a significant reduction in platelet inhibition. For patients, this was observed in 11/18 (61%) studies. The 33 clinical studies showed significant heterogeneity in observed outcomes, with risk ratios for major adverse cardiovascular events varying from 0.64 to 4.58 in the case of PPI use, which was randomly allocated in only two studies. Consequently, imbalances between prognosticators at baseline and PPI prescription bias markedly contributed to the variability in results. Conclusions Despite indications of reduced antiplatelet activity ex vivo in the case of PPI administration in clopidogrel users, data on the clinical consequences are controversial. With the accumulating evidence from better designed, prospective clinical studies, an adverse effect of PPI use on clinical outcome in patients on clopidogrel cannot be substantiated. This review challenges the validity of conclusions based on quantitative analyses of predominantly non-randomised data. C1 [Focks, Jeroen Jaspers; Brouwer, Marc A.; Verheugt, Freek W. A.] Radboud Univ Nijmegen, Med Ctr, Dept Cardiol, NL-6500 HB Nijmegen, Netherlands. [van Oijen, Martijn G. H.] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [van Oijen, Martijn G. H.] Univ Calif Los Angeles, Dept Gastroenterol & Hepatol, Los Angeles, CA USA. [Lanas, Angel] Univ Zaragoza, CIBERehd, Hosp Clin, Dept Gastroenterol, Zaragoza, Spain. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Dept Cardiol, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. RP Focks, JJ (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Cardiol 670, POB 9101, NL-6500 HB Nijmegen, Netherlands. EM j.jaspersfocks@gmail.com RI Brouwer, Marc/B-1158-2014; Verheugt, F.W.A./H-8105-2014 FU AstraZeneca; Nycomed; Pfizer; Amarin; Bristol-Myers Squibb; Eisai; Ethicon; Medtronic; Sanofi Aventis; Medicines Company; Bayer AG; Roche; Eli Lilly; Boehringer Ingelheim FX MGHvO has served as a consultant for and has received unrestricted grant support from AstraZeneca, Nycomed and Pfizer; AL has served as a consultant for AstraZeneca, Pfizer and Bayer AG; DLB discloses the following relationships - Advisory Board: Medscape Cardiology; Board of Directors: Boston VA Research Institute, Society of Chest Pain Centers; Chair: American Heart Association Get With The Guidelines Science Subcommittee; Honoraria: American College of Cardiology (Editor, Clinical Trials, Cardiosource), Duke Clinical Research Institute (clinical trial steering committees), Slack Publications (Chief Medical Editor, Cardiology Today Intervention), WebMD (CME steering committees); Other: Senior Associate Editor, Journal of Invasive Cardiology; Research Grants: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company; Unfunded Research: FlowCo, PLx Pharma, Takeda, and Chair of the COGENT study. FWAV has received educational and research grants from Bayer AG, Roche, Eli Lilly and Boehringer Ingelheim and has received honoraria for consultancies from Daiichi Sankyo, Eli Lilly, Merck, The Medicines Company and Bayer AG. NR 78 TC 41 Z9 44 U1 2 U2 20 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 J9 HEART JI Heart PD APR PY 2013 VL 99 IS 8 BP 520 EP 527 DI 10.1136/heartjnl-2012-302371 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 108SX UT WOS:000316317500004 PM 22851683 ER PT J AU Smith, KR Dahl, HHM Canafoglia, L Andermann, E Damiano, J Morbin, M Bruni, AC Giaccone, G Cossette, P Saftig, P Grotzinger, J Schwake, M Andermann, F Staropoli, JF Sims, KB Mole, SE Franceschetti, S Alexander, NA Cooper, JD Chapman, HA Carpenter, S Berkovic, SF Bahlo, M AF Smith, Katherine R. Dahl, Hans-Henrik M. Canafoglia, Laura Andermann, Eva Damiano, John Morbin, Michela Bruni, Amalia C. Giaccone, Giorgio Cossette, Patrick Saftig, Paul Groetzinger, Joachim Schwake, Michael Andermann, Frederick Staropoli, John F. Sims, Katherine B. Mole, Sara E. Franceschetti, Silvana Alexander, Noreen A. Cooper, Jonathan D. Chapman, Harold A. Carpenter, Stirling Berkovic, Samuel F. Bahlo, Melanie TI Cathepsin F mutations cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis SO HUMAN MOLECULAR GENETICS LA English DT Article ID SEQUENCING DATA; VARIANTS; GENE AB Kufs disease, an adult-onset neuronal ceroid lipofuscinosis, is challenging to diagnose and genetically heterogeneous. Mutations in CLN6 were recently identified in recessive Kufs disease presenting as progressive myoclonus epilepsy (Type A), whereas the molecular basis of cases presenting with dementia and motor features (Type B) is unknown. We performed genome-wide linkage mapping of two families with recessive Type B Kufs disease and identified a single region on chromosome 11 to which both families showed linkage. Exome sequencing of five samples from the two families identified homozygous and compound heterozygous missense mutations in CTSF within this linkage region. We subsequently sequenced CTSF in 22 unrelated individuals with suspected recessive Kufs disease, and identified an additional patient with compound heterozygous mutations. CTSF encodes cathepsin F, a lysosomal cysteine protease, dysfunction of which is a highly plausible candidate mechanism for a storage disorder like ceroid lipofuscinosis. In silico modeling suggested the missense mutations would alter protein structure and function. Moreover, re-examination of a previously published mouse knockout of Ctsf shows that it recapitulates the light and electron-microscopic pathological features of Kufs disease. Although CTSF mutations account for a minority of cases of type B Kufs, CTSF screening should be considered in cases with early-onset dementia and may avoid the need for invasive biopsies. C1 [Smith, Katherine R.; Bahlo, Melanie] Walter & Eliza Hall Inst Med Res, Bioinformat Div, Melbourne, Vic 3052, Australia. [Smith, Katherine R.] Univ Melbourne, Fac Med Biol, Melbourne, Vic 3010, Australia. [Bahlo, Melanie] Univ Melbourne, Dept Math & Stat, Melbourne, Vic 3010, Australia. [Dahl, Hans-Henrik M.; Damiano, John; Berkovic, Samuel F.] Univ Melbourne, Dept Med, Epilepsy Res Ctr, Melbourne, Vic 3081, Australia. [Canafoglia, Laura; Franceschetti, Silvana] IRCCS Fdn, C Besta Neurol Inst, Unit Neurophysiopathol, I-20133 Milan, Italy. [Morbin, Michela; Giaccone, Giorgio] IRCCS Fdn, C Besta Neurol Inst, I-20133 Milan, Italy. [Andermann, Eva; Andermann, Frederick] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. [Andermann, Eva] McGill Univ, Dept Human Genet, Montreal, PQ H3A 2B4, Canada. [Andermann, Eva] McGill Univ, Neurogenet Unit, Montreal, PQ H3A 2B4, Canada. [Andermann, Frederick] McGill Univ, Epilepsy Serv, Montreal, PQ H3A 2B4, Canada. [Andermann, Frederick] McGill Univ, Seizure Clin, Montreal, PQ H3A 2B4, Canada. [Andermann, Frederick] McGill Univ, Montreal Neurol Hosp & Inst, Dept Pediat, Montreal, PQ H3A 2B4, Canada. [Bruni, Amalia C.] Azienda Sanit Prov, Lamezia Terme, Reg Neurogenet Ctr, I-88100 Catanzaro, Italy. [Cossette, Patrick] Univ Montreal, CHUM Hop Notre Dame, Dept Med, Montreal, PQ H3C 3T5, Canada. [Saftig, Paul; Groetzinger, Joachim; Schwake, Michael] Univ Kiel, Inst Biochem, D-24098 Kiel, Germany. [Staropoli, John F.; Sims, Katherine B.] Massachusetts Gen Hosp, Neurogenet DNA Diagnost Lab, Ctr Human Genet Res, Boston, MA 02114 USA. [Mole, Sara E.] UCL, UCL Inst Child Hlth, Mol Med Unit, MRC Lab Mol Cell Biol, London WC1E 6BT, England. [Mole, Sara E.] UCL, Dept Genet Evolut & Environm, London WC1E 6BT, England. [Alexander, Noreen A.; Cooper, Jonathan D.] Kings Coll London, Inst Psychiat, Kings Hlth Partners Ctr Neurodegenerat Res, Dept Neurosci,Ctr Cellular Basis Behav, London SE5 8AF, England. [Chapman, Harold A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Chapman, Harold A.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Carpenter, Stirling] Hosp Sao Joao, Serv Anat Patol, P-4200319 Oporto, Portugal. RP Berkovic, SF (reprint author), Univ Melbourne, Dept Med, Epilepsy Res Ctr, Melbourne, Vic 3081, Australia. EM s.berkovic@unimelb.edu.au; bahlo@wehi.edu.au RI Saftig, Paul/A-7966-2010; Cooper, Jonathan/C-8117-2009; Canafoglia, Laura/K-4787-2016; OI Cooper, Jonathan/0000-0003-1339-4750; Canafoglia, Laura/0000-0002-5385-761X; Morbin, Michela/0000-0001-8034-3123; Berkovic, Samuel/0000-0003-4580-841X; Mole, Sara/0000-0003-4385-4957 FU Australian Government National Health and Medical Research Council [490037, 628952, 466671]; Australian Research Council [FT100100764]; Victorian State Government; Deutsche Forschungsgemeinschaft [SFB877]; National Institutes of Health [NS41930]; Pratt Foundation; Batten Disease Support and Research Association; Natalie Fund FX This work was supported by the Australian Government National Health and Medical Research Council (490037 to M.B., 628952 and 466671 to S.F.B., the Independent Research Institute Infrastructure Support Scheme to M.B. and K.R.S.); The Australian Research Council (FT100100764 to M.B.); the Victorian State Government (Operational Infrastructure Program to M.B. and K.R.S.); the Deutsche Forschungsgemeinschaft (SFB877 to P.S., J.G. and M.S.); the National Institutes of Health (NS41930 to J.D.C.); the Pratt Foundation (to K.R.S.), The Batten Disease Support and Research Association (to S.E.M., J.D.C., J.M.S. and K.B.S.) and the Natalie Fund (to J.D.C.). NR 19 TC 34 Z9 37 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD APR 1 PY 2013 VL 22 IS 7 BP 1417 EP 1423 DI 10.1093/hmg/dds558 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 108MH UT WOS:000316297000013 PM 23297359 ER PT J AU Forman, JP Scott, JB Ng, K Drake, BF Suarez, EG Hayden, DL Bennett, GG Chandler, PD Hollis, BW Emmons, KM Giovannucci, EL Fuchs, CS Chan, AT AF Forman, John P. Scott, Jamil B. Ng, Kimmie Drake, Bettina F. Suarez, Elizabeth Gonzalez Hayden, Douglas L. Bennett, Gary G. Chandler, Paulette D. Hollis, Bruce W. Emmons, Karen M. Giovannucci, Edward L. Fuchs, Charles S. Chan, Andrew T. TI Effect of Vitamin D Supplementation on Blood Pressure in Blacks SO HYPERTENSION LA English DT Article DE black; blood pressure; hypertension; randomized controlled trial; vitamin D ID CARDIOVASCULAR RISK-FACTORS; RENIN-ANGIOTENSIN SYSTEM; PLACEBO-CONTROLLED TRIAL; PLASMA 25-HYDROXYVITAMIN D; DOUBLE-BLIND; CHOLECALCIFEROL SUPPLEMENTATION; INCIDENT HYPERTENSION; DIETARY REQUIREMENT; RANDOMIZED-TRIAL; RENAL PERFUSION AB Blacks have significantly higher rates of hypertension than whites, and lower circulating levels of 25-hydroxyvitamin D. There are few data about the effect of vitamin D3 (cholecalciferol) supplementation on blood pressure in blacks. During 2 winters from 2008 to 2010, 283 blacks (median age, 51 years) were randomized into a 4-arm, double-blind trial for 3 months of placebo, 1000, 2000, or 4000 international units of cholecalciferol per day. At baseline, 3 months, and 6 months, systolic and diastolic pressure and 25-hydroxyvitamin D were measured. The 3-month follow-up was completed in 250 (88%) participants. The difference in systolic pressure between baseline and 3 months was +1.7 mm Hg for those receiving placebo, -0.66 mm Hg for 1000 U/d, -3.4 mm Hg for 2000 U/d, and -4.0 mm Hg for 4000 U/d of cholecalciferol (-1.4 mm Hg for each additional 1000 U/d of cholecalciferol; P=0.04). For each 1-ng/mL increase in plasma 25-hydroxyvitamin D, there was a significant 0.2-mm Hg reduction in systolic pressure (P=0.02). There was no effect of cholecalciferol supplementation on diastolic pressure (P=0.37). Within an unselected population of blacks, 3 months of oral vitamin D3 supplementation significantly, yet modestly, lowered systolic pressure. Future trials of vitamin D supplementation on blood pressure are needed to confirm these promising results, particularly among blacks, a population for whom vitamin D deficiency may play a more specific mechanistic role in the pathogenesis of hypertension. (Hypertension. 2013;61:779-785.). Online Data Supplement C1 [Forman, John P.] Brigham & Womens Hosp, Div Renal, Dept Med, Boston, MA 02115 USA. [Chandler, Paulette D.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Giovannucci, Edward L.; Fuchs, Charles S.; Chan, Andrew T.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Scott, Jamil B.; Emmons, Karen M.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Ng, Kimmie; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Scott, Jamil B.; Giovannucci, Edward L.] Harvard Univ, Sch Med, Dept Nutr, Boston, MA USA. [Drake, Bettina F.] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Hayden, Douglas L.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Dept Med, Boston, MA 02114 USA. [Bennett, Gary G.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Hollis, Bruce W.] Med Univ S Carolina, Div Pediat, Charleston, SC 29425 USA. RP Forman, JP (reprint author), Brigham & Womens Hosp, Div Renal, 41 Ave Louis Pasteur,Suite 120, Boston, MA 02115 USA. EM jforman@partners.org OI Drake, Bettina/0000-0001-9340-5848 FU National Heart, Lung, and Blood Institute [5R01HL105440]; National Cancer Institute [P50CA127003, K07CA148894, K22CA126992, 5K05CA124415]; Department of Defense Prostate Cancer Research Program [PC081669]; American Society of Clinical Oncology Career Development Award; Pharmavite LLC (Mission Hill, CA) FX This trial was funded by the National Heart, Lung, and Blood Institute (5R01HL105440 [Dr Forman]), the National Cancer Institute (P50CA127003; K07CA148894 [Dr Ng]; K22CA126992; 5K05CA124415 [Dr Emmons]), the Department of Defense Prostate Cancer Research Program (PC081669 [Dr Drake]), the American Society of Clinical Oncology Career Development Award (Dr Ng), and Pharmavite LLC (Mission Hill, CA). These funding sources had no role in the conception or conduct of the study, took no part in the data collection or analysis, and had no role in the drafting, review, or approval of the article. NR 51 TC 79 Z9 82 U1 4 U2 27 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD APR PY 2013 VL 61 IS 4 BP 779 EP 785 DI 10.1161/HYPERTENSIONAHA.111.00659 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 106AC UT WOS:000316112800019 PM 23487599 ER PT J AU Kostis, WJ Cabrera, J Hooper, WC Whelton, PK Espeland, MA Cosgrove, NM Cheng, JQ Deng, YZ De Staerck, C Pyle, M Maruthur, N Reyes, I Anderson, CAM Liu, J Kostis, JB AF Kostis, William J. Cabrera, Javier Hooper, W. Craig Whelton, Paul K. Espeland, Mark A. Cosgrove, Nora M. Cheng, Jerry Q. Deng, Yingzi De Staerck, Christine Pyle, Meredith Maruthur, Nisa Reyes, Ingrid Anderson, Cheryl A. M. Liu, Jie Kostis, John B. TI Relationships Between Selected Gene Polymorphisms and Blood Pressure Sensitivity to Weight Loss in Elderly Persons With Hypertension SO HYPERTENSION LA English DT Article DE blood pressure; genetics; obesity; sodium ID SALT SENSITIVITY; NONPHARMACOLOGIC INTERVENTIONS; SODIUM REDUCTION; DIETARY-SODIUM; OLDER PERSONS; TRIAL; ASSOCIATION; PREVENTION; CONTRIBUTE; DISEASE AB Salt sensitivity, the heterogeneity in the response of blood pressure (BP) to alterations in sodium intake, has been studied extensively, whereas weight sensitivity, the heterogeneity in BP response to weight change, has received scant attention. We examined the relationship of 21 gene polymorphisms previously found to be associated with hypertension, diabetes mellitus, or obesity, with weight sensitivity in the Trial of Nonpharmacologic Interventions in the Elderly, where participants with hypertension were randomized to receive intensive dietary intervention of sodium reduction, weight loss, both, or attention control, whereas pharmacological therapy was kept constant. After correcting for multiplicity, we identified significant associations of 3 polymorphisms with weight sensitivity of systolic BP (rs4646994, rs2820037, and rs1800629) and 3 polymorphisms for diastolic BP (rs4646994, rs2820037, and rs5744292). A recursive partitioning algorithm selected the combination of rs4646994, rs1800629, rs1982073, and rs1800896 as the set associated with the highest weight sensitivity. Polymorphisms related to hypertension, obesity, and diabetes mellitus are associated with weight sensitivity of BP. (Hypertension. 2013;61:857-863.) circle Online Data Supplement C1 [Kostis, William J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Cabrera, Javier; Reyes, Ingrid; Liu, Jie] Rutgers State Univ, Dept Stat, Piscataway, NJ USA. [Cabrera, Javier; Cosgrove, Nora M.; Cheng, Jerry Q.; Deng, Yingzi; Kostis, John B.] UMDNJ Robert Wood Johnson Med Sch, Cardiovasc Inst, New Brunswick, NJ USA. [Hooper, W. Craig; De Staerck, Christine; Pyle, Meredith] Ctr Dis Control & Prevent, Atlanta, GA USA. [Whelton, Paul K.] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Espeland, Mark A.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Maruthur, Nisa] Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD USA. [Maruthur, Nisa; Anderson, Cheryl A. M.] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. RP Kostis, WJ (reprint author), Massachusetts Gen Hosp, 55 Fruit St,GRB 800, Boston, MA 02114 USA. EM wkostis@partners.org FU National Institute on Aging; National Heart, Lung, and Blood Institute; Robert Wood Johnson Foundation FX This study was supported, in part, by the National Institute on Aging, the National Heart, Lung, and Blood Institute, and the Robert Wood Johnson Foundation. NR 34 TC 6 Z9 6 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD APR PY 2013 VL 61 IS 4 BP 857 EP + DI 10.1161/HYPERTENSIONAHA.111.00712 PG 23 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 106AC UT WOS:000316112800030 PM 23438931 ER PT J AU Ma, JQ Chen, W Zhang, LJ Tucker, B Zhu, GC Sasaki, H Hao, L Wang, L Ci, HL Jiang, HB Stashenko, P Li, YP AF Ma, Junqing Chen, Wei Zhang, Lijie Tucker, Byron Zhu, Guochun Sasaki, Hajime Hao, Liang Wang, Lin Ci, Hongliang Jiang, Hongbing Stashenko, Philip Li, Yi-Ping TI RNA Interference-Mediated Silencing of Atp6i Prevents Both Periapical Bone Erosion and Inflammation in the Mouse Model of Endodontic Disease SO INFECTION AND IMMUNITY LA English DT Article ID PERIODONTAL-LIGAMENT CELLS; MICRO-COMPUTED TOMOGRAPHY; T-CELL; IN-VITRO; OSTEOCLAST DIFFERENTIATION; APICAL PERIODONTITIS; PARKINSONS-DISEASE; ROOT RESORPTION; B-LYMPHOCYTE; DENTAL-PULP AB Dental caries is one of the most prevalent infectious diseases in the United States, affecting approximately 80% of children and the majority of adults. Dental caries may lead to endodontic disease, where the bacterial infection progresses to the root canal system of the tooth, leading to periapical inflammation, bone erosion, severe pain, and tooth loss. Periapical inflammation may also exacerbate inflammation in other parts of the body. Although conventional clinical therapies for this disease are successful in approximately 80% of cases, there is still an urgent need for increased efficacy of treatment. In this study, we applied a novel gene-therapeutic approach using recombinant adeno-associated virus (AAV)-mediated Atp6i RNA interference (RNAi) knockdown of Atp6i/TIRC7 gene expression to simultaneously target periapical bone resorption and periapical inflammation. We found that Atp6i inhibition impaired osteoclast function in vitro and in vivo and decreased the number of T cells in the periapical lesion. Notably, AAV-mediated Atp6i/TIRC7 knockdown gene therapy reduced bacterial infection-stimulated bone resorption by 80% in the mouse model of endodontic disease. Importantly, Atp6i(+/-) mice with haploinsufficiency of Atp6i exhibited protection similar to that in mice with bacterial infection-stimulated bone erosion and periapical inflammation, which confirms the potential therapeutic effect of AAV-small hairpin RNA (shRNA)-Atp6i/TIRC7. Our results demonstrate that AAV-mediated Atp6i/TIRC7 knockdown in periapical tissues can inhibit endodontic disease development, bone resorption, and inflammation, indicating for the first time that this potential gene therapy may significantly improve the health of those who suffer from endodontic disease. C1 [Ma, Junqing; Chen, Wei; Tucker, Byron; Zhu, Guochun; Hao, Liang; Ci, Hongliang; Jiang, Hongbing; Li, Yi-Ping] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Ma, Junqing; Wang, Lin; Jiang, Hongbing] Nanjing Med Univ, Inst Stomatol, Nanjing, Jiangsu, Peoples R China. [Zhang, Lijie; Sasaki, Hajime; Stashenko, Philip] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. [Tucker, Byron] Harvard Univ, Dept Restorat Dent Endodont, Sch Dent Med, Owings Mills, MD USA. RP Li, YP (reprint author), Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. EM wechen@uab.edu; ypli@uab.edu FU NIH [RC1-DE-020533, R01-AR-055307] FX This work was supported by NIH grants RC1-DE-020533 (Y.P.L.) and R01-AR-055307 (Y.P.L.). NR 46 TC 11 Z9 12 U1 0 U2 20 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD APR PY 2013 VL 81 IS 4 BP 1021 EP 1030 DI 10.1128/IAI.00756-12 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 108RM UT WOS:000316313700001 PM 23166162 ER PT J AU Biswas, A Kobayashi, KS AF Biswas, Amlan Kobayashi, Koichi S. TI Regulation of intestinal microbiota by the NLR protein family SO INTERNATIONAL IMMUNOLOGY LA English DT Review DE Crohns disease; inflammasome; NLRP6; NOD2; microbiome ID INFLAMMATORY-BOWEL-DISEASE; NF-KAPPA-B; ILEAL CROHNS-DISEASE; TOLL-LIKE RECEPTORS; EPITHELIAL-CELLS; PANETH CELLS; DENDRITIC CELLS; INNATE IMMUNITY; NOD2; EXPRESSION AB Regulation of intestinal microbiota by NLR proteins.The human intestine harbors a diverse microbial community consisting of a large number of bacteria and other micro-organisms that have co-evolved with the host intestinal immune system. During this process, microbiota and the host immune system shape one another by various mechanisms to achieve a successful symbiotic relationship. An increasing amount of evidence suggests that dysbiosisuthe breakdown of such harmonized colonizationumay result in infectious and inflammatory disorders, and recent advances in our studies indicate that receptors such as Toll-like receptors and NLR (nucleotide-binding oligomerization domain-like receptor; or nucleotide-binding domain- and leucine-rich repeat-containing receptor) proteins that detect micro-organisms and their products play a critical role in maintaining intestinal homeostasis. In this review, we summarize the role of NLR proteins in the regulation of intestinal microbiota. NLR proteins belong to a diverse family of cytoplasmic microbial sensors, mutations of which are involved in various disorders, including inflammatory bowel diseases. Understanding of the different roles of NLR family proteins in the intestine is, therefore, an important step towards the development of therapeutics against digestive diseases. C1 [Biswas, Amlan; Kobayashi, Koichi S.] Texas A&M Hlth Sci Ctr, Dept Microbial & Mol Pathogenesis, College Stn, TX 77843 USA. [Biswas, Amlan; Kobayashi, Koichi S.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Biswas, Amlan; Kobayashi, Koichi S.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02215 USA. RP Kobayashi, KS (reprint author), Texas A&M Hlth Sci Ctr, Coll Med, Dept Microbial & Mol Pathogenesis, 415A Reynolds Med Bldg, College Stn, TX 77843 USA. EM kobayashi@medicine.tamhsc.edu FU National Institutes of Health [R01DK074738]; Broad Medical Research Program of the Eli and Edythe L. Broad Foundations [IBD-0328]; Cancer Research Institute; Claudia Adams Barr Award; Crohn's and Colitis Foundation of America FX National Institutes of Health (R01DK074738 to K.S.K.); the Broad Medical Research Program of the Eli and Edythe L. Broad Foundations (IBD-0328 to K.S.K.). K.S.K. is a recipient of the Investigator Award from the Cancer Research Institute and the Claudia Adams Barr Award. A.B. is a recipient of fellowship from the Crohn's and Colitis Foundation of America. NR 73 TC 12 Z9 12 U1 0 U2 32 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD APR PY 2013 VL 25 IS 4 BP 207 EP 214 DI 10.1093/intimm/dxs116 PG 8 WC Immunology SC Immunology GA 108KQ UT WOS:000316292200001 PM 23325116 ER PT J AU Mondolfi, AEP Duffey, GB Horton, LE Tirado, M Jaimes, OR Perez-Alvarez, A Zerpa, O AF Paniz Mondolfi, Alberto E. Duffey, Gabrielle Baker Horton, Lucy E. Tirado, Mariantonieta Reyes Jaimes, Oscar Perez-Alvarez, Alexandra Zerpa, Olga TI Intermediate/borderline disseminated cutaneous leishmaniasis SO INTERNATIONAL JOURNAL OF DERMATOLOGY LA English DT Article ID NEW-WORLD; MUCOCUTANEOUS LEISHMANIASIS; RISK-FACTORS; SPECTRUM; CLASSIFICATION; CHEMOTHERAPY; AMAZONENSIS; VENEZUELA; TRAVELERS; FEATURES AB Leishmaniasis is a diverse group of vector-borne diseases caused by a subset of predominantly intracellular protozoal species of the genus Leishmania. Cutaneous disease may be subdivided into localized, intermediate, and diffuse forms. Intermediate cutaneous leishmaniasis is distributed widely in Latin America and is characterized by cutaneous lesions, which may be accompanied by mucosal disease and demonstrate a tendency toward chronicity and relapse as well as resistance to standard treatment regimens. Leishmania parasites of the subgenus Viannia have been identified as the major etiologic agent of this subset of infections. The present review provides a brief perspective on leishmaniasis followed by a review of classification, transmission, clinical presentation, and evolution of disease, immunology, and current treatment approaches for the intermediate/borderline disseminated subset of cutaneous leishmaniasis. C1 [Paniz Mondolfi, Alberto E.; Horton, Lucy E.] Tufts Med Ctr, Dept Dermatol, Boston, MA USA. [Paniz Mondolfi, Alberto E.; Horton, Lucy E.] Miraca Life Sci, Boston, MA USA. [Paniz Mondolfi, Alberto E.; Perez-Alvarez, Alexandra] UCV IVSS, Lab Bioquim, Inst Biomed, Caracas, Venezuela. [Duffey, Gabrielle Baker] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Tirado, Mariantonieta] Baptist Hlth Syst, Dept Pathol, Birmingham, AL USA. [Reyes Jaimes, Oscar] UCV MSDS, Dept Dermatopatol, Inst Biomed, Caracas, Venezuela. [Zerpa, Olga] UCV MSDS, Secc Leishmaniasis, Inst Biomed, Caracas, Venezuela. RP Mondolfi, AEP (reprint author), Tufts Med Ctr, Dept Dermatol, Boston, MA USA. EM albertopaniz@yahoo.com NR 53 TC 9 Z9 9 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0011-9059 EI 1365-4632 J9 INT J DERMATOL JI Int. J. Dermatol. PD APR PY 2013 VL 52 IS 4 BP 446 EP 455 DI 10.1111/j.1365-4632.2012.05709.x PG 10 WC Dermatology SC Dermatology GA 108WS UT WOS:000316327500010 ER PT J AU Esfahani, SA Close, C Yousefzadeh, DK AF Esfahani, Shadi Abdar Close, Clare Yousefzadeh, David K. TI Side-to-side and interpolar renal duplications: the nonpolar variety SO INTERNATIONAL UROLOGY AND NEPHROLOGY LA English DT Article DE Duplication; Kidney; Nonpolar; Variation; Intravenous pyelogram ID URETERAL QUADRUPLICATION; KIDNEY; TRIPLICATION; CHILDREN; GIRLS AB The Weigert-Meyer rule predicts the draining pattern of duplex ureters in bipolar renal duplications. This paper introduces two cases of nonpolar renal duplication. A 3-month-old and a 15-year-old female with history of urinary tract infection were evaluated with intravenous pyelograms (IVP) and eleven different parameters were analyzed. The infant's IVP showed an unobstructed side-to-side right renal duplication with normal-sized nondisplaced lateral moiety and a complete set of calyces, without drooping lily sign. The nonobstructed moiety projected medial and mildly inferior to the lateral moiety which had normal height and axis. The ureters joined each other in lower abdomen. Severe platyspondyly was noted due to hyperalimentation-induced metabolic bone disease. The second case had an unobstructed interpolar extra moiety between the upper and the lower poles with an otherwise unobstructed, normally sized single-system kidney, without drooping lily sign. The paradigm shift from classic anatomic to contemporary cell biological theory validates the nonpolar renal duplication concept, with side-to-side and interpolar arrangements of the moieties, in defiance of Weigert-Meyer rule. C1 [Esfahani, Shadi Abdar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Close, Clare] Close Pediat Urol Ctr, Henderson, NV USA. [Yousefzadeh, David K.] Univ Chicago, Dept Pediat, Comers Children Hosp, Chicago, IL 60076 USA. [Yousefzadeh, David K.] Univ Chicago, Dept Radiol, Comers Children Hosp, Chicago, IL 60076 USA. RP Yousefzadeh, DK (reprint author), Univ Chicago, Dept Pediat, Comers Children Hosp, 8900 Little Elm Bend Skokie, Chicago, IL 60076 USA. EM dyousefz@yahoo.com NR 25 TC 0 Z9 0 U1 1 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-1623 J9 INT UROL NEPHROL JI Int. Urol. Nephrol. PD APR PY 2013 VL 45 IS 2 BP 333 EP 338 DI 10.1007/s11255-013-0383-5 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 108YZ UT WOS:000316333600006 PM 23381502 ER PT J AU Schwartz, GK Carvajal, RD Midgley, R Rodig, SJ Stockman, PK Ataman, O Wilson, D Das, S Shapiro, GI AF Schwartz, Gary K. Carvajal, Richard D. Midgley, Rachel Rodig, Scott J. Stockman, Paul K. Ataman, Ozlem Wilson, David Das, Shampa Shapiro, Geoffrey I. TI Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Barasertib; AZD1152; Aurora B kinase; Solid tumors; Phase I; Pharmacokinetics ID ACUTE MYELOID-LEUKEMIA; CELL LUNG-CARCINOMA; TARGETS; CANCER; PHARMACOKINETICS; OVEREXPRESSION; EFFICACY; FREQUENT; GROWTH; SAFETY AB The purpose of this study was to determine the maximum-tolerated dose (MTD), pharmacokinetics and safety profile for two different dosing regimens of barasertib, a selective inhibitor of Aurora B Kinase. In this Phase I trial, patients with advanced solid malignancies were treated with escalating doses of barasertib, administered as either a 48-h continuous infusion or as two 2-h infusions on consecutive days, both every 14 days of a 28-day cycle. Thirty-five patients were treated. The MTDs were 150 mg as a 48-h continuous infusion and 220 mg administered as two 2-h infusions (110 mg/day, days 1, 2, 15 and 16), with neutropenia the dose-limiting toxicity (DLT) of each schedule. Common Terminology Criteria of Adverse Events (CTCAE) grade a parts per thousand yenaEuro parts per thousand 3 neutropenia (with or without fever) occurred in 34 % of patients overall. Other adverse events, many of hematologic or gastrointestinal etiology, were of mild or moderate intensity. No objective tumor responses were observed, although stable disease was observed in 23 % of patients. Systemic exposure to barasertib-hQPA, the more active moiety to which barasertib is converted, was observed by 1 and 6 h into the 2-h and continuous infusion, respectively, and exhibited linear pharmacokinetics. In summary, barasertib was generally well tolerated, with neutropenia the most frequent and dose-limiting toxicity, irrespective of schedule. Future development of barasertib will depend on better definition of its therapeutic index. C1 [Schwartz, Gary K.; Carvajal, Richard D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Midgley, Rachel] Univ Oxford, Dept Oncol, Oxford, England. [Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Stockman, Paul K.; Ataman, Ozlem; Wilson, David; Das, Shampa] AstraZeneca, Macclesfield, Cheshire, England. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Dept Med Oncol, Early Drug Dev Ctr, Boston, MA 02215 USA. RP Schwartz, GK (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. EM schwartzg@mskcc.org; geoffrey_shapiro@dfci.harvard.edu FU AstraZeneca FX We thank Merran Macpherson of AstraZeneca UK Ltd. Clinical Pharmacology Science, for assistance with interpretation of pharmacokinetic assessments. We also thank the study teams at Memorial Sloan-Kettering Cancer Center and the Dana-Farber Cancer Institute, including Andrew Wolanski NP, Tracy Bell RN and Sarah Scofield. Editorial assistance was provided by Dr. Zoe van Helmond from Mudskipper Bioscience, funded by AstraZeneca. NR 30 TC 26 Z9 27 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD APR PY 2013 VL 31 IS 2 BP 370 EP 380 DI 10.1007/s10637-012-9825-7 PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 105OQ UT WOS:000316081900013 PM 22661287 ER PT J AU Ott, PA Carvajal, RD Pandit-Taskar, N Jungbluth, AA Hoffman, EW Wu, BW Bomalaski, JS Venhaus, R Pan, LD Old, LJ Pavlick, AC Wolchok, JD AF Ott, Patrick A. Carvajal, Richard D. Pandit-Taskar, Neeta Jungbluth, Achim A. Hoffman, Eric W. Wu, Bor-Wen Bomalaski, John S. Venhaus, Ralph Pan, Linda Old, Lloyd J. Pavlick, Anna C. Wolchok, Jedd D. TI Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE Melanoma; Metastatic; Auxotrophy; Arginine deiminase; Argininosuccinate synthetase ID METASTATIC MELANOMA; ARGININOSUCCINATE SYNTHETASE; HEPATOCELLULAR-CARCINOMA; MALIGNANT-MELANOMA; PLUS DACARBAZINE; IN-VIVO; DEPRIVATION; CANCER; INHIBITION; THERAPY AB Background Arginine deiminase (ADI) is an enzyme that degrades arginine, an amino acid that is important for growth and development of normal and neoplastic cells. Melanoma cells are auxotrophic for arginine, because they lack argininosuccinatesynthetase (ASS), a key enzyme required for the synthesis of arginine. Patients and methods Patients with advanced melanoma were treated with 40, 80 or 160 IU/m(2) ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by (18)FDG-PET, pharmacodynamic (PD) effects upon circulating arginine levels, and argininosuccinate synthetase tumor expression by immunohistochemistry. Results 31 previously treated patients were enrolled. The main toxicities were grade 1 and 2 adverse events including injection site pain, rash, and fatigue. No objective responses were seen. Nine patients achieved stable disease (SD), with 2 of these durable for > 6 months. Four of the 9 patients with SD had uveal melanoma. PD analysis showed complete plasma arginine depletion in 30/31 patients by day 8. Mean plasma levels of ADI-PEG 20 correlated inversely with ADI-PEG 20 antibody levels. Immunohistochemical ASS expression analysis in tumor tissue was negative in 24 patients, whereas 5 patients had < 5 % cells positive. Conclusions ADI-PEG 20 is well tolerated in advanced melanoma patients and leads to consistent, but transient, arginine depletion. Although no RECIST responses were observed, the encouraging rate of SD in uveal melanoma patients indicates that it may be worthwhile to evaluate ADI-PEG 20 in this melanoma subgroup. C1 [Ott, Patrick A.; Pavlick, Anna C.] NYU, Sch Med, Dept Med Oncol, New York, NY USA. [Carvajal, Richard D.; Pandit-Taskar, Neeta; Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Jungbluth, Achim A.; Hoffman, Eric W.; Venhaus, Ralph; Pan, Linda; Old, Lloyd J.; Wolchok, Jedd D.] Branch Mem Sloan Kettering Canc Ctr, Ludwig Inst Canc Res, New York, NY USA. [Wu, Bor-Wen; Bomalaski, John S.] Polaris Pharmaceut, San Diego, CA USA. [Ott, Patrick A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Melanoma Dis Ctr, Boston, MA 02215 USA. RP Ott, PA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Melanoma Dis Ctr, 450 Brookline Ave, Boston, MA 02215 USA. EM Patrick_Ott@dfci.harvard.edu FU NCI NIH HHS [P30 CA008748] NR 33 TC 39 Z9 41 U1 0 U2 14 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD APR PY 2013 VL 31 IS 2 BP 425 EP 434 DI 10.1007/s10637-012-9862-2 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 105OQ UT WOS:000316081900019 PM 22864522 ER PT J AU Williams, DL Goldstein, G Minshew, NJ AF Williams, Diane L. Goldstein, Gerald Minshew, Nancy J. TI The Modality Shift Experiment in Adults and Children with High Functioning Autism SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism; Attentional shifting; Speed of processing; Perceptual development ID DIAGNOSTIC OBSERVATION SCHEDULE; SPECTRUM DISORDER; COGNITIVE-STYLE; YOUNG-CHILDREN; ATTENTION; DISENGAGEMENT; DYSFUNCTION; INTERVIEW; DEFICITS AB This study used the modality shift experiment, a relatively simple reaction time measure to visual and auditory stimuli, to examine attentional shifting within and across modalities in 33 children and 42 adults with high-functioning autism as compared to matched numbers of age- and ability-matched typical controls. An exaggerated "modality shift effect" relative to the TD children occurred for the children with autism in conditions involving the reaction time when shifting from sound to light but not from light to sound. No exaggerated MSE was found for the adults with autism; rather, their responses were characterized by a generalized slowness relative to the adults with TD. These results suggest a lag in maturational development in autism in basic information processing mechanisms. C1 [Williams, Diane L.] Duquesne Univ, Dept Speech Language Pathol, Pittsburgh, PA 15219 USA. [Goldstein, Gerald] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15206 USA. [Goldstein, Gerald] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15206 USA. [Minshew, Nancy J.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15206 USA. [Minshew, Nancy J.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15206 USA. RP Goldstein, G (reprint author), VA Pittsburgh Healthcare Syst, 7180 Highland Dr 151R, Pittsburgh, PA 15206 USA. EM williamsd2139@duq.edu; ggold@nb.net RI Williams, Diane/B-4128-2017 FU NICHD NIH HHS [P50 HD055748, P01 HD035469, HD35469, HD055748, U19 HD035469]; NIDCD NIH HHS [K23DC006691, K23 DC006691]; NINDS NIH HHS [R01 NS033355] NR 52 TC 7 Z9 7 U1 2 U2 12 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD APR PY 2013 VL 43 IS 4 BP 794 EP 806 DI 10.1007/s10803-012-1618-5 PG 13 WC Psychology, Developmental SC Psychology GA 109KG UT WOS:000316365400005 PM 22865151 ER PT J AU Cidav, Z Lawer, L Marcus, SC Mandell, DS AF Cidav, Zuleyha Lawer, Lindsay Marcus, Steven C. Mandell, David S. TI Age-Related Variation in Health Service Use and Associated Expenditures Among Children with Autism SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism; Economics; Cost; Expenditures; Utilization; Medicaid; Age variation ID PSYCHOTROPIC MEDICATION USE; SPECTRUM DISORDERS; PSYCHIATRIC-HOSPITALIZATION; CARE EXPENDITURES; ELIGIBLE CHILDREN; ENROLLED CHILDREN; ADULTS; DIAGNOSIS; COSTS; INDIVIDUALS AB This study examined differences by age in service use and associated expenditures during 2005 for Medicaid-enrolled children with autism spectrum disorders. Aging was associated with significantly higher use and costs for restrictive, institution-based care and lower use and costs for community-based therapeutic services. Total expenditures increased by 5 % with each year of age; by 23 % between 3-5 and 6-11 year olds, 23 % between 6-11 and 12-16, and 14 % between 12-16 and 17-20 year olds. Use of and expenditures for long-term care, psychiatric medications, case management, medication management, day treatment/partial hospitalization, and respite services increased with age; use of and expenditures for occupational/physical therapy, speech therapy, mental health services, diagnostic/assessment services, and family therapy declined. C1 [Cidav, Zuleyha; Lawer, Lindsay; Mandell, David S.] Univ Penn, Childrens Hosp Philadelphia, Ctr Mental Hlth Policy & Serv Res, Ctr Autism Res,Perelman Sch Med, Philadelphia, PA 19104 USA. [Marcus, Steven C.] Univ Penn, Ctr Hlth Equ Res & Promot, Philadelphia Vet Affairs Med Ctr, Sch Social Policy & Practice, Philadelphia, PA 19104 USA. RP Cidav, Z (reprint author), Univ Penn, Childrens Hosp Philadelphia, Ctr Mental Hlth Policy & Serv Res, Ctr Autism Res,Perelman Sch Med, Philadelphia, PA 19104 USA. EM zcidav@upenn.edu RI Mandell, David/H-2730-2012 OI Mandell, David/0000-0001-8240-820X FU NIMH NIH HHS [R01 MH077000] NR 39 TC 20 Z9 20 U1 2 U2 31 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD APR PY 2013 VL 43 IS 4 BP 924 EP 931 DI 10.1007/s10803-012-1637-2 PG 8 WC Psychology, Developmental SC Psychology GA 109KG UT WOS:000316365400017 PM 22941343 ER PT J AU Schmidt, K Zimmerman, A Bauman, M Ferrone, C Venter, J Spybrook, J Henry, C AF Schmidt, Karmen Zimmerman, Andrew Bauman, Margaret Ferrone, Christine Venter, Jacob Spybrook, Jessaca Henry, Charles TI Brief Report: Asperger's Syndrome and Sibling Birth Order SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Asperger's syndrome; Pervasive developmental disorders; Birth order; Epidemiology ID AUTISM SPECTRUM DISORDERS; RISK-FACTORS; FETAL-BRAIN; OBSTETRIC COMPLICATIONS; AUTOIMMUNE-DISEASES; PERINATAL FACTORS; PREGNANCY; CHILDREN; AGE; ANTIBODIES AB Prior investigations suggest that birth order position may be associated with the risk for developing a pervasive developmental disorder. This retrospective chart review examined the birth order status of 29 psychiatrically-referred patients with Asperger's Syndrome (AS). Eighty-six percent of the subjects were first born. The finding was statistically significant when compared to an expected random distribution of AS subjects chi(2) (1, N = 29) = 9.18, p < 0.01. The reasons for such an association are unclear though birth stoppage, obstetric complications, and immunological mechanisms may play a role. C1 [Schmidt, Karmen; Zimmerman, Andrew; Bauman, Margaret; Ferrone, Christine] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Venter, Jacob; Henry, Charles] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Spybrook, Jessaca] Western Michigan Univ, Evaluat Measurement & Res Dept, Kalamazoo, MI 49008 USA. [Henry, Charles] Lurie Ctr, Lexington, MA 02421 USA. RP Henry, C (reprint author), Lurie Ctr, 1 Maguire Rd, Lexington, MA 02421 USA. EM charles_henry@hms.harvard.edu NR 55 TC 2 Z9 2 U1 1 U2 16 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 EI 1573-3432 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD APR PY 2013 VL 43 IS 4 BP 973 EP 977 DI 10.1007/s10803-012-1620-y PG 5 WC Psychology, Developmental SC Psychology GA 109KG UT WOS:000316365400021 PM 22872214 ER PT J AU Ai, AL Hall, D Pargament, K Tice, TN AF Ai, Amy L. Hall, Daniel Pargament, Kenneth Tice, Terrence N. TI Posttraumatic growth in patients who survived cardiac surgery: the predictive and mediating roles of faith-based factors SO JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Posttraumatic growth; Cardiovascular diseases and surgery; Religion; faith; and spiritual support; Social support; Optimism and hope ID PERCEIVED SOCIAL SUPPORT; CORONARY-HEART-DISEASE; BREAST-CANCER PATIENTS; ARTERY-BYPASS SURGERY; QUALITY-OF-LIFE; PSYCHOLOGICAL ADJUSTMENT; RELIGIOUS INVOLVEMENT; DEPRESSIVE SYMPTOMS; COPING STRATEGIES; GRAFT-SURGERY AB Despite the growing knowledge of posttraumatic growth, only a few studies have examined personal growth in the context of cardiac health. Similarly, longitudinal research is lacking on the implications of religion/spirituality for patients with advanced cardiac diseases. This paper aims to explore the effect of preoperative religious coping on long-term postoperative personal growth and potential mediation in this effect. Analyses capitalized on a preoperative survey and medical indices from the Society of Thoracic Surgeons' National Database of patients undergoing cardiac surgery. Participants in the current follow-up study completed a mailed survey 30 months after surgery. Hierarchical regression analysis was performed to evaluate the extent to which preoperative use of religious coping predicted growth at follow-up, after controlling for key demographics, medical indices, mental health, and protective factors. Predictors of posttraumatic growth at follow-up were positive religious coping and a living status without a partner. Medical indices, optimistic expectations, social support, and other religious factors were unrelated to posttraumatic growth. Including religious factors diminished effects of gender, age, and race. Including perceived spiritual support completely eliminated the role of positive religious coping, indicating mediation. Preoperative positive religious coping may have a long-term effect on postoperative personal growth, explainable by higher spiritual connections as a part of significance-making. These results suggest that spirituality may play a favorable role in cardiac patients' posttraumatic growth after surviving a life-altering operation. The elimination of demographic effects may help explain previously mixed findings concerning the association between these factors and personal growth. C1 [Ai, Amy L.] Florida State Univ, Tallahassee, FL 32306 USA. [Hall, Daniel] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Pargament, Kenneth] Bowling Green State Univ, Bowling Green, OH 43403 USA. [Tice, Terrence N.] Iliff Univ Theol, Denver, CO USA. RP Ai, AL (reprint author), Florida State Univ, FL 2313,Univ Ctr Bldg C, Tallahassee, FL 32306 USA. EM amyai8@gmail.com RI Hall, Daniel/H-4843-2013; OI Hall, Daniel/0000-0001-6382-0522 FU NCCIH NIH HHS [P50 AT00011]; PHS HHS [1 RO3 AGO 15686-01] NR 70 TC 5 Z9 6 U1 3 U2 20 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0160-7715 J9 J BEHAV MED JI J. Behav. Med. PD APR PY 2013 VL 36 IS 2 BP 186 EP 198 DI 10.1007/s10865-012-9412-6 PG 13 WC Psychology, Clinical SC Psychology GA 109RG UT WOS:000316385600008 PM 22460360 ER PT J AU Oral, E Neils, AL Rowell, SL Lozynsky, AJ Muratoglu, OK AF Oral, Ebru Neils, Andrew L. Rowell, Shannon L. Lozynsky, Andrew J. Muratoglu, Orhun K. TI Increasing irradiation temperature maximizes vitamin E grafting and wear resistance of ultrahigh molecular weight polyethylene SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS LA English DT Article DE wear; vitamin E; joint implants; crosslinking; grafting; oxidation ID CROSS-LINKED POLYETHYLENE; TOTAL HIP-ARTHROPLASTY; ALPHA-TOCOPHEROL; MECHANICAL-PROPERTIES; FOLLOW-UP; UHMWPE; RADIATION; COMPONENTS; OXIDATION; IMPLANTS AB Vitamin E stabilization of radiation crosslinked ultrahigh molecular weight polyethylene (UHMWPE) for total joint implants can be done by blending of UHMWPE resin powder with vitamin E, followed by consolidation and irradiation of the blend. It is well known that vitamin E prevents crosslinking in UHMWPE during ionizing radiation. We hypothesized that there would also be a significant amount of grafting of vitamin E onto UHMWPE during irradiation. Spectroscopic analysis of radiation crosslinked vitamin E-blended UHMWPE before and after extraction with boiling hexane showed vitamin E grafting in up to 30% of the blended vitamin E. Grafting increased with irradiation temperature. We also discovered that increasing irradiation temperature resulted in better preservation of active vitamin E in the polymer and increased crosslinking efficiency of UHMWPE. As a result, warm-irradiated vitamin E-blended UHMWPEs had significantly less wear than those irradiated at ambient temperature. It may be desirable to graft vitamin E on UHMWPE to decrease the possibility of elution and increase long-term stability. Warm irradiation of vitamin E blends may present an advantage in increasing vitamin E potency, as well as decreasing the wear of UHMWPE, which is crucial in decreasing the incidence of periprosthetic osteolysis in total joint replacement patients. (c) 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 101B: 436440, 2013. C1 [Oral, Ebru; Rowell, Shannon L.; Lozynsky, Andrew J.; Muratoglu, Orhun K.] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Oral, Ebru; Neils, Andrew L.; Muratoglu, Orhun K.] Harvard Univ, Sch Med, Dept Orthopaed Surg, Boston, MA USA. RP Oral, E (reprint author), Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. EM eoral@partners.org NR 29 TC 15 Z9 16 U1 0 U2 33 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4973 J9 J BIOMED MATER RES B JI J. Biomed. Mater. Res. Part B PD APR PY 2013 VL 101B IS 3 BP 436 EP 440 DI 10.1002/jbm.b.32807 PG 5 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 112DY UT WOS:000316573600007 PM 23115033 ER PT J AU Fan, XD Liu, E Freudenreich, O Copeland, P Hayden, D Ghebremichael, M Cohen, B Ongur, D Goff, DC Henderson, DC AF Fan, Xiaoduo Liu, Emily Freudenreich, Oliver Copeland, Paul Hayden, Douglas Ghebremichael, Musie Cohen, Bruce Ongur, Dost Goff, Donald C. Henderson, David C. TI No Effect of Adjunctive, Repeated-Dose Intranasal Insulin Treatment on Psychopathology and Cognition in Patients With Schizophrenia SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE intranasal; insulin; schizophrenia; psychopathology; cognition ID CENTRAL-NERVOUS-SYSTEM; PIK3C3 PROMOTER VARIANT; CAENORHABDITIS-ELEGANS; RAT HIPPOCAMPUS; PHENCYCLIDINE; LOCALIZATION; DELIVERY; THERAPY; INHIBITION; MODULATION AB Objective: This study examined the effect of adjunctive intranasal insulin therapy on psychopathology and cognition in patients with schizophrenia. Methods: Each subject had a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia or schizo-affective disorder and been on stable antipsychotics for at least 1 month. In an 8-week randomized, double-blind, placebo-controlled study, subjects received either intranasal insulin (40 IU 4 times per day) or placebo. Psychopathology was assessed using the Positive and Negative Syndrome Scale and the Scale for Assessment of Negative Symptoms. A neuropsychological battery was used to assess cognitive performance. The assessment for psychopathology and cognition was conducted at baseline, week 4, and week 8. Results: A total of 45 subjects were enrolled in the study (21 in the insulin group and 24 in the placebo group). The mixed model analysis showed that there were no significant differences between the 2 groups at week 8 on various psychopathology and cognitive measures (P > 0.1). Conclusions: Adjunctive therapy with intranasal insulin did not seem to be beneficial in improving schizophrenia symptoms or cognition in the present study. The implications for future studies were discussed. C1 [Fan, Xiaoduo] UMass Mem Med Ctr, Psychot Disorders Program, Worcester, MA USA. [Fan, Xiaoduo] Univ Massachusetts, Sch Med, Worcester, MA USA. [Liu, Emily] Partners Community Healthcare Inc, Haverhill, MA USA. [Freudenreich, Oliver; Goff, Donald C.; Henderson, David C.] Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. [Freudenreich, Oliver; Copeland, Paul; Ghebremichael, Musie; Cohen, Bruce; Ongur, Dost; Goff, Donald C.; Henderson, David C.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Copeland, Paul] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hayden, Douglas] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Ghebremichael, Musie] Ragon Inst MGH MIT & Harvard, Charlestown, MA USA. [Cohen, Bruce; Ongur, Dost] McLean Hosp, Belmont, MA 02178 USA. RP Fan, XD (reprint author), Suite 100,365 Plantat St, Worcester, MA 01605 USA. EM xiaoduo.fan@umassmed.edu FU National Institutes of Health [5K23MH082098]; NARSAD Young Investigator Award; National Institutes of Health, National Center for Research Resources General Clinical Research Centers Program (MGH Clinical research Center) [M01-RR-01066, UL1 RR025758-01]; Eli Lilly and Company; AstraZeneca; Bristol-Myer Squibb; Janssen; Eli Lilly; Cephalon; Pfizer; Bristol-Myers Squibb; Indevus Pharmaceuticals; H. Lundbeck; Schering-Plough; Takeda; Biovail; Sovay; Hoffman-La Roche; Cypress; Dainippon Sumitomo; Abbott Laboratories; Genentech; Novartis; PamLab; GlaxoSmithKline; Endo Pharmaceuticals; Solvay; Covance; Alkermis FX This study was supported by Grant 5K23MH082098 from the National Institutes of Health (Dr Fan), the NARSAD Young Investigator Award (Dr Fan), Grant M01-RR-01066 and Grant UL1 RR025758-01 from the National Institutes of Health, National Center for Research Resources General Clinical Research Centers Program (MGH Clinical research Center), and an investigator initiated trial grant from Eli Lilly and Company (Dr Fan).; Dr Fan has received research support or honoraria from Eli Lilly, AstraZeneca, Bristol-Myer Squibb, Janssen, and Pfizer. Dr Freudenreich has received research support or honoraria from AstraZeneca, Bristol-Myer Squibb, Janssen, Eli Lilly, Cephalon, and Pfizer. Dr Goff has received research support or honoraria from Bristol-Myers Squibb, Indevus Pharmaceuticals, H. Lundbeck, Schering-Plough, Eli Lilly, Takeda, Biovail, Sovay, Hoffman-La Roche, Cypress, Dainippon Sumitomo, Abbott Laboratories, Genentech, Pfizer, Janssen, Novartis, PamLab, and GlaxoSmithKline, and Endo Pharmaceuticals. He served on a DSMB for Otsuka. Dr Henderson has received research support or honoraria from Takeda, Janssen, Solvay, Novartis, Covance, Alkermis, and Pfizer. Dr Copeland serves as a consultant for Sanofi. Drs Liu, Ghebremichael, Cohen, and Ongur and Mr Hayden report no competing interests. NR 39 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD APR PY 2013 VL 33 IS 2 BP 226 EP 230 DI 10.1097/JCP.0b013e31828701d0 PG 5 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 108NX UT WOS:000316303700014 PM 23422397 ER PT J AU Meszaros, ZS Abdul-Malak, Y Dimmock, JA Wang, DL Ajagbe, TO Batki, SL AF Meszaros, Zsuzsa Szombathyne Abdul-Malak, Ynesse Dimmock, Jacqueline A. Wang, Dongliang Ajagbe, Tolani O. Batki, Steven L. TI Varenicline Treatment of Concurrent Alcohol and Nicotine Dependence in Schizophrenia A Randomized, Placebo-Controlled Pilot Trial SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE varenicline; schizophrenia; alcohol; nicotine; smoking ID CONSENSUS COGNITIVE BATTERY; USE DISORDERS; SCHIZOAFFECTIVE DISORDER; SUBSTANCE USE; SMOKING; SCALE; STANDARDIZATION; INTERVENTIONS; OUTPATIENTS; PREVALENCE AB Alcohol and nicotine dependence are common in schizophrenia. Varenicline is effective in smoking cessation and has also been shown to decrease alcohol consumption in smokers. The present pilot study assessed the safety and effectiveness of varenicline for treatment of concurrent nicotine and alcohol dependence in schizophrenia. Outpatients with schizophrenia or schizoaffective disorder and concurrent alcohol and nicotine dependence were enrolled in this 8-week, double-blind, randomized, placebo-controlled trial. Alcohol use and smoking were assessed using self-report (Timeline Follow-Back) and biological measures. Adverse events were recorded. Changes in the number of standard drinks per week and cigarettes per week were compared in the 2 groups. Because of safety concerns or loss to follow-up, of 55 patients enrolled, only 10 started study medication, 5 each on varenicline and placebo. Gastrointestinal adverse effects, such as severe abdominal pain, limited study completion to only 4 subjects. Number of standard alcoholic drinks consumed per week decreased by [mean (SD)] 16.6 (20.1) in the varenicline group and by 2.4 (27.4) in the placebo group. Mean (SD) number of cigarettes smoked per week decreased by 66 (65) its the varenicline group and by 47 (77) in the placebo group. Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia may be problematic because of safety concerns limiting recruitment and poor tolerability (gastrointestinal adverse effects) limiting retention. There was no increased number of serious neuropsychiatric adverse events in the varenicline group. Based on this small sample, concurrent alcohol and nicotine dependence in schizophrenia may present special obstacles to successful treatment with varenicline. C1 [Meszaros, Zsuzsa Szombathyne; Abdul-Malak, Ynesse; Dimmock, Jacqueline A.; Ajagbe, Tolani O.; Batki, Steven L.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Wang, Dongliang] SUNY Upstate Med Univ, Dept Publ Hlth & Prevent Med, Syracuse, NY 13210 USA. [Batki, Steven L.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Batki, Steven L.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Meszaros, ZS (reprint author), SUNY Upstate Med Univ, Dept Psychiat, 750 E Adams St,IHP 3302, Syracuse, NY 13210 USA. EM meszaroz@upstate.edu FU Brain & Behavior Research Foundation (NARSAD) Young Investigator Award; NIH/NIAAA [R01 AA013655]; Alkermes, Inc. FX This research was supported by the Brain & Behavior Research Foundation (NARSAD) 2008 Young Investigator Award to Dr Szombathyne Meszaros. Dr Batki has received research funding from NIH/NIAAA (R01 AA013655) and Alkermes, Inc. The authors alone are responsible for the content and writing of the paper. NR 41 TC 11 Z9 11 U1 3 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD APR PY 2013 VL 33 IS 2 BP 243 EP 247 DI 10.1097/JCP.0b013e3182870551 PG 5 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 108NX UT WOS:000316303700018 PM 23422399 ER PT J AU True, G Butler, AE Lamparska, BG Lempa, ML Shea, JA Asch, DA Werner, RM AF True, Gala Butler, Anneliese E. Lamparska, Bozena G. Lempa, Michele L. Shea, Judy A. Asch, David A. Werner, Rachel M. TI Open Access in the Patient-Centered Medical Home: Lessons from the Veterans Health Administration SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE patient-centered access; primary care; continuity of care; veterans health; qualitative evaluation ID PRIMARY-CARE; READINESS AB The Veterans Health Administration (VHA) has undertaken a 5-year initiative to transform to a patient-centered medical home model. An early focus of implementation was on creating open access, defined as continuity and capacity in primary care. We describe the impact of readiness for implementation on efforts of pilot teams to make changes to improve access and identify successful strategies used by early adopters to overcome barriers to change. A qualitative, formative evaluation of the first 18 months of implementation in one Veterans Integrated Service Network (VISN) spread across six states. Members of local implementation teams including administrators, primary care providers, and staff from primary care clinics located at 10 medical centers and 45 outpatient clinics. We conducted site visits during the first 6 months of implementation, observations at Learning Collaboratives, semi-structured interviews, and review of internal organizational documents. All data collection took place between April 2010 and December 2011. Early adopters employed various strategies to enhance access, with a focus on decreasing demand for face-to-face care, increasing supply of different types of primary care encounters, and improving clinic efficiencies. Our interviews with key contacts revealed three important areas where readiness for implementation (or lack thereof) had an impact on interventions to improve access: leadership engagement, staffing resources, and access to information and knowledge. Key factors related to readiness for implementation had an impact on which interventions pilot teams could put into place, as well as the viability and sustainability of access gains. Wide variations in interventions to improve access occurring across sites situated within one organization have important implications for efforts to measure the impact of enhanced access on patient outcomes, costs, and other systems-level indicators of the Medical Home. C1 [True, Gala; Butler, Anneliese E.; Lamparska, Bozena G.; Lempa, Michele L.; Shea, Judy A.; Asch, David A.; Werner, Rachel M.] Philadelphia Vet Affairs Med Ctr, CEPACT, Philadelphia, PA 19104 USA. [True, Gala; Shea, Judy A.; Asch, David A.; Werner, Rachel M.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP True, G (reprint author), Philadelphia Vet Affairs Med Ctr, CEPACT, Bldg 4100,Univ & Woodland Aves, Philadelphia, PA 19104 USA. EM Jennifer.True2@va.gov OI Asch, David/0000-0002-7970-286X FU Office of Primary Care, Veterans Health Administration, Department of Veterans Affairs FX The authors wish to thank the staff of the Center for Evaluation of Patient Aligned Care Teams (CEPACT), members of the CEPACT Advisory Board and the VISN 4 PACT Steering Committee, the VISN 4 Offices, and staff at VISN 4 Medical Facilities. We are also grateful for the insightful comments and suggestions from the three anonymous reviewers. Funding for the VISN 4 Center for Evaluation of PACT is through the Office of Primary Care, Veterans Health Administration, Department of Veterans Affairs. The views expressed in this paper do not necessarily represent the official views of the Department of Veterans Affairs. NR 20 TC 18 Z9 18 U1 4 U2 38 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2013 VL 28 IS 4 BP 539 EP 545 DI 10.1007/s11606-012-2279-y PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 109VV UT WOS:000316398400010 PM 23192447 ER PT J AU Schleifer, JW Centor, RM Heudebert, GR Estrada, CA Morris, JL AF Schleifer, J. William Centor, Robert M. Heudebert, Gustavo R. Estrada, Carlos A. Morris, Jason L. TI NSTEMI or Not: A 59-Year-Old Man with Chest Pain and Troponin Elevation SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material ID AORTIC DISSECTION; FREQUENCY AB A 59-year-old African-American man with a history of hypertension, hyperlipidemia, and cerebrovascular disease presented to the emergency department complaining of chest pain. He stated that the pain began suddenly while he was seated at home several hours prior to presentation. He described the pain as throbbing, 9 out of 10 in intensity, substernal, and associated with nausea, diaphoresis, and dyspnea. He stated that the pain radiated to his left leg but not to his arm or jaw. The pain resolved spontaneously after an hour, but then recurred 3 hours later. He had never experienced pain like this before. He initially delayed coming to the hospital, expecting the chest pain to subside spontaneously again; but finally his family brought him in when he became disoriented and confused. C1 [Schleifer, J. William; Heudebert, Gustavo R.; Morris, Jason L.] Univ Alabama Birmingham, Tinsley Harrison Internal Med Residency Program, Birmingham, AL 35294 USA. [Centor, Robert M.; Heudebert, Gustavo R.; Estrada, Carlos A.; Morris, Jason L.] Univ Alabama Birmingham, Div Gen Internal Med, Birmingham, AL 35294 USA. [Centor, Robert M.] Univ Alabama Birmingham, Huntsville, AL USA. [Centor, Robert M.; Heudebert, Gustavo R.; Estrada, Carlos A.; Morris, Jason L.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Estrada, Carlos A.] Vet Affairs Natl Qual Scholars Program, Birmingham, AL USA. [Morris, Jason L.] Univ Alabama Birmingham, Birmingham, AL 35294 USA. RP Morris, JL (reprint author), Univ Alabama Birmingham, Tinsley Harrison Internal Med Residency Program, BDB 345,1720 2nd Ave South, Birmingham, AL 35294 USA. EM jlmorris@uab.edu OI Schleifer, John/0000-0002-2074-108X NR 14 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 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2013 VL 28 IS 4 BP 583 EP 590 DI 10.1007/s11606-012-2236-9 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 109VV UT WOS:000316398400019 PM 23054926 ER PT J AU Fink, EC Fisher, DE AF Fink, Emma C. Fisher, David E. TI BRAF and MC1R in Melanoma: Different in Head and Neck Tumors? SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID MUTANT MELANOMA; MUTATIONS; VARIANTS; RISK AB In this issue, Hacker et al. (2013) report the largest study to date on the association between MC1R variants and BRAF mutant melanoma. Although they did not observe a significant overall correlation, there was a significant negative association between BRAF and MC1R mutations for head/heck melanomas. This suggests a fundamental difference in pathogenesis between head/neck and truncal melanomas, which could contribute to their divergent prognoses. Journal of Investigative Dermatology (2013) 133,878-880. doi:10.1038/jid.2012.475 C1 [Fink, Emma C.; Fisher, David E.] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Fisher, DE (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. EM dfisher3@partners.org OI , /0000-0002-6589-8558 FU NIGMS NIH HHS [T32 GM007753] NR 12 TC 0 Z9 0 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD APR PY 2013 VL 133 IS 4 BP 878 EP 880 DI 10.1038/jid.2012.475 PG 3 WC Dermatology SC Dermatology GA 106OI UT WOS:000316154000006 PM 23486431 ER PT J AU Markova, A Weinstock, MA AF Markova, Alina Weinstock, Martin A. TI Risk of Skin Cancer Associated with the Use of UV Nail Lamp SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter C1 [Markova, Alina] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Markova, Alina; Weinstock, Martin A.] Brown Univ, Dept Dermatol, Alpert Med Sch, Providence, RI 02912 USA. [Markova, Alina; Weinstock, Martin A.] Vet Affairs Med Ctr, Dermatoepidemiol Unit 111D, Providence, RI USA. RP Markova, A (reprint author), Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. EM alina.markova.md@gmail.com NR 5 TC 4 Z9 4 U1 0 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD APR PY 2013 VL 133 IS 4 BP 1097 EP 1099 DI 10.1038/jid.2012.440 PG 3 WC Dermatology SC Dermatology GA 106OI UT WOS:000316154000032 PM 23223132 ER PT J AU Puntervoll, HE Yang, XHR Vetti, HH Bachmann, IM Avril, MF Benfodda, M Catricala, C Dalle, S Duval-Modeste, AB Ghiorzo, P Grammatico, P Harland, M Hayward, NK Hu, HH Jouary, T Martin-Denavit, T Ozola, A Palmer, JM Pastorino, L Pjanova, D Soufir, N Steine, SJ Stratigos, AJ Thomas, L Tinat, J Tsao, H Veinalde, R Tucker, MA Bressac-de Paillerets, BBD Newton-Bishop, JA Goldstein, AM Akslen, LA Molven, A AF Puntervoll, Hanne Eknes Yang, Xiaohong R. Vetti, Hildegunn Hoberg Bachmann, Ingeborg M. Avril, Marie Francoise Benfodda, Meriem Catricala, Caterina Dalle, Stephane Duval-Modeste, Anne B. Ghiorzo, Paola Grammatico, Paola Harland, Mark Hayward, Nicholas K. Hu, Hui-Han Jouary, Thomas Martin-Denavit, Tanguy Ozola, Aija Palmer, Jane M. Pastorino, Lorenza Pjanova, Dace Soufir, Nadem Steine, Solrun J. Stratigos, Alexander J. Thomas, Luc Tinat, Julie Tsao, Hensin Veinalde, Ruta Tucker, Margaret A. Bressac-de Paillerets, Brigitte Newton-Bishop, Julia A. Goldstein, Alisa M. Akslen, Lars A. Molven, Anders TI Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID 1 RECEPTOR MC1R; CDKN2A MUTATIONS; CUTANEOUS MELANOMA; RED HAIR; MALIGNANT-MELANOMA; PANCREATIC-CANCER; DYSPLASTIC NEVI; INCREASED RISK; ATYPICAL NEVI; GENE VARIANTS AB Background CDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype. Methods All known families with CDK4 germline mutations (n=17) were recruited for the study by contacting the authors of published papers or by requests via the Melanoma Genetics Consortium (GenoMEL). Phenotypic data related to primary melanoma and pigmentation characteristics were collected. The CDK4 exon 2 and the complete coding region of the MC1R gene were sequenced. Results Eleven families carried the CDK4 R24H mutation whereas six families had the R24C mutation. The total number of subjects with verified melanoma was 103, with a median age at first melanoma diagnosis of 39 years. Forty-three (41.7%) subjects had developed multiple primary melanomas (MPM). A CDK4 mutation was found in 89 (including 62 melanoma cases) of 209 tested subjects. CDK4 positive family members (both melanoma cases and unaffected subjects) were more likely to have clinically atypical nevi than CDK4 negative family members (p<0.001). MPM subjects had a higher frequency of MC1R red hair colour variants compared with subjects with one tumour (p=0.010). Conclusion Our study shows that families with CDK4 germline mutations cannot be distinguished phenotypically from CDKN2A melanoma families, which are characterised by early onset of disease, increased occurrence of clinically atypical nevi, and development of MPM. In a clinical setting, the CDK4 gene should therefore always be examined when a melanoma family tests negative for CDKN2A mutation. C1 [Puntervoll, Hanne Eknes; Bachmann, Ingeborg M.; Steine, Solrun J.; Akslen, Lars A.; Molven, Anders] Univ Bergen, Sect Pathol, Gade Inst, N-5021 Bergen, Norway. [Yang, Xiaohong R.; Tucker, Margaret A.; Goldstein, Alisa M.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Vetti, Hildegunn Hoberg] Haukeland Hosp, Ctr Med Genet & Mol Med, Western Norway Familial Canc Ctr, N-5021 Bergen, Norway. [Bachmann, Ingeborg M.] Haukeland Hosp, Dept Dermatol, N-5021 Bergen, Norway. [Avril, Marie Francoise] Univ Paris 05, Hop Cochin Tarnier, AP HP, Paris, France. [Benfodda, Meriem; Hu, Hui-Han; Soufir, Nadem] Univ Paris 07, St Louis Hosp, AP HP, Dept Genet,Bichat Hosp, Paris, France. [Benfodda, Meriem; Hu, Hui-Han; Soufir, Nadem] Univ Paris 07, INSERM, St Louis Hosp, Cutaneous Res Ctr,U976, Paris, France. [Catricala, Caterina] IRCCS, San Gallicano Dermatol Inst, Dept Dermatol Oncol, Rome, Italy. [Dalle, Stephane; Martin-Denavit, Tanguy; Thomas, Luc] Univ Lyon 1, Hosp Civils Lyon, Ctr Hosp Lyon Sud, Unit Dermatol, F-69365 Lyon, France. [Duval-Modeste, Anne B.] Rouen Univ Hosp, Dept Dermatol, Rouen, France. [Ghiorzo, Paola; Pastorino, Lorenza] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [Ghiorzo, Paola; Pastorino, Lorenza] San Martino IST Res Hosp, Lab Genet Rare Hereditary Canc, Genoa, Italy. [Grammatico, Paola] Univ Roma La Sapienza, Dept Mol Med, S Camillo Forlanini Hosp, Rome, Italy. [Harland, Mark; Newton-Bishop, Julia A.] St James Univ Hosp, Leeds Canc Res UK Ctr, Leeds Inst Mol Med, Epidemiol & Biostat Sect, Leeds, W Yorkshire, England. [Hayward, Nicholas K.; Palmer, Jane M.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Jouary, Thomas] Serv Dermatol, Unite Cancerol Cutanee, Bordeaux, France. [Ozola, Aija; Pjanova, Dace; Veinalde, Ruta] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Stratigos, Alexander J.] Univ Athens, Sch Med, Andreas Sygros Hosp, Dept Dermatol,Dermatooncol Unit, GR-11527 Athens, Greece. [Tinat, Julie] Rouen Univ Hosp, Dept Genet, Rouen, France. [Tsao, Hensin] Massachusetts Gen Hosp, MGH Canc Ctr, Dept Dermatol, Wellman Ctr Photomed, Boston, MA 02114 USA. [Bressac-de Paillerets, Brigitte] Inst Cancerol Gustave Roussy, Serv Genet, Dept Biopathol, Villejuif, France. [Bressac-de Paillerets, Brigitte] Fdn Jean Dausset, INSERM, U946, Paris, France. [Akslen, Lars A.] Univ Bergen, Ctr Canc Biomarkers, Gade Inst, N-5021 Bergen, Norway. [Akslen, Lars A.; Molven, Anders] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. RP Molven, A (reprint author), Univ Bergen, Haukeland Univ Hosp, Gade Inst, Sect Pathol, N-5021 Bergen, Norway. EM anders.molven@gades.uib.no RI Tucker, Margaret/B-4297-2015; hayward, nicholas/C-1367-2015; Akslen, Lars /C-1202-2017; OI hayward, nicholas/0000-0003-4760-1033; Akslen, Lars /0000-0003-2710-9543; Newton Bishop, Julia/0000-0001-9147-6802; Veinalde, Ruta/0000-0001-9190-5574 FU European Commission [LSHC-CT-2006-018702]; Cancer Research UK [C588/A4994, C588/A10589, C8216/A6129]; US National Institutes of Health (NIH) [CA83115]; University of Bergen; INSERM Research Fellowship; INCA; Norwegian Cancer Society [71512-PR-2006-0356]; Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Leeds Cancer Research UK Centre [C37059/A11941]; Latvian Council of Science [10.0010.8]; National Health and Medical Research Council of Australia; Italian Ministry of Health; PRIN; Sapienza University of Rome; Institut National du Cancer PHRC [AOM 07, 195, N107004]; Lyon 1 University; Hospices Civils de Lyon; Ligue Contre le Cancer du Rhone; NIH [K24 CA149202] FX The GenoMEL study was funded by the European Commission under the 6th Framework Programme (contract no. LSHC-CT-2006-018702), by Cancer Research UK Programme Awards (C588/A4994 and C588/A10589), by a Cancer Research UK Project grant (C8216/A6129), and by a grant from the US National Institutes of Health (NIH; CA83115). This research was also supported by a PhD fellowship from the University of Bergen to HEP, an INSERM Research Fellowship for hospital based scientists and an INCA coordinator or grant to BB-de P, and grants from the following sources: Norwegian Cancer Society (71512-PR-2006-0356); Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Leeds Cancer Research UK Centre (C37059/A11941); Latvian Council of Science (No. 10.0010.8); National Health and Medical Research Council of Australia; Italian Ministry of Health; PRIN 2008; Sapienza University of Rome; Institut National du Cancer PHRC 2007 (AOM 07, 195, N107004); Lyon 1 University; Hospices Civils de Lyon; Ligue Contre le Cancer du Rhone; and NIH (K24 CA149202). NR 41 TC 38 Z9 39 U1 3 U2 15 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD APR PY 2013 VL 50 IS 4 BP 264 EP U82 DI 10.1136/jmedgenet-2012-101455 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 106AW UT WOS:000316114800008 PM 23384855 ER PT J AU Blumenthal, C Curran, J Benzel, EC Potter, R Magge, SN Harrington, JF Coumans, JV Ghogawala, Z AF Blumenthal, Claire Curran, Jill Benzel, Edward C. Potter, Rachel Magge, Subu N. Harrington, J. Frederick, Jr. Coumans, Jean-Valery Ghogawala, Zoher TI Radiographic predictors of delayed instability following decompression without fusion for degenerative Grade I lumbar spondylolisthesis Clinical article SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Article DE degenerative lumbar spondylolisthesis; reoperation; radiographic predictor; outcome; laminectomy ID UNITED-STATES TRENDS; SPINAL STENOSIS; COST-EFFECTIVENESS; SURGERY; LAMINECTOMY; INSTRUMENTATION; REOPERATION; COMPLICATIONS; ARTHRODESIS; OPERATIONS AB Object. It is not known whether adding fusion to lumbar decompression is necessary for all patients undergoing surgery for degenerative lumbar spondylolisthesis with symptomatic stenosis. Determining specific radiographic traits that might predict delayed instability following decompression surgery might guide clinical decision making regarding the utility of up-front fusion in patients with degenerative Grade I spondylolisthesis. Methods. Patients with Grade I degenerative lumbar spondylolisthesis (3-14 mm) with symptomatic stenosis were prospectively enrolled from a single site between May 2002 and September 2009 and treated with decompressive laminectomy without fusion. Patients with mechanical back pain or with gross motion (>3 mm) on flexion-extension lumbar radiographs were excluded. The baseline radiographic variables measured included amount of slippage, disc height, facet angle, motion at spondylolisthesis (flexion-extension), and sagittal rotation angle. Data were analyzed using multivariate forward selection stepwise logistic regression, chi-square tests, Student t-test, and ANOVA. Results. Forty patients were enrolled and treated with laminectomy without fusion, and all patients had complete radiographic data sets that were available for analysis. Reoperation was performed in 15 (37.5%) of 40 patients, with a mean follow-up duration of 3.6 years. Reoperation was performed for pain caused by instability at the index level in all 15 cases. Using multivariate stepwise logistic regression with a threshold p value of 0.35, motion at spondylolisthesis, disc height, and facet angle were predictors of reoperation following surgery. Facet angle > 50 degrees was associated with a 39% rate of reoperation, disc height > 6.5 mm was associated with a 45% rate of reoperation, and motion at spondylolisthesis > 1.25 mm was associated with a 54% rate of reoperation. Patients with all 3 risk factors for instability had a 75% rate of reoperation, whereas patients with no risk factors for instability had a 0% rate of reoperation (p = 0.14). Conclusions. Patients with motion at spondylolisthesis > 1.25 mm, disc height > 6.5 mm, and facet angle > 50 degrees are more likely to experience instability following decompression surgery for Grade I lumbar spondylolisthesis. Identification of key risk factors for instability might improve patient selection for decompression without fusion surgery. Clinical trial registration no.: NCT00109213 (http://thejns.org/doi/abs/10.3171/2013.1.SPINE12537) C1 [Blumenthal, Claire] Harvard Univ, Cambridge, MA 02138 USA. [Magge, Subu N.; Ghogawala, Zoher] Lahey Clin Med Ctr, Dept Neurosurg, Burlington, MA 01805 USA. [Coumans, Jean-Valery] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Blumenthal, Claire; Curran, Jill; Potter, Rachel; Ghogawala, Zoher] Greenwich Hosp, Wallace Clin Trials Ctr, Greenwich, CT USA. [Benzel, Edward C.] Cleveland Clin, Dept Neurosurg, Cleveland, OH 44106 USA. [Harrington, J. Frederick, Jr.] Univ New Mexico, Dept Neurosurg, Albuquerque, NM 87131 USA. RP Ghogawala, Z (reprint author), Lahey Clin Med Ctr, Dept Neurosurg, 41 Mall Rd, Burlington, MA 01805 USA. EM zoher.ghogawala@lahey.org FU Greenwich Lumbar Stenosis SLIP Study Fund [GH384]; Jean and David Wallace Foundation [GH382] FX Funding was received from the Greenwich Lumbar Stenosis SLIP Study Fund (Grant No. GH384) and the Jean and David Wallace Foundation (Grant No. GH382). The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. NR 29 TC 21 Z9 23 U1 2 U2 5 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1547-5654 J9 J NEUROSURG-SPINE JI J. Neurosurg.-Spine PD APR PY 2013 VL 18 IS 4 BP 340 EP 346 DI 10.3171/2013.1.SPINE12537 PG 7 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 114BU UT WOS:000316715800006 PM 23373567 ER PT J AU Becerra, L Upadhyay, J Chang, PC Bishop, J Anderson, J Baumgartner, R Schwarz, AJ Coimbra, A Wallin, D Nutile, L George, E Maier, G Sunkaraneni, S Iyengar, S Evelhoch, JL Bleakman, D Hargreaves, R Borsook, D AF Becerra, Lino Upadhyay, Jaymin Chang, Pei-Ching Bishop, James Anderson, Julie Baumgartner, Richard Schwarz, Adam J. Coimbra, Alexandre Wallin, Diana Nutile, Lauren George, Edward Maier, Gary Sunkaraneni, Soujanya Iyengar, Smriti Evelhoch, Jeffrey L. Bleakman, David Hargreaves, Richard Borsook, David TI Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PHARMACOLOGICAL MRI; DRUG DISCOVERY; HUMAN BRAIN; TRANSLATIONAL MEDICINE; OPIOID RECEPTORS; ALZHEIMERS-DISEASE; THERMAL STIMULI; PAIN MANAGEMENT; RHESUS-MONKEYS; DEFAULT MODE AB Pharmacological magnetic resonance imaging (phMRI) is one method by which a drug's pharmacodynamic effects in the brain can be assessed. Although phMRI has been frequently used in preclinical and clinical settings, the extent to which a phMRI signature for a compound translates between rodents and humans has not been systematically examined. In the current investigation, we aimed to build on recent clinical work in which the functional response to 0.1 and 0.2 mg/70 kg i.v. buprenorphine (partial mu-opioid receptor agonist) was measured in healthy humans. Here, we measured the phMRI response to 0.04 and 0.1 mg/kg i.v. buprenorphine in conscious, naive rats to establish the parallelism of the phMRI signature of buprenorphine across species. PhMRI of 0.04 and 0.1 mg/kg i.v. buprenorphine yielded dose-dependent activation in a brain network composed of the somatosensory cortex, cingulate, insula, striatum, thalamus, periaqueductal gray, and cerebellum. Similar dose-dependent phMRI activation was observed in the human phMRI studies. These observations indicate an overall preservation of pharmacodynamic responses to buprenorphine between conscious, naive rodents and healthy human subjects, particularly in brain regions implicated in pain and analgesia. This investigation further demonstrates the usefulness of phMRI as a translational tool in neuroscience research that can provide mechanistic insight and guide dose selection in drug development. C1 [Becerra, Lino; Upadhyay, Jaymin; Chang, Pei-Ching; Bishop, James; Anderson, Julie; Baumgartner, Richard; Schwarz, Adam J.; Coimbra, Alexandre; Wallin, Diana; Nutile, Lauren; George, Edward; Maier, Gary; Sunkaraneni, Soujanya; Iyengar, Smriti; Evelhoch, Jeffrey L.; Bleakman, David; Hargreaves, Richard; Borsook, David] Childrens Hosp Boston, PAIN Grp, Imaging Consortium Drug Dev, Waltham, MA USA. [Becerra, Lino; Upadhyay, Jaymin; Chang, Pei-Ching; Bishop, James; Anderson, Julie; Wallin, Diana; Nutile, Lauren; George, Edward] Childrens Hosp Boston, PAIN Grp, Waltham, MA USA. [Becerra, Lino] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Baumgartner, Richard; Coimbra, Alexandre; Evelhoch, Jeffrey L.; Hargreaves, Richard] Merck & Co Inc, Merck Res Labs, West Point, PA USA. [Schwarz, Adam J.; Iyengar, Smriti] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. [Maier, Gary; Sunkaraneni, Soujanya] Sunovion Inc, Marlborough, MA USA. RP Becerra, L (reprint author), Harvard Univ, Sch Med, Children Hosp Boston, 9 Hope Ave, Waltham, MA 02453 USA. EM Lino.Becerra@childrens.harvard.edu OI Wallin, Diana/0000-0003-4244-0314 FU Imaging Consortium for Drug Development FX This work was supported by the Imaging Consortium for Drug Development (to D.B. and L.B.). NR 79 TC 12 Z9 12 U1 1 U2 23 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD APR PY 2013 VL 345 IS 1 BP 41 EP 51 DI 10.1124/jpet.112.201145 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 109KT UT WOS:000316367000006 PM 23370795 ER PT J AU Shen, KZ Johnson, SW AF Shen, Ke-Zhong Johnson, Steven W. TI Group I mGluRs Evoke K-ATP Current by Intracellular Ca2+ Mobilization in Rat Subthalamus Neurons SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID METABOTROPIC GLUTAMATE RECEPTORS; SENSITIVE POTASSIUM CHANNELS; DOPAMINERGIC MIDBRAIN NEURONS; PARKINSONS-DISEASE; NITRIC-OXIDE; SUBSTANTIA-NIGRA; GLOBUS-PALLIDUS; BASAL GANGLIA; NUCLEUS; ACTIVATION AB We reported previously that Ca2+ influx through N-methly-D-aspartate- gated channels evokes ATP-sensitive K+ (K-ATP) currents in rat subthalamic nucleus (STN) neurons. By using whole-cell patch clamp recordings in brain slices, we investigated the ability of (RS)-3,5-dihydroxyphenylglycine (DHPG), a group I metabotropic glutamate receptor (mGluR) agonist, to evoke K-ATP currents. DHPG (20 mu M) evoked outward current at -70 mV and was associated with a positive slope conductance of 2.7 nS. The sulfonylurea agent tolbutamide (100 mu M) converted the positive slope to negative slope conductance, indicating mediation by K-ATP channels (ATP-sensitive K+ channels). Currents evoked by DHPG were significantly reduced by a combination of mGluR1 and mGluR5 negative allosteric modulators. DHPG-evoked outward current was blocked by cyclopiazonic acid and thapsigargin and mimicked by caffeine, suggesting mediation by release of intracellular Ca2+. DHPG outward current was also blocked by ryanodine and 2-aminoethoxydiphenylborane, suggesting mediation by ryanodine-and inositol 1,4,5-triphosphate-sensitive Ca2+ release. The nitric oxide synthase inhibitor N-G-nitro-L-arginine methyl ester and inhibitors of protein kinase G activity also suppressed DHPG-induced outward current. Voltage recordings showed that tolbutamide prolonged depolarizing plateau potentials and increased the spontaneous firing rate of STN neurons recorded in the presence of DHPG. These results show that group I mGluR stimulation generates K-ATP current by a nitric oxide-and protein kinase G-dependent process that is mediated by release of Ca2+ from intracellular stores. Because burst firing is linked to symptoms of Parkinson's disease, we suggest that K-ATP channels might provide a physiologically important inhibitory influence on STN neuronal activity. C1 [Shen, Ke-Zhong; Johnson, Steven W.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Johnson, Steven W.] Portland VA Med Ctr, Portland, OR 97207 USA. RP Johnson, SW (reprint author), Portland VA Med Ctr, RD 61,3710 SW US Vet Hosp Rd, Portland, OR 97207 USA. EM johnsost@ohsu.edu FU National Institutes of Health National Institute of Neurological Disorders and Stroke [NS38715]; Portland Veterans Affairs Parkinson's Disease Research, Education, and Clinical Center FX This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS38715]; and by the Portland Veterans Affairs Parkinson's Disease Research, Education, and Clinical Center. NR 54 TC 3 Z9 3 U1 1 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 APR PY 2013 VL 345 IS 1 BP 139 EP 150 DI 10.1124/jpet.112.201566 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 109KT UT WOS:000316367000016 PM 23335392 ER PT J AU Koyama, A O'Brien, J Weuve, J Blacker, D Metti, AL Yaffe, K AF Koyama, Alain O'Brien, Jacqueline Weuve, Jennifer Blacker, Deborah Metti, Andrea L. Yaffe, Kristine TI The Role of Peripheral Inflammatory Markers in Dementia and Alzheimer's Disease: A Meta-Analysis SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Dementia; Alzheimer; Cognitive decline; Inflammation; c-reactive protein; Interleukin-6 ID C-REACTIVE PROTEIN; MILD COGNITIVE IMPAIRMENT; CARDIOVASCULAR-DISEASE; CONTROLLED-TRIAL; CLINICAL-TRIALS; FOLLOW-UP; RISK; HEALTH; INTERLEUKIN-6; PROGRESSION AB Studies that have investigated the association between markers of inflammation and risk of dementia are conflicting. Therefore, the researchers conducted a systematic review and meta-analysis of observational studies with the hypothesis that an increased level of peripheral proinflammatory markers would be associated with risk of all-cause dementia or Alzheimers disease (AD). The researchers conducted a literature search of observational studies indexed in the PubMed and PsycInfo databases. Selected studies included those with at least one peripheral inflammatory biomarker and its association with risk of all-cause dementia or AD. Random effects models were used to generate pooled hazard ratios (HRs) comparing the top versus bottom quantile of inflammatory marker level. Heterogeneity was assessed using the I-2 statistic. Seven studies were identified, combining for a total 5,717 participants, 746 cases of all-cause dementia and 565 cases of AD. An increased level of C-reactive protein was associated with a 45% increased risk of all-cause dementia (HR: 1.45; 95% CI: 1.10, 1.91). Similarly, a higher level of interleukin-6 was associated with a 32% increased risk (HR: 1.32; 95% CI: 1.06, 1.64) of all-cause dementia. For AD alone, the association with C-reactive protein was less pronounced (HR: 1.21; 95% CI: 1.03, 1.42) and interleukin-6 was not associated with risk of AD (HR: 1.06; 95% CI: 0.83, 1.35). No significant heterogeneity was found in any of the meta-analyses (I-2 = 0%40%, p .16). An increased peripheral level of inflammatory markers is associated with a modest increase in risk of all-cause dementia. Evidence for an association with risk of AD alone is limited. C1 [Koyama, Alain] Northern Calif Inst Res & Educ, San Francisco, CA USA. [Koyama, Alain; Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [O'Brien, Jacqueline; Blacker, Deborah] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Weuve, Jennifer] Rush Univ, Med Ctr, Rush Inst Hlth Aging, Dept Internal Med, Chicago, IL 60612 USA. [Blacker, Deborah] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Metti, Andrea L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [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] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. RP Koyama, A (reprint author), San Francisco VA Med Ctr, 4150 Clement St,VAMC 116H, San Francisco, CA 94121 USA. EM alain.koyama@va.gov FU National Institute of Aging [K24 AG 031155, R01 AG 026720]; Alzheimer's Association [IIRG-08-88872] FX This work was supported by the National Institute of Aging (K24 AG 031155, R01 AG 026720) and the Alzheimer's Association (IIRG-08-88872). NR 35 TC 49 Z9 49 U1 1 U2 29 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD APR PY 2013 VL 68 IS 4 BP 433 EP 440 DI 10.1093/gerona/gls187 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 108DX UT WOS:000316273000013 PM 22982688 ER PT J AU Wang, L Porter, B Maynard, C Evans, G Bryson, C Sun, HL Gupta, I Lowy, E McDonell, M Frisbee, K Nielson, C Kirkland, F Fihn, SD AF Wang, Li Porter, Brian Maynard, Charles Evans, Ginger Bryson, Christopher Sun, Haili Gupta, Indra Lowy, Elliott McDonell, Mary Frisbee, Kathleen Nielson, Christopher Kirkland, Fred Fihn, Stephan D. TI Predicting Risk of Hospitalization or Death Among Patients Receiving Primary Care in the Veterans Health Administration SO MEDICAL CARE LA English DT Article DE primary care; statistical models; hospitalization; death ID READMISSION; MODEL; REGRESSION AB Background: Statistical models that identify patients at elevated risk of death or hospitalization have focused on population subsets, such as those with a specific clinical condition or hospitalized patients. Most models have limitations for clinical use. Our objective was to develop models that identified high-risk primary care patients. Methods: Using the Primary Care Management Module in the Veterans Health Administration (VHA)'s Corporate Data Warehouse, we identified all patients who were enrolled and assigned to a VHA primary care provider on October 1, 2010. The outcome variable was the occurrence of hospitalization or death during the subsequent 90 days and 1 year. We extracted predictors from 6 categories: sociodemographics, medical conditions, vital signs, prior year use of health services, medications, and laboratory tests and then constructed multinomial logistic regression models to predict outcomes for over 4.6 million patients. Results: In the predicted 95th risk percentiles, observed 90-day event rates were 19.6%, 6.2%, and 22.6%, respectively, for hospitalization, death, and either hospitalization or death, compared with population averages of 2.7%, 0.7%, and 3.4%, respectively; 1-year event rates were 42.3%, 19.4%, and 51.3%, respectively, compared with population averages of 8.2%, 2.6%, and 10.8%, respectively. The C-statistics for 90-day outcomes were 0.83, 0.86, and 0.81, respectively, for hospitalization, death, and either hospitalization or death and were 0.81, 0.85, and 0.79, respectively, for 1-year outcomes. Conclusions: Prediction models using electronic clinical data accurately identified patients with elevated risk for hospitalization or death. This information can enhance the coordination of care for patients with complex clinical conditions. C1 [Wang, Li; Maynard, Charles; Evans, Ginger; Bryson, Christopher; Sun, Haili; Gupta, Indra; Lowy, Elliott] VA Puget Sound Hlth Care Syst, Seattle, WA 98101 USA. [Porter, Brian; Evans, Ginger; Bryson, Christopher; Fihn, Stephan D.] Univ Washington, Dept Med, Seattle, WA USA. [Maynard, Charles] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [McDonell, Mary; Frisbee, Kathleen; Nielson, Christopher; Kirkland, Fred; Fihn, Stephan D.] VHA Off Informat & Analyt Analyt & Business Intel, Washington, DC USA. RP Maynard, C (reprint author), VA Puget Sound Hlth Care Syst, HSR&D 1100 Olive Way Suite 1400, Seattle, WA 98101 USA. EM cmaynard@u.washington.edu RI Maynard, Charles/N-3906-2015 OI Maynard, Charles/0000-0002-1644-7814 NR 19 TC 32 Z9 32 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD APR PY 2013 VL 51 IS 4 BP 368 EP 373 DI 10.1097/MLR.0b013e31827da95a PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 107HS UT WOS:000316207100013 PM 23269113 ER PT J AU Herzig, MCS Hildreth, K Huamani, J Perez, M Goins, BA McMahan, CA Reddick, RL Walter, CA AF Herzig, Maryanne C. S. Hildreth, Kim Huamani, Jessica Perez, Marissa Goins, Beth A. McMahan, C. Alex Reddick, Robert L. Walter, Christi A. TI Human O-6-methylguanine-DNA methyltransferase containing C145A does not prevent hepatocellular carcinoma in C3HeB/FeJ transgenic mice SO MOLECULAR CARCINOGENESIS LA English DT Article DE liver cancer; DNA repair; mouse model; computed tomography; imaging ID HUMAN O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; DNA-REPAIR PROTEIN; HUMAN LIVER-CANCER; MOUSE MODELS; ESCHERICHIA-COLI; TUMORS; DIMETHYLNITROSAMINE; EXPRESSION; MUTATIONS; APOPTOSIS AB The prevalence of hepatocellular carcinoma (HCC) was diminished from 60% to 18% at 15 months of age in C3HeB/FeJ male transgenic mice expressing hMGMT in our previous studies. To directly test if the methyltransferase activity is required for diminished tumor prevalence, two separate lines of transgenic mice bearing an enzymatically inactive form of hMGMT were used. In these lines, cysteine 145 was substituted with alanine (C145A). Expression of the hMGMT C145A transgene in liver was demonstrated by Northern blots and Western blots. Immunohistochemistry revealed predominantly nuclear localization of the hMGMT C145A protein. hMGMT C145A transgenic mice were crossed with lacI transgenic mice to assess mutant frequencies in the presence of the mutant protein. Mutant frequencies were similar among livers of lacIxhMGMT C145A bi-transgenic mice and lacIxwild-type (WT) mice. DNA sequence analysis of recovered lacI mutants revealed similar mutation spectra for hMGMT C145A and WT mice. The prevalence of HCC was also similar for the two tested lines of hMGMT C145A mice, 45% and 48% prevalence with median tumor sizes of 11 and 8mm, and WT mice, 40% prevalence and median tumor size of 10mm. These results provide evidence that residue C145 in hMGMT is required to reduce the prevalence of HCC in C3HeB/FeJ mice transgenic for hMGMT. (c) 2011 Wiley Periodicals, Inc. C1 [Herzig, Maryanne C. S.; Hildreth, Kim; Perez, Marissa; Walter, Christi A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Huamani, Jessica] Childrens Healthcare Atlanta, Dept Radiol, Atlanta, GA USA. [Goins, Beth A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [McMahan, C. Alex; Reddick, Robert L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Walter, Christi A.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Walter, Christi A.] Barshop Inst Longev & Aging Studies, San Antonio, TX USA. [Walter, Christi A.] Canc Therapy & Res Inst, San Antonio, TX USA. RP Walter, CA (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU VA Merit Award FX This study was supported by a VA Merit Award (to C.A.W.). The generous gift of the hMGMT C145A cDNA from Dr Anthony Pegg is gratefully acknowledged. We would like to thank Dr. LuZhe Sun and Dr. Thomas J. Slaga for their helpful comments in reviewing this article. We thank Dr. Anu Soundararajan and Dr. Max Amurao for their technical assistance during microCT image acquisition. We also thank Ms. Rebecca Garcia for excellent technical assistance. NR 71 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD APR PY 2013 VL 52 IS 4 BP 275 EP 285 DI 10.1002/mc.21855 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 112CQ UT WOS:000316570000004 PM 22213062 ER PT J AU Jung, MK Kim, KY Lee, NY Kang, YS Hwang, YJ Kim, Y Sung, JJ McKee, A Kowall, N Lee, J Ryu, H AF Jung, Min-Kyung Kim, Ki Yoon Lee, Na-Young Kang, Young-Sook Hwang, Yu Jin Kim, Yunha Sung, Jung-Joon McKee, Ann Kowall, Neil Lee, Junghee Ryu, Hoon TI Expression of Taurine Transporter (TauT) is Modulated by Heat Shock Factor 1 (HSF1) in Motor Neurons of ALS SO MOLECULAR NEUROBIOLOGY LA English DT Review DE Taurine transporter; Heat shock factor 1; Transcription; Taurine uptake; Amyotrophic lateral sclerosis ID AMYOTROPHIC-LATERAL-SCLEROSIS; CU,ZN SUPEROXIDE-DISMUTASE; SPINAL-CORD; AMINO-ACIDS; LINKED SOD1; BIOSYNTHETIC-ENZYMES; GENE-EXPRESSION; NITRIC-OXIDE; CELL MODEL; BRAIN AB Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive paralysis caused by the degeneration of motor neurons throughout the central nervous system. Mutations of the free radical scavenging enzyme Cu/Zn superoxide dismutase 1 (SOD1) are a cause of familial ALS. In the present study, we demonstrated an age-dependent increase in taurine transporter (TauT) immunoreactivity in spinal cord motor neurons of ALS transgenic mice (mutant SOD1 (G93A)) and a similar increase in TauT in spinal motor neurons of patients with ALS. Chromatin immunoprecipitation analysis verified that heat shock factor 1 (HSF1) preferentially occupies the HSF1 binding element in the promoter of TauT under oxidative stress conditions. Knockdown of HSF1 by small interfering RNA reduced the transcriptional activity of TauT. Using [H-3] taurine, we confirmed that an elevated expression of TauT directly contributes to increased taurine uptake in ALS motor neurons. In addition, we showed that taurine plays an antioxidant role and may prevent motor neuron loss due to oxidative stress in ALS. Our findings suggest that HSF1-induced TauT expression partially protects motor neurons by compensating for constitutive oxidative stress, which is thought to be a key mechanism contributing to the pathogenesis of ALS. Taken together, our results suggest that TauT is a novel pathological marker for stressed motor neurons in ALS and that modulation of TauT and taurine may slow neuronal degeneration in ALS. C1 [Jung, Min-Kyung; Kim, Ki Yoon; Hwang, Yu Jin; Kim, Yunha; Ryu, Hoon] Seoul Natl Univ, Coll Med, WCU Neurocyt Grp, Dept Biomed Sci, Seoul 110799, South Korea. [Lee, Na-Young; Kang, Young-Sook] Sookmyung Womens Univ, Coll Pharm, Res Ctr Cell Fate Control, Seoul 140742, South Korea. [Sung, Jung-Joon] Seoul Natl Univ Hosp, Dept Neurol, Seoul 110799, South Korea. [McKee, Ann; Kowall, Neil; Lee, Junghee; Ryu, Hoon] Boston VA Healthcare Syst, Boston, MA 02130 USA. [McKee, Ann; Kowall, Neil; Lee, Junghee; Ryu, Hoon] Boston Univ, Sch Med, Alzheimers Dis Ctr, Boston, MA 02118 USA. [McKee, Ann; Kowall, Neil; Lee, Junghee; Ryu, Hoon] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Lee, J (reprint author), Boston VA Healthcare Syst, Bldg 1A,Room 105,150 South Huntington Ave, Boston, MA 02130 USA. EM junghee@bu.edu; hoonryu@bu.edu RI Kowall, Neil/G-6364-2012 OI Kowall, Neil/0000-0002-6624-0213 FU Rare Disease Research Center Grant from Korea Ministry of Health and Welfare; SRC Grant [2010-0029-403]; WCU Neurocytomics Program Grant [800-20080848]; National Research Foundation of Korea (NRF) [2011-0030701]; Korean government (MEST); VA Merit Award FX This study was supported by the Rare Disease Research Center Grant from Korea Ministry of Health and Welfare (HR), SRC Grant (2010-0029-403) (HR) and WCU Neurocytomics Program Grant (800-20080848) (HR). This study was also supported by the National Research Foundation of Korea (NRF) grant (no. 2011-0030701) (YSK) funded by the Korean government (MEST) and VA Merit Award (JL and NK). NR 38 TC 4 Z9 5 U1 2 U2 15 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0893-7648 J9 MOL NEUROBIOL JI Mol. Neurobiol. PD APR PY 2013 VL 47 IS 2 BP 699 EP 710 DI 10.1007/s12035-012-8371-9 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 106DC UT WOS:000316120900021 PM 23180277 ER PT J AU Ho, NF Hooker, JM Sahay, A Holt, DJ Roffman, JL AF Ho, N. F. Hooker, J. M. Sahay, A. Holt, D. J. Roffman, J. L. TI In vivo imaging of adult human hippocampal neurogenesis: progress, pitfalls and promise SO MOLECULAR PSYCHIATRY LA English DT Review DE Adult human hippocampal neurogenesis; in vivo neuroimaging ID POSTTRAUMATIC-STRESS-DISORDER; NEURAL PROGENITOR CELLS; DENTATE GRANULE CELLS; VOXEL-BASED MORPHOMETRY; TERM LITHIUM TREATMENT; MEDIAL TEMPORAL-LOBE; RAT HIPPOCAMPUS; ELECTROCONVULSIVE SEIZURES; HUMAN BRAIN; ENRICHED ENVIRONMENT AB New neurons are produced within the hippocampus of the mammalian brain throughout life. Evidence from animal studies has suggested that the function of these adult-born neurons is linked to cognition and emotion. Until we are able to detect and measure levels of adult neurogenesis in living human brains-a formidable challenge for now-we cannot establish its functional importance in human health, disease and new treatment development. Current non-invasive neuroimaging modalities can provide live snapshots of the brain's structure, chemistry, activity and connectivity. This review explores whether existing macroscopic imaging methods can be used to understand the microscopic dynamics of adult hippocampal neurogenesis in living individuals. We discuss recent studies that have found correlations between neuroimaging measures of human hippocampal biology and levels of pro- or anti-neurogenic stimuli, weigh whether these correlations reflect changes in adult neurogenesis, detail the conceptual and technical limitations of these studies and elaborate on what will be needed to validate in vivo neuroimaging measures of adult neurogenesis for future investigations. Molecular Psychiatry (2013) 18, 404-416; doi:10.1038/mp.2013.8; published online 26 February 2013 C1 [Ho, N. F.; Holt, D. J.; Roffman, J. L.] Massachusetts Gen Hosp, Dept Psychiat, Schizophrenia Program, Boston, MA 02114 USA. [Ho, N. F.; Holt, D. J.; Roffman, J. L.] Massachusetts Gen Hosp, Psychiat Neurosci Res Program, Charlestown, MA USA. [Hooker, J. M.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Sahay, A.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Sahay, A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Sahay, A.] Harvard Stem Cell Inst, Boston, MA USA. [Ho, N. F.; Hooker, J. M.; Sahay, A.; Holt, D. J.; Roffman, J. L.] Harvard Univ, Sch Med, Boston, MA USA. RP Ho, NF (reprint author), Schizophrenia Res Program, 149 13th St,Suite 2611, Charlestown, MA 02129 USA. EM newfei@nmr.mgh.harvard.edu OI Hooker, Jacob/0000-0002-9394-7708 FU Howard Hughes Medical Institute Early Career Physician-Scientist Award; US National Institute of Mental Health grant [4R00MH086615-03]; Ellison Medical Foundation New Scholar in Aging; Whitehall Foundation FX This work was supported by the Howard Hughes Medical Institute Early Career Physician-Scientist Award (JLR), US National Institute of Mental Health grant 4R00MH086615-03 (AS) and the Ellison Medical Foundation New Scholar in Aging and the Whitehall Foundation (AS). NR 167 TC 29 Z9 30 U1 4 U2 54 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD APR PY 2013 VL 18 IS 4 BP 404 EP 416 DI 10.1038/mp.2013.8 PG 13 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 112CE UT WOS:000316568600007 PM 23439487 ER PT J AU Sullivan, PF Daly, MJ Ripke, S Lewis, CM Lin, DY Wray, NR Neale, B Levinson, DF Breen, G Byrne, EM Wray, NR Levinson, DF Rietschel, M Hoogendijk, W Ripke, S Sullivan, PF Hamilton, SP Levinson, DF Lewis, CM Ripke, S Weissman, MM Wray, NR Breuer, R Cichon, S Degenhardt, F Frank, J Gross, M Herms, S Hoefels, S Maier, W Mattheisen, M Noethen, MM Rietschel, M Schulze, TG Steffens, M Treutlein, J Boomsma, DI De Geus, EJ Hoogendijk, W Hottenga, JJ Jung-Ying, T Lin, DY Middeldorp, CM Nolen, WA Penninx, BP Smit, JH Sullivan, PF van Grootheest, G Willemsen, G Zitman, FG Coryell, WH Knowles, JA Lawson, WB Levinson, DF Potash, JB Scheftner, WA Shi, JX Weissman, MM Holsboer, F Muglia, P Tozzi, F Blackwood, DHR Boomsma, DI De Geus, EJ Hottenga, JJ MacIntyre, DJ McIntosh, A McLean, A Middeldorp, CM Nolen, WA Penninx, BP Ripke, S Smit, JH Sullivan, PF van Grootheest, G Willemsen, G Zitman, FG van den Oord, EJCG Holsboer, F Lucae, S Binder, E Muller-Myhsok, B Ripke, S Czamara, D Kohli, MA Ising, M Uhr, M Bettecken, T Barnes, MR Breen, G Craig, IW Farmer, AE Lewis, CM McGuffin, P Muglia, P Byrne, E Gordon, SD Heath, AC Henders, AK Hickie, IB Madden, PAF Martin, NG Montgomery, GM Nyholt, DR Pergadia, ML Wray, NR Hamilton, SP McGrath, PJ Shyn, SI Slager, SL Oskarsson, H Sigurdsson, E Stefansson, H Stefansson, K Steinberg, S Thorgeirsson, T Levinson, DF Potash, JB Shi, JX Weissman, MM Guipponi, M Lewis, G O'Donovan, M Tansey, KE Uher, R Coryell, WH Knowles, JA Lawson, WB Levinson, DF Potash, JB Scheftner, WA Shi, JX Weissman, MM Castro, VM Churchill, SE Fava, M Gainer, VS Gallagher, PJ Goryachev, S Iosifescu, DV Kohane, IS Murphy, SN Perlis, RH Smoller, JW Weilburg, JB Kutalik, Z Preisig, M Grabe, HJ Nauck, M Schulz, A Teumer, A Volzke, H Landen, M Lichtenstein, P Magnusson, P Pedersen, N Viktorin, A AF Sullivan, Patrick F. Daly, Mark J. Ripke, Stephan Lewis, Cathryn M. Lin, Dan-Yu Wray, Naomi R. Neale, Benjamin Levinson, Douglas F. Breen, Gerome Byrne, Enda M. Wray, Naomi R. Levinson, Douglas F. Rietschel, Marcella Hoogendijk, Witte Ripke, Stephan Sullivan, Patrick F. Hamilton, Steven P. Levinson, Douglas F. Lewis, Cathryn M. Ripke, Stephan Weissman, Myrna M. Wray, Naomi R. Breuer, Rene Cichon, Sven Degenhardt, Franziska Frank, Josef Gross, Magdalena Herms, Stefan Hoefels, Susanne Maier, Wolfgang Mattheisen, Manuel Noeethen, Markus M. Rietschel, Marcella Schulze, Thomas G. Steffens, Michael Treutlein, Jens Boomsma, Dorret I. De Geus, Eco J. Hoogendijk, Witte Hottenga, Jouke Jan Jung-Ying, Tzeng Lin, Dan-Yu Middeldorp, Christel M. Nolen, Willem A. Penninx, Brenda P. Smit, Johannes H. Sullivan, Patrick F. van Grootheest, Gerard Willemsen, Gonneke Zitman, Frans G. Coryell, William H. Knowles, James A. Lawson, William B. Levinson, Douglas F. Potash, James B. Scheftner, William A. Shi, Jianxin Weissman, Myrna M. Holsboer, Florian Muglia, Pierandrea Tozzi, Federica Blackwood, Douglas H. R. Boomsma, Dorret I. De Geus, Eco J. Hottenga, Jouke Jan MacIntyre, Donald J. McIntosh, Andrew McLean, Alan Middeldorp, Christel M. Nolen, Willem A. Penninx, Brenda P. Ripke, Stephan Smit, Johannes H. Sullivan, Patrick F. van Grootheest, Gerard Willemsen, Gonneke Zitman, Frans G. van den Oord, Edwin J. C. G. Holsboer, Florian Lucae, Susanne Binder, Elisabeth Mueller-Myhsok, Bertram Ripke, Stephan Czamara, Darina Kohli, Martin A. Ising, Marcus Uhr, Manfred Bettecken, Thomas Barnes, Michael R. Breen, Gerome Craig, Ian W. Farmer, Anne E. Lewis, Cathryn M. McGuffin, Peter Muglia, Pierandrea Byrne, Enda Gordon, Scott D. Heath, Andrew C. Henders, Anjali K. Hickie, Ian B. Madden, Pamela A. F. Martin, Nicholas G. Montgomery, Grant M. Nyholt, Dale R. Pergadia, Michele L. Wray, Naomi R. Hamilton, Steven P. McGrath, Patrick J. Shyn, Stanley I. Slager, Susan L. Oskarsson, Hoegni Sigurdsson, Engilbert Stefansson, Hreinn Stefansson, Kari Steinberg, Stacy Thorgeirsson, Thorgeir Levinson, Douglas F. Potash, James B. Shi, Jianxin Weissman, Myrna M. Guipponi, Michel Lewis, Glyn O'Donovan, Michael Tansey, Katherine E. Uher, Rudolf Coryell, William H. Knowles, James A. Lawson, William B. Levinson, Douglas F. Potash, James B. Scheftner, William A. Shi, Jianxin Weissman, Myrna M. Castro, Victor M. Churchill, Susanne E. Fava, Maurizio Gainer, Vivian S. Gallagher, Patience J. Goryachev, Sergey Iosifescu, Dan V. Kohane, Isaac S. Murphy, Shawn N. Perlis, Roy H. Smoller, Jordan W. Weilburg, Jeffrey B. Kutalik, Zoltan Preisig, Martin Grabe, Hans J. Nauck, Matthias Schulz, Andrea Teumer, Alexander Voelzke, Henry Landen, Mikael Lichtenstein, Paul Magnusson, Patrik Pedersen, Nancy Viktorin, Alexander CA Psychiat GWAS Consortium TI A mega-analysis of genome-wide association studies for major depressive disorder SO MOLECULAR PSYCHIATRY LA English DT Article DE genetics; genome-wide association study; major depressive disorder; mega-analysis; meta-analysis ID CARDIOVASCULAR RISK-FACTORS; NATIONAL COMORBIDITY SURVEY; SEROTONIN TRANSPORTER GENE; BIPOLAR DISORDER; SUSCEPTIBILITY LOCI; PSYCHIATRIC-DISORDERS; MENTAL-DISORDERS; MOOD DISORDERS; TWIN REGISTRY; HUMAN HEIGHT AB Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5x10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9x10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status. Molecular Psychiatry (2013) 18, 497-511; doi:10.1038/mp.2012.21; published online 3 April 2012 C1 [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Daly, Mark J.; Ripke, Stephan] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Wray, Naomi R.] Univ Queensland, Queensland Inst Med Res, Brisbane, Qld 4072, Australia. [Lewis, Cathryn M.; Breen, Gerome; Craig, Ian W.; Farmer, Anne E.; McGuffin, Peter; Tansey, Katherine E.; Uher, Rudolf] Kings Coll London, Inst Psychiat, London, England. [Hamilton, Steven P.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Weissman, Myrna M.; McGrath, Patrick J.] Columbia Univ, New York, NY 10027 USA. [Blackwood, Douglas H. R.; MacIntyre, Donald J.; McIntosh, Andrew; McLean, Alan] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. [Boomsma, Dorret I.; De Geus, Eco J.; Hottenga, Jouke Jan; Middeldorp, Christel M.; Willemsen, Gonneke] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Cichon, Sven; Degenhardt, Franziska; Gross, Magdalena; Herms, Stefan; Hoefels, Susanne; Maier, Wolfgang; Mattheisen, Manuel; Noeethen, Markus M.; Steffens, Michael] Univ Bonn, Bonn, Germany. [Heath, Andrew C.; Madden, Pamela A. F.; Pergadia, Michele L.] Washington Univ, St Louis, MO USA. [Byrne, Enda M.; Gordon, Scott D.; Henders, Anjali K.; Martin, Nicholas G.; Montgomery, Grant M.; Nyholt, Dale R.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Penninx, Brenda P.; Smit, Johannes H.; van Grootheest, Gerard] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Coryell, William H.; Potash, James B.] Univ Iowa, Iowa City, IA 52242 USA. [Rietschel, Marcella; Breuer, Rene; Frank, Josef; Treutlein, Jens] Heidelberg Univ, Cent Inst Mental Hlth, Heidelberg, Germany. [Sullivan, Patrick F.; Lin, Dan-Yu] Univ N Carolina, Chapel Hill, NC 27515 USA. [Shi, Jianxin] NCI, Bethesda, MD 20892 USA. [Grabe, Hans J.; Nauck, Matthias; Schulz, Andrea; Teumer, Alexander; Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany. [Lichtenstein, Paul; Magnusson, Patrik; Pedersen, Nancy; Viktorin, Alexander] Karolinska Inst, S-10401 Stockholm, Sweden. [Fava, Maurizio; Gallagher, Patience J.; Iosifescu, Dan V.; Murphy, Shawn N.; Smoller, Jordan W.; Weilburg, Jeffrey B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kutalik, Zoltan] Univ Lausanne, CH-1015 Lausanne, Switzerland. [O'Donovan, Michael] Cardiff Univ, Cardiff CF10 3AX, S Glam, Wales. [Guipponi, Michel] Univ Geneva, CH-1211 Geneva 4, Switzerland. [Hickie, Ian B.] Univ Sydney, Sydney, NSW 2006, Australia. Univ Birmingham, Birmingham B15 2TT, W Midlands, England. [Jung-Ying, Tzeng] N Carolina State Univ, Raleigh, NC 27695 USA. [Knowles, James A.] Univ So Calif, Los Angeles, CA 90089 USA. [Kohane, Isaac S.] Brigham & Womens Hosp, Boston, MA 02115 USA. Queen Mary Univ London, London, England. [Lawson, William B.] Howard Univ, Washington, DC USA. [Lewis, Glyn] Univ Bristol, Bristol BS8 1TH, Avon, England. Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. [Nolen, Willem A.] Univ Groningen, Univ Med Ctr Groningen, NL-9700 AB Groningen, Netherlands. [Scheftner, William A.] Rush Univ, Med Ctr, Chicago, IL USA. [Shyn, Stanley I.] Univ Washington, Seattle, WA 98195 USA. [Slager, Susan L.] Mayo Clin, Rochester, MN 55905 USA. [van den Oord, Edwin J. C. G.] Virginia Commonwealth Univ, Richmond, VA 23284 USA. [Zitman, Frans G.] Leiden Univ, Med Ctr, NL-2300 RA Leiden, Netherlands. [Levinson, Douglas F.] Stanford Univ, Stanford, CA 94305 USA. RP Sullivan, PF (reprint author), Univ N Carolina, Dept Genet, CB 7264, Chapel Hill, NC 27599 USA. EM pfsulliv@med.unc.edu RI Lewis, Glyn/E-9944-2012; Breen, Gerome/A-5540-2010; Wray, Naomi/C-8639-2015; Mattheisen, Manuel/B-4949-2012; Magnusson, Patrik/C-4458-2017; Schulze, Thomas/H-2157-2013; Nolen, Willem/E-9006-2014; Lewis, Cathryn/A-5225-2010; Tansey, Katherine/B-1033-2013; McGrath, Patrick/I-6410-2013; McGuffin, Peter/A-1565-2012; McIntosh, Andrew/B-9379-2008; Uher, Rudolf/A-5477-2008; Colaus, PsyColaus/K-6607-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; van Grootheest, Gerard/C-6942-2014; Sigurdsson, Engilbert/D-2486-2014 OI Landen, Mikael/0000-0002-4496-6451; lichtenstein, paul/0000-0003-3037-5287; Viktorin, Alexander/0000-0003-2141-2816; Stefansson, Hreinn/0000-0002-9331-6666; Nothen, Markus/0000-0002-8770-2464; Middeldorp, Christel/0000-0002-6218-0428; Thorgeirsson, Thorgeir/0000-0002-5149-7040; de Geus, Eco/0000-0001-6022-2666; Lewis, Glyn/0000-0001-5205-8245; Breen, Gerome/0000-0003-2053-1792; Wray, Naomi/0000-0001-7421-3357; Mattheisen, Manuel/0000-0002-8442-493X; MacIntyre, Donald J/0000-0001-6963-1335; Hamilton, Steven/0000-0001-8106-6260; Craig, Ian/0000-0002-4063-1005; Lewis, Cathryn/0000-0002-8249-8476; Tansey, Katherine/0000-0002-9663-3376; McGrath, Patrick/0000-0001-7217-7321; McGuffin, Peter/0000-0002-9888-2907; McIntosh, Andrew/0000-0002-0198-4588; Uher, Rudolf/0000-0002-2998-0546; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; van Grootheest, Gerard/0000-0003-4350-6661; Sigurdsson, Engilbert/0000-0001-9404-7982 FU NIMH [MH085520, MH080403, MH061686, MH059542, MH075131, MH059552, MH059541, MH060912, MH086026, MH081802, MH072802, N01MH90003]; German Federal Ministry of Education and Research; National Genome Research Network 2 (NGFN-2); National Genome Research Network plus (NGFNplus); Integrated Genome Research Network (IG) MooDS [01GS08144, 01GS08147]; European Union [LSHM-CT-2006-037761, PIAP-GA-2008-218251, HEALTH-F2-2009-223423]; Medical Research Council (UK); Mental Health Research Network; Innovative Medicines Initiative [115008]; National Alliance for Research on Schizophrenia and Depression; i2b2 Center (Informatics for Integrating Biology and the Bedside); NIH [U54LM008748]; BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression [01ES0811]; Netherlands Organization for Scientific Research (MagW/ZonMW) [904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, 912-100-20, 56-464-14192, 10-000-1002]; Center for Medical Systems Biology (NWO Genomics); Biobanking and Biomolecular Resources Research Infrastructure; VU University's Institutes for Health and Care Research and Neuroscience Campus Amsterdam; NBIC/BioAssist/RK [2008.024]; European Science Foundation [EU/QLRT-2001-01254]; European Community; ENGAGE [HEALTH-F4-2007-201413]; European Science Council (ERC) [230374]; Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health; GAIN; Netherlands Organization for Scientific Research (NOW-VENI grant) [916-76-125]; Swiss National Science Foundation [3200B0-105993, 3200B0-118'308, 33CSC0-122661]; GlaxoSmithKline (Psychiatry Center of Excellence for Drug Discovery and Genetics Division, Drug Discovery - Verona, RD); Australian National Health; Medical Research Council [241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667]; Australian Research Council [FT0991360, FT0991022]; FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]; US National Institutes of Health [AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951, U01 DK066134]; Center for Inherited Disease Research (Baltimore, MD, USA); UK Medical Research Council; GlaxoSmithKline [G0701420]; National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London; Maudsley NHS Foundation Trust; Institute of Psychiatry, King's College London; UK Medical Research Council [G0000647]; European Commission [LSHB-CT-2003-503428]; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Federal Ministry of Education and Research; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania; German Research Foundation [DFG: GR 1912/5-1]; Swedish Ministry for Higher Education; Swedish Research Council [M-2005-1112]; GenomEUtwin [EU/QLRT-2001-01254, QLG2-CT-2002-01254]; Swedish Foundation for Strategic Research; Wellcome Trust [076113, 085475]; [U54 RR020278]; [RC2MH089916] FX We thank the thousands of people with MDD who donated time and effort to make this research possible. The PGC was funded by NIMH Grants MH085520 (lead PI PFS) and MH080403. We thank our colleagues in the PGC Bipolar Disorder Working Group who allowed pre-publication access to their GWAS mega-analysis results for the MDD-BIP cross-disorder analyses. The Bonn/Mannheim (BoMa) GWAS was supported by the German Federal Ministry of Education and Research, within the context of the National Genome Research Network 2 (NGFN-2), the National Genome Research Network plus (NGFNplus) and the Integrated Genome Research Network (IG) MooDS (Grant 01GS08144 to S Cichon and MM Noethen, and Grant 01GS08147 to M Rietschel). The work at deCODE was funded by European Union Grants LSHM-CT-2006-037761 (Project SGENE), PIAP-GA-2008-218251 (Project PsychGene) and HEALTH-F2-2009-223423 (Project PsychCNVs). GenPod was funded by the Medical Research Council (UK) and supported by the Mental Health Research Network. Genotyping of the GenPod sample was funded by the Innovative Medicines Initiative Joint Undertaking under Grant Agreement number 115008 (NEWMEDS). The GenRED GWAS project was supported by NIMH R01 Grants MH061686 (DF Levinson), MH059542 (WH Coryell), MH075131 (WB Lawson), MH059552 (JB Potash), MH059541 (WA Scheftner) and MH060912 (MM Weissman). We acknowledge the contributions of Dr George S Zubenko and Dr Wendy N Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, to the GenRED I project. The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis with support from Grant U54 RR020278 (which partially subsidized the genotyping of the GenRED cases). Collection and quality control analyses of the control data set were supported by grants from NIMH and the National Alliance for Research on Schizophrenia and Depression. We are grateful to Knowledge Networks (Menlo Park, CA, USA) for assistance in collecting the control data set. We express our profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study. The Depression Genes and Networks ARRA grant was funded by RC2MH089916. Funding for the Harvard i2b2 sample was provided by a subcontract to RH Perlis and JW Smoller as part of the i2b2 Center (Informatics for Integrating Biology and the Bedside), an NIH-funded National Center for Biomedical Computing based at Partners HealthCare System (U54LM008748, PI: IS Kohane), and by an NIMH Grant to RH Perlis (MH086026). Max Planck Institute of Psychiatry MARS study was supported by the BMBF Program Molecular Diagnostics: Validation of Biomarkers for Diagnosis and Outcome in Major Depression (01ES0811). Genotyping was supported by the Bavarian Ministry of Commerce, and the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN2 and NGFN-Plus, FKZ 01GS0481 and 01GS08145). The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) contributed to GAIN-MDD and to MDD2000.; Funding was from: the Netherlands Organization for Scientific Research (MagW/ZonMW Grants 904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, 912-100-20; Spinozapremie 56-464-14192; Geestkracht program Grant 10-000-1002); the Center for Medical Systems Biology (NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure, VU University's Institutes for Health and Care Research and Neuroscience Campus Amsterdam, NBIC/BioAssist/RK (2008.024); the European Science Foundation (EU/QLRT-2001-01254); the European Community's Seventh Framework Program (FP7/2007-2013); ENGAGE (HEALTH-F4-2007-201413); and the European Science Council (ERC, 230374). Genotyping was funded in part by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health, and analysis was supported by grants from GAIN and the NIMH (MH081802). CM Middeldorp was supported by the Netherlands Organization for Scientific Research (NOW-VENI grant 916-76-125). The PsyCoLaus study was supported by grants from the Swiss National Science Foundation (#3200B0-105993, #3200B0-118'308, 33CSC0-122661) and from GlaxoSmithKline (Psychiatry Center of Excellence for Drug Discovery and Genetics Division, Drug Discovery - Verona, R&D). We express our gratitude to the Lausanne inhabitants who volunteered to participate in the PsyCoLaus study. We also thank V Mooser, G Weaber and P Vollenweider who initiated the CoLaus project. Funding for the QIMR samples was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, 619667), the Australian Research Council (FT0991360, FT0991022), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, DA019951), and the Center for Inherited Disease Research (Baltimore, MD, USA). We thank the twins and their families registered at the Australian Twin Registry for their participation in the many studies that have contributed to this research. RADIANT was funded by: a joint grant from the UK Medical Research Council and GlaxoSmithKline (G0701420); the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King's College London; and the UK Medical Research Council (G0000647). The GENDEP study was funded by a European Commission Framework 6 grant, EC Contract Ref.: LSHB-CT-2003-503428. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG. SHIP-LEGEND is funded by the German Research Foundation (DFG: GR 1912/5-1). Genotyping of STARstarD was supported by an NIMH Grant to SP Hamilton (MH072802).; STARstarD was funded by the National Institute of Mental Health (contract N01MH90003) to the University of Texas Southwestern Medical Center at Dallas (AJ Rush, principal investigator). The TwinGene study was supported by the Swedish Ministry for Higher Education, the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), the Swedish Foundation for Strategic Research and the US National Institutes of Health (U01 DK066134). This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under awards 076113 and 085475. NR 87 TC 105 Z9 106 U1 12 U2 118 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD APR PY 2013 VL 18 IS 4 BP 497 EP 511 DI 10.1038/mp.2012.21 PG 15 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 112CE UT WOS:000316568600016 ER PT J AU Ferguson, M Bianchi, MT Sutter, R Rosenthal, ES Cash, SS Kaplan, PW Westover, MB AF Ferguson, Matthew Bianchi, Matt T. Sutter, Raoul Rosenthal, Eric S. Cash, Sydney S. Kaplan, Peter W. Westover, M. Brandon TI Calculating the Risk Benefit Equation for Aggressive Treatment of Non-convulsive Status Epilepticus SO NEUROCRITICAL CARE LA English DT Article DE Non-convulsive status epilepticus; Risk benefit analysis; NCSE; Decision analysis ID REFRACTORY STATUS EPILEPTICUS; INTENSIVE-CARE-UNIT; CONVULSIVE STATUS EPILEPTICUS; TRAUMATIC BRAIN-INJURY; QUALITY-OF-LIFE; RESPIRATORY-DISTRESS-SYNDROME; INTRACEREBRAL HEMORRHAGE; ABSENCE STATUS; ELECTROGRAPHIC SEIZURES; HOSPITAL MORTALITY AB To address the question: does non-convulsive status epilepticus warrant the same aggressive treatment as convulsive status epilepticus? We used a decision model to evaluate the risks and benefits of treating non-convulsive status epilepticus with intravenous anesthetics and ICU-level aggressive care. We investigated how the decision to use aggressive versus non-aggressive management for non-convulsive status epilepticus impacts expected patient outcome for four etiologies: absence epilepsy, discontinued antiepileptic drugs, intraparenchymal hemorrhage, and hypoxic ischemic encephalopathy. Each etiology was defined by distinct values for five key parameters: baseline mortality rate of the inciting etiology; efficacy of non-aggressive treatment in gaining control of seizures; the relative contribution of seizures to overall mortality; the degree of excess disability expected in the case of delayed seizure control; and the mortality risk of aggressive treatment. Non-aggressive treatment was favored for etiologies with low morbidity and mortality such as absence epilepsy and discontinued antiepileptic drugs. The risk of aggressive treatment was only warranted in etiologies where there was significant risk of seizure-induced neurologic damage. In the case of post-anoxic status epilepticus, expected outcomes were poor regardless of the treatment chosen. The favored strategy in each case was determined by strong interactions of all five model parameters. Determination of the optimal management approach to non-convulsive status epilepticus is complex and is ultimately determined by the inciting etiology. C1 [Ferguson, Matthew; Bianchi, Matt T.; Rosenthal, Eric S.; Cash, Sydney S.; Westover, M. Brandon] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sutter, Raoul] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Div Neurosci Crit Care, Baltimore, MD 21205 USA. [Sutter, Raoul; Kaplan, Peter W.] Johns Hopkins Bayview Med Ctr, Dept Neurol, Baltimore, MD USA. [Westover, M. Brandon] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Westover, MB (reprint author), Massachusetts Gen Hosp, Wang 7 Neurol,55 Fruit St, Boston, MA 02114 USA. EM gferguson1212@gmail.com; mtbianchi@partners.org; rsutter3@jhmi.edu; erosenthal@partners.org; pkaplan@jhmi.edu; mb.westover@gmail.com OI Sutter, Raoul/0000-0002-6575-356X; Rosenthal, Eric/0000-0003-3900-356X FU NIH/NINDS [NS062092]; American Brain Foundation; National Center for Research Resources: Harvard Clinical and Translational Science Center; Center for Integration of Medicine and Innovative Technology (CIMIT); NIH/NIBIB [5U54EB007954-04]; Department of Defense [W81XWH-08-2-0154]; Andrew David Heitman Neuroendovascular Research Foundation FX MBW receives research support from the NIH/NINDS (NS062092) and American Brain Foundation. MTB receives research support from the National Center for Research Resources: Harvard Clinical and Translational Science Center and the Center for Integration of Medicine and Innovative Technology (CIMIT). ESR receives research support from the Center for Integration of Medicine and Innovative Technology (CIMIT), the NIH/NIBIB (5U54EB007954-04), the Department of Defense (W81XWH-08-2-0154), and the Andrew David Heitman Neuroendovascular Research Foundation. NR 78 TC 12 Z9 12 U1 0 U2 5 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 J9 NEUROCRIT CARE JI Neurocrit. Care PD APR PY 2013 VL 18 IS 2 BP 216 EP 227 DI 10.1007/s12028-012-9785-y PG 12 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA 105PR UT WOS:000316084700009 PM 23065689 ER PT J AU Battey, TWK Falcone, GJ Sheth, KN Goldstein, JN Rosand, J AF Battey, Thomas W. K. Falcone, Guido J. Sheth, Kevin N. Goldstein, Joshua N. Rosand, Jonathan TI Authors' Reply: Confounding by Indication in Retrospective Studies of Intracerebral Hemorrhage: Antiepileptic Treatment and Mortality SO NEUROCRITICAL CARE LA English DT Letter ID VOLUME C1 [Battey, Thomas W. K.; Falcone, Guido J.; Rosand, Jonathan] Massachusetts Gen Hosp, Hemorrhag Stroke Res Grp, Boston, MA 02114 USA. [Battey, Thomas W. K.; Falcone, Guido J.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Div Neurocrit Care & Emergency Neurol, Boston, MA 02114 USA. [Battey, Thomas W. K.; Falcone, Guido J.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Sheth, Kevin N.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. RP Rosand, J (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN 6818, Boston, MA 02114 USA. EM jrosand@partners.org RI Goldstein, Joshua/H-8953-2016; Falcone, Guido/L-2287-2016 OI Falcone, Guido/0000-0002-6407-0302 NR 4 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1541-6933 J9 NEUROCRIT CARE JI Neurocrit. Care PD APR PY 2013 VL 18 IS 2 BP 287 EP 288 DI 10.1007/s12028-013-9820-7 PG 2 WC Critical Care Medicine; Clinical Neurology SC General & Internal Medicine; Neurosciences & Neurology GA 105PR UT WOS:000316084700020 PM 23408339 ER PT J AU Huang, SN Farrar, CT Dai, GP Kwon, SJ Bogdanov, AA Rosen, BR Kim, YR AF Huang, Shuning Farrar, Christian T. Dai, Guangping Kwon, Seon Joo Bogdanov, Alexei A., Jr. Rosen, Bruce R. Kim, Young R. TI Dynamic monitoring of blood-brain barrier integrity using water exchange index (WEI) during mannitol and CO2 challenges in mouse brain SO NMR IN BIOMEDICINE LA English DT Article DE blood-brain barrier; water exchange; cerebral blood volume; mannitol; CO2; mouse ID NUCLEAR-MAGNETIC-RESONANCE; MIDDLE CEREBRAL-ARTERY; QUANTITATIVE-EVALUATION; CONTRAST AGENT; IN-VIVO; VOLUME; PERMEABILITY; ISCHEMIA; RATS; MRI AB The integrity of the bloodbrain barrier (BBB) is critical to normal brain function. Traditional techniques for the assessment of BBB disruption rely heavily on the spatiotemporal analysis of extravasating contrast agents. However, such methods based on the leakage of relatively large molecules are not suitable for the detection of subtle BBB impairment or for the performance of repeated measurements in a short time frame. Quantification of the water exchange rate constant (WER) across the BBB using strictly intravascular contrast agents could provide a much more sensitive method for the quantification of the BBB integrity. To estimate WER, we have recently devised a powerful new method using a water exchange index (WEI) biomarker and demonstrated BBB disruption in an acute stroke model. Here, we confirm that WEI is sensitive to even very subtle changes in the integrity of the BBB caused by: (i) systemic hypercapnia and (ii) low doses of a hyperosmolar solution. In addition, we have examined the sensitivity and accuracy of WEI as a biomarker of WER using computer simulation. In particular, the dependence of the WEIWER relation on changes in vascular blood volume, T1 relaxation of cellular magnetization and transcytolemmal water exchange was explored. Simulated WEI was found to vary linearly with WER for typically encountered exchange rate constants (14Hz), regardless of the blood volume. However, for very high WER (>5Hz), WEI became progressively more insensitive to increasing WER. The incorporation of transcytolemmal water exchange, using a three-compartment tissue model, helped to extend the linear WEI regime to slightly higher WER, but had no significant effect for most physiologically important WERs (WER<4Hz). Variation in cellular T1 had no effect on WEI. Using both theoretical and experimental approaches, our study validates the utility of the WEI biomarker for the monitoring of BBB integrity. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Huang, Shuning; Rosen, Bruce R.] MIT, HST, Cambridge, MA 02139 USA. [Huang, Shuning; Farrar, Christian T.; Dai, Guangping; Kwon, Seon Joo; Rosen, Bruce R.; Kim, Young R.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Bogdanov, Alexei A., Jr.] Univ Massachusetts, Sch Med, Worcester, MA USA. RP Kim, YR (reprint author), Harvard Univ, Harvard MIT HST Athinoula A Martinos Ctr Biomed I, Sch Med, Massachusetts Gen Hosp East, Bldg 149,13th St, Charlestown, MA 02129 USA. EM spmn@nmr.mgh.harvard.edu FU National Institutes of Health (NIH) [5R01EB002066-17]; American Heart Association SDG [0835451N]; NIH [S10RR025563] FX This work was supported by National Institutes of Health (NIH) grant 5R01EB002066-17, the American Heart Association SDG #0835451N and NIH grant S10RR025563. NR 39 TC 2 Z9 2 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD APR PY 2013 VL 26 IS 4 BP 376 EP 385 DI 10.1002/nbm.2871 PG 10 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 107IK UT WOS:000316209200003 PM 23055278 ER PT J AU Wu, WE Tal, A Kirov, II Rusinek, H Charytonowicz, D Babb, JS Ratai, EM Gonzalez, RG Gonen, O AF Wu, William E. Tal, Assaf Kirov, Ivan I. Rusinek, Henry Charytonowicz, Daniel Babb, James S. Ratai, Eva-Maria Gonzalez, R. Gilberto Gonen, Oded TI Global gray and white matter metabolic changes after simian immunodeficiency virus infection in CD8-depleted rhesus macaques: proton MRS imaging at 3 T SO NMR IN BIOMEDICINE LA English DT Article DE animal disease models; brain; HIV-1; Macaca mulatta; MRS; simian immunodeficiency virus ID MAGNETIC-RESONANCE-SPECTROSCOPY; CENTRAL-NERVOUS-SYSTEM; ACTIVE ANTIRETROVIRAL THERAPY; SIV INFECTION; RELAXATION-TIMES; NEURONAL INJURY; HIV-INFECTION; BRAIN-INJURY; DEMENTIA; MODEL AB To test the hypotheses that global decreased neuro-axonal integrity reflected by decreased N-acetylaspartate (NAA) and increased glial activation reflected by an elevation in its marker, the myo-inositol (mI), present in a CD8-depleted rhesus macaque model of HIV-associated neurocognitive disorders. To this end, we performed quantitative MRI and 16x16x4 multivoxel proton MRS imaging (TE/TR=33/1400ms) in five macaques pre- and 46weeks post-simian immunodeficiency virus infection. Absolute NAA, creatine, choline (Cho), and mI concentrations, gray and white matter (GM and WM) and cerebrospinal fluid fractions were obtained. Global GM and WM concentrations were estimated from 224 voxels (at 0.125cm3 spatial resolution over similar to 35% of the brain) using linear regression. Pre- to post-infection global WM NAA declined 8%: 6.6 +/- 0.4 to 6.0 +/- 0.5mM (p=0.05); GM Cho declined 20%: 1.3 +/- 0.2 to 1.0 +/- 0.1mM (p<0.003); global mI increased 11%: 5.7 +/- 0.4 to 6.5 +/- 0.5mM (p<0.03). Global GM and WM brain volume fraction changes were statistically insignificant. These metabolic changes are consistent with global WM (axonal) injury and glial activation, and suggest a possible GM host immune response. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Wu, William E.; Tal, Assaf; Kirov, Ivan I.; Rusinek, Henry; Charytonowicz, Daniel; Babb, James S.; Gonen, Oded] NYU, Dept Radiol, Sch Med, New York, NY 10016 USA. [Ratai, Eva-Maria; Gonzalez, R. Gilberto] Massachusetts Gen Hosp East, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Ratai, Eva-Maria; Gonzalez, R. Gilberto] Massachusetts Gen Hosp East, Neuroradiol Div, Charlestown, MA 02129 USA. RP Gonen, O (reprint author), NYU, Dept Radiol, Sch Med, 660 1st Ave,4th Floor, New York, NY 10016 USA. EM oded.gonen@med.nyu.edu OI Wu, William/0000-0003-0990-4164; Kirov, Ivan/0000-0001-5641-8578; Gonen, Oded/0000-0002-3148-2028 FU NIH [EB01015, NS050520, NS050041, NS051129, NS059331, NS040237]; National Center for Research Resources [P41RR14075]; Human Frontiers Science Project's Cross-Disciplinary Fellowship FX We thank Drs Andrew A. Maudsley and Brian J. Soher for their SITools-FITT software and Dr Joanne Morris and Ms Shannon Luboyeski for animal veterinary care. The study was supported by NIH Grants EB01015, NS050520, NS050041, NS051129, NS059331, NS040237 and NS059331. The Athinoula A. Martinos Center for Biomedical Imaging is supported by National Center for Research Resources grant number P41RR14075. Assaf Tal acknowledges support from the Human Frontiers Science Project's Cross-Disciplinary Fellowship. NR 56 TC 5 Z9 5 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD APR PY 2013 VL 26 IS 4 BP 480 EP 488 DI 10.1002/nbm.2889 PG 9 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 107IK UT WOS:000316209200015 PM 23418159 ER PT J AU Gupta, R Khosroshahi, A Shinagare, S Fernandez, C Ferrone, C Lauwers, GY Stone, JH Deshpande, V AF Gupta, Rajib Khosroshahi, Arezou Shinagare, Shweta Fernandez, Carlos Ferrone, Cristina Lauwers, Gregory Y. Stone, John H. Deshpande, Vikram TI Does Autoimmune Pancreatitis Increase the Risk of Pancreatic Carcinoma? A Retrospective Analysis of Pancreatic Resections SO PANCREAS LA English DT Article DE autoimmune pancreatitis; chronic pancreatitis; IgG4-related disease; pancreatic carcinoma ID INTRAEPITHELIAL NEOPLASIA; SCLEROSING PANCREATITIS; DUCTAL ADENOCARCINOMA; CANCER; DISEASE; CLASSIFICATION; INACTIVATION; METAANALYSIS; LESIONS AB Objectives: To estimate the risk of malignancy in autoimmune pancreatitis (AIP). Methods: We examined resected pancreata to compare the prevalence of pancreatic intraepithelial neoplasia (PanIN) in 28 cases of AIP and 30 cases of chronic pancreatitis not otherwise specified (CP-NOS). We also reviewed a cohort of 84 AIP cases. Results: The mean age of the AIP cohort (57 years) was significantly higher than that of the cohort of CP-NOS (47 years) (P = 0.01). Twenty-three cases (82%) of AIP showed PanIN, and 7 cases (25%) showed grade 2 PanIN. Grade 3 PanIN was identified in one case of AIP. There was no statistically significant difference in the number of cases with high-grade PanIN lesions between the cases of type 1 as opposed to type 2 AIP. In comparison to CP-NOS, a comparable percentage of patients with AIP had PanIN (82% of AIP cases vs 63% of CP-NOS cases) (P = NS) and PanIN 2 (25% AIP vs 20% CP-NOS) (P = NS). Of the 84 AIP cases at our institution (mean follow-up, 49 months), 2 cases of pancreatic carcinoma were identified 6 and 10 years after the diagnoses of AIP. Conclusions: These findings raise concern that AIP is associated with an elevated risk of malignancy and should prompt additional studies. C1 [Gupta, Rajib; Shinagare, Shweta; Lauwers, Gregory Y.; Deshpande, Vikram] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Khosroshahi, Arezou; Stone, John H.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol, Boston, MA 02114 USA. [Fernandez, Carlos; Ferrone, Cristina] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Deshpande, V (reprint author), Massachusetts Gen Hosp Warren 2, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM vdeshpande@partners.org NR 24 TC 23 Z9 25 U1 0 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD APR PY 2013 VL 42 IS 3 BP 506 EP 510 DI 10.1097/MPA.0b013e31826bef91 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 107FZ UT WOS:000316201700018 PM 23271394 ER PT J AU Lim, D Oliva, E AF Lim, D. Oliva, E. TI Precursors and pathogenesis of ovarian carcinoma SO PATHOLOGY LA English DT Article DE Origin; ovarian cancer; pathogenesis; precursors ID GRADE SEROUS CARCINOMA; TUBAL INTRAEPITHELIAL CARCINOMA; CLEAR-CELL CARCINOMA; COMPARATIVE GENOMIC HYBRIDIZATION; MOLECULAR-GENETIC-ANALYSIS; MALIGNANT POTENTIAL TUMORS; MUCINOUS BORDERLINE TUMORS; COMMON EPITHELIAL TUMORS; K-RAS PROTOONCOGENE; FALLOPIAN-TUBE AB The ultimate goal of defining cancer specific precursors is to facilitate early detection and intervention before the development of invasive malignancy. Unlike other malignancies involving the female genital tract such as cervical or endometrial carcinomas, precursor lesions of ovarian carcinomas have not been well characterised, resulting in a failure to develop effective screening programs. Recent clinicopathological and molecular studies have provided new insight into the origin and pathogenesis of ovarian carcinomas. It has been shown that ovarian cancer is comprised of different tumour types differing not only in morphology, but also in pathogenesis, molecular alterations and clinical progression. A dualistic model of ovarian carcinogenesis has been proposed. Type I tumours which include low grade serous, low grade endometrioid, clear cell, mucinous carcinomas and Brenner tumours, are generally indolent and tend to be genetically stable, although clear cell carcinoma would probably belong to an intermediate category. They demonstrate a step-wise progression from a benign precursor such as a benign to borderline tumour or endometriosis and are characterised by genetic aberrations targeting specific cell signalling pathways. Type II tumours comprise high grade serous, high grade endometrioid, and undifferentiated carcinomas as well as malignant mixed mesodermal tumours. They are clinically aggressive and exhibit high genetic instability with frequent p53 mutations. Mounting evidence suggests that many high grade serous carcinomas originate from the epithelium of the distal fallopian tube, and that serous tubal intraepithelial carcinoma (STIC) represents the putative precursor of these neoplasms. Low grade serous carcinomas arise via transformation of benign and borderline serous tumours, thought to be derived from inclusion cysts originating from the ovarian surface or tubal epithelium. Recently it has been suggested that papillary tubal hyperplasia may be a putative precursor lesion for serous borderline tumours. Both endometrioid and clear cell carcinomas develop from endometriosis, via alterations affecting different genetic pathways. The origin of mucinous and transitional cell neoplasms is not well characterised, although new data suggest a possible origin from transitional cell nests present at the tubal-mesothelial junction. Likewise, the pathogenesis of carcinosarcomas is also not well established because of their rarity but there is accumulating evidence that the carcinomatous component determines the course of the disease and gives rise to the malignant mesenchymal component. This review discusses recent developments in the pathogenesis of ovarian carcinoma, with particular emphasis on the putative precursor lesions that give rise to the major histological subtypes. Recognition of these lesions is not only important in improving the understanding of ovarian carcinogenesis, but it will also influence our approach to prevent, detect and treat these tumours. C1 [Lim, D.] Natl Univ Hlth Syst, Dept Pathol, Singapore, Singapore. [Oliva, E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Oliva, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 2, Boston, MA 02114 USA. EM eoliva@partners.org NR 186 TC 37 Z9 38 U1 2 U2 30 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0031-3025 EI 1465-3931 J9 PATHOLOGY JI Pathology PD APR PY 2013 VL 45 IS 3 BP 229 EP 242 DI 10.1097/PAT.0b013e32835f2264 PG 14 WC Pathology SC Pathology GA 107TT UT WOS:000316244400004 PM 23478230 ER PT J AU Liu, TT Glover, GH Mueller, BA Greve, DN Brown, GG AF Liu, Thomas T. Glover, Gary H. Mueller, Bryon A. Greve, Douglas N. Brown, Gregory G. TI An Introduction to Normalization and Calibration Methods in Functional MRI SO PSYCHOMETRIKA LA English DT Article DE functional MRI; arterial spin labeling; cerebral blood flow; quantitative fMRI; calibrated fMRI; hypercapnia ID CEREBRAL-BLOOD-FLOW; BOLD HEMODYNAMIC-RESPONSES; OXYGEN-METABOLISM CHANGES; RAT SOMATOSENSORY CORTEX; MEMORY-ENCODING TASK; NEURAL ACTIVITY; OXIDATIVE-METABOLISM; NEURONAL-ACTIVITY; FMRI RESPONSE; HYPERCAPNIC NORMALIZATION AB In functional magnetic resonance imaging (fMRI), the blood oxygenation level dependent (BOLD) signal is often interpreted as a measure of neural activity. However, because the BOLD signal reflects the complex interplay of neural, vascular, and metabolic processes, such an interpretation is not always valid. There is growing evidence that changes in the baseline neurovascular state can result in significant modulations of the BOLD signal that are independent of changes in neural activity. This paper introduces some of the normalization and calibration methods that have been proposed for making the BOLD signal a more accurate reflection of underlying brain activity for human fMRI studies. C1 [Liu, Thomas T.] Univ Calif San Diego, Ctr Funct MRI, La Jolla, CA 92093 USA. [Glover, Gary H.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Mueller, Bryon A.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Greve, Douglas N.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Brown, Gregory G.] VA San Diego Healthcare Syst, San Diego, CA USA. [Brown, Gregory G.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. RP Liu, TT (reprint author), Univ Calif San Diego, Ctr Funct MRI, 9500 Gilman Dr,MC 0677, La Jolla, CA 92093 USA. EM ttliu@ucsd.edu FU NIH National Center for Research Resources for the FBIRN consortium [U24-RR021992]; [P41-RR009784]; [R01NS051661]; [R01MH084796] FX We acknowledge funding support by the NIH National Center for Research Resources for the FBIRN consortium (Grant U24-RR021992) as well as individual grants to coinvestigators: P41-RR009784 (GHG), R01NS051661, and R01MH084796 (TTL). NR 82 TC 4 Z9 4 U1 2 U2 21 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3123 J9 PSYCHOMETRIKA JI Psychometrika PD APR PY 2013 VL 78 IS 2 BP 308 EP 321 DI 10.1007/s11336-012-9309-x PG 14 WC Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods; Psychology, Mathematical SC Mathematics; Mathematical Methods In Social Sciences; Psychology GA 109CV UT WOS:000316344000007 PM 25107618 ER PT J AU Nambiar, AM AF Nambiar, Anoop M. TI Procalcitonin in acute exacerbations of interstitial pneumonia: Another tool in the toolbox? SO RESPIROLOGY LA English DT Editorial Material DE acute respiratory distress syndrome; interstitial; lung disease; pneumonia; pulmonary fibrosis ID IDIOPATHIC PULMONARY-FIBROSIS; DIAGNOSIS C1 Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, Dept Med, Audie L Murphy Div,Div Pulm Dis & Crit Care Med, San Antonio, TX 78229 USA. RP Nambiar, AM (reprint author), Univ Texas Hlth Sci Ctr San Antonio, South Texas Vet Hlth Care Syst, Dept Med, Audie L Murphy Div,Div Pulm Dis & Crit Care Med, San Antonio, TX 78229 USA. NR 13 TC 1 Z9 1 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-7799 J9 RESPIROLOGY JI Respirology PD APR PY 2013 VL 18 IS 3 BP 389 EP 390 DI 10.1111/resp.12055 PG 2 WC Respiratory System SC Respiratory System GA 112ZV UT WOS:000316636000001 PM 23336530 ER PT J AU Porcel, JM Leung, CC Restrepo, MI Takahashi, K Lee, P AF Porcel, Jose M. Leung, Chi Chiu Restrepo, Marcos I. Takahashi, Kazuhisa Lee, Pyng TI Year in review 2012: Lung cancer, respiratory infections, tuberculosis, pleural diseases, bronchoscopic intervention and imaging SO RESPIROLOGY LA English DT Review DE bronchoscopic intervention and imaging; lung cancer; pleural disease; respiratory infection; tuberculosis ID COMMUNITY-ACQUIRED PNEUMONIA; DRUG-RESISTANT TUBERCULOSIS; OBSTRUCTIVE PULMONARY-DISEASE; EPITHELIAL-MESENCHYMAL TRANSITIONS; C-REACTIVE PROTEIN; ENDOBRONCHIAL ULTRASOUND; PARAPNEUMONIC EFFUSIONS; CONSENSUS GUIDELINES; PREDICTING MORTALITY; THORACIC-SOCIETY C1 [Porcel, Jose M.] Arnau de Vilanova Univ Hosp, Dept Internal Med, Pleural Dis Unit, Biomed Res Inst Lleida, Lleida 25198, Spain. [Leung, Chi Chiu] Dept Hlth, TB & Chest Serv, Hong Kong, Hong Kong, Peoples R China. [Restrepo, Marcos I.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Restrepo, Marcos I.] South Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. [Restrepo, Marcos I.] Vet Evidence Based Res Disseminat & Implement Ctr, San Antonio, TX USA. [Takahashi, Kazuhisa] Juntendo Univ, Grad Sch Med, Dept Resp Med, Tokyo, Japan. [Lee, Pyng] Natl Univ Singapore Hosp, Dept Med, Singapore 117548, Singapore. RP Porcel, JM (reprint author), Arnau de Vilanova Univ Hosp, Dept Internal Med, Avda Alcalde Rovira Roure 80, Lleida 25198, Spain. EM jporcelp@yahoo.es RI Restrepo, Marcos/H-4442-2014 FU National Heart, Lung, and Blood Institute [K23HL096054] FX M.I.R.'s time is partially protected by Award Number K23HL096054 from the National Heart, Lung, and Blood Institute. The content of M.I.R.'s contribution on respiratory infections is solely the responsibility of the author and does not necessarily represent the official views of the National Heart, Lung, And Blood Institute, the National Institutes of Health or the Department of Veterans Affairs. NR 82 TC 2 Z9 2 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1323-7799 EI 1440-1843 J9 RESPIROLOGY JI Respirology PD APR PY 2013 VL 18 IS 3 BP 573 EP 583 DI 10.1111/resp.12048 PG 11 WC Respiratory System SC Respiratory System GA 112ZV UT WOS:000316636000028 PM 23317457 ER PT J AU Brada, M Bortfeld, T AF Brada, Michael Bortfeld, Thomas TI Proton Therapy: The Present and the Future SO SEMINARS IN RADIATION ONCOLOGY LA English DT Editorial Material C1 [Brada, Michael] Univ Coll London Hosp NHS Fdn Trust, Leaders Oncol Care, London, England. [Bortfeld, Thomas] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Bortfeld, Thomas] Harvard Univ, Sch Med, Boston, MA USA. RP Brada, M (reprint author), Univ Coll London Hosp NHS Fdn Trust, Leaders Oncol Care, London, England. NR 0 TC 7 Z9 7 U1 0 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD APR PY 2013 VL 23 IS 2 BP 75 EP 76 DI 10.1016/j.semradonc.2012.11.001 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 111NF UT WOS:000316527300001 PM 23473683 ER PT J AU Paganetti, H van Luijk, P AF Paganetti, Harald van Luijk, Peter TI Biological Considerations When Comparing Proton Therapy. With Photon Therapy SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; EARLY DNA-DAMAGE; INTENSITY-MODULATED PHOTON; VOLUME HISTOGRAM ANALYSIS; CULTURED MAMMALIAN-CELLS; NEUTRON DOSE-EQUIVALENT; PAROTID-GLAND FUNCTION; BIOL-PHYS 2006/65/1-7; CERVICAL-SPINAL CORD; INDUCED 2ND CANCERS AB Owing to the limited availability of data on the outcome of proton therapy, treatments are generally optimized based on broadly available data on photon-based treatments. However, the microscopic pattern of energy deposition of protons differs from that of photons, leading to a different biological effect. Consequently, proton therapy needs a correction factor (relative biological effectiveness) to relate proton doses to photon doses, and currently, a generic value is used. Moreover, the macroscopic distribution of dose in proton therapy differs compared with photon treatments. Although this may offer new opportunities to reduce dose to normal tissues, it raises the question whether data obtained from photon-based treatments offer sufficient information on dose-volume effects to optimally use unique features of protons. In addition, there are potential differences in late effects due to low doses of secondary radiation outside the volume irradiated by the primary beam. This article discusses the controversies associated with these 3 issues when comparing proton and photon therapy. Semin Radiat Oncol 23:77-87 (C) 2013 Elsevier Inc. All rights reserved. C1 [Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Paganetti, Harald] Harvard Univ, Sch Med, Boston, MA USA. [van Luijk, Peter] Univ Groningen, Univ Med Ctr Groningen, Dept Radiat Oncol, Groningen, Netherlands. [van Luijk, Peter] Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, Groningen, Netherlands. RP Paganetti, H (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM hpaganetti@partners.org RI van Luijk, Peter/A-6877-2013 OI van Luijk, Peter/0000-0001-7959-1234 NR 119 TC 20 Z9 20 U1 1 U2 14 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD APR PY 2013 VL 23 IS 2 BP 77 EP 87 DI 10.1016/j.semradonc.2012.11.002 PG 11 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 111NF UT WOS:000316527300002 PM 23473684 ER PT J AU Mouw, KW Trofimov, A Zietman, AL Efstathiou, JA AF Mouw, Kent W. Trofimov, Alexei Zietman, Anthony L. Efstathiou, Jason A. TI Clinical Controversies: Proton Therapy for Prostate Cancer SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID INTENSITY-MODULATED RADIOTHERAPY; CONFORMAL RADIATION-THERAPY; INDUCED DOSE REDUCTION; BEAM TREATMENT; TARGET VOLUME; PHASE-II; MOVEMENT; TRIAL; TOXICITIES; OUTCOMES AB Proton therapy has been used in the treatment of prostate cancer for several decades, and interest surrounding its use continues to grow. Proton-based treatment techniques have evolved significantly over this period, and several centers now routinely use technologies such as pencil-beam scanning. However, whether the theoretical dosimetric advantages of the proton beam translate into clinically meaningful improvements for prostate cancer patients is unknown, and outcomes from single-arm experiences using whole courses of proton beam therapy in the treatment of early-stage prostate cancer have shown mixed results when compared with contemporary intensity-modulated radiotherapy. A randomized trial comparing proton beam therapy with intensity-modulated radiotherapy in early-stage disease has been launched and will be important in defining the role for proton therapy in this setting. We review the available evidence and present the current state of proton beam therapy for prostate cancer. Semin Radiat Oncol 23:109-114 (C) 2013 Elsevier Inc. All rights reserved. C1 [Mouw, Kent W.] Harvard Radiat Oncol Program, Boston, MA USA. [Trofimov, Alexei; Zietman, Anthony L.; Efstathiou, Jason A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Mouw, KW (reprint author), Harvard Radiat Oncol Program, Boston, MA USA. EM kmouw@lroc.harvard.edu FU NCI NIH HHS [C06 CA059267] NR 36 TC 7 Z9 7 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD APR PY 2013 VL 23 IS 2 BP 109 EP 114 DI 10.1016/j.semradonc.2012.11.009 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 111NF UT WOS:000316527300005 PM 23473687 ER PT J AU Flanz, J Bortfeld, T AF Flanz, Jacob Bortfeld, Thomas TI Evolution of Technology to Optimize the Delivery of Proton Therapy: The Third Generation SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; COMPUTED-TOMOGRAPHY; RADIATION-THERAPY; PROSTATE-CANCER; BEAM DELIVERY; PROMPT GAMMA; RANGE; VERIFICATION; RADIOTHERAPY; SIMULATIONS AB The evolution of proton therapy technology will lead to a new generation of systems that allow for greater accuracy and precision of the dose delivery and will be more compact. We envision that over the next 10-15 years, the quality of deliverable proton dose distributions in the patient will be pushed nearly toward the physical limit of proton therapy. Those future proton therapy systems will fit into treatment rooms of similar size as today's conventional radiation treatment rooms. At the same time, due to technological advancements, the cost of proton therapy will come down to the cost of advanced photon therapy. We discuss some of the technologies that will put these speculative improvements within reach. Semin Radiat Oncol 23:142-148 (C) 2013 Elsevier Inc. All rights reserved. C1 [Flanz, Jacob] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Flanz, Jacob] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Flanz, J (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM jflanz@partners.org NR 34 TC 8 Z9 8 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 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD APR PY 2013 VL 23 IS 2 BP 142 EP 148 DI 10.1016/j.semradonc.2012.11.006 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 111NF UT WOS:000316527300010 PM 23473692 ER PT J AU Anaya, HD Butler, JN Solomon, JL Knapp, H Hoang, T Kan, V Rodriguez-Barradas, MC Hare, KA Kertz, B Bokhour, B AF Anaya, Henry D. Butler, Jaimi N. Solomon, Jeffrey L. Knapp, Herschel Hoang, Tuyen Kan, Virginia Rodriguez-Barradas, Maria C. Hare, Katherine A. Kertz, Barbara Bokhour, Barbara TI Implementation of Nurse-Initiated Rapid HIV Testing at High-Prevalence Primary Care Sites Within the US Veterans Affairs Health Care System SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID UNITED-STATES; IMMUNIZATION; DISEASE; RISK AB Nurse-initiated HIV rapid testing (NRT) increases testing/receipt of results compared with traditional testing. We implemented NRT in primary care clinics at 2 Veterans Affairs hospitals. At site 1, 2364 tests were conducted; 5 HIV positives were identified. At site 2, 2522 tests were conducted; 9 HIV positives were identified. Success varied across demographic/clinical strata. C1 [Anaya, Henry D.; Butler, Jaimi N.; Knapp, Herschel; Hoang, Tuyen] VA Greater Los Angeles Healthcare Syst, Vet Affairs VA Qual Enhancement Res Initiat HIV &, Los Angeles, CA USA. [Anaya, Henry D.; Butler, Jaimi N.; Knapp, Herschel; Hoang, Tuyen] VA Greater Los Angeles Healthcare Syst, Ctr Study Healthcare Provider Behav, VA Greater Los Angeles Hlth Serv Res & Dev Ctr Ex, Los Angeles, CA USA. [Anaya, Henry D.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med, Los Angeles, CA 90095 USA. [Anaya, Henry D.] VA Chicago Healthcare Syst, VA Ctr Management Complex Chron Condit, Chicago, IL USA. [Anaya, Henry D.] VA Chicago Healthcare Syst, Qual Enhancement Res Initiat Spinal Cord Injury S, Chicago, IL USA. [Solomon, Jeffrey L.; Bokhour, Barbara] VA New England Healthcare Syst, Bedford, MA USA. [Kan, Virginia; Hare, Katherine A.] VA Med Ctr, Washington, DC USA. [Kan, Virginia] George Washington Univ, Infect Dis Sect, Washington, DC USA. [Rodriguez-Barradas, Maria C.; Kertz, Barbara] Michael E DeBakey VA Med Ctr, Infect Dis Sect, Houston, TX USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. RP Anaya, HD (reprint author), 11301Wilshire Blvd 111G, Los Angeles, CA 90073 USA. EM henry.anaya@va.gov OI Bokhour, Barbara/0000-0001-8238-0745 FU VA Quality Enhancement Research Initiative (QUERI) [SDP07-318]; Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service; Veterans Health Administration FX This research was funded by VA Quality Enhancement Research Initiative (QUERI) grant SDP07-318 awarded to the first author and supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service. The authors thank the primary care clinics and all the nurses who participated in these testing efforts; their participation, dedication, support, and patience were invaluable. The views and opinions expressed in this article are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs. The Veterans Health Administration supported this study but had no input in the design or reporting, or decision to submit this manuscript for publication. This study was reviewed and sanctioned by a US Department of Veterans Affairs institutional review board process. NR 18 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD APR PY 2013 VL 40 IS 4 BP 341 EP 345 DI 10.1097/OLQ.0b013e31828417a5 PG 5 WC Infectious Diseases SC Infectious Diseases GA 107CQ UT WOS:000316192700018 PM 23486502 ER PT J AU Mehtsun, WT Ibrahim, AM Diener-West, M Pronovost, PJ Makary, MA AF Mehtsun, Winta T. Ibrahim, Andrew M. Diener-West, Marie Pronovost, Peter J. Makary, Martin A. TI Surgical never events in the United States SO SURGERY LA English DT Article ID WRONG-SITE SURGERY; QUALITY-OF-CARE; ADVERSE EVENTS; PATIENT SAFETY; PREVENTION; PERFORMANCE; MANAGEMENT; CHECKLIST; PATTERNS AB Background. Surgical never events are being used increasingly as quality metrics in health care in the United States. However, little is known about their costs to the health care system, the outcomes of patients, or the characteristics of the providers involved. We designed a study to describe the number and magnitude of paid malpractice claims for surgical never events, as well as associated patient and provider characteristics. Methods. We used the National Practitioner Data Bank, a federal repository of medical malpractice claims, to identify malpractice settlements and judgments of surgical never events, including retained foreign bodies, wrong-site, wrongpatient, and wrong-procedure surgery. Payment amounts, patient outcomes, and provider characteristics were evaluated. Results. We identified a total of 9,744 paid malpractice settlement and judgments for surgical never events occurring between 1990 and 2010. Malpractice payments for surgical never events totaled $1.3 billion. Mortality occurred in 6.6% of patients, permanent injury in 32.9%, and temporary injury in 59.2%. Based on literature rates of surgical adverse events resulting in paid malpractice claims, we estimated that 4,082 surgical never event claims occur each year in the United States. Increased payments were associated with severe patient outcomes and claims involving a physician with multiple malpractice reports. Of physicians named in a surgical never event claim, 12.4% were later named in at least 1 future surgical never event claim. Conclusion. Surgical never events are costly to the health care system and are associated with serious harm to patients. Patient and provider characteristics may help to guide prevention strategies. (Surgery 2013;153:465-72.) C1 [Mehtsun, Winta T.; Ibrahim, Andrew M.; Pronovost, Peter J.; Makary, Martin A.] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21287 USA. [Pronovost, Peter J.] Johns Hopkins Univ, Sch Med, Dept Anesthesiol Crit Care Med, Baltimore, MD 21287 USA. [Mehtsun, Winta T.; Pronovost, Peter J.; Makary, Martin A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. [Mehtsun, Winta T.; Diener-West, Marie] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Mehtsun, Winta T.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Ibrahim, Andrew M.] Univ Hosp Case Med Ctr, Dept Surg, Cleveland, OH USA. RP Makary, MA (reprint author), Johns Hopkins Univ, Sch Med, Dept Surg, Osler 624,600 N Wolfe St, Baltimore, MD 21287 USA. EM mmakary1@jhmi.edu NR 40 TC 27 Z9 27 U1 0 U2 14 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 APR PY 2013 VL 153 IS 4 BP 465 EP 472 DI 10.1016/j.surg.2012.10.005 PG 8 WC Surgery SC Surgery GA 113FD UT WOS:000316651000006 PM 23257079 ER PT J AU Nguyen, B Tao, M Yu, P Mauro, C Seidman, MA Wang, YYE Mitchell, J Ozaki, CK AF Binh Nguyen Tao, Ming Yu, Peng Mauro, Christine Seidman, Michael A. Wang, Yaoyu E. Mitchell, James Ozaki, C. Keith TI Preoperative diet impacts the adipose tissue response to surgical trauma SO SURGERY LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; ISCHEMIA/REPERFUSION INJURY; INFLAMMATION; FAT; OBESITY; MICE; RESTRICTION; PHENOTYPE; DISEASE; HUMANS AB Background. Short-term changes in preoperative nutrition can have profound effects on surgery-related outcomes such as ischemia/reperfusion injury in preclinical models. Dietary interventions that lend protection against stress in animal models (eg, fasting, dietary restriction [DR]) impact adipose tissue quality/ quantity. Adipose tissue holds high surgical relevance because of its anatomic location and large tissue volume, and it is ubiquitously traumatized during surgery. Yet the response of adipose tissue to trauma under clinically relevant circumstances including dietary status remains poorly defined. We hypothesized that preoperative diet alters the adipose tissue response to surgical trauma. Methods. A novel mouse model of adipose tissue surgical trauma was employed. Dietary conditions (dietinduced obesity [DIM preoperative DR) were modulated before application of surgical adipose tissue trauma in the context of clinically common scenarios. (different ages, simulated bacterial wound contamination). Local/distant adipose tissue phenotypic responses were measured as represented by gene expression of inflammatory, tissue remodeling/growth, and metabolic markers. Results. Surgical trauma had a profound effect on adipose tissue phenotype at the site of trauma. Milder but significant distal effects on non-traumatized adipose tissue were also observed. DIO exacerbated the inflammatory aspects of this response, and preoperative DR tended to reverse these changes. Age and lipopolysaccharide (LPS)-simulated bacterial contamination also impacted the adipose tissue response to trauma, with young adult animals and LPS treatment exacerbating the proinflammatory response. Conclusion. Surgical trauma dramatically impacts both local and distal adipose tissue biology. Shortterm preoperative DR may offer a strategy to attenuate this response. (Surgery 2013;153:584-93.) C1 [Binh Nguyen; Tao, Ming; Yu, Peng; Mauro, Christine; Ozaki, C. Keith] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA. [Seidman, Michael A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol & Lab Med, Boston, MA 02115 USA. [Wang, Yaoyu E.] Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02115 USA. [Mitchell, James] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. RP Ozaki, CK (reprint author), 75 Francis St, Boston, MA 02115 USA. EM CKOzaki@partners.org FU National Heart, Lung, and.Blood Institute [T32HL007734]; American Heart Association [12GRNT9510001]; Carl and Ruth Shapiro Family Foundation; CCCB; Dana-Farber Strategic Plan Initiative FX Supported by the National Heart, Lung, and.Blood Institute (T32HL007734), American Heart Association (12GRNT9510001), and the Carl and Ruth Shapiro Family Foundation. YEW is supported through the CCCB and the Dana-Farber Strategic Plan Initiative. NR 42 TC 5 Z9 6 U1 0 U2 8 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 APR PY 2013 VL 153 IS 4 BP 584 EP 593 DI 10.1016/j.surg.2012.11.901 PG 10 WC Surgery SC Surgery GA 113FD UT WOS:000316651000020 PM 23274098 ER PT J AU Kadauke, S Picarelli, A Di Tola, M Parikh, RK Naylor, P Zhou, WL Bowman, J Bullock, D Tobi, M AF Kadauke, S. Picarelli, A. Di Tola, M. Parikh, R. K. Naylor, P. Zhou, W. -L. Bowman, J. Bullock, D. Tobi, M. TI Letter: Adnab-9 as a potential non-invasive biomarker for prediction of malignancy in coeliac disease SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Letter ID MONOCLONAL-ANTIBODY ADNAB-9; SMALL-INTESTINE; MARKER; CANCER C1 [Kadauke, S.] Perelman Sch Med, Med Scientist Training Program, Philadelphia, PA 19104 USA. [Picarelli, A.; Di Tola, M.] Univ Roma La Sapienza, Dept Internal Med & Med Special, Rome, Italy. [Parikh, R. K.; Naylor, P.; Zhou, W. -L.; Bowman, J.; Bullock, D.; Tobi, M.] Wayne State Univ, Sch Med, John D Dingell VAMC Dept Med, Detroit, MI USA. [Tobi, M.] Philadelphia Vet Affairs Med Ctr, Div Gastroenterol, Gastroenterol Sect, Philadelphia, PA USA. [Tobi, M.] Perelman Sch Med, Philadelphia, PA USA. RP Kadauke, S (reprint author), Perelman Sch Med, Med Scientist Training Program, Philadelphia, PA 19104 USA. EM martin.tobi@va.gov OI Picarelli, Antonio/0000-0002-6104-8193 NR 8 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD APR PY 2013 VL 37 IS 7 BP 761 EP 762 DI 10.1111/apt.12231 PG 2 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 100ZC UT WOS:000315743300023 PM 23458541 ER PT J AU Konstantinidis, IT Warshaw, AL Allen, JN Blaszkowsky, LS Fernandez-del Castillo, C Deshpande, V Hong, TS Kwak, EL Lauwers, GY Ryan, DP Wargo, JA Lillemoe, KD Ferrone, CR AF Konstantinidis, Ioannis T. Warshaw, Andrew L. Allen, Jill N. Blaszkowsky, Lawrence S. Fernandez-del Castillo, Carlos Deshpande, Vikram Hong, Theodore S. Kwak, Eunice L. Lauwers, Gregory Y. Ryan, David P. Wargo, Jennifer A. Lillemoe, Keith D. Ferrone, Cristina R. TI Pancreatic Ductal Adenocarcinoma Is There a Survival Difference for R1 Resections Versus Locally Advanced Unresectable Tumors? What Is a "True" R0 Resection? SO ANNALS OF SURGERY LA English DT Article DE locally advanced; pancreatic adenocarcinoma; R1 resections; 1-mm margin ID QUALITY-OF-LIFE; COMPARING STANDARD PANCREATICODUODENECTOMY; MINIMAL POSTOPERATIVE COMPLICATIONS; SINGLE-INSTITUTION EXPERIENCE; RANDOMIZED CONTROLLED TRIAL; LONG-TERM SURVIVAL; EXTENDED LYMPHADENECTOMY; SURGICAL-TREATMENT; PERIAMPULLARY ADENOCARCINOMA; SURGEONS CONTRIBUTION AB Objective: Patients who undergo an R0 resection of their pancreatic ductal adenocarcinoma (PDAC) have an improved survival compared with patients who undergo an R1 resection. It is unclear whether an R1 resection confers a survival benefit over locally advanced (LA) unresectable tumors. Our aim was to compare the survival of patients undergoing an R1 resection with those having LA tumors and to explore the prognostic significance of a 1-mm surgical margin. Methods: Clinicopathologic data from a pancreatic cancer database between January 1993 and July 2008 were reviewed. Locally advanced tumors had no evidence of metastatic disease at exploration. Results: A total of 1705 patients were evaluated for PDAC in the Department of Surgery. Of the 1084 (64%) patients who were surgically explored, 530 (49%) were considered unresectable (286 locally unresectable, 244 with distant metastasis). One hundred fifty-seven (28%) of the resected PDACs had an R1 resection. Patients undergoing an R1 resection had a slightly longer survival compared with those who had locally advanced unresectable cancers (14 vs 11 months; P < 0.001). Patients with R0 resections had a favorable survival compared with those with R1 resections (23 vs 14 months; P < 0.001), but survival after resections with 1-mm margin or less (R0-close) were similar to R1 resections: both groups had a significantly shorter median survival than patients with amargin of greater than 1mm (R0-wide) (16 vs 14 vs 35 months, respectively; P < 0.001). Conclusions: Patients undergoing an R1 resection still have an improved survival compared with patients with locally advanced unresectable pancreatic adenocarcinoma. R0 resections have an improved survival compared with R1 resections, but this survival benefit is lost when the tumor is within 1 mm of the resection margin. C1 [Konstantinidis, Ioannis T.; Warshaw, Andrew L.; Fernandez-del Castillo, Carlos; Wargo, Jennifer A.; Lillemoe, Keith D.; Ferrone, Cristina R.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Allen, Jill N.; Blaszkowsky, Lawrence S.; Kwak, Eunice L.; Ryan, David P.] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Deshpande, Vikram; Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Ferrone, CR (reprint author), Wang Ambulatory Care Ctr 460,15 Parkman St, Boston, MA 02114 USA. EM cferrone@partners.org NR 41 TC 102 Z9 105 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD APR PY 2013 VL 257 IS 4 BP 731 EP 736 DI 10.1097/SLA.0b013e318263da2f PG 6 WC Surgery SC Surgery GA 104JY UT WOS:000315990100030 PM 22968073 ER PT J AU Ross, SA Allen, DN Goldstein, G AF Ross, Sylvia An Allen, Daniel N. Goldstein, Gerald TI Factor Structure of the Halstead-Reitan Neuropsychological Battery: A Review and Integration SO APPLIED NEUROPSYCHOLOGY-ADULT LA English DT Article DE factor analysis; Halstead-Reitan Neuropsychological Battery; neuropsychological assessment ID BRAIN-DAMAGE; WAIS-R; TESTS; PERFORMANCE; DYSFUNCTION; ATTENTION; VALIDITY; MATRIX; SKILLS AB The Halstead-Reitan Neuropsychological Battery (HRNB) was the first factor-analyzed neuropsychological battery. It was based on a series of tests studied in Ward Halstead's laboratory at the University of Chicago, was accomplished in collaboration with a group of eminent statisticians, and was published in 1947. Four factors were extracted based on Halstead's tests called central integrative field, abstraction, power, and directional and constituted what was described as biological intelligence. Since this original analysis, Reitan's additions to the battery, and the proposal of Reitan and Wolfson's model of neuropsychological functioning, this factor-analytic research continued. This article reviews factor-analytic research concluding that Halstead's analysis has held up reasonably well and there is support for the Reitan and Wolfson model. However, Reitan's revisions of the battery added tests that form a distinct language factor and the sensory-perceptual tests that generally form a separate factor. Other tests and scoring methods used in individual studies modified the core battery and produced somewhat differing solutions. The complexity of the tests prevents the HRNB from being a factorially pure battery, and simple structure is rarely, if ever, reached. Current versions of the HRNB appear to evaluate both biological and psychometric intelligence, which appear to load on separate factors. C1 [Ross, Sylvia An; Allen, Daniel N.] Univ Nevada, Dept Psychol, Las Vegas, NV 89154 USA. [Goldstein, Gerald] VA Pittsburgh Healthcare Syst, Mental Illness Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Allen, DN (reprint author), Univ Nevada, Dept Psychol, 4505 Maryland Pkwy, Las Vegas, NV 89154 USA. EM daniel.allen@unlv.edu FU Mental Illness Research, Education, and Clinical Center (MIRECC), VA Pittsburgh Healthcare System; Medical Research Service, Department of Veterans Affairs FX Indebtedness is expressed to the Mental Illness Research, Education, and Clinical Center (MIRECC), VA Pittsburgh Healthcare System, and the Medical Research Service, Department of Veterans Affairs for support of this research. NR 49 TC 0 Z9 0 U1 1 U2 5 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0908-4282 J9 APPL NEUROPSYCH-ADUL JI Appl. Neuropsychol.-Adult PD APR 1 PY 2013 VL 20 IS 2 BP 120 EP 135 DI 10.1080/09084282.2012.690798 PG 16 WC Clinical Neurology; Psychology SC Neurosciences & Neurology; Psychology GA 100EA UT WOS:000315677400006 PM 23397998 ER PT J AU Bredella, MA Fazeli, PK Lecka-Czernik, B Rosen, CJ Klibanski, A AF Bredella, Miriam A. Fazeli, Pouneh K. Lecka-Czernik, Beata Rosen, Clifford J. Klibanski, Anne TI IGFBP-2 is a negative predictor of cold-induced brown fat and bone young non-obese women SO BONE LA English DT Article DE Brown adipose tissue (BAT); IGFBP-2; Bone mineral density (BMD); Anorexia nervosa (AN) ID GROWTH FACTOR-I; FACTOR-BINDING PROTEIN-2; ADIPOSE-TISSUE; MINERAL DENSITY; ANOREXIA-NERVOSA; INSULIN; DIFFERENTIATION; PROGRAM; NECDIN; IGF-1 AB Recent studies have shown a positive correlation between brown adipose tissue (BAT) and bone mineral density (BMD). However, mechanisms underlying this relationship are unknown. Insulin-like growth factor 1 (IGF-1) is an important regulator of stem cell differentiation promoting bone formation. IGF binding protein 2 (IGFBP-2) binds IGF-1 in the circulation and has been reported to inhibit bone formation in humans. IGF-1 is also a crucial regulator of brown adipocyte differentiation. We hypothesized that IGFBP-2 is a negative and IGF-1 a positive regulator of BAT-mediated osteoblastogenesis. We therefore investigated a cohort of 15 women (mean age 27.7 +/- 5.7 years): 5 with anorexia nervosa (AN) in whom IGF-1 levels were low due to starvation, 5 recovered AN (AN-R), and 5 women of normal weight. All subjects underwent assessment of cold-activated BAT by PET/CT, BMD of the spine, hip, femoral neck, and total body by DXA, thigh muscle area by MRI, IGF-1 and IGFBP-2. There was a positive correlation between BAT and BMD and an inverse association between IGFBP-2 and both BAT and BMD. There was no association between IGF-1 and BAT. We show for the first time that IGFBP-2 is a negative predictor of cold-induced BAT and BMD in young non-obese women, suggesting that IGFBP-2 may serve as a regulator of BAT-mediated osteoblastogenesis. (C) 2013 Elsevier Inc. All rights reserved. C1 [Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Bredella, Miriam A.; Fazeli, Pouneh K.; Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Fazeli, Pouneh K.; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Lecka-Czernik, Beata] Univ Toledo, Dept Orthoped Surg, Ctr Diabet & Endocrine Res, Coll Med, Toledo, OH 43606 USA. [Rosen, Clifford J.] Maine Med Ctr, Res Inst, Scarborough, ME 04074 USA. RP Bredella, MA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. EM mbredella@partners.org FU National Institutes of Health [R24 DK084970, UL1 RR025758] FX This work was supported by National Institutes of Health Grants R24 DK084970 and UL1 RR025758. NR 23 TC 9 Z9 11 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD APR PY 2013 VL 53 IS 2 BP 336 EP 339 DI 10.1016/j.bone.2012.12.046 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 101GR UT WOS:000315763700003 PM 23291564 ER PT J AU Pozzi, S Fulciniti, M Yan, H Vallet, S Eda, H Patel, K Santo, L Cirstea, D Hideshima, T Schirtzinge, L Kuhstoss, S Anderson, KC Munshi, N Scadden, D Kronenberg, HM Raje, N AF Pozzi, Samantha Fulciniti, Mariateresa Yan, Hua Vallet, Sonia Eda, Homare Patel, Kishan Santo, Loredana Cirstea, Diana Hideshima, Teru Schirtzinge, Linda Kuhstoss, Stuart Anderson, Kenneth C. Munshi, Nikhil Scadden, David Kronenberg, Henry M. Raje, Noopur TI In vivo and in vitro effects of a novel anti-Dkk1 neutralizing antibody in multiple myeloma SO BONE LA English DT Article DE Dkk1; wnt; Multiple myeloma; Osteoclast; Osteoblast ID STEM-CELL TRANSPLANTATION; BONE-DISEASE; SERUM CONCENTRATIONS; OSTEOCLAST DIFFERENTIATION; DICKKOPF-1; DKK1; OSTEOBLASTS; INHIBITOR; SUPPRESSION; EXPRESSION AB Over-expression of the protein Dickkopf-1 (Dkk1) has been associated with multiple myeloma bone disease. Previous reports with the use of anti-Dkk1 neutralizing Ab directed strategies have demonstrated a pro-anabolic effect with associated anti-myeloma activity in 2 in vivo mouse models. However new insights on the role of the wnt pathway in osteoclasts (OC) are emerging and the potential effect of a neutralizing Ab to Dkk1 in osteoclastogenesis remains to be elucidated. In order to better define the effect of an anti-Dkkl neutralizing Ab on osteoclastogenesis and myeloma, we studied a novel anti-Dkk1 monoclonal Ab in our pre-clinical models. In vivo data confirmed the pro-anabolic and anti-MM effect. In vitro data in part confirmed the in vivo observation, suggesting an indirect anti-MM effect secondary to inhibition of osteoclastogenesis and thus the interaction between MM and bone microenvironment. However, when studies on osteoclastogenesis were extended to samples derived from MM patients, we observed a variable response to anti-Dkk1 treatment without correlation to expression of surface receptors for Dkk1 in OCs suggesting potential heterogeneity in the efficacy of such a strategy. In conclusion, Dkk1 is a promising target for the treatment of both MM and bone disease, and ongoing clinical studies will help elucidate its efficacy. (C) 2013 Elsevier Inc. All rights reserved. C1 [Pozzi, Samantha; Yan, Hua; Vallet, Sonia; Eda, Homare; Patel, Kishan; Santo, Loredana; Cirstea, Diana; Scadden, David; Raje, Noopur] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Pozzi, Samantha; Fulciniti, Mariateresa; Yan, Hua; Vallet, Sonia; Eda, Homare; Patel, Kishan; Santo, Loredana; Cirstea, Diana; Hideshima, Teru; Anderson, Kenneth C.; Munshi, Nikhil; Scadden, David; Raje, Noopur] Harvard Univ, Sch Med, Boston, MA USA. [Pozzi, Samantha; Fulciniti, Mariateresa; Vallet, Sonia; Santo, Loredana; Cirstea, Diana; Hideshima, Teru; Anderson, Kenneth C.; Munshi, Nikhil; Raje, Noopur] Dana Farber Canc Inst, Boston, MA 02115 USA. [Schirtzinge, Linda; Kuhstoss, Stuart] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Kronenberg, Henry M.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Raje, N (reprint author), Massachusetts Gen Hosp, Div Hematol & Oncol, MGH Canc Ctr, POB 216,55 Fruit St, Boston, MA 02114 USA. EM nraje@partners.org RI Pozzi, Samantha/A-7617-2012 OI Pozzi, Samantha/0000-0001-7917-1774 FU Claflin Distinguished Scholar Award; Brian Dune International Myeloma Foundation FX SZ is the recipient of the Brian Dune International Myeloma Foundation junior fellow award. NR is a LLS Clinical Scholar and recipient of the Claflin Distinguished Scholar Award. NR 33 TC 24 Z9 26 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD APR PY 2013 VL 53 IS 2 BP 487 EP 496 DI 10.1016/j.bone.2013.01.012 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 101GR UT WOS:000315763700020 PM 23333523 ER PT J AU Goy, DP Gorosito, E Coletta, DJ Costa, HS Mortarino, P Pedemonte, NA Toledo, J Abranson, D Zingoni, N Mansur, HS Jamin, A Pereira, MM Battaglino, R Feldman, S AF Goy, D. P. Gorosito, E. Coletta, D. J. Costa, H. S. Mortarino, P. Acosta Pedemonte, N. Toledo, J. Abranson, D. Zingoni, N. Mansur, H. S. Jamin, A. Pereira, M. M. Battaglino, R. Feldman, S. TI Hybrid matrix grafts to favor tissue regeneration in rabbit femur bone lesions SO BONE LA English DT Meeting Abstract CT 29th Annual Meeting of the Argentine-Association-of-Osteology-and-Mineral-Metabolism CY AUG 23-25, 2012 CL Buenos Aires, ARGENTINA SP Argentine Assoc Osteol & Mineral Metab C1 [Goy, D. P.; Gorosito, E.; Coletta, D. J.; Mortarino, P.; Acosta Pedemonte, N.; Toledo, J.; Abranson, D.; Zingoni, N.; Mansur, H. S.; Jamin, A.; Feldman, S.] Univ Nac Rosario, Fac Cs Med, Lab Biol Osteoarticular Ing Tisular & Terapias Em, Rosario, Santa Fe, Argentina. [Costa, H. S.; Pereira, M. M.] Univ Fed Minas Gerais, Dep Eng Met & Mat, Belo Horizonte, MG, Brazil. [Battaglino, R.] Forsyth Inst, Dept Cytokine Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD APR PY 2013 VL 53 IS 2 BP 602 EP 602 DI 10.1016/j.bone.2012.12.031 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 101GR UT WOS:000315763700047 ER PT J AU Doornberg, JN Guitton, TG Ring, D AF Doornberg, Job N. Guitton, Thierry G. Ring, David CA Sci Variation Grp TI Diagnosis of Elbow Fracture Patterns on Radiographs: Interobserver Reliability and Diagnostic Accuracy SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID ANTEROMEDIAL FACET; INSTABILITY; DISLOCATION; AGREEMENT AB Studies of traumatic elbow instability suggest that recognition of a pattern in the combination and character of the fractures and joint displacements helps predict soft tissue injury and guide the treatment of traumatic elbow instability, but there is no evidence that patterns can be identified reliably. We therefore determined (1) the interobserver reliability of identifying specific patterns of traumatic elbow instability on radiographs for subgroups of orthopaedic surgeons; and (2) the diagnostic accuracy of radiographic diagnosis. Seventy-three orthopaedic surgeons evaluated 53 sets of radiographs and diagnosed one of five common patterns of traumatic elbow instability by using a web-based survey. The interobserver reliability was analyzed using Cohen's multirater kappa. Intraoperative diagnosis was the reference for fracture pattern in calculations of the sensitivity, specificity, accuracy, and positive predictive and negative predictive values of radiographic diagnosis. The overall interobserver reliability for patterns of traumatic elbow instability on radiographs was kappa = 0.41. Treatment of greater than five such injuries a year was associated with greater interobserver agreement, but years in practice were not. Diagnostic accuracy ranged from 76% to 93% and was lowest for the terrible triad pattern of injury. Specific patterns of traumatic elbow instability can be diagnosed with moderate interobserver reliability and reasonable accuracy on radiographs. Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. C1 [Doornberg, Job N.; Guitton, Thierry G.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Ring, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv,Yawkey Ctr, Boston, MA 02163 USA. RP Ring, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv,Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02163 USA. EM dring@partners.org RI Page, Richard/K-6327-2015; OI Page, Richard/0000-0002-2225-7144; Guitton, Thierry/0000-0002-2599-1985; Frihagen, Frede/0000-0002-4811-669X FU Wright Medical (DR) (Arlington, TN, USA); Biomet (DR) (Warsaw, IN, USA); Skeletal Dynamics (DR)(Miami, FL, USA); Biomet (DR)(Warsaw, IN, USA) FX One of the authors certifies that he (DR) has or may receive payments or benefits, during the study period, an amount of less than $10,000 from Wright Medical (DR) (Arlington, TN, USA) and Biomet (DR) (Warsaw, IN, USA). The institution of one or more of the authors (DR) has received funding from Skeletal Dynamics (DR)(Miami, FL, USA) and Biomet (DR)(Warsaw, IN, USA). NR 18 TC 12 Z9 12 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD APR PY 2013 VL 471 IS 4 BP 1373 EP 1378 DI 10.1007/s11999-012-2742-4 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 097YW UT WOS:000315510400047 PM 23247817 ER PT J AU Li, CW Shi, L Yan, Y Gordon, BR Gordon, WM Wang, DY AF Li, Chunwei Shi, Li Yan, Yan Gordon, Bruce R. Gordon, William M. Wang, De-Yun TI Gene Expression Signatures: A New Approach to Understanding the Pathophysiology of Chronic Rhinosinusitis SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Review DE Chronic rhinosinusitis (CRS); Pathophysiology; Inflammation; Remodeling; Environmental factors; Nasal epithelium; Host defense mechanisms; Gene expression signatures; Regulatory T cells (T-reg); Glucocorticosteroids; Nasal polyps ID EPITHELIAL-CELL EXPRESSION; CD4(+)CD25(+) T-CELLS; NASAL POLYPS; MESSENGER-RNA; AIRWAY INFLAMMATION; PROSTAGLANDIN D-2; IMMUNE REGULATION; UP-REGULATION; STEM-CELLS; C-JUN AB Chronic rhinosinusitis (CRS) is a complex inflammatory disease with variable disease manifestation. Though external risk factors are associated with development and/or persistence of CRS, the host mucosal response is also important, as nasal epithelium acts as a physical and immune barrier. Under inflammatory stress, the nasal epithelium can undergo injury, followed by a rapid remodeling response ranging from epithelial hyperplasia, to goblet-cell metaplasia, to denudation, loss of cilia, fibrosis, and basement membrane thickening. Identification of gene expression signatures and molecular pathways in CRS pathogenesis have now begun to contribute significantly to a better understanding of the genetic and molecular alterations underlying CRS development and progression. Genetic studies are especially illuminating when multiple gene variants synergize within a permissive environmental context, and are expected to guide development of more effective therapeutic targets for CRS treatment. C1 [Li, Chunwei; Yan, Yan; Wang, De-Yun] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Otolaryngol, Singapore 119228, Singapore. [Shi, Li] Shandong Univ, Qilu Hosp, Dept Otolaryngol, Jinan 250012, Shandong, Peoples R China. [Gordon, Bruce R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. [Gordon, Bruce R.] Cape Cod Hosp, Div Otolaryngol, Hyannis, MA USA. [Gordon, William M.] Univ Calif Irvine, Dept Med & Biol Chem, Irvine, CA USA. RP Wang, DY (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Otolaryngol, 1E Kent Ridge Rd, Singapore 119228, Singapore. EM shili126@sina.com; entwdy@nus.edu.sg FU National Medical Research Council (NMRC) [IRG10may086]; Singapore Immunology Network (SIgN) of Singapore [SIgN 10-028]; National Nature Science Foundation of China [81170897] FX This work was supported by grants from the National Medical Research Council (NMRC, IRG10may086), from Singapore Immunology Network (SIgN, SIgN 10-028) of Singapore, and from the National Nature Science Foundation of China (no. 81170897). NR 74 TC 8 Z9 8 U1 0 U2 6 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1529-7322 J9 CURR ALLERGY ASTHM R JI Curr. Allergy Asthma Rep. PD APR PY 2013 VL 13 IS 2 BP 209 EP 217 DI 10.1007/s11882-012-0328-6 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 100XI UT WOS:000315738100009 PM 23225138 ER PT J AU Battle, CL Greer, JA Ortiz-Hernandez, S Todd, DM AF Battle, Cynthia L. Greer, Joseph A. Ortiz-Hernandez, Samia Todd, David M. TI Developing and Implementing a Bereavement Support Program for College Students SO DEATH STUDIES LA English DT Article AB The death of a loved one can be particularly difficult for college students, as significant losses are not anticipated during this time. Bereavement experiences are, however, not uncommon among college students, and campus environments can be isolating and nonconducive to recovery. To date, few interventions have been developed to meet bereaved college students' needs. The authors describe the rationale, development, and structure of a campus-based bereavement support program in New England, which provided a series of 17 support groups serving 105 students. They present feedback data from a subset of participants and discuss issues to consider in providing similar on-campus services. C1 [Battle, Cynthia L.] Brown Univ, Dept Psychiat & Human Behav, Alpert Med Sch, Butler Hosp,Psychosocial Res Program, Providence, RI 02912 USA. [Greer, Joseph A.] Harvard Univ, Sch Med, Ctr Psychiat Oncol & Behav Sci, Massachusetts Gen Hosp,Canc Ctr, Boston, MA USA. [Ortiz-Hernandez, Samia] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. [Todd, David M.] Univ Massachusetts Amherst, Dept Psychol, Amherst, MA USA. RP Battle, CL (reprint author), Butler Hosp Psychosocial Res, Dept Psychiat, 345 Blackstone Blvd, Providence, RI 02906 USA. EM cbattle@butler.org NR 27 TC 0 Z9 0 U1 1 U2 7 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0748-1187 J9 DEATH STUD JI Death Stud. PD APR 1 PY 2013 VL 37 IS 4 BP 362 EP 382 DI 10.1080/07481187.2011.634087 PG 21 WC Psychology, Multidisciplinary; Social Issues; Social Sciences, Biomedical SC Psychology; Social Issues; Biomedical Social Sciences GA 100HM UT WOS:000315689000004 PM 24520892 ER PT J AU Parmelee, PA Harralson, TL McPherron, JA Schumacher, HR AF Parmelee, Patricia A. Harralson, Tina L. McPherron, Jesse A. Schumacher, H. Ralph TI The structure of affective symptomatology in older adults with osteoarthritis SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE affective symptoms; comorbidity; depression; anxiety; osteoarthritis ID GENERALIZED ANXIETY DISORDER; PRIMARY-CARE PATIENTS; SELF-RATED HEALTH; SOMATIC SYMPTOMS; ELDERLY-PATIENTS; STATUS QUESTIONNAIRE; PHYSICAL SYMPTOMS; MIXED ANXIETY; DEPRESSION; PAIN AB Objective To examine the structure of symptoms of affective disorder among older adults with a chronic health problem (osteoarthritis) and to explore cross-sectional and longitudinal associations of obtained affective symptom clusters with key health outcomes (pain, functional disability, perceived health). Methods One-year longitudinal study of older adults with diagnosed osteoarthritis of the knee. Symptoms of DSM depression and anxiety were assessed in a research diagnostic interview by using a DSM-IV symptom checklist; self-reports captured demographic characteristics, objective health, pain, disability, and perceived health. Confirmatory factor analysis tested comparability of affective symptom structure in this sample to findings of previous research; ordinary least squares regression examined cross-sectional and longitudinal associations of affective symptoms with health outcomes, controlling for demographics and objective health. Results The current sample displayed an affective symptom structure comparable with that observed in previous research, with symptoms clustering into depressed mood (DM), somatic symptoms (SS), and psychic anxiety (PA) factors. DM was cross-sectionally associated with pain and disability and marginally with perceived health; SS predicted current pain and perceived health. Only DM predicted 1year change in disability and perceived health (but not pain). Conclusions This research confirms the role of SS of distress in fueling disability and perceived ill health among older adults who are chronically ill. However, it is DM that drives changes in perceived health and functional ability. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Parmelee, Patricia A.; McPherron, Jesse A.] Univ Alabama, Ctr Mental Hlth & Aging, Tuscaloosa, AL 35487 USA. [Parmelee, Patricia A.; McPherron, Jesse A.] Univ Alabama, Dept Psychol, Tuscaloosa, AL USA. [Harralson, Tina L.] Polaris Hlth Care, Philadelphia, PA USA. [Schumacher, H. Ralph] Vet Affairs Med Ctr, Philadelphia, PA USA. [Schumacher, H. Ralph] Univ Penn, Sch Med, Dept Rheumatol, Philadelphia, PA 19104 USA. RP Parmelee, PA (reprint author), Univ Alabama, Ctr Mental Hlth & Aging, Tuscaloosa, AL 35487 USA. EM pparmelee@ua.edu FU National Institute of Mental Health [1-R01-MH51800] FX This research was supported by the National Institute of Mental Health grant 1-R01-MH51800 to the first author for research conducted at the Philadelphia Geriatric Center and the University of Pennsylvania. We thank Lori Smith for project management, James Hollander, Meredith Olderman, and Beth Chmar for collecting the data, Hui Wu and Yunqi Zhang for data management, and Elaine Benoff and Susan Gallagher for administrative support. NR 55 TC 4 Z9 7 U1 1 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-6230 J9 INT J GERIATR PSYCH JI Int. J. Geriatr. Psychiatr. PD APR PY 2013 VL 28 IS 4 BP 393 EP 401 DI 10.1002/gps.3837 PG 9 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 103ZR UT WOS:000315958800009 PM 22653754 ER PT J AU Maust, DT Mavandadi, S Benson, A Streim, JE DiFilippo, S Snedden, T Weber, AL Oslin, DW AF Maust, Donovan T. Mavandadi, Shahrzad Benson, Amy Streim, Joel E. DiFilippo, Suzanne Snedden, Thomas Weber, Anita L. Oslin, David W. TI Telephone-based care management for older adults initiated on psychotropic medication SO INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE care management; telepsychiatry; psychotropics; depression ID LATE-LIFE DEPRESSION; RANDOMIZED CONTROLLED-TRIAL; MENTAL-HEALTH; RISK; BENZODIAZEPINE; VALIDATION; DISABILITY; SEVERITY; SYMPTOMS; VALIDITY AB Objective This study aimed to explore the longitudinal, 6-month symptom course of older adults newly started on an antidepressant or anxiolytic by non-psychiatrist physicians and enrolled in a care management program. Method This is a naturalistic cohort study of older adults (age 65years) receiving pharmacotherapy and telephone-based care management. Participants are non-institutionalized adults participating in Pennsylvania's Pharmaceutical Assistance Contract for the Elderly who completed telephone-based clinical assessments including demographic data, self-report on history of psychiatric treatment and adherence, and standardized symptom scales. Results A total of 162 participants with an average age of 77.2years (SD 6.8) were followed and, for analysis, split into two groups by PHQ-9 score: 75 (46.3%) scoring 04 (minimally symptomatic group, MSG) and 87 (53.7%) scoring 5 (symptomatic group, SG). Over 6months, the SG improved with PHQ-9 scores beginning on average at 10.0 (SD 4.6) and falling to 5.4 (SD 4.2) (F(1, 86)=29.53, p<0.0001). The MSG had no significant change in depressive symptoms. Emotional health as measured by SF-12 Mental Composite Score mirrored the PHQ-9 change and lack thereof in the SG and MSG, respectively. No clinical or demographic features were associated with symptom improvement in the SG although they were more likely to report medication adherence (66.7% vs. 44.0%, 2(1)=8.4, p=0.0037) compared with the MSG. Conclusions Participation of symptomatic older adults initiated on psychotropic medication in a telephone-based care management program was associated with improvement in depressive symptoms and overall emotional well-being, notable findings given participants' advanced age, state-wide distribution, and history of limited utilization of mental health care. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Maust, Donovan T.; Mavandadi, Shahrzad; Benson, Amy; Streim, Joel E.; DiFilippo, Suzanne; Oslin, David W.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Mavandadi, Shahrzad; Streim, Joel E.; DiFilippo, Suzanne; Oslin, David W.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Mavandadi, Shahrzad; Streim, Joel E.; DiFilippo, Suzanne; Oslin, David W.] VISN 4 Mental Illness Res Educ & Clin Ctr MIRECC, Philadelphia, PA USA. [Snedden, Thomas] Penn Dept Aging, PACE Program, Harrisburg, PA USA. [Weber, Anita L.] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Maust, DT (reprint author), Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. EM Donovan.Maust@uphs.upenn.edu FU PACE Program, Pennsylvania Department of Aging, Harrisburg, PA, USA; NIMH [R25-MH060490] FX This study has been supported by the PACE Program, Pennsylvania Department of Aging, Harrisburg, PA, USA. D. T. M. was supported by the NIMH-funded Clinical Research Scholars Program (R25-MH060490) of the Department of Psychiatry, University of Pennsylvania. NR 39 TC 5 Z9 5 U1 5 U2 12 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 APR PY 2013 VL 28 IS 4 BP 410 EP 416 DI 10.1002/gps.3839 PG 7 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 103ZR UT WOS:000315958800011 PM 22678956 ER PT J AU Tipper, C Sodroski, J AF Tipper, Christopher Sodroski, Joseph TI Enhanced Autointegration in Hyperstable Simian Immunodeficiency Virus Capsid Mutants Blocked after Reverse Transcription SO JOURNAL OF VIROLOGY LA English DT Article ID TYPE-1 PREINTEGRATION COMPLEXES; INTEGRATION IN-VIVO; CYCLOPHILIN-A; HIV-1 REPLICATION; NUCLEAR IMPORT; RESTRICTION FACTORS; NONDIVIDING CELLS; VIRAL REPLICATION; INFECTION; PROTEIN AB After entering a host cell, retroviruses such as simian immunodeficiency virus (SIV) uncoat, disassembling the viral capsid. Rates of uncoating that are too high and too low can be detrimental to the efficiency of infection. Rapid uncoating typically leads to blocks in reverse transcription, but the basis for replication defects associated with slow uncoating is less clear. Here we characterize the phenotypes of two SIVmac239 mutants with changes, A87E and A87D, in the helix 4/5 loop of the capsid protein. These mutant viruses exhibited normal capsid morphology but were significantly attenuated for infectivity. The infectivity of wild-type and mutant SIVmac239 was not decreased by aphidicolin-induced growth arrest of the target cells. In the cytosol of infected cells, the A87E and A87D capsids remained in particulate form longer than the wild-type SIVmac239 capsid, suggesting that the mutants uncoat more slowly than the wild-type capsid. Both mutants exhibited much higher levels of autointegrated DNA forms than wild-type SIVmac239. Thus, some changes in the helix 4/5 loop of the SIVmac239 capsid protein result in capsid hyperstability and an increase in autointegration. C1 [Tipper, Christopher; Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Sodroski, Joseph] Massachusetts Gen Hosp, Ragon Inst, Massachusetts Inst Technol & Harvard, Boston, MA 02114 USA. RP Sodroski, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu FU National Institutes of Health [AI063987]; National Institutes of Health (Center for AIDS Research) [AI06354]; International AIDS Vaccine Initiative FX We thank the National Institutes of Health (award AI063987 and Center for AIDS Research award AI06354), the International AIDS Vaccine Initiative, and the late William F. McCarty-Cooper. NR 55 TC 4 Z9 4 U1 0 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2013 VL 87 IS 7 BP 3628 EP 3639 DI 10.1128/JVI.03239-12 PG 12 WC Virology SC Virology GA 103ZC UT WOS:000315957100002 PM 23345510 ER PT J AU Wang, X Helfer, CM Pancholi, N Bradner, JE You, JX AF Wang, Xin Helfer, Christine M. Pancholi, Neha Bradner, James E. You, Jianxin TI Recruitment of Brd4 to the Human Papillomavirus Type 16 DNA Replication Complex Is Essential for Replication of Viral DNA SO JOURNAL OF VIROLOGY LA English DT Article ID BROMODOMAIN PROTEIN BRD4; POLYMERASE ALPHA-PRIMASE; INVASIVE CERVICAL-CANCER; E1 PROTEIN; E2 PROTEIN; TRANSCRIPTIONAL ACTIVATION; BOVINE PAPILLOMAVIRUS; S-PHASE; E2-DEPENDENT TRANSCRIPTION; ACETYLATED CHROMATIN AB Replication of the human papillomavirus (HPV) DNA genome relies on viral factors E1 and E2 and the cellular replication machinery. Bromodomain-containing protein 4 (Brd4) interacts with viral E2 protein to mediate papillomavirus (PV) genome maintenance and viral transcription. However, the functional role of Brd4 in the HPV life cycle remains to be clearly defined. In this study, we provide the first look into the E2-Brd4 interaction in the presence of other important viral factors, such as the HPV16 E1 protein and the viral genome. We show that Brd4 is recruited to actively replicating HPV16 origin foci together with HPV16 E1, E2, and a number of the cellular replication factors: replication protein A70 (RPA70), replication factor C1 (RFC1), and DNA polymerase delta. Mutagenesis disrupting the E2-Brd4 interaction abolishes the formation of the HPV16 replication complex and impairs HPV16 DNA replication in cells. Brd4 was further demonstrated to be necessary for HPV16 viral DNA replication using a cell-free replication system in which depletion of Brd4 by small interfering RNA (siRNA) silencing leads to impaired HPV16 viral DNA replication and recombinant Brd4 protein is able to rescue viral DNA replication. In addition, releasing endogenous Brd4 from cellular chromatin by using the bromodomain inhibitor JQ1(+) enhances HPV16 DNA replication, demonstrating that the role of Brd4 in HPV DNA replication could be uncoupled from its function in chromatin-associated transcriptional regulation and cell cycle control. Our study reveals a new role for Brd4 in HPV genome replication, providing novel insights into understanding the life cycle of this oncogenic DNA virus. C1 [Wang, Xin; Helfer, Christine M.; Pancholi, Neha; You, Jianxin] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP You, JX (reprint author), Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA. EM jianyou@mail.med.upenn.edu FU HIV-Associated Malignancies Pilot Project Award (National Cancer Institute); National Institutes of Health (NIH) [R01CA148768, R01CA142723] FX This work was supported by the HIV-Associated Malignancies Pilot Project Award (National Cancer Institute) and by National Institutes of Health (NIH) grants R01CA148768 and R01CA142723. NR 56 TC 30 Z9 31 U1 1 U2 12 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2013 VL 87 IS 7 BP 3871 EP 3884 DI 10.1128/JVI.03068-12 PG 14 WC Virology SC Virology GA 103ZC UT WOS:000315957100024 PM 23365439 ER PT J AU Medjahed, H Pacheco, B Desormeaux, A Sodroski, J Finzi, A AF Medjahed, Halima Pacheco, Beatriz Desormeaux, Anik Sodroski, Joseph Finzi, Andres TI The HIV-1 gp120 Major Variable Regions Modulate Cold Inactivation SO JOURNAL OF VIROLOGY LA English DT Article ID ENVELOPE GLYCOPROTEIN; GP41; ANTIBODIES; COFACTOR; RECEPTOR AB HIV-1 entry involves the viral envelope glycoproteins (Env gps) and receptors on the target cell. Receptor binding channels the intrinsic high potential energy of Env into the force required to fuse the membranes of virus and target cell. For some HIV-1 strains, prolonged incubation on ice decreases Env potential energy and results in functional inactivation. By characterizing chimeras between two primary clade C HIV-1 strains that differ in sensitivities to cold, soluble CD4, and neutralizing antibodies, we found that these properties were largely determined by discrete elements within the gp120 variable regions V1V2 and V3. C1 [Medjahed, Halima; Desormeaux, Anik; Finzi, Andres] Univ Montreal, Ctr Rech CHUM, Montreal, PQ, Canada. [Medjahed, Halima; Finzi, Andres] Univ Montreal, Dept Microbiol & Immunol, Montreal, PQ H3C 3J7, Canada. [Finzi, Andres] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada. [Pacheco, Beatriz; Sodroski, Joseph] Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA USA. [Pacheco, Beatriz; Sodroski, Joseph] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Aids, Boston, MA USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Sodroski, Joseph] Ragon Inst Massachusetts Gen Hosp, Massachusetts Inst Technol & Harvard, Charlestown, MA USA. RP Finzi, A (reprint author), Univ Montreal, Ctr Rech CHUM, Montreal, PQ, Canada. EM andres.finzi@umontreal.ca FU Canada Foundation for Innovation [29866]; CIHR [257792]; FRQS [24639]; FRSQ Chercheur Boursier Junior 1 fellowship [24639]; National Institutes of Health [AI24755, AI67854]; International AIDS Vaccine Initiative FX This work was supported by Canada Foundation for Innovation Program Leader grant 29866, by CIHR operating grant 257792, and by FRQS Establishment of Young Scientist grant 24639 to A. F. A. F. is the recipient of an FRSQ Chercheur Boursier Junior 1 fellowship (no. 24639). This work was also supported by grants from the National Institutes of Health (AI24755 and AI67854), the International AIDS Vaccine Initiative, and a gift from the late William F. McCarty-Cooper. NR 18 TC 10 Z9 10 U1 0 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2013 VL 87 IS 7 BP 4103 EP 4111 DI 10.1128/JVI.03124-12 PG 9 WC Virology SC Virology GA 103ZC UT WOS:000315957100047 PM 23345516 ER PT J AU Luke, JJ Rubinstein, LV Smith, GL Ivy, SP Harris, PJ AF Luke, Jason J. Rubinstein, Lawrence V. Smith, Gary L. Ivy, S. Percy Harris, Pamela J. TI Similar efficacy for phase I trials in comparison with DTIC for advanced malignant melanoma: an analysis of melanoma outcomes in CTEP-sponsored phase I trials 1995-2011 SO MELANOMA RESEARCH LA English DT Article DE chemotherapy; CTEP; dacarbazine; melanoma; phase I ID METASTATIC MELANOMA; CLINICAL-TRIALS; ONCOLOGY TRIALS; SOLID TUMORS; CANCER; DACARBAZINE; SURVIVAL; THERAPY; ETHICS; TEMOZOLOMIDE AB After ipilimumab, vemurafenib, and interleukin-2, standard of care chemotherapy for melanoma remains dacarbazine (response rate similar to 9%). Despite this, many physicians hesitate to refer patients to phase I protocols given a perceived lack of clinical benefit and potential for harm. To better understand the validity of these perceptions, the experience of all patients with melanoma treated on phase I trials sponsored by the National Cancer Institute-Cancer Therapy Evaluation Program (NCI-CTEP) from 1995 to 2011 were analyzed and compared with the pooled results of six contemporary phase III trials of dacarbazine. A total of 937 patients with melanoma were treated in 148 CTEP phase I trials. The majority were men with a median of two prior therapies (46% receiving prior dacarbazine). Response and clinical benefit rates in these trials were not clinically different from those of dacarbazine (phase I: 6.3 and 26.8% vs. dacarbazine: 8.8 and 27.9%) although grades 3 and 4 toxicity was significantly higher (54 vs. 28%). Efficacy and toxicity were generally consistent within phase I subgroups (targeted agents, immunotherapies, or chemotherapeutics) though targeted therapy was associated with a lower response rate, immunotherapy higher incidence of grade 4 toxicity. Thus, the perception of limited efficacy of phase I trials for patients with melanoma was disproven, whereas the perception of toxicity was observed. However, this difference in toxicity may have been largely because of the nature of phase I vs. phase III trials (i.e. more heavily pretreated) and because of the phase I trials often being multiagent as opposed to dacarbazine alone. Melanoma Res 23:152-158 (c) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Luke, Jason J.] Dana Farber Canc Inst, Melanoma Dis Ctr, Boston, MA 02215 USA. [Rubinstein, Lawrence V.; Smith, Gary L.; Ivy, S. Percy; Harris, Pamela J.] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP Luke, JJ (reprint author), Dana Farber Canc Inst, Melanoma Dis Ctr, 450 Brookline Ave, Boston, MA 02215 USA. EM jason_luke@dfci.harvard.edu NR 29 TC 2 Z9 2 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-8931 J9 MELANOMA RES JI Melanoma Res. PD APR PY 2013 VL 23 IS 2 BP 152 EP 158 DI 10.1097/CMR.0b013e32835f73b2 PG 7 WC Oncology; Dermatology; Medicine, Research & Experimental SC Oncology; Dermatology; Research & Experimental Medicine GA 101YM UT WOS:000315810300009 PM 23411478 ER PT J AU Caplan, D Waters, G AF Caplan, David Waters, Gloria TI Memory mechanisms supporting syntactic comprehension SO PSYCHONOMIC BULLETIN & REVIEW LA English DT Review DE Language/memory interactions; Language comprehension ID SHORT-TERM-MEMORY; GARDEN PATH SENTENCES; VERB-PHRASE ELLIPSIS; WORKING-MEMORY; EYE-MOVEMENTS; SERIAL ORDER; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; PHONOLOGICAL SIMILARITY; INDIVIDUAL-DIFFERENCES AB Efforts to characterize the memory system that supports sentence comprehension have historically drawn extensively on short-term memory as a source of mechanisms that might apply to sentences. The focus of these efforts has changed significantly in the past decade. As a result of changes in models of short-term working memory (ST-WM) and developments in models of sentence comprehension, the effort to relate entire components of an ST-WM system, such as those in the model developed by Baddeley (Nature Reviews Neuroscience 4: 829-839, 2003) to sentence comprehension has largely been replaced by an effort to relate more specific mechanisms found in modern models of ST-WM to memory processes that support one aspect of sentence comprehension-the assignment of syntactic structure (parsing) and its use in determining sentence meaning (interpretation) during sentence comprehension. In this article, we present the historical background to recent studies of the memory mechanisms that support parsing and interpretation and review recent research into this relation. We argue that the results of this research do not converge on a set of mechanisms derived from ST-WM that apply to parsing and interpretation. We argue that the memory mechanisms supporting parsing and interpretation have features that characterize another memory system that has been postulated to account for skilled performance-long-term working memory. We propose a model of the relation of different aspects of parsing and interpretation to ST-WM and long-term working memory. C1 [Caplan, David] Massachusetts Gen Hosp, Dept Neurol, Neuropsychol Lab, Boston, MA 02114 USA. [Waters, Gloria] Boston Univ, Dept Speech & Hearing Sci, Sargent Coll, Boston, MA 02215 USA. RP Caplan, D (reprint author), Massachusetts Gen Hosp, Dept Neurol, Neuropsychol Lab, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM dcaplan@partners.org FU NIDCD NIH HHS [DC00942, DC011032, R01 DC000942, R01 DC011032] NR 170 TC 24 Z9 25 U1 6 U2 38 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1069-9384 EI 1531-5320 J9 PSYCHON B REV JI Psychon. Bull. Rev. PD APR PY 2013 VL 20 IS 2 BP 243 EP 268 DI 10.3758/s13423-012-0369-9 PG 26 WC Psychology, Mathematical; Psychology, Experimental SC Psychology GA 104PO UT WOS:000316006900004 PM 23319178 ER PT J AU Lou, E Peters, KB Sumrall, AL Desjardins, A Reardon, DA Lipp, ES Herndon, JE Coan, A Bailey, L Turner, S Friedman, HS Vredenburgh, JJ AF Lou, Emil Peters, Katherine B. Sumrall, Ashley L. Desjardins, Annick Reardon, David A. Lipp, Eric S. Herndon, James E., II Coan, April Bailey, Leighann Turner, Scott Friedman, Henry S. Vredenburgh, James J. TI Phase II trial of upfront bevacizumab and temozolomide for unresectable or multifocal glioblastoma SO CANCER MEDICINE LA English DT Article DE Bevacizumab; glioblastoma; neoadjuvant therapy; temozolomide; unresectable; upfront AB Patients with unresectable glioblastomas have a poor prognosis, with median survival of 6-10 months. We conducted a phase II trial of upfront 5-day temozolomide (TMZ) and bevacizumab (BV) in patients with newly diagnosed unresectable or multifocal glioblastoma. Patients received up to four cycles of TMZ at 200 mg/m(2) on days 1-5, and BV at 10 mg/kg on days 1 and 15 of a 28-day cycle. Brain magnetic resonance imaging (MRI) was performed monthly. Therapy was continued as long as there was no tumor progression, grade 4 non-hematologic toxicity, or recurrent grade 4 hematologic toxicity after dose reduction. The primary end point was best tumor response as measured on MRI. Forty-one patients were accrued over 12 months; 39 had a full set of MRI scans available for evaluation. Assessment for best radiographic responses was as follows: partial responses in 24.4%, stable disease in 68.3%, and progressive disease in 2.4%. Treatment-related toxicities included seven grade 4 toxicities and one grade 5 toxicity (myocardial infarction). From this study, it was concluded that an upfront regimen of TMZ and BV for unresectable glioblastoma was well tolerated and provided a significant level of disease stabilization. Therapeutic toxicities were consistent with those seen in the adjuvant setting using these agents. The upfront approach to treatment of glioblastoma in the unresectable population warrants further investigation in randomized controlled phase III trials. C1 [Lou, Emil; Lipp, Eric S.; Turner, Scott] Duke Univ, Med Ctr, Dept Surg, Preston Robert Tisch Brain Tumor Ctr Duke, Durham, NC 27710 USA. [Peters, Katherine B.; Sumrall, Ashley L.; Desjardins, Annick; Bailey, Leighann; Vredenburgh, James J.] Duke Univ, Med Ctr, Dept Med, Preston Robert Tisch Brain Tumor Ctr Duke, Durham, NC 27710 USA. [Reardon, David A.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. [Herndon, James E., II; Coan, April] Duke Univ, Med Ctr, Dept Biostat, Ctr Canc, Durham, NC USA. [Friedman, Henry S.] Duke Univ, Med Ctr, Dept Surg & Pediat, Preston Robert Tisch Brain Tumor Ctr Duke, Durham, NC USA. RP Lou, E (reprint author), Div Hematol Oncol & Transplantat, Mayo Mail Code 480,420 Delaware St SE, Minneapolis, MN 55455 USA. EM emil-lou@umn.edu OI Sykes, April/0000-0002-7667-8155 FU National Institutes of Health [5 P50 NS20023, 5 P50 CA108786]; Genentech Pharmaceuticals FX This work was supported by National Institutes of Health Grants 5 P50 NS20023 and 5 P50 CA108786; and a grant from Genentech Pharmaceuticals. NR 37 TC 22 Z9 25 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD APR PY 2013 VL 2 IS 2 BP 185 EP 195 DI 10.1002/cam4.58 PG 11 WC Oncology SC Oncology GA V36KI UT WOS:000209210600007 PM 23634286 ER PT J AU Katz, DL Grant, DL McGuire, TJ McQuigg, S Voci, K Volpp, K AF Katz, David L. Grant, Deborah Lewison McGuire, Todd J. McQuigg, Scott Voci, Karen Volpp, Kevin TI Working on the Health of Families: Where Children Fit in Worksite Health Promotion Efforts SO CHILDHOOD OBESITY LA English DT Editorial Material ID GLOBAL CAPACITY C1 [Katz, David L.] Yale Univ, Prevent Res Ctr, Griffin Hosp, Derby, CT 06418 USA. [Grant, Deborah Lewison] FoodFight, New York, NY USA. [McGuire, Todd J.] IncentaHLTH LLC, Denver, CO USA. [McQuigg, Scott] HealthTeacher Inc, Nashville, TN USA. [Voci, Karen] Harvard Pilgrim Hlth Care Fdn, Harvard Pilgrim Hlth Care, Wellesley, MA USA. [Volpp, Kevin] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Volpp, Kevin] Leonard Davis Inst, Ctr Hlth Incent & Behav Econ, Philadelphia, PA USA. [Volpp, Kevin] Penn CMU Roybal Ctr Behav Econ & Hlth P30, Philadelphia, PA USA. [Volpp, Kevin] UPHS Ctr Innovat Hlth Care Financing, Philadelphia, PA USA. [Volpp, Kevin] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Volpp, Kevin] Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. RP Katz, DL (reprint author), Yale Univ, Prevent Res Ctr, Griffin Hosp, 2nd Floor 130 Div St, Derby, CT 06418 USA. EM david.katz@yale.edu OI Katz, David/0000-0001-6845-6192 NR 6 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2153-2168 EI 2153-2176 J9 CHILD OBES JI Child Obes. PD APR PY 2013 VL 9 IS 2 BP 95 EP 103 DI 10.1089/chi.2013.9202 PG 9 WC Pediatrics SC Pediatrics GA AI4PB UT WOS:000336846200003 PM 23517280 ER PT J AU Bartley, J Garrett, J Grant, CC Camargo, CA AF Bartley, Jim Garrett, Jeff Grant, Cameron C. Camargo, Carlos A., Jr. TI Could Vitamin D Have a Potential Anti-Inflammatory and Anti-Infective Role in Bronchiectasis? SO CURRENT INFECTIOUS DISEASE REPORTS LA English DT Article DE Bronchiectasis; Inflammation; Obstructive lung disease; Pathophysiology; Pathology; Vitamin D; Innate immunity; Adaptive immunity; Antimicrobial peptides; Chronic rhinosinusitis; Microbiotia ID CYSTIC FIBROSIS BRONCHIECTASIS; RANDOMIZED CONTROLLED-TRIAL; REGULATORY T-CELLS; OBSTRUCTIVE PULMONARY-DISEASE; PLACEBO-CONTROLLED TRIAL; QUALITY-OF-LIFE; D SUPPLEMENTATION; 1,25-DIHYDROXYVITAMIN D-3; PEPTIDE LL-37; MYCOBACTERIUM-TUBERCULOSIS AB Bronchiectasis is a chronic infective and inflammatory respiratory disease that causes significant morbidity and mortality. Patients with non-cystic-fibrosis bronchiectasis are frequently vitamin D deficient, and vitamin D levels correlate with disease severity. Infection-specific actions of vitamin D include the enhancement of innate immunity and the moderation of inflammation caused by the adaptive immune response. Potentially, vitamin D could influence the processes that lead to bronchiectasis and the frequency and severity of acute exacerbations. Randomized trials of vitamin D supplementation have shown effects that are likely to be protective against the development of bronchiectasis. Several issues need to be clarified before the development of clinical trials to investigate the role of vitamin D in bronchiectasis. These include an optimal vitamin D supplementation dose and appropriate and sensitive outcome measures that include assessment of exacerbation frequency and severity, lung function, and health-related quality of life. C1 [Bartley, Jim] Univ Auckland, Dept Surg, Auckland 1023, New Zealand. [Garrett, Jeff] Univ Auckland, Dept Med, Auckland 1023, New Zealand. [Grant, Cameron C.] Univ Auckland, Dept Paediat, Auckland 1023, New Zealand. [Grant, Cameron C.] Univ Auckland, Ctr Longitudinal Res He Ara Ki Mua, Auckland 1023, New Zealand. [Grant, Cameron C.] Auckland City Hosp, Starship Childrens Hosp, Auckland Dist Hlth Board, Auckland 1023, New Zealand. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Bartley, J (reprint author), Univ Auckland, Dept Surg, 10 Owens Rd, Auckland 1023, New Zealand. EM jbartley@ihug.co.nz; jegarrett@middlemore.co.nz; cc.grant@auckland.ac.nz; ccamargo@partners.org OI Grant, Cameron/0000-0002-4032-7230 FU Health Research Council of New Zealand grant FX Dr. Bartley, Dr. Garrett, and Professor Camargo Jr. have received a Health Research Council of New Zealand grant with which they are investigating the role of Vitamin D supplementation in adult bronchiectasis. NR 102 TC 4 Z9 4 U1 0 U2 9 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 APR PY 2013 VL 15 IS 2 BP 148 EP 157 DI 10.1007/s11908-013-0321-9 PG 10 WC Infectious Diseases SC Infectious Diseases GA AK2YP UT WOS:000338286800009 PM 23371406 ER PT J AU Mitin, T Shipley, WU Efstathiou, JA Heney, NM Kaufman, DS Lee, RJ Zietman, AL AF Mitin, Timur Shipley, William U. Efstathiou, Jason A. Heney, Niall M. Kaufman, Donald S. Lee, Richard J. Zietman, Anthony L. TI Trimodality Therapy for Bladder Conservation in Treatment of Invasive Bladder Cancer SO CURRENT UROLOGY REPORTS LA English DT Article DE Bladder cancer; Radiation therapy; Trimodality therapy; Bladder preservation; Muscle invasive; Cystectomy ID SELECTIVE ORGAN PRESERVATION; TRANSITIONAL-CELL CARCINOMA; RADICAL CYSTECTOMY; UROTHELIAL CARCINOMA; RADIATION-THERAPY; ONCOLOGY-GROUP; NEOADJUVANT CHEMOTHERAPY; TRANSURETHRAL SURGERY; ADJUVANT CHEMOTHERAPY; SPARING TREATMENT AB During the past 25 years, prospective clinical trials have established that bladder preservation therapy for select patients with muscle-invasive bladder cancer is a safe and effective alternative to an immediate cystectomy. Cisplatin-based chemoradiation is the most well-studied and accepted component of trimodality therapy; however, other systemic agents have recently been shown effective in combination with radiation therapy, increasing the range of options to allow for better personalization of care. In this review, the most recent advances in the field of bladder-preserving trimodality therapy are presented, and future directions for improving the outcomes are outlined. C1 [Mitin, Timur; Shipley, William U.; Efstathiou, Jason A.; Zietman, Anthony L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. [Heney, Niall M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA 02114 USA. [Kaufman, Donald S.; Lee, Richard J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Hematol & Oncol, Boston, MA 02114 USA. RP Shipley, WU (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. EM wshipley@partners.org NR 34 TC 8 Z9 8 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1527-2737 J9 CURR UROL REP JI Curr. Urol. Rep. PD APR PY 2013 VL 14 IS 2 BP 109 EP 115 DI 10.1007/s11934-012-0301-x PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AI1FC UT WOS:000336594700008 PM 23341373 ER PT J AU Rehman, MQ Beal, D Liang, YM Noronha, A Winter, H Farraye, FA Ganley-Leal, L AF Rehman, Mian Qasim Beal, Dominic Liang, YanMei Noronha, Ansu Winter, Harland Farraye, Francis A. Ganley-Leal, Lisa TI B Cells Secrete Eotaxin-1 in Human Inflammatory Bowel Disease SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE eosinophil; B cell; eotaxin-1; inflammatory bowel disease ID ESCHERICHIA-COLI LIPOPOLYSACCHARIDE; PERIPHERAL-BLOOD EOSINOPHILS; CHEMOKINE RECEPTOR CCR3; ULCERATIVE-COLITIS; CROHNS-DISEASE; GASTROINTESTINAL EOSINOPHILS; INCREASED EXPRESSION; CYTOKINE PRODUCTION; EPITHELIAL-CELLS; IN-VITRO AB Background: Our previous studies have demonstrated that B cells in human inflammatory bowel disease (IBD) are highly activated and produce copious amounts of chemokines. Here, we showed that B cells produce eotaxin-1, a selective chemokine for acute eosinophilia. Increased levels of activated eosinophils have been found in the intestinal mucosa in patients with IBD, but their role(s) and the regulation of their migration patterns remain poorly defined. Methods: To determine how B-cell secretion of eotaxin-1 influences eosinophil activation and migration, we performed immunoepidemiological approaches coupled with in vitro studies. B cells and eosinophils from patients with Crohn's disease and ulcerative colitis were isolated, and responses to Toll-like receptor ligands (TLR) were measured and assessed for the relationship with clinical disease. Results: Eotaxin-1 from recirculating B cells, and TLR ligands, regulated eosinophil homing mechanisms in IBD. B cells stimulated with hypo-acylated lipopolysaccharide (LPS) produced copious amounts of eotaxin-1, which influenced eosinophil activation profiles in the bloodstream. We also found that hexa-acylated LPS, such Escherichia coli LPS, directly activated TLR2-expressing and TLR4-expressing eosinophils from patients with IBD to express a different repertoire of mucosal homing receptors, namely CCR9 and CCR10. Whereas B-cell production of eotaxin-1 was correlated with reduced disease activity, eosinophil activation by hexa-acylated LPS was associated with increased disease activity. Conclusions: These results suggest that systemic TLR ligands influence eosinophil migration patterns, both directly and indirectly, through B cells. Our report uncovers unexpected mechanisms of cross talk between certain immune cells that shed new light on IBD immunology. C1 [Rehman, Mian Qasim; Liang, YanMei; Ganley-Leal, Lisa] Boston Univ, Sch Med, Infect Dis Sect, Dept Med,Boston Med Ctr, Boston, MA 02118 USA. [Beal, Dominic] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. [Noronha, Ansu; Farraye, Francis A.] Boston Med Ctr, Gastroenterol Sect, Boston, MA USA. [Winter, Harland] MassGen Hosp Children, Div Pediat Gastroenterol & Nutr, Boston, MA USA. RP Ganley-Leal, L (reprint author), Boston Univ, Sch Med, Infect Dis Sect, Dept Med,Boston Med Ctr, 650 Albany St,Room 630, Boston, MA 02118 USA. EM lisaganley@comcast.net OI Farraye, Francis/0000-0001-6371-2441 FU Broad Medical Research Program of the Broad Foundation, a Department of Medicine CTSI Pilot Award [1ULIRR025771]; Evans Medical Foundation Blood Microbiome ARC FX This study was supported by the Broad Medical Research Program of the Broad Foundation, a Department of Medicine CTSI Pilot Award 1ULIRR025771, and the Evans Medical Foundation Blood Microbiome ARC. NR 61 TC 7 Z9 7 U1 0 U2 0 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 APR PY 2013 VL 19 IS 5 BP 922 EP 933 DI 10.1097/MIB.0b013e3182802950 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AH4GA UT WOS:000336084200017 PM 23511032 ER PT J AU Herfarth, HH Katz, JA Hanauer, SB Sandborn, WJ Loftus, EV Sands, BE Galanko, JA Walkup, D Isaacs, KL Martin, CF Sandler, RS Sartor, RB AF Herfarth, Hans H. Katz, Jeffry A. Hanauer, Stephen B. Sandborn, William J. Loftus, Edward V., Jr. Sands, Bruce E. Galanko, Joseph A. Walkup, Dolly Isaacs, Kim L. Martin, Christopher F. Sandler, Robert S. Sartor, Ryan B. TI Ciprofloxacin for the Prevention of Postoperative Recurrence in Patients with Crohn's Disease: A Randomized, Double-blind, Placebo-controlled Pilot Study SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE Crohn's disease/surgery; ciprofloxacin; quinolone; anti-infective agents/adverse effects; inflammatory bowel diseases ID INFLAMMATORY-BOWEL-DISEASE; CONTROLLED-TRIAL; ENDOSCOPIC RECURRENCE; ULCERATIVE-COLITIS; ILEAL RESECTION; FOLLOW-UP; SURGERY; PROPHYLAXIS; THERAPY; RISK AB Background: The commensal bacterial flora plays a critical role in the postoperative recurrence of Crohn's disease (CD). We conducted a randomized, double-blind, placebo-controlled 6-month pilot trial of ciprofloxacin for the prevention of endoscopic recurrence in patients with CD who underwent surgery. Methods: Thirty-three patients with CD, who had undergone surgery with ileocolonic anastomosis within the previous 2 weeks, were randomized to treatment with ciprofloxacin (500 mg twice daily) or placebo tablets for 6 months. Endpoints were endoscopic recurrence at 6 months and safety and tolerability of long-term ciprofloxacin therapy. Results: Thirty-three patients were randomized; 14 patients discontinued the study early. Significant endoscopic recurrence was observed in 3 of 9 patients (33%) in the ciprofloxacin group and 5 of 10 patients (50%) in the placebo group at 6 months after surgery (P < 0.578). The intention-to-treat analysis demonstrated endoscopic recurrence in 11 of 17 patients (65%) in the ciprofloxacin group and 11 of 16 patients (69%) in the placebo group at month 6 (P < 0.805). Thirty-six adverse events occurred in 19 of 33 patients (58%). Possible drug-associated adverse events occurred significantly more often in the ciprofloxacin group (P < 0.043), leading to study drug discontinuation in 24% (4 of 17) and 6% of patients (1 of 16) in the ciprofloxacin and placebo groups, respectively (P < 0.166). Conclusions: In this pilot study, ciprofloxacin was not more effective than placebo for the prevention of postoperative recurrence in patients with CD. Long-term ciprofloxacin therapy is limited by drug-associated side effects. Future studies in postoperative prevention of CD should evaluate antibiotic approaches with a more favorable safety profile. C1 [Herfarth, Hans H.; Galanko, Joseph A.; Walkup, Dolly; Isaacs, Kim L.; Martin, Christopher F.; Sandler, Robert S.; Sartor, Ryan B.] Univ N Carolina, Div Gastroenterol & Hepatol, Chapel Hill, NC 27599 USA. [Katz, Jeffry A.] Case Western Reserve Univ, Sch Med, Univ Hosp Case Med Ctr, Div Gastroenterol & Liver Dis, Cleveland, OH USA. [Hanauer, Stephen B.] Univ Chicago, Sect Gastroenterol & Nutr, Chicago, IL 60637 USA. [Sandborn, William J.; Loftus, Edward V., Jr.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Sandborn, William J.] Univ Calif San Diego, Div Gastroenterol, La Jolla, CA 92093 USA. [Sands, Bruce E.] Massachusetts Gen Hosp, Crohns & Colitis Ctr, Boston, MA 02114 USA. [Sands, Bruce E.] Harvard Univ, Sch Med, Boston, MA USA. [Sands, Bruce E.] Mt Sinai Sch Med, Dept Med, Henry D Janowitz Div Gastroenterol, New York, NY USA. RP Herfarth, HH (reprint author), Univ N Carolina, Dept Med, Div Gastroenterol & Hepatol, Bioinformat Bldg,CB 7080, Chapel Hill, NC 27599 USA. EM hherf@med.unc.edu RI Loftus, Edward/E-8304-2011 FU Crohn's and Colitis Foundation of America (CCFA); National Institute of Diabetes & Digestive & Kidney Diseases [1R21DK080408-01, P30 DK034987] FX Supported by a Senior Research Award of the Crohn's and Colitis Foundation of America (CCFA) and by grants of the National Institute of Diabetes & Digestive & Kidney Diseases (1R21DK080408-01; P30 DK034987). NR 35 TC 14 Z9 14 U1 0 U2 5 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 APR PY 2013 VL 19 IS 5 BP 1073 EP 1079 DI 10.1097/01.MIB.0000428910.36091.10 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AH4GA UT WOS:000336084200035 PM 23511031 ER PT J AU Gheorghiade, M Vaduganathan, M Shah, SJ AF Gheorghiade, Mihai Vaduganathan, Muthiah Shah, Sanjiv J. TI Evaluative Framework for Phase II Studies in Patients With Heart Failure and Preserved Ejection Fraction SO JACC-HEART FAILURE LA English DT Editorial Material DE diastolic dysfunction; heart failure with preserved ejection fraction; late sodium current inhibition C1 [Gheorghiade, Mihai] Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, Chicago, IL 60611 USA. [Vaduganathan, Muthiah] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Shah, Sanjiv J.] Northwestern Univ, Div Cardiol, Feinberg Sch Med, Chicago, IL 60611 USA. RP Gheorghiade, M (reprint author), Northwestern Univ, Ctr Cardiovasc Innovat, Feinberg Sch Med, 645 North Michigan Ave,Suite 1006, Chicago, IL 60611 USA. EM m-gheorghiade@northwestern.edu NR 12 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2213-1779 EI 2213-1787 J9 JACC-HEART FAIL JI JACC-Heart Fail. PD APR PY 2013 VL 1 IS 2 BP 123 EP 126 DI 10.1016/j.jchf.2013.01.001 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA V41GT UT WOS:000209535400005 PM 24621837 ER PT J AU Hill, RR Vorderstrasse, A Turner, B Pereira, K Thompson, J AF Hill, Rebecca Russo Vorderstrasse, Allison Turner, Barbara Pereira, Katherine Thompson, Julie TI Screening for Depression in Patients with Diabetes: Addressing the Challenge SO JNP-JOURNAL FOR NURSE PRACTITIONERS LA English DT Article DE depression screening; diabetes mellitus; patient health questionnaire-9; primary care AB This quality improvement project instituted a routine depression screening using the Patient Health Questionnaire-9 for patients in a primary care practice with the goal of earlier identification and treatment of depression. A total of 115 patients were screened. A retrospective chart review revealed a statistically significant difference in the incidence and new diagnoses of depression among those with diabetes. The use of this screening was devoid of significant barriers to implementation. Although several new cases of depression were diagnosed, many patients refused treatment of any kind, necessitating future research in the area of patient barriers to depression management. C1 [Hill, Rebecca Russo] Duke Univ, Durham, NC 27706 USA. [Hill, Rebecca Russo] MCPHS Univ, Sch Nursing, Boston, MA USA. [Hill, Rebecca Russo] Massachusetts Gen Hosp, Emergency Med, Boston, MA 02114 USA. [Vorderstrasse, Allison; Pereira, Katherine; Thompson, Julie] Duke Univ, Sch Nursing, Durham, NC USA. [Turner, Barbara] Duke Univ, Sch Nursing, Nursing Practice Program, Durham, NC USA. RP Hill, RR (reprint author), Duke Univ, Durham, NC 27706 USA. EM Rebecca.Hill1@mcphs.edu NR 13 TC 2 Z9 2 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1555-4155 EI 1878-058X J9 JNP-J NURSE PRACT JI JNP-J. Nurse Pract. PD APR PY 2013 VL 9 IS 4 BP 208 EP 213 DI 10.1016/j.nurpra.2013.01.009 PG 6 WC Nursing SC Nursing GA V39HV UT WOS:000209403000009 ER PT J AU Tonetti, MS Van Dyke, TE AF Tonetti, Maurizio S. Van Dyke, Thomas E. CA Joint EFP AAP Workshop TI Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases (Reprinted from Journal of Clinical Periodontology, vol 40, pg S24-S29, 2013) SO JOURNAL OF PERIODONTOLOGY LA English DT Reprint DE atherosclerosis; bacteremia; cardiovascular diseases; clinical trials; C-reactive protein; epidemiology; inflammation; myocardial infarction; periodontal diseases; periodontitis; stroke ID OF-CARDIOLOGY; INTERVENTIONS; PROGRESSION; GUIDELINES; MANAGEMENT; HEALTH AB Background: This consensus report is concerned with the association between periodontitis and atherosclerotic cardiovascular disease (ACVD). Periodontitis is a chronic multifactorial inflammatory disease caused by microorganisms and characterized by progressive destruction of the tooth supporting apparatus leading to tooth loss; as such, it is a major public health issue. Aims: This report examined biological plausibility, epidemiology and early results from intervention trials. Plausibility: Periodontitis leads to entry of bacteria in the blood stream. The bacteria activate the host inflammatory response by multiple mechanisms. The host immune response favors atheroma formation, maturation and exacerbation. Epidemiology: In longitudinal studies assessing incident cardiovascular events, statistically significant excess risk for ACVD was reported in individuals with periodontitis. This was independent of established cardiovascular risk factors. The amount of the adjusted excess risk varies by type of cardiovascular outcome and across populations by age and gender. Given the high prevalence of periodontitis, even low to moderate excess risk is important from a public health perspective. Intervention: There is moderate evidence that periodontal treatment: (i) reduces systemic inflammation as evidenced by reduction in C-reactive protein (CRP) and improvement of both clinical and surrogate measures of endothelial function; but (ii) there is no effect on lipid profiles - supporting specificity. Limited evidence shows improvements in coagulation, biomarkers of endothelial cell activation, arterial blood pressure and subclinical atherosclerosis after periodontal therapy. The available evidence is consistent and speaks for a contributory role of periodontitis to ACVD. There are no periodontal intervention studies on primary ACVD prevention and there is only one feasibility study on secondary ACVD prevention. Conclusions: It was concluded that: (i) there is consistent and strong epidemiologic evidence that periodontitis imparts increased risk for future cardiovascular disease; and (ii) while in vitro, animal and clinical studies do support the interaction and biological mechanism, intervention trials to date are not adequate to draw further conclusions. Well-designed intervention trials on the impact of periodontal treatment on prevention of ACVD hard clinical outcomes are needed. C1 [Tonetti, Maurizio S.] European Res Grp Periodontol, I-16149 Genoa, Italy. [Van Dyke, Thomas E.] Forsyth Inst, Cambridge, MA USA. RP Tonetti, MS (reprint author), European Res Grp Periodontol, WTC Tower Genoa, Via De Marini 1, I-16149 Genoa, Italy. EM maurizio.tonetti@ergoperio.eu FU Colgate-Palmolive; American Academy of Periodontology FX The workshop was funded by an unrestricted educational grant from Colgate-Palmolive to the European Federation of Periodontology and the American Academy of Periodontology. NR 15 TC 14 Z9 14 U1 1 U2 4 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 EI 1943-3670 J9 J PERIODONTOL JI J. Periodont. PD APR PY 2013 VL 84 IS 4 SU S SI SI BP S24 EP S29 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V40CD UT WOS:000209455800004 ER PT J AU Van Dyke, TE van Winkelhoff, AJ AF Van Dyke, Thomas E. van Winkelhoff, Arie Jan TI Infection and inflammatory mechanisms (Reprinted from Journal of Clinical Periodontology, vol 40, pg S1-S7, 2013) SO JOURNAL OF PERIODONTOLOGY LA English DT Reprint DE cardiovascular disease; infection; inflammation; pathogenesis; periodontitis; systemic diseases ID HUMAN PERIODONTAL-LIGAMENT; CORONARY-HEART-DISEASE; TUMOR-NECROSIS-FACTOR; REGULATORY T-CELLS; ATHEROSCLEROTIC CARDIOVASCULAR-DISEASE; ANTIINFLAMMATORY LIPID MEDIATORS; EDITORS CONSENSUS PERIODONTITIS; JOURNAL-OF-CARDIOLOGY; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; PORPHYROMONAS-GINGIVALIS AB This introductory article examines the potential mechanisms that may play a role in the associations between periodontitis and the systemic conditions being considered in the EFP/AAP Workshop in Segovia, Spain. Three basic mechanisms have been postulated to play a role in these interactions; metastatic infections, inflammation and inflammatory injury, and adaptive immunity. The potential role of each alone and together is considered in in vitro and animal studies and in human studies when available. This is not a systematic or critical review, but rather an overview of the field to set the stage for the critical reviews in each of the working groups. C1 [Van Dyke, Thomas E.] Forsyth Inst, Cambridge, MA 02142 USA. [van Winkelhoff, Arie Jan] Univ Groningen, Dept Dent & Oral Hyg, Groningen, Netherlands. RP Van Dyke, TE (reprint author), Forsyth Inst, Dept Appl Oral Sci, Clin & Translat Res Chair, 245 First St, Cambridge, MA 02142 USA. EM tvandyke@forsyth.org OI Van Dyke, Thomas/0000-0003-0568-124X FU Colgate-Palmolive; American Academy of Periodontology FX The workshop was funded by an unrestricted educational grant from Colgate-Palmolive to the European Federation of Periodontology and the American Academy of Periodontology. NR 94 TC 10 Z9 10 U1 1 U2 1 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 EI 1943-3670 J9 J PERIODONTOL JI J. Periodont. PD APR PY 2013 VL 84 IS 4 SU S SI SI BP S1 EP S7 DI 10.1902/jop.2013.1340018 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V40CD UT WOS:000209455800001 PM 23631571 ER PT J AU Halford, C Gau, V Churchill, BM Haake, DA AF Halford, Colin Gau, Vincent Churchill, Bernard M. Haake, David A. TI Bacterial Detection & Identification Using Electrochemical Sensors SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Bioengineering; Issue 74; Microbiology; Genetics; Molecular Biology; Cellular Biology; Biochemistry; Biomedical Engineering; Medicine; Immunology; Bacteria; Electrochemical sensor; ribosomal RNA; rRNA; 16S RNA; DNA; probe; assay AB Electrochemical sensors are widely used for rapid and accurate measurement of blood glucose and can be adapted for detection of a wide variety of analytes. Electrochemical sensors operate by transducing a biological recognition event into a useful electrical signal. Signal transduction occurs by coupling the activity of a redox enzyme to an amperometric electrode. Sensor specificity is either an inherent characteristic of the enzyme, glucose oxidase in the case of a glucose sensor, or a product of linkage between the enzyme and an antibody or probe. Here, we describe an electrochemical sensor assay method to directly detect and identify bacteria. In every case, the probes described here are DNA oligonucleotides. This method is based on sandwich hybridization of capture and detector probes with target ribosomal RNA (rRNA). The capture probe is anchored to the sensor surface, while the detector probe is linked to horseradish peroxidase (HRP). When a substrate such as 3,3', 5,5'-tetramethylbenzidine (TMB) is added to an electrode with capture-target-detector complexes bound to its surface, the substrate is oxidized by HRP and reduced by the working electrode. This redox cycle results in shuttling of electrons by the substrate from the electrode to HRP, producing current flow in the electrode. C1 [Halford, Colin] Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA USA. [Halford, Colin; Churchill, Bernard M.; Haake, David A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Gau, Vincent] GeneFluidics, Duarte, CA USA. [Haake, David A.] Vet Affairs Greater Los Angeles Healthcare Syst, Div Infect Dis, Los Angeles, CA USA. [Haake, David A.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. RP Haake, DA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. EM dhaake@ucla.edu FU National Institute of Allergy and Infectious Diseases [AI075565]; Wendy and Ken Ruby Fund for Excellence in Pediatric Urology Research FX This study was supported by Cooperative Agreement Award AI075565 (to D.A.H.) from the National Institute of Allergy and Infectious Diseases and by the Wendy and Ken Ruby Fund for Excellence in Pediatric Urology Research. B.M.C. is the Judith and Robert Winston Chair in Pediatric Urology. NR 12 TC 0 Z9 0 U1 2 U2 14 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD APR PY 2013 IS 74 AR UNSP e4282 DI 10.3791/4282 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36QY UT WOS:000209227100006 PM 23644406 ER PT J AU Timpone, V Schneider, BE Sherman, PM AF Timpone, Vincent Schneider, Brett E. Sherman, Paul M. TI Screening CT Angiography for Detection of Blunt Carotid and Vertebral Artery Injury in the Setting of Combat-Related Trauma SO MILITARY MEDICINE LA English DT Article ID COMPUTED TOMOGRAPHIC ANGIOGRAPHY; CEREBROVASCULAR INJURIES; DIAGNOSIS; THERAPY AB Blunt carotid and vertebral artery injury (BCVI) is a relatively rare injury reported in the civilian sector and is associated with high morbidity and mortality. The purpose of our study was to use an optimized computed tomography angiography protocol in the deployed setting to determine the prevalence of BCVI in a consecutive patient population having experienced recent wartime-related traumatic injuries. From July 2008 to September 2009, a total of 307 consecutive trauma patients were included in this study. At least 233 (76%) patients were known to have experienced blast-related traumatic injuries. 135 (44%) patients had injuries to the head, face, or neck. 4 patients (1.3%) sustained BCVI. There was no statistically significant difference between the prevalence of BCVI in the deployed setting and the civilian sector. We speculate that in our study population, the relatively decreased prevalence of cervical spinal fractures (3.3%) observed may counter the theoretical increased risk of vascular injury from blast trauma, ultimately producing a similar prevalence of overall BCVI compared to civilian study populations. Based on our observations, we cannot advocate for or against more liberalized screening of BCVI in the deployed setting, and military physicians may elect to continue screening for these injuries with currently established and accepted practice guidelines developed in civilian trauma populations. C1 [Timpone, Vincent] Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Boston, MA 02114 USA. [Schneider, Brett E.] David Grant USAF Med Ctr, Dept Radiol, Div Neuroradiol, Travis Afb, CA 94535 USA. [Sherman, Paul M.] Wilford Hall USAF Med Ctr, Dept Radiol, Div Neuroradiol, Lackland AFB, TX 78236 USA. RP Timpone, V (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, 55 Fruit St, Boston, MA 02114 USA. NR 20 TC 1 Z9 1 U1 0 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD APR PY 2013 VL 178 IS 4 BP 416 EP 420 DI 10.7205/MILMED-D-12-00108 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA AN7TY UT WOS:000340805100013 PM 23707827 ER PT J AU La Fountaine, MF Wecht, JM Bauman, WA AF La Fountaine, M. F. Wecht, J. M. Bauman, W. A. TI Acute nitric oxide synthase inhibition and cardiac conduction in persons with spinal cord injury: a short report SO PHARMAZIE LA English DT Article ID AUTONOMIC NERVOUS-SYSTEM; HEART-RATE-VARIABILITY; BLOOD-PRESSURE; INCREASED SUSCEPTIBILITY; VENTRICULAR-ARRHYTHMIAS; SARCOPLASMIC-RETICULUM; EXCHANGER EXPRESSION; PARAPLEGIC RATS; RATE RESPONSE; TETRAPLEGIA AB N-G-nitro L-arginine methyl ester (L-NAME) is a potent and non-specific inhibitor of nitric oxide synthase (NOS). NOS inhibition with L-NAME has been shown to adversely prolong electrocardiogram (ECG) intervals in an animal model, an observation which has yet to be evaluated in humans. We determined the effects of several weight-based L-NAME doses on ECG intervals in persons with tetraplegia and a neurologically-intact control group. This two-part investigation determined the effects of different weight-based doses of L-NAME in the supine (Study 1) and orthostatic position (Study 2). Subjects completed an open-label trial with intravenous administration of L-NAME at specific doses [i.e., 0, 1, 2 or 4 mg.kg(-1)] in the supine position. The SCI group completed an orthostatic challenge with or without L-NAME [i.e., 0, 1 or 2 mg.kg(-1)] and controls completed only a single visit [0 mg-kg(-1)]. Digital ECGs were obtained at baseline (BL), after infusion (60 minutes) and 1 hour post-infusion (120 minutes) in Study 1, and at BL, 60 minutes and at two, 10 minute post-infusion time points after head up tilt (Post-Tilt 1 and 2) in Study 2. Heart rate, PQ, QT, and heart rate corrected QT (QTC) intervals were determined. The groups were matched for demographics. Seven subjects with tetraplegia and 6 controls participated in Study 1; 7 subjects with tetraplegia and 7 controls participated in Study 2. No statistical differences were noted between or within groups at baseline on each study visit for the ECG variables. L-NAME, regardless of dose, did not significantly change any ECG interval. NOS inhibition with L-NAME, at the weight-based doses tested do not induce hypertensive crises and, did not adversely affect any ECG interval in persons with SCI or neurologically intact control subjects during supine rest or orthostatic provocation. C1 [La Fountaine, M. F.; Wecht, J. M.; Bauman, W. A.] James J Peters VA Med Ctr, VA RR&D Natl Ctr Excellence Med Consequences Spin, Bronx, NY 10468 USA. [La Fountaine, M. F.; Wecht, J. M.; Bauman, W. A.] James J Peters VA Med Ctr, Med Serv, Bronx, NY 10468 USA. [La Fountaine, M. F.; Bauman, W. A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [La Fountaine, M. F.] Seton Hall Univ, Sch Hlth & Med Sci, Dept Phys Therapy, S Orange, NJ 07079 USA. [Wecht, J. M.; Bauman, W. A.] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY USA. RP La Fountaine, MF (reprint author), James J Peters VA Med Ctr, VA RR&D Natl Ctr Excellence Med Consequences Spin, Room 7A-13 M,130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM michael.lafountaine@va.gov FU Veteran Affairs Rehabilitation Research and Development Service [B9212C, B3600R, B3346 V]; James J. Peters VA Medical Center FX This research was supported by the Veteran Affairs Rehabilitation Research and Development Service (#B9212C, #B3600R, and #B3346 V) and the James J. Peters VA Medical Center. NR 35 TC 2 Z9 2 U1 0 U2 1 PU GOVI-VERLAG PHARMAZEUTISCHER VERLAG GMBH PI ESCHBORN PA PHARMAZEUTISCCARL MANNICH STR 26, D-65760 ESCHBORN, GERMANY SN 0031-7144 J9 PHARMAZIE JI Pharmazie PD APR PY 2013 VL 68 IS 4 BP 245 EP 250 DI 10.1691/ph.2013.2794 PG 6 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA AE8NZ UT WOS:000334259900003 PM 23700789 ER PT J AU Maselli, DJ Adams, SG Peters, JI Levine, SM AF Maselli, Diego J. Adams, Sandra G. Peters, Jay I. Levine, Stephanie M. TI Management of asthma during pregnancy SO THERAPEUTIC ADVANCES IN RESPIRATORY DISEASE LA English DT Review DE asthma; management of asthma; pregnancy ID RANDOMIZED CONTROLLED-TRIAL; PROTON-PUMP INHIBITORS; SEVERE ALLERGIC-ASTHMA; DOUBLE-BLIND-TRIAL; PERINATAL OUTCOMES; CONGENITAL-MALFORMATIONS; INHALED BECLOMETHASONE; NEDOCROMIL SODIUM; MATERNAL ASTHMA; MODERATE ASTHMA AB Asthma is an inflammatory lung condition that is the most common chronic disease affecting pregnancy. The changes in pulmonary physiology during pregnancy include increased minute ventilation, decreased functional residual capacity, increased mucus production, and airway mucosa hyperemia and edema. Pregnancy is also associated with a physiological suppression of the immune system. Many studies have described the heterogeneous immune system response in women with asthma during pregnancy, which partly explains why asthma has been shown to worsen, improve, or remain stable in equal proportions of women during pregnancy. Asthma may be associated with poor maternal and fetal outcomes. However, better maternal and fetal outcomes are observed with better asthma control. Asthma controller medications are generally thought to be safe during pregnancy, but limited data are available for some of the medicines. Newer medications like omalizumab open avenues for the treatment of asthma, but also pose a challenge, as there is limited experience with their use. Therefore, a multidisciplinary approach, including obstetricians, asthma specialists, and pediatricians should collaborate with the patient to carefully weigh the risks and benefits to determine an optimal management plan for each individual patient. The aim of this review article is to summarize the most recent literature about the immunological changes that occur during pregnancy, physiological and clinical implications of asthma on pregnancy, and asthma management and medication use in pregnant women. C1 [Maselli, Diego J.; Adams, Sandra G.; Peters, Jay I.; Levine, Stephanie M.] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm Dis & Crit Care, San Antonio, TX 78229 USA. [Adams, Sandra G.; Peters, Jay I.; Levine, Stephanie M.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Maselli, DJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Pulm Dis & Crit Care, 7400 Merton Minter MC 111E, San Antonio, TX 78229 USA. EM masellicacer@uthscsa.edu NR 82 TC 10 Z9 10 U1 0 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1753-4658 EI 1753-4666 J9 THER ADV RESPIR DIS JI Ther. Adv. Respir. Dis. PD APR PY 2013 VL 7 IS 2 BP 87 EP 100 DI 10.1177/1753465812464287 PG 14 WC Respiratory System SC Respiratory System GA AH3KU UT WOS:000336023000003 PM 23129568 ER PT J AU Milos, G Kuenzli, C Soelch, CM Schumacher, S Moergeli, H Mueller-Pfeiffer, C AF Milos, Gabriella Kuenzli, Cornelia Soelch, Chantal Martin Schumacher, Sonja Moergeli, Hanspeter Mueller-Pfeiffer, Christoph TI How much should I eat? Estimation of meal portions in anorexia nervosa SO APPETITE LA English DT Article DE Anorexia nervosa; Portion size; Intent-to-eat; Food amount; Eating behavior ID BULIMIA-NERVOSA; SIZE; FOOD; BEHAVIOR; SAMPLE AB Pathological concern regarding one's weight and weight gain is a crucial feature of anorexia nervosa. Consequently, anorexia nervosa patients often claim that they are uncertain regarding the amount of food they should eat. The present study investigated whether individuals with anorexia nervosa show an altered estimation of meal portion sizes and whether this estimation is modulated by an intent-to-eat instruction (where patients are asked to imagine having to eat the presented meal), meal type and meal portion size. Twenty-four women with anorexia nervosa and 27 healthy women estimated, using a visual analogue scale, the size of six different portions of three different meals, with and without intent-to-eat instructions. Subjects with anorexia nervosa estimated the size of small and medium meal portions (but not large meal servings) as being significantly larger, compared to estimates of healthy controls. The overestimation of small meal portions by anorexia nervosa subjects was significantly greater in the intent-to-eat, compared to general, condition. These findings suggest that disturbed perceptions associated with anorexia nervosa not only include interoceptive awareness (i.e., body weight and shape), but also extend to external disorder-related objects such as meal portion size. Specific therapeutic interventions, such as training regarding meal portion evaluation, could address these difficulties. (C) 2013 Published by Elsevier Ltd. C1 [Milos, Gabriella; Kuenzli, Cornelia; Schumacher, Sonja; Moergeli, Hanspeter; Mueller-Pfeiffer, Christoph] Univ Zurich Hosp, Dept Psychiat & Psychotherapy, CH-8091 Zurich, Switzerland. [Soelch, Chantal Martin] Univ Fribourg, Dept Psychol, CH-1700 Fribourg, Switzerland. [Mueller-Pfeiffer, Christoph] Psychiat Serv Cty St Gallen North, Ctr Educ & Res COEUR, Wil, Switzerland. [Mueller-Pfeiffer, Christoph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. RP Milos, G (reprint author), Univ Zurich Hosp, Dept Psychiat & Psychotherapy, CH-8091 Zurich, Switzerland. EM gabriella.milos@usz.ch NR 30 TC 4 Z9 4 U1 1 U2 39 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 J9 APPETITE JI Appetite PD APR 1 PY 2013 VL 63 BP 42 EP 47 DI 10.1016/j.appet.2012.12.016 PG 6 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA 095WV UT WOS:000315366600007 PM 23276722 ER PT J AU Horton, LC Frosch, MP Vangel, MG Weigel-DiFranco, C Berson, EL Schmahmann, JD AF Horton, Laura C. Frosch, Matthew P. Vangel, Mark G. Weigel-DiFranco, Carol Berson, Eliot L. Schmahmann, Jeremy D. TI Spinocerebellar Ataxia Type 7: Clinical Course, Phenotype-Genotype Correlations, and Neuropathology SO CEREBELLUM LA English DT Article DE Trinucleotide repeat expansion; Cerebellum; Ataxia; Pathology; Electroretinography ID DOMINANT CEREBELLAR-ATAXIA; RESTLESS LEGS SYNDROME; RETINITIS-PIGMENTOSA; SUBTHALAMIC STIMULATION; MACULAR DYSTROPHY; CAG REPEATS; SCA7; DEGENERATION; DISORDER; FEATURES AB Spinocerebellar ataxia type 7 is a neurodegenerative polyglutamine disease characterized by ataxia and retinal degeneration. The longitudinal course is unknown, and relationships between repeat expansion, clinical manifestations, and neuropathology remain uncertain. We followed 16 affected individuals of a 61-member kindred over 27 years with electroretinograms, neurological examinations including the Brief Ataxia Rating Scale, neuroimaging in five, and autopsy in four cases. We identified four stages of the illness: Stage 0, gene-positive but phenotypically silent; Stage 1, no symptoms, but hyperreflexia and/or abnormal electroretinograms; Stage 2, symptoms and signs progress modestly; and Stage 3, rapid clinical progression. CAG repeat length correlated inversely with age of onset of visual or motor signs (r = -0.74, p = 0.002). Stage 3 rate of progression did not differ between cases (p = 0.18). Electroretinograms correlated with Brief Ataxia Rating Scale score and were a biomarker of disease onset and progression. All symptomatic patients developed gait ataxia, extremity dysmetria, dysarthria, dysrhythmia, and oculomotor abnormalities. Funduscopy revealed pale optic discs and pigmentary disturbances. Visual acuity declined to blindness in those with longer CAG expansions. Hyperreflexia was present from Stage 1 onwards. Restless legs syndrome and sensory impairment were common. Neuropathological hallmarks were neuronal loss in cerebellar cortex, deep cerebellar nuclei, inferior olive, and anterior horns of the spinal cord, and axonal loss in spinocerebellar tracts, dorsal nerve roots, and posterior columns. Retinal pathology included photoreceptor degeneration and disruption of retinal pigment epithelium. Spinocerebellar ataxia type 7 evolves through four clinical stages; neuropathological findings underlie the clinical presentation; electroretinograms are a potential biomarker of disease progression. C1 [Horton, Laura C.; Schmahmann, Jeremy D.] Massachusetts Gen Hosp, Dept Neurol, Lab Neuroanat & Cerebellar Neurobiol, Ataxia Unit,Cognit & Behav Neurol Unit, Boston, MA 02114 USA. [Horton, Laura C.; Schmahmann, Jeremy D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, Pathol Serv, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. [Vangel, Mark G.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Weigel-DiFranco, Carol; Berson, Eliot L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Berman Gund Lab Study Retinal Degenerat, Dept Ophthalmol,Med Sch, Boston, MA 02114 USA. RP Schmahmann, JD (reprint author), Massachusetts Gen Hosp, Dept Neurol, Lab Neuroanat & Cerebellar Neurobiol, Ataxia Unit,Cognit & Behav Neurol Unit, Suite 340,Charles River Plaza South,175 Cambridge, Boston, MA 02114 USA. EM jschmahmann@partners.org OI Horton, Laura/0000-0002-7098-3650 FU NIA NIH HHS [P50 AG005134]; NIMH NIH HHS [R01 MH067980] NR 34 TC 20 Z9 20 U1 0 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1473-4222 J9 CEREBELLUM JI Cerebellum PD APR PY 2013 VL 12 IS 2 BP 176 EP 193 DI 10.1007/s12311-012-0412-4 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 099RJ UT WOS:000315638600007 PM 22915085 ER PT J AU Halperin, F Goldfine, AB AF Halperin, Florencia Goldfine, Allison B. TI Metabolic surgery for type 2 diabetes: efficacy and risks SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Review DE bariatric surgery; glycemic control; type 2 diabetes ID GASTRIC-BYPASS-SURGERY; MORBIDLY OBESE SUBJECTS; GLUCAGON-LIKE PEPTIDE-1; BETA-CELL FUNCTION; INDUCED WEIGHT-LOSS; BARIATRIC SURGERY; SLEEVE GASTRECTOMY; INSULIN SENSITIVITY; GUT HORMONE; HYPERINSULINEMIC HYPOGLYCEMIA AB Purpose of review Bariatric surgery has emerged as a highly effective treatment for obesity and is increasingly recognized to have benefits for glycemic management in patients with pre-existing type 2 diabetes mellitus (T2DM), and for diabetes prevention. This article will review the efficacy and mechanisms of metabolic surgery for the treatment of T2DM. Recent findings Recent small randomized studies with 1-2 years of follow-up begin to provide level 1 data of the effects of surgical procedures compared to medical management on glycemic control. Physiology studies using sophisticated metabolic techniques to evaluate insulin secretion, action, and entero-endocrine changes in patients preoperatively and postoperatively have shed light on the mechanisms that lead to changes in glycemia observed after bariatric surgery. Summary Understanding the efficacy and physiologic effects of bariatric surgery on metabolism will help guide patient management in the context of a growing epidemic of obesity and T2DM, and may also ultimately enable us to develop less invasive but equally effective therapeutic strategies for weight loss and metabolic control. C1 [Halperin, Florencia; Goldfine, Allison B.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Halperin, Florencia; Goldfine, Allison B.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Halperin, Florencia; Goldfine, Allison B.] Harvard Univ, Sch Med, Boston, MA USA. RP Goldfine, AB (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM allison.goldfine@joslin.harvard.edu FU National Institutes of Health (NIH) [5RC1DK086918-02, 1R56DK095451-01]; KL2/MeRIT program of Harvard Catalyst/The Harvard Clinical and Translational Science Center [UL1 RR 025758]; Harvard University FX The authors wish to acknowledge that this work was supported by the National Institutes of Health (NIH) grants 5RC1DK086918-02 and 1R56DK095451-01 (A.B.G.), as well as the KL2/MeRIT program of Harvard Catalyst/The Harvard Clinical and Translational Science Center (Award #UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic healthcare centers) (F.H.). NR 96 TC 8 Z9 9 U1 1 U2 30 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD APR PY 2013 VL 20 IS 2 BP 98 EP 105 DI 10.1097/MED.0b013e32835edbb0 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 097ND UT WOS:000315479900003 PM 23403742 ER PT J AU Restrepo, MI Faverio, P Anzueto, A AF Restrepo, Marcos I. Faverio, Paola Anzueto, Antonio TI Long-term prognosis in community-acquired pneumonia SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE biomarkers; community-acquired pneumonia; outcome ID RESPIRATORY-DISTRESS-SYNDROME; PRACTICE POPULATION COHORT; GERMAN COMPETENCE NETWORK; ACUTE CORONARY SYNDROMES; OLD MANS FRIEND; FOLLOW-UP; INFLAMMATORY MARKERS; SEVERITY ASSESSMENT; ELDERLY-PATIENTS; ACUTE INFECTION AB Purpose of review Pneumonia is considered the leading infectious diseases cause of death and the seventh leading cause of death overall in the US. There is significant interest in understanding the relationship between community-acquired pneumonia (CAP) and mortality. Recent findings Most clinical studies examining patients with CAP have used an arbitrary in-hospital or 30-day mortality as a short-term mortality clinical end point. However, long-term mortality (arbitrary >3 months) factors, incidence, prediction, and implications on patient care are important issues that require further evaluation in patients with CAP. This review focuses on the most recent literature assessing the importance and the frequency of long-term associated outcomes in patients with CAP, the risk factors, and possible implications for future strategies. Multiple risk factors that include age, sex, comorbid conditions, type of pneumonia, and severity of illness are associated with higher long-term mortality. In addition, several biomarkers were demonstrated to be independently associated with long-term mortality. Summary Despite advances in the understanding of long-term mortality among CAP patients, there is still a high unacceptable long-term mortality. Public health programs should address this important gap, considering the high level of complexity factors in patients with CAP. C1 [Restrepo, Marcos I.; Faverio, Paola; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Restrepo, Marcos I.; Anzueto, Antonio] S Texas Vet Healthcare Syst, Audie L Murphy Div, San Antonio, TX USA. [Restrepo, Marcos I.] Vet Evidence Based Res Disseminat & Implementat C, San Antonio, TX USA. [Faverio, Paola] Univ Milano Bicocca, Monza, Italy. [Faverio, Paola] San Gerardo Hosp, Dept Resp Med, Monza, Italy. RP Restrepo, MI (reprint author), 7400 Merton Minter Blvd 11C6, San Antonio, TX 78229 USA. EM restrepom@uthscsa.edu RI Restrepo, Marcos/H-4442-2014 FU National Heart, Lung, and Blood Institute [K23HL096054] FX Dr Restrepo time is partially protected by Award Number K23HL096054 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, And Blood Institute or the National Institutes of Health. The funding agencies had no role in the preparation, review, or approval of the manuscript. The views expressed in this article are those of the author and do not necessarily represent the views of the Department of Veterans Affairs. NR 85 TC 29 Z9 30 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7375 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD APR PY 2013 VL 26 IS 2 BP 151 EP 158 DI 10.1097/QCO.0b013e32835ebc6d PG 8 WC Infectious Diseases SC Infectious Diseases GA 097IY UT WOS:000315468400008 PM 23426328 ER PT J AU Moon, HS Liu, XW Nagel, JM Chamberland, JP Diakopoulos, KN Brinkoetter, MT Hatziapostolou, M Wu, Y Robson, SC Iliopoulos, D Mantzoros, CS AF Moon, Hyun-Seuk Liu, Xiaowen Nagel, Jutta M. Chamberland, John P. Diakopoulos, Kalliope N. Brinkoetter, Mary T. Hatziapostolou, Maria Wu, Yan Robson, Simon C. Iliopoulos, Dimitrios Mantzoros, Christos S. TI Salutary effects of adiponectin on colon cancer: in vivo and in vitro studies in mice SO GUT LA English DT Article ID ACTIVATED PROTEIN-KINASE; GROWTH-FACTOR-D; COLORECTAL-CANCER; CELL-PROLIFERATION; CIRCULATING ADIPONECTIN; MAMMARY CARCINOMAS; SIGNALING PATHWAY; OBESITY; RISK; MECHANISMS AB Background Obesity and a high-fat diet are associated with the risk and progression of colon cancer. Low adiponectin levels may play an important role in the development of colon and other obesity-related malignancies. No previous studies have directly investigated the mechanistic effects of adiponectin on colon cancer in the settings of obesity, a high-fat diet and/or adiponectin deficiency. Objective To investigate the effects of adiponectin on the growth of colorectal cancer in adiponectin-deficient or wild-type-C57BL/6 mice fed a low-fat or high-fat diet. Results Mice fed a high-fat-diet gained more weight and had larger tumours than mice fed a low-fat-diet. Adiponectin administration suppressed implanted tumour growth, causing larger central necrotic areas. Adiponectin treatment also suppressed angiogenesis assessed by CD31 staining and VEGFb and VEGFd mRNA expression in tumours obtained from mice fed a high-fat-diet and from adiponectin-deficient mice. Adiponectin treatment decreased serum insulin levels in mice on a high-fat-diet and increased serum-interleukin (IL)-12 levels in adiponectin-deficient mice. In vitro, it was found that adiponectin directly controls malignant potential (cell proliferation, adhesion, invasion and colony formation) and regulates metabolic (AMPK/S6), inflammatory (STAT3/VEGF) and cell cycle (p21/p27/p53/cyclins) signalling pathways in both mouse MCA38 and human HT29, HCT116 and LoVo colon cancer cell lines in a LKB1-dependent way. Conclusion These new mechanistic and pathophysiology studies provide evidence for an important role of adiponectin in colon cancer. The data indicate that adiponectin or analogues might be useful agents in the management or chemoprevention of colon cancer. C1 [Moon, Hyun-Seuk; Liu, Xiaowen; Nagel, Jutta M.; Chamberland, John P.; Diakopoulos, Kalliope N.; Brinkoetter, Mary T.; Mantzoros, Christos S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02130 USA. [Hatziapostolou, Maria; Iliopoulos, Dimitrios] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Hatziapostolou, Maria; Iliopoulos, Dimitrios] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02130 USA. [Wu, Yan; Robson, Simon C.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Gastroenterol & Transplantat Inst, Boston, MA 02130 USA. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Endocrinol Sect, Boston VA Healthcare Syst, Boston, MA 02130 USA. RP Mantzoros, CS (reprint author), Harvard Univ, Sch Med, JP9B52A,150 S Huntington Ave, Boston, MA 02130 USA. EM cmantzor@bidmc.harvard.edu RI Moon, Hyun-Seuk/G-8576-2015; Hatziapostolou, Maria/N-1820-2015; OI Moon, Hyun-Seuk/0000-0002-5216-2090; Hatziapostolou, Maria/0000-0003-2493-7028; Chamberland, John/0000-0002-7862-1371; Diakopoulos, Kalliope/0000-0002-9236-0489 FU joint California Walnut Commission; AICR grant; National Institute of Diabetes and Digestive and Kidney Diseases [DK79929-02, DK058785-08, DK081913-02]; NIH [HL076540, HL094400]; Beth Israel Deaconess Medical Center; VA Merit award [10684957] FX This study was supported by a joint California Walnut Commission and AICR grant. The Mantzoros Laboratory is supported by DK79929-02, DK058785-08 and DK081913-02 grants from the National Institute of Diabetes and Digestive and Kidney Diseases. The Robson laboratory acknowledges support from NIH via HL076540 and HL094400. The Mantzoros Laboratory is also supported by a discretionary grant from Beth Israel Deaconess Medical Center and a VA Merit award (grant 10684957). NR 45 TC 36 Z9 39 U1 0 U2 21 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD APR PY 2013 VL 62 IS 4 BP 561 EP 570 DI 10.1136/gutjnl-2012-302092 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 099CB UT WOS:000315595800012 PM 22735569 ER PT J AU Babson, KA Boden, MT Harris, AH Stickle, TR Bonn-Miller, MO AF Babson, Kimberly A. Boden, Matthew Tyler Harris, Alex H. Stickle, Timothy R. Bonn-Miller, Marcel O. TI Poor sleep quality as a risk factor for lapse following a cannabis quit attempt SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Sleep; Marijuana; Cannabis; Lapse ID MARIJUANA DEPENDENCE; ANXIETY SENSITIVITY; SEEKING TREATMENT; COPING MOTIVES; WITHDRAWAL; ALCOHOL; USERS; PREVALENCE; SYMPTOMS; NICOTINE AB Treatments for cannabis dependence are associated with high rates of lapse/relapse, underscoring the importance of identifying malleable risk factors that are associated with quit failure. Whereas research has demonstrated that poor sleep quality following cannabis discontinuation is related to subsequent use, there has yet to be an examination of whether poor sleep quality prior to a quit attempt results in a similar pattern of lapse. The present study addressed this gap by examining the role of pre-quit sleep quality on early lapse to cannabis use following a self-guided quit attempt, among 55 cannabis dependent military veterans. Results indicated that participants who experienced poor pre-quit sleep quality had greater risk for lapse within the first 2 days (out of 7) following their quit attempt. Findings are discussed in terms of improving treatments for individuals who report poor sleep quality prior to a cannabis quit attempt. Published by Elsevier Inc. C1 [Babson, Kimberly A.] Stanford Univ, Ctr Hlth Care Evaluat, Vet Affairs Palo Alto Hlth Care Syst, Menlo Pk, CA 94025 USA. [Babson, Kimberly A.] Stanford Univ, Dept Psychiat & Behav Sci, Menlo Pk, CA 94025 USA. [Boden, Matthew Tyler; Harris, Alex H.] Vet Affairs Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk, CA 94025 USA. [Stickle, Timothy R.] Univ Vermont, Dept Psychol, Burlington, VT 05405 USA. [Bonn-Miller, Marcel O.] Philadelphia Vet Affairs Med Ctr, Ctr Excellence Substance Abuse Treatment & Educ, Philadelphia, PA 19104 USA. [Bonn-Miller, Marcel O.] Vet Affairs Palo Alto Hlth Care Syst, Natl Ctr PTSD, Menlo Pk, CA 94025 USA. [Bonn-Miller, Marcel O.] Vet Affairs Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk, CA 94025 USA. RP Babson, KA (reprint author), 795 Willow Rd 152 MPD, Menlo Pk, CA 94025 USA. EM Kimberly.Babson@va.gov OI Babson, Kimberly/0000-0002-9233-8230 NR 46 TC 9 Z9 9 U1 0 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD APR PY 2013 VL 44 IS 4 BP 438 EP 443 DI 10.1016/j.jsat.2012.08.224 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 096TD UT WOS:000315426300011 PM 23098380 ER PT J AU Arakaki, R Kroshinsky, D AF Arakaki, Ryan Kroshinsky, Daniela TI Analyzing inpatient dermatology consultations for pediatric patients SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 71st Annual Meeting of the American-Academy-of-Dermatology (AAD) CY MAR 01-05, 2013 CL Miami Beach, FL SP Amer Acad Dermatol (AAD) C1 [Arakaki, Ryan] Harvard Univ, Sch Med, Boston, MA USA. [Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD APR PY 2013 VL 68 IS 4 SU 1 BP AB171 EP AB171 PG 1 WC Dermatology SC Dermatology GA 096NZ UT WOS:000315412600677 ER PT J AU Arakaki, R Kroshinsky, D AF Arakaki, Ryan Kroshinsky, Daniela TI Treatment of cutaneous dystrophic calcification with intralesional sodium thiosulfate SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 71st Annual Meeting of the American-Academy-of-Dermatology (AAD) CY MAR 01-05, 2013 CL Miami Beach, FL SP Amer Acad Dermatol (AAD) C1 [Arakaki, Ryan] Harvard Univ, Sch Med, Boston, MA USA. [Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 APR PY 2013 VL 68 IS 4 SU 1 BP AB73 EP AB73 PG 1 WC Dermatology SC Dermatology GA 096NZ UT WOS:000315412600289 ER PT J AU Coley, M Kroshinsky, D AF Coley, Marcelyn Kroshinsky, Daniela TI Neuro-Sweet syndrome responds to hydroxychloroquine SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 71st Annual Meeting of the American-Academy-of-Dermatology (AAD) CY MAR 01-05, 2013 CL Miami Beach, FL SP Amer Acad Dermatol (AAD) C1 [Coley, Marcelyn] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Kroshinsky, Daniela] Harvard Univ, Massachusetts Gen Hosp, Med Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 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 APR PY 2013 VL 68 IS 4 SU 1 BP AB55 EP AB55 PG 1 WC Dermatology SC Dermatology GA 096NZ UT WOS:000315412600220 ER PT J AU Hartman, R Kroshinsky, D Tsiaras, W AF Hartman, Rebecca Kroshinsky, Daniela Tsiaras, William TI Voriconazole-induced photosensitivity concerning for Stevens-Johnson syndrome SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 71st Annual Meeting of the American-Academy-of-Dermatology (AAD) CY MAR 01-05, 2013 CL Miami Beach, FL SP Amer Acad Dermatol (AAD) C1 [Hartman, Rebecca] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kroshinsky, Daniela; Tsiaras, William] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD APR PY 2013 VL 68 IS 4 SU 1 BP AB187 EP AB187 PG 1 WC Dermatology SC Dermatology GA 096NZ UT WOS:000315412600743 ER PT J AU Hartman, R Kroshinsky, D Tsiaras, W AF Hartman, Rebecca Kroshinsky, Daniela Tsiaras, William TI Adult-onset Still disease in a geriatric patient: Updates and pearls in diagnosis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 71st Annual Meeting of the American-Academy-of-Dermatology (AAD) CY MAR 01-05, 2013 CL Miami Beach, FL SP Amer Acad Dermatol (AAD) C1 [Hartman, Rebecca] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kroshinsky, Daniela; Tsiaras, William] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD APR PY 2013 VL 68 IS 4 SU 1 BP AB8 EP AB8 PG 1 WC Dermatology SC Dermatology GA 096NZ UT WOS:000315412600031 ER PT J AU Higgins, HW Kroumpouzos, G Jenkins, SJ Horn, T AF Higgins, H. William, II Kroumpouzos, George Jenkins, States Jennifer Horn, Thomas TI Pregnancy-associated hyperkeratosis of the nipple: A study of 25 cases SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 71st Annual Meeting of the American-Academy-of-Dermatology (AAD) CY MAR 01-05, 2013 CL Miami Beach, FL SP Amer Acad Dermatol (AAD) C1 [Higgins, H. William, II; Kroumpouzos, George] Brown Univ, Providence, RI 02912 USA. [Jenkins, States Jennifer] Miraca Life Sci Tufts Med Ctr, Newton, MA USA. [Horn, Thomas] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 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 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD APR PY 2013 VL 68 IS 4 SU 1 BP AB58 EP AB58 PG 1 WC Dermatology SC Dermatology GA 096NZ UT WOS:000315412600232 ER PT J AU Javorsky, E Kimball, AB AF Javorsky, Emilia Kimball, Alexa Boer TI Hidradenitis suppurativa: Patient experiences with bariatric surgery SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 71st Annual Meeting of the American-Academy-of-Dermatology (AAD) CY MAR 01-05, 2013 CL Miami Beach, FL SP Amer Acad Dermatol (AAD) C1 [Javorsky, Emilia] Massachusetts Gen Hosp, Clin Unit Res Trials Skin, Boston, MA 02114 USA. [Kimball, Alexa Boer] Harvard Univ, Sch Med, Massachuetts Gen Hosp, Dept Dermatol, Boston, MA USA. NR 0 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 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD APR PY 2013 VL 68 IS 4 SU 1 BP AB89 EP AB89 PG 1 WC Dermatology SC Dermatology GA 096NZ UT WOS:000315412600354 ER PT J AU Kauvar, A Gilchrest, BA Yu, B Ross, EV Anderson, RR Langer, RS Kilmer, S AF Kauvar, Arielle Gilchrest, Barbara A. Yu, Betty Ross, E. Victor Anderson, Richard Rox Langer, Robert S. Kilmer, Suzanne TI A pilot study of a novel noninvasive topical under-eye contouring technology SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 71st Annual Meeting of the American-Academy-of-Dermatology (AAD) CY MAR 01-05, 2013 CL Miami Beach, FL SP Amer Acad Dermatol (AAD) C1 [Kauvar, Arielle] New York Laser & Skin Care, New York, NY USA. [Gilchrest, Barbara A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Yu, Betty] Living Proof, Cambridge, MA USA. [Ross, E. Victor] Scripps Clin Carmel Valley, San Diego, CA USA. [Anderson, Richard Rox] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Langer, Robert S.] MIT, Boston, MA USA. [Kilmer, Suzanne] Laser & Skin Surg Ctr Northern Calif, Sacramento, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 6 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 APR PY 2013 VL 68 IS 4 SU 1 BP AB20 EP AB20 PG 1 WC Dermatology SC Dermatology GA 096NZ UT WOS:000315412600081 ER PT J AU King, SDW Fitchett, G Berry, DL AF King, Stephen D. W. Fitchett, George Berry, Donna L. TI Screening for religious/spiritual struggle in blood and marrow transplant patients SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Cancer; Oncology; Screening; Religious/spiritual struggle; Chaplain ID QUALITY-OF-LIFE; ADVANCED CANCER-PATIENTS; LONG-TERM ADJUSTMENT; ILL ELDERLY-PATIENTS; BREAST-CANCER; RELIGIOUS STRUGGLE; SPIRITUAL CONCERNS; HEALTH; CARE; PREDICTORS AB A growing body of research documents the harmful effects of religious/spiritual (R/S) struggle (e.g., feeling abandoned or punished by God) among patients with a wide variety of diagnoses. Documented effects include poorer quality of life, greater emotional distress, poorer recovery, and increased disability. This study reports the use of a screening protocol that identified patients who may have been experiencing R/S struggle. We also examined the prevalence and correlates of possible R/S struggle, its association with quality of life, pain, and depressive symptoms and compared the results from the screening protocol with social workers' assessments. One hundred seventy-eight blood and marrow transplant patients completed the Electronic Self-Report Assessment-Cancer (ESRA-C) which included the Rush Religious Struggle Screening Protocol and other measures of quality of life, pain, and depressive symptoms prior to transplant therapy. All participants were assessed by a social worker, 90 % within 2 weeks of the ESRA-C assessment. Using the Rush Protocol, 18 % of the patients were identified as potentially experiencing R/S struggle. R/S struggle was not reported in any social work assessments. In a multivariable model, potential R/S struggle was more likely in patients who were more recently diagnosed, male, and Asian/Pacific Islanders. There were no significant associations between potential R/S struggle and quality of life, pain, or depressive symptoms. Early identification of patients with R/S struggle will facilitate their referral for further assessment and appropriate intervention. Further research is needed to identify the best methods of screening patients for R/S struggle. C1 [King, Stephen D. W.] Seattle Canc Care Alliance, Seattle, WA 98109 USA. [Fitchett, George] Rush Univ, Med Ctr, Dept Relig Hlth & Human Values, Chicago, IL 60612 USA. [Berry, Donna L.] Harvard Univ, Sch Med, Boston, MA USA. [Berry, Donna L.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP King, SDW (reprint author), Seattle Canc Care Alliance, POB 19023,G-1035, Seattle, WA 98109 USA. EM sking@seattlecca.org FU National Institute of Nursing Research [R01 NR008726] FX The ESRA-C trial was funded by the National Institute of Nursing Research, R01 NR008726), PI Donna Berry. We also express appreciation to Geila Rajaee who assisted with coding the social work assessments. NR 54 TC 11 Z9 11 U1 4 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD APR PY 2013 VL 21 IS 4 BP 993 EP 1001 DI 10.1007/s00520-012-1618-1 PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 096ZV UT WOS:000315444600012 PM 23052922 ER PT J AU Lee, EQ Norden, AD Drappatz, J Wen, PY AF Lee, Eudocia Q. Norden, Andrew D. Drappatz, Jan Wen, Patrick Y. TI Application of Targeted Therapy to Malignant Gliomas and Response to Treatment SO CURRENT SIGNAL TRANSDUCTION THERAPY LA English DT Article DE Targeted therapy; malignant glioma; angiogenesis; clinical trials; multi-targeted therapy ID PHASE-II TRIAL; GROWTH-FACTOR-RECEPTOR; RECURRENT GLIOBLASTOMA-MULTIFORME; HIGH-GRADE GLIOMAS; BEVACIZUMAB PLUS IRINOTECAN; NEWLY-DIAGNOSED GLIOBLASTOMA; PROGRESSION-FREE SURVIVAL; BRAIN-TUMOR CONSORTIUM; SCATTER FACTOR EXPRESSION; CANCER STEM-CELLS AB The prognosis for malignant gliomas remains poor despite multimodality therapy. An increased understanding of the molecular pathogenesis involved in glioma development and growth has resulted in development of agents that specifically target these molecular processes and pathways. Except for inhibitors of the vascular endothelial growth factor pathway, results from most single agent trials have been modest at best. Tailoring therapy to the individual patients is an attractive strategy although most studies have failed to determine predictive biomarkers. Numerous novel agents, multi-targeted agents, and combination therapies are now in clinical trials for malignant glioma. C1 [Lee, Eudocia Q.; Norden, Andrew D.; Wen, Patrick Y.] Brigham & Womens Hosp, Dept Neurol, Div Canc Neurol, Ctr Neurooncol,Dana Farber Brigham & Womens Canc, Boston, MA 02115 USA. [Lee, Eudocia Q.; Norden, Andrew D.; Wen, Patrick Y.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Drappatz, Jan] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. RP Wen, PY (reprint author), Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, 450 Brookline Ave,SW 430, Boston, MA 02215 USA. EM pwen@partners.org FU Genentech; Schering; Novartis; Astra Zeneca; Exelixis; Boehringer Ingelheim; Melinda M. Wanatick Brain Tumor Research Fund; Par Fore The Cure Brain Tumor Research Fund FX Patrick Wen receives research support Genentech, Schering, Novartis, Astra Zeneca, Exelixis, Boehringer Ingelheim, and Amgen as acts as a consultant for Angiochem and Nexgenix.; We gratefully acknowledge the support of the Melinda M. Wanatick and Par Fore The Cure Brain Tumor Research Funds. NR 136 TC 0 Z9 0 U1 0 U2 10 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1574-3624 EI 2212-389X J9 CURR SIGNAL TRANSD T JI Curr. Signal Transduct. Ther. PD APR PY 2013 VL 8 IS 1 BP 14 EP 24 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 093NK UT WOS:000315198400004 ER PT J AU Sonpavde, G Pond, GR Fougeray, R Choueiri, TK Qu, AQ Vaughn, DJ Niegisch, G Albers, P James, ND Wong, YN Ko, YJ Sridhar, SS Galsky, MD Petrylak, DP Vaishampayan, UN Khan, A Vogelzang, NJ Beer, TM Stadler, WM O'Donnell, PH Sternberg, CN Rosenberg, JE Bellmunt, J AF Sonpavde, Guru Pond, Gregory R. Fougeray, Ronan Choueiri, Toni K. Qu, Angela Q. Vaughn, David J. Niegisch, Guenter Albers, Peter James, Nicholas D. Wong, Yu-Ning Ko, Yoo-Joung Sridhar, Srikala S. Galsky, Matthew D. Petrylak, Daniel P. Vaishampayan, Ulka N. Khan, Awais Vogelzang, Nicholas J. Beer, Tomasz M. Stadler, Walter M. O'Donnell, Peter H. Sternberg, Cora N. Rosenberg, Jonathan E. Bellmunt, Joaquim TI Time from Prior Chemotherapy Enhances Prognostic Risk Grouping in the Second-line Setting of Advanced Urothelial Carcinoma: A Retrospective Analysis of Pooled, Prospective Phase 2 Trials SO EUROPEAN UROLOGY LA English DT Article DE Urothelial carcinoma; Second line; Prognosis; Time from prior chemotherapy; Hemoglobin; Liver metastasis; Performance status ID TRANSITIONAL-CELL CARCINOMA; PLATINUM-CONTAINING REGIMEN; III TRIAL; CANCER; PACLITAXEL; VINFLUNINE; TRACT; GEMCITABINE; THERAPY; PLUS AB Background: Outcomes for patients in the second-line setting of advanced urothelial carcinoma (UC) are dismal. The recognized prognostic factors in this context are Eastern Cooperative Oncology Group (ECOG) performance status (PS) >0, hemoglobin level (Hb) <10 g/dl, and liver metastasis (LM). Objectives: The purpose of this retrospective study of prospective trials was to investigate the prognostic value of time from prior chemotherapy (TFPC) independent of known prognostic factors. Design, setting, and participants: Data from patients from seven prospective trials with available baseline TFPC, Hb, PS, and LM values were used for retrospective analysis (n = 570). External validation was conducted in a second-line phase 3 trial comparing best supportive care (BSC) versus vinflunine plus BSC (n = 352). Outcome measurements and statistical analysis: Cox proportional hazards regression was used to evaluate the association of factors, with overall survival (OS) and progression-free survival (PFS) being the respective primary and secondary outcome measures. Results and limitations: ECOG-PS >0, LM, Hb <10 g/dl, and shorter TFPC were significant prognostic factors for OS and PFS on multivariable analysis. Patients with zero, one, two, and three to four factors demonstrated median OS of 12.2, 6.7, 5.1, and 3.0 mo, respectively (concordance statistic = 0.638). Setting of prior chemotherapy (metastatic disease vs perioperative) and prior platinum agent (cisplatin or carboplatin) were not prognostic factors. External validation demonstrated a significant association of TFPC with PFS on univariable and most multivariable analyses, and with OS on univariable analyses. Limitations of retrospective analyses are applicable. Conclusions: Shorter TFPC enhances prognostic classification independent of ECOG-PS >0, Hb <10 g/dl, and LM in the setting of second-line therapy for advanced UC. These data may facilitate drug development and interpretation of trials. (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved. C1 [Sonpavde, Guru; Khan, Awais] Univ Alabama Birmingham, Birmingham Comprehens Canc Ctr, Birmingham, AL USA. [Pond, Gregory R.] McMaster Univ, Hamilton, ON, Canada. [Pond, Gregory R.] Ontario Clin Oncol Grp, Hamilton, ON, Canada. [Fougeray, Ronan] Inst Rech Pierre Fabre, Boulogne, France. [Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Choueiri, Toni K.; Qu, Angela Q.] Harvard Univ, Sch Med, Boston, MA USA. [Vaughn, David J.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Niegisch, Guenter; Albers, Peter] Univ Dusseldorf, D-40225 Dusseldorf, Germany. [James, Nicholas D.] Univ Birmingham, Birmingham, W Midlands, England. [Wong, Yu-Ning] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Ko, Yoo-Joung] Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Sridhar, Srikala S.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Galsky, Matthew D.] Mt Sinai Sch Med, Tisch Canc Ctr Inst, New York, NY USA. [Petrylak, Daniel P.] Yale Canc Ctr, New Haven, CT USA. [Vaishampayan, Ulka N.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Vogelzang, Nicholas J.] Comprehens Canc Ctr Nevada, Las Vegas, NV USA. [Beer, Tomasz M.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Stadler, Walter M.; O'Donnell, Peter H.] Univ Chicago, Chicago, IL 60637 USA. [Sternberg, Cora N.] San Camillo Hosp, Rome, Italy. [Sternberg, Cora N.] Forlanini Hosp, Rome, Italy. [Rosenberg, Jonathan E.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Bellmunt, Joaquim] Univ Hosp Mar IMIM, Barcelona, Spain. RP Bellmunt, J (reprint author), Hosp Mar, Paseig Maritim 25-29, Barcelona, Spain. EM joaquim.bellmunt@gmail.com OI Niegisch, Gunter/0000-0001-6929-8691; Rosenberg, Jonathan/0000-0003-2637-4249 FU Boehringer-Ingelheim; AstraZeneca; Pierre-Fabre; BMS; Celgene; GSK; Eli Lilly FX Joaquim Bellmunt certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: G. Sonpavde, N.J. Vogelzang, W. M. Stadler, P. H. O'Donnell, and D.J. Vaughn have received research support from Boehringer-Ingelheim. R Fougeray is an employee of Pierre-Fabre. T. K. Choueiri, A. Q. Qu, J.E. Rosenberg, and G. Sonpavde have received research support from AstraZeneca. N.D. James, D.J. Vaughn, and J.M. Bellmunt have received research support from Pierre-Fabre. N.D. James also has received speaker fees from Pierre-Fabre. Y.N. Wong has received research support from BMS. Y. Ko, S. Sridhar, and G. Sonpavde have received research support from Celgene. U.N. Vaishampayan and W. M. Stadler have received research support from GSK, and G. Sonpavde has received speaker fees from GSK. M. D. Galsky has received research support from Eli Lilly. G. Niegisch and P. Albers have received research support from Eli Lilly and BMS. NR 21 TC 43 Z9 43 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD APR PY 2013 VL 63 IS 4 BP 717 EP 723 DI 10.1016/j.eururo.2012.11.042 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 093LC UT WOS:000315192400032 PM 23206856 ER PT J AU Taneja, AK Bierry, G Simeone, FJ Chang, CY Bredella, MA Torriani, M AF Taneja, Atul K. Bierry, Guillaume Simeone, F. Joseph Chang, Connie Y. Bredella, Miriam A. Torriani, Martin TI Diagnostic yield of CT-guided sampling in suspected sternoclavicular joint infection SO SKELETAL RADIOLOGY LA English DT Article DE Sternoclavicular joint; Biopsy; Infectious arthritis; CT-guided ID SEPTIC ARTHRITIS; COMPUTED-TOMOGRAPHY; BONE-BIOPSY; OSTEOMYELITIS; CULTURES; STERNUM AB To determine the prevalence of infection diagnosed by percutaneous computed tomography (CT)-guided sternoclavicular (SC) sampling in cases of suspected joint infection. A retrospective search was performed in reports of SC joint CT-guided biopsies in adults from July 1992 to July 2012. We reviewed medical records, radiology, microbiology, laboratory, and surgical reports. A positive result was defined as demonstration of a pathogenic organism, either by microscopy or growth in culture, confirming the diagnosis of SC joint infection. A negative result was defined as the absence of such findings. Patients in whom sampling was unsuccessful or not subjected to microbiology were excluded. In addition, CT images were reviewed by the consensus of two musculoskeletal radiologists. A total of 41 patients (mean age 57.1 years) underwent CT-guided SC joint sampling, 27 of whom underwent microbiology studies. Sampling was performed using core biopsy alone in 19 %, fine needle aspiration alone in 44 %, and aspiration combined with core biopsy in 37 %. Positive results were found in 52 % (14/27) of patients. Related diseases and predisposing conditions for infection were found in 79 % of positive patients. Negative results were found in 48 % (13/27) of patients. There were no procedure-related complications. The dominant CT findings were soft tissue swelling (negative group), and effusion and/or capsular hypertrophy/distension (positive group). CT-guided sampling is a safe procedure with positive microbiological cultures in slightly more than half of cases. C1 [Taneja, Atul K.; Bierry, Guillaume; Simeone, F. Joseph; Chang, Connie Y.; Bredella, Miriam A.; Torriani, Martin] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Taneja, Atul K.; Bierry, Guillaume; Simeone, F. Joseph; Chang, Connie Y.; Bredella, Miriam A.; Torriani, Martin] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Torriani, M (reprint author), Massachusetts Gen Hosp, 55 Fruit St,YAW 6048, Boston, MA 02114 USA. EM torriani.martin@mgh.harvard.edu RI Taneja, Atul/N-3133-2014 OI Taneja, Atul/0000-0002-4655-2033 NR 25 TC 2 Z9 2 U1 0 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 J9 SKELETAL RADIOL JI Skeletal Radiol. PD APR PY 2013 VL 42 IS 4 BP 479 EP 485 DI 10.1007/s00256-012-1535-x PG 7 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 090KN UT WOS:000314978100004 PM 23179735 ER PT J AU Makris, N Swaab, DF van der Kouwe, A Abbs, B Boriel, D Handa, RJ Tobet, S Goldstein, JM AF Makris, Nikos Swaab, Dick F. van der Kouwe, Andre Abbs, Brandon Boriel, Denise Handa, Robert J. Tobet, Stuart Goldstein, Jill M. TI Volumetric parcellation methodology of the human hypothalamus in neuroimaging: Normative data and sex differences SO NEUROIMAGE LA English DT Article DE Structural MRI; Volumetry; Hypothalamus; Hypothalamic nuclei; Tuberal region; Sex differences ID CORTICOTROPIN-RELEASING HORMONE; ADULT HUMAN BRAIN; PARAVENTRICULAR NUCLEUS; AROUSAL CIRCUITRY; CEREBRAL-CORTEX; IN-VIVO; MRI; NEURONS; SYSTEM; SCHIZOPHRENIA AB There is increasing evidence regarding the importance of the hypothalamus for understanding sex differences in relation to neurological, psychiatric, endocrine and sleep disorders. Although different in histology, physiology, connections and function, multiple hypothalamic nuclei subserve non-voluntary functions and are nodal points for the purpose of maintaining homeostasis of the organism. Thus, given the critical importance of hypothalamic nuclei and their key multiple roles in regulating basic functions, it is important to develop the ability to conduct in vivo human studies of anatomic structure, volume, connectivity, and function of hypothalamic regions represented at the level of its nuclei. The goals of the present study were to develop a novel method of semi-automated volumetric parcellation for the human hypothalamus that could be used to investigate clinical conditions using MRI and to demonstrate its applicability. The proposed new method subdivides the hypothalamus into five parcels based on visible anatomic landmarks associated with specific nuclear groupings and was confirmed using two ex vivo hypothalami that were imaged in a 7 T (7 T) scanner and processed histologically. Imaging results were compared with histology from the same brain. Further, the method was applied to 44 healthy adults (26 men: 18 women, comparable on age, handedness, ethnicity, SES) to derive normative volumes and assess sex differences in hypothalamic regions using 1.5 T MRI. Men compared to women had a significantly larger total hypothalamus, relative to cerebrum size, similar for both hemispheres, a difference that was primarily driven by the tuberal region, with the sex effect size being largest in the superior tuberal region and, to a lesser extent, inferior tuberal region. Given the critical role of hypothalamic nuclei in multiple chronic diseases and the importance of sex differences, we argue that the use of the novel methodology presented here will allow for critical investigations of these disorders and further delineation of potential treatments, particularly sex-specific approaches to gene and drug discoveries that involve hypothalamic nuclei. (c) 2012 Elsevier Inc. All rights reserved. C1 [Makris, Nikos; Goldstein, Jill M.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Makris, Nikos] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Makris, Nikos; Boriel, Denise] MGH Ctr Morphometr Anal, Charlestown, MA 02129 USA. [Makris, Nikos; van der Kouwe, Andre; Abbs, Brandon; Boriel, Denise; Goldstein, Jill M.] MGH & MIT Athinoula Martinos Biomed Imaging Ctr, Charlestown, MA 02129 USA. [Swaab, Dick F.] Netherlands Inst Neurosci, Dept Neuropsychiat Disorders, NL-1105 BA Amsterdam, Netherlands. [van der Kouwe, Andre] MGH, Dept Radiol, Charlestown, MA 02129 USA. [Abbs, Brandon; Goldstein, Jill M.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02120 USA. [Abbs, Brandon; Goldstein, Jill M.] BWH, Dept Med, Div Womens Hlth, Connors Ctr Womens Hlth & Gender Biol, Boston, MA 02120 USA. [Abbs, Brandon; Goldstein, Jill M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Abbs, Brandon; Goldstein, Jill M.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Handa, Robert J.] Univ Arizona, Coll Med, Dept Basic Med Sci, Phoenix, AZ 85004 USA. [Tobet, Stuart] Colorado State Univ, Dept Biomed Sci, Ft Collins, CO 80523 USA. RP Goldstein, JM (reprint author), Brigham & Womens Hosp, Div Womens Hlth, 1 Brigham Circle,1620 Tremont St,3rd Flr, Boston, MA 02120 USA. EM nikos@cma.mgh.harvard.edu; d.f.swaab@nin.knaw.nl; andre@nmr.mgh.harvard.edu; babbs@partners.org; dlb@cma.mgh.harvard.edu; rhanda@arizona.edu; Stuart.Tobet@colostate.edu; jill_goldstein@hms.harvard.edu RI Kruisbrink, Jenneke/D-8060-2013; OI Tobet, Stuart/0000-0002-1615-7331 FU ORWH-NIMH [R21MH084041]; ORWH-NIMH SCOR [P50MH082679]; NIDA [R01DA027804] FX This study was primarily supported by ORWH-NIMH R21MH084041 (Makris, PI) and ORWH-NIMH SCOR P50MH082679, (Goldstein, Tobet, Handa, PI). Some of the methodological work related to addiction was in part supported by NIDA R01DA027804 (Makris, PI). The authors also thank Larry Seidman, Ph.D. [NIMH R01 MH63951 (Seidman, PI) and NIMH R01 MH56956 (Goldstein, PI)] for contributing to original collection of the healthy control subjects used in these analyses, Bruce Rosen, MD, PhD for his administrative support in the use of the 7 T magnet at MGH, and Jonathan Kaiser, M.S. for help in image construction. NR 53 TC 13 Z9 15 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 J9 NEUROIMAGE JI Neuroimage PD APR 1 PY 2013 VL 69 BP 1 EP 10 DI 10.1016/j.neuroimage.2012.12.008 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 085PX UT WOS:000314627800001 PM 23247186 ER PT J AU McNab, JA Polimeni, JR Wang, RP Augustinack, JC Fujimoto, K Stevens, A Janssens, T Farivar, R Folkerth, RD Vanduffel, W Wald, LL AF McNab, Jennifer A. Polimeni, Jonathan R. Wang, Ruopeng Augustinack, Jean C. Fujimoto, Kyoko Stevens, Allison Janssens, Thomas Farivar, Reza Folkerth, Rebecca D. Vanduffel, Wim Wald, Lawrence L. TI Surface based analysis of diffusion orientation for identifying architectonic domains in the in vivo human cortex SO NEUROIMAGE LA English DT Article DE Cerebral cortex; Diffusion tensor imaging; Laminar analysis; Human; Brain ID ANISOTROPIC WATER DIFFUSION; MAGNETIC-RESONANCE IMAGES; HUMAN CEREBRAL-CORTEX; HUMAN BRAIN; CORTICAL THICKNESS; MRI; ORGANIZATION; SEGMENTATION; REGISTRATION; CONNECTIONS AB Diffusion tensor MRI is sensitive to the coherent structure of brain tissue and is commonly used to study large-scale white matter structure. Diffusion in gray matter is more isotropic, however, several groups have observed coherent patterns of diffusion anisotropy within the cerebral cortical gray matter. We extend the study of cortical diffusion anisotropy by relating it to the local coordinate system of the folded cerebral cortex. We use 1 mm and sub-millimeter isotropic resolution diffusion imaging to perform a laminar analysis of the principal diffusion orientation, fractional anisotropy, mean diffusivity and partial volume effects. Data from 6 in vivo human subjects, a fixed human brain specimen and an anesthetized macaque were examined. Large regions of cortex show a radial diffusion orientation. In vivo human and macaque data displayed a sharp transition from radial to tangential diffusion orientation at the border between primary motor and somatosensory cortex, and some evidence of tangential diffusion in secondary somatosensory cortex and primary auditory cortex. Ex vivo diffusion imaging in a human tissue sample showed some tangential diffusion orientation in S1 but mostly radial diffusion orientations in both M1 and S1. (c) 2012 Elsevier Inc. All rights reserved. C1 [McNab, Jennifer A.] Stanford Univ, RM Lucas Ctr Imaging, Stanford, CA 94305 USA. [McNab, Jennifer A.; Polimeni, Jonathan R.; Wang, Ruopeng; Augustinack, Jean C.; Fujimoto, Kyoko; Stevens, Allison; Janssens, Thomas; Farivar, Reza; Vanduffel, Wim; Wald, Lawrence L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Imaging, Boston, MA USA. [Vanduffel, Wim] KU Leuven Med Sch, Lab Neuro & Psychophysiol, Louvain, Belgium. [Farivar, Reza] McGill Univ, Dept Opthalmol, McGill Vis Res Unit, Montreal, PQ, Canada. [Folkerth, Rebecca D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Folkerth, Rebecca D.] Harvard Univ, Sch Med, Dept Pathol, Childrens Hosp Boston, Boston, MA 02115 USA. RP McNab, JA (reprint author), Stanford Univ, Dept Radiol, RM Lucas Ctr Imaging, 1201 Welch Rd,Room P270, Stanford, CA 94305 USA. EM mcnabj@stanford.edu RI Polimeni, Jonathan/P-1395-2014; Wald, Lawrence/D-4151-2009; OI Polimeni, Jonathan/0000-0002-1348-1179; Fujimoto, Kyoko/0000-0002-0087-1397 FU Canadian Institute for Health Research (Fellowship); NIH [U01MH093765, P41RR014075/R01EB006847, S10RR019307] FX Many thanks to Drs. George Dai and Karl Helmer for their assistance in scanning on the 4.7 T scanner. Thanks to Michelle Roy, Sita Kakunoori and Louis Vinke for their help with sample preparation. Many thanks for informative discussions with Drs. Bruce Rosen, Julien Cohen-Adad, Thomas Witzel, Thomas Benner, Himanshu Bhat, Keith Heberlein, Thorsten Feiweier and Brian Edlow. Thanks to Annelies Gerits and Helen Deng for help with animal imaging experiments. Thanks to Marian Slaney for her assistance in the neuropathology lab. This work was funded by the Canadian Institute for Health Research (Fellowship) and NIH: U01MH093765, P41RR014075/R01EB006847, and S10RR019307. NR 64 TC 29 Z9 29 U1 1 U2 19 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD APR 1 PY 2013 VL 69 BP 87 EP 100 DI 10.1016/j.neuroimage.2012.11.065 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 085PX UT WOS:000314627800010 PM 23247190 ER PT J AU Wang, Q Wu, PC Dong, DZ Ivanova, I Chu, E Zeliadt, S Vesselle, H Wu, DY AF Wang, Qin Wu, Peter C. Dong, David Z. Ivanova, Iana Chu, Elizabeth Zeliadt, Steven Vesselle, Hubert Wu, Daniel Y. TI Polyploidy road to therapy-induced cellular senescence and escape SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE polyploidy; cellular senescence; Cdc2; Cdk1; cancer therapeutics ID ADRIAMYCIN-INDUCED SENESCENCE; BREAST-TUMOR CELLS; MITOTIC CATASTROPHE; CANCER CELLS; GIANT-CELLS; DNA-DAMAGE; ACTIVATION; KINASE; APOPTOSIS; DIVISION AB Therapy-induced cellular senescence (TCS), characterized by prolonged cell cycle arrest, is an in vivo response of human cancers to chemotherapy and radiation. Unfortunately, TCS is reversible for a subset of senescent cells, leading to cellular reproliferation and ultimately tumor progression. This invariable consequence of TCS recapitulates the clinical treatment experience of patients with advanced cancer. We report the findings of a clinicopathological study in patients with locally advanced non-small cell lung cancer demonstrating that marker of in vivo TCS following neoadjuvant therapy prognosticate adverse clinical outcome. In our efforts to elucidate key molecular pathways underlying TCS and cell cycle escape, we have previously shown that the deregulation of mitotic kinase Cdk1 and its downstream effectors are important mediators of survival and cell cycle reentry. We now report that aberrant expression of Cdk1 interferes with apoptosis and promotes the formation of polyploid senescent cells during TCS. These polyploid senescent cells represent important transition states through which escape preferentially occurs. The Cdk1 pathway is in part modulated differentially by p21 and p27 two members of the KIP cyclin-dependent kinase inhibitor family during TCS. Altogether, these studies underscore the importance of TCS in cancer therapeutics. C1 [Wang, Qin; Wu, Peter C.; Ivanova, Iana; Chu, Elizabeth; Wu, Daniel Y.] VA Puget Sound Hlth Care Syst, Seattle Inst Biomed & Clin Res, Seattle, WA 98108 USA. [Wu, Peter C.] VA Puget Sound Hlth Care Syst, Dept Surg, Seattle, WA 98108 USA. [Wu, Peter C.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Dong, David Z.] VA Puget Sound Hlth Care Syst, Dept Pathol, Seattle, WA 98108 USA. [Zeliadt, Steven] VA Puget Sound Hlth Care Syst, Dept Hlth Serv, Seattle, WA 98108 USA. [Vesselle, Hubert] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Wu, Daniel Y.] Univ Washington, Dept Med, Div Oncol, Seattle, WA 98195 USA. [Wu, Daniel Y.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Wang, Q (reprint author), VA Puget Sound Hlth Care Syst, Seattle Inst Biomed & Clin Res, 1660 S Columbian Way, Seattle, WA 98108 USA. EM proteins@hotmail.com FU National Cancer Institute [R01-CA113892-01]; Veteran Affairs Office of Research and Development Medical Research Service; Veteran Affairs Office of Research & Development Medical Research Service (Biomedical Laboratory R&D Career Development Award-2) FX Grant sponsor: National Cancer Institute; Grant number: R01-CA113892-01; Grant sponsor: Veteran Affairs Office of Research and Development Medical Research Service; This material is based upon work supported by the National Cancer Institute (R01-CA113892-01, D. Wu) and Veteran Affairs Office of Research & Development Medical Research Service (Biomedical Laboratory R&D Career Development Award-2, P. Wu). The authors thank Dr. Liu Yang for his critical reading of our manuscript and his insightful suggestions. They also thank Dr. Chris Guthrie for assisting to obtain the time lapse images. NR 49 TC 21 Z9 21 U1 0 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD APR 1 PY 2013 VL 132 IS 7 BP 1505 EP 1515 DI 10.1002/ijc.27810 PG 11 WC Oncology SC Oncology GA 079NN UT WOS:000314177500003 PM 22945332 ER PT J AU Cuk, K Zucknick, M Heil, J Madhavan, D Schott, S Turchinovich, A Arlt, D Rath, M Sohn, C Benner, A Junkermann, H Schneeweiss, A Burwinkel, B AF Cuk, Katarina Zucknick, Manuela Heil, Joerg Madhavan, Dharanija Schott, Sarah Turchinovich, Andrey Arlt, Dorit Rath, Michelle Sohn, Christof Benner, Axel Junkermann, Hans Schneeweiss, Andreas Burwinkel, Barbara TI Circulating microRNAs in plasma as early detection markers for breast cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE microRNA; circulating microRNA; breast cancer; early detection; molecular marker ID BLOOD-BASED MARKERS; SERUM; BIOMARKERS; MECHANISM; CARCINOMA; LEUKEMIA; PCR AB In recent years, circulating miRNAs have attracted a great deal of attention as promising novel markers for various diseases. Here, we investigated their potential to serve as minimally invasive, early detection markers for breast cancer in blood plasma. We profiled miRNAs extracted from the plasma of early stage breast cancer patients (taken at the time-point of diagnosis) and healthy control individuals using TaqMan low-density arrays (TLDA). Selected candidates identified in the initial screen were further validated in an extended study cohort of 207 individuals including 127 sporadic breast cancer cases and 80 healthy controls via RT-qPCR. Four miRNAs (miR-148b, miR-376c, miR-409-3p and miR-801) were shown to be significantly upregulated in the plasma of breast cancer patients. ROC curve analysis showed that the combination of only three miRNAs (miR-148b, miR-409-3p and miR-801) had an equal discriminatory power between breast cancer cases and healthy controls as all four miRNAs together (AUC = 0.69). In conclusion, the identified miRNAs might be of potential use in the development of a multimarker blood-based test to complement and improve early detection of breast cancer. Such a multimarker blood test might for instance provide a prescreening tool, especially for younger women, to facilitate decisions about which individuals to recommend for further diagnostic tests. C1 [Cuk, Katarina; Zucknick, Manuela; Benner, Axel] German Canc Res Ctr, Div Biostat, Heidelberg, BW, Germany. [Heil, Joerg; Schott, Sarah; Sohn, Christof; Junkermann, Hans; Schneeweiss, Andreas] Univ Womens Clin, Dept Gynecol & Obstet, Heidelberg, BW, Germany. [Arlt, Dorit] Univ Med Ctr Freiburg, CCI, Freiburg, BW, Germany. [Arlt, Dorit] Univ Freiburg, D-79106 Freiburg, BW, Germany. [Rath, Michelle] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. [Schneeweiss, Andreas; Burwinkel, Barbara] Natl Ctr Tumor Dis NCT, Heidelberg, BW, Germany. RP Cuk, K (reprint author), German Canc Res Ctr, Div Biostat, Heidelberg, BW, Germany. EM k.cuk@dkfz.de RI turchinovich, andrey/B-2700-2014; OI Heil, Joerg/0000-0002-4684-9099 FU Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ) FX Grant sponsors: Dietmar-Hopp Foundation, Helmholtz Society and German Cancer Research Center (DKFZ) NR 45 TC 91 Z9 99 U1 3 U2 77 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 APR 1 PY 2013 VL 132 IS 7 BP 1602 EP 1612 DI 10.1002/ijc.27799 PG 11 WC Oncology SC Oncology GA 079NN UT WOS:000314177500013 PM 22927033 ER PT J AU Cacciola, JS Alterman, AI DePhilippis, D Drapkin, ML Valadez, C Fala, NC Oslin, D Mckay, JR AF Cacciola, John S. Alterman, Arthur I. DePhilippis, Dominick Drapkin, Michelle L. Valadez, Charles, Jr. Fala, Natalie C. Oslin, David Mckay, James R. TI Development and initial evaluation of the Brief Addiction Monitor (BAM) SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Addiction; Substance abuse; Reliability; Validity; Assessment ID SUBSTANCE-ABUSE TREATMENT; RECOVERY MANAGEMENT CHECKUPS; USE DISORDERS; FOLLOW-UP; TREATMENT RETENTION; ARBITRARY METRICS; SEVERITY INDEX; ALCOHOL-USE; RELIABILITY; VALIDITY AB This project developed and tested a 17-item monitoring instrument covering important substance use related behaviors to support measurement-based care and outcomes assessment. The study consisted of two phases, an instrument development phase and an initial study to examine its psychometric properties. Participants were 175 patients entering VA outpatient substance abuse treatment. The findings revealed that this Brief Addiction Monitor (BAM) exhibited acceptable characteristics. Exploratory factor analysis yielded three summary factors; recovery protection, physical and psychological problems, and substance use and risk. The root mean square error of approximation estimate was acceptable and the factors had alpha values exceeding or approaching 0.70. All three factors were sensitive to change and had excellent test-retest reliability. Predictive validity was demonstrated for two factors; recovery protection, and substance use and risk. At the item level, there was little indication of inappropriate response patterns. Change over time was significant for most items, and test-retest reliability was acceptable for nearly all items. Additional research is warranted to further establish the BAM's reliability, validity and usefulness. (C) 2013 Elsevier Inc. All rights reserved. C1 [Cacciola, John S.] Treatment Res Inst, Philadelphia, PA 19106 USA. [Cacciola, John S.; Alterman, Arthur I.; DePhilippis, Dominick; Drapkin, Michelle L.; Oslin, David; Mckay, James R.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [DePhilippis, Dominick; Drapkin, Michelle L.; Oslin, David; Mckay, James R.] Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Valadez, Charles, Jr.] La Salle Univ, Philadelphia, PA 19141 USA. [Fala, Natalie C.] Florida Inst Technol, Melbourne, FL 32901 USA. RP Cacciola, JS (reprint author), Treatment Res Inst, 600 Publ Ledger Bldg,150 S Independence Mall W, Philadelphia, PA 19106 USA. EM jcacciola@tresearch.org FU NIDA NIH HHS [R01 DA021154, K24 DA029062, R01 DA21154]; PHS HHS [NIDA K24DA029062] NR 55 TC 24 Z9 24 U1 2 U2 24 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD APR PY 2013 VL 44 IS 3 BP 256 EP 263 DI 10.1016/j.jsat.2012.07.013 PG 8 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 077EQ UT WOS:000314011100002 PM 22898042 ER PT J AU Ataer-Cansizoglu, E Bas, E Kalpathy-Cramer, J Sharp, GC Erdogmus, D AF Ataer-Cansizoglu, Esra Bas, Erhan Kalpathy-Cramer, Jayashree Sharp, Greg C. Erdogmus, Deniz TI Contour-based shape representation using principal curves SO PATTERN RECOGNITION LA English DT Article DE Shape representation and analysis; Curve/contour matching ID DIGITAL PLANAR CURVES; POLYGONAL-APPROXIMATION; DOMINANT POINTS; SEGMENTATION; ALGORITHM AB Extraction and representation of contours are challenging problems and are crucial for many image processing applications. In this study, given a membership function that returns the score of a point belonging to a contour, we propose a method for contour representation based on the principal curve (PC) of this function. The proposed method provides a piecewise linear representation of the contour with fewer points while preserving shape. Varied experiments are conducted, including lung boundary representation in CT images and shape representation in handwritten images. The results show that the technique provides accurate shape representation. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Ataer-Cansizoglu, Esra; Erdogmus, Deniz] Northeastern Univ, Cognit Syst Lab, Boston, MA 02115 USA. [Bas, Erhan] GE Global Res, Niskayuna, NY USA. [Kalpathy-Cramer, Jayashree] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Ataer-Cansizoglu, E (reprint author), Northeastern Univ, Cognit Syst Lab, Boston, MA 02115 USA. EM ataer@ece.neu.edu OI Kalpathy-Cramer, Jayashree/0000-0001-8906-9618 FU NSF [BCS-1027724, IIS1118061, IIS-1149570]; NIH [8P41GM103545-14] FX We thank Murat Akcakaya and Sarah Brown for assistance with editing the manuscript. This work was partially supported by NSF under grants BCS-1027724, IIS1118061, IIS-1149570, and by NIH under grant 8P41GM103545-14. NR 37 TC 4 Z9 4 U1 3 U2 29 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0031-3203 EI 1873-5142 J9 PATTERN RECOGN JI Pattern Recognit. PD APR PY 2013 VL 46 IS 4 BP 1140 EP 1150 DI 10.1016/j.patcog.2012.10.014 PG 11 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 075BI UT WOS:000313858400004 ER PT J AU Leshner, AF Tom, SR Kern, RS AF Leshner, Anna F. Tom, Shelley R. Kern, Robert S. TI Errorless learning and social problem solving ability in schizophrenia: An examination of the compensatory effects of training SO PSYCHIATRY RESEARCH LA English DT Article DE Cognitive rehabilitation; Errorless learning; Compensatory; Memory; Severe mental illness ID OF-THE-LITERATURE; COGNITIVE REHABILITATION; NEUROCOGNITIVE DEFICITS; RETROGRADE-AMNESIA; ALZHEIMERS-DISEASE; MEMORY; INDIVIDUALS; PERFORMANCE; METAANALYSIS; REMEDIATION AB Compensatory approaches to cognitive rehabilitation in schizophrenia aim to improve functioning by bypassing or compensating for impaired areas of cognition. At present, there is little empirical evidence that these approaches actually compensate for neurocognitive impairments in improving community functioning. This study examined the effects of errorless learning (EL), a compensatory cognitive rehabilitation approach, on social problem solving ability in schizophrenia. The study included 60 outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder. Participants received a baseline battery to assess explicit and implicit memory functioning. Participants were stratified according to gender and level of memory functioning and then randomized to EL or symptom management training. Training was conducted over two days lasting a total of 6 h for each group. Assessment of social problem-solving ability, using the Assessment of Interpersonal Problem Solving Skills (AIPSS), was conducted after completion of training and at a 3-month follow-up without further intervention. Results from hierarchical multiple regression and analysis of covariance each supported the compensatory effects of training. These findings indicate that EL facilitates learning of new skills across varying levels of memory impairment. Future efforts may aim to explore the specific neurocognitive mechanisms involved in EL Published by Elsevier Ireland Ltd. C1 [Leshner, Anna F.; Tom, Shelley R.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Kern, Robert S.] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Kern, Robert S.] VISN 22 Mental Illness Res Educ & Clin Ctr, Dept Vet Affairs, Los Angeles, CA USA. RP Kern, RS (reprint author), VA Greater Los Angeles Healthcare Ctr MIRECC 210, Bldg 210,Room 116,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM rkern@ucla.edu FU Stanley Medical Research Institute; NIMH [R01 MH082939]; VA Merit Award FX This project was supported in part by Stanley Medical Research Institute, the NIMH Grant R01 MH082939, and a VA Merit Award received by R. Kern (Principal Investigator). NR 46 TC 6 Z9 6 U1 2 U2 26 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 MAR 30 PY 2013 VL 206 IS 1 BP 1 EP 7 DI 10.1016/j.psychres.2012.10.007 PG 7 WC Psychiatry SC Psychiatry GA 124DB UT WOS:000317442900001 PM 23158835 ER PT J AU Pilkonis, PA Choi, SW Salsman, JM Butt, Z Moore, TL Lawrence, SM Zill, N Cyranowski, JM Kelly, MAR Knox, SS Cella, D AF Pilkonis, Paul A. Choi, Seung W. Salsman, John M. Butt, Zeeshan Moore, Tara L. Lawrence, Suzanne M. Zill, Nicholas Cyranowski, Jill M. Kelly, Morgen A. R. Knox, Sarah S. Cella, David TI Assessment of self-reported negative affect in the NIH Toolbox SO PSYCHIATRY RESEARCH LA English DT Article DE Sadness; Fear; Anger; Item response theory; Measurement ID ITEM RESPONSE THEORY; QUALITY-OF-LIFE; DEPRESSIVE SYMPTOMS; TRIPARTITE MODEL; EMOTIONAL DISORDERS; CHILDRENS REPORTS; ANXIETY; MOTHERS; SCALES; PARENT AB We report on the selection of self-report measures for inclusion in the NIH Toolbox that are suitable for assessing the full range of negative affect including sadness, fear, and anger. The Toolbox is intended to serve as a "core battery" of assessment tools for cognition, sensation, motor function, and emotional health that will help to overcome the lack of consistency in measures used across epidemiological, observational, and intervention studies. A secondary goal of the NIH Toolbox is the identification of measures that are flexible, efficient, and precise, an agenda best fulfilled by the use of item banks calibrated with models from item response theory (IRT) and suitable for adaptive testing. Results from a sample of 1763 respondents supported use of the adult and pediatric item banks for emotional distress from the Patient-Reported Outcomes Measurement Information System (PROMIS) as a starting point for capturing the full range of negative affect in healthy individuals. Content coverage for the adult Toolbox was also enhanced by the development of a scale for somatic arousal using items from the Mood and Anxiety Symptom Questionnaire (MASQ) and scales for hostility and physical aggression using items from the Buss-Perry Aggression Questionnaire (BPAQ). (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Pilkonis, Paul A.; Moore, Tara L.; Lawrence, Suzanne M.; Cyranowski, Jill M.; Kelly, Morgen A. R.] Univ Pittsburgh, Western Psychiat Inst & Clin, Med Ctr, Dept Psychiat, Pittsburgh, PA 15213 USA. [Choi, Seung W.; Salsman, John M.; Butt, Zeeshan; Cella, David] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Salsman, John M.; Butt, Zeeshan; Cella, David] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Butt, Zeeshan] Northwestern Univ, Feinberg Sch Med, Comprehens Transplant Ctr, Chicago, IL 60611 USA. [Butt, Zeeshan; Cella, David] Northwestern Univ, Feinberg Sch Med, Inst Healthcare Studies, Chicago, IL 60611 USA. [Zill, Nicholas] Westat Corp, Rockville, MD USA. [Kelly, Morgen A. R.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Knox, Sarah S.] W Virginia Univ, Sch Med, Dept Community Med, Morgantown, WV 26506 USA. RP Pilkonis, PA (reprint author), Univ Pittsburgh, Western Psychiat Inst & Clin, Med Ctr, Dept Psychiat, 3811 OHara St, Pittsburgh, PA 15213 USA. EM pilkonispa@upmc.edu FU Federal funds from the Blueprint for Neuroscience Research; Office of Behavioral and Social Sciences Research, National Institutes of Health [HHS-N-260-2006-00007-C] FX This project is funded in whole or in part with Federal funds from the Blueprint for Neuroscience Research and the Office of Behavioral and Social Sciences Research, National Institutes of Health, under Contract no. HHS-N-260-2006-00007-C. NR 67 TC 5 Z9 5 U1 6 U2 19 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 MAR 30 PY 2013 VL 206 IS 1 BP 88 EP 97 DI 10.1016/j.psychres.2012.09.034 PG 10 WC Psychiatry SC Psychiatry GA 124DB UT WOS:000317442900015 PM 23083918 ER PT J AU Roussos, P McClure, MM Hazlett, EA New, AS Siever, LJ Bitsios, P Giakoumaki, SG AF Roussos, Panos McClure, Margaret M. Hazlett, Erin A. New, Antonia S. Siever, Larry J. Bitsios, Panos Giakoumaki, Stella G. TI CACNA1C as a risk factor for schizotypal personality disorder and schizotypy in healthy individuals SO PSYCHIATRY RESEARCH LA English DT Letter ID BIPOLAR DISORDER; ASSOCIATION ANALYSIS; SCHIZOPHRENIA; ANK3 C1 [Roussos, Panos; McClure, Margaret M.; Hazlett, Erin A.; New, Antonia S.; Siever, Larry J.] Mt Sinai Sch Med, Dept Psychiat, Bronx, NY 10468 USA. [Roussos, Panos; McClure, Margaret M.; Hazlett, Erin A.; New, Antonia S.; Siever, Larry J.] James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr VISN 3, Bronx, NY USA. [Roussos, Panos; Bitsios, Panos; Giakoumaki, Stella G.] Univ Crete, Fac Med, Dept Psychiat & Behav Sci, Iraklion, Crete, Greece. RP Roussos, P (reprint author), Mt Sinai Sch Med, Dept Psychiat, Room 4F-21,130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM panagiotis.roussos@mssm.edu RI Roussos, Panos/J-7090-2013 OI Roussos, Panos/0000-0002-4640-6239 FU NIMH NIH HHS [R01 MH056140] NR 10 TC 16 Z9 16 U1 0 U2 10 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 MAR 30 PY 2013 VL 206 IS 1 BP 122 EP 123 DI 10.1016/j.psychres.2012.08.039 PG 2 WC Psychiatry SC Psychiatry GA 124DB UT WOS:000317442900021 PM 22985546 ER PT J AU Foland-Ross, LC Thompson, PM Sugar, CA Narr, KL Penfold, C Vasquez, RE Townsend, J Fischer, J Saharan, P Bearden, CE Altshuler, LL AF Foland-Ross, Lara C. Thompson, Paul M. Sugar, Catherine A. Narr, Katherine L. Penfold, Conor Vasquez, Roxanne E. Townsend, Jennifer Fischer, Jeffrey Saharan, Priya Bearden, Carrie E. Altshuler, Lori L. TI Three-dimensional mapping of hippocampal and amygdalar structure in euthymic adults with bipolar disorder not treated with lithium SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Mood disorder; Magnetic resonance imaging; Hippocampus; Amygdala; Lithium; Bipolar disorder ID FACIAL EMOTION RECOGNITION; TEMPORAL-LOBE STRUCTURES; RATING-SCALE; WHITE-MATTER; YOUNG-ADULTS; MRI; VOLUME; SCHIZOPHRENIA; BRAIN; MANIA AB Structural neuroimaging studies of the amygdala and hippocampus in bipolar disorder have been largely inconsistent. This may be due in part to differences in the proportion of subjects taking lithium or experiencing an acute mood state, as both factors have recently been shown to influence gray matter structure. To avoid these problems, we evaluated euthymic subjects not currently taking lithium. Thirty-two subjects with bipolar type I disorder and 32 healthy subjects were scanned using magnetic resonance imaging. Subcortical regions were manually traced, and converted to three-dimensional meshes to evaluate the main effect of bipolar illness on radial distance. Statistical analyses found no evidence for a main effect of bipolar illness in either region, although exploratory analyses found a significant age by diagnosis interaction in the right amygdala, as well as positive associations between radial distance of the left amygdala and both prior hospitalizations for mania and current medication status. These findings suggest that, when not treated with lithium or in an acute mood state, patients with bipolar disorder exhibit no structural abnormalities of the amygdala or hippocampus. Future studies, nevertheless, that further elucidate the impact of age, course of illness, and medication on amygdala structure in bipolar disorder are warranted. Published by Elsevier Ireland Ltd. C1 [Foland-Ross, Lara C.; Thompson, Paul M.; Saharan, Priya] Univ Calif Los Angeles, Sch Med, Dept Neurol, Lab Neuro Imaging, Los Angeles, CA 90024 USA. [Sugar, Catherine A.; Narr, Katherine L.; Penfold, Conor; Vasquez, Roxanne E.; Townsend, Jennifer; Fischer, Jeffrey; Bearden, Carrie E.; Altshuler, Lori L.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Sugar, Catherine A.] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA USA. [Altshuler, Lori L.] West Los Angeles Healthcare Ctr, Dept Psychiat, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Altshuler, LL (reprint author), UCLA Mood Disorders Res Program, Dept Psychiat & Biobehav Sci, 300 Med Plaza,Suite 1544,Box 957057, Los Angeles, CA 90095 USA. EM laltshuler@mednet.ucla.edu FU National Institute of Mental Health [MH078556, MH075944, MH01848]; National Association for Research on Schizophrenia and Affective Disorders (NARSAD); Brain Mapping Medical Research Organization; Brain Mapping Support Foundation; Pierson-Lovelace Foundation; Ahmanson Foundation; William M. and Linda R. Dietel Philanthropic Fund at the Northern Piedmont Community Foundation; Tamkin Foundation; Jennifer Jones-Simon Foundation; Capital Group Companies Charitable Foundation; Robson Family; Northstar Fund; National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [RR12169, RR13642, RR00865] FX This work was supported by Grants from the National Institute of Mental Health (MH078556 to LCFR, and MH075944 and MH01848 to LLA). Additional support for algorithm development was provided by the NIA, NIBIB, and the National Center for Research Resources (AG016570, EB01651, RR019771 to PT). For their generous support, the authors also thank the National Association for Research on Schizophrenia and Affective Disorders (NARSAD), Brain Mapping Medical Research Organization, Brain Mapping Support Foundation, Pierson-Lovelace Foundation, The Ahmanson Foundation, William M. and Linda R. Dietel Philanthropic Fund at the Northern Piedmont Community Foundation, Tamkin Foundation, Jennifer Jones-Simon Foundation, Capital Group Companies Charitable Foundation, Robson Family and Northstar Fund. The project was also supported by Grants RR12169, RR13642 and RR00865 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). NR 54 TC 7 Z9 7 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD MAR 30 PY 2013 VL 211 IS 3 BP 195 EP 201 DI 10.1016/j.pscychresns.2012.08.002 PG 7 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 123HN UT WOS:000317379100002 PM 23149020 ER PT J AU Hoogenboom, WS Perlis, RH Smoller, JW Zeng-Treitler, Q Gainer, VS Murphy, SN Churchill, SE Kohane, IS Shenton, ME Iosifescu, DV AF Hoogenboom, Wouter S. Perlis, Roy H. Smoller, Jordan W. Zeng-Treitler, Qing Gainer, Vivian S. Murphy, Shawn N. Churchill, Susanne E. Kohane, Isaac S. Shenton, Martha E. Iosifescu, Dan V. TI Feasibility of studying brain morphology in major depressive disorder with structural magnetic resonance imaging and clinical data from the electronic medical record: A pilot study SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Major depressive disorder (MDD); Refractory depression; Structural MRI; Hippocampus; Legacy data; Natural language processing ID TREATMENT-RESISTANT DEPRESSION; HUMAN CEREBRAL-CORTEX; OF-THE-ART; HIPPOCAMPAL VOLUME; DISCOVERY RESEARCH; SEGMENTATION; MRI; ABNORMALITIES; SCHIZOPHRENIA; METAANALYSIS AB For certain research questions related to long-term outcomes or to rare disorders, designing prospective studies is impractical or prohibitively expensive. Such studies could instead utilize clinical and magnetic resonance imaging data (MRI) collected as part of routine clinical care, stored in the electronic medical record (EMR). Using major depressive disorder (MDD) as a disease model, we examined the feasibility of studying brain morphology and associations with remission using clinical and MRI data exclusively drawn from the EMR. Advanced automated tools were used to select MDD patients and controls from the EMR who had brain MRI data, but no diagnosed brain pathology. MDD patients were further assessed for remission status by review of clinical charts. Twenty MDD patients (eight full-remitters, six partial-remitters, and six non-remitters), and 15 healthy control subjects met all study criteria for advanced morphometric analyses. Compared to controls, MDD patients had significantly smaller right rostral-anterior cingulate volume, and level of non-remission was associated with smaller left hippocampus and left rostral-middle frontal gyrus volume. The use of EMR data for psychiatric research may provide a timely and cost-effective approach with the potential to generate large study samples reflective of the real population with the illness studied. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Hoogenboom, Wouter S.; Perlis, Roy H.; Iosifescu, Dan V.] Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program, Boston, MA 02114 USA. [Hoogenboom, Wouter S.; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Psychiat Neuroimaging Lab, Dept Psychiat,Med Sch, Boston, MA 02215 USA. [Perlis, Roy H.] Massachusetts Gen Hosp, Lab Psychiat Pharmacogen, Ctr Human Genet Res, Boston, MA 02114 USA. [Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat Genet Program Mood & Anxiety Disorders, Boston, MA 02114 USA. [Zeng-Treitler, Qing] Univ Utah, Dept Biomed Informat, Salt Lake City, UT 84112 USA. [Zeng-Treitler, Qing] VA Salt Lake City Hlth Care Syst, Salt Lake City, UT 84148 USA. [Gainer, Vivian S.; Murphy, Shawn N.] Partners HealthCare Syst Inc, Informat Syst, Charlestown, MA 02129 USA. [Murphy, Shawn N.] Massachusetts Gen Hosp, Comp Sci Lab, Boston, MA 02114 USA. [Churchill, Susanne E.; Kohane, Isaac S.] Brigham & Womens Hosp, Natl Ctr Biomed Comp 2B2, Boston, MA 02215 USA. [Shenton, Martha E.] VA Boston Healthcare Syst, Clin Neurosci Div, Lab Neurosci, Dept Psychiat,Brockton Div, Brockton, MA 02301 USA. [Iosifescu, Dan V.] Mt Sinai Sch Med, Mood & Anxiety Disorders Program, New York, NY 10029 USA. RP Hoogenboom, WS (reprint author), Harvard Univ, Brigham & Womens Hosp, Psychiat Neuroimaging Lab, Dept Psychiat,Med Sch, 1249 Boylston St, Boston, MA 02215 USA. EM hoogenboomw@gmail.com FU Driving Biological Project by the i2b2 grant (National Institutes of Health) [NIH U54-LM008748]; National Institutes of Health Career Development Award [K23 MH067111]; National Institutes of Health [R01 MH 50740]; Department of Veterans Affairs (VA) (VA Merit Award); Department of Veterans Affairs (VA) (VA Schizophrenia Research Center Grant); National Institute of Mental Health [MH086026] FX This work is funded as a Driving Biological Project (PI: Dr. Iosifescu) by the i2b2 grant (National Institutes of Health, NIH U54-LM008748; PI: Dr. Kohane). Dr. Iosifescu is supported by the National Institutes of Health Career Development Award K23 MH067111. Dr. Shenton is supported by grants from the National Institutes of Health (R01 MH 50740), and the Department of Veterans Affairs (VA) (VA Merit Award and VA Schizophrenia Research Center Grant). Dr. Perlis is supported by a grant from the National Institute of Mental Health (MH086026). The authors thank Victor Castro, B.S., for his assistance in collecting data from the Research Patient Data Registry; Sergey Goryachev, M.S., for his assistance with natural language processing; Kenneth Nesbitt, for providing access to magnetic resonance imaging data from Massachusetts General Hospital; Dr. Bouix and Dr. Kubicki, for their advice in the development of the imaging study; and special thanks to all research assistants at the psychiatry neuroimaging laboratory for their kind help at the time of this study. NR 52 TC 7 Z9 8 U1 0 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD MAR 30 PY 2013 VL 211 IS 3 BP 202 EP 213 DI 10.1016/j.pscychresns.2012.07.007 PG 12 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 123HN UT WOS:000317379100003 PM 23149041 ER PT J AU Xiang, SH Pacheco, B Bowder, D Yuan, W Sodroski, J AF Xiang, Shi-hua Pacheco, Beatriz Bowder, Dane Yuan, Wen Sodroski, Joseph TI Characterization of a dual-tropic Human immunodeficiency virus (HIV-1) strain derived from the prototypical X4 isolate HXBc2 SO VIROLOGY LA English DT Article DE HIV-1; Envelope glycoproteins; Entry; Tropism; Gp120; V3 loop; CCR5; CXCR4; Chemokine receptor; Trimer ID 2ND EXTRACELLULAR LOOP; ENVELOPE GLYCOPROTEIN TRIMERS; T-CELL-LINE; V3 LOOP; CORECEPTOR USAGE; CHEMOKINE RECEPTORS; MONOCLONAL-ANTIBODY; SYNCYTIUM FORMATION; MACROPHAGE TROPISM; MEMBRANE-FUSION AB Human immunodeficiency virus type 1 (HIV-1) coreceptor usage and tropism can be modulated by the V3 loop sequence of the gp120 exterior envelope glycoprotein. For coreceptors, R5 viruses use CCR5, X4 viruses use CXCR4, and dual-tropic (R5X4) viruses use either CCR5 or CXCR4. To understand the requirements for dual tropism, we derived and analyzed a dual-tropic variant of an X4 virus. Changes in the V3 base, which allow gp120 to interact with the tyrosine-sulfated CCR5 N-terminus, and deletion of residues 310/311 in the V3 tip were necessary for efficient CCR5 binding and utilization. Thus, both sets of V3 changes allowed CCR5 utilization with retention of the ability to use CXCR4. We also found that the stable association of gp120 with the trimeric envelope glycoprotein complex in R5X4 viruses, as in X4 viruses, is less sensitive to V3 loop changes than gp120-trimer association in R5 viruses. Published by Elsevier Inc. C1 [Xiang, Shi-hua; Pacheco, Beatriz; Yuan, Wen; Sodroski, Joseph] Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02215 USA. [Xiang, Shi-hua; Pacheco, Beatriz; Yuan, Wen; Sodroski, Joseph] Harvard Univ, Sch Med, Div Aids, Dept Microbiol & Immunobiol, Boston, MA 02215 USA. [Xiang, Shi-hua; Bowder, Dane] Univ Nebraska, Nebraska Ctr Virol, Sch Vet Med & Biomed Sci, Lincoln, NE 68583 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Sodroski, Joseph] MIT, Ragon Inst MGH, Cambridge, MA 02139 USA. [Sodroski, Joseph] Harvard Univ, Cambridge, MA 02138 USA. RP Xiang, SH (reprint author), Univ Nebraska, Nebraska Ctr Virol, Sch Vet Med & Biomed Sci, Morrison Ctr 337,4240 Fair St, Lincoln, NE 68583 USA. EM sxiang2@unl.edu FU National Institutes of Health [AI24755, AI67854]; International AIDS Vaccine Initiative; Bill and Melinda Gates Foundation FX We thank Yvette McLaughlin and Elizabeth Carpelan for manuscript preparation. We thank Dr. James Robinson for the 412d and E51 monoclonal antibodies. This work was supported by grants from the National Institutes of Health (AI24755 and AI67854), by the International AIDS Vaccine Initiative, by the Bill and Melinda Gates Foundation, and by the late William F. McCarty-Cooper. NR 60 TC 7 Z9 7 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 30 PY 2013 VL 438 IS 1 BP 5 EP 13 DI 10.1016/j.virol.2013.01.002 PG 9 WC Virology SC Virology GA 104ZW UT WOS:000316036400002 PM 23369572 ER PT J AU Pezzolesi, MG Jeong, J Smiles, AM Skupien, J Mychaleckyj, JC Rich, SS Warram, JH Krolewski, AS AF Pezzolesi, Marcus G. Jeong, Jackson Smiles, Adam M. Skupien, Jan Mychaleckyj, Josyf C. Rich, Stephen S. Warram, James H. Krolewski, Andrzej S. TI Family-Based Association Analysis Confirms the Role of the Chromosome 9q21.32 Locus in the Susceptibility of Diabetic Nephropathy SO PLOS ONE LA English DT Article ID URINARY ALBUMIN EXCRETION; STAGE RENAL-DISEASE; KIDNEY-DISEASE; GENE; VARIANTS; TYPE-1; HERITABILITY; SCAN; PVT1 AB A genome-wide association scan of type 1 diabetic patients from the GoKinD collections previously identified four novel diabetic nephropathy susceptibility loci that have subsequently been shown to be associated with diabetic nephropathy in unrelated patients with type 2 diabetes. To expand these findings, we examined whether single nucleotide polymorphisms (SNPs) at these susceptibility loci were associated with diabetic nephropathy in patients from the Joslin Study of Genetics of Nephropathy in Type 2 Diabetes Family Collection. Six SNPs across the four loci identified in the GoKinD collections and 7 haplotype tagging SNPs, were genotyped in 66 extended families of European ancestry. Pedigrees from this collection contained an average of 18.5 members, including 2 to 14 members with type 2 diabetes. Among diabetic family members, the 9q21.32 locus approached statistical significance with advanced diabetic nephropathy (P=0.037 [adjusted P=0.222]). When we expanded our definition of diabetic nephropathy to include individuals with high microalbuminuria, the strength of this association improved significantly (P=1.42x10(-3) [adjusted P=0.009]). This same locus also trended toward statistical significance with variation in urinary albumin excretion in family members with type 2 diabetes (P=0.032 [adjusted P=0.192]) and in analyses expanded to include all relatives (P=0.019 [adjusted P=0.114]). These data increase support that SNPs identified in the GoKinD collections on chromosome 9q21.32 are true diabetic nephropathy susceptibility loci. C1 [Pezzolesi, Marcus G.; Jeong, Jackson; Smiles, Adam M.; Skupien, Jan; Warram, James H.; Krolewski, Andrzej S.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Pezzolesi, Marcus G.; Skupien, Jan; Krolewski, Andrzej S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Mychaleckyj, Josyf C.; Rich, Stephen S.] Univ Virginia, Sch Med, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. RP Pezzolesi, MG (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. EM marcus.pezzolesi@joslin.harvard.edu FU National Institutes of Health (NIH) [DK090125, DK096628, DK58549, DK77532, DK36836]; Juvenile Diabetes Research Foundation (JDRF) [3-2009-397] FX The authors acknowledge grant support from the National Institutes of Health (NIH) (DK090125 and DK096628 to M.G.P., DK58549 and DK77532 to A.S.K., and DK36836 to the Genetics Core of the Diabetes and Endocrinology Research Center at the Joslin Diabetes Center). The authors also acknowledge support from the Juvenile Diabetes Research Foundation (JDRF) (3-2009-397 to J.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 9 Z9 9 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 29 PY 2013 VL 8 IS 3 AR e60301 DI 10.1371/journal.pone.0060301 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 121SG UT WOS:000317263900067 PM 23555951 ER PT J AU Lobo, GP Amengual, J Baus, D Shivdasani, RA Taylor, D von Lintig, J AF Lobo, Glenn P. Amengual, Jaume Baus, Diane Shivdasani, Ramesh A. Taylor, Derek von Lintig, Johannes TI Genetics and Diet Regulate Vitamin A Production via the Homeobox Transcription Factor ISX SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-CAROTENE 15,15'-MONOOXYGENASE; RETINOIC ACID; CELLULAR UPTAKE; DOUBLE-TRACER; SR-BI; METABOLISM; EXPRESSION; CONVERSION; TRANSPORT; EMBRYOGENESIS AB Low dietary intake of beta-carotene is associated with chronic disease and vitamin A deficiency. beta-Carotene is converted to vitamin A in the intestine by the enzyme beta-carotene-15,15'-monoxygenase (BCMO1) to support vision, reproduction, immune function, and cell differentiation. Considerable variability for this key step in vitamin A metabolism, as reported in the human population, could be related to genetics and individual vitamin A status, but it is unclear how these factors influence beta-carotene metabolism and vitamin A homeostasis. Here we show that the intestine-specific transcription factor ISX binds to the Bcmo1 promoter. Moreover, upon induction by the beta-carotene derivative retinoic acid, this ISX binding decreased expression of a luciferase reporter gene in human colonic CaCo-2 cells indicating that ISX acts as a transcriptional repressor of BCMO1 expression. Mice deficient for this transcription factor displayed increased intestinal BCMO1 expression and produced significantly higher amounts of vitamin A from supplemental beta-carotene. The ISX binding site in the human BCMO1 promoter contains a common single nucleotide polymorphism that is associated with decreased conversion rates and increased fasting blood levels of beta-carotene. Thus, our study establishes ISX as a critical regulator of vitamin A production and provides a mechanistic explanation for how both genetics and diet can affect this process. C1 [Lobo, Glenn P.; Amengual, Jaume; Baus, Diane; Taylor, Derek; von Lintig, Johannes] Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA. [Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP von Lintig, J (reprint author), Case Western Reserve Univ, Sch Med, Dept Pharmacol W341, 10900 Euclid Ave, Cleveland, OH 44106 USA. EM johannes.vonlintig@case.edu FU National Institutes of Health [EY019641, EY020551] FX This work was supported, in whole or in part, by National Institutes of Health Grants EY019641 and EY020551. NR 34 TC 21 Z9 22 U1 1 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 29 PY 2013 VL 288 IS 13 BP 9017 EP 9027 DI 10.1074/jbc.M112.444240 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 116DG UT WOS:000316862200021 PM 23393141 ER PT J AU Suva, ML Riggi, N Bernstein, BE AF Suva, Mario L. Riggi, Nicolo Bernstein, Bradley E. TI Epigenetic Reprogramming in Cancer SO SCIENCE LA English DT Review ID B-CELL LYMPHOMAS; STEM-CELLS; SOMATIC MUTATIONS; GENOMIC ANALYSIS; PROSTATE-CANCER; SELF-RENEWAL; HISTONE H3; C-MYC; GENE; PLURIPOTENCY AB The demonstration of induced pluripotency and direct lineage conversion has led to remarkable insights regarding the roles of transcription factors and chromatin regulators in mediating cell state transitions. Beyond its considerable implications for regenerative medicine, this body of work is highly relevant to multiple stages of oncogenesis, from the initial cellular transformation to the hierarchical organization of established malignancies. Here, we review conceptual parallels between the respective biological phenomena, highlighting important interrelationships among transcription factors, chromatin regulators, and preexisting epigenetic states. The shared mechanisms provide insights into oncogenic transformation, tumor heterogeneity, and cancer stem cell models. C1 [Suva, Mario L.; Riggi, Nicolo; Bernstein, Bradley E.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Suva, Mario L.; Riggi, Nicolo; Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Suva, Mario L.; Riggi, Nicolo; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Suva, Mario L.; Riggi, Nicolo; Bernstein, Bradley E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Suva, Mario L.; Riggi, Nicolo; Bernstein, Bradley E.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Bernstein, BE (reprint author), Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. EM bernstein.bradley@mgh.harvard.edu FU Howard Hughes Medical Institute; National Human Genome Research Institute; NIH Common Fund; National Heart, Lung, and Blood Institute; Harvard Stem Cell Institute; Burroughs Wellcome Fund; Medic Foundation; Nuovo Soldati Foundation; Swiss National Science Foundation; Oncosuisse FX We thank E. Rheinbay, R. Ryan, M. Rivera, I. Bernstein, and A. Meissner for critical comments, and L. Gaffney for figure design. This work was supported by the Howard Hughes Medical Institute, the National Human Genome Research Institute, the NIH Common Fund, the National Heart, Lung, and Blood Institute, the Harvard Stem Cell Institute, the Burroughs Wellcome Fund, the Medic Foundation, the Nuovo Soldati Foundation, the Swiss National Science Foundation, and Oncosuisse. NR 64 TC 233 Z9 238 U1 16 U2 157 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAR 29 PY 2013 VL 339 IS 6127 BP 1567 EP 1570 DI 10.1126/science.1230184 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 114HL UT WOS:000316731600039 PM 23539597 ER PT J AU Losman, JA Looper, RE Koivunen, P Lee, S Schneider, RK McMahon, C Cowley, GS Root, DE Ebert, BL Kaelin, WG AF Losman, Julie-Aurore Looper, Ryan E. Koivunen, Peppi Lee, Sungwoo Schneider, Rebekka K. McMahon, Christine Cowley, Glenn S. Root, David E. Ebert, Benjamin L. Kaelin, William G., Jr. TI (R)-2-Hydroxyglutarate Is Sufficient to Promote Leukemogenesis and Its Effects Are Reversible SO SCIENCE LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ISOCITRATE DEHYDROGENASE 1; ONCOMETABOLITE 2-HYDROXYGLUTARATE; 2 MUTATIONS; IN-VIVO; DIFFERENTIATION; HYPOXIA; CELLS; TET2; TRANSFORMATION AB Mutations in IDH1 and IDH2, the genes coding for isocitrate dehydrogenases 1 and 2, are common in several human cancers, including leukemias, and result in overproduction of the (R)-enantiomer of 2-hydroxyglutarate [(R)-2HG]. Elucidation of the role of IDH mutations and (R)-2HG in leukemogenesis has been hampered by a lack of appropriate cell-based models. Here, we show that a canonical IDH1 mutant, IDH1 R132H, promotes cytokine independence and blocks differentiation in hematopoietic cells. These effects can be recapitulated by (R)-2HG, but not (S)-2HG, despite the fact that (S)-2HG more potently inhibits enzymes, such as the 5'-methylcytosine hydroxylase TET2, that have previously been linked to the pathogenesis of IDH mutant tumors. We provide evidence that this paradox relates to the ability of (S)-2HG, but not (R)-2HG, to inhibit the EglN prolyl hydroxylases. Additionally, we show that transformation by (R)-2HG is reversible. C1 [Losman, Julie-Aurore; Lee, Sungwoo; McMahon, Christine; Kaelin, William G., Jr.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Losman, Julie-Aurore; Schneider, Rebekka K.; Ebert, Benjamin L.] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02215 USA. [Looper, Ryan E.] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. [Koivunen, Peppi] Univ Oulu, Oulu Ctr Cell Matrix Res, Dept Med Biochem & Mol Biol, Bioctr Oulu, FIN-90014 Oulu, Finland. [Cowley, Glenn S.; Root, David E.; Ebert, Benjamin L.] Broad Inst MIT & Harvard, Cambridge, MA 02143 USA. [Kaelin, William G., Jr.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Kaelin, WG (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM william_kaelin@dfci.harvard.edu OI Looper, Ryan/0000-0003-1626-1363 FU NIH; HHMI FX We thank K. Yen, M. Su, and Agios Pharmaceuticals for the IDH1 inhibitor and for sharing unpublished data; R. Bejar and A. Mullally for their valuable input; A. Lane and D. Sykes for assistance with the SCF ER-Hoxb8 cells; M. Paktinat and R. Mathieu for assistance with flow cytometry; and members of the Kaelin and Ebert lab for technical help and valuable discussion. This work was supported by the NIH (W. G. K. and J.-A.L.) and HHMI (W. G. K.). W. G. K. is a HHMI Investigator and a paid Scientific Advisor for Agios, a biotechnology company developing IDH inhibitors. W. G. K. is also a paid consultant for and owns equity in Fibrogen, Inc., a biotechnology company developing EglN inhibitors. NR 28 TC 212 Z9 217 U1 4 U2 53 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAR 29 PY 2013 VL 339 IS 6127 BP 1621 EP 1625 DI 10.1126/science.1231677 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 114HL UT WOS:000316731600053 PM 23393090 ER PT J AU Gotlib, J Pardanani, A Akin, C Reiter, A George, T Hermine, O Kluin-Nelemans, H Hartmann, K Sperr, WR Brockow, K Schwartz, LB Orfao, A DeAngelo, DJ Arock, M Sotlar, K Horny, HP Metcalfe, DD Escribano, L Verstovsek, S Tefferi, A Valent, P AF Gotlib, Jason Pardanani, Animesh Akin, Cem Reiter, Andreas George, Tracy Hermine, Olivier Kluin-Nelemans, Hanneke Hartmann, Karin Sperr, Wolfgang R. Brockow, Knut Schwartz, Lawrence B. Orfao, Alberto DeAngelo, Daniel J. Arock, Michel Sotlar, Karl Horny, Hans-Peter Metcalfe, Dean D. Escribano, Luis Verstovsek, Srdan Tefferi, Ayalew Valent, Peter TI International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; TYROSINE KINASE INHIBITOR; MAST-CELL LEUKEMIA; OF-THE-LITERATURE; PHASE-II TRIAL; C-KIT MUTATION; INTERFERON-ALPHA; IMATINIB MESYLATE; SPANISH NETWORK; CLADRIBINE AB Systemic mastocytosis (SM) is characterized by accumulation of neoplastic mast cells and is classified into indolent and aggressive forms. The latter include aggressive SM (ASM), mast cell leukemia (MCL), and SM associated with a myeloid neoplasm wherein 1 or both disease compartments exhibit advanced features. These variants, henceforth collectively referred to as advanced SM for the purposes of this report, are typically characterized by organ damage and shortened survival duration. In contrast to indolent SM, in which symptoms are usually managed by noncytotoxic antimediator therapy, cytoreduction is usually necessary for disease control in advanced SM. Unfortunately, current drug treatment of these patients rarely results in complete clinical and histopathologic remissions or improved survival time. Previously defined response criteria were adapted to the heterogeneous presentations of advanced SM and the limited effects of available drugs. However, recent advances in understanding the molecular pathogenesis of SM and the corresponding prospect in targeted therapy make it a priority to modify these criteria. Our current study is the product of an international group of experts and summarizes the challenges in accomplishing this task and forwards a new proposal for response criteria, which builds on prior proposals and should facilitate response evaluation in clinical trials. C1 [Gotlib, Jason; George, Tracy] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Pardanani, Animesh; Tefferi, Ayalew] Mayo Clin, Rochester, MN USA. [Akin, Cem] Harvard Univ, Sch Med, Boston, MA USA. [Akin, Cem] Brigham & Womens Hosp, Boston, MA 02115 USA. [Reiter, Andreas] Univ Med Mannheim, Med Klin 3, Mannheim, Germany. [Hermine, Olivier] Paris Descartes Univ, CNRS, Unite Mixte Rech 8147, Paris, France. [Hermine, Olivier] Paris Descartes Univ, Necker Hosp, Paris, France. [Kluin-Nelemans, Hanneke] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Hartmann, Karin] Univ Cologne, D-50931 Cologne, Germany. [Sperr, Wolfgang R.; Valent, Peter] Med Univ Vienna, Vienna, Austria. [Brockow, Knut] Biederstein Tech Univ, Munich, Germany. [Schwartz, Lawrence B.] Virginia Commonwealth Univ, Richmond, VA USA. [Orfao, Alberto; Escribano, Luis] Univ Salamanca, E-37008 Salamanca, Spain. [DeAngelo, Daniel J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Arock, Michel] Grp Hosp Pitie Salpetriere, Cent Hematol Lab, F-75634 Paris, France. [Arock, Michel] Ecole Normale Super, LBPA, CNRS UMR 8113, F-75231 Paris, France. [Sotlar, Karl; Horny, Hans-Peter] Univ Munich, Munich, Germany. [Metcalfe, Dean D.] NIAID, NIH, Bethesda, MD 20892 USA. [Verstovsek, Srdan] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Gotlib, J (reprint author), Stanford Canc Inst, 875 Blake Wilbur Dr,Room 2324, Stanford, CA 94305 USA. EM jason.gotlib@stanford.edu RI Hartmann, Karin/N-4865-2015; OI Hartmann, Karin/0000-0002-4595-8226; Akin, Cem/0000-0001-6301-4520 FU Charles and Ann Johnson Foundation; Division of Intramural Research, NIAID, National Institutes of Health; Ministerio de Sanidad y Asuntos Sociales [FIS PS09/00032]; Austrian Science Fund (FWF) SFB-project [F4704-B20] FX This work was supported in part by the Charles and Ann Johnson Foundation (J.G.), the Division of Intramural Research, NIAID, National Institutes of Health (D. D. M), a grant by the Ministerio de Sanidad y Asuntos Sociales (FIS PS09/00032) (L. E.), and by the Austrian Science Fund (FWF) SFB-project F4704-B20. NR 58 TC 35 Z9 35 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 28 PY 2013 VL 121 IS 13 BP 2393 EP 2401 DI 10.1182/blood-2012-09-458521 PG 9 WC Hematology SC Hematology GA 182RT UT WOS:000321762400009 PM 23325841 ER PT J AU Harris, JM Esain, V Frechette, GM Harris, LJ Cox, AG Cortes, M Garnaas, MK Carroll, KJ Cutting, CC Khan, T Elks, PM Renshaw, SA Dickinson, BC Chang, CJ Murphy, MP Paw, BH Vander Heiden, MG Goessling, W North, TE AF Harris, James M. Esain, Virginie Frechette, Gregory M. Harris, Lauren J. Cox, Andrew G. Cortes, Mauricio Garnaas, Maija K. Carroll, Kelli J. Cutting, Claire C. Khan, Tahsin Elks, Philip M. Renshaw, Stephen A. Dickinson, Bryan C. Chang, Christopher J. Murphy, Michael P. Paw, Barry H. Vander Heiden, Matthew G. Goessling, Wolfram North, Trista E. TI Glucose metabolism impacts the spatiotemporal onset and magnitude of HSC induction in vivo SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; INDUCIBLE FACTOR-I; AORTIC ENDOTHELIUM; CHILDHOOD LEUKEMIA; ENERGY-METABOLISM; BIRTH-WEIGHT; MOUSE EMBRYO; HIF-ALPHA; HYPOXIA; ZEBRAFISH AB Many pathways regulating blood formation have been elucidated, yet how each coordinates with embryonic biophysiology to modulate the spatiotemporal production of hematopoietic stem cells (HSCs) is currently unresolved. Here, we report that glucose metabolism impacts the onset and magnitude of HSC induction in vivo. In zebrafish, transient elevations in physiological glucose levels elicited dose-dependent effects on HSC development, including enhanced runx1 expression and hematopoietic cluster formation in the aorta-gonad-mesonephros region; embryonic-to-adult transplantation studies confirmed glucose increased functional HSCs. Glucose uptake was required to mediate the enhancement in HSC development; likewise, metabolic inhibitors diminished nascent HSC production and reversed glucose-mediated effects on HSCs. Increased glucose metabolism preferentially impacted hematopoietic and vascular targets, as determined by gene expression analysis, through mitochondrial-derived reactive oxygen species (ROS)-mediated stimulation of hypoxia-inducible factor 1 alpha (hif1 alpha). Epistasis assays demonstrated that hif1 alpha regulates HSC formation in vivo and mediates the dose-dependent effects of glucose metabolism on the timing and magnitude of HSC production. We propose that this fundamental metabolic-sensing mechanism enables the embryo to respond to changes in environmental energy input and adjust hematopoietic output to maintain embryonic growth and ensure viability. C1 [Harris, James M.; Esain, Virginie; Frechette, Gregory M.; Harris, Lauren J.; Cortes, Mauricio; Carroll, Kelli J.; North, Trista E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Cox, Andrew G.; Garnaas, Maija K.; Cutting, Claire C.; Goessling, Wolfram] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [Cox, Andrew G.; Garnaas, Maija K.; Cutting, Claire C.; Goessling, Wolfram] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gastroenterol, Boston, MA 02115 USA. [Khan, Tahsin; Vander Heiden, Matthew G.] MIT, Koch Inst, Cambridge, MA 02139 USA. [Elks, Philip M.; Renshaw, Stephen A.] Ctr Dev & Biomed Genet, MRC, Sheffield, S Yorkshire, England. [Dickinson, Bryan C.; Chang, Christopher J.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. [Dickinson, Bryan C.; Chang, Christopher J.] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA. [Murphy, Michael P.] MRC Mitochondrial Biol Unit, Cambridge, England. [Paw, Barry H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Hematol, Boston, MA 02115 USA. [Paw, Barry H.; Vander Heiden, Matthew G.; Goessling, Wolfram] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Goessling, Wolfram; North, Trista E.] Harvard Stem Cell Inst, Cambridge, MA USA. RP Goessling, W (reprint author), Brigham & Womens Hosp, Div Genet, NRB458,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM wgoessling@partners.org; tnorth@bidmc.harvard.edu RI Renshaw, Stephen/E-6192-2010; OI Renshaw, Stephen/0000-0003-1790-1641; Elks, Philip/0000-0003-1683-0749; Goessling, Wolfram/0000-0001-9972-1569 FU Harvard Stem Cell Institute Blood Program; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [5K01DK080226, 1R01DK090311] FX This work was supported by the Harvard Stem Cell Institute Blood Program (T.E.N.) and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 5K01DK080226 (T.E.N.) and 1R01DK090311 (W.G.). NR 50 TC 28 Z9 30 U1 0 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 28 PY 2013 VL 121 IS 13 BP 2483 EP 2493 DI 10.1182/blood-2012-12-471201 PG 11 WC Hematology SC Hematology GA 182RT UT WOS:000321762400018 PM 23341543 ER PT J AU Stefater, JA Rao, S Bezold, K Aplin, AC Nicosia, RF Pollard, JW Ferrara, N Lang, RA AF Stefater, James A., III Rao, Sujata Bezold, Katie Aplin, Alfred C. Nicosia, Roberto F. Pollard, Jeffrey W. Ferrara, Napoleone Lang, Richard A. TI Macrophage Wnt-Calcineurin-Flt1 signaling regulates mouse wound angiogenesis and repair SO BLOOD LA English DT Article ID IMMUNOSUPPRESSED MICE; INFLAMMATORY CELLS; TGF-BETA; VEGF; RECEPTOR; CALCINEURIN; PROTEIN; INHIBITION; LETHALITY; SECRETION AB The treatment of festering wounds is one of the most important aspects of medical care. Macrophages are important components of wound repair, both in fending off infection and in coordinating tissue repair. Here we show that macrophages use a Wnt-Calcineurin-Flt1 signaling pathway to suppress wound vasculature and delay repair. Conditional mutants deficient in both Wntless/GPR177, the secretory transporter of Wnt ligands, and CNB1, the essential component of the nuclear factor of activated T cells dephosporylation complex, displayed enhanced angiogenesis and accelerated repair. Furthermore, in myeloid-like cells, we show that noncanonical Wnt activates Flt1, a naturally occurring inhibitor of vascular endothelial growth factor-A-mediated angiogenesis, but only when calcineurin function is intact. Then, as expected, conditional deletion of Flt1 in macrophages resulted in enhanced wound angiogenesis and repair. These results are consistent with the published link between enhanced angiogenesis and enhanced repair, and establish novel therapeutic approaches for treatment of wounds. C1 [Stefater, James A., III; Rao, Sujata; Bezold, Katie; Lang, Richard A.] Cincinnati Childrens Hosp Med Ctr, Div Pediat Ophthalmol, Visual Syst Grp, Cincinnati, OH 45229 USA. [Stefater, James A., III; Rao, Sujata; Bezold, Katie; Lang, Richard A.] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA. [Stefater, James A., III; Rao, Sujata; Bezold, Katie; Lang, Richard A.] Univ Cincinnati, Dept Ophthalmol, Cincinnati, OH USA. [Aplin, Alfred C.; Nicosia, Roberto F.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Aplin, Alfred C.; Nicosia, Roberto F.] VA Puget Sound Hlth Care Syst, Pathol & Lab Med, Seattle, WA USA. [Pollard, Jeffrey W.] Yeshiva Univ, Albert Einstein Coll Med, Bronx, NY USA. [Ferrara, Napoleone] Genentech Inc, San Francisco, CA 94080 USA. RP Lang, RA (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Pediat Ophthalmol, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM richard.lang@cchmc.org FU National Institutes of Health [R01CA131270, T32GM063483-08S1] FX This work was supported by grants from the National Institutes of Health (R01CA131270) (J.P. and R. A. L) and (T32GM063483-08S1) (J.A.S). NR 40 TC 19 Z9 19 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 28 PY 2013 VL 121 IS 13 BP 2574 EP 2578 DI 10.1182/blood-2012-06-434621 PG 5 WC Hematology SC Hematology GA 182RT UT WOS:000321762400029 PM 23303818 ER PT J AU Hong, FX Bosco, JLF Bush, N Berry, DL AF Hong, Fanxing Bosco, Jaclyn L. F. Bush, Nigel Berry, Donna L. TI Patient self-appraisal of change and minimal clinically important difference on the European organization for the research and treatment of cancer quality of life questionnaire core 30 before and during cancer therapy SO BMC CANCER LA English DT Article DE Cancer treatment; Health related quality of life; Quality of life questionnaire-core; Subject significance questionnaire; Minimal clinically important differences ID EORTC QLQ-C30; SCORES AB Background: Clinical interpretation of health related quality of life (HRQOL) scores is challenging. The purpose of this analysis was to interpret score changes and identify minimal clinically important differences (MCID) on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) before (T1) and during (T2) cancer treatment. Methods: Patients (N = 627) in stem cell transplant (SCT) and medical (MED) or radiation (RAD) oncology at two comprehensive cancer centers, enrolled in the Electronic Self-Report Assessment-Cancer study and completed the QLQ-C30 at T1 and T2. Perceived changes in five QOL domains, physical (PF), emotional (EF), social (SF), cognitive functioning (CF) and global quality of life (QOL), were reported using the Subject Significance Questionnaire (SSQ) at T2. Anchored on SSQ ratings indicating "improvement", "the same", or "deterioration", means and effect sizes were calculated for QLQ-C30 score changes. MCID was calculated as the mean difference in QLQ-C30 score changes reflecting one category change on SSQ rating, using a two-piece linear regression model. Results: A majority of SCT patients (54%) perceived deteriorating global HRQOL versus improvement (17%), while approximately equal proportions of MED/RAD patients perceived improvement (25%) and deterioration (26%). Global QOL decreased 14.2 (SCT) and 2.0 (MED/RAD) units, respectively, among patients reporting "the same" in the SSQ. The MCID ranged 5.7-11.4 (SCT) and 7.2-11.8 (MED/RAD) units among patients reporting deteriorated HRQOL; ranged 2.7-3.4 units among MED/RAD patients reporting improvement. Excepting for the global QOL (MCID = 6.9), no meaningful MCID was identified among SCT patients reporting improvement. Conclusions: Cancer treatment has greater impact on HRQOL among SCT patients than MED/RAD patients. The MCID for QLQ-C30 score change differed across domains, and differed for perceived improvement and deterioration, suggesting different standards for self-evaluating changes in HRQOL during cancer treatment. Specifically, clinical attention can be focused on patients who report at least a 6 point decrease, and for patients who report at least a 3 point increase on QLQ-C30 domains. C1 [Hong, Fanxing] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Bosco, Jaclyn L. F.; Berry, Donna L.] Harvard Univ, Sch Med, Phyllis F Cantor Ctr, Dana Farber Canc Inst,Dept Med, Boston, MA 02115 USA. [Bush, Nigel] Natl Ctr Telehlth & Technol, Joint Base Lewis McChord, Tacoma, WA USA. RP Hong, FX (reprint author), Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM fxhong@jimmy.harvard.edu FU National Institute of Nursing Research [NR008726] FX The study was supported by the National Institute of Nursing Research grant NR008726. The authors acknowledge Barbara Halpenny for constructive discussions, the time and effort of all study participants, the dedication of the research staff, the generous support from the clinicians and administrators at the study sites for the original ESRA-C study. NR 23 TC 4 Z9 5 U1 2 U2 6 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 MAR 28 PY 2013 VL 13 AR 165 DI 10.1186/1471-2407-13-165 PG 8 WC Oncology SC Oncology GA 136YA UT WOS:000318398500001 PM 23537330 ER PT J AU Garraway, LA Lander, ES AF Garraway, Levi A. Lander, Eric S. TI Lessons from the Cancer Genome SO CELL LA English DT Review ID ACUTE MYELOID-LEUKEMIA; ISLAND METHYLATOR PHENOTYPE; CHROMATIN REMODELING GENES; LINEAGE-SURVIVAL ONCOGENE; SQUAMOUS-CELL CARCINOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; RECURRENT SOMATIC MUTATIONS; CLINICAL TUMOR SAMPLES; LONG-RANGE INTERACTION; 21 BREAST CANCERS AB Systematic studies of the cancer genome have exploded in recent years. These studies have revealed scores of new cancer genes, including many in processes not previously known to be causal targets in cancer. The genes affect cell signaling, chromatin, and epigenomic regulation; RNA splicing; protein homeostasis; metabolism; and lineage maturation. Still, cancer genomics is in its infancy. Much work remains to complete the mutational catalog in primary tumors and across the natural history of cancer, to connect recurrent genomic alterations to altered pathways and acquired cellular vulnerabilities, and to use this information to guide the development and application of therapies. C1 [Garraway, Levi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Garraway, Levi A.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. [Garraway, Levi A.] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Lander, Eric S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Garraway, Levi A.; Lander, Eric S.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Lander, Eric S.] MIT, Dept Biol, Cambridge, MA 02139 USA. RP Lander, ES (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. EM lander@broadinstitute.org FU U.S. National Human Genome Research Institute; U.S. National Cancer Institute; Slim Initiative for Genomic Medicine; Broad Institute; Department of Defense; Starr Cancer Consortium; Prostate Cancer Foundation; Melanoma Research Alliance; Adelson Medical Research Foundation FX We thank Todd Golub, Matthew Meyerson, and Michael Stratton for reviewing the manuscript and for valuable comments. We thank Gad Getz, Charles Roberts, and Matthew Freedman for helpful discussions. The design of figures was aided by materials from ScienceSlides (http://www.visiscience.com). L.A.G. and E.S.L. are supported by the U.S. National Human Genome Research Institute, the U.S. National Cancer Institute, the Slim Initiative for Genomic Medicine, and the Broad Institute. L.A.G. also receives support from the Department of Defense, the Starr Cancer Consortium, the Prostate Cancer Foundation, the Melanoma Research Alliance, and the Adelson Medical Research Foundation. L.A.G. and E.S.L. are consultants and equity holders in Foundation Medicine, Inc. NR 191 TC 357 Z9 368 U1 21 U2 218 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 28 PY 2013 VL 153 IS 1 BP 17 EP 37 DI 10.1016/j.cell.2013.03.002 PG 21 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 116AI UT WOS:000316853700004 PM 23540688 ER PT J AU Kaelin, WG McKnight, SL AF Kaelin, William G., Jr. McKnight, Steven L. TI Influence of Metabolism on Epigenetics and Disease SO CELL LA English DT Review ID HISTONE LYSINE DEMETHYLASES; OFFSPRING DNA METHYLATION; ACETYL-COA SYNTHETASE; COMBINED FOLIC-ACID; OXIDATIVE STRESS; GENE-EXPRESSION; CELL-CYCLE; ONCOMETABOLITE 2-HYDROXYGLUTARATE; MYELOID MALIGNANCIES; S-ADENOSYLMETHIONINE AB Chemical modifications of histones and DNA, such as histone methylation, histone acetylation, and DNA methylation, play critical roles in epigenetic gene regulation. Many of the enzymes that add or remove such chemical modifications are known, or might be suspected, to be sensitive to changes in intracellular metabolism. This knowledge provides a conceptual foundation for understanding how mutations in the metabolic enzymes SDH, FH, and IDH can result in cancer and, more broadly, for how alterations in metabolism and nutrition might contribute to disease. Here, we review literature pertinent to hypothetical connections between metabolic and epigenetic states in eukaryotic cells. C1 [Kaelin, William G., Jr.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Kaelin, William G., Jr.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02215 USA. [Kaelin, William G., Jr.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [McKnight, Steven L.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. RP Kaelin, WG (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM william_kaelin@dfci.harvard.edu; steven.mcknight@utsouthwestern.edu FU Howard Hughes Medical Institute; NCI NIH HHS [R01 CA068490, R01 CA076120] NR 127 TC 222 Z9 225 U1 32 U2 219 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 28 PY 2013 VL 153 IS 1 BP 56 EP 69 DI 10.1016/j.cell.2013.03.004 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 116AI UT WOS:000316853700006 PM 23540690 ER PT J AU Huang, SC Do, J Mahalanabis, M Fan, A Zhao, L Jepeal, L Singh, SK Klapperich, CM AF Huang, Shichu Do, Jaephil Mahalanabis, Madhumita Fan, Andy Zhao, Lei Jepeal, Lisa Singh, Satish K. Klapperich, Catherine M. TI Low Cost Extraction and Isothermal Amplification of DNA for Infectious Diarrhea Diagnosis SO PLOS ONE LA English DT Article ID IMMUNOCHROMATOGRAPHIC STRIP TEST; DISPOSABLE DETECTION DEVICE; REAL-TIME PCR; ON-A-CHIP; CLOSTRIDIUM-DIFFICILE; GLOBAL HEALTH; IDENTIFICATION; MICROFLUIDICS; TECHNOLOGIES; SYSTEMS AB In order to counter the common perception that molecular diagnostics are too complicated to work in low resource settings, we have performed a difficult sample preparation and DNA amplification protocol using instrumentation designed to be operated without wall or battery power. In this work we have combined a nearly electricity-free nucleic acid extraction process with an electricity-free isothermal amplification assay to detect the presence of Clostridium difficile (C. difficile) DNA in the stool of infected patients. We used helicase-dependent isothermal amplification (HDA) to amplify the DNA in a low-cost, thermoplastic reaction chip heated with a pair of commercially available toe warmers, while using a simple Styrofoam insulator. DNA was extracted from known positive and negative stool samples. The DNA extraction protocol utilized an air pressure driven solid phase extraction device run using a standard bicycle pump. The simple heater setup required no electricity or battery and was capable of maintaining the temperature at 65 degrees C +/- 62 degrees C for 55 min, suitable for repeatable HDA amplification. Experiments were performed to explore the adaptability of the system for use in a range of ambient conditions. When compared to a traditional centrifuge extraction protocol and a laboratory thermocycler, this disposable, no power platform achieved approximately the same lower limit of detection (1.25 x 10(-2) pg of C. difficile DNA) while requiring much less raw material and a fraction of the lab infrastructure and cost. This proof of concept study could greatly impact the accessibility of molecular assays for applications in global health. C1 [Huang, Shichu; Do, Jaephil; Mahalanabis, Madhumita; Fan, Andy; Klapperich, Catherine M.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Zhao, Lei] Boston Univ, Dept Biol, Boston, MA 02215 USA. [Jepeal, Lisa; Singh, Satish K.] Boston Univ, Dept Gastroenterol, Boston, MA 02215 USA. [Singh, Satish K.] VA Boston Hlth Care Syst, Dept Med, Boston, MA USA. [Klapperich, Catherine M.] Boston Univ, Dept Mech Engn, Boston, MA 02215 USA. RP Klapperich, CM (reprint author), Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. EM catherin@bu.edu OI Klapperich, Catherine /0000-0001-6103-849X; Singh, Satish/0000-0002-7664-3155 FU NIH [R21 AI71261] FX This work was funded by NIH Grant R21 AI71261 to CMK and SS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 22 Z9 23 U1 3 U2 59 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 MAR 28 PY 2013 VL 8 IS 3 AR e60059 DI 10.1371/journal.pone.0060059 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 121RP UT WOS:000317262200075 PM 23555883 ER PT J AU Epstein, AJ Srinivas, SK Nicholson, S Herrin, J Asch, DA AF Epstein, Andrew J. Srinivas, Sindhu K. Nicholson, Sean Herrin, Jeph Asch, David A. TI Association between physicians' experience after training and maternal obstetrical outcomes: cohort study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID LEARNING-CURVE; MORTALITY; SURGEONS; CARE AB Objective To assess the association between obstetricians' years of experience after training and the maternal complications of their patients during their first 40 years of post-residency practice. Design Retrospective cohort analysis. Setting Obstetrical discharges from acute care hospitals in Florida and New York between academic years 1992 and 2009. Population 6 704 311 deliveries performed by 5175 obstetricians. Main outcome measure Three composite measures of maternal complication rates per physician year from vaginal and cesarean births separately and combined, adjusted for secular trends. Results Obstetricians' maternal complication rates declined during the first three decades after completion of residency. The improvement was largest in the first decade and diminished thereafter. For all deliveries, the change was -0.21 (95% confidence interval -0.23 to -0.19) percentage points per year in the first decade, -0.11 (-0.13 to -0.09) percentage points per year in the second decade, and -0.05 (-0.08 to -0.01) percentage points in the third decade (P<0.001 for second to first decade comparison; P=0.001 for third to second decade comparison). The patterns were comparable for cesarean deliveries and vaginal deliveries and across several sensitivity checks. Conclusions Among obstetricians practicing in Florida and New York, those with more years of experience had fewer maternal complications. This association persisted over the first three decades of practice but diminished in magnitude. C1 [Epstein, Andrew J.; Asch, David A.] Philadelphia Vet Affairs Med Ctr, Dept Vet Affairs, Ctr Hlth Equity Res & Promot, Philadelphia, PA 19104 USA. [Epstein, Andrew J.; Asch, David A.] Univ Penn, Div Gen Internal Med, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Epstein, Andrew J.; Srinivas, Sindhu K.; Asch, David A.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Srinivas, Sindhu K.] Univ Penn, Dept Obstet & Gynecol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Nicholson, Sean] Cornell Univ, Dept Policy Anal & Management, Coll Human Ecol, Ithaca, NY 14853 USA. [Herrin, Jeph] Yale Univ, Sect Cardiovasc Med, Dept Med, Sch Med, New Haven, CT 06510 USA. [Herrin, Jeph] Hlth Res & Educ Trust, Chicago, IL 60606 USA. RP Epstein, AJ (reprint author), Philadelphia Vet Affairs Med Ctr, Dept Vet Affairs, Ctr Hlth Equity Res & Promot, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM eandrew@mail.med.upenn.edu OI Asch, David/0000-0002-7970-286X NR 17 TC 2 Z9 2 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD MAR 28 PY 2013 VL 346 AR f1596 DI 10.1136/bmj.f1596 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 117XI UT WOS:000316986200003 PM 23538919 ER PT J AU Hanada, T Weitzer, S Mair, B Bernreuther, C Wainger, BJ Ichida, J Hanada, R Orthofer, M Cronin, SJ Komnenovic, V Minis, A Sato, F Mimata, H Yoshimura, A Tamir, I Rainer, J Kofler, R Yaron, A Eggan, KC Woolf, CJ Glatzel, M Herbst, R Martinez, J Penninger, JM AF Hanada, Toshikatsu Weitzer, Stefan Mair, Barbara Bernreuther, Christian Wainger, Brian J. Ichida, Justin Hanada, Reiko Orthofer, Michael Cronin, Shane J. Komnenovic, Vukoslav Minis, Adi Sato, Fuminori Mimata, Hiromitsu Yoshimura, Akihiko Tamir, Ido Rainer, Johannes Kofler, Reinhard Yaron, Avraham Eggan, Kevin C. Woolf, Clifford J. Glatzel, Markus Herbst, Ruth Martinez, Javier Penninger, Josef M. TI CLP1 links tRNA metabolism to progressive motor-neuron loss SO NATURE LA English DT Article ID 3-END FORMATION; PHOSPHORYLATION; ENDONUCLEASE; STRESS; ENZYME; MOUSE; HCLP1; SITE; IA AB CLP1 was the first mammalian RNA kinase to be identified. However, determining its in vivo function has been elusive. Here we generated kinase-dead Clp1 (Clp1(K/K)) mice that show a progressive loss of spinal motor neurons associated with axonal degeneration in the peripheral nerves and denervation of neuromuscular junctions, resulting in impaired motor function, muscle weakness, paralysis and fatal respiratory failure. Transgenic rescue experiments show that CLP1 functions in motor neurons. Mechanistically, loss of CLP1 activity results in accumulation of a novel set of small RNA fragments, derived from aberrant processing of tyrosine pre-transfer RNA. These tRNA fragments sensitize cells to oxidative-stress-induced p53 (also known as TRP53) activation and p53-dependent cell death. Genetic inactivation of p53 rescues Clp1(K/K) mice from the motor neuron loss, muscle denervation and respiratory failure. Our experiments uncover a mechanistic link between tRNA processing, formation of a new RNA species and progressive loss of lower motor neurons regulated by p53. C1 [Hanada, Toshikatsu; Weitzer, Stefan; Mair, Barbara; Hanada, Reiko; Orthofer, Michael; Komnenovic, Vukoslav; Martinez, Javier; Penninger, Josef M.] Austrian Acad Sci, IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria. [Bernreuther, Christian; Glatzel, Markus] Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, D-20246 Hamburg, Germany. [Wainger, Brian J.; Cronin, Shane J.; Woolf, Clifford J.] Boston Childrens Hosp, Program Neurobiol, Boston, MA 02115 USA. [Wainger, Brian J.; Cronin, Shane J.; Woolf, Clifford J.] Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Wainger, Brian J.] Massachusetts Gen Hosp, Department Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Ichida, Justin; Eggan, Kevin C.] Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Howard Hughes Med Inst, Boston, MA 02115 USA. [Minis, Adi; Yaron, Avraham] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. [Sato, Fuminori; Mimata, Hiromitsu] Oita Univ, Dept Urol, Fac Med, Oita 8795593, Japan. [Yoshimura, Akihiko] Keio Univ, Dept Microbiol & Immunol, Sch Med, Shinjuku Ku, Tokyo 1608582, Japan. [Tamir, Ido] Campus Sci Support Facil GmbH, A-1030 Vienna, Austria. [Rainer, Johannes; Kofler, Reinhard] Med Univ Innsbruck, Div Mol Pathophysiol, Bioctr, A-6020 Innsbruck, Austria. [Woolf, Clifford J.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Herbst, Ruth] Med Univ Vienna, Ctr Brain Res, A-1090 Vienna, Austria. RP Martinez, J (reprint author), Austrian Acad Sci, IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria. EM javier.martinez@imba.oeaw.ac.at; josef.penninger@imba.oeaw.ac.at RI Penninger, Josef/I-6860-2013; Glatzel, Markus/G-3356-2011; Yoshimura, Akihiko/K-5515-2013; OI Penninger, Josef/0000-0002-8194-3777; Glatzel, Markus/0000-0002-7720-8817; Mair, Barbara/0000-0001-6982-2529 FU Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA); Austrian Ministry of Sciences; Austrian Academy of Sciences; AustroMouse network of Genome Research in Austria (GEN-AU); Apoptosis systems biology applied to cancer and AIDS (ApoSys); European Research Council Advanced Grant from the European Union; IMBA; GEN-AU (AustroMouse); Japan Society for the Promotion of Science; Astellas Foundation; National Institutes of Health (NIH) [K99NS077435-01A1]; German Research Foundation (DFG) [FG885, GRK 1459]; Landesexzellenzinitiative Hamburg (Neurodapt); Austrian Science Fund [P19223, P21667]; NIH [NS038253] FX We thank A. Meixner, M. Foong, T. Nakashima, H. C. Theussl, J. R. Wojciechowski, A. Bichl, the mouse pathology unit of the Universitatsklinikum Hamburg-Eppendorf, and G. P. Resch for discussions and technical support. We also thank T. Buerckstuemmer for providing the pRV-NTAP vector. J. M. P. is supported by grants from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), the Austrian Ministry of Sciences, the Austrian Academy of Sciences, AustroMouse network of Genome Research in Austria (GEN-AU), Apoptosis systems biology applied to cancer and AIDS (ApoSys) and a European Research Council Advanced Grant from the European Union. J. M., S. W. and B. M. are supported by IMBA and GEN-AU (AustroMouse). T. H. is supported by the Japan Society for the Promotion of Science and the Astellas Foundation. J. K. I. was supported by National Institutes of Health (NIH) grant K99NS077435-01A1. M. G. is supported by grants from the German Research Foundation (DFG) (FG885 and GRK 1459), the Landesexzellenzinitiative Hamburg (Neurodapt). R. H. was supported by the Austrian Science Fund (P19223, P21667). C. J. W. is supported by the NIH (NS038253). NR 27 TC 54 Z9 59 U1 3 U2 33 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 28 PY 2013 VL 495 IS 7442 BP 474 EP 480 DI 10.1038/nature11923 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 113QN UT WOS:000316682800038 PM 23474986 ER PT J AU Stone, JH Murali, MR AF Stone, John H. Murali, Mandakolathur R. TI Case 10-2013: A 30-Year-Old Man with Fever, Myalgias, Arthritis, and Rash SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; MIDLINE DESTRUCTIVE LESIONS; RHEUMATIC MANIFESTATIONS; INFECTIVE ENDOCARDITIS; COCAINE; HEROIN; LEVAMISOLE; VASCULITIS; PURPURA; EARS C1 [Stone, John H.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. FU Roche; Genentech FX Dr. Stone reports receiving consulting fees from Roche and Genentech, grant support through his institution from Roche and Genentech, and travel support from Genentech, Biogen-IDEC, and Genzyme. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. NR 21 TC 2 Z9 2 U1 0 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 28 PY 2013 VL 368 IS 13 BP 1239 EP 1245 DI 10.1056/NEJMcpc1210260 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 116FU UT WOS:000316869000014 PM 23514249 ER PT J AU Ecker, JL MacGillivray, TE Fitzsimons, MG AF Ecker, Jeffrey L. MacGillivray, Thomas E. Fitzsimons, Michael G. TI Case 40-2012: A Woman with Cardiorespiratory Arrest after a Cesarean Section REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Ecker, Jeffrey L.; MacGillivray, Thomas E.; Fitzsimons, Michael G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ecker, JL (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 28 PY 2013 VL 368 IS 13 BP 1261 EP 1261 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 116FU UT WOS:000316869000028 PM 23534575 ER PT J AU Palumbo, T Faucz, FR Azevedo, M Xekouki, P Iliopoulos, D Stratakis, CA AF Palumbo, T. Faucz, F. R. Azevedo, M. Xekouki, P. Iliopoulos, D. Stratakis, C. A. TI Functional screen analysis reveals miR-26b and miR-128 as central regulators of pituitary somatomammotrophic tumor growth through activation of the PTEN-AKT pathway SO ONCOGENE LA English DT Article DE microRNAs; growth-hormone producing adenomas; Carney complex; acromegaly; pituitary hyperplasia; protein kinase A ID MCCUNE-ALBRIGHT-SYNDROME; CELL SELF-RENEWAL; CARNEY COMPLEX; MICRORNA GENES; BREAST-CANCER; BMI-1; EXPRESSION; ADENOMAS; PROLIFERATION; MUTATIONS AB MicroRNAs (miRNAs) have been involved in the pathogenesis of different types of cancer; however, their function in pituitary tumorigenesis remains poorly understood. Cyclic-AMP-dependent protein kinase-defective pituitaries occasionally form aggressive growth-hormone (GH)-producing pituitary tumors in the background of hyperplasia caused by haploinsufficiency of the protein kinase's main regulatory subunit, PRKAR1A. The molecular basis for this development remains unknown. We have identified a 17-miRNA signature of pituitary tumors formed in the background of hyperplasia (caused in half of the cases by PRKAR1A-mutations). We selected two miRNAs on the basis of their functional screen analysis: inhibition of miR-26b expression and upregulation of miR-128 suppressed the colony formation ability and invasiveness of pituitary tumor cells. Furthermore, we identified that miR-26b and miR-128 affected pituitary tumor cell behavior through regulation of their direct targets, PTEN and BMI1, respectively. In addition, we found that miR-128 through BMI1 direct binding on the PTEN promoter affected PTEN expression levels and AKT activity in the pituitary tumor cells. Our in vivo data revealed that inhibition of miR-26b and overexpression of miR-128 could suppress pituitary GH3 tumor growth in xenografts. Taken together, we have identified a miRNA signature for GH-producing pituitary tumors and found that miR-26b and miR-128 regulate the activity of the PTEN-AKT pathway in these tumors. This is the first suggestion of the possible involvement of miRNAs regulating the PTEN-AKT pathway in GH-producing pituitary tumor formation in the context of hyperplasia or due to germline PRKAR1A defects. MiR-26b suppression and miR-128 upregulation could have therapeutic potential in GH-producing pituitary tumor patients. Oncogene (2013) 32, 1651-1659; doi: 10.1038/onc.2012.190; published online 21 May 2012 C1 [Palumbo, T.; Iliopoulos, D.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Palumbo, T.; Iliopoulos, D.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Faucz, F. R.; Azevedo, M.; Xekouki, P.; Stratakis, C. A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Bethesda, MD USA. [Faucz, F. R.] Pontificia Univ Catolica Parana, Grp Adv Mol Invest, Grad Program Hlth Sci, Ctr Biol & Sci, Curitiba, Parana, Brazil. RP Iliopoulos, D (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. EM Dimitrios_iliopoulos@dfci.harvard.edu; stratakc@mail.nih.gov FU Intramural NIH HHS [ZIA HD008920-02] NR 49 TC 45 Z9 52 U1 4 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 28 PY 2013 VL 32 IS 13 BP 1651 EP 1659 DI 10.1038/onc.2012.190 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 116AY UT WOS:000316855800005 PM 22614013 ER PT J AU Liu, Z Zanata, SM Kim, J Peterson, MA Di Vizio, D Chirieac, LR Pyne, S Agostini, M Freeman, MR Loda, M AF Liu, Z. Zanata, S. M. Kim, J. Peterson, M. A. Di Vizio, D. Chirieac, L. R. Pyne, S. Agostini, M. Freeman, M. R. Loda, M. TI The ubiquitin-specific protease USP2a prevents endocytosis-mediated EGFR degradation SO ONCOGENE LA English DT Article DE USP2a; DUB; EGFR; endocytosis ID EPIDERMAL-GROWTH-FACTOR; DEUBIQUITINATING ENZYME USP2A; RECEPTOR TYROSINE KINASES; CLATHRIN-COATED PITS; DOWN-REGULATION; PROSTATE-CANCER; MEMBRANE-PROTEIN; PLASMA-MEMBRANE; LUNG-CANCER; CELL-GROWTH AB Ubiquitination of epidermal growth factor receptor (EGFR) is required for downregulation of the receptor by endocytosis. Impairment of this pathway results in constitutively active EGFR, which is associated with carcinogenesis, particularly in lung cancer. We previously demonstrated that the deubiquitinating enzyme ubiquitin-specific protease 2a (USP2a) has oncogenic properties. Here, we show a new role for USP2a as a regulator of EGFR endocytosis. USP2a localizes to early endosomes and associates with EGFR, stabilizing the receptor, which retains active downstream signaling. HeLa cells transiently expressing catalytically active, but not mutant (MUT), USP2a show increased plasma membrane-localized EGFR, as well as decreased internalized and ubiquitinated EGFR. Conversely, USP2a silencing reverses this phenotype. Importantly, USP2a prevents the degradation of MUT in addition to wild-type EGFR. Finally, we observed that USP2a and EGFR proteins are coordinately overexpressed in non-small cell lung cancers. Taken together, our data indicate that USP2a antagonizes EGFR endocytosis and thus amplifies signaling activity from the receptor. Our findings suggest that regulation of deubiquitination could be exploited therapeutically in cancers overexpressing EGFR. Oncogene (2013) 32, 1660-1669; doi:10.1038/onc.2012.188; published online 18 June 2012 C1 [Liu, Z.; Zanata, S. M.; Peterson, M. A.; Chirieac, L. R.; Pyne, S.; Agostini, M.; Loda, M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Liu, Z.; Zanata, S. M.; Peterson, M. A.; Chirieac, L. R.; Pyne, S.; Agostini, M.; Loda, M.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02215 USA. [Liu, Z.; Loda, M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Zanata, S. M.] Univ Fed Parana, Dept Basic Pathol, BR-80060000 Curitiba, Parana, Brazil. [Zanata, S. M.] Univ Fed Parana, Dept Cell Biol, BR-80060000 Curitiba, Parana, Brazil. [Kim, J.; Di Vizio, D.; Freeman, M. R.] Childrens Hosp, Urol Dis Res Ctr, Boston, MA 02115 USA. [Kim, J.; Di Vizio, D.; Freeman, M. R.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Freeman, M. R.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Loda, M.] Kings Coll London, Div Canc Studies, London WC2R 2LS, England. RP Loda, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, DA1536,450 Brookline Ave, Boston, MA 02215 USA. EM Massimo_loda@dfci.harvard.edu RI Agostini, Michelle/I-1275-2012 FU National Cancer Institute [RO1CA131945, PO1CA89021, P50 CA90381]; Prostate Cancer Foundation; CAPES, Brazil [3665/10-0] FX We thank Tomas Kirchhausen for AMSH constructs, Mihee Ji and Erik McCauley for technical assistance, Jane Hayward for help with preparation of the figures, Giulio Draetta and Richard J Flavin for critical reading of the manuscript. This work was supported by the National Cancer Institute (RO1CA131945, PO1CA89021, P50 CA90381 and the Prostate Cancer Foundation). SMZ was supported by CAPES (no. 3665/10-0), Brazil. NR 61 TC 15 Z9 16 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 28 PY 2013 VL 32 IS 13 BP 1660 EP 1669 DI 10.1038/onc.2012.188 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 116AY UT WOS:000316855800006 PM 22710717 ER PT J AU Utzschneider, KM Bayer-Carter, JL Arbuckle, MD Tidwell, JM Richards, TL Craft, S AF Utzschneider, Kristina M. Bayer-Carter, Jennifer L. Arbuckle, Matthew D. Tidwell, Jaime M. Richards, Todd L. Craft, Suzanne TI Beneficial effect of a weight-stable, low-fat/low-saturated fat/low-glycaemic index diet to reduce liver fat in older subjects SO BRITISH JOURNAL OF NUTRITION LA English DT Article DE Non-alcoholic fatty liver; Dietary fat; Glycaemic index; Saturated fat ID MAGNETIC-RESONANCE-SPECTROSCOPY; HIGH-CARBOHYDRATE DIET; HEPATIC STEATOSIS; NONALCOHOLIC STEATOHEPATITIS; INSULIN SENSITIVITY; ACID SYNTHESIS; GLUCOSE; DISEASE; OBESE; RESISTANCE AB Non-alcoholic fatty liver disease is associated with insulin resistance and dyslipidaemia and can progress to steatohepatitis and cirrhosis. We sought to determine whether dietary fat and saturated fat content alter liver fat in the absence of weight change in an older population. Liver fat was quantified by magnetic resonance spectroscopy before and after 4 weeks on an isoenergetic low-fat/low-saturated fat/low-glycaemic index (LGI) (LSAT: 23% fat/7% saturated fat/GI < 55) or a high-fat/high-saturated fat/high-GI (HSAT: 43% fat/24% saturated fat/GI > 70) diet in older subjects. In the present study, twenty subjects (seven males/thirteen females; age 69.3 (SEM 1.6) years, BMI 26.9 (SEM 0.8) kg/m(2)) were randomised to the LSAT diet and fifteen subjects (six males/nine females; age 68.6 (SEM 1.8) years, BMI 28.1 (SEM 0.9) kg/m(2)) to the HSAT diet. Weight remained stable. Liver fat decreased significantly on the LSAT diet (median 2.2 (interquartile range (IQR) 3.1) to 1.7 (IQR 1.8) %, P = 0.002) but did not change on the HSAT diet (median 1.2 (IQR 4.1) to 1.6 (IQR 3.9) %). The LSAT diet lowered fasting glucose and total cholesterol, HDL-cholesterol and LDL-cholesterol and raised TAG (P<0.05), while the HSAT diet had no effect on glucose or HDL-cholesterol but increased total cholesterol and LDL-cholesterol (P<0.05). Fasting insulin and homeostasis model of insulin resistance did not change significantly on either diet, but the Matsuda index of insulin sensitivity improved on the LSAT diet (P<0.05). Assignment to the LSAT v. HSAT diet was a predictor of changes in lipid parameters but not liver fat. We conclude that diet composition may be an important factor in the accumulation of liver fat, with a low-fat/low-saturated fat/LGI diet being beneficial. C1 [Utzschneider, Kristina M.] VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98108 USA. [Utzschneider, Kristina M.] Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. [Bayer-Carter, Jennifer L.; Arbuckle, Matthew D.; Tidwell, Jaime M.; Craft, Suzanne] VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA 98108 USA. [Bayer-Carter, Jennifer L.; Craft, Suzanne] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Richards, Todd L.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. RP Utzschneider, KM (reprint author), VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, 1660 South Columbian Way, Seattle, WA 98108 USA. EM kutzschn@u.washington.edu FU VA Office of Research and Development Medical Research Service [R37 AG-10880, UL1RR025014, P30 DK017047]; University of Washington Diagnostic Imaging Science Center FX We are grateful to the study participants for their contribution and time. This study was supported in part by the VA Office of Research and Development Medical Research Service, grant no. R37 AG-10880, UL1RR025014, P30 DK017047 and the University of Washington Diagnostic Imaging Science Center. The funding agencies had no role in the design, implementation, analysis or interpretation of the data. The authors' responsibilities were as follows: K. M. U. designed the MRS sub-study, analysed the data and wrote the manuscript; J. L. B.-C. designed the diet interventions; M. D. A. and J. M. T. coordinated the study and data entry; T. L. R. designed the MRS protocol and interpreted the scans; S. C. designed the parent study and assisted with the data analysis. All authors read and approved the final manuscript. None of the authors had a conflict of interest to disclose. NR 53 TC 20 Z9 20 U1 1 U2 11 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 J9 BRIT J NUTR JI Br. J. Nutr. PD MAR 28 PY 2013 VL 109 IS 6 BP 1096 EP 1104 DI 10.1017/S0007114512002966 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 107GE UT WOS:000316202300015 PM 22849970 ER PT J AU Kettl, P AF Kettl, Paul TI The NRA Let Me Down SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 Philadelphia VA Med Ctr, Philadelphia, PA USA. RP Kettl, P (reprint author), Philadelphia VA Med Ctr, Philadelphia, PA USA. EM paul.kettl@va.gov NR 2 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 27 PY 2013 VL 309 IS 12 BP 1239 EP 1240 DI 10.1001/jama.2013.1302 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 112WO UT WOS:000316625200023 PM 23532239 ER PT J AU Redfield, MM Chen, HH Borlaug, BA Semigran, MJ Lee, KL Lewis, G LeWinter, MM Rouleau, JL Bull, DA Mann, DL Deswal, A Stevenson, LW Givertz, MM Ofili, EO O'Connor, CM Felker, GM Goldsmith, SR Bart, BA McNulty, SE Ibarra, JC Lin, G Oh, JK Patel, MR Kim, RJ Tracy, RP Velazquez, EJ Anstrom, KJ Hernandez, AF Mascette, AM Braunwald, E AF Redfield, Margaret M. Chen, Horng H. Borlaug, Barry A. Semigran, Marc J. Lee, Kerry L. Lewis, Gregory LeWinter, Martin M. Rouleau, Jean L. Bull, David A. Mann, Douglas L. Deswal, Anita Stevenson, Lynne W. Givertz, Michael M. Ofili, Elizabeth O. O'Connor, Christopher M. Felker, G. Michael Goldsmith, Steven R. Bart, Bradley A. McNulty, Steven E. Ibarra, Jenny C. Lin, Grace Oh, Jae K. Patel, Manesh R. Kim, Raymond J. Tracy, Russell P. Velazquez, Eric J. Anstrom, Kevin J. Hernandez, Adrian F. Mascette, Alice M. Braunwald, Eugene CA RELAX Trial TI Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PULMONARY-HYPERTENSION; RIGHT VENTRICLE; OXYGEN-UPTAKE; SILDENAFIL; DYSFUNCTION; PREVENTS; 1-YEAR; RATS; HEMODYNAMICS; ASSOCIATION AB Importance Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF). Objective To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF. Design Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction >= 50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012. Interventions Sildenafil (n=113) or placebo (n=103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. Main Outcome Measures Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. Results Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m(2)), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P=.90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P=.85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P=.92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). Conclusion and Relevance Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status. Trial Registration clinicaltrials.gov Identifier: NCT00763867 JAMA. 2013; 309(12): 1268-1277 Published online March 11, 2013. doi: 10.1001/jama.2013.2024 www.jama.com C1 [Redfield, Margaret M.; Chen, Horng H.; Borlaug, Barry A.; Lin, Grace; Oh, Jae K.] Mayo Clin, Dept Med, Rochester, MN 55905 USA. [Semigran, Marc J.; Lewis, Gregory] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lee, Kerry L.; Anstrom, Kevin J.] Duke Clin Res Inst, Dept Biostat & Bioinformat, Durham, NC USA. [Velazquez, Eric J.; Hernandez, Adrian F.] Duke Clin Res Inst, Dept Med, Durham, NC USA. [McNulty, Steven E.] Duke Clin Res Inst, Dept Stat, Durham, NC USA. [Ibarra, Jenny C.] Duke Clin Res Inst, Dept Project Management, Durham, NC USA. [LeWinter, Martin M.] Univ Vermont, Dept Med, Burlington, VT 05405 USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol & Biochem, Burlington, VT 05405 USA. [Rouleau, Jean L.] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Rouleau, Jean L.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Bull, David A.] Univ Utah, Dept Surg, Salt Lake City, UT USA. [Mann, Douglas L.] Barnes Jewish Hosp, Dept Med, St Louis, MO 63110 USA. [Deswal, Anita] Michael E DeBakey VA Med Ctr, Dept Med, Houston, TX USA. [Deswal, Anita] Baylor Coll Med, Houston, TX 77030 USA. [Stevenson, Lynne W.; Givertz, Michael M.; Braunwald, Eugene] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Ofili, Elizabeth O.] Morehouse Sch Med, Dept Med, Atlanta, GA 30310 USA. [O'Connor, Christopher M.; Felker, G. Michael; Patel, Manesh R.; Kim, Raymond J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Kim, Raymond J.] Duke Univ, Med Ctr, Duke Cardiovasc Magnet Resonance Ctr, Durham, NC USA. Duke Heart Ctr, Durham, NC USA. [Goldsmith, Steven R.; Bart, Bradley A.] Hennepin Cty Med Ctr, Dept Med, Minneapolis, MN 55415 USA. [Mascette, Alice M.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Redfield, MM (reprint author), Mayo Clin, Div Cardiovasc Dis, 200 1st St SW,Guggenheim 9, Rochester, MN 55905 USA. EM redfield.margaret@mayo.edu RI Hernandez, Adrian F./A-7818-2016; OI Hernandez, Adrian F./0000-0003-3387-9616; Mann, Douglas /0000-0002-2516-0145 FU National Institutes of Health (NIH); Medscape; Medscape, Amgen; GlaxoSmithKline; Atcor Medical and Gilead; National Heart, Lung, and Blood Institute; National Institute on Minority Health and Health Disparities; Roche Diagnostics; Amgen; Novartis; Ikaria; Acetlion Pharma; Heartware; ResMed; Pozen; GE Healthcare; Johnson Johnson; Gilead; Critical Diagnostics; BG Medicine; Otsuka; Astellas; Novella; Novella, Cytokinetics; Capricor; Singulex; Bristol-Myers Squibb; Amylin; National Heart, Lung, and Blood Institute [U10HL084904, U10HL084861, U10HL084875, U10HL084877, U10HL084889, U10HL084890, U10HL084891, U10HL084899, U10HL084907, U10HL084931]; National Center for Advancing Translational Sciences [UL1TR000454]; National Institute on Minority Health and Health Disparities [8 U54 MD007588] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Redfield reported receiving financial support from the National Institutes of Health (NIH) and royalties from Annexon. Dr Chen reported receiving funding for patents that his institution has licensed to Nile Therapeutics and Annexon with other patents pending at the US Patent and Trademark Office. He also reported that he has royalties with Nile Therapeutics, Annexon, and Up To Date. Dr Borlaug reported receiving consulting fees from Medscape, Amgen, and GlaxoSmithKline and receiving financial support from Atcor Medical and Gilead. Dr Semigran reported receiving financial support from the NIH for participation in the Heart Failure Network and from Bayer. Dr Lee reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr LeWinter reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Bull reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Deswal reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Stevenson reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Givertz reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Ofili reported receiving financial support from the NIH, receiving consulting fees from Merck, Novartis, and Arbor Pharmaceuticals and lecture fees from Arbor Pharmaceuticals. She is currently employed by the Morehouse School of Medicine and has grants pending from the National Heart, Lung, and Blood Institute and National Institute on Minority Health and Health Disparities. DrO'Connor reported receiving consulting fees from Roche Diagnostics, Amgen, Novartis, Ikaria, Acetlion Pharma, Heartware, ResMed, Pozen, GE Healthcare, Johnson & Johnson, Gilead, Critical Diagnostics, BG Medicine, Otsuka, Astellas, Novella, Cytokinetics, and Capricor; holding stock options with Neurotronik/Interventional Autonomics Corporation; editing American College of Cardiology; and coowning Cardiology Consulting Associates. Dr Felker reported receiving financial support from the NIH; consulting fees from Novartis, Amgen, Trevena, Roche Diagnostics, Merck, Singulex, and BG Medicine; and funding from Amgen, Otsuka, and Roche Diagnostics. Dr Bart reported receiving financial support from the NIH for participation in the Heart Failure Network. Ms Ibarra reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Oh received financial support from the NIH for the Echo Core Lab. Dr Patel has received consulting fees from Genzyme, Baxter, Jensen, and Bayer, and his financial institution receives financial support from AstraZeneca, Johnson & Johnson, and Maquet. Dr Kim reported receiving financial support from the NIH as the Heart Failure Network Data Coordinating Center and MRI Core Lab, and funding for a patent with Northwestern University. His institution has received a grant from Siemens. Dr Tracy reported receiving financial support from the NIH for participation in the Heart Failure Network, and consulting fees fromMerck, Tibotec-Johnson & Johnson, and Abbott. He has also given expert testimony about biomarkers in blood clotting and is the owner of Haematologic Technologies. Dr Velazquez reported receiving financial support from the NIH for participation in the Heart Failure Network.; Dr Anstrom reported receiving financial support from the NIH for participation in the Heart Failure Network. Dr Hernandez reported receiving financial support from the NIH for participation in the Heart Failure Network and consulting fees from AstraZeneca, Corthera, Janseen, and Bristol-Myers Squibb. His institution has received funding from Amylin, Johnson & Johnson, and Bristol-Myers Squibb. Dr Braunwald reported receiving consulting fees from Merck, Daiichi Sankyo, Genzyme, Amorcyte, Medicines Co, MC Communications, Ikaria, CardioRentis, sanofiaventis; funding (or pending funding) from AstraZeneca, Johnson & Johnson, Merck, sanofi-aventis, Daiichi Sankyo, GlaxoSmithKline, Bristol-Myers Squibb, Beckman Coulter, Roche Diagnostics, and Pfizer; compensation for lectures for Eli Lilly, Merck, CVRx (no compensation), CV Therapeutics (now Gilead), Daiichi Sankyo, MC Communications, Manarini International, Medscape, and Bayer; and payment for devel-opment of educational presentations from MC Communications. No other disclosures were reported.; This work was supported by grants U10HL084904 (for the data coordinating center), and U10HL084861, U10HL084875, U10HL084877, U10HL084889, U10HL084890, U10HL084891, U10HL084899, U10HL084907, and U10HL084931 (for the clinical centers) from the National Heart, Lung, and Blood Institute. This work is also supported by grant UL1TR000454 from the National Center for Advancing Translational Sciences and grant 8 U54 MD007588 from the National Institute on Minority Health and Health Disparities. Pfizer provided study drug (sildenafil and matched placebo). NR 31 TC 305 Z9 313 U1 5 U2 36 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 27 PY 2013 VL 309 IS 12 BP 1268 EP 1277 DI 10.1001/jama.2013.2024 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 112WO UT WOS:000316625200027 PM 23478662 ER PT J AU Maison, SF Usubuchi, H Liberman, MC AF Maison, Stephane F. Usubuchi, Hajime Liberman, M. Charles TI Efferent Feedback Minimizes Cochlear Neuropathy from Moderate Noise Exposure SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CROSSED OLIVOCOCHLEAR BUNDLE; AUDITORY-NERVE FIBERS; ELECTRICAL-STIMULATION; MAMMALIAN COCHLEA; ACOUSTIC INJURY; CELL SYNAPSES; BRAIN-STEM; CAT; RESPONSES; MOUSE AB Although protective effects of the cochlea's efferent feedback pathways have been well documented, prior work has focused on hair cell damage and cochlear threshold elevation and, correspondingly, on the high sound pressure levels (>100 dB SPL) necessary to produce them. Here we explore the noise-induced loss of cochlear neurons that occurs with lower-intensity exposures and in the absence of permanent threshold shifts. Using confocal microscopy to count synapses between hair cells and cochlear nerve fibers, and using measurement of auditory brainstem responses and otoacoustic emissions to assess cochlear presynaptic and postsynaptic function, we compare the damage from a weeklong exposure to moderate-level noise (84 dB SPL) in mice with varying degrees of cochlear de-efferentation induced by surgical lesion to the olivocochlear pathway. Such exposure causes minimal acute threshold shifts and no chronic shifts in mice with normal efferent feedback. In de-efferented animals, there was up to 40% loss of cochlear nerve synapses and a corresponding decline in the amplitude of the auditory brainstem response. Quantitative analysis of the de-efferentation in inner versus outer hair cell areas suggested that outer hair cell efferents are the most important in minimizing this neuropathy, presumably by virtue of their sound-evoked feedback reduction of cochlear amplification. The moderate nature of this acoustic overexposure suggests that cochlear neurons are at risk even in everyday acoustic environments, so the need for cochlear protection is plausible as a driving force in the design of this feedback pathway. C1 [Maison, Stephane F.; Usubuchi, Hajime; Liberman, M. Charles] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Maison, Stephane F.; Usubuchi, Hajime; Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Maison, Stephane F.; Liberman, M. Charles] Harvard Program Speech & Hearing Biosci & Technol, Boston, MA 02114 USA. RP Maison, SF (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM stephane_maison@meei.harvard.edu FU National Institute on Deafness and Other Communication Disorders [R01 DC 0188, P30 DC 05209] FX This work was supported by the National Institute on Deafness and Other Communication Disorders (Grants R01 DC 0188 and P30 DC 05209). We thank Leslie Liberman for flawless technical support in the preparation and immunostaining of cochlear whole mounts. NR 50 TC 55 Z9 55 U1 0 U2 14 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 MAR 27 PY 2013 VL 33 IS 13 BP 5542 EP 5552 DI 10.1523/JNEUROSCI.5027-12.2013 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 117JD UT WOS:000316948600012 PM 23536069 ER PT J AU Foerde, K Race, E Verfaellie, M Shohamy, D AF Foerde, Karin Race, Elizabeth Verfaellie, Mieke Shohamy, Daphna TI A Role for the Medial Temporal Lobe in Feedback-Driven Learning: Evidence from Amnesia SO JOURNAL OF NEUROSCIENCE LA English DT Article ID FREE-OPERANT ACQUISITION; MULTIPLE MEMORY-SYSTEMS; SHORT-TERM-MEMORY; DELAYED REINFORCEMENT; DOPAMINE NEURONS; HUMAN BRAIN; WORKING-MEMORY; PARKINSONS-DISEASE; RELATIONAL MEMORY; REWARD AB The ability to learn from feedback is a key component of adaptive behavior. This type of learning is traditionally thought to depend on neural substrates in the striatum and not on the medial temporal lobe (MTL). Here we show that in humans the MTL becomes necessary for feedback-based learning when feedback is delayed. Specifically, amnesic patients with MTL damage were impaired at probabilistic learning of cue-outcome associations when response-contingent feedback was delayed by a few seconds, but not when feedback was immediate. By contrast, patients with striatal dysfunction due to Parkinson's disease demonstrated the opposite pattern: impaired learning when trial-by-trial feedback was immediate but not when feedback was delayed, indicating that the striatum is necessary for learning only when feedback is immediate. Together, these results reveal that multiple complementary learning processes support what appears to be identical behavior in healthy individuals and point to an important role for the MTL in feedback-driven learning. C1 [Foerde, Karin; Shohamy, Daphna] Columbia Univ, Dept Psychol, New York, NY 10027 USA. [Race, Elizabeth; Verfaellie, Mieke] VA Boston Healthcare Syst, Memory Disorders Res Ctr, Boston, MA 02118 USA. [Race, Elizabeth; Verfaellie, Mieke] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Foerde, K (reprint author), Schermerhorn Hall 312,1190 Amsterdam Ave,MC 5501, New York, NY 10027 USA. EM kf2265@columbia.edu; ds2619@columbia.edu OI Verfaellie, Mieke/0000-0001-5535-4584; Foerde, Karin/0000-0002-5804-9312 FU NIH [NIDA 1R03DA026957, NINDS NRSA 5F32NS063632, F32NS073212]; NSF Career Development Award; Clinical Science Research and Development Service of the Department of Veterans Affairs FX This work was supported by the NIH (NIDA 1R03DA026957 to D. S., NINDS NRSA 5F32NS063632 to K. F., and F32NS073212 to E. R.), an NSF Career Development Award to D. S., and the Clinical Science Research and Development Service of the Department of Veterans Affairs. We are grateful to Dr. Lucien Cote for recruitment of participants with Parkinson's disease and to Erin Kendall Braun for assistance with data collection. NR 67 TC 24 Z9 24 U1 1 U2 16 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 MAR 27 PY 2013 VL 33 IS 13 BP 5698 EP 5704 DI 10.1523/JNEUROSCI.5217-12.2013 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 117JD UT WOS:000316948600026 PM 23536083 ER PT J AU Loving, GS Mukherjee, S Caravan, P AF Loving, Galen S. Mukherjee, Shreya Caravan, Peter TI Redox-Activated Manganese-Based MR Contrast Agent SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MAGNETIC-RESONANCE; THIOL/DISULFIDE REDOX; TUMOR HYPOXIA; COMPLEXES; CELL; STATE; METABOLISM; BINDING; THIOLS; CANCER AB Here we report a simple Mn coordination complex with utility as a redox-sensitive MR probe. The HBET ligand stabilizes both the Mn2+ and Mn3+ oxidation states. In the presence of glutathione (GSH), low relaxivity Mn-III-HBET is converted to high relaxivity Mn-II-HBET with a 3-fold increase in relaxivity, and concomitant increase in MR signal. Alternately, hydrogen peroxide can convert Mn-II-HBET to Mn-III-HBET with a reduction in MR signal. C1 [Loving, Galen S.; Mukherjee, Shreya; Caravan, Peter] Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Caravan, P (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM caravan@nmr.mgh.harvard.edu FU National Cancer Institute [CA161221, CA009502]; National Center for Research Resources [RR14075] FX Dr. Anna Moore is gratefully acknowledged for providing access to a spectrophotometer. This work was supported by grants from the National Cancer Institute (CA161221 to PC and a T32 post-doctoral fellowship to GSL, CA009502) and instrumentation funded by the National Center for Research Resources (RR14075). NR 34 TC 45 Z9 45 U1 4 U2 81 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 MAR 27 PY 2013 VL 135 IS 12 BP 4620 EP 4623 DI 10.1021/ja312610j PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 118NK UT WOS:000317032000012 PM 23510406 ER PT J AU Liou, AP Paziuk, M Luevano, JM Machineni, S Turnbaugh, PJ Kaplan, LM AF Liou, Alice P. Paziuk, Melissa Luevano, Jesus-Mario, Jr. Machineni, Sriram Turnbaugh, Peter J. Kaplan, Lee M. TI Conserved Shifts in the Gut Microbiota Due to Gastric Bypass Reduce Host Weight and Adiposity SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID DIET-INDUCED OBESITY; CHAIN FATTY-ACIDS; PROTEIN-COUPLED RECEPTOR; ENERGY-EXPENDITURE; GASTROINTESTINAL-TRACT; SURGERY; MECHANISMS; MOUSE; MICE; DIVERSITY AB Roux-en-Y gastric bypass (RYGB) results in rapid weight loss, reduced adiposity, and improved glucose metabolism. These effects are not simply attributable to decreased caloric intake or absorption, but the mechanisms linking rearrangement of the gastrointestinal tract to these metabolic outcomes are largely unknown. Studies in humans and rats have shown that RYGB restructures the gut microbiota, prompting the hypothesis that some of the effects of RYGB are caused by altered host-microbial interactions. To test this hypothesis, we used a mouse model of RYGB that recapitulates many of the metabolic outcomes in humans. 16S ribosomal RNA gene sequencing of murine fecal samples collected after RYGB surgery, sham surgery, or sham surgery coupled to caloric restriction revealed that alterations to the gut microbiota after RYGB are conserved among humans, rats, and mice, resulting in a rapid and sustained increase in the relative abundance of Gammaproteobacteria (Escherichia) and Verrucomicrobia (Akkermansia). These changes were independent of weight change and caloric restriction, were detectable throughout the length of the gastrointestinal tract, and were most evident in the distal gut, downstream of the surgical manipulation site. Transfer of the gut microbiota from RYGB-treated mice to nonoperated, germ-free mice resulted in weight loss and decreased fat mass in the recipient animals relative to recipients of microbiota induced by sham surgery, potentially due to altered microbial production of short-chain fatty acids. These findings provide the first empirical support for the claim that changes in the gut microbiota contribute to reduced host weight and adiposity after RYGB surgery. C1 [Liou, Alice P.; Paziuk, Melissa; Machineni, Sriram; Kaplan, Lee M.] Massachusetts Gen Hosp, Obes Metab & Nutr Inst, Boston, MA 02114 USA. [Liou, Alice P.; Paziuk, Melissa; Machineni, Sriram; Kaplan, Lee M.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Luevano, Jesus-Mario, Jr.; Turnbaugh, Peter J.] Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA. RP Turnbaugh, PJ (reprint author), Harvard Univ, FAS Ctr Syst Biol, Cambridge, MA 02138 USA. EM pturnbaugh@fas.harvard.edu; LMKaplan@partners.org RI Biguzzi, Felipe/E-4724-2015; OI Turnbaugh, Peter/0000-0002-0888-2875 FU NIH [DK088661, P50 GM068763, F32 DK095561, P30DK034854]; Ethicon Surgical Care FX NIH DK088661 (L. M. K.), NIH P50 GM068763 (P.J.T.), F32 DK095561 (A. P. L.), P30DK034854 (Harvard Digestive Diseases Center), and Ethicon Surgical Care (L.M.K.). NR 56 TC 119 Z9 126 U1 7 U2 73 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAR 27 PY 2013 VL 5 IS 178 AR 178ra41 DI 10.1126/scitranslmed.3005687 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 115EL UT WOS:000316795300005 PM 23536013 ER PT J AU Luiz, CR Machado, CM Canto, CLM Christ, SCC Pestana, JOM Kotton, CN Camargo, LFA AF Luiz, Claudia R. Machado, Clarisse M. Canto, Cynthia L. M. Christ, Silvia C. C. Pestana, Jose O. M. Kotton, Camille N. Camargo, Luis F. A. TI Monitoring for HHV-6 Infection After Renal Transplantation: Evaluation of Risk Factors for Sustained Viral Replication SO TRANSPLANTATION LA English DT Article DE Human herpesvirus 6 (HHV-6); Renal transplantation; PCR; Active viral infection; Sustained viral replication ID HUMAN-HERPESVIRUS 6; STEM-CELL TRANSPLANTATION; HUMAN-HERPESVIRUS-6 DNA; LIVER-TRANSPLANTATION; RECIPIENTS; PCR; ENCEPHALITIS; BLOOD; PATHOGENESIS; DISEASE AB Background. Human herpesvirus-6 (HHV-6) is known to reactivate after renal transplantation and has been associated with several clinical manifestations. Risk factors for sustained viral replication, however, remain unclear. Methods. Thirty consecutive kidney transplant patients were prospectively followed for HHV-6 replication between February 2007 and February 2008. Plasma samples for DNA detection were collected from the donor and the recipient before transplantation and from the recipient weekly for the first 2 months after transplantation and then every 2 weeks for 2 additional months. HHV-6 active infection was defined as detection of viral DNA in plasma, by polymerase chain reaction, in at least two consecutive samples over an interval of at least 1 week. Results. Active viral infection was detected in 25% of the recipients before transplantation and 27% (8 of 30) of the patients after transplantation. The mean time to onset of viral replication was 28.1 days after transplantation and 7 of 8 (87.5%) were asymptomatic. Risk factors associated with active HHV-6 infection were receiving an organ from a living donor (P=0.028), recipients with IgM antibodies detected before transplantation (P=0.005), and pretransplantation recipient HHV-6 viral load more than 10,000 copies/mL plasma (P=0.034). Conclusions. Active HHV-6 infection occurs early after renal transplantation and is mostly asymptomatic. Donor or recipient infection may occur at the time of transplantation and are related to higher rates of posttransplantation infections. C1 [Luiz, Claudia R.; Camargo, Luis F. A.] Univ Fed Sao Paulo UNIFESP, Dept Infect Dis, BR-05685090 Sao Paulo, Brazil. [Machado, Clarisse M.; Canto, Cynthia L. M.] Univ Sao Paulo, Inst Med Trop Sao Paulo, Virol Lab, Sao Paulo, Brazil. [Christ, Silvia C. C.] Univ Fed Sao Paulo, Dept Infect Dis, Sao Paulo, Brazil. [Pestana, Jose O. M.] Univ Fed Sao Paulo UNIFESP, Dept Med, Div Nephrol, BR-05685090 Sao Paulo, Brazil. [Kotton, Camille N.] Massachusetts Gen Hosp, Div Infect Dis, Transplant Infect Dis & Compromised Host Serv, Boston, MA 02114 USA. RP Camargo, LFA (reprint author), Univ Fed Sao Paulo UNIFESP, Dept Infect Dis, Rua Barao Santa Eulalia 170 Ap 21, BR-05685090 Sao Paulo, Brazil. EM Luis_camargo@einstein.br FU FAPESP FX This work was supported by a grant from FAPESP. NR 31 TC 2 Z9 2 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAR 27 PY 2013 VL 95 IS 6 BP 842 EP 846 DI 10.1097/TP.0b013e3182807ab7 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 109CO UT WOS:000316343000017 PM 23354300 ER PT J AU Wilson, LB Rojas, DC Shatti, S Tregellas, JR AF Wilson, Lisa B. Rojas, Donald C. Shatti, Shireen Tregellas, Jason R. TI Greater neuronal responses during automatic semantic processing in schizophrenia SO NEUROREPORT LA English DT Article DE functional magnetic resonance imaging; fusiform gyrus; schizophrenia; semantic priming; superior temporal gyrus ID MRC PSYCHOLINGUISTIC DATABASE; ACTIVATION; BRAIN AB A core feature of schizophrenia is a disturbance of associative processes. To date, no functional MRI studies have investigated semantic priming in schizophrenia under experimental conditions that measure automatic, as opposed to strategic, processing. The present study's focus was to investigate hemodynamic responses during indirect semantic priming at a short stimulus onset asynchrony (i.e. 350 ms), conditions which are considered to be a particularly sensitive measure of automatic spreading activation during semantic processing and of the associative disturbances in schizophrenia. Seventeen individuals with DSM-IV, schizophrenia and 15 comparison participants underwent functional scanning while performing a lexical decision task on directly related, indirectly related, unrelated, and word/nonword pairs. A random-effects region of interest analysis within a priori temporal and frontal regions was performed. Whereas comparison individuals exhibited hemodynamic suppression in response to priming, individuals with schizophrenia exhibited hemodynamic enhancement. Relative to the comparison group, these enhancements were observed in the left fusiform and superior temporal gyri for indirectly related word pairs relative to unrelated pairs. Greater priming-related responses within temporal regions may reflect increased and prolonged automatic spreading activation during semantic processing in schizophrenia. NeuroReport 24:212-216 (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Wilson, Lisa B.; Rojas, Donald C.; Shatti, Shireen; Tregellas, Jason R.] Univ Colorado Denver, Dept Psychiat, Aurora, CO 80045 USA. [Tregellas, Jason R.] Denver VA Med Ctr, Res Serv, Denver, CO USA. RP Wilson, LB (reprint author), Univ Colorado Denver, Dept Psychiat, 13001 East 17th Pl, Aurora, CO 80045 USA. EM lisa.wilson@ucdenver.edu RI Tregellas, Jason/J-3637-2015; OI Rojas, Don/0000-0001-6560-9616 FU National Institute of Mental Health (NIMH) [MH60214]; National Institute of Child Health and Human Development (NICHHD) [HD041697]; Brain and Behavior Research Foundation; Blowitz-Ridgeway Foundation FX Funding for this study was provided by the National Institute of Mental Health (NIMH) Grant MH60214, the National Institute of Child Health and Human Development (NICHHD) Grant HD041697 the Brain and Behavior Research Foundation and the Blowitz-Ridgeway Foundation. NR 24 TC 4 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD MAR 27 PY 2013 VL 24 IS 5 BP 212 EP 216 DI 10.1097/WNR.0b013e32835eb688 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 103VD UT WOS:000315946700002 PM 23399997 ER PT J AU Cornes, BK Brody, J Morrison, AC Siscovick, D Meigs, JB AF Cornes, Belinda K. Brody, Jennifer Morrison, Alanna C. Siscovick, David Meigs, James B. CA CHARGE-S Diabet WG TI Rare Variants in and Near IRS1 are Associated with Fasting Insulin in CHARGE-S Cohorts SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Diabetes mellitus; Genetics; Insulin C1 [Cornes, Belinda K.; Meigs, James B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Brody, Jennifer; Siscovick, David] Univ Washington, Seattle, WA 98195 USA. [Morrison, Alanna C.] Univ Texas Hlth Sci Cntr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P054 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100195 ER PT J AU Lopez, L Porneala, B deLemos, JA Ayers, CR Albert, MA AF Lopez, Lenny Porneala, Bianca deLemos, James A. Ayers, Colby R. Albert, Michelle A. TI Perceived Discrimination and Subclinical Atherosclerosis in the Dallas Heart Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Atherosclerosis; Racial/ethnic disparities; Coronary artery disease C1 [Lopez, Lenny; Porneala, Bianca] Massachusetts Gen Hosp, Boston, MA 02114 USA. [deLemos, James A.; Ayers, Colby R.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Albert, Michelle A.] Howard Univ, Washington, DC 20059 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P237 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100357 ER PT J AU Lopez, L Marceau, L Piccolo, R Liu, G Vassy, J Grant, R Meigs, JB McKinlay, J AF Lopez, Lenny Marceau, Lisa Piccolo, Rebecca Liu, Gretchen Vassy, Jason Grant, Richard Meigs, James B. McKinlay, John TI Impact of Acculturation and Health Literacy on Prevalent Fasting Glycemia Among Latinos: Results From the Boston Area Community Health (BACH) Survey SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Diabetes mellitus; Racial/ethnic disparities C1 [Lopez, Lenny; Vassy, Jason; Meigs, James B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Marceau, Lisa; Piccolo, Rebecca; Liu, Gretchen; McKinlay, John] New England Rsch Inst, Watertown, MA USA. [Grant, Richard] Kaiser Permanente, Oakland, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P236 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100356 ER PT J AU McMahon, GM O'Seaghdha, CM Hwang, SJ Meigs, JB Fox, CS AF McMahon, Gearoid M. O'Seaghdha, Conall M. Hwang, Shih-Jen Meigs, James B. Fox, Caroline S. TI The Association of the CUBN Polymorphism rs1801239 and the Association of Albuminuria and Cardiovascular Disease in the Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Cardiovascular disease; Risk factors; Renal function C1 [McMahon, Gearoid M.; O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [McMahon, Gearoid M.; O'Seaghdha, Conall M.; Hwang, Shih-Jen; Fox, Caroline S.] Cntr Populat Studies, Framingham, MA USA. [Meigs, James B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P309 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100428 ER PT J AU Miedema, MD Petrone, A Pankow, J Hunt, SC Kraja, AT Arnett, DK Gaziano, JM Djousse, L AF Miedema, Michael D. Petrone, Andrew Pankow, James Hunt, Steven C. Kraja, Aldi T. Arnett, Donna K. Gaziano, J. Michael Djousse, Luc TI Adult Height and Coronary Artery Calcium in the NHLBI Family Heart Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Subclinical atherosclerosis C1 [Miedema, Michael D.; Gaziano, J. Michael; Djousse, Luc] VA Boston Healthcare Syst, Boston, MA USA. [Petrone, Andrew] Brigham & Womens Hosp, Boston, MA 02115 USA. [Pankow, James] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Hunt, Steven C.] Univ Utah, Salt Lake City, UT USA. [Kraja, Aldi T.] Washington Univ, Div Stat Genom, St Louis, MO USA. [Arnett, Donna K.] Univ Alabama Birmingham, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P386 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100504 ER PT J AU Rodriguez, F Meigs, JB Porneala, B Lopez, L AF Rodriguez, Fatima Meigs, James B. Porneala, Bianca Lopez, Lenny TI The Impact of Acculturation on Hyperglycemia and Cardio-Metabolic Risk Factors among Hispanic Adults: Results from the National and Nutrition Examination Survey 1999-2008 SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Diabetes mellitus; Obesity C1 [Rodriguez, Fatima; Meigs, James B.; Porneala, Bianca; Lopez, Lenny] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P232 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100352 ER PT J AU Rosenquist, KJ Massaro, JM Krieger, BE Murabito, JM Hoffmann, U Fox, CS AF Rosenquist, Klara J. Massaro, Joseph M. Krieger, Bernard E. Murabito, Joanne M. Hoffmann, Udo Fox, Caroline S. TI Fat Quality Estimated by Computed Tomography and Associations with Incident Cardiovascular Disease and All Cause Mortality SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Obesity; Outcomes C1 [Rosenquist, Klara J.] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Rosenquist, Klara J.] Harvard Univ, Sch Med, Boston, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Krieger, Bernard E.; Murabito, Joanne M.] Boston Med Cntr, Gen Internal Med Sect, Boston, MA USA. [Krieger, Bernard E.; Murabito, Joanne M.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] NHLBI, Div Intra Mural Rsch, Framingham, MA USA. [Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP63 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100111 ER PT J AU Suchindran, S Regan, S Meigs, JB Grinspoon, SK Triant, VA AF Suchindran, Sujit Regan, Susan Meigs, James B. Grinspoon, Steven K. Triant, Virginia A. TI Aspirin Use and Myocardial Infarction in HIV versus Non-HIV Patients SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Aspirin; Myocardial infarction; Viruses C1 [Suchindran, Sujit; Regan, Susan; Meigs, James B.; Grinspoon, Steven K.; Triant, Virginia A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA 030 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100028 ER PT J AU Thorndike, AN Riis, J Sonnenberg, L Levy, DE AF Thorndike, Anne N. Riis, Jason Sonnenberg, Lillian Levy, Douglas E. TI Long-term Effectiveness of a Color-coded Food Labeling Intervention in Promoting Healthy Choices SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Nutrition; Public health; Obesity C1 [Thorndike, Anne N.; Sonnenberg, Lillian; Levy, Douglas E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Riis, Jason] Harvard Univ, Sch Business, Boston, MA 02163 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA 060 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100052 ER PT J AU Tsao, CW Pencina, K Massaro, JM Levy, D Vasan, RS Hoffmann, U O'Donnell, CJ Mitchell, GF AF Tsao, Connie W. Pencina, Karol Massaro, Joseph M. Levy, Daniel Vasan, Ramachandran S. Hoffmann, Udo O'Donnell, Christopher J. Mitchell, Gary F. TI Relations of Subclinical Measures of Arterial Stiffness and Pulsatility with Arterial Calcification in Men and Women SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Aortic diseases; Calcification; Subclinical atherosclerosis C1 [Tsao, Connie W.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Tsao, Connie W.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Boston, MA USA. [Tsao, Connie W.] Beth Israel Deaconess Med Ctr, Framingham, MA USA. [Tsao, Connie W.; Levy, Daniel; Vasan, Ramachandran S.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Pencina, Karol; Massaro, Joseph M.; Vasan, Ramachandran S.] Boston Univ, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Framingham, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc F, Norwood, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P381 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100499 ER PT J AU Vassy, JL Porneala, B Florez, JC Dupuis, J Meigs, JB AF Vassy, Jason L. Porneala, Bianca Florez, Jose C. Dupuis, Josee Meigs, James B. TI Type 2 Diabetes Prediction with 17-, 40-, and 62-variant Genotype Risk Scores: The Framingham Offspring Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Diabetes mellitus; Genomics; Risk factors C1 [Vassy, Jason L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Porneala, Bianca; Florez, Jose C.; Meigs, James B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP58 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100106 ER PT J AU Weinberg, I Gona, P O'Donnell, CJ Jaff, MR Murabito, J AF Weinberg, Ido Gona, Philimon O'Donnell, Christopher J. Jaff, Michael R. Murabito, Joanne TI Inter-arm Blood Pressure Difference and Cardiovascular Disease Risk in the Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Subclinical atherosclerosis; Cardiovascular disease; Risk factors C1 [Weinberg, Ido; Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gona, Philimon] Univ Massachusetts, Sch Med, Boston, MA 02125 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Boston, MA USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Murabito, Joanne] Framingham Heart Dis Epidemiol Study, Boston, MA USA. [Murabito, Joanne] Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA P075 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100216 ER PT J AU Xanthakis, V Larson, M Vasan, RS Wollert, KC Januzzi, JL Wang, TJ AF Xanthakis, Vanessa Larson, Martin Vasan, Ramachandran S. Wollert, Kai C. Januzzi, James L. Wang, Thomas J. TI Screening for Left Ventricular Dysfunction and Hypertrophy with Novel Biomarkers of Cardiovascular Stress SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Epidemiology and Prevention/Physical Activity, Nutrition and Metabolism CY MAR 19-22, 2013 CL New Orleans, LA SP Amer Heart Assoc DE Cardiac markers; Cardiovascular disease prevention; Heart failure C1 [Xanthakis, Vanessa; Larson, Martin; Vasan, Ramachandran S.] Boston Univ, Boston, MA 02215 USA. [Wollert, Kai C.] Hans Borst Cntr Heart & Stem Cell Rsch, Hannover, Germany. [Januzzi, James L.; Wang, Thomas J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 SU S MA MP05 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 302HW UT WOS:000330596100057 ER PT J AU Kurra, V Krajewski, KM Jagannathan, J Giardino, A Berlin, S Ramaiya, N AF Kurra, Vikram Krajewski, Katherine M. Jagannathan, Jyothi Giardino, Angela Berlin, Suzanne Ramaiya, Nikhil TI Typical and atypical metastatic sites of recurrent endometrial carcinoma SO CANCER IMAGING LA English DT Review DE Recurrent endometrial carcinoma; oncologic imaging; computed tomography; magnetic resonance imaging; positron emission tomography ID PROGNOSTIC-FACTORS; CANCER; PET/CT AB The purpose of this article is to illustrate the imaging findings of typical and atypical metastatic sites of recurrent endometrial carcinoma. Typical sites include local pelvic recurrence, pelvic and para-aortic nodes, peritoneum, and lungs. Atypical sites include extra-abdominal lymph nodes, liver, adrenals, brain, bones and soft tissue. It is important for radiologists to recognize the typical and atypical sites of metastases in patients with recurrent endometrial carcinoma to facilitate earlier diagnosis and treatment. C1 [Kurra, Vikram; Krajewski, Katherine M.; Jagannathan, Jyothi; Giardino, Angela; Berlin, Suzanne; Ramaiya, Nikhil] Brigham & Womens Hosp, Dept Imaging, Boston, MA 02115 USA. [Krajewski, Katherine M.; Jagannathan, Jyothi; Giardino, Angela; Berlin, Suzanne; Ramaiya, Nikhil] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. RP Kurra, V (reprint author), Brigham & Womens Hosp, Dept Imaging, 75 Francis St, Boston, MA 02115 USA. EM vkurra@partners.org NR 14 TC 5 Z9 5 U1 1 U2 3 PU E-MED PI LONDON PA PO BOX 29761, LONDON, NW3 7ZS, ENGLAND SN 1470-7330 J9 CANCER IMAGING JI Cancer Imaging PD MAR 26 PY 2013 VL 13 IS 1 BP 113 EP 122 DI 10.1102/1470-7330.2013.0011 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 173CY UT WOS:000321056900001 PM 23545091 ER PT J AU Desmet, CJ Gallenne, T Prieur, A Reyal, F Visser, NL Wittner, BS Smit, MA Geiger, TR Laoukili, J Iskit, S Rodenko, B Zwart, W Evers, B Horlings, H Ajouaou, A Zevenhoven, J Van Vliet, M Ramaswamy, S Wessels, LFA Peeper, DS AF Desmet, Christophe J. Gallenne, Tristan Prieur, Alexandre Reyal, Fabien Visser, Nils L. Wittner, Ben S. Smit, Marjon A. Geiger, Thomas R. Laoukili, Jamila Iskit, Sedef Rodenko, Boris Zwart, Wilbert Evers, Bastiaan Horlings, Hugo Ajouaou, Abderrahrim Zevenhoven, John Van Vliet, Martin Ramaswamy, Sridhar Wessels, Lodewyk F. A. Peeper, Daniel S. TI Identification of a pharmacologically tractable Fra-1/ADORA2B axis promoting breast cancer metastasis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE epithelial-mesenchymal transition; invasion ID EPITHELIAL-MESENCHYMAL TRANSITION; NEUROTROPHIC RECEPTOR TRKB; GENE-EXPRESSION PROFILES; ANOIKIS RESISTANCE; TRANSCRIPTION FACTORS; FRA-1 EXPRESSION; THYROID-CELLS; TUMOR-GROWTH; IN-VITRO; TRANSFORMATION AB Metastasis confronts clinicians with two major challenges: estimating the patient's risk of metastasis and identifying therapeutic targets. Because they are key signal integrators connecting cellular processes to clinical outcome, we aimed to identify transcriptional nodes regulating cancer cell metastasis. Using rodent xenograft models that we previously developed, we identified the transcription factor Fos-related antigen-1 (Fra-1) as a key coordinator of metastasis. Because Fra-1 often is overexpressed in human metastatic breast cancers and has been shown to control their invasive potential in vitro, we aimed to assess the implication and prognostic significance of the Fra-1-dependent genetic program in breast cancer metastasis and to identify potential Fra-1-dependent therapeutic targets. In several in vivo assays in mice, we demonstrate that stable RNAi depletion of Fra-1 from human breast cancer cells strongly suppresses their ability to metastasize. These results support a clinically important role for Fra-1 and the genetic program it controls. We show that a Fra-1-dependent gene-expression signature accurately predicts recurrence of breast cancer. Furthermore, a synthetic lethal drug screen revealed that antagonists of the adenosine receptor A(2B) (ADORA2B) are preferentially toxic to breast tumor cells expressing Fra-1. Both RNAi silencing and pharmacologic blockade of ADORA2B inhibited filopodia formation and invasive activity of breast cancer cells and correspondingly reduced tumor outgrowth in the lungs. These data show that Fra-1 activity is causally involved in and is a prognostic indicator of breast cancer metastasis. They suggest that Fra-1 activity predicts responsiveness to inhibition of pharmacologically tractable targets, such as ADORA2B, which may be used for clinical interference of metastatic breast cancer. C1 [Desmet, Christophe J.; Gallenne, Tristan; Prieur, Alexandre; Visser, Nils L.; Smit, Marjon A.; Geiger, Thomas R.; Laoukili, Jamila; Iskit, Sedef; Zevenhoven, John; Peeper, Daniel S.] Netherlands Canc Inst, Dept Mol Oncol, NL-1066 CX Amsterdam, Netherlands. [Reyal, Fabien; Horlings, Hugo; Ajouaou, Abderrahrim] Netherlands Canc Inst, Dept Pathol, NL-1066 CX Amsterdam, Netherlands. [Rodenko, Boris; Van Vliet, Martin] Netherlands Canc Inst, Dept Cell Biol 2, NL-1066 CX Amsterdam, Netherlands. [Zwart, Wilbert] Netherlands Canc Inst, Dept Mol Pathol, NL-1066 CX Amsterdam, Netherlands. [Evers, Bastiaan; Van Vliet, Martin; Wessels, Lodewyk F. A.] Netherlands Canc Inst, Dept Mol Carcinogenesis, NL-1066 CX Amsterdam, Netherlands. [Wittner, Ben S.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Ramaswamy, Sridhar] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Wessels, Lodewyk F. A.] Delft Univ Technol, Fac Elect Engn Math & Comp Sci, NL-2628 CD Delft, Netherlands. RP Peeper, DS (reprint author), Netherlands Canc Inst, Dept Mol Oncol, NL-1066 CX Amsterdam, Netherlands. EM d.peeper@nki.nl RI Rodenko, Boris /E-5492-2010 OI Rodenko, Boris /0000-0001-5223-4296 FU Netherlands Organization for Scientific research; Association for Cancer Research; French Medical Academy; Dutch Cancer Society; European Union; A Sister's Hope FX We thank E. Mesman for histochemical analysis; W. Mooi, R. Sneepers, J.-Y. Song, M. van der Valk, and T. Westphal for help with animal pathology, pathological analysis, and experiments; K. Flach for help with ChIP experiments; S. Greven, H. Grimminck, L. Rijswijk, T. Schrauwers, and M. Voetel for technical assistance with animal experiments; M. Heimerikx, M. Nieuwland, J. de Ronde, D. Sie, and R. Kerkhoven for performing the microarray analyses and for helpful discussions; M. Lopez Yarda for help with statistical analyses; A. Gerard, S. Mertens, J. Collard, and W. Mooi for various reagents and for helpful discussions; S. Douma and A. Rosado for technical assistance; A. Berns, R. Bernards, W. Meuleman, L. van 't Veer, and J. Wesseling for valuable comments and critical reading of the manuscript; and the members of our laboratory and division for helpful suggestions and discussions. A.P. was funded by the Netherlands Organization for Scientific research. F.R. is funded by the Association for Cancer Research and the French Medical Academy. H.H. and A.A. were funded by the Dutch Cancer Society. C.J.D., T.G., and D.S.P. were funded by the Dutch Cancer Society and by grants from the European Union Sixth Framework Programme. T.G., N.L.V., and D.S.P. also received support from A Sister's Hope. NR 48 TC 54 Z9 54 U1 1 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 MAR 26 PY 2013 VL 110 IS 13 BP 5139 EP 5144 DI 10.1073/pnas.1222085110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 131XN UT WOS:000318031900062 PM 23483055 ER PT J AU Robinson, EB Lichtenstein, P Anckarsater, H Happe, F Ronald, A AF Robinson, Elise B. Lichtenstein, Paul Anckarsater, Henrik Happe, Francesca Ronald, Angelica TI Examining and interpreting the female protective effect against autistic behavior SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE epidemiology; genetics; family studies ID RARE DE-NOVO; GENERAL-POPULATION; SPECTRUM DISORDERS; SEX-DIFFERENCES; TELEPHONE INTERVIEW; A-TAC; TRAITS; TWIN; GIRLS; RISK AB Male preponderance in autistic behavioral impairment has been explained in terms of a hypothetical protective effect of female sex, yet little research has tested this hypothesis empirically. If females are protected, they should require greater etiologic load to manifest the same degree of impairment as males. The objective of this analysis was to examine whether greater familial etiologic load was associated with quantitative autistic impairments in females compared with males. Subjects included 3,842 dizygotic twin pairs from the Twins Early Development Study (TEDS) and 6,040 dizygotic twin pairs from the Child and Adolescent Twin Study of Sweden (CATSS). In both samples, we compared sibling autistic traits between female and male probands, who were identified as children scoring in the top 90th and 95th percentiles of the population autistic trait distributions. In both TEDS and CATSS, siblings of female probands above the 90th percentile had significantly more autistic impairments than the siblings of male probands above the 90th percentile. The siblings of female probands above the 90th percentile also had greater categorical recurrence risk in both TEDS and CATSS. Results were similar in probands above the 95th percentile. This finding, replicated across two nationally-representative samples, suggests that female sex protects girls from autistic impairments and that girls may require greater familial etiologic load to manifest the phenotype. It provides empirical support for the hypothesis of a female protective effect against autistic behavior and can be used to inform and interpret future gene finding efforts in autism spectrum disorders. C1 [Robinson, Elise B.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Robinson, Elise B.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Lichtenstein, Paul] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Anckarsater, Henrik] Univ Gothenburg, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, S-40530 Gothenburg, Sweden. [Happe, Francesca; Ronald, Angelica] Kings Coll London, Inst Psychiat, Med Res Council Social Genet & Dev Psychiat Ctr, London SE5 8AF, England. [Ronald, Angelica] Univ London, Ctr Brain & Cognit Dev, Dept Psychol Sci, London WC1E 7HX, England. RP Robinson, EB (reprint author), Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. EM erobinson@atgu.mgh.harvard.edu RI Ronald, Angelica/C-7812-2009; OI Ronald, Angelica/0000-0002-9576-2176; Robinson, Elise/0000-0003-2314-2792; lichtenstein, paul/0000-0003-3037-5287; Happe, Francesca/0000-0001-9226-4000 FU Medical Research Council [G0500079]; Swedish Council for Working Life and Social Research; Swedish Research Council; Training Program in Psychiatric Genetics and Translational Research Grant at the Harvard School of Public Health [T32MH017119] FX We thank the participants of the Twins Early Development Study (TEDS) and Child and Adolescent Twin Study of Sweden for making this research possible as well as Prof. Robert Plomin for use of the TEDS data. TEDS is funded by Medical Research Council Grant G0500079. CATSS is supported in part by the Swedish Council for Working Life and Social Research and the Swedish Research Council. E.B.R. was supported by the Training Program in Psychiatric Genetics and Translational Research Grant T32MH017119 at the Harvard School of Public Health. NR 43 TC 81 Z9 83 U1 3 U2 30 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 MAR 26 PY 2013 VL 110 IS 13 BP 5258 EP 5262 DI 10.1073/pnas.1211070110 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 131XN UT WOS:000318031900082 PM 23431162 ER PT J AU Brizendine, KD Baddley, JW Pappas, PG AF Brizendine, Kyle D. Baddley, John W. Pappas, Peter G. TI Predictors of Mortality and Differences in Clinical Features among Patients with Cryptococcosis According to Immune Status SO PLOS ONE LA English DT Article ID ORGAN TRANSPLANT RECIPIENTS; VIRUS-NEGATIVE PATIENTS; AMPHOTERICIN-B; PULMONARY CRYPTOCOCCOSIS; NEOFORMANS INFECTION; RANDOMIZED-TRIAL; MENINGITIS; FLUCYTOSINE; FLUCONAZOLE; DISEASE AB Introduction: Cryptococcosis is an invasive fungal infection causing substantial morbidity and mortality. Prognostic factors are largely derived from trials conducted prior to the modern era of antifungal and potent combination antiretroviral therapies, immunosuppression, and transplantation. Data describing the clinical features and predictors of mortality in a modern cohort are needed. Methods: We conducted a retrospective cohort study of patients at our institution diagnosed with cryptococcosis from 1996 through 2010. Data included demographics, clinical features, diagnostics, treatment, and outcomes. Results: We identified 302 individuals: 108 (36%) human immunodeficiency virus (HIV)-positive, 84 (28%) organ transplant recipients (OTRs), and 110 (36%) non-HIV, non-transplant (NHNT) patients including 39 with no identifiable immunodeficiency. Mean age was 49 years, 203 (67%) were male and 170 (56%) were white. All-cause mortality at 90 days was 21%. In multivariable logistic regression analyses, cryptococcemia (OR 5.09, 95% CI 2.54-10.22) and baseline opening pressure >25 cmH(2)O (OR 2.93, 95% CI 1.25-6.88) were associated with increased odds of mortality; HIV-positive patients (OR 0.46, 95% CI 0.19-1.16) and OTRs (OR 0.46, 95% CI 0.21-1.05) had lower odds of death compared to NHNT patients. Conclusions: Predictors of mortality from cryptococcosis in the modern period include cryptococcemia, high intracranial pressure, and NHNT status while drug(s) used for induction and historical prognostic factors including organ failure syndromes and hematologic malignancy were not associated with mortality. C1 [Brizendine, Kyle D.] Cleveland Clin, Dept Infect Dis, Cleveland, OH 44106 USA. [Baddley, John W.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Baddley, John W.; Pappas, Peter G.] Univ Alabama Birmingham, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. RP Brizendine, KD (reprint author), Cleveland Clin, Dept Infect Dis, Cleveland, OH 44106 USA. EM brizenk@ccf.org; pappas@uab.edu FU National Institutes of Health [T32AI520699] FX KDB acknowledges National Institutes of Health mentored training grant, T32AI520699. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 35 Z9 36 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 MAR 26 PY 2013 VL 8 IS 3 AR e60431 DI 10.1371/journal.pone.0060431 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 123VE UT WOS:000317418500134 PM 23555970 ER PT J AU Sotnikov, I Veremeyko, T Starossom, SC Barteneva, N Weiner, HL Ponomarev, ED AF Sotnikov, Ilya Veremeyko, Tatyana Starossom, Sarah C. Barteneva, Natalia Weiner, Howard L. Ponomarev, Eugene D. TI Platelets Recognize Brain-Specific Glycolipid Structures, Respond to Neurovascular Damage and Promote Neuroinflammation SO PLOS ONE LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MICROVASCULAR ENDOTHELIAL-CELLS; SIALIC-ACID; MULTIPLE-SCLEROSIS; ALZHEIMER-DISEASE; PERTUSSIS TOXIN; ISCHEMIC-STROKE; SPINAL-CORD; GANGLIOSIDES; BLOOD AB Platelets respond to vascular damage and contribute to inflammation, but their role in the neurodegenerative diseases is unknown. We found that the systemic administration of brain lipid rafts induced a massive platelet activation and degranulation resulting in a life-threatening anaphylactic-like response in mice. Platelets were engaged by the sialated glycosphingolipids (gangliosides) integrated in the rigid structures of astroglial and neuronal lipid rafts. The brain-abundant gangliosides GT1b and GQ1b were specifically recognized by the platelets and this recognition involved multiple receptors with P-selectin (CD62P) playing the central role. During the neuroinflammation, platelets accumulated in the central nervous system parenchyma, acquired an activated phenotype and secreted proinflammatory factors, thereby triggering immune response cascades. This study determines a new role of platelets which directly recognize a neuronal damage and communicate with the cells of the immune system in the pathogenesis of neurodegenerative diseases. C1 [Sotnikov, Ilya; Veremeyko, Tatyana; Starossom, Sarah C.; Weiner, Howard L.; Ponomarev, Eugene D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. [Sotnikov, Ilya] Emory Univ, Sch Med, Div Neonatal Perinatal Med, Atlanta, GA USA. [Barteneva, Natalia] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. [Ponomarev, Eugene D.] Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China. RP Weiner, HL (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. EM hweiner@rics.bwh.harvard.edu; eponomarev@cuhk.edu.hk OI Starossom, Sarah/0000-0001-7935-9910 FU [R01 NS071039-01A1] FX The work was supported in part by R01 NS071039-01A1 grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 86 TC 12 Z9 12 U1 1 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 26 PY 2013 VL 8 IS 3 AR e58979 DI 10.1371/journal.pone.0058979 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 123VE UT WOS:000317418500019 PM 23555611 ER PT J AU Atkinson, C Floerchinger, B Qiao, F Casey, S Williamson, T Moseley, E Stoica, S Goddard, M Ge, XP Tullius, SG Tomlinson, S AF Atkinson, Carl Floerchinger, Bernhard Qiao, Fei Casey, Sarah Williamson, Tucker Moseley, Ellen Stoica, Serban Goddard, Martin Ge, Xupeng Tullius, Stefan G. Tomlinson, Stephen TI Donor Brain Death Exacerbates Complement-Dependent Ischemia/Reperfusion Injury in Transplanted Hearts SO CIRCULATION LA English DT Article DE inflammation; ischemia; reperfusion injury; transplantation ID ISCHEMIA-REPERFUSION INJURY; P-SELECTIN LIGAND; LIVER-REGENERATION; ACTIVATION; RAT; C3A; ALLOGRAFT; C5A; MEDIATORS; KIDNEY AB Background-Brain death (BD) can immunologically prime the donor organ and is thought to lead to exacerbated ischemia/reperfusion injury after transplantation. Using a newly developed mouse model of BD, we investigated the effect of donor BD on posttransplantation cardiac ischemia/reperfusion injury. We further investigated the therapeutic effect of a targeted complement inhibitor in recipients of BD donor hearts and addressed the clinical relevance of these studies by analyzing human heart biopsies from BD and domino (living) donors. Methods and Results-Hearts from living or BD donor C57BL/6 mice were transplanted into C57BL/6 or BALB/c recipients. Recipient mice were treated with the complement inhibitor CR2-Crry or vehicle control (n=6). Isografts were analyzed 48 hours after transplantation for injury, inflammation, and complement deposition, and allografts were monitored for graft survival. Human cardiac biopsies were analyzed for complement deposition and inflammatory cell infiltration. In the murine model, donor BD exacerbated ischemia/reperfusion injury and graft rejection, as demonstrated by increased myocardial injury, serum cardiac troponin, cellular infiltration, complement deposition, inflammatory chemokine and cytokine levels, and by decreased graft survival. CR2-Crry treatment of recipients significantly reduced all measured outcomes in grafts from both BD and living donors compared with controls. Analysis of human samples documented the relevance of our experimental findings and revealed exacerbated complement deposition and inflammation in grafts from BD donors compared with grafts from living donors. Conclusions-BD exacerbates posttransplantation cardiac ischemia/reperfusion injury in mice and humans and decreases survival of mouse allografts. Furthermore, targeted complement inhibition in recipient mice ameliorates BD-exacerbated ischemia/reperfusion injury. (Circulation. 2013; 127: 1290-1299.) C1 [Atkinson, Carl; Qiao, Fei; Casey, Sarah; Williamson, Tucker; Tomlinson, Stephen] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Floerchinger, Bernhard; Tullius, Stefan G.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Transplant Surg, Boston, MA 02115 USA. [Floerchinger, Bernhard; Tullius, Stefan G.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Transplant Surg Res Lab, Boston, MA 02115 USA. [Floerchinger, Bernhard] Univ Med Ctr Regensburg, Dept Cardiothorac Surg, Regensburg, Germany. [Moseley, Ellen; Stoica, Serban; Goddard, Martin] Papworth Hosp NHS Trust, Dept Pathol, Cambridge, England. [Stoica, Serban] Bristol Childrens Hosp, Bristol, Avon, England. [Stoica, Serban] Inst Heart, Bristol, Avon, England. [Ge, Xupeng] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Tomlinson, Stephen] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Tomlinson, S (reprint author), Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. EM stullius@partners.org; tomlinss@musc.edu FU National Institutes of Health [RO1 HL 86562, HL082485]; US Department of Veterans Affairs [1BX001218]; American Heart Association [SDG AHA 065100]; Fundacion Carlos Slim de la Salud; Deutsche Forschungsgemeinschaft [DFG/FL 703/1-1]; University of Regensburg; South Carolina Clinical & Translational Research Institute, Medical University of South Carolina's CTSA, National Institutes of Health/National Center for Advancing Translational Sciences [UL1TR000062] FX This study was supported by grants from the National Institutes of Health (RO1 HL 86562 and HL082485 to Dr Tomlinson), the US Department of Veterans Affairs (1BX001218 to Dr Tomlinson), the American Heart Association (SDG AHA 065100 to Dr Atkinson), the Fundacion Carlos Slim de la Salud (to Dr Tullius), Deutsche Forschungsgemeinschaft (DFG/FL 703/1-1) and the University of Regensburg (to Dr Floerchinger), and South Carolina Clinical & Translational Research Institute, Medical University of South Carolina's CTSA, National Institutes of Health/National Center for Advancing Translational Sciences grant UL1TR000062. NR 36 TC 17 Z9 18 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 26 PY 2013 VL 127 IS 12 BP 1290 EP + DI 10.1161/CIRCULATIONAHA.112.000784 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 113NQ UT WOS:000316675100021 PM 23443736 ER PT J AU Grutzner, C Wibral, M Sun, LM Rivolta, D Singer, W Maurer, K Uhlhaas, PJ AF Gruetzner, Christine Wibral, Michael Sun, Limin Rivolta, Davide Singer, Wolf Maurer, Konrad Uhlhaas, Peter J. TI Deficits in high- (> 60 Hz) gamma-band oscillations during visual processing in schizophrenia SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE MEG; gamma; schizophrenia; perceptual organization; synchrony ID WORKING-MEMORY; PERCEPTUAL ORGANIZATION; NEURAL ACTIVITY; EEG RECORDINGS; CORTEX; SYNCHRONIZATION; FREQUENCY; STIMULATION; ABNORMALITIES; INTERNEURONS AB Current theories of the pathophysiology of schizophrenia have focused on abnormal temporal coordination of neural activity. Oscillations in the gamma-band range (>25 Hz) are of particular interest as they establish synchronization with great precision in local cortical networks. However, the contribution of high gamma (>60 Hz) oscillations toward the pathophysiology is less established. To address this issue, we recorded magnetoencephalographic (MEG) data from 16 medicated patients with chronic schizophrenia and 16 controls during the perception of Mooney faces. MEG data were analysed in the 25150 Hz frequency range. Patients showed elevated reaction times and reduced detection rates during the perception of upright Mooney faces while responses to inverted stimuli were intact. Impaired processing of Mooney faces in schizophrenia patients was accompanied by a pronounced reduction in spectral power between 60120 Hz (effect size: d = 1.26) which was correlated with disorganized symptoms (r = -0.72). Our findings demonstrate that deficits in high gamma-band oscillations as measured by MEG are a sensitive marker for aberrant cortical functioning in schizophrenia, suggesting an important aspect of the pathophysiology of the disorder. C1 [Gruetzner, Christine; Sun, Limin; Rivolta, Davide; Singer, Wolf; Uhlhaas, Peter J.] Max Planck Inst Brain Res, Dept Neurophysiol, Frankfurt, Germany. [Wibral, Michael] Goethe Univ Frankfurt, Brain Imaging Ctr, MEG Unit, D-60054 Frankfurt, Germany. [Sun, Limin] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Cambridge, MA 02138 USA. [Rivolta, Davide; Singer, Wolf; Uhlhaas, Peter J.] Max Planck Gesell, Ernst Strungmann Inst Neurosci Cooperat, Frankfurt, Germany. [Singer, Wolf] Goethe Univ Frankfurt, Frankfurt Inst Adv Studies, D-60054 Frankfurt, Germany. [Maurer, Konrad] Goethe Univ Frankfurt, Dept Psychiat, D-60054 Frankfurt, Germany. [Uhlhaas, Peter J.] Univ Glasgow, Inst Neurosci & Psychol, Glasgow G12 8QB, Lanark, Scotland. RP Uhlhaas, PJ (reprint author), Univ Glasgow, Inst Neurosci & Psychol, Hillead Str 58, Glasgow G12 8QB, Lanark, Scotland. EM peter.uhlhaas@glasgow.ac.uk RI Singer, Wolf/D-6874-2012; OI Wibral, Michael/0000-0001-8010-5862 FU Max Planck Society; BMBF [01GWS055]; LOWE grant Neuronale Koordination Forschungsschwerpunkt Frankfurt (NeFF) FX This work was supported by the Max Planck Society (Peter J. Uhlhaas) and through the BMBF (Grant: 01GWS055) (Peter J. Uhlhaas, Wolf Singer). Davide Rivolta is supported by the LOWE grant Neuronale Koordination Forschungsschwerpunkt Frankfurt (NeFF). NR 64 TC 32 Z9 32 U1 4 U2 30 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD MAR 26 PY 2013 VL 7 AR 88 DI 10.3389/fnhum.2013.00088 PG 11 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 114FJ UT WOS:000316726200001 PM 23532620 ER PT J AU Shunk, RL AF Shunk, Rebecca Lesto TI Professionalism A Piercing Dilemma SO JAMA INTERNAL MEDICINE LA English DT Editorial Material C1 [Shunk, Rebecca Lesto] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Shunk, Rebecca Lesto] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. RP Shunk, RL (reprint author), San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM rebecca.shunk@va.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR 25 PY 2013 VL 173 IS 6 BP 406 EP 406 DI 10.1001/jamainternmed.2013.2744 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 154NA UT WOS:000319681400001 PM 23420355 ER PT J AU Singh, H Giardina, TD Meyer, AND Forjuoh, SN Reis, MD Thomas, EJ AF Singh, Hardeep Giardina, Traber Davis Meyer, Ashley N. D. Forjuoh, Samuel N. Reis, Michael D. Thomas, Eric J. TI Types and Origins of Diagnostic Errors in Primary Care Settings SO JAMA INTERNAL MEDICINE LA English DT Article ID ADVERSE EVENTS; MALPRACTICE CLAIMS; CANCER-DIAGNOSIS; MISSED OPPORTUNITIES; MULTISITE SURVEY; GENERAL-PRACTICE; MEDICAL ERRORS; INTERVENTIONS; PHYSICIANS; HARM AB Importance: Diagnostic errors are an understudied aspect of ambulatory patient safety. Objectives: To determine the types of diseases missed and the diagnostic processes involved in cases of confirmed diagnostic errors in primary care settings and to determine whether record reviews could shed light on potential contributory factors to inform future interventions. Design: We reviewed medical records of diagnostic errors detected at 2 sites through electronic health record-based triggers. Triggers were based on patterns of patients' unexpected return visits after an initial primary care index visit. Setting: A large urban Veterans Affairs facility and a large integrated private health care system. Participants: Our study focused on 190 unique instances of diagnostic errors detected in primary care visits between October 1, 2006, and September 30, 2007. Main Outcome Measures: Through medical record reviews, we collected data on presenting symptoms at the index visit, types of diagnoses missed, process breakdowns, potential contributory factors, and potential for harm from errors. Results: In 190 cases, a total of 68 unique diagnoses were missed. Most missed diagnoses were common conditions in primary care, with pneumonia (6.7%), decompensated congestive heart failure (5.7%), acute renal failure (5.3%), cancer (primary) (5.3%), and urinary tract infection or pyelonephritis (4.8%) being most common. Process breakdowns most frequently involved the patient-practitioner clinical encounter (78.9%) but were also related to referrals (19.5%), patient-related factors (16.3%), follow-up and tracking of diagnostic information (14.7%), and performance and interpretation of diagnostic tests (13.7%). A total of 43.7% of cases involved more than one of these processes. Patient-practitioner encounter breakdowns were primarily related to problems with history-taking (56.3%), examination (47.4%), and/or ordering diagnostic tests for further workup (57.4%). Most errors were associated with potential for moderate to severe harm. Conclusions and Relevance: Diagnostic errors identified in our study involved a large variety of common diseases and had significant potential for harm. Most errors were related to process breakdowns in the patient-practitioner clinical encounter. Preventive interventions should target common contributory factors across diagnoses, especially those that involve data gathering and synthesis in the patient-practitioner encounter. C1 [Singh, Hardeep; Giardina, Traber Davis; Meyer, Ashley N. D.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston VA Hlth Serv Res & Dev Ctr Excellence, Houston, TX 77030 USA. [Singh, Hardeep; Giardina, Traber Davis; Meyer, Ashley N. D.] Baylor Coll Med, Sect Hlth Serv Res, Dept Med, Houston, TX USA. [Forjuoh, Samuel N.; Reis, Michael D.] Texas A&M Hlth Sci Ctr, Coll Medi, Dept Family & Community Med, Temple, TX USA. [Thomas, Eric J.] Univ Texas Houston, Mem Hermann Ctr Health care Qual & Safety, Houston, TX USA. [Thomas, Eric J.] Univ Texas Houston, Div Gen Med, Dept Med, Sch Med, Houston, TX USA. RP Singh, H (reprint author), Michael E DeBakey Vet Affairs Med Ctr 152, Houston VA Hlth Serv Res & Dev Ctr Excellence, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hrdeeps@bcm.edu OI Davis Giardina, Traber/0000-0002-9184-6524; Meyer, Ashley/0000-0001-7993-8584 FU National Institutes of Health K23 Career Development Award [K23CA125585]; Agency for Health Care Research and Quality Health Services Research Demonstration and Dissemination grant [R18HS17244-02]; Houston VA HSR&D Center of Excellence [HFP90-020]; VA Office of Academic Affiliations Fellowship Program FX The study was supported by National Institutes of Health K23 Career Development Award K23CA125585 to Dr Singh, by Agency for Health Care Research and Quality Health Services Research Demonstration and Dissemination grant R18HS17244-02 to Dr Thomas, and in part by Houston VA HSR&D Center of Excellence grant HFP90-020 and the VA Office of Academic Affiliations Fellowship Program to Dr Meyer. NR 38 TC 69 Z9 69 U1 2 U2 18 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR 25 PY 2013 VL 173 IS 6 BP 418 EP 425 DI 10.1001/jamainternmed.2013.2777 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 154NA UT WOS:000319681400004 PM 23440149 ER PT J AU Beach, MC Fitzgerald, A Saha, S AF Beach, Mary Catherine Fitzgerald, April Saha, Somnath TI White Coat Hype: Branding Physicians With Professional Attire SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID APPEARANCE C1 [Beach, Mary Catherine; Fitzgerald, April] Johns Hopkins Univ Hosp, Div Gen Internal Med, Baltimore, MD 21287 USA. [Saha, Somnath] Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, Sect Gen Internal Med, Portland, OR 97201 USA. RP Beach, MC (reprint author), Johns Hopkins Univ Hosp, Div Gen Internal Med, 2024 Monument St,Room 2-511, Baltimore, MD 21287 USA. EM mcbeach@jhmi.edu NR 10 TC 3 Z9 3 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR 25 PY 2013 VL 173 IS 6 BP 467 EP 468 DI 10.1001/jamainternmed.2013.3766 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 154NA UT WOS:000319681400017 PM 23420503 ER PT J AU Prigerson, HG Zhang, BH Nilsson, ME AF Prigerson, Holly G. Zhang, Baohui Nilsson, Matthew E. TI End-of-Life Care: Where Does the Standard Oncology Care Fail Our Patients and What Do We, as Oncologists, Need to Do Differently? Reply SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Prigerson, Holly G.; Zhang, Baohui; Nilsson, Matthew E.] Dana Farber Canc Inst, Ctr Psychosocial Epidemiol & Outcomes Res, Boston, MA 02115 USA. [Prigerson, Holly G.] Dana Farber Canc Inst, Div Populat Sci, Dept Med Oncol, Boston, MA 02115 USA. [Prigerson, Holly G.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Prigerson, HG (reprint author), Dana Farber Canc Inst, Ctr Psychosocial Epidemiol & Outcomes Res, 1134 Dana Bldg,450 Brookline Ave, Boston, MA 02115 USA. EM Holly_Prigerson@dfci.harvard.edu NR 0 TC 1 Z9 1 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR 25 PY 2013 VL 173 IS 6 BP 475 EP 475 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 154NA UT WOS:000319681400023 PM 23529553 ER PT J AU Gao, Y Geng, LY Orson, F Kinsey, B Kosten, TR Shen, XY Brimijoin, S AF Gao, Yang Geng, Liyi Orson, Frank Kinsey, Berma Kosten, Thomas R. Shen, Xiaoyun Brimijoin, Stephen TI Effects of anti-cocaine vaccine and viral gene transfer of cocaine hydrolase in mice on cocaine toxicity including motor strength and liver damage SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article; Proceedings Paper CT International Meeting on Cholinesterases CY JUN 04-09, 2012 CL Kazan, RUSSIA DE Cocaine toxicity; Anti-cocaine vaccine; Mouse; Alanine transaminase; Histopathology; Grip strength ID HUMAN BUTYRYLCHOLINESTERASE; INDUCED HEPATOTOXICITY; ABUSE; INTERCEPTION AB In developing an vivo drug-interception therapy to treat cocaine abuse and hinder relapse into drug seeking provoked by re-encounter with cocaine, two promising agents are: (1) a cocaine hydrolase enzyme (CocH) derived from human butyrylcholinesterase and delivered by gene transfer; (2) an anti-cocaine antibody elicited by vaccination. Recent behavioral experiments showed that antibody and enzyme work in a complementary fashion to reduce cocaine-stimulated locomotor activity in rats and mice. Our present goal was to test protection against liver damage and muscle weakness in mice challenged with massive doses of cocaine at or near the LD50 level (100-120 mg/kg, i.p.). We found that, when the interceptor proteins were combined at doses that were only modestly protective in isolation (enzyme, 1 mg/kg; antibody, 8 mg/kg), they provided complete protection of liver tissue and motor function. When the enzyme levels were similar to 400-fold higher, after in vivo transduction by adeno-associated viral vector, similar protection was observed from CocH alone. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Gao, Yang; Geng, Liyi; Brimijoin, Stephen] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA. [Orson, Frank; Kinsey, Berma; Shen, Xiaoyun] Dept Med, Houston, TX USA. [Kosten, Thomas R.] Dept Psychiat & Neurosci, Houston, TX USA. [Orson, Frank; Kosten, Thomas R.] Dept Pathol & Immunol, Houston, TX USA. [Orson, Frank; Kinsey, Berma; Kosten, Thomas R.; Shen, Xiaoyun] Dept Vet Affairs Med Ctr, Houston, TX USA. RP Brimijoin, S (reprint author), Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA. EM brimijoin@mayo.edu FU NIDA [DP1 DA031340, R01 DA023979, R01 DA023979 S1]; Mayo Foundation FX We thank Drs D. Baltimore and S. J. Russell for generously providing crucial viral vectors for this research. Our work was supported by NIDA grants DP1 DA031340, R01 DA023979, and R01 DA023979 S1, and by Mayo Foundation. NR 21 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 EI 1872-7786 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD MAR 25 PY 2013 VL 203 IS 1 SI SI BP 208 EP 211 DI 10.1016/j.cbi.2012.08.006 PG 4 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 134HU UT WOS:000318201800042 PM 22935511 ER PT J AU Kung, JTY Lee, JT AF Kung, Johnny T. Y. Lee, Jeannie T. TI RNA in the Loop SO DEVELOPMENTAL CELL LA English DT Editorial Material ID LONG NONCODING RNAS; CHROMATIN ARCHITECTURE; HUMAN-CELLS; TRANSCRIPTION; MEDIATOR; ENHANCER C1 [Kung, Johnny T. Y.; Lee, Jeannie T.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Kung, Johnny T. Y.; Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Kung, Johnny T. Y.; Lee, Jeannie T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Lee, JT (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. EM lee@molbio.mgh.harvard.edu FU NIGMS NIH HHS [R01 GM090278, R37 GM058839] NR 10 TC 5 Z9 5 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD MAR 25 PY 2013 VL 24 IS 6 BP 565 EP 567 DI 10.1016/j.devcel.2013.03.009 PG 3 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 126PW UT WOS:000317634500002 PM 23537627 ER PT J AU Beidas, RS Aarons, G Barg, F Evans, A Hadley, T Hoagwood, K Marcus, S Schoenwald, S Walsh, L Mandell, DS AF Beidas, Rinad S. Aarons, Gregory Barg, Frances Evans, Arthur Hadley, Trevor Hoagwood, Kimberly Marcus, Steven Schoenwald, Sonja Walsh, Lucia Mandell, David S. TI Policy to implementation: evidence-based practice in community mental health - study protocol SO IMPLEMENTATION SCIENCE LA English DT Article DE Evidence-based practice; Community mental health; Policy; Implementation; Fidelity; Organizational variables ID CHILD-WELFARE SYSTEMS; SOCIAL-CONTEXT OSC; ORGANIZATIONAL READINESS; SERVICES; CLIMATE; LEADERSHIP; THERAPY; INTERVENTIONS; ATTITUDES; FIDELITY AB Background: Evidence-based treatments (EBTs) are not widely available in community mental health settings. In response to the call for implementation of evidence-based treatments in the United States, states and counties have mandated behavioral health reform through policies and other initiatives. Evaluations of the impact of these policies on implementation are rare. A systems transformation about to occur in Philadelphia, Pennsylvania, offers an important opportunity to prospectively study implementation in response to a policy mandate. Methods/design: Using a prospective sequential mixed-methods design, with observations at multiple points in time, we will investigate the responses of staff from 30 community mental health clinics to a policy from the Department of Behavioral Health encouraging and incentivizing providers to implement evidence-based treatments to treat youth with mental health problems. Study participants will be 30 executive directors, 30 clinical directors, and 240 therapists. Data will be collected prior to the policy implementation, and then at two and four years following policy implementation. Quantitative data will include measures of intervention implementation and potential moderators of implementation (i.e., organizational-and leader-level variables) and will be collected from executive directors, clinical directors, and therapists. Measures include self-reported therapist fidelity to evidence-based treatment techniques as measured by the Therapist Procedures Checklist-Revised, organizational variables as measured by the Organizational Social Context Measurement System and the Implementation Climate Assessment, leader variables as measured by the Multifactor Leadership Questionnaire, attitudes towards EBTs as measured by the Evidence-Based Practice Attitude Scale, and knowledge of EBTs as measured by the Knowledge of Evidence-Based Services Questionnaire. Qualitative data will include semi-structured interviews with a subset of the sample to assess the implementation experience of high-, average-, and low-performing agencies. Mixed methods will be integrated through comparing and contrasting results from the two methods for each of the primary hypotheses in this study. Discussion: Findings from the proposed research will inform both future policy mandates around implementation and the support required for the success of these policies, with the ultimate goal of improving the quality of treatment provided to youth in the public sector. C1 [Beidas, Rinad S.; Evans, Arthur; Hadley, Trevor; Walsh, Lucia; Mandell, David S.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Aarons, Gregory] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Barg, Frances] Univ Penn, Dept Family Med & Community Hlth, Perelman Sch Med, Philadelphia, PA 19104 USA. [Evans, Arthur] Dept Behav Hlth & Intellectual DisAbil Serv, Philadelphia, PA USA. [Hoagwood, Kimberly] NYU, Dept Psychiat, New York, NY 10016 USA. [Marcus, Steven] Univ Penn, Ctr Hlth Equ Res & Promot, Philadelphia Vet Affairs Med Ctr, Sch Social Policy & Practice, Philadelphia, PA 19104 USA. [Schoenwald, Sonja] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. RP Beidas, RS (reprint author), Univ Penn, Dept Psychiat, Perelman Sch Med, 3535 Market St,3rd Floor, Philadelphia, PA 19104 USA. EM rbeidas@upenn.edu RI Mandell, David/H-2730-2012 OI Mandell, David/0000-0001-8240-820X FU Department of Behavioral Health and Intellectual DisAbility Services; Evidence Based Practice and Innovation (EPIC) group; NIMH [K23 MH099179]; National Institute of Mental Health [R25 MH080916]; Quality Enhancement Research Initiative (QUERI); Department of Veterans Affairs Contract; Veterans Health Administration; Office of Research & Development, Health Services Research & Development Service FX We are especially grateful for the support the Department of Behavioral Health and Intellectual DisAbility Services has provided for this project, and for the Evidence Based Practice and Innovation (EPIC) group. Funding for this research project was supported by the following grants from NIMH: (K23 MH099179, Beidas). Additionally, the preparation of this article was supported in part by the Implementation Research Institute (IRI), at the George Warren Brown School of Social Work, Washington University in St. Louis; through an award from the National Institute of Mental Health (R25 MH080916) and Quality Enhancement Research Initiative (QUERI), Department of Veterans Affairs Contract, Veterans Health Administration, Office of Research & Development, Health Services Research & Development Service. Dr. Beidas is an IRI fellow. We would like to thank the following experts who provided their time and input on this project: Dr. Marc Atkins, Dr. Ross Brownson, Dr. David Chambers, Dr. Charles Glisson, Dr. Nicholas Ialongo, Dr. John Landsverk, and Dr. Enola Proctor. We are also grateful for the time and effort provided by Steven Lucas and Margaret Mary Downey with this project. NR 38 TC 13 Z9 14 U1 3 U2 38 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 MAR 24 PY 2013 VL 8 AR 38 DI 10.1186/1748-5908-8-38 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 137EU UT WOS:000318419100001 PM 23522556 ER PT J AU MacDonald, SM Jimenez, R Paetzold, P Adams, J Beatty, J DeLaney, TF Kooy, H Taghian, AG Lu, HM AF MacDonald, Shannon M. Jimenez, Rachel Paetzold, Peter Adams, Judith Beatty, Jonathan DeLaney, Thomas F. Kooy, Hanne Taghian, Alphonse G. Lu, Hsiao-Ming TI Proton radiotherapy for chest wall and regional lymphatic radiation; dose comparisons and treatment delivery SO RADIATION ONCOLOGY LA English DT Article DE Breast cancer; Treatment planning; Proton beam radiation ID BREAST-CANCER PATIENTS; ADJUVANT CHEMOTHERAPY; RANDOMIZED-TRIALS; THERAPY; RISK; PNEUMONITIS; MORTALITY; PHOTONS; SURGERY AB Purpose: The delivery of post-mastectomy radiation therapy (PMRT) can be challenging for patients with left sided breast cancer that have undergone mastectomy. This study investigates the use of protons for PMRT in selected patients with unfavorable cardiac anatomy. We also report the first clinical application of protons for these patients. Methods and materials: Eleven patients were planned with protons, partially wide tangent photon fields (PWTF), and photon/electron (P/E) fields. Plans were generated with the goal of achieving 95% coverage of target volumes while maximally sparing cardiac and pulmonary structures. In addition, we report on two patients with unfavorable cardiac anatomy and IMN involvement that were treated with a mix of proton and standard radiation. Results: PWTF, P/E, and proton plans were generated and compared. Reasonable target volume coverage was achieved with PWTF and P/E fields, but proton therapy achieved superior coverage with a more homogeneous plan. Substantial cardiac and pulmonary sparing was achieved with proton therapy as compared to PWTF and P/E. In the two clinical cases, the delivery of proton radiation with a 7.2 to 9 Gy photon and electron component was feasible and well tolerated. Akimbo positioning was necessary for gantry clearance for one patient; the other was treated on a breast board with standard positioning (arms above her head). LAO field arrangement was used for both patients. Erythema and fatigue were the only noted side effects. Conclusions: Proton RT enables delivery of radiation to the chest wall and regional lymphatics, including the IMN, without compromise of coverage and with improved sparing of surrounding normal structures. This treatment is feasible, however, optimal patient set up may vary and field size is limited without multiple fields/matching. C1 [MacDonald, Shannon M.; Jimenez, Rachel; Paetzold, Peter; Adams, Judith; Beatty, Jonathan; DeLaney, Thomas F.; Kooy, Hanne; Taghian, Alphonse G.; Lu, Hsiao-Ming] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. RP MacDonald, SM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Cox 340,100 Blossom St, Boston, MA 02114 USA. EM smacdonald@partners.org NR 19 TC 17 Z9 17 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD MAR 24 PY 2013 VL 8 AR 71 DI 10.1186/1748-717X-8-71 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 128RR UT WOS:000317787000001 PM 23521809 ER PT J AU Vollset, SE Clarke, R Lewington, S Ebbing, M Halsey, J Lonn, E Armitage, J Manson, JE Hankey, GJ Spence, JD Galan, P Bonaa, KH Jamison, R Gaziano, JM Guarino, P Baron, JA Logan, RFA Giovannucci, EL den Heijer, M Ueland, PM Bennett, D Collins, R Peto, R AF Vollset, Stein Emil Clarke, Robert Lewington, Sarah Ebbing, Marta Halsey, Jim Lonn, Eva Armitage, Jane Manson, Joann E. Hankey, Graeme J. Spence, J. David Galan, Pilar Bonaa, Kaare H. Jamison, Rex Gaziano, J. Michael Guarino, Peter Baron, John A. Logan, Richard F. A. Giovannucci, Edward L. den Heijer, Martin Ueland, Per M. Bennett, Derrick Collins, Rory Peto, Richard CA B-Vitamin Treatment Trialists' Co TI Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50 000 individuals SO LANCET LA English DT Article ID NEURAL-TUBE DEFECTS; PERICONCEPTIONAL VITAMIN SUPPLEMENTATION; PLACEBO-CONTROLLED TRIAL; B-VITAMINS; MYOCARDIAL-INFARCTION; VASCULAR-DISEASE; RISK-FACTOR; CARDIOVASCULAR-DISEASE; LOWERING HOMOCYSTEINE; FLOUR FORTIFICATION AB Background Some countries fortify flour with folic acid to prevent neural tube defects but others do not, partly because of concerns about possible cancer risks. We aimed to assess any effects on site-specific cancer rates in the randomised trials of folic acid supplementation, at doses higher than those from fortification. Methods In these meta-analyses, we sought all trials completed before 2011 that compared folic acid versus placebo, had scheduled treatment duration at least 1 year, included at least 500 participants, and recorded data on cancer incidence. We obtained individual participant datasets that included 49 621 participants in all 13 such trials (ten trials of folic acid for prevention of cardiovascular disease [n=46 969] and three trials in patients with colorectal adenoma [n=2652]). All these trials were evenly randomised. The main outcome was incident cancer (ignoring non-melanoma skin cancer) during the scheduled treatment period (among participants who were still free of cancer). We compared those allocated folic acid with those allocated placebo, and used log-rank analyses to calculate the cancer incidence rate ratio (RR). Findings During a weighted average scheduled treatment duration of 5.2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57.3 nmol/L for the folic acid groups vs 13.5 nmol/L for the placebo groups), but had no significant effect on overall cancer incidence (1904 cancers in the folic acid groups vs 1809 cancers in the placebo groups, RR 1.06, 95% CI 0.99-1.13, p=0.10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p=0.23), or between the two overall results in the cadiovascular prevention trials and the adenoma trials (p=0.13). Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site. Interpretation Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials. C1 [Vollset, Stein Emil] Univ Bergen, Norwegian Inst Publ Hlth, Bergen, Norway. [Vollset, Stein Emil] Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway. [Clarke, Robert; Lewington, Sarah; Halsey, Jim; Armitage, Jane; Bennett, Derrick; Collins, Rory; Peto, Richard] Univ Oxford, Clin Trial Serv Unit, Oxford OX3 7LF, England. [Clarke, Robert; Lewington, Sarah; Halsey, Jim; Armitage, Jane; Bennett, Derrick; Collins, Rory; Peto, Richard] Univ Oxford, Epidemiol Studies Unit CTSU, Oxford OX3 7LF, England. [Ebbing, Marta] Haukeland Hosp, Dept Heart Dis, N-5021 Bergen, Norway. [Lonn, Eva] McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada. [Lonn, Eva] McMaster Univ, Dept Med, Div Cardiol, Hamilton, ON, Canada. [Manson, Joann E.] Harvard Univ, Brigham & Womens Hosp, Dept Med, Sch Med, Boston, MA 02115 USA. [Hankey, Graeme J.] Royal Perth Hosp, Dept Neurol, Perth, WA, Australia. [Spence, J. David] Univ Western Ontario, Dept Neurol, Robarts Res Inst, London, ON, Canada. [Bonaa, Kaare H.] Univ Hosp Northern Norway, Dept Heart Dis, Tromso, Norway. [Jamison, Rex] Vet Affairs Palo Alto Hlth Care Syst, Dept Med, Palo Alto, CA USA. [Jamison, Rex] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Guarino, Peter] Connecticut VA Healthcare Syst, Dept Vet airs, Cooperat Studies Program, West Haven, CT USA. [Baron, John A.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Logan, Richard F. A.] Univ Nottingham, Div Epidemiol & Publ Hlth, Nottingham NG7 2RD, England. [Giovannucci, Edward L.] Harvard Univ, Sch Med, Dept Epidemiol, Boston, MA USA. [Giovannucci, Edward L.] Harvard Univ, Sch Med, Dept Nutr, Boston, MA USA. [den Heijer, Martin] Radboud Univ Nijmegen, Dept Endocrinol, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Ueland, Per M.] Haukeland Hosp, Lab Clin Biochem, N-5021 Bergen, Norway. RP Clarke, R (reprint author), Univ Oxford, Clin Trial Serv Unit, Richard Doll Bldg,Old Rd Campus, Oxford OX3 7LF, England. EM robert.clarke@ctsu.ox.ac.uk RI Spence, J. David/K-6396-2013; Ueland, Per/C-7340-2013; Hankey, Graeme /H-4968-2014; OI Spence, J. David/0000-0001-7478-1098; Hankey, Graeme /0000-0002-6044-7328; Blom, Henk/0000-0001-5202-9241 FU British Heart Foundation; Medical Research Council; Cancer Research UK; Food Standards Agency; UK Medical Research Council; UK Food Standards Agency [N05072] FX British Heart Foundation, Medical Research Council, Cancer Research UK, Food Standards Agency.; Sources of funding for individual trials are described in their separate publications. The Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), where the BVTT secretariat is located, has a policy of not accepting fees, honoraria, or paid consultancies directly or indirectly from any industry. It receives its core funding from the British Heart Foundation, UK Medical Research Council, and Cancer Research UK. Support for this project was also provided by a grant from the UK Food Standards Agency (N05072). NR 43 TC 94 Z9 99 U1 2 U2 47 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD MAR 23 PY 2013 VL 381 IS 9871 BP 1029 EP 1036 DI 10.1016/S0140-6736(12)62001-7 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 117EU UT WOS:000316936800032 PM 23352552 ER PT J AU Crabtree, D Boyer-Guittaut, M Ouyang, XS Fineberg, N Zhang, JH AF Crabtree, Donna Boyer-Guittaut, Michael Ouyang, Xiaosen Fineberg, Naomi Zhang, Jianhua TI Dopamine and its metabolites in cathepsin D heterozygous mice before and after MPTP administration SO NEUROSCIENCE LETTERS LA English DT Article DE MPTP; Monoamine; Lysosome; Heterozygotes; Behavioral assessment ID ALPHA-SYNUCLEIN; RAT-BRAIN; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE; TRANSFERASE; RESISTANCE; MECHANISM; TRANSPORT; TOXICITY; OXIDASE; ENZYMES AB Cathepsin D (CD) is a lysosomal aspartyl protease which plays an important role in alpha-synuclein degradation, and neuronal survival. CD knockout mice die by post-natal day 25 +/- 1 due to intestinal necrosis. We analyzed the young adult male heterozygous mice, and found no behavior abnormalities in the heterozygous mice compared to wildtype littermates. LC3-II, p62, and alpha-synuclein levels are similar, while LAMP1 is higher in the striatum in CD heterozygous compared to wildtype mice. Interestingly, we found that dopamine and metabolites in the striatum and olfactory bulbs are at higher levels than wildtype littermates, while the DOPAC/DA and HVA/DA ratio remain similar between wildtype and CD heterozygous mice. In response to sub-chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, dopamine, DOPAC, and HVA are depleted to similar levels in the striatum in both heterozygous and wildtype mice. Dopamine synthesizing enzyme tyrosine hydroxylase, metabolic enzyme monoamine oxidase, and catechol-O-methyltransferase (COMT) levels are similar in the striatum in wild-type and heterozygous mice. These studies provide valuable information regarding how lysosomal function may contribute to neurochemical homeostasis in animal models. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Crabtree, Donna; Boyer-Guittaut, Michael; Ouyang, Xiaosen; Zhang, Jianhua] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Boyer-Guittaut, Michael; Ouyang, Xiaosen; Zhang, Jianhua] Univ Alabama Birmingham, Ctr Free Rad Biol, Birmingham, AL USA. [Ouyang, Xiaosen; Zhang, Jianhua] Birmingham VA Med Ctr, Dept Vet Affairs, Birmingham, AL USA. [Fineberg, Naomi] UAB Sch Publ Hlth, Dept Biostat, Birmingham, AL USA. [Boyer-Guittaut, Michael] Univ Franche Comte, Biochim Lab, SFR IBCT,FED 4234, UFR Sci & Tech,EA3922, F-25030 Besancon, France. RP Zhang, JH (reprint author), Univ Alabama Birmingham, Dept Pathol, BMRII-534,901 19th St S, Birmingham, AL 35294 USA. EM zhanja@uab.edu RI di Ronza, Alberto/H-7674-2016; OI di Ronza, Alberto/0000-0002-9813-5143; Zhang, Jianhua/0000-0002-2128-9574 FU Michael J Fox Foundation; VA merit award; UAB Behavioral Assessment Core [P30 NS47466]; [NIHR01-NS064090] FX We thank members of the Zhang Laboratory for technical help and discussions. We thank Dr. Paul Saftig for the cathepsin D knockout mice, Dr. Thomas Van Groen for his help and expertise with the behavioral assessments. This work was supported by Michael J Fox Foundation, NIHR01-NS064090 and a VA merit award (to JZ), and in part by P30 NS47466 (UAB Behavioral Assessment Core). NR 21 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 22 PY 2013 VL 538 BP 3 EP 8 DI 10.1016/j.neulet.2013.01.035 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 120FH UT WOS:000317155700002 PM 23391753 ER PT J AU Aguirre, JD Clark, HM McIlvin, M Vazquez, C Palmere, SL Grab, DJ Seshu, J Hart, PJ Saito, M Culotta, VC AF Aguirre, J. Dafhne Clark, Hillary M. McIlvin, Matthew Vazquez, Christine Palmere, Shaina L. Grab, Dennis J. Seshu, J. Hart, P. John Saito, Mak Culotta, Valeria C. TI A Manganese-rich Environment Supports Superoxide Dismutase Activity in a Lyme Disease Pathogen, Borrelia burgdorferi SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; STAPHYLOCOCCUS-AUREUS; ESCHERICHIA-COLI; LEUCINE AMINOPEPTIDASE; NEISSERIA-GONORRHOEAE; OXIDATIVE STRESS; BINDING PROTEIN; TYROSINE 34; IRON; RESISTANCE AB The Lyme disease pathogen Borrelia burgdorferi represents a novel organism in which to study metalloprotein biology in that this spirochete has uniquely evolved with no requirement for iron. Not only is iron low, but we show here that B. burgdorferi has the capacity to accumulate remarkably high levels of manganese. This high manganese is necessary to activate the SodA superoxide dismutase (SOD) essential for virulence. Using a metalloproteomic approach, we demonstrate that a bulk of B. burgdorferi SodA directly associates with manganese, and a smaller pool of inactive enzyme accumulates as apoprotein. Other metalloproteins may have similarly adapted to using manganese as co-factor, including the BB0366 aminopeptidase. Whereas B. burgdorferi SodA has evolved in a manganese-rich, iron-poor environment, the opposite is true for Mn-SODs of organisms such as Escherichia coli and bakers' yeast. These Mn-SODs still capture manganese in an iron-rich cell, and we tested whether the same is true for Borrelia SodA. When expressed in the iron-rich mitochondria of Saccharomyces cerevisiae, B. burgdorferi SodA was inactive. Activity was only possible when cells accumulated extremely high levels of manganese that exceeded cellular iron. Moreover, there was no evidence for iron inactivation of the SOD. B. burgdorferi SodA shows strong overall homology with other members of the Mn-SOD family, but computer-assisted modeling revealed some unusual features of the hydrogen bonding network near the enzyme's active site. The unique properties of B. burgdorferi SodA may represent adaptation to expression in the manganese-rich and iron-poor environment of the spirochete. C1 [Aguirre, J. Dafhne; Clark, Hillary M.; Vazquez, Christine; Palmere, Shaina L.; Culotta, Valeria C.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. [McIlvin, Matthew; Saito, Mak] Woods Hole Oceanog Inst, Woods Hole, MA 02543 USA. [Grab, Dennis J.] Johns Hopkins Univ, Sch Med, Div Med Microbiol, Dept Pathol, Baltimore, MD 21205 USA. [Seshu, J.] Univ Texas San Antonio, Dept Biol, San Antonio, TX 78249 USA. [Hart, P. John] South Texas Vet Hlth Care Syst, Dept Vet Affairs, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. [Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. RP Culotta, VC (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. EM vculotta@jhsph.edu FU National Institutes of Health [R01 ES08996, GM50016, SC1 AI078559, T32 GM080189]; Johns Hopkins University NIEHS, National Institutes of Health, center; Robert A. Welch Foundation [AQ-1399]; Veterans Affairs Department Grant, South Texas Veterans Health Care System [I01BX000506]; Gordon and Betty Moore Foundation Marine Microbiology Program; National Science Foundation Chemical Oceanography Grant [OCE-1031271] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 ES08996 and GM50016 (to V. C. C.) and SC1 AI078559 (to J. S.). This work was also supported in part by the Johns Hopkins University NIEHS, National Institutes of Health, center, by Robert A. Welch Foundation Grant AQ-1399, and in part by Veterans Affairs Department Grant I01BX000506, South Texas Veterans Health Care System (to P. J. H.). Metalloproteomic studies were funded by the Gordon and Betty Moore Foundation Marine Microbiology Program and National Science Foundation Chemical Oceanography Grant OCE-1031271 (to M. A. S.).; Supported by National Institutes of Health Grant T32 GM080189. NR 57 TC 29 Z9 29 U1 2 U2 49 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 MAR 22 PY 2013 VL 288 IS 12 BP 8468 EP 8478 DI 10.1074/jbc.M112.433540 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 112AS UT WOS:000316564500044 PM 23376276 ER PT J AU Buffen, K Oosting, M Mennens, S Anand, PK Plantinga, TS Sturm, P van de Veerdonk, FL van der Meer, JWM Xavier, RJ Kanneganti, TD Netea, MG Joosten, LAB AF Buffen, Kathrin Oosting, Marije Mennens, Svenja Anand, Paras K. Plantinga, Theo S. Sturm, Patrick van de Veerdonk, Frank L. van der Meer, Jos W. M. Xavier, Ramnik J. Kanneganti, Thirumala-Devi Netea, Mihai G. Joosten, Leo A. B. TI Autophagy Modulates Borrelia burgdorferi-induced Production of Interleukin-1 beta (IL-1 beta) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INNATE IMMUNE ACTIVATION; NF-KAPPA-B; LYME BORRELIOSIS; TREPONEMA-PALLIDUM; HUMAN MONOCYTES; DISEASE; INFLAMMASOME; CELLS; LIPOPROTEINS; ARTHRITIS AB Borrelia burgdorferi sensu lato is the causative agent of Lyme disease. Recent studies have shown that recognition of the spirochete is mediated by TLR2 and NOD2. The latter receptor has been associated with the induction of the intracellular degradation process called autophagy. The present study demonstrated for the first time the induction of autophagy by exposure to B. burgdorferi and that autophagy modulates the B. burgdorferi-dependent cytokine production. Human peripheral blood mononuclear cells treated with autophagy inhibitors showed an increased IL-1 beta and IL-6 production in response to the exposure of the spirochete, whereas TNF alpha production was unchanged. Autophagy induction against B. burgdorferi was dependent on reactive oxygen species (ROS) because cells from patients with chronic granulomatous disease, which are defective in ROS production, also produced elevated IL-1 beta. Further, the enhanced production of the proinflammatory cytokines was because of the elevated mRNA expression in the absence of autophagy. Our results thus demonstrate the induction of autophagy, which, in turn, modulates cytokine production by B. burgdorferi for the first time. C1 [Buffen, Kathrin; Oosting, Marije; Mennens, Svenja; Plantinga, Theo S.; van de Veerdonk, Frank L.; van der Meer, Jos W. M.; Netea, Mihai G.; Joosten, Leo A. B.] Radboud Univ Nijmegen, Med Ctr, Dept Med, NL-6525 GA Nijmegen, Netherlands. [Buffen, Kathrin; Oosting, Marije; Plantinga, Theo S.; van de Veerdonk, Frank L.; van der Meer, Jos W. M.; Netea, Mihai G.; Joosten, Leo A. B.] Radboud Univ Nijmegen, Med Ctr, Nijmegen Inst Infect Inflammat & Immun N4i, NL-6525 GA Nijmegen, Netherlands. [Mennens, Svenja; Anand, Paras K.; Kanneganti, Thirumala-Devi] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. [Sturm, Patrick] Radboud Univ Nijmegen, Dept Microbiol, Med Ctr, NL-6525 GA Nijmegen, Netherlands. [Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. RP Joosten, LAB (reprint author), Radboud Univ Nijmegen, Dept Med 463, Med Ctr, Geert Grootepl Zuid 8, NL-6525 GA Nijmegen, Netherlands. EM l.joosten@aig.umcn.nl RI van de Veerdonk, Frank/C-7256-2008; Plantinga, Theo/A-6895-2015; Joosten, Leo/H-3138-2015; Netea, Mihai/N-5155-2014; van der Meer, Jos/C-8521-2013; Mennens, Svenja/F-3106-2016; Oosting, Marije/H-7437-2015 OI van de Veerdonk, Frank/0000-0002-1121-4894; van der Meer, Jos/0000-0001-5120-3690; FU Dutch Arthritis Association [NR 10-1-303]; Veni Grant from the Netherlands Organization for Scientific Research; National Institute of Health [R01AR056296]; Vici grant from The Netherlands Organization for Scientific Research FX This work was supported in part by Dutch Arthritis Association Grant NR 10-1-303.; Supported by a Veni Grant from the Netherlands Organization for Scientific Research.; Supported by National Institute of Health Grant R01AR056296.; Supported by a Vici grant from The Netherlands Organization for Scientific Research. NR 46 TC 11 Z9 11 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 22 PY 2013 VL 288 IS 12 BP 8658 EP 8666 DI 10.1074/jbc.M112.412841 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 112AS UT WOS:000316564500066 PM 23386602 ER PT J AU Nag, A Bochukova, EG Kremeyer, B Campbell, DD Muller, H Valencia-Duarte, AV Cardona, J Rivas, IC Mesa, SC Cuartas, M Garcia, J Bedoya, G Cornejo, W Herrera, LD Romero, R Fournier, E Reus, VI Lowe, TL Farooqi, IS Mathews, CA McGrath, LM Yu, DM Cook, E Wang, K Scharf, JM Pauls, DL Freimer, NB Plagnol, V Ruiz-Linares, A AF Nag, Abhishek Bochukova, Elena G. Kremeyer, Barbara Campbell, Desmond D. Muller, Heike Valencia-Duarte, Ana V. Cardona, Julio Rivas, Isabel C. Mesa, Sandra C. Cuartas, Mauricio Garcia, Jharley Bedoya, Gabriel Cornejo, William Herrera, Luis D. Romero, Roxana Fournier, Eduardo Reus, Victor I. Lowe, Thomas L. Farooqi, I. Sadaf Mathews, Carol A. McGrath, Lauren M. Yu, Dongmei Cook, Ed Wang, Kai Scharf, Jeremiah M. Pauls, David L. Freimer, Nelson B. Plagnol, Vincent Ruiz-Linares, Andres CA Tourette Syndrome Assoc Int TI CNV Analysis in Tourette Syndrome Implicates Large Genomic Rearrangements in COL8A1 and NRXN1 SO PLOS ONE LA English DT Article ID COPY NUMBER VARIATION; NERVOUS-SYSTEM; VARIANTS; GENES; SCHIZOPHRENIA; ASSOCIATION; DISORDER; FAMILY; AUTISM; SUSCEPTIBILITY AB Tourette syndrome (TS) is a neuropsychiatric disorder with a strong genetic component. However, the genetic architecture of TS remains uncertain. Copy number variation (CNV) has been shown to contribute to the genetic make-up of several neurodevelopmental conditions, including schizophrenia and autism. Here we describe CNV calls using SNP chip genotype data from an initial sample of 210 TS cases and 285 controls ascertained in two Latin American populations. After extensive quality control, we found that cases (N = 179) have a significant excess (P = 0.006) of large CNV (. 500 kb) calls compared to controls (N = 234). Amongst 24 large CNVs seen only in the cases, we observed four duplications of the COL8A1 gene region. We also found two cases with similar to 400kb deletions involving NRXN1, a gene previously implicated in neurodevelopmental disorders, including TS. Follow-up using multiplex ligation-dependent probe amplification (and including 53 more TS cases) validated the CNV calls and identified additional patients with rearrangements in COL8A1 and NRXN1, but none in controls. Examination of available parents indicates that two out of three NRXN1 deletions detected in the TS cases are de-novo mutations. Our results are consistent with the proposal that rare CNVs play a role in TS aetiology and suggest a possible role for rearrangements in the COL8A1 and NRXN1 gene regions. C1 [Nag, Abhishek; Kremeyer, Barbara; Campbell, Desmond D.; Muller, Heike; Plagnol, Vincent; Ruiz-Linares, Andres] UCL, UCL Genet Inst, Dept Genet Evolut & Environm, London, England. [Bochukova, Elena G.; Farooqi, I. Sadaf] Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Cambridge CB2 2QQ, England. [Valencia-Duarte, Ana V.; Cuartas, Mauricio; Garcia, Jharley; Bedoya, Gabriel] Univ Antioquia, Genet Mol Lab, SIU, Medellin, Colombia. [Valencia-Duarte, Ana V.; Cornejo, William] Univ Pontificia Bolivariana, Escuela Ciencias Salud, Medellin, Colombia. [Cardona, Julio; Rivas, Isabel C.; Mesa, Sandra C.; Cornejo, William] Univ Antioquia, Dept Pediat, Fac Med, Medellin, Colombia. [Herrera, Luis D.; Romero, Roxana; Fournier, Eduardo] Hosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa Rica. [Reus, Victor I.; Lowe, Thomas L.; Mathews, Carol A.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [McGrath, Lauren M.; Scharf, Jeremiah M.; Pauls, David L.] Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA USA. [McGrath, Lauren M.; Yu, Dongmei; Scharf, Jeremiah M.; Pauls, David L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Cook, Ed] Univ Illinois, Chicago, IL USA. [Wang, Kai] Univ So Calif, Los Angeles, CA USA. [Scharf, Jeremiah M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Freimer, Nelson B.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA. RP Ruiz-Linares, A (reprint author), UCL, UCL Genet Inst, Dept Genet Evolut & Environm, London, England. EM a.ruizlin@ucl.ac.uk RI reus, victor/I-7923-2015; OI reus, victor/0000-0002-8193-5697; Campbell, Desmond/0000-0003-1085-714X; McGrath, Lauren/0000-0001-6928-9656; Plagnol, Vincent/0000-0002-5597-9215; Farooqi, Sadaf/0000-0001-7609-3504; Bochukova, Elena/0000-0003-0275-1548 FU National Institutes of Health [NS043538, NS037484, MH085057, NS40024, NS16648]; CODI; Judah Foundation; Tourette Syndrome Association; United Kingdom Medical Research Council [G1001158]; NIHR Moorfields Biomedical Research Council FX This work was funded by National Institutes of Health (http://www.nih.gov/) grants NS043538 (to ARL), NS037484 (to NBF), MH085057 (to JMS), NS40024 (to DLP and JMS) and NS16648 (the Tourette Syndrome Association International Consortium for Genetics), a CODI grant (http://www.udea.edu.co/portal/page/portal/Programas/GruposInvestigacion /h.Convocatorias/CODI/estrategiaSostenibilidad) (Sostenibilidad, Universidad de Antioquia), a grant from the Judah Foundation (http://www.judahfoundation.org/), and the Tourette Syndrome Association (http://tsa-usa.org/) (fellowship to BK and a grant to DLP). VP is supported by a grant from the United Kingdom Medical Research Council (http://www.mrc.ac.uk) (G1001158) and by the NIHR Moorfields Biomedical Research Council (http://www.brcophthalmology.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 24 Z9 24 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 22 PY 2013 VL 8 IS 3 AR e59061 DI 10.1371/journal.pone.0059061 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 111VQ UT WOS:000316549400037 PM 23533600 ER PT J AU Cattaneo, Z Vecchi, T Monegato, M Pece, A Merabet, LB Carbon, CC AF Cattaneo, Zaira Vecchi, Tomaso Monegato, Maura Pece, Alfredo Merabet, Lotfi B. Carbon, Claus-Christian TI Strabismic amblyopia affects relational but not featural and Gestalt processing of faces SO VISION RESEARCH LA English DT Article DE Face processing; Amblyopia; Relational; Featural; Holistic; Face detection; Hemisphere; Laterality; Recognition; Strabismus; Dissociation ID EARLY VISUAL DEPRIVATION; FACIAL IDENTITY; RECOGNITION; PERCEPTION; DEFICIT; IDENTIFICATION; INFORMATION; SENSITIVITY; PROSOPAGNOSIA; PATTERN AB The ability to identify faces is of critical importance for normal social interactions. Previous evidence suggests that early visual deprivation may impair certain aspects of face recognition. The effects of strabismic amblyopia on face processing have not been investigated previously. In this study, a group of individuals with amblyopia were administered two tasks known to selectively measure face detection based on a Gestalt representation of a face (Mooney faces task) and featural and relational processing of faces (Jane faces task). Our data show that - when relying on their amblyopic eye only - strabismic amblyopes perform as well as normally sighted individuals in face detection and recognition on the basis of their single features. However, they are significantly impaired in discriminating among different faces on the basis of the spacing of their single features (i.e., configural processing of relational information). Our findings are the first to demonstrate that strabismic amblyopia may cause specific deficits in face recognition, and add to previous reports characterizing visual perceptual deficits associated in amblyopia as high-level and not only as low-level processing. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Cattaneo, Zaira] Univ Milano Bicocca, Dept Psychol, Milan, Italy. [Cattaneo, Zaira; Vecchi, Tomaso] IRCCS Mondino, Brain Connect Ctr, Pavia, Italy. [Vecchi, Tomaso; Monegato, Maura] Univ Pavia, Dept Brain & Behav Sci, I-27100 Pavia, Italy. [Monegato, Maura; Pece, Alfredo] Melegnano Hosp, Ophthalmol Unit, Melegnano, Italy. [Merabet, Lotfi B.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Carbon, Claus-Christian] Univ Bamberg, Dept Gen Psychol & Methodol, Bamberg, Germany. RP Cattaneo, Z (reprint author), Univ Milano Bicocca, Dept Psychol, Milan, Italy. EM zaira.cattaneo@unimib.it RI Carbon, Claus-Christian/A-7494-2008 OI Carbon, Claus-Christian/0000-0002-3446-9347 FU Vigoni/DAAD; FIRB grant [RBFR12F0BD_003] FX The authors thank Cathy Mondloch and her colleagues for providing the original stimuli of Mondloch, Le Grand, and Maurer (2002) as stimuli for the "Jane Face task". This work was supported by Vigoni/DAAD grants (years 2012-2013) to Z.C. and C.C.C. and by a FIRB grant (RBFR12F0BD_003) to Z.C. NR 73 TC 2 Z9 2 U1 1 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 EI 1878-5646 J9 VISION RES JI Vision Res. PD MAR 22 PY 2013 VL 80 BP 19 EP 30 DI 10.1016/j.visres.2013.01.007 PG 12 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 108OA UT WOS:000316304000003 PM 23376210 ER PT J AU Mattila, PK Feest, C Depoil, D Treanor, B Montaner, B Otipoby, KL Carter, R Justement, LB Bruckbauer, A Batista, FD AF Mattila, Pieta K. Feest, Christoph Depoil, David Treanor, Bebhinn Montaner, Beatriz Otipoby, Kevin L. Carter, Robert Justement, Louis B. Bruckbauer, Andreas Batista, Facundo D. TI The Actin and Tetraspanin Networks Organize Receptor Nanoclusters to Regulate B Cell Receptor-Mediated Signaling SO IMMUNITY LA English DT Article ID IMMUNE-SYNAPSE FORMATION; ANTIGEN RECEPTOR; MICROCLUSTER FORMATION; LYMPHOCYTE DEVELOPMENT; MEMBRANE; MICE; ACTIVATION; RESPONSES; TRANSDUCTION; EXPRESSION AB A key role is emerging for the cytoskeleton in coordinating receptor signaling, although the underlying molecular requirements remain unclear. Here we show that cytoskeleton disruption triggered signaling requiring not only the B cell receptor (BCR), but also the coreceptor CD19 and tetraspanin CD81, thus providing a mechanism for signal amplification upon surface-bound antigen stimulation. By using superresolution microscopy, we demonstrated that endogenous IgM, IgD, and CD19 exhibited distinct nanoscale organization within the plasma membrane of primary B cells. Upon stimulation, we detect a local convergence of receptors, although their global organization was not dramatically altered. Thus, we postulate that cytoskeleton reorganization releases BCR nanoclusters, which can interact with CD19 held in place by the tetraspanin network. These results not only suggest that receptor compartmentalization regulates antigen-induced activation but also imply a potential role for CD19 in mediating ligand-independent "tonic'' BCR signaling necessary for B cell survival. C1 [Mattila, Pieta K.; Feest, Christoph; Depoil, David; Treanor, Bebhinn; Montaner, Beatriz; Bruckbauer, Andreas; Batista, Facundo D.] Canc Res UK, London Res Inst, Lymphocyte Interact Lab, London WC2A 3LY, England. [Otipoby, Kevin L.] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA 02115 USA. [Otipoby, Kevin L.] Immune Dis Inst, Boston, MA 02115 USA. [Carter, Robert] NIAMSD, NIH, Bethesda, MD 20892 USA. [Justement, Louis B.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. RP Batista, FD (reprint author), Canc Res UK, London Res Inst, Lymphocyte Interact Lab, 44 Lincolns Inn Fields, London WC2A 3LY, England. EM facundo.batista@cancer.org.uk RI Mattila, Pieta/G-6815-2013; Feest, Christoph/C-7874-2013; OI Mattila, Pieta/0000-0003-2805-0686; Feest, Christoph/0000-0002-0772-7267; Justement, Louis/0000-0001-7058-867X FU Cancer Research UK; Royal Society Wolfson Research Merit Award; Human Frontier Science Program FX We are extremely thankful to K. Rajewsky, K. Okkenhaug, and S. Levy for providing B1-8f Igh, Cd21-cre, E mu-Bcl2 transgenic, PI3K delta-mutant, and CD81-deficient mice, respectively. We would also like to thank D. Bray and members of the Lymphocyte Interaction Laboratory for critically reading the manuscript and for helpful discussions and comments. This work was supported by Cancer Research UK, Royal Society Wolfson Research Merit Award (F. D. B.), and Human Frontier Science Program (P.K.M.). NR 43 TC 97 Z9 99 U1 1 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAR 21 PY 2013 VL 38 IS 3 BP 461 EP 474 DI 10.1016/j.immuni.2012.11.019 PG 14 WC Immunology SC Immunology GA AA2RJ UT WOS:000330941500012 PM 23499492 ER PT J AU Ferguson, AL Mann, JK Omarjee, S Ndung'u, T Walker, BD Chakraborty, AK AF Ferguson, Andrew L. Mann, Jaclyn K. Omarjee, Saleha Ndung'u, Thumbi Walker, Bruce D. Chakraborty, Arup K. TI Translating HIV Sequences into Quantitative Fitness Landscapes Predicts Viral Vulnerabilities for Rational Immunogen Design SO IMMUNITY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL RESPONSES; REPLICATION CAPACITY; CLASS-I; ELITE CONTROLLERS; LYMPHOCYTE ESCAPE; VACCINE DESIGN; HLA ALLELES; P24 GAG; INFECTION AB A prophylactic or therapeutic vaccine offers the best hope to curb the HIV-AIDS epidemic gripping sub-Saharan Africa, but it remains elusive. A major challenge is the extreme viral sequence variability among strains. Systematic means to guide immunogen design for highly variable pathogens like HIV are not available. Using computational models, we have developed an approach to translate available viral sequence data into quantitative landscapes of viral fitness as a function of the amino acid sequences of its constituent proteins. Predictions emerging from our computationally defined landscapes for the proteins of HIV-1 clade B Gag were positively tested against new in vitro fitness measurements and were consistent with previously defined in vitro measurements and clinical observations. These landscapes chart the peaks and valleys of viral fitness as protein sequences change and inform the design of immunogens and therapies that can target regions of the virus most vulnerable to selection pressure. C1 [Ferguson, Andrew L.; Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Ferguson, Andrew L.; Ndung'u, Thumbi; Walker, Bruce D.; Chakraborty, Arup K.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02129 USA. [Ferguson, Andrew L.; Ndung'u, Thumbi; Walker, Bruce D.; Chakraborty, Arup K.] Harvard Univ, Boston, MA 02129 USA. [Mann, Jaclyn K.; Omarjee, Saleha; Ndung'u, Thumbi] Univ KwaZulu Natal, HIV Pathogenesis Programme, Doris Duke Med Res Inst, ZA-4013 Durban, South Africa. [Mann, Jaclyn K.; Omarjee, Saleha; Ndung'u, Thumbi] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV K RITH, ZA-4013 Durban, South Africa. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Phys, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. RP Chakraborty, AK (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA. EM arupc@mit.edu OI Ndung'u, Thumbi/0000-0003-2962-3992; Ferguson, Andrew/0000-0002-8829-9726 FU Ragon Institute; National Institutes of Health Director's Pioneers Award; NIH [AI30914]; Howard Hughes Medical Institute; South African Department of Science and Technology/National Research Foundation Research Chair Initiative; Ragon Postdoctoral Fellowship FX We thank Todd Allen, Herman Eisen, and John Barton for fruitful discussions. Financial support was provided by the Ragon Institute (B. D. W., A. K. C., J.K.M., S.O., T.N.), a National Institutes of Health Director's Pioneers Award (A. K. C.), NIH Award AI30914 (B. D. W.), the Howard Hughes Medical Institute (B. D. W., T.N.), the South African Department of Science and Technology/National Research Foundation Research Chair Initiative (J.K.M., S.O., T.N.), and a Ragon Postdoctoral Fellowship (A.L.F.). NR 52 TC 56 Z9 59 U1 3 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD MAR 21 PY 2013 VL 38 IS 3 BP 606 EP 617 DI 10.1016/j.immuni.2012.11.022 PG 12 WC Immunology SC Immunology GA AA2RJ UT WOS:000330941500023 PM 23521886 ER PT J AU Musallam, KM Taher, AT Cappellini, MD Sankaran, VG AF Musallam, Khaled M. Taher, Ali T. Cappellini, Maria Domenica Sankaran, Vijay G. TI Clinical experience with fetal hemoglobin induction therapy in patients with beta-thalassemia SO BLOOD LA English DT Review ID SICKLE-CELL-ANEMIA; RECOMBINANT-HUMAN-ERYTHROPOIETIN; SODIUM PHENYLBUTYRATE THERAPY; GLOBIN GENE-EXPRESSION; RED-BLOOD-CELLS; HYDROXYUREA THERAPY; TRANSFUSION REQUIREMENTS; INTERMEDIA PATIENTS; DNA METHYLATION; EXTRAMEDULLARY HEMATOPOIESIS AB Recent molecular studies of fetal hemoglobin (HbF) regulation have reinvigorated the field and shown promise for the development of clinical HbF inducers to be used in patients with beta-thalassemia and sickle cell disease. However, while numerous promising inducers of HbF have been studied in the past in beta-thalassemia patient populations, with limited success in some cases, no universally effective agents have been found. Here we examine the clinical studies of such inducers in an attempt to systematically review the field. We examine trials of agents, including 5-azacytidine, hydroxyurea, and short-chain fatty acids. This review highlights the heterogeneity of clinical studies done on these agents, including both the patient populations examined and the study end points. By examining the published studies of these agents, we hope to provide a resource that will be valuable for the design of future studies of HbF inducers in beta-thalassemia patient populations. C1 [Musallam, Khaled M.; Cappellini, Maria Domenica] Univ Milan, Dept Med & Med Specialties, Fdn IRCCS Ca Granda, Osped Maggiore Policlin, Milan, Italy. [Musallam, Khaled M.; Taher, Ali T.] Amer Univ Beirut, Med Ctr, Dept Internal Med, Beirut, Lebanon. [Sankaran, Vijay G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Oncol,Boston Childrens Hosp, Boston, MA 02115 USA. [Sankaran, Vijay G.] Broad Inst, Cambridge, MA USA. [Sankaran, Vijay G.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. RP Sankaran, VG (reprint author), Boston Childrens Hosp, Div Hematol Oncol, 300 Longwood Ave, Boston, MA 02115 USA. EM sankaran@broadinstitute.org NR 146 TC 41 Z9 44 U1 3 U2 18 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 21 PY 2013 VL 121 IS 12 BP 2199 EP 2212 DI 10.1182/blood-2012-10-408021 PG 14 WC Hematology SC Hematology GA 182RI UT WOS:000321761100010 PM 23315167 ER PT J AU Hoggatt, J Mohammad, KS Singh, P Hoggatt, AF Chitteti, BR Speth, JM Hu, PR Poteat, BA Stilger, KN Ferraro, F Silberstein, L Wong, FK Farag, SS Czader, M Milne, GL Breyer, RM Serezani, CH Scadden, DT Guise, TA Srour, EF Pelus, LM AF Hoggatt, Jonathan Mohammad, Khalid S. Singh, Pratibha Hoggatt, Amber F. Chitteti, Brahmananda R. Speth, Jennifer M. Hu, Peirong Poteat, Bradley A. Stilger, Kayla N. Ferraro, Francesca Silberstein, Lev Wong, Frankie K. Farag, Sherif S. Czader, Magdalena Milne, Ginger L. Breyer, Richard M. Serezani, Carlos H. Scadden, David T. Guise, Theresa A. Srour, Edward F. Pelus, Louis M. TI Differential stem- and progenitor-cell trafficking by prostaglandin E-2 SO NATURE LA English DT Article ID BONE-MARROW NICHE; HEMATOPOIETIC STEM; RECEPTOR; MICROENVIRONMENT; OSTEOPONTIN; IMPACT; SIZE AB To maintain lifelong production of blood cells, haematopoietic stem cells (HSCs) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSCs reside in several, perhaps overlapping, niches that produce regulatory molecules and signals necessary for homeostasis and for increased output after stress or injury(1-5). Despite considerable advances in the specific cellular or molecular mechanisms governing HSC-niche interactions, little is known about the regulatory function in the intact mammalian haematopoietic niche. Recently, we and others described a positive regulatory role for prostaglandin E-2 (PGE(2)) on HSC function ex vivo(6,7). Here we show that inhibition of endogenous PGE(2) by nonsteroidal anti-inflammatory drug (NSAID) treatment in mice results in modest HSC egress from the bone marrow. Surprisingly, this was independent of the SDF-1-CXCR4 axis implicated in stem-cell migration. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on niche attenuation and reduction in the retentive molecule osteopontin. Haematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in other species. PGE(2) receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced E-prostanoid 4 (EP4) receptor signalling. These results not only uncover unique regulatory roles for EP4 signalling in HSC retention in the niche, but also define a rapidly translatable strategy to enhance transplantation therapeutically. C1 [Hoggatt, Jonathan; Mohammad, Khalid S.; Singh, Pratibha; Hoggatt, Amber F.; Speth, Jennifer M.; Hu, Peirong; Stilger, Kayla N.; Czader, Magdalena; Serezani, Carlos H.; Guise, Theresa A.; Srour, Edward F.; Pelus, Louis M.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Hoggatt, Jonathan; Ferraro, Francesca; Silberstein, Lev; Wong, Frankie K.; Scadden, David T.] Harvard Univ, Harvard Stem Cell Inst, Harvard Med Sch, Ctr Regenerat Med,Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hoggatt, Amber F.] Univ Illinois, Biol Resources Lab, Chicago, IL 60612 USA. [Chitteti, Brahmananda R.; Poteat, Bradley A.; Farag, Sherif S.; Srour, Edward F.] Indiana Univ Sch Med, Div Hematol & Oncol, Indianapolis, IN 46202 USA. [Milne, Ginger L.] Vanderbilt Univ, Div Clin Pharmacol, Eicosanoid Core Lab, Nashville, TN 37232 USA. [Breyer, Richard M.] Vanderbilt Univ, Div Nephrol & Hypertens, Nashville, TN 37232 USA. RP Pelus, LM (reprint author), Indiana Univ Sch Med, Indianapolis, IN 46202 USA. EM lpelus@iupui.edu RI Milne, Ginger/D-7648-2014; OI Milne, Ginger/0000-0003-3890-151X; serezani, carlos/0000-0002-5363-415X FU National Institutes of Health (NIH) [HL096305, CA143057, CA069158, HL100402, DK37097]; NIH [DK07519, HL07910, HL087735]; Center of Excellence in Hematology [P01 DK090948] FX These studies were supported by National Institutes of Health (NIH) grants HL096305 (L.M.P.), CA143057, CA069158 (T.A.G., K.S.M.), HL100402 (D.T.S.) and DK37097 (R.M.B.). J.H. was supported by NIH training grants DK07519, HL07910 and HL087735. Flow cytometry was performed in the Flow Cytometry Resource Facility of the Indiana University Simon Cancer Center (NCI P30 CA082709). Additional core support was provided by a Center of Excellence in Hematology grant P01 DK090948. The authors would like to thank H. E. Broxmeyer and B. Saez for critically reading the manuscript. NR 26 TC 50 Z9 51 U1 0 U2 22 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 MAR 21 PY 2013 VL 495 IS 7441 BP 365 EP 369 DI 10.1038/nature11929 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 113EY UT WOS:000316650500042 PM 23485965 ER PT J AU Schulz, TJ Huang, P Huang, TL Xue, RD McDougall, LE Townsend, KL Cypess, AM Mishina, Y Gussoni, E Tseng, YH AF Schulz, Tim J. Huang, Ping Huang, Tian Lian Xue, Ruidan McDougall, Lindsay E. Townsend, Kristy L. Cypess, Aaron M. Mishina, Yuji Gussoni, Emanuela Tseng, Yu-Hua TI Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat SO NATURE LA English DT Article ID ADIPOSE-TISSUE; TRANSCRIPTIONAL CONTROL; ADULT HUMANS; ADIPOCYTES; THERMOGENESIS; MICE; DISTINCT; REVEALS; MUSCLE; MOUSE AB Maintenance of body temperature is essential for the survival of homeotherms. Brown adipose tissue (BAT) is a specialized fat tissue that is dedicated to thermoregulation(1). Owing to its remarkable capacity to dissipate stored energy and its demonstrated presence in adult humans(2-5), BAT holds great promise for the treatment of obesity and metabolic syndrome(1). Rodent data suggest the existence of two types of brown fat cells: constitutive BAT (cBAT), which is of embryonic origin and anatomically located in the imterscapular region of mice; and recruitable BAT (rBAT), which resides within white adipose tissue (WAT)(6) and skeletal muscle(7), and has alternatively been called beige(8), brite(9) or inducible BAT(10). Bone morphogenetic proteins (BMPs) regulate the formation and thermogenic activity of BAT(10-12). Here we use mouse models to provide evidence for a systemically active regulatory mechanism that controls whole-body BAT activity for thermoregulation and energy homeostasis. Genetic ablation of the type 1A BMP receptor (Bmpr1a) in brown adipogenic progenitor cells leads to a severe paucity of cBAT. This in turn increases sympathetic input to WAT, thereby promoting the formation of rBAT within white fat depots. This previously unknown compensatory mechanism, aimed at restoring total brown-fat-mediated thermogenic capacity in the body, is sufficient to maintain normal temperature homeostasis and resistance to diet-induced obesity. These data suggest an important physiological cross-talk between constitutive and recruitable brown fat cells. This sophisticated regulatory mechanism of body temperature may participate in the control of energy balance and metabolic disease. C1 [Schulz, Tim J.; Huang, Tian Lian; Xue, Ruidan; McDougall, Lindsay E.; Townsend, Kristy L.; Cypess, Aaron M.; Tseng, Yu-Hua] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. [Huang, Ping; Gussoni, Emanuela] Harvard Univ, Sch Med, Boston Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Huang, Ping; Gussoni, Emanuela] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Xue, Ruidan] Fudan Univ, Shanghai Med Coll, Huashan Hosp, Div Endocrinol & Metab, Shanghai 200032, Peoples R China. [Mishina, Yuji] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Tseng, Yu-Hua] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Tseng, YH (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. EM yu-hua.tseng@joslin.harvard.edu RI Schulz, Tim/F-4842-2013 OI Schulz, Tim/0000-0002-8413-3972 FU National Institutes of Health (NIH) [R01 DK077097]; Joslin Diabetes Center's Diabetes Research Center (DRC from the NIDDK) [P30 DK036836]; Eli Lilly Research Foundation; Harvard Stem Cell Institute; Mary K. Iacocca Foundation; German Research Foundation (DFG) [SCHU2445/1-1]; American Heart Association [0730285N]; NIH [T32 DK007260, F32 DK091996]; National Natural Science Foundation of China [985III-YFX0302, NSFC81070680] FX This work was supported in part by National Institutes of Health (NIH) grants R01 DK077097 (Y.-H.T.), and Joslin Diabetes Center's Diabetes Research Center (DRC; P30 DK036836 from the NIDDK), a research grant from the Eli Lilly Research Foundation, and by funding from the Harvard Stem Cell Institute (to Y.-H.T.), T.J.S. was supported by the Mary K. Iacocca Foundation and the German Research Foundation (DFG; SCHU2445/1-1). P.H. was supported by a Scientist Development Grant from the American Heart Association (0730285N). K.L.T. was supported by NIH fellowships (T32 DK007260 and F32 DK091996). R.X. was supported by Project 985III-YFX0302 and NSFC81070680 from the National Natural Science Foundation of China. The authors thank Stryker Regenerative Medicine for the gift of recombinant BMP7. We acknowledge V. Kaartinen, B. Kahn, K. Lyons and P. Soriano for providing floxed Acvr1 mice, FABP4-Cre mice, Bmpr1b heterozygous mice and Myf5-Cre mice, respectively. The authors thank C. R. Kahn, L.J. Goodyear, E. Kokkotou and D. Breault for comments on the manuscript The authors wish to thank J. LaVecchio, G. Buruzula, A. Wakabayashi, A. Pinkhasov, A. Clermont, M. Mulvey, C. Cahill and G. Sankaranarayanan for technical assistance, and E. Caniano for editorial contributions. NR 30 TC 123 Z9 126 U1 5 U2 64 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 MAR 21 PY 2013 VL 495 IS 7441 BP 379 EP 383 DI 10.1038/nature11943 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 113EY UT WOS:000316650500045 PM 23485971 ER PT J AU Fracchia, MS El Saleeby, CM Murali, MR Sagar, P Mino-Kenudson, M AF Fracchia, Mary Shannon El Saleeby, Chadi M. Murali, Mandakolathur R. Sagar, Pallavi Mino-Kenudson, Mari TI Case 9-2013: A 9-Year-Old Boy with Fever, Cough, Respiratory Distress, and Chest Pain SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HYPERSENSITIVITY PNEUMONITIS; DISEASE; EPIDEMIOLOGY; DIAGNOSIS; EVOLUTION; CHILDREN C1 [Fracchia, Mary Shannon; El Saleeby, Chadi M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Murali, Mandakolathur R.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Sagar, Pallavi] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Fracchia, Mary Shannon; El Saleeby, Chadi M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Murali, Mandakolathur R.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Sagar, Pallavi] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Mino-Kenudson, Mari] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Fracchia, MS (reprint author), Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. FU Department of Continuing Education, Harvard Medical School FX This case was discussed at the postgraduate course, Primary Care Pediatrics; course directors: Ronni L. Goldsmith, M. D., Peter T. Greenspan, M. D., Ronald E. Kleinman, M. D., Janice A. Lowe, M. D., and John Patrick T. Co, M. D., M. P. H., sponsored by the Department of Continuing Education, Harvard Medical School. NR 19 TC 3 Z9 3 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 21 PY 2013 VL 368 IS 12 BP 1141 EP 1150 DI 10.1056/NEJMcpc1208144 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 108TH UT WOS:000316318600009 PM 23514292 ER PT J AU Nejad, SH Bajwa, EK AF Nejad, Shamim H. Bajwa, Ednan K. TI Case 39-2012: A Man with Alcoholism, Recurrent Seizures, and Agitation Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Nejad, Shamim H.; Bajwa, Ednan K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Nejad, SH (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 21 PY 2013 VL 368 IS 12 BP 1164 EP 1165 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 108TH UT WOS:000316318600028 PM 23514305 ER PT J AU Yigit, MV Ghosh, SK Kumar, M Petkova, V Kavishwar, A Moore, A Medarova, Z AF Yigit, M. V. Ghosh, S. K. Kumar, M. Petkova, V. Kavishwar, A. Moore, A. Medarova, Z. TI Context-dependent differences in miR-10b breast oncogenesis can be targeted for the prevention and arrest of lymph node metastasis SO ONCOGENE LA English DT Article DE imaging; miRNA; metastasis; miR-10b; nanoparticle; therapy ID SUPERPARAMAGNETIC IRON-OXIDE; CANCER; MICRORNA; THERAPEUTICS; LNA AB Metastases, and not the primary tumor from which they originate, are the main reason for mortality from carcinoma. Although the molecular mechanisms behind metastasis are poorly understood, it is clear that epigenetic dysregulation at the level of microRNA expression is a key characteristic of the metastatic process that can be exploited for therapy. Here, we describe an miRNA-targeted therapeutic approach for the prevention and arrest of lymph node metastasis. Therapy relies on the inhibition of the pro-metastatic microRNA-10b. It is delivered to primary and lymph node metastatic tumor cells using an imaging-capable nanodrug that is designed to specifically home to these tissues. Treatment of invasive human breast tumor cells (MDA-MB-231) with the nanodrug in vitro downregulates miR-10b and abolishes the invasion and migration of the tumor cells. After intravenous delivery to mice bearing orthotopic MDA-MB-231-luc-D3H2LN tumors, the nanodrug accumulates in the primary tumor and lymph nodes. When treatment is initiated before metastasis to lymph nodes, metastasis is prevented. Treatment after the formation of lymph node metastases arrests the metastatic process without a concomitant effect on primary tumor growth raising the possibility of a context-dependent variation in miR-10b breast oncogenesis. Oncogene (2013) 32, 1530-1538; doi:10.1038/onc.2012.173; published online 14 May 2012 C1 [Yigit, M. V.; Ghosh, S. K.; Kumar, M.; Kavishwar, A.; Moore, A.; Medarova, Z.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Mol Imaging Lab, Dept Radiol, Charlestown, MA USA. [Yigit, M. V.; Ghosh, S. K.; Kumar, M.; Kavishwar, A.; Moore, A.; Medarova, Z.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Petkova, V.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Moore, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Mol Imaging Lab,MGH MIT HMS Athinoula, Bldg 75,13th St, Charlestown, MA 02129 USA. EM amoore@helix.mgh.harvard.edu; zmedarova@partners.org OI Kavishwar, Amol/0000-0001-8214-6625 FU National Cancer Institute [R00CA129070]; Breast Cancer Alliance FX We thank Pamela Pantazopoulos and Alana Ross for help with the in-vitro, in-vivo and ex-vivo studies and Marytheresa Ifediba for proofreading the manuscript. Confocal microscopy was performed at the Confocal Microscopy Core at MGH with technical assistance from Igor A Bagayev, MS Work at the Martinos Center for Biomedical Imaging was supported in part under Grant R00CA129070 from the National Cancer Institute and a Research Grant from the Breast Cancer Alliance. NR 26 TC 34 Z9 34 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 21 PY 2013 VL 32 IS 12 BP 1530 EP 1538 DI 10.1038/onc.2012.173 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 110PC UT WOS:000316456000006 PM 22580603 ER PT J AU Nunes, FP Merker, VL Jennings, D Caruso, PA di Tomaso, E Muzikansky, A Barker, FG Stemmer-Rachamimov, A Plotkin, SR AF Nunes, Fabio P. Merker, Vanessa L. Jennings, Dominique Caruso, Paul A. di Tomaso, Emmanuelle Muzikansky, Alona Barker, Fred G., II Stemmer-Rachamimov, Anat Plotkin, Scott R. TI Bevacizumab Treatment for Meningiomas in NF2: A Retrospective Analysis of 15 Patients SO PLOS ONE LA English DT Article ID PHASE-II; NEUROFIBROMATOSIS TYPE-2; RECURRENT MENINGIOMAS; HYDROXYUREA; REGRESSION; THERAPY; ADULTS AB Bevacizumab treatment can result in tumor shrinkage of progressive vestibular schwannomas in some neurofibromatosis 2 (NF2) patients but its effect on meningiomas has not been defined. To determine the clinical activity of bevacizumab against NF2-related meningiomas, we measured changes in volume of meningiomas in NF2 patients who received bevacizumab for treatment of progressive vestibular schwannomas. A radiographic response was defined as a 20% decrease in tumor size by volumetric MRI analysis. In addition, we determined the expression pattern of growth factors associated with tumor angiogenesis in paraffin-embedded tissues from 26 unrelated meningiomas. A total of 48 meningiomas in 15 NF2 patients were included in this study with a median follow up time of 18 months. A volumetric radiographic response was seen in 29% of the meningiomas (14/48). Tumor shrinkage was not durable: the median duration of response was 3.7 months and the median time to progression was 15 months. There was no significant correlation between pre-treatment growth rate and meningioma response in regression models. Tissue analysis showed no correlation between tumor microvascular density and expression of VEGF pathway components. This data suggests that, in contrast to schwannomas, activation of VEGF pathway is not the primary driver of angiogenesis in meningiomas. Our results suggest that a minority of NF2-associated meningiomas shrink during bevacizumab therapy and that these responses were of short duration. These results are comparable to previous studies of bevacizumab in sporadic meningiomas. C1 [Nunes, Fabio P.; Merker, Vanessa L.; Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Nunes, Fabio P.] Massachusetts Gen Hosp, Dept Genet, Boston, MA 02114 USA. [Merker, Vanessa L.; Plotkin, Scott R.] Massachusetts Gen Hosp, Stephen E & Catherine Pappas Ctr Neurooncol, Boston, MA 02114 USA. [Jennings, Dominique] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Caruso, Paul A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [di Tomaso, Emmanuelle; Stemmer-Rachamimov, Anat] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Muzikansky, Alona] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. [Barker, Fred G., II] Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02114 USA. RP Plotkin, SR (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM splotkin@partners.org OI Merker, Vanessa/0000-0002-4542-5227 FU United States National Institutes of Heath [5-T32-GM007748-32] FX This work was supported by a United States National Institutes of Heath grant (5-T32-GM007748-32) to FPN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 31 Z9 33 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 MAR 21 PY 2013 VL 8 IS 3 AR e59941 DI 10.1371/journal.pone.0059941 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 111UM UT WOS:000316546400070 PM 23555840 ER PT J AU Li, R Sharp, G AF Li, Rui Sharp, Gregory TI Robust fluoroscopic tracking of fiducial markers: exploiting the spatial constraints SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID REAL-TIME TUMOR; GATED RADIATION-THERAPY; LUNG-TUMORS; RADIOTHERAPY; MOTION; SYSTEM; RADIOSURGERY; FEASIBILITY; PROJECTIONS; MANAGEMENT AB Two new fluoroscopic fiducial tracking methods that exploit the spatial relationship among the multiple implanted fiducial to achieve fast, accurate and robust tracking are proposed in this paper. The spatial relationship between multiple implanted markers are modeled as Gaussian distributions of their pairwise distances over time. The means and standard deviations of these distances are learned from training sequences, and pairwise distances that deviate from these learned distributions are assigned a low spatial matching score. The spatial constraints are incorporated in two different algorithms: a stochastic tracking method and a detection based method. In the stochastic method, hypotheses of the 'true' fiducial position are sampled from a pretrained respiration motion model. Each hypothesis is assigned an importance value based on image matching score and spatial matching score. Learning the parameters of the motion model is needed in addition to learning the distribution parameters of the pairwise distances in the proposed stochastic tracking approach. In the detection based method, a set of possible marker locations are identified by using a template matching based fiducial detector. The best location is obtained by optimizing the image matching score and spatial matching score through non-serial dynamic programming. In this detection based approach, there is no need to learn the respiration motion model. The two proposed algorithms are compared with a recent work using a multiple hypothesis tracking (MHT) algorithm which is denoted by MHT, Tang et al (2007 Phys. Med. Biol. 52 4081-98). Phantom experiments were performed using fluoroscopic videos captured with known motion relative to an anthropomorphic phantom. The patient experiments were performed using a retrospective study of 16 fluoroscopic videos of liver cancer patients with implanted fiducials. For the motion phantom data sets, the detection based approach has the smallest tracking error (mu(err): 0.78-1.74 mm, sigma(err): 0.39-1.16 mm) for the images taken at low exposure (50 mAs). At higher exposure (500 mAs), the stochastic method gave the best performance (mu(err) :similar to 0.39 sigma(err) :similar to 0.27 mm). In contrast, the tracker (MHT) that does not model the spatial constraints only performs well when there is no occluded fiducial. With the RANDO phantom data, both of our proposed methods performed well and have the mean tracking errors around similar to 1.8 mm with the standard deviations similar to 0.93 mm at 100 mAs and similar to 0.91 mm with 0.88 mm standard deviation at 500 mAs. The MHT tracker has the largest tracking errors with mean similar to 4.8 mm) and standard deviation similar to 2.4mmin both sessions with the Rondo phantom data. On the patient data sets, the detection based method gave the smallest error (mu(err): 0.39 mm, sigma(err): similar to 0.19 mm). The stochastic method performed well (mu(err): similar to 0.58 mm, sigma(err): similar to 0.39 mm) when the patient breathed consistently, the accuracy dropped to (mu(err): similar to 1.55 mm) when the patient breathed differently across sessions. C1 [Li, Rui] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Li, R (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM bucslirui@gmail.com FU NIH/NCI [P01-CA21239] FX This research was supported by NIH/NCI grant P01-CA21239. NR 39 TC 4 Z9 4 U1 0 U2 7 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD MAR 21 PY 2013 VL 58 IS 6 BP 1789 EP 1808 DI 10.1088/0031-9155/58/6/1789 PG 20 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 100WL UT WOS:000315735400008 PM 23442336 ER PT J AU Bahl, S Chiang, C Beauchamp, RL Neale, BM Daly, MJ Gusella, JF Talkowski, ME Ramesh, V AF Bahl, Samira Chiang, Colby Beauchamp, Roberta L. Neale, Benjamin M. Daly, Mark J. Gusella, James F. Talkowski, Michael E. Ramesh, Vijaya TI Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder SO MOLECULAR AUTISM LA English DT Article DE Autism spectrum disorder; Tuberous sclerosis complex; Mammalian target of rapamycin; Next-generation sequencing; Rare variants ID TUBEROUS SCLEROSIS COMPLEX; DE-NOVO MUTATIONS; DNA-SEQUENCING DATA; PROTEIN; LIGASE; INDIVIDUALS; GROWTH; TSC1; RHEB; PAM AB Background: Autism spectrum disorder (ASD) is reported in 30 to 60% of patients with tuberous sclerosis complex (TSC) but shared genetic mechanisms that exist between TSC-associated ASD and idiopathic ASD have yet to be determined. Through the small G-protein Rheb, the TSC proteins, hamartin and tuberin, negatively regulate mammalian target of rapamycin complex 1 (mTORC1) signaling. It is well established that mTORC1 plays a pivotal role in neuronal translation and connectivity, so dysregulation of mTORC1 signaling could be a common feature in many ASDs. Pam, an E3 ubiquitin ligase, binds to TSC proteins and regulates mTORC1 signaling in the CNS, and the FBXO45-Pam ubiquitin ligase complex plays an essential role in neurodevelopment by regulating synapse formation and growth. Since mounting evidence has established autism as a disorder of the synapses, we tested whether rare genetic variants in TSC1, TSC2, MYCBP2, RHEB and FBXO45, genes that regulate mTORC1 signaling and/ or play a role in synapse development and function, contribute to the pathogenesis of idiopathic ASD. Methods: Exons and splice junctions of TSC1, TSC2, MYCBP2, RHEB and FBXO45 were resequenced for 300 ASD trios from the Simons Simplex Collection (SSC) using a pooled PCR amplification and next-generation sequencing strategy, targeted to the discovery of deleterious coding variation. These detected, potentially functional, variants were confirmed by Sanger sequencing of the individual samples comprising the pools in which they were identified. Results: We identified a total of 23 missense variants in MYCBP2, TSC1 and TSC2. These variants exhibited a near equal distribution between the proband and parental pools, with no statistical excess in ASD cases (P > 0.05). All proband variants were inherited. No putative deleterious variants were confirmed in RHEB and FBXO45. Three intronic variants, identified as potential splice defects in MYCBP2 did not show aberrant splicing upon RNA assay. Overall, we did not find an over-representation of ASD causal variants in the genes studied to support them as contributors to autism susceptibility. Conclusions: We did not observe an enrichment of rare functional variants in TSC1 and TSC2 genes in our sample set of 300 trios. C1 [Bahl, Samira; Chiang, Colby; Beauchamp, Roberta L.; Neale, Benjamin M.; Daly, Mark J.; Gusella, James F.; Talkowski, Michael E.; Ramesh, Vijaya] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Neale, Benjamin M.; Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Neale, Benjamin M.; Daly, Mark J.; Gusella, James F.; Talkowski, Michael E.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02143 USA. [Gusella, James F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Ramesh, V (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM ramesh@helix.mgh.harvard.edu OI Chiang, Colby/0000-0002-4113-6065 FU Simons Foundation for Autism Research Initiative [SFARI 95345]; National Institute of Health [NS024279, MH095867]; TS Alliance FX We sincerely thank all the families who have participated in the Simons Simplex study. We are grateful to Tammy Gillis and Mary Anne Anderson in the Center for Human Genetic Research Genomics Resource and Tissue Culture Facility for technical assistance. This work was supported by a grant from Simons Foundation for Autism Research Initiative (SFARI 95345 to VR), National Institute of Health Grants NS024279 (to VR and JFG), MH095867 (to MET) and a fellowship from TS Alliance (to SB). NR 47 TC 4 Z9 6 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2040-2392 J9 MOL AUTISM JI Mol. Autism PD MAR 20 PY 2013 VL 4 AR 5 DI 10.1186/2040-2392-4-5 PG 11 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 254UI UT WOS:000327192900001 PM 23514105 ER PT J AU Braverman, ER Blum, K Damle, UJ Kerner, M Dushaj, K Oscar-Berman, M AF Braverman, Eric R. Blum, Kenneth Damle, Uma J. Kerner, Mallory Dushaj, Kristina Oscar-Berman, Marlene TI Evoked Potentials and Neuropsychological Tests Validate Positron Emission Topography (PET) Brain Metabolism in Cognitively Impaired Patients SO PLOS ONE LA English DT Article ID MINI-MENTAL-STATE; FAMILIAL ALZHEIMER-DISEASE; CORTICAL THICKNESS; AMYLOID PATHOLOGY; MEMORY IMPAIRMENT; FDG-PET; DECLINE; DEMENTIA; MCI; CSF AB Fluorodeoxyglucose (FDG) Positron Emission Topography (PET) brain hypometabolism (HM) correlates with diminished cognitive capacity and risk of developing dementia. However, because clinical utility of PET is limited by cost, we sought to determine whether a less costly electrophysiological measure, the P300 evoked potential, in combination with neuropsychological test performance, would validate PET HM in neuropsychiatric patients. We found that patients with amnestic and non-amnestic cognitive impairment and HM (n = 43) evidenced significantly reduced P300 amplitudes, delayed latencies, and neuropsychological deficits, compared to patients with normal brain metabolism (NM; n = 187). Data from patients with missing cognitive test scores (n = 57) were removed from the final sample, and logistic regression modeling was performed on the modified sample (n = 173, p = .000004). The logistic regression modeling, based on P300 and neuropsychological measures, was used to validate membership in the HM vs. NM groups. It showed classification validation in 13/25 HM subjects (52.0%) and in 125/148 NM subjects (84.5%), correlating with total classification accuracy of 79.8%. In this paper, abnormal P300 evoked potentials coupled with cognitive test impairment validates brain metabolism and mild/moderate cognitive impairment (MCI). To this end, we cautiously propose incorporating electrophysiological and neuropsychological assessments as cost-effective brain metabolism and MCI indicators in primary care. Final interpretation of these results must await required additional studies confirming these interesting results. C1 [Braverman, Eric R.; Blum, Kenneth; Damle, Uma J.; Kerner, Mallory; Dushaj, Kristina] PATH Fdn NY, Dept Clin Neurol, New York, NY 10010 USA. [Braverman, Eric R.; Blum, Kenneth] Univ Florida, Dept Psychiat, Coll Med, Gainesville, FL 32611 USA. [Braverman, Eric R.; Blum, Kenneth] Univ Florida, Coll Med, McKnight Brain Inst, Gainesville, FL USA. [Blum, Kenneth] Univ Vermont, Coll Med, Ctr Clin & Translat Sci, Global Integrated Serv Unit, Burlington, VT 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 USA. RP Braverman, ER (reprint author), PATH Fdn NY, Dept Clin Neurol, New York, NY 10010 USA. EM info@pathfoundationny.org FU Life Extension Foundation; National Institute on Alcohol Abuse and Alcoholism (NIAAA) [R01 AA07112, K05 AA 00219]; Medical Research Service of the US Department of Veterans Affairs FX The authors are grateful to the Life Extension Foundation for their generous financial support to KB and the PATH Foundation NY. MOB is the recipient of grants from National Institute on Alcohol Abuse and Alcoholism (NIAAA) (R01 AA07112, K05 AA 00219) and from the Medical Research Service of the US Department of Veterans Affairs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 5 Z9 6 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 20 PY 2013 VL 8 IS 3 AR e55398 DI 10.1371/journal.pone.0055398 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125SW UT WOS:000317562600003 PM 23526928 ER PT J AU Buys, ES Ko, YC Alt, C Hayton, SR Jones, A Tainsh, LT Ren, RY Giani, A Clerte, M Abernathy, E Tainsh, RET Oh, DJ Malhotra, R Arora, P de Waard, N Yu, BL Turcotte, R Nathan, D Scherrer-Crosbie, M Loomis, SJ Kang, JH Lin, CP Gong, HY Rhee, DJ Brouckaert, P Wiggs, JL Gregory, MS Pasquale, LR Bloch, KD Ksander, BR AF Buys, Emmanuel S. Ko, Yu-Chieh Alt, Clemens Hayton, Sarah R. Jones, Alexander Tainsh, Laurel T. Ren, Ruiyi Giani, Andrea Clerte, Maeva Abernathy, Emma Tainsh, Robert E. T. Oh, Dong-Jin Malhotra, Rajeev Arora, Pankaj de Waard, Nadine Yu, Binglan Turcotte, Raphael Nathan, Daniel Scherrer-Crosbie, Marielle Loomis, Stephanie J. Kang, Jae H. Lin, Charles P. Gong, Haiyan Rhee, Douglas J. Brouckaert, Peter Wiggs, Janey L. Gregory, Meredith S. Pasquale, Louis R. Bloch, Kenneth D. Ksander, Bruce R. TI Soluble Guanylate Cyclase alpha(1)-Deficient Mice: A Novel Murine Model for Primary Open Angle Glaucoma SO PLOS ONE LA English DT Article ID NITRIC-OXIDE SYNTHASE; I COLLAGEN MUTATION; OCULAR PERFUSION-PRESSURE; HUMOR OUTFLOW FACILITY; OPTIC-NERVE HEAD; TRABECULAR MESHWORK; BLOOD-FLOW; ENDOTHELIAL DYSFUNCTION; INTRAOCULAR-PRESSURE; CLINICAL-TRIAL AB Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the alpha(1) subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase alpha(1)-deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the alpha(1) and beta(1) subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG. C1 [Buys, Emmanuel S.; Hayton, Sarah R.; Tainsh, Laurel T.; Tainsh, Robert E. T.; Yu, Binglan; Nathan, Daniel; Bloch, Kenneth D.] Harvard Univ, Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, Dept Anesthesia Crit Care & Pain Med,Med Sch, Boston, MA 02215 USA. [Ko, Yu-Chieh; Jones, Alexander; Abernathy, Emma; de Waard, Nadine; Gregory, Meredith S.; Pasquale, Louis R.; Ksander, Bruce R.] Harvard Univ, Schepens Eye Res Inst, Dept Ophthalmol, Sch Med, Boston, MA USA. [Ko, Yu-Chieh] Natl Yang Ming Univ, Sch Med, Dept Ophthalmol, Taipei 112, Taiwan. [Alt, Clemens; Turcotte, Raphael; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Alt, Clemens; Turcotte, Raphael; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Ren, Ruiyi; Gong, Haiyan] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Giani, Andrea; Oh, Dong-Jin; Loomis, Stephanie J.; Rhee, Douglas J.; Wiggs, Janey L.; Gregory, Meredith S.; Pasquale, Louis R.; Ksander, Bruce R.] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Clerte, Maeva; Malhotra, Rajeev; Arora, Pankaj; Scherrer-Crosbie, Marielle; Bloch, Kenneth D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA USA. [Turcotte, Raphael] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Kang, Jae H.; Pasquale, Louis R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Brouckaert, Peter] Univ Ghent VIB, Dept Mol Biomed Res, Ghent, Belgium. RP Buys, ES (reprint author), Harvard Univ, Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, Dept Anesthesia Crit Care & Pain Med,Med Sch, Boston, MA 02215 USA. EM Ebuys@partners.org FU Harvard Catalyst-the Harvard Clinical and Translational Science Center (NIH) [UL1 RR 025758]; Harvard University; Shaffer Fund Grant from the Glaucoma Research Foundation; NEI [R21 EY020987, R01 EY022746-01, R01 EY015872, R01 EY015473]; American Heart Association Fellow-to-Faculty Transition Award [11FTF7290032]; NCRR [1S10RR022586]; NIH [CA87969, CA49449, EY09611, CA055075]; Massachusetts Lions Eye Research Fund; FWO-Flanders fund; UGent-GOA fund; Harvard Glaucoma Center of Excellence; Harvard Ophthalmology Scholar award; Physician-Scientist award from Research to Prevent Blindness in NYC; Allergan Horizon grant; NHGRI [5U01HG004728] FX This work was conducted with support from Harvard Catalyst-the Harvard Clinical and Translational Science Center (NIH Award #UL1 RR 025758, and financial contributions from Harvard University and its affiliated academic health care centers) (ESB, BRK); a Shaffer Fund Grant from the Glaucoma Research Foundation (ESB); NEI R21 EY020987 (ESB, BRK); NEI R01 EY022746-01 (ESB); an American Heart Association Fellow-to-Faculty Transition Award #11FTF7290032 (RM); NCRR 1S10RR022586 (MSC); NIH CA87969, CA49449, EY09611, CA055075 (JHK); the Massachusetts Lions Eye Research Fund (HG, RR); the FWO-Flanders and UGent-GOA funds (PB); NEI R01 EY015872 (JLW); the Harvard Glaucoma Center of Excellence (LRP and JLW); a Harvard Ophthalmology Scholar award (LRP); a Physician-Scientist award from Research to Prevent Blindness in NYC (LRP); an Allergan Horizon grant (LRP); NEI R01 EY015473 (LRP); and NHGRI 5U01HG004728 (LRP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 82 TC 21 Z9 21 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 20 PY 2013 VL 8 IS 3 AR e60156 DI 10.1371/journal.pone.0060156 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125SW UT WOS:000317562600124 PM 23527308 ER PT J AU Contreras-Shannon, V Heart, DL Paredes, RM Navaira, E Catano, G Maffi, SK Walss-Bass, C AF Contreras-Shannon, Veronica Heart, Dylan L. Paredes, R. Madelaine Navaira, Erica Catano, Gabriel Maffi, Shivani Kaushal Walss-Bass, Consuelo TI Clozapine-Induced Mitochondria Alterations and Inflammation in Brain and Insulin-Responsive Cells SO PLOS ONE LA English DT Article ID INDUCED METABOLIC ALTERATIONS; OXIDATIVE STRESS; RAT-BRAIN; ANTIPSYCHOTIC MEDICATIONS; POSSIBLE MECHANISM; ENERGY-METABOLISM; OBESITY; DYSFUNCTION; RESISTANCE; SCHIZOPHRENIA AB Background: Metabolic syndrome (MetS) is a constellation of factors including abdominal obesity, hyperglycemia, dyslipidemias, and hypertension that increase morbidity and mortality from diabetes and cardiovascular diseases and affects more than a third of the population in the US. Clozapine, an atypical antipsychotic used for the treatment of schizophrenia, has been found to cause drug-induced metabolic syndrome (DIMS) and may be a useful tool for studying cellular and molecular changes associated with MetS and DIMS. Mitochondria dysfunction, oxidative stress and inflammation are mechanisms proposed for the development of clozapine-related DIMS. In this study, the effects of clozapine on mitochondrial function and inflammation in insulin responsive and obesity-associated cultured cell lines were examined. Methodology/Principal Findings: Cultured mouse myoblasts (C2C12), adipocytes (3T3-L1), hepatocytes (FL-83B), and monocytes (RAW 264.7) were treated with 0, 25, 50 and 75 mu M clozapine for 24 hours. The mitochondrial selective probe TMRM was used to assess membrane potential and morphology. ATP levels from cell lysates were determined by bioluminescence assay. Cytokine levels in cell supernatants were assessed using a multiplex array. Clozapine was found to alter mitochondria morphology, membrane potential, and volume, and reduce ATP levels in all cell lines. Clozapine also significantly induced the production of proinflammatory cytokines IL-6, GM-CSF and IL12-p70, and this response was particularly robust in the monocyte cell line. Conclusions/ Significance: Clozapine damages mitochondria and promotes inflammation in insulin responsive cells and obesity-associated cell types. These phenomena are closely associated with changes observed in human and animal studies of MetS, obesity, insulin resistance, and diabetes. Therefore, the use of clozapine in DIMS may be an important and relevant tool for investigating cellular and molecular changes associated with the development of these diseases in the general population. C1 [Contreras-Shannon, Veronica; Heart, Dylan L.] St Marys Univ, Dept Biol Sci, San Antonio, TX USA. [Paredes, R. Madelaine; Navaira, Erica; Walss-Bass, Consuelo] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Catano, Gabriel] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Catano, Gabriel] Univ Texas Hlth Sci Ctr San Antonio, Vet Adm Ctr Personalized Med, South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Maffi, Shivani Kaushal] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Maffi, Shivani Kaushal] Reg Acad Hlth Ctr Edinburg, Div Med Res, Edinburg, TX USA. RP Walss-Bass, C (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. EM walss@uthscsa.edu FU St. Mary's University Undergraduate Research Office, Biaggini Undergraduate Research Scholarships, St. Mary's University; Department of Psychiatry, University of Texas Health Science Center at San Antonio FX Summer Undergraduate Research Fellowship from the St. Mary's University Undergraduate Research Office, Biaggini Undergraduate Research Scholarships, St. Mary's University. Friends for Psychiatric Research Grant from the Department of Psychiatry, University of Texas Health Science Center at San Antonio. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 23 Z9 23 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 20 PY 2013 VL 8 IS 3 AR e59012 DI 10.1371/journal.pone.0059012 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125SW UT WOS:000317562600051 PM 23527073 ER PT J AU Lee, JE Gohda, T Walker, WH Skupien, J Smiles, AM Holak, RR Jeong, J McDonnell, KP Krolewski, AS Niewczas, MA AF Lee, Jung Eun Gohda, Tomohito Walker, William H. Skupien, Jan Smiles, Adam M. Holak, Rita R. Jeong, Jackson McDonnell, Kevin P. Krolewski, Andrzej S. Niewczas, Monika A. TI Risk of ESRD and All Cause Mortality in Type 2 Diabetes According to Circulating Levels of FGF-23 and TNFR1 SO PLOS ONE LA English DT Article ID CHRONIC KIDNEY-DISEASE; GROWTH-FACTOR 23; STAGE RENAL-DISEASE; RECEPTORS 1; KLOTHO; INFLAMMATION; FACTOR-23; FGF23; FIBROBLAST-GROWTH-FACTOR-23; MICROALBUMINURIA AB Introduction: Recent studies demonstrated that circulating fibroblast growth factor (FGF)-23 was associated with risk of end stage renal disease (ESRD) and mortality. This study aims to examine whether the predictive effect of FGF-23 is independent from circulating levels of tumor necrosis factor receptor 1 (TNFR1), a strong predictor of ESRD in Type 2 diabetes (T2D). Methods: We studied 380 patients with T2D who were followed for 8-12 years and were used previously to examine the effect of TNFR1. Baseline plasma FGF-23 was measured by immunoassay. Results: During follow-up, 48 patients (13%) developed ESRD and 83 patients (22%) died without ESRD. In a univariate analysis, baseline circulating levels of FGF-23 and TNFR1 were significantly higher in subjects who subsequently developed ESRD or died without ESRD than in those who remained alive. In a Cox proportional hazard model, baseline concentration of FGF-23 was associated with increased risk of ESRD, however its effect was no longer significant after controlling for TNFR1 and other clinical characteristics (HR 1.3, p = 0.15). The strong effect of circulating level of TNFR1 on risk of ESRD was not changed by including circulating levels of FGF-23 (HR 8.7, p<0.001). In the Cox multivariate model, circulating levels of FGF-23 remained a significant independent predictor of all-cause mortality unrelated to ESRD (HR 1.5, p<0.001). Conclusions: We demonstrated that the effect of circulating levels of FGF-23 on the risk of ESRD is accounted for by circulating levels of TNFR1. We confirmed that circulating levels of FGF-23 have an independent effect on all-cause mortality in T2D. C1 [Lee, Jung Eun; Gohda, Tomohito; Walker, William H.; Skupien, Jan; Smiles, Adam M.; Holak, Rita R.; Jeong, Jackson; McDonnell, Kevin P.; Krolewski, Andrzej S.; Niewczas, Monika A.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Lee, Jung Eun] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Div Nephrol, Seoul, South Korea. [Lee, Jung Eun; Gohda, Tomohito; Skupien, Jan; Krolewski, Andrzej S.; Niewczas, Monika A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Gohda, Tomohito] Juntendo Univ, Sch Med, Dept Internal Med, Div Nephrol, Tokyo 113, Japan. [Skupien, Jan] Jagiellonian Univ, Coll Med, Dept Metab Dis, Krakow, Poland. RP Niewczas, MA (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. EM Monika.Niewczas@joslin.harvard.edu RI lee, je/O-6247-2014 FU National Institutes of Health [DK041526, DK067638]; DERC Joslin Diabetes Center Pilot and Feasibility grant; JDRF [3-2009-397] FX This study was supported by grants from the National Institutes of Health DK041526 and DK067638 (ASK), DERC Joslin Diabetes Center Pilot and Feasibility grant (MAN) and a JDRF fellowship grant 3-2009-397 (JS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 7 Z9 7 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 MAR 20 PY 2013 VL 8 IS 3 AR e58007 DI 10.1371/journal.pone.0058007 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125SW UT WOS:000317562600012 PM 23526964 ER PT J AU Vrooman, LM Stevenson, KE Supko, JG O'Brien, J Dahlberg, SE Asselin, BL Athale, UH Clavell, LA Kelly, KM Kutok, JL Laverdiere, C Lipshultz, SE Michon, B Schorin, M Relling, MV Cohen, HJ Neuberg, DS Sallan, SE Silverman, LB AF Vrooman, Lynda M. Stevenson, Kristen E. Supko, Jeffrey G. O'Brien, Jane Dahlberg, Suzanne E. Asselin, Barbara L. Athale, Uma H. Clavell, Luis A. Kelly, Kara M. Kutok, Jeffery L. Laverdiere, Caroline Lipshultz, Steven E. Michon, Bruno Schorin, Marshall Relling, Mary V. Cohen, Harvey J. Neuberg, Donna S. Sallan, Stephen E. Silverman, Lewis B. TI Postinduction Dexamethasone and Individualized Dosing of Escherichia Coli L-Asparaginase Each Improve Outcome of Children and Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia: Results From a Randomized Study-Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID STANDARD-RISK; CEREBROSPINAL-FLUID; CHILDHOOD; INDUCTION; OSTEONECROSIS; CHEMOTHERAPY; PREDNISONE; THERAPY; TRIAL; PHARMACOKINETICS AB Purpose We assessed the toxicity and efficacy of dexamethasone and a novel dosing method of Escherichia coli L-asparaginase (EC-Asnase) in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). Patients and Methods Patients achieving complete remission (CR) on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 were eligible for random assignment to 1) dexamethasone or prednisone, administered as 5-day pulses, every 3 weeks, and 2) weekly EC-Asnase, administered as a 25,000 IU/m(2) fixed dose (FD) or individualized dose (ID) starting at 12,500-IU/m(2), adjusted every 3 weeks based on nadir serum asparaginase activity (NSAA) determinations. Results Between 2000 and 2004, 492 evaluable patients (ages 1 to 18 years) enrolled; 473 patients (96%) achieved CR. Four hundred eight patients (86%) participated in the corticosteroid randomization and 384 patients (81%) in the EC-Asnase randomization. With 4.9 years of median follow-up, dexamethasone was associated with superior 5-year event-free survival (EFS; 90% v 81% for prednisone; P = .01) but higher rates of infection (P = .03) and, in older children, higher cumulative incidence of osteonecrosis (P = .02) and fracture (P = .06). ID EC-Asnase had superior 5-year EFS (90% v 82% for FD; P = .04), but did not reduce the frequency of asparaginase-related toxicity. Multivariable analysis identified both dexamethasone and ID EC-Asnase as independent predictors of favorable EFS. Conclusion There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL. J Clin Oncol 31:1202-1210. (C) 2013 by American Society of Clinical Oncology C1 [Vrooman, Lynda M.; Stevenson, Kristen E.; O'Brien, Jane; Dahlberg, Suzanne E.; Neuberg, Donna S.; Sallan, Stephen E.; Silverman, Lewis B.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Vrooman, Lynda M.; Sallan, Stephen E.; Silverman, Lewis B.] Boston Childrens Hosp, Boston, MA USA. [Supko, Jeffrey G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kutok, Jeffery L.] Infin Pharmaceut, Cambridge, MA USA. [Asselin, Barbara L.] Univ Rochester, Med Ctr, Rochester, NY 14627 USA. [Kelly, Kara M.] Columbia Univ, Morgan Stanley Childrens Hosp New York Presbyteri, Med Ctr, New York, NY USA. [Clavell, Luis A.] San Jorge Childrens Hosp, San Juan, PR USA. [Lipshultz, Steven E.] Univ Miami, Leonard M Miller Sch Med, Miami, FL USA. [Schorin, Marshall] Inova Fairfax Hosp Children, Falls Church, VA USA. [Relling, Mary V.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Cohen, Harvey J.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Athale, Uma H.] McMaster Univ, Hamilton, ON, Canada. [Laverdiere, Caroline] Univ Montreal, Hop St Justine, Montreal, PQ H3T 1C5, Canada. [Michon, Bruno] Ctr Hosp Univ Quebec, Quebec City, PQ, Canada. RP Vrooman, LM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM lynda_vrooman@dfci.harvard.edu FU EUSA Pharma; Sigma-Tau Pharmaceuticals; Enzon Pharmaceuticals; National Cancer Institute [5 P01CA068484, P30 21765]; American Lebanese Syrian Associated Charities; Linde Family Foundation FX Although all authors completed the disclosure declaration, the following author(s) and/or an author's immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Lewis B. Silverman, Enzon Pharmaceuticals (C), EUSA Pharma (C) Stock Ownership: None Honoraria: None Research Funding: Jeffrey G. Supko, EUSA Pharma; Mary V. Relling, Sigma-Tau Pharmaceuticals, Enzon Pharmaceuticals; Stephen E. Sallan, Enzon Pharmaceuticals, EUSA Pharma Expert Testimony: None Other Remuneration: None; Supported in part by Grants No. 5 P01CA068484 and P30 21765 from the National Cancer Institute, by the American Lebanese Syrian Associated Charities, and by the Linde Family Foundation. NR 33 TC 85 Z9 93 U1 2 U2 11 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2013 VL 31 IS 9 BP 1202 EP 1210 DI 10.1200/JCO.2012.43.2070 PG 9 WC Oncology SC Oncology GA 107AS UT WOS:000316187600021 PM 23358966 ER PT J AU Metzger, ML Meacham, LR Patterson, B Casillas, JS Constine, LS Hijiya, N Kenney, LB Leonard, M Lockart, BA Likes, W Green, DM AF Metzger, Monika L. Meacham, Lillian R. Patterson, Briana Casillas, Jacqueline S. Constine, Louis S. Hijiya, Nobuko Kenney, Lisa B. Leonard, Marcia Lockart, Barbara A. Likes, Wendy Green, Daniel M. TI Female Reproductive Health After Childhood, Adolescent, and Young Adult Cancers: Guidelines for the Assessment and Management of Female Reproductive Complications SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ANTI-MULLERIAN HORMONE; CENTRAL PRECOCIOUS PUBERTY; TERM-FOLLOW-UP; ACUTE LYMPHOBLASTIC-LEUKEMIA; CRYOPRESERVED OVARIAN TISSUE; VERSUS-HOST-DISEASE; FERTILITY PRESERVATION; HODGKINS-DISEASE; BREAST-CANCER; REPLACEMENT THERAPY AB Purpose As more young female patients with cancer survive their primary disease, concerns about reproductive health related to primary therapy gain relevance. Cancer therapy can often affect reproductive organs, leading to impaired pubertal development, hormonal regulation, fertility, and sexual function, affecting quality of life. Methods The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer (COG-LTFU Guidelines) are evidence-based recommendations for screening and management of late effects of therapeutic exposures. The guidelines are updated every 2 years by a multidisciplinary panel based on current literature review and expert consensus. Results This review summarizes the current task force recommendations for the assessment and management of female reproductive complications after treatment for childhood, adolescent, and young adult cancers. Experimental pretreatment as well as post-treatment fertility preservation strategies, including barriers and ethical considerations, which are not included in the COG-LTFU Guidelines, are also discussed. Conclusion Ongoing research will continue to inform COG-LTFU Guideline recommendations for follow-up care of female survivors of childhood cancer to improve their health and quality of life. J Clin Oncol 31:1239-1247. (C) 2013 by American Society of Clinical Oncology C1 [Metzger, Monika L.; Green, Daniel M.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Metzger, Monika L.; Likes, Wendy] Univ Tennessee, Memphis, TN USA. [Meacham, Lillian R.; Patterson, Briana] Emory Univ, Atlanta, GA 30322 USA. [Casillas, Jacqueline S.] Univ Calif Los Angeles, Los Angeles, CA USA. [Constine, Louis S.] Univ Rochester, Rochester, NY USA. [Hijiya, Nobuko] Northwestern Univ, Evanston, IL 60208 USA. [Lockart, Barbara A.] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA. [Kenney, Lisa B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kenney, Lisa B.] Childrens Hosp, Boston, MA 02115 USA. [Leonard, Marcia] Univ Michigan, Ann Arbor, MI 48109 USA. RP Metzger, ML (reprint author), 262 Danny Thomas Pl, Memphis, TN 38105 USA. EM monika.metzger@stjude.org FU NCI NIH HHS [U10 CA095861, U10 CA098543] NR 147 TC 43 Z9 44 U1 1 U2 20 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 MAR 20 PY 2013 VL 31 IS 9 BP 1239 EP 1247 DI 10.1200/JCO.2012.43.5511 PG 9 WC Oncology SC Oncology GA 107AS UT WOS:000316187600025 PM 23382474 ER PT J AU Cosker, KE Pazyra-Murphy, MF Fenstermacher, SJ Segal, RA AF Cosker, Katharina E. Pazyra-Murphy, Maria F. Fenstermacher, Sara J. Segal, Rosalind A. TI Target-Derived Neurotrophins Coordinate Transcription and Transport of Bclw to Prevent Axonal Degeneration SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ACTIN MESSENGER-RNA; ROOT GANGLION NEURONS; NERVE GROWTH-FACTOR; SYMPATHETIC NEURONS; RETROGRADE TRANSPORT; LOCAL TRANSLATION; SURVIVAL RESPONSE; PROTEIN-SYNTHESIS; MAMMALIAN-CELLS; DEFICIENT MICE AB Establishment of neuronal circuitry depends on both formation and refinement of neural connections. During this process, target-derived neurotrophins regulate both transcription and translation to enable selective axon survival or elimination. However, it is not known whether retrograde signaling pathways that control transcription are coordinated with neurotrophin-regulated actions that transpire in the axon. Here we report that target-derived neurotrophins coordinate transcription of the antiapoptotic gene bclw with transport of bclw mRNA to the axon, and thereby prevent axonal degeneration in rat and mouse sensory neurons. We show that neurotrophin stimulation of nerve terminals elicits new bclw transcripts that are immediately transported to the axons and translated into protein. Bclw interacts with Bax and suppresses the caspase6 apoptotic cascade that fosters axonal degeneration. The scope of bclw regulation at the levels of transcription, transport, and translation provides a mechanism whereby sustained neurotrophin stimulation can be integrated over time, so that axonal survival is restricted to neurons connected within a stable circuit. C1 [Cosker, Katharina E.; Pazyra-Murphy, Maria F.; Fenstermacher, Sara J.; Segal, Rosalind A.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Cosker, Katharina E.; Pazyra-Murphy, Maria F.; Fenstermacher, Sara J.; Segal, Rosalind A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Cosker, Katharina E.; Pazyra-Murphy, Maria F.; Fenstermacher, Sara J.; Segal, Rosalind A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. RP Segal, RA (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 450 Brookline Ave, Boston, MA 02215 USA. EM Rosalind_segal@dfci.harvard.edu FU National Institutes of Health [R01 NS050674, F31NS077620]; Massachusetts General Hospital Neurology Clinical Trials Unit; Harvard NeuroDiscovery Center FX This work was supported by National Institutes of Health Grant R01 NS050674 to R. A. S. and Grant F31NS077620 to S.J.F., K. E. C. is a David Mahoney Fellow at Harvard Medical School and a recipient of a Neurodegenerative Disease Pilot Study grant from Massachusetts General Hospital Neurology Clinical Trials Unit and Harvard NeuroDiscovery Center. S.J.F. is a Victoria Quan Fellow at Harvard Medical School. Confocal microscopy imaging was performed at the Harvard NeuroDiscovery Center Optical Imaging Program. We thank Stephanie Courchesne for help in generating in vivo samples, Jose Alfaro and Emily Chadwick for assistance with bclw-/- mice, Eugene Vaios for assistance with designing probes for ISH, and the members of the R. A. A. laboratory and the Qiufu Ma laboratory for helpful advice. NR 56 TC 16 Z9 16 U1 0 U2 6 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 MAR 20 PY 2013 VL 33 IS 12 BP 5195 EP + DI 10.1523/JNEUROSCI.3862-12.2013 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 111XB UT WOS:000316553800013 PM 23516285 ER PT J AU Scimemi, A Meabon, JS Woltjer, RL Sullivan, JM Diamond, JS Cook, DG AF Scimemi, Annalisa Meabon, James S. Woltjer, Randall L. Sullivan, Jane M. Diamond, Jeffrey S. Cook, David G. TI Amyloid-beta(1-42) Slows Clearance of Synaptically Released Glutamate by Mislocalizing Astrocytic GLT-1 SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ALZHEIMERS-DISEASE; TRANSPORTER GLT-1; BRAIN; BETA; NEURODEGENERATION; EXPRESSION; MECHANISM; NEURONS; PATHWAY; PROTECT AB GLT-1, the major glutamate transporter in the adult brain, is abundantly expressed in astrocytic processes enveloping synapses. By limiting glutamate escape into the surrounding neuropil, GLT-1 preserves the spatial specificity of synaptic signaling. Here we show that the amyloid-beta peptide A beta(1-42) markedly prolongs the extracellular lifetime of synaptically released glutamate by reducing GLT-1 surface expression in mouse astrocytes and that this effect is prevented by the vitamin E derivative Trolox. These findings indicate that astrocytic glutamate transporter dysfunction may play an important role in the pathogenesis of Alzheimer's disease and suggest possible mechanisms by which several current treatment strategies could protect against the disease. C1 [Scimemi, Annalisa; Diamond, Jeffrey S.] NINDS, Synapt Physiol Sect, NIH, Bethesda, MD 20892 USA. [Meabon, James S.] Univ Washington, Dept Psychiat, Seattle, WA 98108 USA. [Cook, David G.] Univ Washington, Dept Med, Seattle, WA 98108 USA. [Cook, David G.] Univ Washington, Dept Pharmacol, Seattle, WA 98108 USA. [Sullivan, Jane M.] Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA. [Meabon, James S.; Cook, David G.] VA Puget Sound Hlth Care Syst, Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Woltjer, Randall L.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97239 USA. RP Cook, DG (reprint author), VA Med Ctr, GRECC, 1660 S Columbian Way, Seattle, WA 98108 USA. EM dgcook@u.washington.edu RI Scimemi, Annalisa/O-5396-2014; Diamond, Jeffrey/C-1835-2015 OI Scimemi, Annalisa/0000-0003-4975-093X; Diamond, Jeffrey/0000-0002-1770-2629 FU Veteran's Affairs Office of Research and Development Medical Research Service; NIH [T32 AG000258, RO1 NS055804]; NINDS [NS002986] FX This work was supported by the Veteran's Affairs Office of Research and Development Medical Research Service (D. G. C.), NIH (Grants T32 AG000258, J.S.M.; and RO1 NS055804, J.M.S.), and NINDS Intramural Research Program (Grant NS002986, J.S.D.). We thank Mike Ahlquist, Ping Zhu, and Ning Li for excellent technical assistance. NR 28 TC 29 Z9 30 U1 1 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 20 PY 2013 VL 33 IS 12 BP 5312 EP 5318 DI 10.1523/JNEUROSCI.5274-12.2013 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 111XB UT WOS:000316553800023 PM 23516295 ER PT J AU Arsenault, JT Nelissen, K Jarraya, B Vanduffel, W AF Arsenault, John T. Nelissen, Koen Jarraya, Bechir Vanduffel, Wim TI Dopaminergic Reward Signals Selectively Decrease fMRI Activity in Primate Visual Cortex SO NEURON LA English DT Article ID NEURONAL-ACTIVITY; CONTRAST AGENT; HUMAN BRAIN; ATTENTION; RESPONSES; DORSAL; REPRESENTATIONS; REINFORCERS; PREDICTION; MOTIVATION AB Stimulus-reward coupling without attention can induce highly specific perceptual learning effects, suggesting that reward triggers selective plasticity within visual cortex. Additionally, dopamine-releasing events temporally surrounding stimulus-reward associations selectively enhance memory. These forms of plasticity may be evoked by selective modulation of stimulus representations during dopamine-inducing events. However, it remains to be shown whether dopaminergic signals can selectively modulate visual cortical activity. We measured fMRI activity in monkey visual cortex during reward-only trials apart from intermixed cue-reward trials. Reward without visual stimulation selectively decreased fMRI activity within the cue representations that had been paired with reward during other trials. Behavioral tests indicated that these same uncued reward trials strengthened cue-reward associations. Furthermore, such spatially-specific activity modulations depended on prediction error, as shown by manipulations of reward magnitude, cue-reward probability, cue-reward familiarity, and dopamine signaling. This cue-selective negative reward signal offers a mechanism for selectively gating sensory cortical plasticity. C1 [Arsenault, John T.; Nelissen, Koen; Jarraya, Bechir; Vanduffel, Wim] KU Leuven Med Sch, Lab Neuro & Psychophysiol, B-3000 Louvain, Belgium. [Arsenault, John T.; Jarraya, Bechir; Vanduffel, Wim] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Vanduffel, Wim] Harvard Univ, Sch Med, Dept Radiol, Charlestown, MA 02129 USA. RP Vanduffel, W (reprint author), KU Leuven Med Sch, Lab Neuro & Psychophysiol, Campus Gasthuisberg, B-3000 Louvain, Belgium. EM wim@nmr.mgh.harvard.edu OI Jarraya, Bechir/0000-0003-0878-763X FU Inter-University Attraction Pole [PFV10/008]; Geconcerteerde Onderzoeks Actie 10/19; Impulsfinanciering Zware Apparatuur; Katholieke Universiteit Leuven; Fonds Wetenschappelijk Onderzoek-Vlaanderen [G062208.10, G083111.10, G.0719.12, G0888.13]; National Center for Research Resources [P41RR14075] FX We thank C. Fransen, C. Van Eupen, and A. Coeman for animal training and care; D. Mantini, O. Joly, H. Kolster, W. Depuydt, G. Meulemans, P. Kayenbergh, M. De Paep, M. Docx, and I. Puttemans for technical assistance; and P. Roelfsema, T Knapen, T, Donner, and S. Raiguel for their comments on the manuscript. This work received support from Inter-University Attraction Pole 7/11, Programme Financing PFV10/008, Geconcerteerde Onderzoeks Actie 10/19, Impulsfinanciering Zware Apparatuur and Hercules funding of the Katholieke Universiteit Leuven, Fonds Wetenschappelijk Onderzoek-Vlaanderen G062208.10, G083111.10 and G.0719.12, and G0888.13. K.N. is postdoctoral fellow of the Fonds Wetenschappelijk Onderzoek-Vlaanderen. The Martinos Center for Biomedical Imaging is supported by National Center for Research Resources grant P41RR14075. NR 59 TC 37 Z9 37 U1 4 U2 39 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR 20 PY 2013 VL 77 IS 6 BP 1174 EP 1186 DI 10.1016/j.neuron.2013.01.008 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 113CX UT WOS:000316645000017 PM 23522051 ER PT J AU Miller, CJ Abraham, KM Bajor, LA Lai, ZS Kim, HM Nord, KM Goodrich, DE Bauer, MS Kilbourne, AM AF Miller, Christopher J. Abraham, Kristen M. Bajor, Laura A. Lai, Zongshan Kim, Hyungjin Myra Nord, Kristina M. Goodrich, David E. Bauer, Mark S. Kilbourne, Amy M. TI Quality of life among patients with bipolar disorder in primary care versus community mental health settings SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Quality of life; Primary care; Community mental health ID ALCOHOL-USE DISORDERS; GENERAL-POPULATION; AUDIT-C; PSYCHIATRIC-DISORDERS; SUBSTANCE-ABUSE; RISK DRINKING; I DISORDER; SCALE; STATES; RELIABILITY AB Introduction: Bipolar disorder is associated with functional impairment across a number of domains, including health-related quality of life (HRQOL). Many patients are treated exclusively in primary care (PC) settings, yet little is known how HRQOL outcomes compare between PC and community mental health (CMH) settings. This study aimed to explore the correlates of HRQOL across treatment settings using baseline data from a multisite, randomized controlled trial for adults with bipolar disorder. Methods: HRQOL was measured using the SF-12 physical (PCS) and mental (MCS) composite scale scores. Independent sample t-tests were calculated to compare differences in HRQOL between settings. Multivariate regression models then examined the effect of treatment setting on HRQOL, adjusting for covariate demographic factors, mood symptoms (Internal State Scale), hazardous drinking (AUDIT-C), and substance abuse. Results: A total of 384 enrolled participants completed baseline surveys. MCS and PCS scores reflected similar impairment in HRQOL across PC and CMH settings (p=0.98 and p=0.49, respectively). Depressive symptoms were associated with lower MCS scores (B=0.68, p < 0.001) while arthritis/chronic pain was strongly related to lower PCS scores (B=5.23, p < 0.001). Limitations: This study lacked a formal diagnostic interview, relied on cross-sectional self-report, and sampled from a small number of sites in two states. Discussion: Participants reported similar impairments in both mental and physical HRQOL in PC and CMH treatment settings, emphasizing the need for integrated care for patients with bipolar disorder regardless of where they present for treatment. Published by Elsevier B.V. C1 [Miller, Christopher J.; Bajor, Laura A.; Lai, Zongshan; Bauer, Mark S.] VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, Boston, MA 02130 USA. [Miller, Christopher J.; Bajor, Laura A.; Bauer, Mark S.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Abraham, Kristen M.; Lai, Zongshan; Kim, Hyungjin Myra; Nord, Kristina M.; Goodrich, David E.; Kilbourne, Amy M.] VA Ann Arbor Ctr Clin Management Res, Ann Arbor, MI USA. [Abraham, Kristen M.; Nord, Kristina M.; Goodrich, David E.; Kilbourne, Amy M.] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI USA. [Kim, Hyungjin Myra] Univ Michigan, Ctr Stat Consultat & Res, Ann Arbor, MI 48109 USA. RP Miller, CJ (reprint author), VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, 150 S Huntington Ave 152M, Boston, MA 02130 USA. EM Christopher.Miller8@va.gov OI Goodrich, David/0000-0003-3232-2189 FU National Institute of Mental Health [R01 MH79994] FX This work was supported by the National Institute of Mental Health (R01 MH79994). The views expressed in this article are those of the authors and do not necessarily represent the views of the VA. NR 46 TC 11 Z9 11 U1 2 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAR 20 PY 2013 VL 146 IS 1 BP 100 EP 105 DI 10.1016/j.jad.2012.08.045 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 098WE UT WOS:000315579000013 PM 22981021 ER PT J AU Zhang, RY Zhao, Y Chu, MJ Mehta, A Wei, YY Liu, Y Xun, PC Bai, JL Yu, H Su, L Zhang, HX Hu, ZB Shen, HB Chen, F Christiani, DC AF Zhang, Ruyang Zhao, Yang Chu, Minjie Mehta, Amar Wei, Yongyue Liu, Yao Xun, Pengcheng Bai, Jianling Yu, Hao Su, Li Zhang, Hongxi Hu, Zhibin Shen, Hongbing Chen, Feng Christiani, David C. TI A Large Scale Gene-Centric Association Study of Lung Function in Newly-Hired Female Cotton Textile Workers with Endotoxin Exposure SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS; AIRWAY EPITHELIUM; FUNCTION DECLINE; CANCER; DUST; SUSCEPTIBILITY; POLYMORPHISMS; POPULATION; DISEASE AB Background: Occupational exposure to endotoxin is associated with decrements in pulmonary function, but how much variation in this association is explained by genetic variants is not well understood. Objective: We aimed to identify single nucleotide polymorphisms (SNPs) that are associated with the rate of forced expiratory volume in one second (FEV1) decline by a large scale genetic association study in newly-hired healthy young female cotton textile workers. Methods: DNA samples were genotyped using the Illumina Human CVD BeadChip. Change rate in FEV1 was modeled as a function of each SNP genotype in linear regression model with covariate adjustment. We controlled the type 1 error in study-wide level by permutation method. The false discovery rate (FDR) and the family-wise error rate (FWER) were set to be 0.10 and 0.15 respectively. Results: Two SNPs were found to be significant (P<6.29x10(-5)), including rs1910047 (P = 3.07x10(-5), FDR = 0.0778) and rs9469089 (P = 6.19x10(-5), FDR = 0.0967), as well as other eight suggestive (P<5x10(-4)) associated SNPs. Gene-gene and gene-environment interactions were also observed, such as rs1910047 and rs1049970 (P = 0.0418, FDR = 0.0895); rs9469089 and age (P = 0.0161, FDR = 0.0264). Genetic risk score analysis showed that the more risk loci the subjects carried, the larger the rate of FEV1 decline occurred (P-trend = 3.01x10(-18)). However, the association was different among age subgroups (P = 7.11x10(-6)) and endotoxin subgroups (P = 1.08x10(-2)). Functional network analysis illustrates potential biological connections of all interacted genes. Conclusions: Genetic variants together with environmental factors interact to affect the rate of FEV1 decline in cotton textile workers. C1 [Zhang, Ruyang; Zhao, Yang; Chu, Minjie; Wei, Yongyue; Liu, Yao; Bai, Jianling; Yu, Hao; Hu, Zhibin; Shen, Hongbing; Chen, Feng] Nanjing Med Univ, Dept Epidemiol & Biostat, Nanjing, Jiangsu, Peoples R China. [Zhang, Ruyang; Zhao, Yang; Chu, Minjie; Wei, Yongyue; Liu, Yao; Bai, Jianling; Yu, Hao; Hu, Zhibin; Shen, Hongbing; Chen, Feng] Nanjing Med Univ, Minist Educ MOE, Key Lab Modern Toxicol, Sch Publ Hlth, Nanjing, Jiangsu, Peoples R China. [Zhang, Ruyang; Chu, Minjie; Liu, Yao; Hu, Zhibin; Shen, Hongbing] Nanjing Med Univ, Clin Epidemiol Sect, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Ctr Canc, Nanjing, Jiangsu, Peoples R China. [Zhao, Yang; Mehta, Amar; Wei, Yongyue; Su, Li; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Mehta, Amar] Swiss Trop & Publ Hlth Inst, Basel, Switzerland. [Mehta, Amar] Univ Basel, Basel, Switzerland. [Xun, Pengcheng] Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN USA. [Zhang, Hongxi] Shanghai Med Univ 2, Putuo Dist Peoples Hosp, Shanghai, Peoples R China. [Christiani, David C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit,Dept Med, Boston, MA USA. RP Chen, F (reprint author), Nanjing Med Univ, Dept Epidemiol & Biostat, Nanjing, Jiangsu, Peoples R China. EM fengchen@njmu.edu.cn; dchris@hsph.harvard.edu RI Xun, Pengcheng/D-3411-2013 FU USA: The National Institute for Occupational Safety and Health [RO104241]; USA: National Institute of Environmental Health Sciences [ES00002]; China: National Natural Science Foundation of China [81072389, 30901232]; China: Natural Science Foundation of the Jiangsu Higher Education Institutions of China [10KJA33034]; China: Research Fund for the Doctoral Program of Higher Education of China [20113234110002]; China: Research and Innovation Project for College Graduates of Jiangsu Province [CXZZ11_0733]; China: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) FX This study was supported by grants from USA: The National Institute for Occupational Safety and Health (RO104241), National Institute of Environmental Health Sciences (ES00002) and China: National Natural Science Foundation of China (81072389, 30901232), Natural Science Foundation of the Jiangsu Higher Education Institutions of China (10KJA33034), the Research Fund for the Doctoral Program of Higher Education of China (20113234110002), the Research and Innovation Project for College Graduates of Jiangsu Province (CXZZ11_0733), and the grant from the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 2 Z9 3 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 19 PY 2013 VL 8 IS 3 AR e59035 DI 10.1371/journal.pone.0059035 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125SR UT WOS:000317562100068 PM 23527081 ER PT J AU Hu, D Weiner, HL Ritz, J AF Hu, Dan Weiner, Howard L. Ritz, Jerome TI Identification of Cytolytic CD161(-)CD56(+) Regulatory CD8 T Cells in Human Peripheral Blood SO PLOS ONE LA English DT Article ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; NATURAL-KILLER-CELLS; DENDRITIC CELLS; SELF-TOLERANCE; EXPRESSION; SUBSET; CD27; STIMULATION; LYMPHOCYTES; BIOLOGY AB We previously developed methods for establishing CD8 regulatory T cell (Treg) clones from normal human peripheral blood and demonstrated that these clones were capable of killing T cell receptor (TCR)-activated autologous CD4 T cells. Based on phenotypic and functional characterization of the CD8 Treg clones, we have identified a corresponding population of endogenous CD8 Treg in normal human peripheral blood. These cells appear morphologically as large lymphocytes with abundant cytoplasm and have the following unique phenotype: CD3(+)CD8(+)CD161(-)CD56(+). The majority of CD8 Treg express CD45RA and CD62L with low or negative expression of CD45RO, CD25, CD27, CD28 and CCR7. The expression of CD94 and NKG2a on CD8 Treg was elevated compared to conventional CD8 T cells. Following in vitro activation, this T cell subset is capable of killing TCR-activated CD4 T cells. These studies identify an endogenous CD8 Treg population in humans and it will now be possible to characterize these cells in a variety of clinical conditions. C1 [Hu, Dan; Weiner, Howard L.] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Hu, Dan; Ritz, Jerome] Dana Farber Canc Inst, Div Hematol Malignancies, Canc Vaccine Ctr, Boston, MA 02115 USA. [Hu, Dan; Weiner, Howard L.; Ritz, Jerome] Harvard Univ, Sch Med, Boston, MA USA. RP Ritz, J (reprint author), Dana Farber Canc Inst, Div Hematol Malignancies, Canc Vaccine Ctr, Boston, MA 02115 USA. EM Jerome_Ritz@dfci.harvard.edu RI Hu, Dan/D-9642-2015 FU National Institutes of Health [AI29530, CA142106]; National Multiple Sclerosis Society FX The research was supported by National Institutes of Health (AI29530 and CA142106 to J.R.) and the National Multiple Sclerosis Society (to H. L. W.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 5 Z9 5 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 19 PY 2013 VL 8 IS 3 AR e59545 DI 10.1371/journal.pone.0059545 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125SR UT WOS:000317562100146 PM 23527216 ER PT J AU Wang, Z Ocampo, MA Pang, RD Bota, M Bradesi, S Mayer, EA Holschneider, DP AF Wang, Zhuo Ocampo, Marco A. Pang, Raina D. Bota, Mihail Bradesi, Sylvie Mayer, Emeran A. Holschneider, Daniel P. TI Alterations in Prefrontal-Limbic Functional Activation and Connectivity in Chronic Stress-Induced Visceral Hyperalgesia SO PLOS ONE LA English DT Article ID BRAIN-GUT AXIS; IRRITABLE-BOWEL-SYNDROME; CHRONIC RESTRAINT STRESS; CENTRAL-NERVOUS-SYSTEM; DENDRITIC REORGANIZATION; VOLUNTARY SUPPRESSION; PERIAQUEDUCTAL GRAY; CEREBRAL ACTIVATION; PYRAMIDAL NEURONS; FOS EXPRESSION AB Repeated water avoidance stress (WAS) induces sustained visceral hyperalgesia (VH) in rats measured as enhanced visceromotor response to colorectal distension (CRD). This model incorporates two characteristic features of human irritable bowel syndrome (IBS), VH and a prominent role of stress in the onset and exacerbation of IBS symptoms. Little is known regarding central mechanisms underlying the stress-induced VH. Here, we applied an autoradiographic perfusion method to map regional and network-level neural correlates of VH. Adult male rats were exposed to WAS or sham treatment for 1 hour/day for 10 days. The visceromotor response was measured before and after the treatment. Cerebral blood flow (CBF) mapping was performed by intravenous injection of radiotracer ([C-14]-iodoantipyrine) while the rat was receiving a 60-mmHg CRD or no distension. Regional CBF-related tissue radioactivity was quantified in autoradiographic images of brain slices and analyzed in 3-dimensionally reconstructed brains with statistical parametric mapping. Compared to sham rats, stressed rats showed VH in association with greater CRD-evoked activation in the insular cortex, amygdala, and hypothalamus, but reduced activation in the prelimbic area (PrL) of prefrontal cortex. We constrained results of seed correlation analysis by known structural connectivity of the PrL to generate structurally linked functional connectivity (SLFC) of the PrL. Dramatic differences in the SLFC of PrL were noted between stressed and sham rats under distension. In particular, sham rats showed negative correlation between the PrL and amygdala, which was absent in stressed rats. The altered pattern of functional brain activation is in general agreement with that observed in IBS patients in human brain imaging studies, providing further support for the face and construct validity of the WAS model for IBS. The absence of prefrontal cortex-amygdala anticorrelation in stressed rats is consistent with the notion that impaired corticolimbic modulation acts as a central mechanism underlying stress-induced VH. C1 [Wang, Zhuo; Ocampo, Marco A.; Holschneider, Daniel P.] Univ So Calif, Dept Psychiat & Behav Sci, Los Angeles, CA 93385 USA. [Pang, Raina D.; Holschneider, Daniel P.] Univ So Calif, Program Neurosci, Los Angeles, CA USA. [Bota, Mihail] Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. [Holschneider, Daniel P.] Univ So Calif, Dept Neurol, Los Angeles, CA USA. [Bradesi, Sylvie; Mayer, Emeran A.] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Bradesi, Sylvie; Mayer, Emeran A.; Holschneider, Daniel P.] Univ Calif Los Angeles, Dept Med, Ctr Neurobiol Stress, Los Angeles, CA 90024 USA. [Mayer, Emeran A.] Univ Calif Los Angeles, Dept Physiol, Los Angeles, CA 90024 USA. [Mayer, Emeran A.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Mayer, Emeran A.] Univ Calif Los Angeles, Dept Biobehav Sci, Los Angeles, CA USA. RP Holschneider, DP (reprint author), Univ So Calif, Dept Psychiat & Behav Sci, Los Angeles, CA 93385 USA. EM holschne@usc.edu FU United States National Institutes of Health [P50DK064539, R24AT002681] FX The research was supported by United States National Institutes of Health grants P50DK064539 (Mayer) and R24AT002681 (Mayer). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 81 TC 13 Z9 13 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 19 PY 2013 VL 8 IS 3 AR e59138 DI 10.1371/journal.pone.0059138 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125SR UT WOS:000317562100082 PM 23527114 ER PT J AU Xiao, WC Peng, YY Liu, Y Li, Z Li, SL Zheng, XF AF Xiao, Weichun Peng, Yanyan Liu, Yong Li, Zhi Li, Senlin Zheng, Xiaofeng TI HSCARG Inhibits NADPH Oxidase Activity through Regulation of the Expression of p47phox SO PLOS ONE LA English DT Article ID NF-KAPPA-B; SENSOR PROTEIN; TUMOR-CELLS; ACTIVATION; DIPHENYLENEIODONIUM; MODULATION; INDUCTION; APOPTOSIS; INCREASE; ASSAY AB Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase catalyzes the transfer of electrons from NADPH to O-2, which is the main source of reactive oxygen species (ROS) in nonphagocytic cells. Excess ROS are toxic; therefore, keeping ROS in homeostasis in cells can protect cells from oxidative damage. It is meaningful to further understand the molecular mechanism by which ROS homeostasis is mediated. Human protein HSCARG is a newly identified oxidative sensor and a negative regulator of NF-kappa B. Here, we find that HSCARG represses the cellular ROS generation through inhibiting mRNA and protein expression of p47phox, a subunit of NADPH oxidase. In contrast, shRNA-mediated HSCARG knockdown increases endogenous p47phox expression level. And HSCARG has no obvious effect on ROS production in p47phox-depleted cells. Furthermore, HSCARG regulates p47phox through inhibition of NF-kappa B activity. Our findings identify HSCARG as a novel regulator in regulation of the activity of NADPH oxidase and ROS homeostasis. C1 [Xiao, Weichun; Peng, Yanyan; Liu, Yong; Li, Zhi; Zheng, Xiaofeng] State Key Lab Prot & Plant Gene Res, Beijing, Peoples R China. [Xiao, Weichun; Peng, Yanyan; Liu, Yong; Li, Zhi; Zheng, Xiaofeng] Peking Univ, Sch Life Sci, Dept Biochem & Mol Biol, Beijing 100871, Peoples R China. [Li, Senlin] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Li, Senlin] South Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. RP Zheng, XF (reprint author), State Key Lab Prot & Plant Gene Res, Beijing, Peoples R China. EM xiaofengz@pku.edu.cn FU National Science Foundation of China [30930020, 31170709]; National High Technology and Development Program of China 973 programs [2010CB911800]; International Centre for Genetic Engineering and Biotechnology [CRP/CHN09-01] FX This work was supported by grants from the National Science Foundation of China (30930020 and 31170709) the National High Technology and Development Program of China 973 programs (No. 2010CB911800), and the International Centre for Genetic Engineering and Biotechnology (Project No. CRP/CHN09-01). The funders had no roles in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 2 Z9 3 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 19 PY 2013 VL 8 IS 3 AR e59301 DI 10.1371/journal.pone.0059301 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125SR UT WOS:000317562100101 PM 23527155 ER PT J AU Li, Y Meloni, EG Carlezon, WA Milad, MR Pitman, RK Nader, K Bolshakov, VY AF Li, Yan Meloni, Edward G. Carlezon, William A., Jr. Milad, Mohammed R. Pitman, Roger K. Nader, Karim Bolshakov, Vadim Y. TI Learning and reconsolidation implicate different synaptic mechanisms SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LONG-TERM-MEMORY; FEAR MEMORY; PROTEIN-SYNTHESIS; MAMMALIAN TARGET; LATERAL AMYGDALA; CONTEXTUAL FEAR; RNA-SYNTHESIS; CONSOLIDATION; PLASTICITY; HIPPOCAMPUS AB Synaptic mechanisms underlying memory reconsolidation after retrieval are largely unknown. Here we report that synapses in projections to the lateral nucleus of the amygdala implicated in auditory fear conditioning, which are potentiated by learning, enter a labile state after memory reactivation, and must be restabilized through a postsynaptic mechanism implicating the mammalian target of rapamycin kinase-dependent signaling. Fear-conditioning-induced synaptic enhancements were primarily presynaptic in origin. Reconsolidation blockade with rapamycin, inhibiting mammalian target of rapamycin kinase activity, suppressed synaptic potentiation in slices from fear-conditioned rats. Surprisingly, this reduction of synaptic efficacy was mediated by post-but not presynaptic mechanisms. These findings suggest that different plasticity rules may apply to the processes underlying the acquisition of original fear memory and postreactivational stabilization of fear-conditioning-induced synaptic enhancements mediating fear memory reconsolidation. C1 [Li, Yan; Meloni, Edward G.; Carlezon, William A., Jr.; Bolshakov, Vadim Y.] Harvard Univ, Sch Med, McLean Hosp, Dept Psychiat, Belmont, MA 02478 USA. [Milad, Mohammed R.; Pitman, Roger K.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02129 USA. [Milad, Mohammed R.; Pitman, Roger K.] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Nader, Karim] McGill Univ, Dept Psychol, Montreal, PQ H3A 1B1, Canada. RP Nader, K (reprint author), McGill Univ, Dept Psychol, 1205 Dr Penfield Ave, Montreal, PQ H3A 1B1, Canada. EM karim.nader@mcgill.ca; vadimb@mclean.harvard.edu FU National Institutes of Health [MH083011, MH090464]; US Army Medical Research Acquisition Activity Grant [W81XWH-08-2-0126] FX This study was supported by National Institutes of Health Grants MH083011 (to V.Y.B) and MH090464 (to V.Y.B.), and US Army Medical Research Acquisition Activity Grant W81XWH-08-2-0126 (to R.K.P.). NR 39 TC 25 Z9 26 U1 0 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 19 PY 2013 VL 110 IS 12 BP 4798 EP 4803 DI 10.1073/pnas.1217878110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125EK UT WOS:000317521600080 PM 23487762 ER PT J AU Purdon, PL Pierce, ET Mukamel, EA Prerau, MJ Walsh, JL Wong, KFK Salazar-Gomez, AF Harrell, PG Sampson, AL Cimenser, A Ching, SN Kopell, NJ Tavares-Stoeckel, C Habeeb, K Merhar, R Brown, EN AF Purdon, Patrick L. Pierce, Eric T. Mukamel, Eran A. Prerau, Michael J. Walsh, John L. Wong, Kin Foon K. Salazar-Gomez, Andres F. Harrell, Priscilla G. Sampson, Aaron L. Cimenser, Aylin Ching, ShiNung Kopell, Nancy J. Tavares-Stoeckel, Casie Habeeb, Kathleen Merhar, Rebecca Brown, Emery N. TI Electroencephalogram signatures of loss and recovery of consciousness from propofol SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SPECTRAL EDGE FREQUENCY; INDUCED ALPHA-RHYTHM; GENERAL-ANESTHESIA; BISPECTRAL ANALYSIS; STATE INDEX; EEG CHANGES; SLEEP; MECHANISMS; OSCILLATIONS; SEVOFLURANE AB Unconsciousness is a fundamental component of general anesthesia (GA), but anesthesiologists have no reliable ways to be certain that a patient is unconscious. To develop EEG signatures that track loss and recovery of consciousness under GA, we recorded high-density EEGs in humans during gradual induction of and emergence from unconsciousness with propofol. The subjects executed an auditory task at 4-s intervals consisting of interleaved verbal and click stimuli to identify loss and recovery of consciousness. During induction, subjects lost responsiveness to the less salient clicks before losing responsiveness to the more salient verbal stimuli; during emergence they recovered responsiveness to the verbal stimuli before recovering responsiveness to the clicks. The median frequency and bandwidth of the frontal EEG power tracked the probability of response to the verbal stimuli during the transitions in consciousness. Loss of consciousness was marked simultaneously by an increase in low-frequency EEG power (<1 Hz), the loss of spatially coherent occipital alpha oscillations (8-12 Hz), and the appearance of spatially coherent frontal alpha oscillations. These dynamics reversed with recovery of consciousness. The low-frequency phase modulated alpha amplitude in two distinct patterns. During profound unconsciousness, alpha amplitudes were maximal at low-frequency peaks, whereas during the transition into and out of unconsciousness, alpha amplitudes were maximal at low-frequency nadirs. This latter phase-amplitude relationship predicted recovery of consciousness. Our results provide insights into the mechanisms of propofol-induced unconsciousness, establish EEG signatures of this brain state that track transitions in consciousness precisely, and suggest strategies for monitoring the brain activity of patients receiving GA. C1 [Purdon, Patrick L.; Pierce, Eric T.; Prerau, Michael J.; Walsh, John L.; Wong, Kin Foon K.; Salazar-Gomez, Andres F.; Harrell, Priscilla G.; Sampson, Aaron L.; Cimenser, Aylin; Ching, ShiNung; Tavares-Stoeckel, Casie; Merhar, Rebecca; Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Habeeb, Kathleen] Massachusetts Gen Hosp, Clin Res Ctr, Boston, MA 02114 USA. [Purdon, Patrick L.; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Mukamel, Eran A.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02139 USA. [Mukamel, Eran A.] Univ Calif San Diego, Ctr Theoret Biol Phys, La Jolla, CA 92093 USA. [Kopell, Nancy J.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Purdon, PL (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM patrickp@nmr.mgh.harvard.edu; nk@bu.edu; enb@neurostat.mit.edu RI Wong, Kin Foon Kevin/C-7896-2014 FU National Institutes of Health (NIH) Director's Pioneer Award [DP1-OD003646]; NIH Grant [R01-MH071847]; NIH New Innovator Award [DP2-OD006454]; NIH K-Award [K25-NS057580]; Massachusetts General Hospital Department of Anesthesia, Critical Care, and Pain Medicine; Harvard Catalyst; Harvard Clinical and Translational Science Center (NIH Award) [UL1 RR 025758]; [R01-EB006385] FX This work was supported by National Institutes of Health (NIH) Director's Pioneer Award DP1-OD003646 and NIH Grant R01-MH071847 (to E.N.B.), by NIH New Innovator Award DP2-OD006454 and K-Award K25-NS057580 (to P.L.P.), and by R01-EB006385 (to E.N.B., P.L.P., and K.F.K.W.) This work was also supported by the Massachusetts General Hospital Department of Anesthesia, Critical Care, and Pain Medicine, as well as the Harvard Catalyst and The Harvard Clinical and Translational Science Center (NIH Award UL1 RR 025758). NR 78 TC 89 Z9 90 U1 1 U2 34 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 MAR 19 PY 2013 VL 110 IS 12 BP E1142 EP E1151 DI 10.1073/pnas.1221180110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125EK UT WOS:000317521600010 PM 23487781 ER PT J AU Barton, JP Sontag, ED AF Barton, John P. Sontag, Eduardo D. TI The Energy Costs of Insulators in Biochemical Networks SO BIOPHYSICAL JOURNAL LA English DT Article ID ACTIVATED PROTEIN-KINASE; SIGNAL-TRANSDUCTION NETWORKS; NEGATIVE FEEDBACK-AMPLIFIER; MATHEMATICAL-MODELS; TRADE-OFFS; RETROACTIVITY; DYNAMICS; BIOLOGY; SYSTEMS; COMPLEXITY AB Complex networks of biochemical reactions, such as intracellular protein signaling pathways and genetic networks, are often conceptualized in terms of modules-semiindependent collections of components that perform a well-defined function and which may be incorporated in multiple pathways. However, due to sequestration of molecular messengers during interactions and other effects, collectively referred to as retroactivity, real biochemical systems do not exhibit perfect modularity. Biochemical signaling pathways can be insulated from impedance and competition effects, which inhibit modularity, through enzymatic futile cycles that consume energy, typically in the form of ATP. We hypothesize that better insulation necessarily requires higher energy consumption. We test this hypothesis through a combined theoretical and computational analysis of a simplified physical model of covalent cycles, using two innovative measures of insulation, as well as a possible new way to characterize optimal insulation through the balancing of these two measures in a Pareto sense. Our results indicate that indeed better insulation requires more energy. While insulation may facilitate evolution by enabling a modular plug-and-play interconnection architecture, allowing for the creation of new behaviors by adding targets to existing pathways, our work suggests that this potential benefit must be balanced against the metabolic costs of insulation necessarily incurred in not affecting the behavior of existing processes. C1 [Barton, John P.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Barton, John P.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Barton, John P.] Harvard Univ, Boston, MA 02115 USA. [Sontag, Eduardo D.] Rutgers State Univ, Dept Math, Piscataway, NJ 08855 USA. RP Sontag, ED (reprint author), Rutgers State Univ, Dept Math, Piscataway, NJ 08855 USA. EM sontag@math.rutgers.edu OI Barton, John/0000-0003-1467-421X; Sontag, Eduardo/0000-0001-8020-5783 FU National Institutes of Health [NIH 1R01GM086881, 1R01GM100473, AFOSR FA9550-11-1-0247] FX Work was supported in part by National Institutes of Health grants No. NIH 1R01GM086881, No. 1R01GM100473, and No. AFOSR FA9550-11-1-0247. NR 53 TC 10 Z9 10 U1 0 U2 13 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 MAR 19 PY 2013 VL 104 IS 6 BP 1380 EP 1390 DI 10.1016/j.bpj.2013.01.056 PG 11 WC Biophysics SC Biophysics GA 111MO UT WOS:000316525600022 PM 23528097 ER PT J AU Meyer, MJ Bateman, BT Kurth, T Eikermann, M AF Meyer, Matthew J. Bateman, Brian T. Kurth, Tobias Eikermann, Matthias TI INTERMEDIATE ACTING NEUROMUSCULAR BLOCKING AGENTS AND POSTOPERATIVE RESPIRATORY COMPLICATIONS Neostigmine reversal doesn't improve postoperative respiratory safety SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Letter C1 [Meyer, Matthew J.; Bateman, Brian T.; Eikermann, Matthias] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anaesthesia Crit Care & Pain Med, Boston, MA 02163 USA. [Bateman, Brian T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pharmacoepidemiol & Pharmacoecon,Dept Med, Boston, MA 02115 USA. [Kurth, Tobias] INSERM, Neuroepidemiol U708, Bordeaux, France. [Kurth, Tobias] Univ Bordeaux, Bordeaux, France. [Kurth, Tobias] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Prevent Med, Boston, MA 02115 USA. [Eikermann, Matthias] Univ Klinikum Essen, Klin Anaesthesie & Intens Med, Essen, Germany. RP Meyer, MJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anaesthesia Crit Care & Pain Med, Boston, MA 02163 USA. EM meikermann@partners.org RI Kurth, Tobias/A-9243-2012 OI Kurth, Tobias/0000-0001-7169-2620 NR 4 TC 10 Z9 10 U1 0 U2 4 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 MAR 19 PY 2013 VL 346 AR f1460 DI 10.1136/bmj.f1460 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 113LX UT WOS:000316670500017 PM 23512446 ER PT J AU Iezzoni, LI AF Iezzoni, Lisa I. TI Ups and Downs of Improving Physical Examination Access for Patients and Physicians SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Iezzoni, LI (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,Room 901B, Boston, MA 02114 USA. EM liezzoni@partners.org NR 6 TC 1 Z9 1 U1 0 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 MAR 19 PY 2013 VL 158 IS 6 BP 491 EP 492 DI 10.7326/0003-4819-158-6-201303190-00010 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 112AY UT WOS:000316565100019 PM 23552461 ER PT J AU Cryer, PE Axelrod, L Grossman, AB Heller, SR Seaquist, ER Service, FJ AF Cryer, Philip E. Axelrod, Lloyd Grossman, Ashley B. Heller, Simon R. Seaquist, Elizabeth R. Service, F. John CA Endocrine Soc Task Force TI Diagnostic Accuracy of an "Amended" Insulin-Glucose Ratio for the Biochemical Diagnosis of Insulinomas SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID BASAL INSULIN; HYPOGLYCEMIA; MANAGEMENT C1 [Cryer, Philip E.] Washington Univ, St Louis, MO 63130 USA. [Axelrod, Lloyd] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Axelrod, Lloyd] Harvard Univ, Sch Med, Boston, MA USA. [Grossman, Ashley B.] Oxford Ctr Diabet Endocrinol & Metab, Headington, Oxon, England. [Heller, Simon R.] Sheffield Teaching Hosp, Sheffield, S Yorkshire, England. [Seaquist, Elizabeth R.] Univ Minnesota, Minneapolis, MN USA. [Service, F. John] Mayo Clin, Rochester, MN USA. RP Cryer, PE (reprint author), Washington Univ, St Louis, MO 63130 USA. OI Heller, Simon/0000-0002-2425-9565 FU NCRR NIH HHS [MO1-RR00036]; NIDDK NIH HHS [P60-DK20579, R37-DK27085, T32-DK07120] NR 7 TC 1 Z9 1 U1 0 U2 0 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 MAR 19 PY 2013 VL 158 IS 6 BP 500 EP 501 DI 10.7326/0003-4819-158-6-201303190-00020 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 112AY UT WOS:000316565100026 PM 23552360 ER PT J AU Adams, SG Peters, JI AF Adams, Sandra G. Peters, Jay I. TI Amoxicillin/clavulanate vs placebo: more exacerbation cures, fewer recurrences in mild-to-moderate COPD SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Adams, Sandra G.] Univ Texas San Antonio, Hlth Sci Ctr, San Antonio, TX 78249 USA. South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Adams, SG (reprint author), Univ Texas San Antonio, Hlth Sci Ctr, San Antonio, TX 78249 USA. OI Miravitlles, Marc/0000-0002-9850-9520 NR 2 TC 0 Z9 0 U1 0 U2 2 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 MAR 19 PY 2013 VL 158 IS 6 AR JC3 DI 10.7326/0003-4819-158-6-201303190-02003 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 112AY UT WOS:000316565100002 PM 23552686 ER PT J AU Kinlay, S AF Kinlay, Scott TI Outcomes for Clinical Studies Assessing Drug and Revascularization Therapies for Claudication and Critical Limb Ischemia in Peripheral Artery Disease SO CIRCULATION LA English DT Article ID SUPERFICIAL FEMORAL-ARTERY; QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; NITINOL STENT IMPLANTATION; PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; PACLITAXEL-ELUTING STENTS; ANKLE-BRACHIAL INDEX; INTERMITTENT CLAUDICATION; BALLOON ANGIOPLASTY; LOWER-EXTREMITY C1 [Kinlay, Scott] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Kinlay, Scott] Harvard Univ, Sch Med, Boston, MA USA. RP Kinlay, S (reprint author), VA Boston Healthcare Syst, Div Cardiovasc, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM scott.kinlay@va.gov FU Clinical Science Research and Development Service of the VA Office of Research and Development [I01CX000440] FX This work was supported by Award Number I01CX000440 from the Clinical Science Research and Development Service of the VA Office of Research and Development. NR 86 TC 16 Z9 17 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 19 PY 2013 VL 127 IS 11 BP 1241 EP 1250 DI 10.1161/CIRCULATIONAHA.112.001232 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 108DN UT WOS:000316271800018 PM 23509032 ER PT J AU Aneja, A Esquitin, R Shah, K Iyengar, R Nisenbaum, R Melo, M Matthewkutty, S Sethi, SS Mamdani, M Farkouh, ME AF Aneja, Ashish Esquitin, Ricardo Shah, Kshitij Iyengar, Rupa Nisenbaum, Rosane Melo, Magda Matthewkutty, Shiny Sethi, Sanjum S. Mamdani, Muhammad Farkouh, Michael E. TI Authors' Self-Declared Financial Conflicts of Interest Do Not Impact the Results of Major Cardiovascular Trials SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular; clinical trial; conflicts of interest; financial; industry; randomized controlled trials ID CLINICAL-TRIALS; PHARMACEUTICAL-INDUSTRY; INTEREST DISCLOSURE; DRUG TRIALS; ASSOCIATION; OUTCOMES; TIES AB Objectives This study assessed whether the results of major, potentially practice-altering cardiovascular trials were influenced by the authors' self-declared financial conflicts of interest (FCOI). Secondary objectives included assessment of trial outcomes by source of funding, by FCOI subtype, and by trial endpoints. Background Financial conflicts of interest, ubiquitous in cardiovascular medicine because of significant investigator-industry collaborations, potentially can influence trial outcomes. Methods A MEDLINE search was performed using the MeSH term cardiovascular disease limited to randomized controlled trials and clinical trials published from January 1, 2000, through April 15, 2008, in 3 high-impact journals. Two reviewers independently abstracted data from the published article. Chi-square tests, Fisher exact tests, and multivariate logistic regression were used to assess the associations between FCOI and study characteristics and between FCOI and trial outcomes. Results Of the 550 articles reviewed, 51.1% satisfied FCOI criteria, including at least one of the following: stock ownership, employee, speaker's bureau, and consultant). Of the 538 articles providing sponsorship information, 34.6% reported funding solely by nonprofit organizations, 48.3% reported funding solely by industry, and 17.1% reported funding by a combination. Prevalence of FCOI significantly increased with level of industry funding: 21.5% (none), 50.0% (shared), 75.0% (industry solely, n = 281, p < 0.0001). However, no differences in reporting of favorable results were detected when articles were analyzed by self-declared FCOI (60.5% vs. 59.5% in those with and without, odds ratio: 1.04, p = 0.81). This result was upheld in multivariate analysis. Conclusions Authors' self-declared FCOI and source of funding do not seem to impact outcomes in major cardiovascular clinical trials. (J Am Coll Cardiol 2013;61:1137-43) (C) 2013 by the American College of Cardiology Foundation C1 [Aneja, Ashish] Case Western Reserve Univ, Heart & Vasc Ctr, Cleveland, OH 44106 USA. [Esquitin, Ricardo] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Cardiol, Boston, MA 02215 USA. [Shah, Kshitij] James J Peters VA Med Ctr, Dept Med, Bronx, NY USA. [Iyengar, Rupa; Matthewkutty, Shiny; Sethi, Sanjum S.; Farkouh, Michael E.] Mt Sinai Sch Med, Zena & Michael A Weiner Cardiovasc Inst, New York, NY 10029 USA. [Nisenbaum, Rosane] Univ Toronto, St Michaels Hosp, Li Ka Shing Knowledge Inst, Ctr Res Inner City Hlth,Keenan Res Ctr, Toronto, ON M5B 1W8, Canada. [Nisenbaum, Rosane] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Nisenbaum, Rosane; Melo, Magda; Mamdani, Muhammad; Farkouh, Michael E.] Univ Toronto, Li Ka Shing Knowledge Inst, Appl Hlth Res Ctr, Toronto, ON, Canada. [Farkouh, Michael E.] Univ Toronto, Peter Munk Cardiac Ctr, Toronto, ON, Canada. RP Farkouh, ME (reprint author), Mt Sinai Sch Med, Cardiovasc Inst, 1 Gustave L Levy Pl,Box 1074, New York, NY 10029 USA. EM Michael.Farkouh@mssm.edu OI Esquitin, Ricardo/0000-0002-3475-3671 NR 30 TC 9 Z9 10 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 19 PY 2013 VL 61 IS 11 BP 1137 EP 1143 DI 10.1016/j.jacc.2012.10.056 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 103UO UT WOS:000315945200003 PM 23395075 ER PT J AU Mandawat, A Mandawat, A Mandawat, MK AF Mandawat, Aditya Mandawat, Anant Mandawat, Mahendra K. TI Percutaneous Coronary Intervention After ST-Segment Elevation Myocardial Infarction in Nonagenarians Use Rates and In-Hospital Mortality SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter C1 [Mandawat, Aditya] Brigham & Womens Hosp, Boston, MA 02115 USA. [Mandawat, Aditya; Mandawat, Anant] Harvard Univ, Sch Med, Boston, MA USA. [Mandawat, Anant] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mandawat, Mahendra K.] Georgia Hlth Sci Univ, Augusta, GA USA. [Mandawat, Mahendra K.] Charlie Norwood VA Med Ctr, Augusta, GA 30904 USA. RP Mandawat, MK (reprint author), Charlie Norwood VA Med Ctr, 1 Freedom Way, Augusta, GA 30904 USA. EM mahendra.mandawat@va.gov NR 5 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 19 PY 2013 VL 61 IS 11 BP 1207 EP 1208 DI 10.1016/j.jacc.2012.12.019 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 103UO UT WOS:000315945200015 PM 23375924 ER PT J AU Vazquez, F Lim, JH Chim, H Bhalla, K Girnun, G Pierce, K Clish, CB Granter, SR Widlund, HR Spiegelman, BM Puigserver, P AF Vazquez, Francisca Lim, Ji-Hong Chim, Helen Bhalla, Kavita Girnun, Geoff Pierce, Kerry Clish, Clary B. Granter, Scott R. Widlund, Hans R. Spiegelman, Bruce M. Puigserver, Pere TI PGC1 alpha Expression Defines a Subset of Human Melanoma Tumors with Increased Mitochondrial Capacity and Resistance to Oxidative Stress SO CANCER CELL LA English DT Article ID PROMOTES CELL-SURVIVAL; ERR-ALPHA; TRANSCRIPTIONAL COACTIVATOR; METABOLIC REGULATOR; MALIGNANT-MELANOMA; GLUCOSE-METABOLISM; CANCER-CELLS; LUNG-CANCER; PGC-1-ALPHA; MITF AB Cancer cells reprogram their metabolism using different strategies to meet energy and anabolic demands to maintain growth and survival. Understanding the molecular and genetic determinants of these metabolic programs is critical to successfully exploit them for therapy. Here, we report that the oncogenic melanocyte lineage-specification transcription factor MITF drives PGC1 alpha (PPARGC1A) overexpression in a subset of human melanomas and derived cell lines. Functionally, PGC1 alpha positive melanoma cells exhibit increased mitochondrial energy metabolism and reactive oxygen species (ROS) detoxification capacities that enable survival under oxidative stress conditions. Conversely, PGC1 alpha negative melanoma cells are more glycolytic and sensitive to ROS-inducing drugs. These results demonstrate that differences in PGC1 alpha levels in melanoma tumors have a profound impact in their metabolism, biology, and drug sensitivity. C1 [Vazquez, Francisca; Lim, Ji-Hong; Chim, Helen; Spiegelman, Bruce M.; Puigserver, Pere] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Vazquez, Francisca; Lim, Ji-Hong; Chim, Helen; Spiegelman, Bruce M.; Puigserver, Pere] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Bhalla, Kavita; Girnun, Geoff] Univ Maryland, Sch Med, Dept Pathol, Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Pierce, Kerry; Clish, Clary B.] Broad Inst MIT & Harvard, Metabolite Profiling Initiat, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Granter, Scott R.] Brigham & Womens Hosp, Harvard Skin Dis Res Ctr, Dept Pathol, Boston, MA 02115 USA. [Widlund, Hans R.] Brigham & Womens Hosp, Harvard Skin Dis Res Ctr, Dept Dermatol, Boston, MA 02115 USA. RP Puigserver, P (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM pere_puigserver@dfci.harvard.edu FU Claudia Adams Barr Program in Cancer Research; Dana-Farber Cancer Institute; [P50CA093683] FX We thank the Dana-Farber Cancer Institute Microarray Core Facility for performing the gene-expression arrays and the Dana-Farber RNAi facility for the shRNA constructs. These studies were funded by the Claudia Adams Barr Program in Cancer Research and Dana-Farber Cancer Institute funds. H.R.W. acknowledges support from P50CA093683. NR 45 TC 135 Z9 139 U1 5 U2 45 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD MAR 18 PY 2013 VL 23 IS 3 BP 287 EP 301 DI 10.1016/j.ccr.2012.11.020 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 110JS UT WOS:000316439000008 PM 23416000 ER PT J AU Haq, R Shoag, J Andreu-Perez, P Yokoyama, S Edelman, H Rowe, GC Frederick, DT Hurley, AD Nellore, A Kung, AL Wargo, JA Song, JS Fisher, DE Arany, Z Widlund, HR AF Haq, Rizwan Shoag, Jonathan Andreu-Perez, Pedro Yokoyama, Satoru Edelman, Hannah Rowe, Glenn C. Frederick, Dennie T. Hurley, Aeron D. Nellore, Abhinav Kung, Andrew L. Wargo, Jennifer A. Song, Jun S. Fisher, David E. Arany, Zolt Widlund, Hans R. TI Oncogenic BRAF Regulates Oxidative Metabolism via PGC1 alpha and MITF SO CANCER CELL LA English DT Article ID TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; CONTROLLING MITOCHONDRIAL BIOGENESIS; B-RAF; METASTATIC MELANOMA; HEPATIC GLUCONEOGENESIS; CELL PROLIFERATION; PGC-1 COACTIVATORS; MALIGNANT-MELANOMA; SKELETAL-MUSCLE; CANCER CELLS AB Activating mutations in BRAF are the most common genetic alterations in melanoma. Inhibition of BRAF by small molecules leads to cell-cycle arrest and apoptosis. We show here that BRAF inhibition also induces an oxidative phosphorylation gene program, mitochondrial biogenesis, and the increased expression of the mitochondrial master regulator, PGC1 alpha. We further show that a target of BRAF, the melanocyte lineage factor MITF, directly regulates the expression of PGC1 alpha. Melanomas with activation of the BRAF/MAPK pathway have suppressed levels of MITF and PGC1 alpha and decreased oxidative metabolism. Conversely, treatment of BRAF-mutated melanomas with BRAF inhibitors renders them addicted to oxidative phosphorylation. Our data thus identify an adaptive metabolic program that limits the efficacy of BRAF inhibitors. C1 [Haq, Rizwan; Fisher, David E.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Haq, Rizwan; Andreu-Perez, Pedro; Yokoyama, Satoru; Edelman, Hannah; Fisher, David E.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Dept Dermatol, Boston, MA 02114 USA. [Frederick, Dennie T.; Wargo, Jennifer A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Shoag, Jonathan; Rowe, Glenn C.; Arany, Zolt] Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02116 USA. [Yokoyama, Satoru] Toyama Univ, Inst Nat Med, Div Pathogen Biochem, Toyama 9300194, Japan. [Hurley, Aeron D.; Widlund, Hans R.] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Nellore, Abhinav; Song, Jun S.] Univ Calif San Francisco, Inst Human Genet, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kung, Andrew L.] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10032 USA. RP Fisher, DE (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA. EM dfisher3@partners.org; zarany@bidmc.harvard.edu; hwidlund@bics.bwh.harvard.edu FU American Skin Association; NIAMS/NIH [R01 AR043369-16]; Melanoma Research Alliance; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; National Cancer Institute [R01CA163336, P50CA093683] FX We thank A. Winant for assistance with manuscript writing, M. McKee for electron microscopy, and A. Saur at the Luria Family Imaging Center (Dana-Farber Cancer Institute) for assistance with mouse xenograft experiments. This work was supported by the American Skin Association (to R.H.), NIAMS/NIH (R01 AR043369-16), Melanoma Research Alliance, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to D.E.F.), and The National Cancer Institute (R01CA163336 to J.S.S. and P50CA093683 to H.R.W.). NR 76 TC 172 Z9 175 U1 8 U2 45 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD MAR 18 PY 2013 VL 23 IS 3 BP 302 EP 315 DI 10.1016/j.ccr.2013.02.003 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 110JS UT WOS:000316439000009 PM 23477830 ER PT J AU Roti, G Carlton, A Ross, KN Markstein, M Pajcini, K Su, AH Perrimon, N Pear, WS Kung, AL Blacklow, SC Aster, JC Stegmaier, K AF Roti, Giovanni Carlton, Anne Ross, Kenneth N. Markstein, Michele Pajcini, Kostandin Su, Angela H. Perrimon, Norbert Pear, Warren S. Kung, Andrew L. Blacklow, Stephen C. Aster, Jon C. Stegmaier, Kimberly TI Complementary Genomic Screens Identify SERCA as a Therapeutic Target in NOTCH1 Mutated Cancer SO CANCER CELL LA English DT Article ID SQUAMOUS-CELL CARCINOMA; ACUTE LYMPHOBLASTIC-LEUKEMIA; GAMMA-SECRETASE INHIBITORS; T-ALL; MYELOID-LEUKEMIA; CA2+ PUMP; C-MYC; MUTATIONS; GENE; DROSOPHILA AB Notch1 is a rational therapeutic target in several human cancers, but as a transcriptional regulator, it poses a drug discovery challenge. To identify Notch1 modulators, we performed two cell-based, high-throughput screens for small-molecule inhibitors and cDNA enhancers of a NOTCH1 allele bearing a leukemia-associated mutation. Sarco/endoplasmic reticulum calcium ATPase (SERCA) channels emerged at the intersection of these complementary screens. SERCA inhibition preferentially impairs the maturation and activity of mutated Notch1 receptors and induces a G(0)/G(1) arrest in NOTCH1-mutated human leukemia cells. A small-molecule SERCA inhibitor has on-target activity in two mouse models of human leukemia and interferes with Notch signaling in Drosophila. These studies "credential" SERCA as a therapeutic target in cancers associated with NOTCH1 mutations. C1 [Roti, Giovanni; Carlton, Anne; Su, Angela H.; Stegmaier, Kimberly] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Blacklow, Stephen C.] Dana Farber Canc Inst, Canc Biol Program, Boston, MA 02215 USA. [Roti, Giovanni; Carlton, Anne; Su, Angela H.; Stegmaier, Kimberly] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Ross, Kenneth N.; Stegmaier, Kimberly] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Markstein, Michele] Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. [Pajcini, Kostandin; Pear, Warren S.] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Pajcini, Kostandin; Pear, Warren S.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Perrimon, Norbert] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Blacklow, Stephen C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Aster, Jon C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Perrimon, Norbert] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Kung, Andrew L.] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA. RP Stegmaier, K (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM kimberly_stegmaier@dfci.harvard.edu OI Markstein, Michele/0000-0003-2635-8118; Kung, Andrew/0000-0002-9091-488X; Carlton, Anne/0000-0002-5921-6004 FU Leukemia and Lymphoma Society (LLS); William Lawrence and Blanche Hughes Foundation; SynCure Cancer Research Foundation; National Cancer Institute [P01 CA 068484-11A1]; European Hematology Association-American Society of Hematology International Fellowship Award; American-Italian Cancer Foundation; Lady Tata International Award for Research in Leukaemia; LLS; Fondazione Umberto Veronesi; National Institutes of Health (NIH)/National Center for Research Resources [5 UL1 RR025758]; NIH [R01 CA 092433]; AULL (Associazione Umbra per lo studio e la terapia delle Leucemie e Linfomi) FX This work was supported by the Leukemia and Lymphoma Society (LLS) and the William Lawrence and Blanche Hughes Foundation (to K.S., J.C.A., and S.C.B.); the SynCure Cancer Research Foundation and the National Cancer Institute grant P01 CA 068484-11A1 (to K.S.); the European Hematology Association-American Society of Hematology International Fellowship Award, the American-Italian Cancer Foundation Post-Doctoral Research Fellowship, the Lady Tata International Award for Research in Leukaemia, and the LLS Special Fellow award and Fondazione Umberto Veronesi (to G.R.); the LLS Fellow (to K.P.); National Institutes of Health (NIH)/National Center for Research Resources grants 5 UL1 RR025758 (to N.P. and M.M.); and NIH grant R01 CA 092433 (to S.C.B.). We thank Zi Peng Fan and Amanda L. Christie for their technical support, Nicola Tolliday for stewardship of the chemical screen, the TRiP at Harvard Medical School for providing transgenic RNAi fly stocks used in this study, and Maria Pia Briziarelli, AULL (Associazione Umbra per lo studio e la terapia delle Leucemie e Linfomi), for grant management (G.R.). NR 64 TC 37 Z9 38 U1 1 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD MAR 18 PY 2013 VL 23 IS 3 BP 390 EP 405 DI 10.1016/j.ccr.2013.01.015 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 110JS UT WOS:000316439000015 PM 23434461 ER PT J AU Bested, AC Logan, AC Selhub, EM AF Bested, Alison C. Logan, Alan C. Selhub, Eva M. TI Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part I - autointoxication revisited SO GUT PATHOGENS LA English DT Review DE Intestinal microbiota; Autointoxication; Depression; Anxiety; Probiotics; Microbial ecology; Lipopolysaccharide endotoxin; Diet; Intestinal permeability ID HELICOBACTER-PYLORI INFECTION; IRRITABLE-BOWEL-SYNDROME; BACILLUS ACIDOPHILUS; TOOTH LOSS; CHRONIC CONSTIPATION; BACTERIAL-FLORA; DEPRESSION; THERAPY; DISEASE; SKIN AB Mental health disorders, depression in particular, have been described as a global epidemic. Research suggests that a variety of lifestyle and environmental changes may be driving at least some portion of the increased prevalence. One area of flourishing research involves the relationship between the intestinal microbiota (as well as the related functional integrity of the gastrointestinal tract) and mental health. In order to appreciate the recent scientific gains in this area, and its potential future directions, it is critical to review the history of the topic. Probiotic administration (e.g. Lactobacillus) and fecal microbiota transfer for conditions associated with depression and anxiety is not a new concept. Here, in the first of a 3-part series, we begin by reviewing the origins of the contemporary research, providing a critical appraisal of what has become a revisionist history of the controversial term 'autointoxication'. We argue that legitimate interests in the gut-brain-microbiota connection were obscured for decades by its association with a narrow historical legacy. Historical perspectives provide a very meaningful context to the current state of the contemporary research as outlined in parts II and III. C1 [Bested, Alison C.] BC Womens Hosp, Complex Chron Dis Program, Vancouver, BC V6H 3N1, Canada. [Bested, Alison C.] Ctr Hlth, Vancouver, BC V6H 3N1, Canada. [Logan, Alan C.] CAMNR, Mill Valley, CA 94941 USA. [Selhub, Eva M.] Harvard Univ, Sch Med, Waltham, MA 02453 USA. [Selhub, Eva M.] Massachusetts Gen Hosp, Waltham, MA 02453 USA. RP Logan, AC (reprint author), CAMNR, 775 Blithedale Ave,Suite 364, Mill Valley, CA 94941 USA. EM aclnd@cfs-fm.org FU Genuine Health, Toronto, Canada FX ACB and EMS have no competing interests. ACL has received consulting fees from Genuine Health, Toronto, Canada. NR 155 TC 27 Z9 29 U1 2 U2 65 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-4749 J9 GUT PATHOG JI Gut Pathogens PD MAR 18 PY 2013 VL 5 AR 5 DI 10.1186/1757-4749-5-5 PG 16 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA 118GS UT WOS:000317013700001 PM 23506618 ER PT J AU Caceres, IA Arcaya, M Declercq, E Belanoff, CM Janakiraman, V Cohen, B Ecker, J Smith, LA Subramanian, SV AF Caceres, Isabel A. Arcaya, Mariana Declercq, Eugene Belanoff, Candice M. Janakiraman, Vanitha Cohen, Bruce Ecker, Jeffrey Smith, Lauren A. Subramanian, S. V. TI Hospital Differences in Cesarean Deliveries in Massachusetts (US) 2004-2006: The Case against Case-Mix Artifact SO PLOS ONE LA English DT Article ID BIRTH-RATES; PHYSICIAN FACTOR; VAGINAL BIRTHS; UNITED-STATES; RISK; SECTION; ADJUSTMENT; OUTCOMES; WOMEN; TERM AB Objective: We examined the extent to which differences in hospital-level cesarean delivery rates in Massachusetts were attributable to hospital-level, rather than maternal, characteristics. Methods: Birth certificate and maternal in-patient hospital discharge records for 2004-06 in Massachusetts were linked. The study population was nulliparous, term, singleton, and vertex births (NTSV) (n = 80,371) in 49 hospitals. Covariates included mother's age, race/ethnicity, education, infant birth weight, gestational age, labor induction (yes/no), hospital shift at time of birth, and preexisting health conditions. We estimated multilevel logistic regression models to assess the likelihood of a cesarean delivery Results: Overall, among women with NTSV births, 26.5% births were cesarean, with a range of 14% to 38.3% across hospitals. In unadjusted models, the between-hospital variance was 0.103 (SE 0.022); adjusting for demographic, socioeconomic and preexisting medical conditions did not reduce any hospital-level variation 0.108 (SE 0.023). Conclusion: Even after adjusting for both socio-demographic and clinical factors, the chance of a cesarean delivery for NTSV pregnancies varied according to hospital, suggesting the importance of hospital practices and culture in determining a hospital's cesarean rate. C1 [Caceres, Isabel A.; Cohen, Bruce] Massachusetts Dept Publ Hlth, Bur Hlth Informat Stat Res & Evaluat, Boston, MA USA. [Arcaya, Mariana; Subramanian, S. V.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Declercq, Eugene; Belanoff, Candice M.] Boston Univ, Dept Community Hlth Sci, Boston, MA 02215 USA. [Janakiraman, Vanitha; Ecker, Jeffrey] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Smith, Lauren A.] Massachusetts Dept Hlth, Boston, MA USA. RP Subramanian, SV (reprint author), Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, 665 Huntington Ave, Boston, MA 02115 USA. EM svsubram@hsph.harvard.edu OI Declercq, Eugene/0000-0001-5411-3033; Belanoff, Candice/0000-0002-2491-7548 FU Centers for Disease Control and Prevention [200-2009-31671CDC]; National Cancer Institute's joint Harvard School of Public Health-Dana-Farber Cancer Institute Educational Program in Cancer Prevention Research; National Institutes of Health (NIH) [3R25CA057711-18S1]; NIH [NHLBI K25 HL081275]; Robert Wood Johnson Investigator Award in Healthy Policy Research FX No direct funding was available for this study. The data for this study was provided by the Pregnancy to Early Life Longitudinal (PELL) data system which is supported by the Centers for Disease Control and Prevention Contract 200-2009-31671CDC. MA is supported as a predoctoral fellow by the National Cancer Institute's joint Harvard School of Public Health-Dana-Farber Cancer Institute Educational Program in Cancer Prevention Research, supported by National Institutes of Health (NIH) grant number 3R25CA057711-18S1. S.V. Subramanian is supported by the NIH Career Development Award (NHLBI K25 HL081275) and the Robert Wood Johnson Investigator Award in Healthy Policy Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 9 Z9 10 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 MAR 18 PY 2013 VL 8 IS 3 AR e57817 DI 10.1371/journal.pone.0057817 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109ZS UT WOS:000316411600006 PM 23526952 ER PT J AU Desai, BM Villanueva, J Nguyen, TTK Lioni, M Xiao, M Kong, J Krepler, C Vultur, A Flaherty, KT Nathanson, KL Smalley, KSM Herlyn, M AF Desai, Brijal M. Villanueva, Jessie Nguyen, Thierry-Thien K. Lioni, Mercedes Xiao, Min Kong, Jun Krepler, Clemens Vultur, Adina Flaherty, Keith T. Nathanson, Katherine L. Smalley, Keiran S. M. Herlyn, Meenhard TI The Anti-Melanoma Activity of Dinaciclib, a Cyclin-Dependent Kinase Inhibitor, Is Dependent on p53 Signaling SO PLOS ONE LA English DT Article ID MEK INHIBITION; MELANOMA-CELLS; MALIGNANT-MELANOMA; LINEAGE SURVIVAL; RAF KINASE; BRAF; RESISTANCE; GROWTH; EXPRESSION; MUTATIONS AB Although cyclin dependent kinase (CDK)-2 is known to be dispensable for the growth of most tumors, it is thought to be important for the proliferation of melanoma cells, where its expression is controlled by the melanocyte-lineage specific transcription factor MITF. Treatment of a panel of melanoma cells with the CDK inhibitor dinaciclib led to a concentration-dependent inhibition of growth under both 2D adherent and 3D organotypic cell culture conditions. Dinaciclib targeted melanoma cell lines regardless of cdk2 or MITF levels. Inhibition of growth was associated with a rapid induction of G2/M cell arrest and apoptosis. Treatment of human melanoma mouse xenografts with dinaciclib led to tumor regression associated with reduced retinoblastoma protein phosphorylation and Bcl-2 expression. Further mechanistic studies revealed that dinaciclib induces p53 expression whilst simultaneously downregulating the expression of the anti-apoptotic factors Mcl-1 and XIAP. To clarify the role of p53 activation in the dinaciclib-induced cell death, we generated melanoma cell lines in which p53 expression was knocked down using a shRNA lentiviral vector. Knockdown of p53 completely abolished the induction of apoptosis seen following dinaciclib treatment as shown by a lack of annexin-V staining and caspase-3 cleavage. Altogether, these data show that dinaciclib induces apoptosis in a large panel of melanoma cell lines through a mechanism requiring p53 expression. C1 [Desai, Brijal M.; Villanueva, Jessie; Nguyen, Thierry-Thien K.; Lioni, Mercedes; Xiao, Min; Kong, Jun; Krepler, Clemens; Vultur, Adina; Herlyn, Meenhard] Wistar Inst Anat & Biol, Philadelphia, PA USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nathanson, Katherine L.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Smalley, Keiran S. M.] H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, Tampa, FL USA. RP Herlyn, M (reprint author), Wistar Inst Anat & Biol, Philadelphia, PA USA. EM herlynm@wistar.org OI Nathanson, Katherine/0000-0002-6740-0901 FU National Institutes of Health [CA 76674, CA 25874,, CA 10815,, CA 93372, CA 47159, CA 80999, CA 098101, CA117881, GM071695]; Commonwealth Universal Research Enhancement Program; Pennsylvania Department of Health; American Skin Association; Schering-Plough, Kenilworth, New Jersey; Adelson Medical Research Foundation FX This work was supported by grants from the National Institutes of Health (CA 76674, CA 25874, CA 10815, CA 93372, CA 47159, CA 80999, CA 098101, CA117881, GM071695); funds from the Commonwealth Universal Research Enhancement Program; Pennsylvania Department of Health; the American Skin Association; Schering-Plough, Kenilworth, New Jersey; and the Adelson Medical Research Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 22 Z9 22 U1 2 U2 18 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 18 PY 2013 VL 8 IS 3 AR e59588 DI 10.1371/journal.pone.0059588 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109ZS UT WOS:000316411600067 PM 23527225 ER PT J AU Madsen, J Gaiha, GD Palaniyar, N Dong, T Mitchell, DA Clark, HW AF Madsen, Jens Gaiha, Gaurav D. Palaniyar, Nades Dong, Tao Mitchell, Daniel A. Clark, Howard W. TI Surfactant Protein D Modulates HIV Infection of Both T-Cells and Dendritic Cells SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MANNOSE-BINDING LECTIN; HELICAL COILED-COIL; INFLUENZA-A VIRUS; CARBOHYDRATE-RECOGNITION; ENVELOPE GLYCOPROTEIN; PULMONARY COLLECTINS; ALVEOLAR MACROPHAGES; TYPE-1 INFECTIVITY; LIGAND-BINDING AB Surfactant Protein D (SP-D) is an oligomerized C-type lectin molecule with immunomodulatory properties and involvement in lung surfactant homeostasis in the respiratory tract. SP-D binds to the enveloped viruses, influenza A virus and respiratory syncytial virus and inhibits their replication in vitro and in vivo. SP-D has been shown to bind to HIV via the HIV envelope protein gp120 and inhibit infectivity in vitro. Here we show that SP-D binds to different strains of HIV (BaL and IIIB) and the binding occurs at both pH 7.4 and 5.0 resembling physiological relevant pH values found in the body and the female urogenital tract, respectively. The binding of SP-D to HIV particles and gp120 was inhibited by the presence of several hexoses with mannose found to be the strongest inhibitor. Competition studies showed that soluble CD4 and CVN did not interfere with the interaction between SP-D and gp120. However, soluble recombinant DC-SIGN was shown to inhibit the binding between SP-D and gp120. SP-D agglutinated HIV and gp120 in a calcium dependent manner. SP-D inhibited the infectivity of HIV strains at both pH values of 7.4 and 5.0 in a concentration dependent manner. The inhibition of the infectivity was abolished by the presence of mannose. SP-D enhanced the binding of HIV to immature monocyte derived dendritic cells (iMDDCs) and was also found to enhance HIV capture and transfer to the T-cell like line PM1. These results suggest that SP-D can bind to and inhibit direct infection of T-cells by HIV but also enhance the transfer of infectious HIV particles from DCs to T-cells in vivo. C1 [Madsen, Jens; Clark, Howard W.] Univ Southampton, Southampton Gen Hosp, Dept Child Hlth, Sir Henry Wellcome Labs,Fac Med, Southampton, Hants, England. [Madsen, Jens; Clark, Howard W.] Univ Southampton, Inst Life Sci, Southampton, Hants, England. [Gaiha, Gaurav D.] Massachusetts Gen Hosp, Massachusetts Inst Technol & Harvard, Ragon Inst, Charlestown, MA USA. [Palaniyar, Nades] Univ Toronto, SickKids Res Inst, Toronto, ON, Canada. [Dong, Tao] Univ Oxford, Weatherall Inst Mol Med, Human Immunol Unit, MRC, Oxford, England. [Mitchell, Daniel A.] Univ Warwick, Warwick Med Sch, Clin Sci Res Inst, Coventry CV4 7AL, W Midlands, England. RP Madsen, J (reprint author), Univ Southampton, Southampton Gen Hosp, Dept Child Hlth, Sir Henry Wellcome Labs,Fac Med, Southampton, Hants, England. EM j.madsen@soton.ac.uk RI Mitchell, Daniel/A-6580-2009; Madsen, Jens/N-8082-2013; OI Mitchell, Daniel/0000-0003-0936-6212; Madsen, Jens/0000-0003-1664-7645; Clark, Howard/0000-0001-7354-2028; Palaniyar, Nades/0000-0002-2170-8548 FU Medical Research Council (UK) FX This work was supported by the Medical Research Council (UK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 7 Z9 7 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 18 PY 2013 VL 8 IS 3 AR e59047 DI 10.1371/journal.pone.0059047 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109ZS UT WOS:000316411600031 PM 23527085 ER PT J AU Sun, Y Hu, ZT Goeb, Y Dreier, L AF Sun, Yu Hu, Zhitao Goeb, Yannick Dreier, Lars TI The F-Box Protein MEC-15 (FBXW9) Promotes Synaptic Transmission in GABAergic Motor Neurons in C. elegans SO PLOS ONE LA English DT Article ID GLR-1 GLUTAMATE RECEPTORS; UBIQUITIN LIGASE COMPLEX; CAENORHABDITIS-ELEGANS; NEUROMUSCULAR-JUNCTION; SYSTEMATIC ANALYSIS; TOUCH SENSITIVITY; ABUNDANCE; MUTANTS; BETA; DIFFERENTIATION AB Ubiquitination controls the activity of many proteins and has been implicated in almost every aspect of neuronal cell biology. Characterizing the precise function of ubiquitin ligases, the enzymes that catalyze ubiquitination of target proteins, is key to understanding distinct functions of ubiquitination. F-box proteins are the variable subunits of the large family of SCF ubiquitin ligases and are responsible for binding and recognizing specific ubiquitination targets. Here, we investigated the function of the F-box protein MEC-15 (FBXW9), one of a small number of F-box proteins evolutionarily conserved from C. elegans to mammals. mec-15 is widely expressed in the nervous system including GABAergic and cholinergic motor neurons. Electrophysiological and behavioral analyses indicate that GABAergic synaptic transmission is reduced in mec-15 mutants while cholinergic transmission appears normal. In the absence of MEC-15, the abundance of the synaptic vesicle protein SNB-1 (synaptobrevin) is reduced at synapses and increased in cell bodies of GABAergic motor neurons, suggesting that MEC-15 affects the trafficking of SNB-1 between cell bodies and synapses and may promote GABA release by regulating the abundance of SNB-1 at synapses. C1 [Sun, Yu; Goeb, Yannick; Dreier, Lars] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Hu, Zhitao] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Dreier, L (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. EM larsdreier@ucla.edu FU University of California Los Angeles FX This work received start-up funds from University of California Los Angeles. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 1 Z9 4 U1 1 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 MAR 18 PY 2013 VL 8 IS 3 AR e59132 DI 10.1371/journal.pone.0059132 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109ZS UT WOS:000316411600042 ER PT J AU Vandenwijngaert, S Pokreisz, P Hermans, H Gillijns, H Pellens, M Bax, NAM Coppiello, G Oosterlinck, W Balogh, A Papp, Z Bouten, CVC Bartunek, J D'hooge, J Luttun, A Verbeken, E Herregods, MC Herijgers, P Bloch, KD Janssens, S AF Vandenwijngaert, Sara Pokreisz, Peter Hermans, Hadewich Gillijns, Hilde Pellens, Marijke Bax, Noortje A. M. Coppiello, Giulia Oosterlinck, Wouter Balogh, Agnes Papp, Zoltan Bouten, Carlijn V. C. Bartunek, Jozef D'hooge, Jan Luttun, Aernout Verbeken, Erik Herregods, Marie Christine Herijgers, Paul Bloch, Kenneth D. Janssens, Stefan TI Increased Cardiac Myocyte PDE5 Levels in Human and Murine Pressure Overload Hypertrophy Contribute to Adverse LV Remodeling SO PLOS ONE LA English DT Article ID PHOSPHODIESTERASE TYPE 5; ADVANCED HEART-FAILURE; PULMONARY-HYPERTENSION; INHIBITION; SILDENAFIL; EXPRESSION; CONTRACTILITY; MYOCARDIUM; STIFFNESS; 1-YEAR AB Background: The intracellular second messenger cGMP protects the heart under pathological conditions. We examined expression of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cGMP, in human and mouse hearts subjected to sustained left ventricular (LV) pressure overload. We also determined the role of cardiac myocyte-specific PDE5 expression in adverse LV remodeling in mice after transverse aortic constriction (TAC). Methodology/Principal Findings: In patients with severe aortic stenosis (AS) undergoing valve replacement, we detected greater myocardial PDE5 expression than in control hearts. We observed robust expression in scattered cardiac myocytes of those AS patients with higher LV filling pressures and BNP serum levels. Following TAC, we detected similar, focal PDE5 expression in cardiac myocytes of C57BL/6NTac mice exhibiting the most pronounced LV remodeling. To examine the effect of cell-specific PDE5 expression, we subjected transgenic mice with cardiac myocyte-specific PDE5 overexpression (PDE5TG) to TAC. LV hypertrophy and fibrosis were similar as in WT, but PDE5-TG had increased cardiac dimensions, and decreased dP/dt(max) and dP/dt(min) with prolonged tau (P, 0.05 for all). Greater cardiac dysfunction in PDE5-TG was associated with reduced myocardial cGMP and SERCA2 levels, and higher passive force in cardiac myocytes in vitro. Conclusions/Significance: Myocardial PDE5 expression is increased in the hearts of humans and mice with chronic pressure overload. Increased cardiac myocyte-specific PDE5 expression is a molecular hallmark in hypertrophic hearts with contractile failure, and represents an important therapeutic target. C1 [Vandenwijngaert, Sara; Pokreisz, Peter; Hermans, Hadewich; Gillijns, Hilde; Pellens, Marijke; Coppiello, Giulia; Oosterlinck, Wouter; Bartunek, Jozef; D'hooge, Jan; Luttun, Aernout; Herregods, Marie Christine; Herijgers, Paul; Janssens, Stefan] Katholieke Univ Leuven, Dept Cardiovasc Sci, Louvain, Belgium. [Bax, Noortje A. M.; Bouten, Carlijn V. C.] Eindhoven Univ Technol, Dept Biomed Engn, NL-5600 MB Eindhoven, Netherlands. [Balogh, Agnes; Papp, Zoltan] Univ Debrecen, Med & Hlth Sci Ctr, Res Ctr Mol Med, Div Clin Physiol,Inst Cardiol, H-4012 Debrecen, Hungary. [Bartunek, Jozef] Onze Lieve Vrouw Hosp, Ctr Cardiovasc, Aalst, Belgium. [Verbeken, Erik] Katholieke Univ Leuven, Dept Imaging & Pathol, Louvain, Belgium. [Bloch, Kenneth D.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Bloch, Kenneth D.] Harvard Univ, Sch Med, Boston, MA USA. RP Janssens, S (reprint author), Katholieke Univ Leuven, Dept Cardiovasc Sci, Louvain, Belgium. EM stefan.janssens@med.kuleuven.be OI Luttun, Aernout/0000-0001-7902-9524 FU Fund for Scientific Research Flanders; Departmental Research Grant of KU Leuven [PF10/014]; European Research Council [FP-7-StG-IMAGINED 203291]; [TAMOP-4.2.2.A-11/1/KONV-2012-0045] FX This work was supported by the Fund for Scientific Research Flanders (to SV, PP, and SJ), and a Departmental Research Grant of KU Leuven (PF10/014). The work was also supported by the TAMOP-4.2.2.A-11/1/KONV-2012-0045 project (to AB and ZP), and a European Research Council Starting Grant FP-7-StG-IMAGINED 203291 (to AL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 13 Z9 13 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 18 PY 2013 VL 8 IS 3 AR e58841 DI 10.1371/journal.pone.0058841 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109ZS UT WOS:000316411600013 PM 23527037 ER PT J AU Bested, AC Logan, AC Selhub, EM AF Bested, Alison C. Logan, Alan C. Selhub, Eva M. TI Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: part III - convergence toward clinical trials SO GUT PATHOGENS LA English DT Review DE Intestinal microbiota; Autointoxication; Depression; Anxiety; Probiotics; Microbial ecology; Lipopolysaccharide endotoxin; Diet; Intestinal permeability; MMP-9; Microbial ecosystems ID IRRITABLE-BOWEL-SYNDROME; BIFIDOBACTERIUM-INFANTIS 35624; FERMENTED DAIRY PRODUCT; ANXIETY-LIKE BEHAVIOR; QUALITY-OF-LIFE; GUT-BRAIN AXIS; CAMPYLOBACTER-JEJUNI; VISCERAL HYPERSENSITIVITY; LACTOBACILLUS-HELVETICUS; COLORECTAL DISTENSION AB Rapid scientific and technological advances have allowed for a more detailed understanding of the relevance of intestinal microbiota, and the entire body-wide microbiome, to human health and well-being. Rodent studies have provided suggestive evidence that probiotics (e.g. lactobacillus and bifidobacteria) can influence behavior. More importantly, emerging clinical studies indicate that the administration of beneficial microbes, via supplementation and/or fecal microbial transplant (FMT), can influence end-points related to mood state (glycemic control, oxidative status, uremic toxins), brain function (functional magnetic resonance imaging fMRI), and mental outlook (depression, anxiety). However, despite the advances in the area of gastro-biological psychiatry, it becomes clear that there remains an urgent need to explore the value of beneficial microbes in controlled clinical investigations. With the history explored in this series, it is fair to ask if we are now on the cusp of major clinical breakthroughs, or are we merely in the quicksand of Autointoxication II? C1 [Bested, Alison C.] BC Womens Hosp & Hlth Ctr, Complex Chron Dis Program, Vancouver, BC V6H 3N1, Canada. [Logan, Alan C.] CAMNR, Mill Valley, CA 94941 USA. [Selhub, Eva M.] Harvard Univ, Sch Med, Waltham, MA 02453 USA. [Selhub, Eva M.] Massachusetts Gen Hosp, Waltham, MA 02453 USA. RP Logan, AC (reprint author), CAMNR, 775 Blithedale Ave Suite 364, Mill Valley, CA 94941 USA. EM aclnd@cfs-fm.org FU Genuine Health, Toronto, Canada FX ACB and EMS have no competing interests. ACL has received consulting fees from Genuine Health, Toronto, Canada. NR 132 TC 25 Z9 29 U1 9 U2 107 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-4749 J9 GUT PATHOG JI Gut Pathogens PD MAR 16 PY 2013 VL 5 AR 4 DI 10.1186/1757-4749-5-4 PG 13 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA 118GQ UT WOS:000317013300001 PM 23497650 ER PT J AU Wang, X Yu, QM Wu, Q Bu, Y Chang, NN Yan, SY Zhou, XH Zhu, XJ Xiong, JW AF Wang, Xu Yu, Qingming Wu, Qing Bu, Ye Chang, Nan-Nan Yan, Shouyu Zhou, Xiao-Hai Zhu, Xiaojun Xiong, Jing-Wei TI Genetic interaction between pku300 and fbn2b controls endocardial cell proliferation and valve development in zebrafish SO JOURNAL OF CELL SCIENCE LA English DT Article DE Scotch tape; Cardiac valve development; Endocardial cell proliferation; Zebrafish ID ATRIOVENTRICULAR-CANAL FORMATION; CARDIOVASCULAR DEVELOPMENT; CUSHION DEVELOPMENT; MESENCHYMAL TRANSITION; TRANSCRIPTION FACTOR; CARDIAC DEVELOPMENT; DEVELOPING HEART; NF-ATC; MORPHOGENESIS; PROGENITORS AB Abnormal cardiac valve morphogenesis is a common cause of human congenital heart disease. The molecular mechanisms regulating endocardial cell proliferation and differentiation into cardiac valves remain largely unknown, although great progress has been made on the endocardial contribution to the atrioventricular cushion and valve formation. We found that scotch tape(te382) (sco(te382)) encodes a novel transmembrane protein that is crucial for endocardial cell proliferation and heart valve development. The zebrafish sco(te382) mutant showed diminished endocardial cell proliferation, lack of heart valve leaflets and abnormal common cardinal and caudal veins. Positional cloning revealed a C946T nonsense mutation of a novel gene pku300 in the sco(te382) locus, which encoded a 540-amino-acid protein on cell membranes with one putative transmembrane domain and three IgG domains. A known G3935T missense mutation of fbn2b was also found similar to 570 kb away from pku300 in sco(te382) mutants. The genetic mutant sco(pku300), derived from sco(te382), only had the C946T mutation of pku300 and showed reduced numbers of atrial endocardial cells and an abnormal common cardinal vein. Morpholino knockdown of fbn2b led to fewer atrial endocardial cells and an abnormal caudal vein. Knockdown of both pku300 and fbn2b phenocopied these phenotypes in sco(te382) genetic mutants. pku300 transgenic expression in endocardial and endothelial cells, but not myocardial cells, partially rescued the atrial endocardial defects in sco(te382)mutants. Mechanistically, pku300 and fbn2b were required for endocardial cell proliferation, endocardial Notch signaling and the proper formation of endocardial cell adhesion and tight junctions, all of which are crucial for cardiac valve development. We conclude that pku300 and fbn2b represent the few genes capable of regulating endocardial cell proliferation and signaling in zebrafish cardiac valve development. C1 [Wang, Xu; Wu, Qing; Bu, Ye; Chang, Nan-Nan; Yan, Shouyu; Zhou, Xiao-Hai; Zhu, Xiaojun; Xiong, Jing-Wei] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. [Yu, Qingming] Massachusetts Gen Hosp, Dept Med Nephrol, Boston, MA 02129 USA. [Yu, Qingming] Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Xiong, JW (reprint author), Peking Univ, Inst Mol Med, Yi He Yuan Lu 5, Beijing 100871, Peoples R China. EM jingwei_xiong@pku.edu.cn RI Xiong, Jing-Wei/A-7113-2011 FU National Key Basic Research Program of China [2010CB529503, 2012CB944501]; National Natural Science Foundation of China [30971662, 31271549]; National Institutes of Health (NIH) [T32-DK07540-22]; March of Dimes Birth Defects Foundation [1-FY2007-471]; Harvard University FX This research was funded by the National Key Basic Research Program of China [grant numbers 2010CB529503 and 2012CB944501]; the National Natural Science Foundation of China [grant numbers 30971662 and 31271549]; a National Institutes of Health (NIH) training grant [grant number T32-DK07540-22]; the March of Dimes Birth Defects Foundation [grant number 1-FY2007-471]; and the Milton Fund from Harvard University. Deposited in PMC for release after 12 months. NR 58 TC 6 Z9 6 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAR 15 PY 2013 VL 126 IS 6 BP 1381 EP 1391 DI 10.1242/jcs.116996 PG 11 WC Cell Biology SC Cell Biology GA 139CQ UT WOS:000318559500010 PM 23418350 ER PT J AU Frenkel, D Huang, ZH Maron, R Koldzic, DN Moskowitz, MA Weiner, HL AF Frenkel, Dan Huang, Zhihong Maron, Ruth Koldzic, Djordje N. Moskowitz, Michael A. Weiner, Howard L. TI Neuroprotection by IL-10 producing MOG CD4+ T-cells following ischemic stroke (vol 233, pg 125, 2005) SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Correction C1 [Frenkel, Dan; Maron, Ruth; Koldzic, Djordje N.; Weiner, Howard L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. [Huang, Zhihong; Moskowitz, Michael A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Stroke & Neurovasc Regulat Lab, Boston, MA USA. [Huang, Zhihong; Moskowitz, Michael A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Alzheimers Dis Res Unit, Boston, MA USA. [Huang, Zhihong; Moskowitz, Michael A.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. RP Weiner, HL (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. EM hweiner@rics.bwh.harvard.edu NR 1 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD MAR 15 PY 2013 VL 326 IS 1-2 BP 123 EP 123 DI 10.1016/j.jns.2013.01.027 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 128WA UT WOS:000317799200024 ER PT J AU Li, YX Wang, XY Zheng, HY Wang, CY Minvielle, S Magrangeas, F Avet-Loiseau, H Shah, PK Zhang, Y Munshi, NC Li, C AF Li, Yingxiang Wang, Xujun Zheng, Haiyang Wang, Chengyang Minvielle, Stephane Magrangeas, Florence Avet-Loiseau, Herve Shah, Parantu K. Zhang, Yong Munshi, Nikhil C. Li, Cheng TI Classify Hyperdiploidy Status of Multiple Myeloma Patients Using Gene Expression Profiles SO PLOS ONE LA English DT Article ID PROBE LEVEL; ABNORMALITIES; PATHOGENESIS; PREDICTION; ANEUPLOIDY; PROGNOSIS AB Multiple myeloma (MM) is a cancer of antibody-making plasma cells. It frequently harbors alterations in DNA and chromosome copy numbers, and can be divided into two major subtypes, hyperdiploid (HMM) and non-hyperdiploid multiple myeloma (NHMM). The two subtypes have different survival prognosis, possibly due to different but converging paths to oncogenesis. Existing methods for identifying the two subtypes are fluorescence in situ hybridization (FISH) and copy number microarrays, with increased cost and sample requirements. We hypothesize that chromosome alterations have their imprint in gene expression through dosage effect. Using five MM expression datasets that have HMM status measured by FISH and copy number microarrays, we have developed and validated a K-nearest-neighbor method to classify MM into HMM and NHMM based on gene expression profiles. Classification accuracy for test datasets ranges from 0.83 to 0.88. This classification will enable researchers to study differences and commonalities of the two MM subtypes in disease biology and prognosis using expression datasets without need for additional subtype measurements. Our study also supports the advantages of using cancer specific characteristics in feature design and pooling multiple rounds of classification results to improve accuracy. We provide R source code and processed datasets at www.ChengLiLab.org/software. C1 [Li, Yingxiang; Wang, Xujun; Zheng, Haiyang; Wang, Chengyang; Zhang, Yong; Li, Cheng] Tongji Univ, Sch Life Sci & Technol, Dept Bioinformat, Shanghai 200092, Peoples R China. [Minvielle, Stephane; Magrangeas, Florence; Avet-Loiseau, Herve] Univ Nantes, Unite Mixte Genom Canc, Ctr Hosp Univ Nantes, Inserm UMR892,CNRS 6299, Nantes, France. [Shah, Parantu K.; Li, Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Shah, Parantu K.; Li, Cheng] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Munshi, Nikhil C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Munshi, Nikhil C.] Harvard Univ, Sch Med, Boston, MA USA. [Munshi, Nikhil C.] Boston VA Healthcare Syst, Boston, MA USA. RP Li, C (reprint author), Tongji Univ, Sch Life Sci & Technol, Dept Bioinformat, Shanghai 200092, Peoples R China. EM lch3000@gmail.com RI Zhang, Yong/B-4838-2011; Magrangeas, Florence/L-3080-2015; Minvielle, Stephane/K-8251-2015 OI Zhang, Yong/0000-0001-6316-2734; FU National Basic Research Program of China (973 Program) [2010CB944904]; National Institutes of Health (NIH) [R01 GM077122]; NIH [RO1-124929, PO1-155258, P50-100007, PO1-78378]; Dept. of Veterans Affairs Merit Review Awards; Claudia Adams Barr Program in Innovative Basic Cancer Research; Multiple Myeloma Career Development Award; French National Research Agency [R08079NS] FX This work was supported by National Basic Research Program of China (973 Program; No. 2010CB944904) (YL, XW, HZ, CW, YZ) and National Institutes of Health (NIH) R01 GM077122 (CL). This work was also supported in part by NIH grants RO1-124929, PO1-155258, P50-100007 and PO1-78378 to NCM and CL and from the Dept. of Veterans Affairs Merit Review Awards to NCM. PKS was supported by Claudia Adams Barr Program in Innovative Basic Cancer Research and the Multiple Myeloma Career Development Award. SM and FM were supported by French National Research Agency, Grant R08079NS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 22 TC 2 Z9 2 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 15 PY 2013 VL 8 IS 3 AR e58809 DI 10.1371/journal.pone.0058809 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109ZC UT WOS:000316409800032 PM 23554930 ER PT J AU Qiu, HB Zhang, LY Ren, C Zeng, ZL Wu, WJ Luo, HY Zhou, ZW Xu, RH AF Qiu, Hai-bo Zhang, Li-yi Ren, Chao Zeng, Zhao-lei Wu, Wen-jing Luo, Hui-yan Zhou, Zhi-wei Xu, Rui-hua TI Targeting CDH17 Suppresses Tumor Progression in Gastric Cancer by Downregulating Wnt/beta-Catenin Signaling SO PLOS ONE LA English DT Article ID LIVER-INTESTINE-CADHERIN; CELL-ADHESION; CARCINOMA; EXPRESSION; METAPLASIA; CDX2; ACTIVATION; STOMACH; PEPTIDE; RISK AB Purpose: Gastric cancer remains one of the leading causes of cancer death worldwide. Patients usually present late with local invasion or metastasis, for which there are no effective therapies available. Following previous studies that identified the adhesion molecule Cadherin-17(CDH17) as a potential marker for gastric carcinoma, we performed proof-of-principle studies to develop rational therapeutic approaches targeting CDH17 for treating this disease. Methods: Immunohistochemistry was used to study the expression of CDH17 in 156 gastric carcinomas, and the relationship between survival and CDH17 expression was studied by multivariate analyses. The effect of RNA interference-mediated knockdown of CDH17 on proliferation of gastric carcinoma cell lines was examined in vitro and in vivo, as well as the effects on downstream signaling by immunoblotting. Results: CDH17 was consistently up-regulated in human gastric cancers, and overall survival in patients with CDH17 upregulation was poorer than in those without expression of this gene (5 yrs overall survival rate 29.0% vs. 45.0%, P < 0.01). Functional assays demonstrated that CDH17 knockdown inhibited cell proliferation, adhesion, migration, invasion, clonogenicity and induce G0/G1 arrest. In mice, shRNA-mediated CDH17 knockdown markedly inhibits tumor growth; intratumoral injection of CDH17 shRNAs results in significant antitumor effects on transplanted tumor models. The antitumor mechanisms underlying CDH17 inhibition involve inactivation of Wnt/beta-catenin signaling. Conclusion: Our results identify CDH17 as a biomarker of gastric carcinoma and attractive therapeutic target for this aggressive malignancy. C1 [Qiu, Hai-bo; Ren, Chao; Zeng, Zhao-lei; Wu, Wen-jing; Luo, Hui-yan; Zhou, Zhi-wei; Xu, Rui-hua] State Key Lab Oncol South China, Guangzhou, Guangdong, Peoples R China. [Qiu, Hai-bo; Ren, Chao; Zeng, Zhao-lei; Wu, Wen-jing; Luo, Hui-yan; Xu, Rui-hua] Sun Yat Sen Univ, Dept Med Oncol, Ctr Canc, Guangzhou 510275, Guangdong, Peoples R China. [Qiu, Hai-bo; Zhou, Zhi-wei] Sun Yat Sen Univ, Dept Gastr & Pancreat Surg, Ctr Canc, Guangzhou 510275, Guangdong, Peoples R China. [Zhang, Li-yi] Univ Hong Kong, Dept Clin Oncol, Pokfulam, Hong Kong, Peoples R China. [Qiu, Hai-bo] Dana Farber Canc Inst, Div Surg Oncol, Boston, MA 02115 USA. [Qiu, Hai-bo] Harvard Univ, Sch Med, Boston, MA USA. RP Xu, RH (reprint author), State Key Lab Oncol South China, Guangzhou, Guangdong, Peoples R China. EM xurh@sysucc.org.cn FU National Natural Science Foundation [30672408] FX This work was supported by National Natural Science Foundation (30672408 to RHX). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 13 Z9 18 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 15 PY 2013 VL 8 IS 3 AR e56959 DI 10.1371/journal.pone.0056959 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109ZC UT WOS:000316409800005 PM 23554857 ER PT J AU McDaid, J Farkash, EA Steele, DJR Martins, PN Kotton, CN Elias, N Ko, DSC Colvin, RB Hertl, M AF McDaid, James Farkash, Evan A. Steele, David J. R. Martins, Paulo N. Kotton, Camille N. Elias, Nahel Ko, Dicken S. C. Colvin, Robert B. Hertl, Martin TI Transitional Cell Carcinoma Arising Within a Pediatric Donor Renal Transplant in Association With BK Nephropathy SO TRANSPLANTATION LA English DT Letter ID POLYOMAVIRUS; RECIPIENTS C1 [McDaid, James; Martins, Paulo N.; Elias, Nahel; Ko, Dicken S. C.; Hertl, Martin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Transplant Surg, Boston, MA 02114 USA. [Farkash, Evan A.; Colvin, Robert B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Steele, David J. R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol, Boston, MA 02114 USA. [Kotton, Camille N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. [Ko, Dicken S. C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA 02114 USA. RP McDaid, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Transplant Surg, White 5, Boston, MA 02114 USA. EM jmcdaid@doctors.net.uk NR 7 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAR 15 PY 2013 VL 95 IS 5 BP E28 EP E30 DI 10.1097/TP.0b013e31828235ec PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 102UX UT WOS:000315870900003 PM 23503509 ER PT J AU Andrews, JR Morrow, C Wood, R AF Andrews, Jason R. Morrow, Carl Wood, Robin TI Modeling the Role of Public Transportation in Sustaining Tuberculosis Transmission in South Africa SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE HIV; indoor air quality; mathematical model; transmission; tuberculosis ID HIGH-INCIDENCE AREA; MYCOBACTERIUM-TUBERCULOSIS; AIRBORNE INFECTION; MIXING PATTERNS; HIGH HIV; COMMUNITY; RISK; PREVALENCE; AIR; ADOLESCENTS AB Current tuberculosis notification rates in South Africa are among the highest ever recorded. Although the human immunodeficiency virus epidemic has been a critical factor, the density of respiratory contacts in high-risk environments may be an important and underappreciated driver. Using a modified Wells-Riley model for airborne disease transmission, we estimated the risk of tuberculosis transmission on 3 modes of public transit (minibus taxis, buses, and trains) in Cape Town, South Africa, using exhaled carbon dioxide as a natural tracer gas to evaluate air exchange. Carbon dioxide measurements were performed between October and December of 2011. Environmental risk, reflected in the rebreathed fraction of air, was highest in minibus taxis and lowest in trains; however, the average number of passengers sharing an indoor space was highest in trains and lowest in minibus taxis. Among daily commuters, the annual risk of tuberculosis infection was projected to be 3.5%-5.0% and was highest among minibus taxi commuters. Assuming a duration of infectiousness of 1 year, the basic reproductive number attributable to transportation was more than 1 in all 3 modes of transportation. Given its poor ventilation and high respiratory contact rates, public transportation may play a critical role in sustaining tuberculosis transmission in South African cities. C1 [Andrews, Jason R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA USA. [Morrow, Carl; Wood, Robin] Univ Cape Town, Desmond Tutu HIV Ctr, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. RP Andrews, JR (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM Jandrews6@partners.org OI Andrews, Jason/0000-0002-5967-251X FU National Institute of Allergy and Infectious Diseases [R01 AI058736, T32AI007433]; Harvard Global Health Institute FX This work was supported by the National Institute of Allergy and Infectious Diseases (grants R01 AI058736 and T32AI007433) and the Harvard Global Health Institute. NR 27 TC 20 Z9 20 U1 3 U2 19 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 15 PY 2013 VL 177 IS 6 BP 556 EP 561 DI 10.1093/aje/kws331 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 109NE UT WOS:000316374500009 PM 23423215 ER PT J AU Naeije, R Vanderpool, R Dhakal, BP Saggar, R Saggar, R Vachiery, JL Lewis, GD AF Naeije, Robert Vanderpool, Rebecca Dhakal, Bishnu P. Saggar, Rajeev Saggar, Rajan Vachiery, Jean-Luc Lewis, Gregory D. TI Exercise-induced Pulmonary Hypertension Physiological Basis and Methodological Concerns SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE pulmonary circulation; pulmonary vascular resistance; pulmonary arterial compliance; cardiac output; exercise capacity ID STRESS DOPPLER-ECHOCARDIOGRAPHY; PRESSURE-FLOW RELATIONSHIPS; ARTERY SYSTOLIC PRESSURE; HEALTHY OLD MEN; SYSTEMIC-SCLEROSIS; CARDIAC-OUTPUT; HEART-FAILURE; ASYMPTOMATIC CARRIERS; VASCULAR-DISEASE; CIRCULATION AB Exercise stresses the pulmonary circulation through increases in cardiac output ((Q) over dot) and left atrial pressure. Invasive as well as noninvasive studies in healthy volunteers show that the slope of mean pulmonary artery pressure (mPAP)-flow relationships ranges from 0.5 to 3 mm Hg.min.L-1. The upper limit of normal mPAP at exercise thus approximates 30 mm Hg at a (Q) over dot of less than 10 L.min(-1) or a total pulmonary vascular resistance at exercise of less than 3 Wood units. Left atrial pressure increases at exercise with an average upstream transmission to PAP in a close to one-for-one mm Hg fashion. Multi-point PAP-flow relationships are usually described by a linear approximation, but present with a slight curvilinearity, which is explained by resistive vessel distensibility. When mPAP is expressed as a function of oxygen uptake or workload, plateau patterns may be observed in patients with systolic heart failure who cannot further increase (Q) over dot at the highest levels of exercise. Exercise has to be dynamic to avoid the increase in systemic vascular resistance and abrupt changes in intrathoracic pressure that occur with resistive exercise and can lead to unpredictable effects on the pulmonary circulation. Postexercise measurements are unreliable because of the rapid return of pulmonary vascular pressures and flows to the baseline resting state. Recent studies suggest that exercise-induced increase in PAP to a mean higher than 30 mm Hg may be associated with dyspnea-fatigue symptomatology. C1 [Naeije, Robert; Vanderpool, Rebecca; Vachiery, Jean-Luc] Erasme Acad Hosp, Dept Cardiol, Pulm Hypertens Clin, Brussels, Belgium. [Dhakal, Bishnu P.; Lewis, Gregory D.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Saggar, Rajeev; Saggar, Rajan] St Joseph Hosp & Med Ctr, Heart Lung Inst, Phoenix, AZ USA. RP Naeije, R (reprint author), Univ Libre Brussels, Dept Pathophysiol, Erasme Campus,808 Lennik Rd, B-1070 Brussels, Belgium. EM rnaeije@ulb.ac.be FU National Institutes of Health [NIH-K23HL091106]; Fonds de la Recherche Scientifique Medicale [3.4637.09]; Actelion Chair; Pfizer Aspire Award; Marie Curie postdoctoral grant, European Respiratory Society FX Supported by National Institutes of Health grant NIH-K23HL091106 (G.D.L.) Fonds de la Recherche Scientifique Medicale-3.4637.09 (R.N.), Actelion Chair (R.N.), Pfizer Aspire Award (G.D.L.), Marie Curie postdoctoral grant, European Respiratory Society (R.V.). NR 65 TC 74 Z9 76 U1 0 U2 7 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAR 15 PY 2013 VL 187 IS 6 BP 576 EP 583 DI 10.1164/rccm.201211-2090CI PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 110DW UT WOS:000316423800006 PM 23348976 ER PT J AU Ganz, PA Bower, JE Kwan, L Castellon, SA Silverman, DHS Geist, C Breen, EC Irwin, MR Cole, SW AF Ganz, Patricia A. Bower, J. E. Kwan, L. Castellon, S. A. Silverman, D. H. S. Geist, C. Breen, E. C. Irwin, M. R. Cole, S. W. TI Does tumor necrosis factor-alpha (TNF-alpha) play a role in post-chemotherapy cerebral dysfunction? SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Breast cancer; Cognitive complaints; Chemotherapy; Proinflammatory cytokines; TNF-alpha; Neuropsychological testing; Brain imaging ID BREAST-CANCER SURVIVORS; FATIGUE SYMPTOM INVENTORY; QUALITY-OF-LIFE; ADJUVANT CHEMOTHERAPY; COGNITIVE FUNCTION; INFLAMMATORY BIOMARKERS; LONGITUDINAL ASSESSMENT; CHEMORADIATION THERAPY; SYSTEMIC CHEMOTHERAPY; POSTMENOPAUSAL WOMEN AB Post-chemotherapy treated cancer patients frequently report cognitive difficulties. The biology of this phenomenon is poorly understood, with uncertainty about possible direct toxic effects on the brain, secondary effects from systemic inflammation, host factors/genetic predisposition to cognitive complaints, or hormonal changes influencing cognitive function. To elucidate possible mechanisms associated with post-treatment cognitive dysfunction among breast cancer survivors, in 2007 we established a prospective, longitudinal, observational cohort study of early stage breast cancer patients, recruited at the end of initial treatments (primary treatment exposure included surgery, +/- radiation, +/- chemotherapy), and prior to the initiation of adjuvant endocrine therapy. We assessed cognitive complaints, neuropsychological (NP) test performance, markers of inflammation, and brain imaging at baseline, 6 months and 12 months after enrollment. In this analysis of data from the first 93 patients enrolled in the cohort study, we focus on the relationship of circulating levels of proinflammatory cytokines to cerebral functioning and chemotherapy exposure. Among the proinflammatory cytokines tested (IL-1ra, sTNE-RII, CRP, and IL-6) at baseline, only sTNE-RII was increased among chemotherapy exposed patients, with a significant decline in the year after treatment (p = 0.003). Higher baseline sTNE-RII in chemotherapy patients was significantly associated with increased memory complaints. In chemotherapy exposed patients, the longitudinal decline in sTNE-RII was significantly correlated with fewer memory complaints over 12 months (r = -0.34, p = 0.04). Higher baseline sTNE-RII was also associated with relatively diminished brain metabolism in the inferior frontal cortex (r = -0.55, p = 0.02), as well as relatively increased inferior frontal metabolism after 1 year, in chemotherapy-exposed subjects. These preliminary findings suggest that post-chemotherapy increases in TNF-alpha, may be playing an important role in the manifestations of cognitive complaints in breast cancer survivors. (C) 2012 Elsevier Inc. All rights reserved. C1 [Ganz, Patricia A.] Univ Calif Los Angeles, Dept Hlth Policy & Management, Fielding Sch Publ Hlth, Los Sangeles, CA USA. [Ganz, Patricia A.; Cole, S. W.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Ganz, Patricia A.; Bower, J. E.; Kwan, L.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA 90095 USA. [Bower, J. E.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Bower, J. E.; Breen, E. C.; Irwin, M. R.; Cole, S. W.] Semel Inst Neurosci, Cousins Ctr Psychoneuroimmunol, Los Angeles, CA USA. [Castellon, S. A.] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. [Silverman, D. H. S.; Geist, C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med & Mol Pharmacol, Los Angeles, CA 90095 USA. [Breen, E. C.; Irwin, M. R.; Cole, S. W.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Ganz, PA (reprint author), Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, A2-125 CHS,650 Charles Young Dr South,Box 956900, Los Angeles, CA 90095 USA. EM pganz@mednet.ucla.edu RI Irwin, Michael/H-4870-2013 OI Irwin, Michael/0000-0002-1502-8431 FU Breast Cancer Research Foundation (BCRF) [NIH/NCI R01 CA 109650]; an American Society Clinical Research Professorship; UCLA Older Americans Independence Center (OAIC); OAIC Inflammatory Biology Core [NIH/NIA P30-AG028748]; Norman Cousins Center [PNI. R01-AG034588, R01-AG026364, R01-CA119159, R01-HL079955, R01-HL095799, P30-AG028748, UL RR 033176] FX NIH/NCI R01 CA 109650; the Breast Cancer Research Foundation (BCRF); an American Society Clinical Research Professorship to Dr. Ganz; the UCLA Older Americans Independence Center (OAIC) and the OAIC Inflammatory Biology Core (NIH/NIA P30-AG028748); the Norman Cousins Center for PNI. R01-AG034588; R01-AG026364; R01-CA119159; R01-HL079955; R01-HL095799; P30-AG028748; UL RR 033176 to Dr. Irwin. NR 60 TC 50 Z9 51 U1 3 U2 24 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD MAR 15 PY 2013 VL 30 SI SI BP S99 EP S108 DI 10.1016/j.bbi.2012.07.015 PG 10 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 111GW UT WOS:000316510800012 PM 22884417 ER PT J AU Deutsch, MA Sturzu, A Wu, SM AF Deutsch, Marcus-Andre Sturzu, Anthony Wu, Sean M. TI At a Crossroad Cell Therapy for Cardiac Repair SO CIRCULATION RESEARCH LA English DT Article DE cardiomyocytes; cardiovascular disease; stem cells; regeneration ID ACUTE MYOCARDIAL-INFARCTION; MESENCHYMAL STEM-CELLS; LEFT-VENTRICULAR FUNCTION; CARDIOSPHERE-DERIVED CELLS; RANDOMIZED PHASE-1 TRIAL; MARROW MONONUCLEAR-CELLS; BONE-MARROW; ISCHEMIC CARDIOMYOPATHY; HUMAN FIBROBLASTS; PROGENITOR CELLS C1 [Deutsch, Marcus-Andre; Sturzu, Anthony] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Deutsch, Marcus-Andre] Tech Univ Munich, Dept Cardiovasc Surg, German Heart Ctr Munich, D-80290 Munich, Germany. [Wu, Sean M.] Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford Cardiovasc Inst, Stanford, CA 94305 USA. [Wu, Sean M.] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. RP Wu, SM (reprint author), G1120A Lokey Stem Cell Bldg,265 Campus Dr, Stanford, CA 94305 USA. EM smwu@stanford.edu FU NHLBI NIH HHS [U01 HL099776]; NIH HHS [DP2 OD004411] NR 70 TC 14 Z9 14 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAR 15 PY 2013 VL 112 IS 6 BP 884 EP 890 DI 10.1161/CIRCRESAHA.112.275974 PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 107BO UT WOS:000316189900005 PM 23493304 ER PT J AU Jung, K Kim, P Leuschner, F Gorbatov, R Kim, JK Ueno, T Nahrendorf, M Yun, SH AF Jung, Keehoon Kim, Pilhan Leuschner, Florian Gorbatov, Rostic Kim, Jun Ki Ueno, Takuya Nahrendorf, Matthias Yun, Seok Hyun TI Endoscopic Time-Lapse Imaging of Immune Cells in Infarcted Mouse Hearts SO CIRCULATION RESEARCH LA English DT Article DE circulation; imaging; leukocytes; monocyte; myocardial infarction ID FRACTALKINE RECEPTOR CX(3)CR1; GREEN FLUORESCENT PROTEIN; MYOCARDIAL-INFARCTION; VIVO; MONOCYTES; ATHEROSCLEROSIS; MICROSCOPY; RESOLUTION; IDENTIFICATION; INFLAMMATION AB Rationale: High-resolution imaging of the heart in vivo is challenging owing to the difficulty in accessing the heart and the tissue motion caused by the heartbeat. Objective: Here, we describe a suction-assisted endoscope for visualizing fluorescently labeled cells and vessels in the beating heart tissue through a small incision made in the intercostal space. Methods and Results: A suction tube with a diameter of 2 to 3 mm stabilizes the local tissue motion safely and effectively at a suction pressure of 50 mm Hg. Using a minimally invasive endoscope integrated into a confocal microscope, we performed fluorescence cellular imaging in both normal and diseased hearts in live mice for an hour per session repeatedly over a few weeks. Real-time imaging revealed the surprisingly rapid infiltration of CX(3)CR1(+) monocytes into the injured site within several minutes after acute myocardial infarction. Conclusions: The time-lapse analysis of flowing and rolling (patrolling) monocytes in the heart and the peripheral circulation provides evidence that the massively recruited monocytes come first from the vascular reservoir and later from the spleen. The imaging method requires minimal surgical preparation and can be implemented into standard intravital microscopes. Our results demonstrate the applicability of our imaging method for a wide range of cardiovascular research. (Circ Res. 2013;112:891-899.) C1 [Jung, Keehoon; Kim, Pilhan; Kim, Jun Ki; Yun, Seok Hyun] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol,Wellman Ctr Photomed, Cambridge, MA 02139 USA. [Leuschner, Florian; Gorbatov, Rostic; Ueno, Takuya; Nahrendorf, Matthias] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Cambridge, MA 02139 USA. [Kim, Pilhan; Kim, Jun Ki; Yun, Seok Hyun] Korea Adv Inst Sci & Technol, Grad Sch Nanosci & Technol WCU, Taejon 305701, South Korea. [Yun, Seok Hyun] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. [Leuschner, Florian] Heidelberg Univ, Dept Internal Med 3, Heidelberg, Germany. [Leuschner, Florian] DZHK German Ctr Cardiovasc Res, Heidelberg, Germany. RP Yun, SH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 65 Landsdowne St Rm 525, Cambridge, MA 02139 USA. EM syun@hms.harvard.edu RI Kim, Pilhan/C-1836-2011 OI Kim, Pilhan/0000-0001-8388-1840 FU Massachusetts General Hospital The Executive Committee on Research Postdoctoral Fellowship; National Institutes of Health [U54CA143837, R01AI 081734, P41EB015903]; Ministry of Education, Science, and Technology of Korea [R31-2008-000-10071-0, 2011-0009503, WCI 2011-001] FX This work was supported by grants from Massachusetts General Hospital The Executive Committee on Research Postdoctoral Fellowship, National Institutes of Health (U54CA143837, R01AI 081734, P41EB015903), and the Ministry of Education, Science, and Technology of Korea (World Class University R31-2008-000-10071-0, 2011-0009503, and WCI 2011-001). NR 33 TC 42 Z9 45 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD MAR 15 PY 2013 VL 112 IS 6 BP 891 EP U75 DI 10.1161/CIRCRESAHA.111.300484 PG 29 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 107BO UT WOS:000316189900006 PM 23392842 ER PT J AU Gregoire, S Karra, R Passer, D Deutsch, MA Krane, M Feistritzer, R Sturzu, A Domian, I Saga, Y Wu, SM AF Gregoire, Serge Karra, Ravi Passer, Derek Deutsch, Marcus-Andre Krane, Markus Feistritzer, Rebecca Sturzu, Anthony Domian, Ibrahim Saga, Yumiko Wu, Sean M. TI Essential and Unexpected Role of Yin Yang 1 to Promote Mesodermal Cardiac Differentiation SO CIRCULATION RESEARCH LA English DT Article DE cardiac development; congenital heart disease; progenitor cell; stem cell ID CARDIOVASCULAR PROGENITOR CELLS; ENHANCER-BINDING-PROTEIN; SERUM RESPONSE FACTOR; HEART TUBE FORMATION; TRANSCRIPTION FACTOR; GENE-EXPRESSION; OUTFLOW TRACT; SMOOTH-MUSCLE; VENTRAL MORPHOGENESIS; YY1 AB Rationale: Cardiogenesis is regulated by a complex interplay between transcription factors. However, little is known about how these interactions regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs). Objective: To identify novel regulators of mesodermal cardiac lineage commitment. Methods and Results: We performed a bioinformatic-based transcription factor binding site analysis on upstream promoter regions of genes that are enriched in embryonic stem cell-derived CPCs. From 32 candidate transcription factors screened, we found that Yin Yang 1 (YY1), a repressor of sarcomeric gene expression, is present in CPCs in vivo. Interestingly, we uncovered the ability of YY1 to transcriptionally activate Nkx2.5, a key marker of early cardiogenic commitment. YY1 regulates Nkx2.5 expression via a 2.1-kb cardiac-specific enhancer as demonstrated by in vitro luciferase-based assays, in vivo chromatin immunoprecipitation, and genome-wide sequencing analysis. Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with Gata4 at a nearby chromatin. Cardiac mesoderm-specific loss-of-function of YY1 resulted in early embryonic lethality. This was corroborated in vitro by embryonic stem cell-based assays in which we showed that the overexpression of YY1 enhanced the cardiogenic differentiation of embryonic stem cells into CPCs. Conclusions: These results demonstrate an essential and unexpected role for YY1 to promote cardiogenesis as a transcriptional activator of Nkx2.5 and other CPC-enriched genes. (Circ Res. 2013;112:900-910.) C1 [Gregoire, Serge; Passer, Derek; Deutsch, Marcus-Andre; Krane, Markus; Feistritzer, Rebecca; Sturzu, Anthony; Domian, Ibrahim; Wu, Sean M.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Karra, Ravi] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. [Deutsch, Marcus-Andre; Krane, Markus] Clin Tech Univ Muenchen, German Heart Ctr, Dept Cardiovasc Surg, Munich, Germany. [Saga, Yumiko] Natl Inst Genet, Div Mammalian Dev, Mishima, Shizuoka 411, Japan. [Domian, Ibrahim; Wu, Sean M.] Harvard Stem Cell Inst, Cambridge, MA USA. RP Wu, SM (reprint author), G1120A Lokey Stem Cell Bldg,265 Campus Dr, Stanford, CA 94305 USA. EM smwu@stanford.edu FU Massachusetts General Hospital Fund for Medical Discovery; American Heart Association; German Research Foundation; German Heart Foundation; National Institute of Health; National Heart, Lung, and Blood Institute; Harvard Stem Cell Institute FX Financial support was provided by the Massachusetts General Hospital Fund for Medical Discovery and the American Heart Association (S. G.), by the German Research Foundation (M. K.) and the German Heart Foundation (M-A. D.), and by National Institute of Health Director's New Innovator Award, the National Heart, Lung, and Blood Institute, and the Harvard Stem Cell Institute (S.M.W.) NR 66 TC 18 Z9 19 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD MAR 15 PY 2013 VL 112 IS 6 BP 900 EP U104 DI 10.1161/CIRCRESAHA.113.259259 PG 28 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 107BO UT WOS:000316189900007 PM 23307821 ER PT J AU Schott, AF Landis, MD Dontu, G Griffith, KA Layman, RM Krop, I Paskett, LA Wong, H Dobrolecki, LE Lewis, MT Froehlich, AM Paranilam, J Hayes, DF Wicha, MS Chang, JC AF Schott, Anne F. Landis, Melissa D. Dontu, Gabriela Griffith, Kent A. Layman, Rachel M. Krop, Ian Paskett, Lacey A. Wong, Helen Dobrolecki, Lacey E. Lewis, Michael T. Froehlich, Amber M. Paranilam, Jaya Hayes, Daniel F. Wicha, Max S. Chang, Jenny C. TI Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID MAMMARY STEM-CELLS; CANCER CELLS; NOTCH; CHEMOTHERAPY; EXPRESSION; RESISTANCE; RECEPTOR; MK-0752; CULTURE; GROWTH AB Purpose: Accumulating evidence supports the existence of breast cancer stem cells (BCSC), which are characterized by their capacity to self-renew and divide indefinitely and resistance to conventional therapies. The Notch pathway is important for stem cell renewal and is a potential target for BCSC-directed therapy. Experimental Design: Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in patients with advanced breast cancer, designed to determine the maximum-tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies. Results: Treatment with GSI reduced BCSCs in MC1 and BCM-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically, meaningful doses of both drugs were possible with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44(+)/CD24(-), ALDH(+), and mammosphere-forming efficiency were observed in tumors of patients undergoing serial biopsies. Conclusions: These preclinical data show that pharmacologic inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial shows feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer. Clin Cancer Res; 19(6); 1512-24. (C) 2012 AACR. C1 [Schott, Anne F.; Griffith, Kent A.; Hayes, Daniel F.; Wicha, Max S.] Univ Michigan, Ann Arbor, MI 48109 USA. [Landis, Melissa D.; Paskett, Lacey A.; Wong, Helen; Dobrolecki, Lacey E.; Froehlich, Amber M.; Paranilam, Jaya; Chang, Jenny C.] Methodist Hosp, Res Inst, Houston, TX 77030 USA. [Lewis, Michael T.] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Dontu, Gabriela] Kings Coll London, Sch Med, London, England. [Layman, Rachel M.] Ohio State Univ, Columbus, OH 43210 USA. [Krop, Ian] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chang, Jenny C.] Weill Cornell Med Sch, New York, NY USA. RP Schott, AF (reprint author), Univ Michigan, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM aschott@umich.edu RI Layman, Rachel/E-3475-2011 FU Merck; Sharpe; Dohme [IISP 31841]; NIH [1R01CA138197, U54 1 U54CA149196-01] FX This work was supported by Merck, Sharpe, and Dohme [grant: IISP #31841 (A.F. Schott, Principal Investigator)]. Preclinical work was also supported by the NIH (1R01CA138197 and U54 1 U54CA149196-01). NR 29 TC 71 Z9 75 U1 1 U2 20 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2013 VL 19 IS 6 BP 1512 EP 1524 DI 10.1158/1078-0432.CCR-11-3326 PG 13 WC Oncology SC Oncology GA 107BE UT WOS:000316188900023 PM 23340294 ER PT J AU Zhu, AX Ancukiewicz, M Supko, JG Sahani, DV Blaszkowsky, LS Meyerhardt, JA Abrams, TA McCleary, NJ Bhargava, P Muzikansky, A Sheehan, S Regan, E Vasudev, E Knowles, M Fuchs, CS Ryan, DP Jain, RK Duda, DG AF Zhu, Andrew X. Ancukiewicz, Marek Supko, Jeffrey G. Sahani, Dushyant V. Blaszkowsky, Lawrence S. Meyerhardt, Jeffrey A. Abrams, Thomas A. McCleary, Nadine Jackson Bhargava, Pankaj Muzikansky, Alona Sheehan, Susan Regan, Eileen Vasudev, Eamala Knowles, Michelle Fuchs, Charles S. Ryan, David P. Jain, Rakesh K. Duda, Dan G. TI Efficacy, Safety, Pharmacokinetics, and Biomarkers of Cediranib Monotherapy in Advanced Hepatocellular Carcinoma: A Phase II Study SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; TUMOR ANGIOGENESIS; MYELOID CELLS; SOLID TUMORS; CANCER; INHIBITOR; AZD2171; RECEPTOR; THERAPY; TARGETS AB Purpose: We conducted a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC). Experimental Design: Patients with histologically confirmed measurable advanced HCC and adequate hematologic, hepatic, and renal functions received cediranib 30-mg orally once daily (4 weeks/cycle). The primary endpoint was progression-free survival (PFS) rate at 3 months. Other endpoints included response rates, overall survival (OS), pharmacokinetics (PK), and biomarkers for cediranib. Results: Cediranib treatment resulted in an estimated 3-month PFS rate of 77% (60%, 99%). Median PFS was 5.3 (3.5,9.7) months, stable disease was seen in 5/17 patients (29%), and median OS was 11.7 (7.5-13.6) months. Grade 3 toxicities included hypertension (29%), hyponatremia (29%), and hyperbilirubinemia (18%). Cediranib PK were comparable to those seen in cancer patients with normal hepatic function. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2, and Ang-2 decreased after cediranib treatment. PFS was inversely correlated with baseline levels of VEGF, sVEGFR2, and bFGF and with on-treatment levels of bFGF and IGF-1, and directly associated with on-treatment levels of IFN-gamma. OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-alpha, CAIX, and CD34(+)CD133(+)CD45(dim) circulating progenitor cells and on-treatment levels of sVEGFR2. Conclusions: Despite the limitations of primary endpoint selection, cediranib at 30-mg daily showed a high incidence of toxicity and preliminary evidence of antitumor activity in advanced HCC. Hepatic dysfunction did not seem to affect the steady-state PK of cediranib. Exploratory studies suggested proangiogenic and inflammatory factors as potential biomarkers of anti-VEGF therapy in HCC. Clin Cancer Res; 19(6); 1557-66. (C)2013 AACR. C1 [Zhu, Andrew X.; Ancukiewicz, Marek; Supko, Jeffrey G.; Sahani, Dushyant V.; Blaszkowsky, Lawrence S.; Muzikansky, Alona; Sheehan, Susan; Vasudev, Eamala; Knowles, Michelle; Ryan, David P.; Jain, Rakesh K.; Duda, Dan G.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Meyerhardt, Jeffrey A.; Abrams, Thomas A.; McCleary, Nadine Jackson; Bhargava, Pankaj; Regan, Eileen; Fuchs, Charles S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Zhu, Andrew X.; Ancukiewicz, Marek; Supko, Jeffrey G.; Sahani, Dushyant V.; Blaszkowsky, Lawrence S.; Meyerhardt, Jeffrey A.; Abrams, Thomas A.; McCleary, Nadine Jackson; Bhargava, Pankaj; Vasudev, Eamala; Fuchs, Charles S.; Ryan, David P.; Jain, Rakesh K.; Duda, Dan G.] Harvard Univ, Sch Med, Boston, MA USA. RP Zhu, AX (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,LH POB 232, Boston, MA 02114 USA. EM azhu@partners.org; duda@steele.mgh.harvard.edu FU Dyax; MedImmune; Roche; US National Cancer Center (NCI) Cancer Therapy Evaluation Program (CTEP); AstraZeneca; NCI [P01-CA80124, R01-CA115767, R01-CA126642, R21-CA139168, R01-CA159258]; Department of Defense [W81XWH-10-1-0016]; American Cancer Society [RSG-11-073-01TBG] FX A.X. Zhu is a consultant/advisory board member of Sanofi-Aventis, Bristol-Myers-Squibb, Eisai, Daiichi Sankyo, and Ecelixis. P. Bhargava is employed by Sanofi Oncology. D. P. Ryan is a consultant/advisory board member of Genomic Health and Boerhinger Ingelheim. R. K. Jain has commercial research grants from Dyax, MedImmune, and Roche; ownership interest (including patents) in XTuit, Enlight, and SynDevRx; and is a consultant/advisory board member of Dyax, Noxxon, Enlight, XTuit, H&Q Healthcare Investors, H&Q Life Sciences Investors, and SynDevRx. The other authors disclosed no potential conflicts of interest.; This study was supported by US National Cancer Center (NCI) Cancer Therapy Evaluation Program (CTEP) and AstraZeneca. The research of R. K. Jain is supported by NCI grants P01-CA80124, R01-CA115767, and R01-CA126642 and Department of Defense Innovator Award W81XWH-10-1-0016. D. G. Duda is supported by NCI grants R21-CA139168 and R01-CA159258 and American Cancer Society grant RSG-11-073-01TBG. NR 29 TC 29 Z9 33 U1 1 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2013 VL 19 IS 6 BP 1557 EP 1566 DI 10.1158/1078-0432.CCR-12-3041 PG 10 WC Oncology SC Oncology GA 107BE UT WOS:000316188900027 PM 23362324 ER PT J AU Drappatz, J Brenner, A Wong, ET Eichler, A Schiff, D Groves, MD Mikkelsen, T Rosenfeld, S Sarantopoulos, J Meyers, CA Fielding, RM Elian, K Wang, XL Lawrence, B Shing, MN Kelsey, S Castaigne, JP Wen, PY AF Drappatz, Jan Brenner, Andrew Wong, Eric T. Eichler, April Schiff, David Groves, Morris D. Mikkelsen, Tom Rosenfeld, Steve Sarantopoulos, John Meyers, Christina A. Fielding, Robert M. Elian, Kelly Wang, Xiaolin Lawrence, Betty Shing, Mona Kelsey, Stephen Castaigne, Jean Paul Wen, Patrick Y. TI Phase I Study of GRN1005 in Recurrent Malignant Glioma SO CLINICAL CANCER RESEARCH LA English DT Article ID BLOOD-BRAIN-BARRIER; RECEPTOR-RELATED PROTEIN; DENSITY-LIPOPROTEIN RECEPTOR; DELIVERY VECTOR ANGIOPEP-2; MEDIATED TRANSCYTOSIS; PACLITAXEL; TUMORS; GLIOBLASTOMA; TISSUE; VITRO AB Purpose: GRN1005 is a peptide-drug conjugate with the ability to penetrate the blood-brain barrier (BBB) and tumor cells by targeting the low-density lipoprotein receptor-related protein-1. We conducted a first-in-human phase I trial of GRN1005 in patients with recurrent glioma. Methods: Patients received GRN1005 by intravenous infusion every 3 weeks. Doses were escalated using a modified Fibonacci scheme. Study objectives included safety, tolerability, identification of the maximum tolerated dose (MTD), pharmacokinetics, and preliminary evidence of efficacy. Tumor extracted from patients undergoing surgery following administration of GRN1005 was analyzed to determine whether therapeutic concentrations of GRN1005 were achieved. Results: Sixty-three patients received GRN1005 at doses of 30 to 700 mg/m(2) every 3 weeks. Therapy was well tolerated with neutropenia, leucopenia, and fatigue as the most frequent drug-associated grade 3/4 or higher toxicities. The MTD was 650 mg/m(2) every 3 weeks. Dose-limiting toxicities were grade 3 mucositis and grade 4 neutropenia. There was no evidence of central nervous system toxicity or antibody production. Pharmacokinetic analysis showed that exposure to GRN1005 was dose proportional. We observed one complete and two partial responses. Eight of 27 patients dosed >= 420 mg/m(2) had stable disease, which lasted a median of 51 days. Therapeutic concentrations of GRN1005 and free paclitaxel were shown in tumor tissue of surgical patients dosed with >= 200 mg/m(2). Conclusion: GRN1005 delivers paclitaxel across the BBB and achieves therapeutic concentrations in tumor tissue. It has similar toxicity to paclitaxel and appears to have activity in recurrent glioma. The recommended phase II dose is 650 mg/m(2) every 3 weeks. Clin Cancer Res; 19(6); 1567-76. (C)2013 AACR. C1 [Drappatz, Jan; Wen, Patrick Y.] Dana Farber Canc Inst, Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA. [Drappatz, Jan; Wen, Patrick Y.] Brigham & Womens Hosp, Div Neurol, Div Canc Neurol, Boston, MA 02115 USA. [Wong, Eric T.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Eichler, April] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Drappatz, Jan; Wong, Eric T.; Eichler, April; Wen, Patrick Y.] Harvard Univ, Sch Med, Boston, MA USA. [Drappatz, Jan] UPMC Canc Ctr, Dept Neurol, Div Hematol & Oncol, Pittsburgh, PA USA. [Drappatz, Jan] UPMC Canc Ctr, Dept Med, Div Hematol & Oncol, Pittsburgh, PA USA. [Brenner, Andrew; Sarantopoulos, John] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Groves, Morris D.; Meyers, Christina A.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Schiff, David] Univ Virginia, Hlth Sci Ctr, Dept Neurol, Div Neurooncol, Charlottesville, VA 22908 USA. [Mikkelsen, Tom] Henry Ford Hosp, Detroit, MI 48202 USA. [Rosenfeld, Steve] Columbia Univ, Neurol Inst, New York, NY USA. [Fielding, Robert M.] Biol Serv, Boulder, CO USA. [Elian, Kelly; Lawrence, Betty; Castaigne, Jean Paul] Angiochem Inc, Montreal, PQ, Canada. [Wang, Xiaolin; Shing, Mona; Kelsey, Stephen] Geron Corp, Menlo Pk, CA USA. RP Wen, PY (reprint author), Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, 450 Brookline Ave, Boston, MA 02215 USA. EM pwen@partners.org FU Genentech; Angiochem; Geron Corporation; Angiochem, Inc. FX J. Drappatz is a consultant/advisory board member of Angiochem. M. D. Groves has received a commercial research grant from Genentech and honoraria from speakers bureau of Merck, and is a consultant/advisory board member of Genentech. R. M. Fielding is a consultant/advisory board member of Angiochem. Immediate family members of K. Elian have ownership interest (including patents) in Angiochem. S. Kelsey has ownership interest (including patents) in Geron Corporation. P.Y. Wen has other commercial research support from Angiochem and Geron Corporation. No potential conflicts of interest were disclosed by the other authors.; The study was supported by Angiochem, Inc. NR 47 TC 33 Z9 34 U1 1 U2 23 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2013 VL 19 IS 6 BP 1567 EP 1576 DI 10.1158/1078-0432.CCR-12-2481 PG 10 WC Oncology SC Oncology GA 107BE UT WOS:000316188900028 PM 23349317 ER PT J AU Schoenfeld, JD Margalit, DN Kasperzyk, JL Shui, IM Rider, JR Epstein, MM Meisner, A Kenfield, SA Martin, NE Nguyen, PL Kantoff, PW Giovannucci, EL Stampfer, MJ Mucci, LA AF Schoenfeld, Jonathan D. Margalit, Danielle N. Kasperzyk, Julie L. Shui, Irene M. Rider, Jennifer R. Epstein, Mara M. Meisner, Allison Kenfield, Stacey A. Martin, Neil E. Nguyen, Paul L. Kantoff, Philip W. Giovannucci, Edward L. Stampfer, Meir J. Mucci, Lorelei A. TI A Single Nucleotide Polymorphism in Inflammatory Gene RNASEL Predicts Outcome after Radiation Therapy for Localized Prostate Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID RIBONUCLEASE-L GENE; RISK; VARIANTS; ASSOCIATION; RADIOTHERAPY; CELLS; HPC1; PHARMACOGENETICS; HEREDITARY; APOPTOSIS AB Purpose: To study associations between single nucleotide polymorphisms (SNP) in Ribonuclease L (RNASEL), a gene implicated in inflammation and prostate cancer risk, and outcomes after radiation therapy. Experimental Design: We followed participants in the prospective US Health Professionals Follow-Up Study treated with radiation therapy for early-stage prostate cancer. Three SNPs were genotyped based on previously determined functional and biological significance. We used multivariable Cox proportional hazards models to assess per-allele associations with the primary outcome defined as time to a composite endpoint including development of lethal prostate cancer or biochemical recurrence. Results: We followed 434 patients treated with radiation therapy for a median of 9 years. On multivariate analysis, the rs12757998 variant allele was associated with significantly decreased risk of the composite endpoint [HR: 0.65; 95% confidence interval (CI), 0.45-0.94%; P = 0.02] driven by decreased biochemical recurrence (HR: 0.60; 95% CI, 0.40-0.89%; P = 0.01) and men treated with external beam (HR: 0.58; 95% CI, 0.36-0.93%; P = 0.02). In contrast, in 516 men from the same cohort treated with radical prostatectomy, we found no significant impact of this variant on outcome. Furthermore, the rs12757998 variant allele significantly modified the association between androgen deprivation therapy and outcomes after radiation therapy (p-interaction 0.02). Conclusion: We show an association between RNASEL SNP rs12757998 and outcome after radiation therapy for prostate cancer. This SNP is associated with increased circulating C-reactive protein and interleukin-6, suggesting a potential role for inflammation in the response to radiation. If validated, genetic predictors of outcome may help inform prostate cancer management. Clin Cancer Res; 19(6); 1612-9. (C)2013 AACR. C1 [Schoenfeld, Jonathan D.] Harvard Radiat Oncol Program, Boston, MA USA. [Margalit, Danielle N.; Kasperzyk, Julie L.; Rider, Jennifer R.; Martin, Neil E.; Nguyen, Paul L.; Kantoff, Philip W.; Stampfer, Meir J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Margalit, Danielle N.; Martin, Neil E.; Nguyen, Paul L.; Kantoff, Philip W.; Stampfer, Meir J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kasperzyk, Julie L.; Shui, Irene M.; Rider, Jennifer R.; Epstein, Mara M.; Meisner, Allison; Kenfield, Stacey A.; Giovannucci, Edward L.; Stampfer, Meir J.; Mucci, Lorelei A.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Schoenfeld, JD (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,ASB1-L2, Boston, MA 02115 USA. EM jdschoenfeld@partners.org RI Martin, Neil/E-2193-2014; OI Martin, Neil/0000-0002-8164-8516; Rider, Jennifer/0000-0002-2637-6036 FU NIH [5 T32 CA09001-36, R25 CA098566]; US Army Prostate Cancer Post-doctoral Fellowship; anonymous family foundation; Prostate Cancer Foundation; National Institutes of Health/National Cancer Institute [R01 CA133891, R01CA141298-02, P01 CA055075] FX J. D. Schoenfeld, J. L. Kasperzyk, and I. M. Shui were supported by NIH Training Grant 5 T32 CA09001-36 and I. M. Shui was additionally supported by US Army Prostate Cancer Post-doctoral Fellowship; M. M. Epstein is supported by National Institutes of Health research training grant R25 CA098566; P. L. Nguyen was supported by a grant from an anonymous family foundation; and L. A. Mucci, P. L. Nguyen, and N. E. Martin are supported by the Prostate Cancer Foundation. The project was supported by grants from the National Institutes of Health/National Cancer Institute (grant numbers R01 CA133891, R01CA141298-02, and P01 CA055075). NR 45 TC 10 Z9 11 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2013 VL 19 IS 6 BP 1612 EP 1619 DI 10.1158/1078-0432.CCR-12-2718 PG 8 WC Oncology SC Oncology GA 107BE UT WOS:000316188900033 PM 23382116 ER PT J AU Wang, QQ Moore, MJ Adelmant, G Marto, JA Silver, PA AF Wang, Qingqing Moore, Michael J. Adelmant, Guillaume Marto, Jarrod A. Silver, Pamela A. TI PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth SO GENES & DEVELOPMENT LA English DT Article DE PQBP1; alternative splicing; neurite outgrowth; neurological disorders ID PRE-MESSENGER-RNA; DOMINANT RETINITIS-PIGMENTOSA; POLYGLUTAMINE TRACT; NERVOUS-SYSTEM; PROTEIN PQBP1; AXON GROWTH; WW DOMAIN; VASE EXON; GENE; EXPRESSION AB Polyglutamine-binding protein 1 (PQBP1) is a highly conserved protein associated with neurodegenerative disorders. Here, we identify PQBP1 as an alternative messenger RNA (mRNA) splicing (AS) effector capable of influencing splicing of multiple mRNA targets. PQBP1 is associated with many splicing factors, including the key U2 small nuclear ribonucleoprotein (snRNP) component SF3B1 (subunit 1 of the splicing factor 3B [SF3B] protein complex). Loss of functional PQBP1 reduced SF3B1 substrate mRNA association and led to significant changes in AS patterns. Depletion of PQBP1 in primary mouse neurons reduced dendritic outgrowth and altered AS of mRNAs enriched for functions in neuron projection development. Disease-linked PQBP1 mutants were deficient in splicing factor associations and could not complement neurite outgrowth defects. Our results indicate that PQBP1 can affect the AS of multiple mRNAs and indicate specific affected targets whose splice site determination may contribute to the disease phenotype in PQBP1-linked neurological disorders. C1 [Wang, Qingqing; Silver, Pamela A.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Moore, Michael J.] Rockefeller Univ, Mol Neurooncol Lab, New York, NY 10065 USA. [Adelmant, Guillaume; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Adelmant, Guillaume; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02215 USA. [Adelmant, Guillaume; Marto, Jarrod A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Silver, Pamela A.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. RP Silver, PA (reprint author), Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. EM pamela_silver@hms.harvard.edu FU National Institutes of Health [GM057476, GM36373] FX We thank Hsi-Wen Liao, Athar Malik, David Lipton, and Seth Margolis for help with neuron culture and RNAi; Alan Mardinly for help with Sholl analysis; Jennifer Waters for help with imaging; and Daniel Ducat and Yvonne Chen for thoughtful critiques. We are indebted to Michael Greenberg's laboratory for the generous sharing of mouse embryonic cortical neurons. Microscope imaging was done in the Nikon Imaging Center at Harvard Medical School. Sequencing was performed by the biopolymer facility at Harvard Medical School. This work was supported by grants GM36373 and GM057476 to P.A.S. from the National Institutes of Health. NR 49 TC 20 Z9 23 U1 0 U2 15 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD MAR 15 PY 2013 VL 27 IS 6 BP 615 EP 626 DI 10.1101/gad.212308.112 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 108VB UT WOS:000316323200005 PM 23512658 ER PT J AU Baena, E Shao, Z Linn, DE Glass, K Hamblen, MJ Fujiwara, Y Kim, J Nguyen, M Zhang, X Godinho, FJ Bronson, RT Mucci, LA Loda, M Yuan, GC Orkin, SH Li, Z AF Baena, Esther Shao, Zhen Linn, Douglas E. Glass, Kimberly Hamblen, Melanie J. Fujiwara, Yuko Kim, Jonghwan Minh Nguyen Zhang, Xin Godinho, Frank J. Bronson, Roderick T. Mucci, Lorelei A. Loda, Massimo Yuan, Guo-Cheng Orkin, Stuart H. Li, Zhe TI ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients SO GENES & DEVELOPMENT LA English DT Article DE ERG; ETS transcription factor; ETV1; Pten; androgen receptor; metabolism ID ETS TRANSCRIPTION FACTORS; EMBRYONIC STEM-CELLS; IN-VIVO; ERG IMMUNOHISTOCHEMISTRY; RADICAL PROSTATECTOMY; TUMOR-SUPPRESSOR; PSA RECURRENCE; GENE FUSIONS; EXPRESSION; RECEPTOR AB Distinguishing aggressive from indolent disease and developing effective therapy for advanced disease are the major challenges in prostate cancer research. Chromosomal rearrangements involving ETS transcription factors, such as ERG and ETV1, occur frequently in prostate cancer. How they contribute to tumorigenesis and whether they play similar or distinct in vivo roles remain elusive. Here we show that in mice with ERG or ETV1 targeted to the endogenous Tmprss2 locus, either factor cooperated with loss of a single copy of Pten, leading to localized cancer, but only ETV1 appeared to support development of invasive adenocarcinoma under the background of full Pten loss. Mechanistic studies demonstrated that ERG and ETV1 control a common transcriptional network but largely in an opposing fashion. In particular, while ERG negatively regulates the androgen receptor (AR) transcriptional program, ETV1 cooperates with AR signaling by favoring activation of the AR transcriptional program. Furthermore, we found that ETV1 expression, but not that of ERG, promotes autonomous testosterone production. Last, we confirmed the association of an ETV1 expression signature with aggressive disease and poorer outcome in patient data. The distinct biology of ETV1-associated prostate cancer suggests that this disease class may require new therapies directed to underlying programs controlled by ETV1. C1 [Baena, Esther; Shao, Zhen; Hamblen, Melanie J.; Fujiwara, Yuko; Kim, Jonghwan; Minh Nguyen; Godinho, Frank J.; Orkin, Stuart H.; Li, Zhe] Boston Childrens Hosp, Div Hematol & Oncol, Boston, MA 02115 USA. [Baena, Esther; Shao, Zhen; Hamblen, Melanie J.; Fujiwara, Yuko; Kim, Jonghwan; Minh Nguyen; Godinho, Frank J.; Orkin, Stuart H.; Li, Zhe] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Shao, Zhen; Glass, Kimberly; Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Linn, Douglas E.; Zhang, Xin; Li, Zhe] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Hamblen, Melanie J.; Fujiwara, Yuko; Godinho, Frank J.; Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Bronson, Roderick T.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Mucci, Lorelei A.] Harvard Univ, Sch Publ Hlth, Brigham & Womens Hosp, Dept Epidemiol, Boston, MA 02115 USA. [Loda, Massimo] Brigham & Womens Hosp, Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Boston Childrens Hosp, Div Hematol & Oncol, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu; zli4@rics.bwh.harvard.edu FU Career Development Award from Dana-Farber/Harvard Cancer Center Prostate Cancer SPORE; Spanish Ministry of Science [EX2006-0958]; Department of Defense [PC060492, PC100704, PC080097]; NIH [U01CA105423] FX We thank Drs. Larisa Litovchick, Carmen Priolo, and Fatima Al-Shahrour for reagents, mouse surgical techniques, analysis support, and helpful discussions, and Dr. Maaike van Bragt for FACS analysis of knock-in mammary glands. This work was supported by a Career Development Award from Dana-Farber/Harvard Cancer Center Prostate Cancer SPORE (to Z.L.), a post-doctoral award from the Spanish Ministry of Science (EX2006-0958 to E.B.), and grants from the Department of Defense (PC060492 to S.H.O., PC100704 to Z.L., and PC080097 to E.B.) and NIH (U01CA105423 to S.H.O.). S.H.O. is an Investigator of Howard Hughes Medical Institute. NR 72 TC 52 Z9 52 U1 0 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD MAR 15 PY 2013 VL 27 IS 6 BP 683 EP 698 DI 10.1101/gad.211011.112 PG 16 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 108VB UT WOS:000316323200010 PM 23512661 ER PT J AU Valencia, A Sapp, E Kimm, JS McClory, H Reeves, PB Alexander, J Ansong, KA Masso, N Frosch, MP Kegel, KB Li, XY DiFiglia, M AF Valencia, Antonio Sapp, Ellen Kimm, Jeffrey S. McClory, Hollis Reeves, Patrick B. Alexander, Jonathan Ansong, Kwadwo A. Masso, Nicholas Frosch, Matthew P. Kegel, Kimberly B. Li, Xueyi DiFiglia, Marian TI Elevated NADPH oxidase activity contributes to oxidative stress and cell death in Huntington's disease SO HUMAN MOLECULAR GENETICS LA English DT Article ID TRANSGENIC MOUSE MODEL; LIPID RAFTS; INTRANUCLEAR INCLUSIONS; NEURITE OUTGROWTH; MUTANT HUNTINGTIN; CYTOCHROME-C; EARLY MOTOR; ACTIVATION; NEURONS; BRAIN AB A mutation in the huntingtin (Htt) gene produces mutant Htt and Huntington's disease (HD), a neurodegenerative disorder. HD patients have oxidative damage in the brain, but the causes are unclear. Compared with controls, we found brain levels of NADPH oxidase (NOX) activity, which produces reactive oxygen species (ROS), elevated in human HD postmortem cortex and striatum and highest in striatum of presymptomatic individuals. Synaptosome fractions from cortex and striatum of HD140Q/140Q mice had elevated NOX activity at 3 months of age and a further rise at 6 and 12 months compared with synaptosomes of age-matched wild-type (WT) mice. High NOX activity in primary cortical and striatal neurons of HD140Q/140Q mice correlated with more ROS and neurite swellings. These features and neuronal cell death were markedly reduced by treatment with NOX inhibitors such as diphenyleneiodonium (DPI), apocynin (APO) and VAS2870. The rise in ROS levels in mitochondria of HD140Q/140Q neurons followed the rise in NOX activity and inhibiting only mitochondrial ROS was not neuroprotective. Mutant Htt colocalized at plasma membrane lipid rafts with gp91-phox, a catalytic subunit for the NOX2 isoform. Assembly of NOX2 components at lipid rafts requires activation of Rac1 which was also elevated in HD140Q/140Q neurons. HD140Q/140Q mice bred to gp91-phox knock-out mice had lower NOX activity in the brain and in primary neurons, and neurons had normal ROS levels and significantly improved survival. These findings suggest that increased NOX2 activity at lipid rafts is an early and major source of oxidative stress and cell death in HD140Q/140Q neurons. C1 [Valencia, Antonio; Sapp, Ellen; Kimm, Jeffrey S.; McClory, Hollis; Reeves, Patrick B.; Alexander, Jonathan; Ansong, Kwadwo A.; Masso, Nicholas; Kegel, Kimberly B.; Li, Xueyi; DiFiglia, Marian] Massachusetts Gen Hosp East, Dept Neurol, Charlestown, MA 02129 USA. [Valencia, Antonio; Sapp, Ellen; Kimm, Jeffrey S.; McClory, Hollis; Reeves, Patrick B.; Alexander, Jonathan; Ansong, Kwadwo A.; Masso, Nicholas; Kegel, Kimberly B.; Li, Xueyi; DiFiglia, Marian] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Pathol Serv, Boston, MA 02114 USA. [Frosch, Matthew P.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP DiFiglia, M (reprint author), Massachusetts Gen Hosp East, Dept Neurol, 114,16th St,Room 2002, Charlestown, MA 02129 USA. EM difiglia@helix.mgh.harvard.edu FU Hereditary Disease Foundation; Fundacion Mexico en Harvard A.C.; CHDI Foundation; HDSA Foundation; NIH-NINDS [NS74381] FX This study was supported by fellowships from the Hereditary Disease Foundation to A.V. and X.L., Fundacion Mexico en Harvard A.C. to A.V., and CHDI and HDSA Foundations and NIH-NINDS NS74381 to M.D. NR 86 TC 50 Z9 53 U1 2 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAR 15 PY 2013 VL 22 IS 6 BP 1112 EP 1131 DI 10.1093/hmg/dds516 PG 20 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 108MD UT WOS:000316296600005 PM 23223017 ER PT J AU Das, F Ghosh-Choudhury, N Bera, A Dey, N Abboud, HE Kasinath, BS Choudhury, GG AF Das, Falguni Ghosh-Choudhury, Nandini Bera, Amit Dey, Nirmalya Abboud, Hanna E. Kasinath, Balakuntalam S. Choudhury, Goutam Ghosh TI Transforming Growth Factor beta Integrates Smad 3 to Mechanistic Target of Rapamycin Complexes to Arrest Deptor Abundance for Glomerular Mesangial Cell Hypertrophy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA TRANSLATION; PLASMINOGEN-ACTIVATOR INHIBITOR-1; SMOOTH-MUSCLE-CELLS; RICTOR-MTOR COMPLEX; HIGH GLUCOSE; DIABETIC-NEPHROPATHY; SIGNAL-TRANSDUCTION; MAMMALIAN TARGET; FIBRONECTIN EXPRESSION; MESENCHYMAL TRANSITION AB In many renal diseases, transforming growth factor beta (TGF beta)-stimulated canonical Smad 3 and noncanonical mechanistic target of rapamycin (mTOR) promote increased protein synthesis and mesangial cell hypertrophy. The cellular underpinnings involving these signaling molecules to regulate mesangial cell hypertrophy are not fully understood. Deptor has recently been identified as an mTOR interacting protein and functions as an endogenous inhibitor of the kinase activity for both TORC1 and TORC2. Prolonged incubation of mesangial cells with TGF beta reduced the levels of deptor concomitant with an increase in TORC1 and TORC2 activity. Sustained TGF beta activation was required to inhibit association of deptor with mTOR, whereas rapid activation had no effect. Using the mTOR inhibitor PP242, we found that TGF beta-induced both early and sustained activation of TORC1 and TORC2 was necessary for deptor suppression. PP242-induced reversal of deptor suppression by TGF beta was associated with a significant inhibition of TGF beta-stimulated protein synthesis and hypertrophy. Interestingly, expression of siRNA against Smad 3 or Smad 7, which blocks TGF beta receptor-specific Smad 3 signaling, prevented TGF beta-induced suppression of deptor abundance and TORC1/2 activities. Furthermore, overexpression of Smad 3 decreased deptor expression similar to TGF beta stimulation concomitant with increased TORC1 and TORC2 activities. Finally, knockdown of deptor reversed Smad 7-mediated inhibition of protein synthesis and mesangial cell hypertrophy induced by TGF beta. These data reveal the requirement of both early and late activation of mTOR for TGF beta-induced protein synthesis. Our results support that TGF beta-stimulated Smad 3 acts as a key node to instill a feedback loop between deptor down-regulation and TORC1/2 activation in driving mesangial cell hypertrophy. C1 [Ghosh-Choudhury, Nandini; Abboud, Hanna E.; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, Vet Affairs Res, San Antonio, TX 78229 USA. [Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. [Das, Falguni; Bera, Amit; Dey, Nirmalya; Abboud, Hanna E.; 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, RO1 AR 52425, RO1 DK 78971, RO1 DK 077295, RC2A 036613]; Veterans Affairs Merit Review grants; Ronald P. Williams Orthopedic Oncology Developmental Research Award from the Cancer Therapy and Research Center, San Antonio; Juvenile Diabetes Research Foundation; Veterans Affairs Research Service; Veterans Affairs Senior Research Career Scientist Award; Juvenile Diabetes Research Foundation [1-2008-185] FX This work was supported, in whole or in part, by National Institutes of Health Grant RO1 DK50190 and Veterans Affairs Merit Review grants (to G. G. C.).; Supported by National Institutes of Health Grant RO1 AR 52425, Veterans Affairs Merit Review grants, and a Ronald P. Williams Orthopedic Oncology Developmental Research Award from the Cancer Therapy and Research Center, San Antonio.; Supported by National Institutes of Health Grant RO1 DK 78971 and Veterans Affairs Merit Review and Juvenile Diabetes Research Foundation grants.; Supported by National Institutes of Health Grants RO1 DK 077295 and RC2A 036613 and the Veterans Affairs Research Service.; Recipient of Veterans Affairs Senior Research Career Scientist Award and supported by Juvenile Diabetes Research Foundation Grant 1-2008-185. NR 65 TC 10 Z9 12 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 15 PY 2013 VL 288 IS 11 BP 7756 EP 7768 DI 10.1074/jbc.M113.455782 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 110OW UT WOS:000316455300031 PM 23362262 ER PT J AU Villiger, M Zhang, EZ Nadkarni, S Oh, WY Bouma, BE Vakoc, BJ AF Villiger, Martin Zhang, Ellen Ziyi Nadkarni, Seemantini Oh, Wang-Yuhl Bouma, Brett E. Vakoc, Benjamin J. TI Artifacts in polarization-sensitive optical coherence tomography caused by polarization mode dispersion SO OPTICS LETTERS LA English DT Article ID FIBERS; NOISE AB Polarization mode dispersion (PMD) severely degrades images of biological tissue measured with polarization-sensitive optical coherence tomography. It adds a bias to the local retardation value that can be spatially confined, resulting in regions of seemingly high sample birefringence that are purely artificial. Here, we demonstrate and analyze this effect, both experimentally and with numerical simulations, and show that artifacts can be avoided by limiting the system PMD to less than the system axial resolution. Even then, spatial averaging over a dimension larger than that characteristic of speckle is required to remove a PMD-induced bias of the local retardation values. (C) 2013 Optical Society of America C1 [Villiger, Martin; Zhang, Ellen Ziyi; Nadkarni, Seemantini; Bouma, Brett E.; Vakoc, Benjamin J.] Harvard Univ, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Villiger, Martin; Zhang, Ellen Ziyi; Nadkarni, Seemantini; Bouma, Brett E.; Vakoc, Benjamin J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Oh, Wang-Yuhl] Korea Adv Inst Sci & Technol, Dept Mech Engn, Taejon 305701, South Korea. [Bouma, Brett E.; Vakoc, Benjamin J.] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Cambridge, MA 02142 USA. RP Villiger, M (reprint author), Harvard Univ, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. EM mvilliger@partners.org FU NIH [P41EB015903, ROI CA163528]; NRF of Korea [2012-0005633]; Swiss National Science Foundation FX Research in this publication was supported in part by the NIH grants P41EB015903 and ROI CA163528, and by the NRF of Korea, grant 2012-0005633. M. V. was supported by a fellowship from the Swiss National Science Foundation. NR 10 TC 13 Z9 13 U1 1 U2 8 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 J9 OPT LETT JI Opt. Lett. PD MAR 15 PY 2013 VL 38 IS 6 BP 923 EP 925 PG 3 WC Optics SC Optics GA 111SK UT WOS:000316540800039 PM 23503261 ER PT J AU Rhee, HW Zou, P Udeshi, ND Martell, JD Mootha, VK Carr, SA Ting, AY AF Rhee, Hyun-Woo Zou, Peng Udeshi, Namrata D. Martell, Jeffrey D. Mootha, Vamsi K. Carr, Steven A. Ting, Alice Y. TI Proteomic Mapping of Mitochondria in Living Cells via Spatially Restricted Enzymatic Tagging SO SCIENCE LA English DT Article ID PROTOPORPHYRINOGEN OXIDASE; CROSS-LINK; HEME; PEROXIDASE; BIOTINYLATION; BIOSYNTHESIS; MICROSCOPY; TYRAMIDE; DISEASE; COMPLEX AB Microscopy and mass spectrometry (MS) are complementary techniques: The former provides spatiotemporal information in living cells, but only for a handful of recombinant proteins at a time, whereas the latter can detect thousands of endogenous proteins simultaneously, but only in lysed samples. Here, we introduce technology that combines these strengths by offering spatially and temporally resolved proteomic maps of endogenous proteins within living cells. Our method relies on a genetically targetable peroxidase enzyme that biotinylates nearby proteins, which are subsequently purified and identified by MS. We used this approach to identify 495 proteins within the human mitochondrial matrix, including 31 not previously linked to mitochondria. The labeling was exceptionally specific and distinguished between inner membrane proteins facing the matrix versus the intermembrane space (IMS). Several proteins previously thought to reside in the IMS or outer membrane, including protoporphyrinogen oxidase, were reassigned to the matrix by our proteomic data and confirmed by electron microscopy. The specificity of peroxidase-mediated proteomic mapping in live cells, combined with its ease of use, offers biologists a powerful tool for understanding the molecular composition of living cells. C1 [Rhee, Hyun-Woo; Zou, Peng; Martell, Jeffrey D.; Ting, Alice Y.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Udeshi, Namrata D.; Mootha, Vamsi K.; Carr, Steven A.; Ting, Alice Y.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Mootha, Vamsi K.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02115 USA. [Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Ting, AY (reprint author), MIT, Dept Chem, Cambridge, MA 02139 USA. EM ating@mit.edu FU NIH [DP1 OD003961, R01 GM077465]; Dreyfus Foundation; American Chemical Society; Broad Institute of MIT and Harvard FX We thank N. Watson (Whitehead Institute Keck Microscopy Facility) and E. Vasile (Koch Institute Microscopy Core Facility) for performing EM imaging, H. B. Fraser for assistance with data analysis and manuscript editing, C. Uttamapinant for picoyl azide-AF647, X. Zhuang and her lab for advice on STORM, H. A. Dailey for advice on CPOX and PPOX, and S. Calvo for assistance with data analysis. Funding was provided by the NIH (grants DP1 OD003961 to A.Y.T. and R01 GM077465 to V. K. M.), the Dreyfus Foundation (A.Y.T.), the American Chemical Society (A.Y.T.), and the Broad Institute of MIT and Harvard (S. A. C.). The authors have no conflicting financial interests. A patent application relating to the use of enzymes for proteomic mapping in live cells has been filed by MIT. Proteomic data can be found in supplementary tables S1 to S9. The authors will make the genetic constructs used in this work widely available to the academic community through Addgene (www.addgene.org/). NR 26 TC 150 Z9 153 U1 11 U2 163 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAR 15 PY 2013 VL 339 IS 6125 BP 1328 EP 1331 DI 10.1126/science.1230593 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 105GC UT WOS:000316053400040 PM 23371551 ER PT J AU Tevaarwerk, AJ Gray, RJ Schneider, BP Smith, ML Wagner, LI Fetting, JH Davidson, N Goldstein, LJ Miller, KD Sparano, JA AF Tevaarwerk, Amye J. Gray, Robert J. Schneider, Bryan P. Smith, Mary Lou Wagner, Lynne I. Fetting, John H. Davidson, Nancy Goldstein, Lori J. Miller, Kathy D. Sparano, Joseph A. TI Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy Little Evidence of Improvement Over the Past 30 Years SO CANCER LA English DT Article DE breast cancer; distant disease recurrence; survival; distant recurrence-free interval; metastatic disease ID COOPERATIVE-ONCOLOGY-GROUP; PROGNOSTIC-FACTORS; RANDOMIZED-TRIALS; PLUS DOCETAXEL; PHASE-III; STAGE IV; THERAPY; WOMEN; INTERGROUP; POSTMENOPAUSAL AB BACKGROUND: Population-based studies have shown improved survival for patients diagnosed with metastatic breast cancer over time, presumably because of the availability of new and more effective therapies. The objective of the current study was to determine whether survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy. METHODS: Adjuvant chemotherapy trials coordinated by the Eastern Cooperative Oncology Group that accrued patients between 1978 and 2002 were reviewed. Survival after distant disease recurrence was estimated for progressive time periods, and adjusted for baseline covariates in a Cox proportional hazards model. RESULTS: Of the 13,785 patients who received adjuvant chemotherapy in 11 trials, 3447 (25%) developed distant disease recurrence; the median survival after recurrence was 20 months (95% confidence interval, 19 months-21 months). Factors associated with inferior survival included a shorter distant recurrence-free interval (DRFI), estrogen receptor-negative and progesterone receptor-negative disease, the number of positive axillary lymph nodes present at the time of diagnosis, and black race (P < .0001 for all). When the time period of recurrence was added to the model, it was not found to be significantly associated with survival for the general population with disease recurrence. Survival improved over time only in those patients with hormone receptor-negative disease with a DRFI 3 years, both among the 5 most recent and the entire trial data sets (P = .01 and P = .05, respectively). CONCLUSIONS: In contrast to reports from population-based studies, no general improvement in survival was observed over the last 30 years for patients who developed distant disease recurrence after adjuvant chemotherapy after adjusting for DRFI. Improved survival for patients with hormone receptor-negative disease with a short DRFI suggests a benefit from trastuzumab. Cancer 2013. (c) 2012 American Cancer Society. C1 [Tevaarwerk, Amye J.] Univ Wisconsin, Med Oncol Clin, Carbone Comprehens Canc Ctr, Madison, WI 53705 USA. [Gray, Robert J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Schneider, Bryan P.; Miller, Kathy D.] Indiana Univ, Dept Med, Div Hematol Oncol, Melvin & Bren Simon Canc Ctr, Indianapolis, IN USA. [Smith, Mary Lou] Res Advocacy Network, Plano, TX USA. [Wagner, Lynne I.] Northwestern Univ, Dept Psychiat & Behav Sci, Dept Med Social Sci, Feinberg Sch Med, Chicago, IL 60611 USA. [Fetting, John H.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD USA. [Davidson, Nancy] Univ Pittsburgh, Dept Med, Inst Canc, Pittsburgh, PA USA. [Goldstein, Lori J.] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. [Sparano, Joseph A.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. RP Tevaarwerk, AJ (reprint author), Univ Wisconsin, Med Oncol Clin, Carbone Comprehens Canc Ctr, 1111 Highland Ave,Room 6037, Madison, WI 53705 USA. EM at4@medicine.wisc.edu FU Public Health Service grants [CA23318, CA66636, CA21115, CA21076, CA49883, CA17145, CA16116, CA39229, CA27525, CA14958]; Department of Health and Human Services; National Cancer Institute, National Institutes of Health FX This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service grants CA23318, CA66636, CA21115, CA21076, CA49883, CA17145, CA16116, CA39229, CA27525, and CA14958 and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. NR 31 TC 35 Z9 35 U1 1 U2 14 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 MAR 15 PY 2013 VL 119 IS 6 BP 1140 EP 1148 DI 10.1002/cncr.27819 PG 9 WC Oncology SC Oncology GA 100JW UT WOS:000315696600007 PM 23065954 ER PT J AU Hur, C Miller, M Kong, CY Dowling, EC Nattinger, KJ Dunn, M Feuer, EJ AF Hur, Chin Miller, Melecia Kong, Chung Yin Dowling, Emily C. Nattinger, Kevin J. Dunn, Michelle Feuer, Eric J. TI Trends in esophageal adenocarcinoma incidence and mortality SO CANCER LA English DT Article DE esophageal neoplasms; adenocarcinoma; incidence; mortality; epidemiology; SEER program ID BARRETTS-ESOPHAGUS; UNITED-STATES; RISING INCIDENCE; GASTRIC CARDIA; CANCER; SURVEILLANCE; SURVIVAL; EPIDEMIOLOGY; DIAGNOSIS; RATES AB BACKGROUND: Over the past several decades, the incidence of esophageal adenocarcinoma (EAC) has rapidly increased. The purpose of this analysis was to examine temporal trends in EAC incidence and mortality within the US population and, in addition, to explore these trends within subgroups of the population. METHODS: The National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER 9) data were used to examine incidence and incidence-based (IB) mortality in EAC from 1975 to 2009. Secular trends in incidence and IB mortality by cancer stage, sex, and race were further characterized using the NCI's Joinpoint Regression program. RESULTS: Based on SEER 9 data, EAC incidence and IB mortality continues to increase in the United States. However, since the mid-1990s, the overall rate of increase in both EAC incidence and IB mortality appears to be slowing. In addition, in early-stage cancers, there is a noticeable leveling off of IB mortality rates and divergence from incidence starting in the late 1990s. Over the study period, the average annual percentage increase in incidence was 6.1% in men and 5.9% in women. CONCLUSIONS: EAC incidence and IB mortality rates continue to rise in the United States, although at a slower rate in more recent years. In early-stage cancers, IB mortality and incidence rates have diverged primarily because IB mortality rates have plateaued beginning in the late 1990s. Although EAC continues to be less common in women, the rate of increase in EAC incidence is similar in both sexes. Cancer 2013. (c) 2012 American Cancer Society. C1 [Hur, Chin; Miller, Melecia; Kong, Chung Yin; Dowling, Emily C.; Nattinger, Kevin J.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Hur, Chin; Nattinger, Kevin J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Hur, Chin; Kong, Chung Yin] Harvard Univ, Sch Med, Boston, MA USA. [Dunn, Michelle; Feuer, Eric J.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Hur, C (reprint author), ITA, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM chur@partners.org OI Hur, Chin/0000-0002-2819-7576 FU National Institutes of Health [R01CA140574, U01CA152926, K25CA133141] FX This work was supported by the National Institutes of Health (grants R01CA140574 and U01CA152926 to Dr. Hur and grant K25CA133141 to Dr. Kong). NR 22 TC 102 Z9 103 U1 2 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD MAR 15 PY 2013 VL 119 IS 6 BP 1149 EP 1158 DI 10.1002/cncr.27834 PG 10 WC Oncology SC Oncology GA 100JW UT WOS:000315696600008 PM 23303625 ER PT J AU Brawarsky, P Neville, BA Fitzmaurice, GM Earle, C Haas, JS AF Brawarsky, Phyllis Neville, Bridget A. Fitzmaurice, Garrett M. Earle, Craig Haas, Jennifer S. TI Surveillance after resection for colorectal cancer SO CANCER LA English DT Article DE colorectal cancer; survivorship; disparities; race; ethnicity; surveillance ID FOLLOW-UP; RACIAL-DIFFERENCES; CLINICAL-ONCOLOGY; AMERICAN-SOCIETY; UNITED-STATES; POPULATION; COLONOSCOPY; GUIDELINES; DIAGNOSIS; SURVIVORS AB BACKGROUND: Professional societies recommend posttreatment surveillance for colorectal cancer (CRC) survivors. This study describes the use of surveillance over time, with a particular focus on racial/ethnic disparities, and also examines the role of area characteristics, such as capacity for CRC screening, on surveillance. METHODS: Surveillance, Epidemiology, and End Results (SEER)-Medicare data were used to identify individuals aged 66 to 85 years who were diagnosed with CRC from 1993 to 2005 and treated with surgery. The study examined factors associated with subsequent receipt of a colonoscopy, carcinoembryonic antigen (CEA) testing, primary care (PC) visits, and a composite measure of overall surveillance. RESULTS: Of eligible subjects, 61.0% had a colonoscopy, 68.0% had CEA testing, 77.1% had PC visits, and 43.0% received overall surveillance. After adjustment, blacks were less likely than whites to undergo colonoscopy (odds ratio [OR] 0.76, 95% confidence interval [CI] = 0.69-0.83) and to receive CEA testing and overall surveillance, whereas white/Hispanic rates did not differ. Rates for all outcomes increased from 1993 to 2005, but black/white disparities remained. Individuals in areas with greatest capacity for CRC screening were more likely (OR = 1.09, 95% CI = 1.02-1.18) to receive colonoscopy, and those in areas with the greatest percentage of blacks were less likely (OR = 0.89, 95% CI = 0.83-0.95) to receive colonoscopy. Those living in areas with shortage of PC were less likely to receive PC visits (OR = 0.55, 95% CI = 0.48-0.64) and overall surveillance (OR = 0.83, 95% CI = 0.71-0.98). CONCLUSIONS: Many CRC survivors do not get recommended surveillance, and black/white disparities in rates of surveillance have not improved. Characteristics of the area where an individual lives contribute to the use of surveillance. Cancer 2013. (c) 2012 American Cancer Society. C1 [Brawarsky, Phyllis; Haas, Jennifer S.] Brigham & Womens Hosp, Div Gen Med & Primary Care, Dept Med, Boston, MA 02120 USA. [Neville, Bridget A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fitzmaurice, Garrett M.] McLean Hosp, Lab Psychiat Biostat, Belmont, MA 02178 USA. [Fitzmaurice, Garrett M.; Haas, Jennifer S.] Harvard Univ, Sch Med, Boston, MA USA. [Earle, Craig] Canc Care Ontario, Toronto, ON, Canada. [Earle, Craig] Ontario Inst Canc Res, Toronto, ON, Canada. RP Haas, JS (reprint author), Brigham & Womens Hosp, Div Gen Med & Primary Care, 1620 Tremont St, Boston, MA 02120 USA. EM jhaas@partners.org FU American Cancer Society [RSGT CPHPS-114979] FX This study was supported by a grant from the American Cancer Society (RSGT CPHPS-114979). NR 28 TC 6 Z9 7 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD MAR 15 PY 2013 VL 119 IS 6 BP 1235 EP 1242 DI 10.1002/cncr.27852 PG 8 WC Oncology SC Oncology GA 100JW UT WOS:000315696600018 PM 23184361 ER PT J AU Chubiz, JEC Lee, JM Gilmore, ME Kong, CY Lowry, KP Halpern, EF McMahon, PM Ryan, PD Gazelle, GS AF Chubiz, Jessica E. Cott Lee, Janie M. Gilmore, Michael E. Kong, Chung Y. Lowry, Kathryn P. Halpern, Elkan F. McMahon, Pamela M. Ryan, Paula D. Gazelle, G. Scott TI Cost-effectiveness of alternating magnetic resonance imaging and digital mammography screening in BRCA1 and BRCA2 gene mutation carriers SO CANCER LA English DT Article DE BRCA1 gene; BRCA2 gene; breast neoplasms; cancer screening; cost effectiveness ID REDUCING SALPINGO-OOPHORECTOMY; HIGH FAMILIAL RISK; BREAST-CANCER; FILM MAMMOGRAPHY; PERFORMANCE BENCHMARKS; AMERICAN-COLLEGE; WOMEN; CARE; MRI; SURVEILLANCE AB BACKGROUND: Current clinical guidelines recommend earlier, more intensive breast cancer screening with both magnetic resonance imaging (MRI) and mammography for women with breast cancer susceptibility gene (BRCA) mutations. Unspecified details of screening schedules are a challenge for implementing guidelines. METHODS: A Markov Monte Carlo computer model was used to simulate screening in asymptomatic women who were BRCA1 and BRCA2 mutation carriers. Three dual-modality strategies were compared with digital mammography (DM) alone: 1) DM and MRI alternating at 6-month intervals beginning at age 25 years (Alt25), 2) annual MRI beginning at age 25 years with alternating DM added at age 30 years (MRI25/Alt30), and 3) DM and MRI alternating at 6-month intervals beginning at age 30 years (Alt30). Primary outcomes were quality-adjusted life years (QALYs), lifetime costs (in 2010 US dollars), and incremental cost-effectiveness (dollars per QALY gained). Additional outcomes included potential harms of screening, and lifetime costs stratified into component categories (screening and diagnosis, treatment, mortality, and patient time costs). RESULTS: All 3 dual-modality screening strategies increased QALYs and costs. Alt30 screening had the lowest incremental costs per additional QALY gained (BRCA1, $74,200 per QALY; BRCA2, $215,700 per QALY). False-positive test results increased substantially with dual-modality screening and occurred more frequently in BRCA2 carriers. Downstream savings in both breast cancer treatment and mortality costs were outweighed by increases in up-front screening and diagnosis costs. The results were influenced most by estimates of breast cancer risk and MRI costs. CONCLUSIONS: Alternating MRI and DM screening at 6-month intervals beginning at age 30 years was identified as a clinically effective approach to applying current guidelines, and was more cost-effective in BRCA1 gene mutation carriers compared with BRCA2 gene mutation carriers. Cancer 2013. (c) 2012 American Cancer Society. C1 [Chubiz, Jessica E. Cott; Lee, Janie M.; Gilmore, Michael E.; Kong, Chung Y.; Lowry, Kathryn P.; Halpern, Elkan F.; McMahon, Pamela M.; Gazelle, G. Scott] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Lee, Janie M.; Kong, Chung Y.; Lowry, Kathryn P.; Halpern, Elkan F.; McMahon, Pamela M.; Gazelle, G. Scott] Harvard Univ, Sch Med, Boston, MA USA. [Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Ryan, Paula D.] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. RP Lee, JM (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM janie@mgh-ita.org FU National Institutes of Health (NIH) [NIH K07-CA128816, NIH K25-CA133141, NIH R00-CA126147]; Harvard Medical School Office for Enrichment Programming; National Cancer Institute [U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040, HHSN261201100031C] FX This work was supported by National Institutes of Health (NIH) grants NIH K07-CA128816 (Dr. Lee), NIH K25-CA133141 (Dr. Kong), and NIH R00-CA126147 (Dr. McMahon) and by the Harvard Medical School Office for Enrichment Programming (Dr. Lowry). Provision of selected model input parameter values by the Breast Cancer Surveillance Consortium (BCSC) was supported by the National Cancer Institute (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040, and HHSN261201100031C). NR 56 TC 12 Z9 12 U1 1 U2 25 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD MAR 15 PY 2013 VL 119 IS 6 BP 1266 EP 1276 DI 10.1002/cncr.27864 PG 11 WC Oncology SC Oncology GA 100JW UT WOS:000315696600022 ER PT J AU Winkfield, KM Gabeau, D AF Winkfield, Karen M. Gabeau, Darlene TI Why Workforce Diversity in Oncology Matters SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID DISPARITIES; IMPACT C1 [Winkfield, Karen M.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Gabeau, Darlene] Roger Williams Radiat Therapy, 21st Century Oncol, Providence, RI USA. RP Winkfield, KM (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM kwinkfield@partners.org NR 10 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2013 VL 85 IS 4 BP 900 EP 901 DI 10.1016/j.ijrobp.2012.11.004 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 101YC UT WOS:000315809300017 PM 23452453 ER PT J AU Childs, SK Chen, YH Duggan, MM Golshan, M Pochebit, S Punglia, RS Wong, JS Bellon, JR AF Childs, Stephanie K. Chen, Yu-Hui Duggan, Margaret M. Golshan, Mehra Pochebit, Stephen Punglia, Rinaa S. Wong, Julia S. Bellon, Jennifer R. TI Impact of Margin Status on Local Recurrence After Mastectomy for Ductal Carcinoma In Situ SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID SKIN-SPARING MASTECTOMY; BREAST-CONSERVATION; RADIATION-THERAPY; RADIOTHERAPY; CANCER; DCIS AB Purpose: To examine the rate of local recurrence according to the margin status for patients with pure ductal carcinoma in situ (DCIS) treated by mastectomy. Methods and Materials: One hundred forty-five consecutive women who underwent mastectomy with or without radiation therapy for DCIS from 1998 to 2005 were included in this retrospective analysis. Only patients with pure DCIS were eligible; patients with microinvasion were excluded. The primary endpoint was local recurrence, defined as recurrence on the chest wall; regional and distant recurrences were secondary endpoints. Outcomes were analyzed according to margin status (positive, close (<= 2 mm), or negative), location of the closest margin (superficial, deep, or both), nuclear grade, necrosis, receptor status, type of mastectomy, and receipt of hormonal therapy. Results: The primary cohort consisted of 142 patients who did not receive postmastectomy radiation therapy (PMRT). For those patients, the median follow-up time was 7.6 years (range, 0.6-13.0 years). Twenty-one patients (15%) had a positive margin, and 23 patients (16%) had a close (<= 2 mm) margin. The deep margin was close in 14 patients and positive in 6 patients. The superficial margin was close in 13 patients and positive in 19 patients. One patient experienced an isolated invasive chest wall recurrence, and 1 patient had simultaneous chest wall, regional nodal, and distant metastases. The crude rates of chest wall recurrence were 2/142 (1.4%) for all patients, 1/21 (4.8%) for those with positive margins, 1/23 (4.3%) for those with close margins, and 0/98 for patients with negative margins. PMRT was given as part of the initial treatment to 3 patients, 1 of whom had an isolated chest wall recurrence. Conclusions: Mastectomy for pure DCIS resulted in a low rate of local or distant recurrences. Even with positive or close mastectomy margins, the rates of chest wall recurrences were so low that PMRT is likely not warranted. (C) 2013 Elsevier Inc. C1 [Childs, Stephanie K.] Dana Farber Canc Inst, Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Chen, Yu-Hui] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Chen, Yu-Hui] Faulkner Hosp, Dept Surg, Boston, MA USA. [Pochebit, Stephen] Faulkner Hosp, Dept Pathol, Boston, MA USA. [Golshan, Mehra] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Punglia, Rinaa S.; Wong, Julia S.; Bellon, Jennifer R.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Duggan, Margaret M.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Bellon, JR (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM jbellon@lroc.harvard.edu NR 15 TC 8 Z9 8 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2013 VL 85 IS 4 BP 948 EP 952 DI 10.1016/j.ijrobp.2012.07.2377 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 101YC UT WOS:000315809300026 PM 22975615 ER PT J AU Elnahal, SM Kerstiens, J Helsper, RS Zietman, AL Johnstone, PAS AF Elnahal, Shereef M. Kerstiens, John Helsper, Richard S. Zietman, Anthony L. Johnstone, Peter A. S. TI Proton Beam Therapy and Accountable Care: The Challenges Ahead SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID COST-EFFECTIVENESS; MEDICARE; ORGANIZATIONS AB Purpose: Proton beam therapy (PBT) centers have drawn increasing public scrutiny for their high cost. The behavior of such facilities is likely to change under the Affordable Care Act. We modeled how accountable care reform may affect the financial standing of PBT centers and their incentives to treat complex patient cases. Methods and Materials: We used operational data and publicly listed Medicare rates to model the relationship between financial metrics for PBT center performance and case mix (defined as the percentage of complex cases, such as pediatric central nervous system tumors). Financial metrics included total daily revenues and debt coverage (daily revenues - daily debt payments). Fee-for-service (FFS) and accountable care (ACO) reimbursement scenarios were modeled. Sensitivity analyses were performed around the room time required to treat noncomplex cases: simple (30 minutes), prostate (24 minutes), and short prostate (15 minutes). Sensitivity analyses were also performed for total machine operating time (14, 16, and 18 h/d). Results: Reimbursement under ACOs could reduce daily revenues in PBT centers by up to 32%. The incremental revenue gained by replacing 1 complex case with noncomplex cases was lowest for simple cases and highest for short prostate cases. ACO rates reduced this incremental incentive by 53.2% for simple cases and 41.7% for short prostate cases. To cover daily debt payments after ACO rates were imposed, 26% fewer complex patients were allowable at varying capital costs and interest rates. Only facilities with total machine operating times of 18 hours per day would cover debt payments in all scenarios. Conclusions: Debt-financed PBT centers will face steep challenges to remain financially viable after ACO implementation. Paradoxically, reduced reimbursement for noncomplex cases will require PBT centers to treat more such cases over cases for which PBT has demonstrated superior outcomes. Relative losses will be highest for those facilities focused primarily on treating noncomplex cases. (C) 2013 Elsevier Inc. C1 [Elnahal, Shereef M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Kerstiens, John; Johnstone, Peter A. S.] Indiana Univ, Proton Therapy Ctr, Bloomington, IN USA. [Helsper, Richard S.] Genesis HealthCare Syst, Zanesville, OH USA. [Zietman, Anthony L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Johnstone, Peter A. S.] Indiana Univ Sch Med, Dept Radiat Oncol, Indianapolis, IN USA. RP Elnahal, SM (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM selnahal@partners.org NR 16 TC 10 Z9 10 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2013 VL 85 IS 4 BP E165 EP E172 DI 10.1016/j.ijrobp.2012.10.038 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 101YC UT WOS:000315809300001 PM 23265572 ER PT J AU Shah, A Paly, JJ Efstathiou, JA Bekelman, JE AF Shah, Anand Paly, Jonathan J. Efstathiou, Jason A. Bekelman, Justin E. TI Physician Evaluation of Internet Health Information on Proton Therapy for Prostate Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 54th Annual Meeting of the American-Society-of-Radiation-Oncology (ASTRO) CY OCT 28-31, 2012 CL Boston, MA SP Amer Soc Radiat Oncol (ASTRO) ID QUALITY AB Purpose: Many patients considering prostate cancer (PCa) treatment options report seeking proton beam therapy (PBT) based in part on information readily available on the Internet. There is, however, potential for considerable variation in Internet health information (IHI). We thus evaluated the characteristics, quality, and accuracy of IHI on PBT for PCa. Methods and Materials: We undertook a qualitative research study using snowball-purposive sampling in which we evaluated the top 50 Google search results for "proton prostate cancer." Quality was evaluated on a 5-point scale using the validated 15-question DISCERN instrument. Accuracy was evaluated by comparing IHI with the best available evidence. Results: Thirty-seven IHI websites were included in the final sample. These websites most frequently were patient information/support resources (46%), were focused exclusively on PBT (51%), and had a commercial affiliation (38%). There was a significant difference in quality according to the type of IHI. Substantial inaccuracies were noted in the study sample compared with best available or contextual evidence. Conclusions: There are shortcomings in quality and accuracy in consumer-oriented IHI on PBT for PCa. Providers must be prepared to educate patients how to critically evaluate IHI related to PBT for PCa to best inform their treatment decisions. (C) 2013 Elsevier Inc. C1 [Shah, Anand; Bekelman, Justin E.] Univ Penn, Perelman Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Bekelman, Justin E.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Bekelman, Justin E.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Shah, Anand] Columbia Univ, Med Ctr, Dept Radiat Oncol, New York, NY 10032 USA. [Paly, Jonathan J.; Efstathiou, Jason A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. RP Shah, A (reprint author), Columbia Univ, Med Ctr, Dept Radiat Oncol, 622 W 168th St, New York, NY 10032 USA. EM as4351@columbia.edu FU NCI NIH HHS [L30 CA142482] NR 17 TC 8 Z9 8 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2013 VL 85 IS 4 BP E173 EP E177 DI 10.1016/j.ijrobp.2012.10.039 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 101YC UT WOS:000315809300002 PM 23245278 ER PT J AU Sandoval, GJ Graham, DB Bhattacharya, D Sleckman, BP Xavier, RJ Swat, W AF Sandoval, Gabriel J. Graham, Daniel B. Bhattacharya, Deepta Sleckman, Barry P. Xavier, Ramnik J. Swat, Wojciech TI Cutting Edge: Cell-Autonomous Control of IL-7 Response Revealed in a Novel Stage of Precursor B Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LIGHT-CHAIN RECOMBINATION; LYMPHOCYTE DEVELOPMENT; REGULATORY FACTOR-4; MYC; GENE; EXPRESSION; LEUKEMIA; RECEPTOR; SLP-65; ACTIVATION AB During early stages of B-lineage differentiation in bone marrow, signals emanating from IL-7R and pre-BCR are thought to synergistically induce proliferative expansion of progenitor cells. Paradoxically, loss of pre-BCR-signaling components is associated with leukemia in both mice and humans. Exactly how progenitor B cells perform the task of balancing proliferative burst dependent on IL-7 with the termination of IL-7 signals and the initiation of L chain gene rearrangement remains to be elucidated. In this article, we provide genetic and functional evidence that the cessation of the IL-7 response of pre-B cells is controlled via a cell-autonomous mechanism that operates at a discrete developmental transition inside Fraction C' (large pre-BII) marked by transient expression of c-Myc. Our data indicate that pre-BCR cooperates with IL-7R in expanding the pre-B cell pool, but it is also critical to control the differentiation program shutting off the c-Myc gene in large pre-B cells. The Journal of Immunology, 2013, 190: 2485-2489. C1 [Sandoval, Gabriel J.; Graham, Daniel B.; Bhattacharya, Deepta; Sleckman, Barry P.; Swat, Wojciech] Washington Univ, Sch Med, Dept Pathol & Immunol, Div Immunobiol, St Louis, MO 63110 USA. [Sleckman, Barry P.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Broad Inst, Cambridge, MA 02138 USA. RP Swat, W (reprint author), Washington Univ, Sch Med, Dept Pathol & Immunol, 660 South Euclid Ave, St Louis, MO 63110 USA. EM swat@wustl.edu FU National Institutes of Health [R01AI061077, R01AI073718, DK083756, DK043351, AI047829, K01 DK078318]; Leukemia and Lymphoma Society FX This work was supported by National Institutes of Health Grants R01AI061077 and R01AI073718 (to W.S.), DK083756 and DK043351 (to R.J.X.), AI047829 (to B.P.S.), and K01 DK078318 (to D.B.) as well as a Leukemia and Lymphoma Society Scholar Award (to W.S.) and Special Fellowship Award (to D.B.G.). NR 27 TC 5 Z9 5 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2013 VL 190 IS 6 BP 2485 EP 2489 DI 10.4049/jimmunol.1203208 PG 5 WC Immunology SC Immunology GA 099XG UT WOS:000315657200004 PM 23420891 ER PT J AU Balkaya, M Krober, J Gertz, K Peruzzaro, S Endres, M AF Balkaya, Mustafa Kroeber, Jan Gertz, Karen Peruzzaro, Sarah Endres, Matthias TI Characterization of long-term functional outcome in a murine model of mild brain ischemia SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Mild brain ischemia; Middle cerebral artery occlusion; Long-term functional outcome; Behavioral characterization ID MIDDLE CEREBRAL-ARTERY; ADHESIVE REMOVAL TEST; ENVIRONMENTAL ENRICHMENT; STROKE RESEARCH; AGED RATS; MOUSE; MICE; DEFICITS; NEUROPROTECTION; SENSORIMOTOR AB Evaluation of functional outcome over the course of several weeks after ischemia is a key component in improving the clinical relevance of experimental stroke studies. Using a battery of behavioral tests, we characterized functional outcome in mice over 4 weeks following 30 min of proximal middle cerebral artery occlusion (MCAo). We evaluated rotarod, chimney, pole and cylinder tests to assess short term functional deficits in a transient stroke model which induces infarcts mainly in the striatum. The corner test, adhesive removal test, cylinder test, catwalk, paw preference test and novel tests of rotation were evaluated for long-term functional outcome. Rotarod detected deficits within the first week and pole test was reliable up to intermediate time points after MCAo. Corner test, adhesive removal test, catwalk and paw preference test detected deficits for up to 4 weeks, as did the novel corner rotation and bowl tests. Chimney and cylinder test did not prove useful in our model of mild stroke. In summary, we established the pole test and rotarod as useful tools to evaluate sensory motor deficits early after mild stroke, and corner test and adhesive removal test at later time-points. Alternatively, corner rotation may be a suitable test of long-term function. Test batteries may be further complemented by catwalk and paw preference test for clinically relevant deficits. There was no correlation of behavioral outcome with lesion size at 28 days, and determining whether these tests are useful for detecting a potential benefit of neuroprotective or regenerative therapies requires further testing. (c) 2012 Elsevier B.V. All rights reserved. C1 [Balkaya, Mustafa; Kroeber, Jan; Gertz, Karen; Peruzzaro, Sarah; Endres, Matthias] Charite, Klin Hsch Ambulanz Neurol, D-10117 Berlin, Germany. [Kroeber, Jan; Gertz, Karen; Endres, Matthias] Charite, Ctr Stroke Res Berlin, D-10117 Berlin, Germany. [Endres, Matthias] Charite, Ctr Excellence Neurocure, D-10117 Berlin, Germany. RP Balkaya, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, Neurovasc Res Lab, 149 13th St, Charlestown, MA 02129 USA. EM mgokalpbalkaya@partners.org RI Gertz, Karen/J-1603-2015 FU Deutsche Forschungsgemeinschaft [SFB TRR43, Exc257]; Volkswagen Stiftung (Lichtenberg Program); Bundesministerium fur Bildung und Forschung (Center for Stroke Research Berlin); European Union's Seventh Framework Programme (FP7) [201024, 202213] FX This work was supported by the Deutsche Forschungsgemeinschaft (SFB TRR43 and Exc257 to M.E.), the Volkswagen Stiftung (Lichtenberg Program to M.E.), the Bundesministerium fur Bildung und Forschung (Center for Stroke Research Berlin), the European Union's Seventh Framework Programme (FP7/2008-2013) under grant agreements No 201024 and No 202213 (European Stroke Network, WP7 'stroke model platform'). NR 28 TC 28 Z9 29 U1 0 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD MAR 15 PY 2013 VL 213 IS 2 BP 179 EP 187 DI 10.1016/j.jneumeth.2012.12.021 PG 9 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 098NY UT WOS:000315557200003 PM 23291083 ER PT J AU van Scheltinga, AFT Bakker, SC van Haren, NEM Derks, EM Buizer-Voskamp, JE Boos, HBM Cahn, W Pol, HEH Ripke, S Ophoff, RA Kahn, RS AF van Scheltinga, Afke F. Terwisscha Bakker, Steven C. van Haren, Neeltje E. M. Derks, Eske M. Buizer-Voskamp, Jacobine E. Boos, Heleen B. M. Cahn, Wiepke Pol, Hilleke E. Hulshoff Ripke, Stephan Ophoff, Roel A. Kahn, Rene S. CA Psychiat Genome-wide Assoc Study TI Genetic Schizophrenia Risk Variants Jointly Modulate Total Brain and White Matter Volume SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Endophenotype; genome-wide; imaging; psychiatric; SNPs; structural MRI ID COMMON SNPS; IN-VIVO; ASSOCIATION; SUSCEPTIBILITY; ABNORMALITIES; HERITABILITY; METAANALYSIS; MORPHOLOGY; DISORDERS; PSYCHOSIS AB Background: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. Methods: Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. Results: In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume (R-2 = 048, p = 1.6 x 10(-4)) and white matter volume (R-2 = .051, p = 8.6 x 10(-5)) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n = 2020) was much smaller than the entire set of SNPs that modulated disease status (n = 14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. Conclusions: These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia. C1 [van Scheltinga, Afke F. Terwisscha; Bakker, Steven C.; van Haren, Neeltje E. M.; Buizer-Voskamp, Jacobine E.; Boos, Heleen B. M.; Cahn, Wiepke; Pol, Hilleke E. Hulshoff; Ophoff, Roel A.; Kahn, Rene S.] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Psychiat, NL-3584 CX Utrecht, Netherlands. [Derks, Eske M.] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands. [Ripke, Stephan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Ophoff, Roel A.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA USA. RP van Scheltinga, AFT (reprint author), Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Psychiat, Huispost A00-241,Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands. EM aterwiss@umcutrecht.nl RI Cichon, Sven/H-8803-2013; Hulshoff Pol, Hilleke/B-4795-2014; Hansen, Thomas/O-5965-2014; Melle, Ingrid /B-4858-2011; McQuillin, Andrew/C-1623-2008; Derks, Eske/A-1652-2017; OI Thygesen, Johan H/0000-0002-7479-3459; Mattheisen, Manuel/0000-0002-8442-493X; Suvisaari, Jaana/0000-0001-7167-0990; Bruggeman, Richard/0000-0002-3238-8471; Stefansson, Hreinn/0000-0002-9331-6666; Agartz, Ingrid/0000-0002-9839-5391; Nothen, Markus/0000-0002-8770-2464; Donohoe, Gary/0000-0003-3037-7426; Andreassen, Ole A./0000-0002-4461-3568; Visscher, Peter/0000-0002-2143-8760; Cichon, Sven/0000-0002-9475-086X; Hulshoff Pol, Hilleke/0000-0002-2038-5281; Myin-Germeys, Inez/0000-0002-3731-4930; lichtenstein, paul/0000-0003-3037-5287; Hansen, Thomas/0000-0001-6703-7762; Melle, Ingrid /0000-0002-9783-548X; McQuillin, Andrew/0000-0003-1567-2240; Derks, Eske/0000-0002-6292-6883; Rethelyi, Janos/0000-0002-3641-012X; Bergen, Sarah/0000-0002-5888-0034; KELLER, MATTHEW/0000-0002-6075-9882; Zammit, Stanley/0000-0002-2647-9211 FU Zorg Onderzoek Nederland; Medische Wetenschappen [91686137]; Dutch Brain Foundation [14F06(2)-34]; Top Institute Pharma [T5-203]; Medische Wetenschappen, within the Mental Health program [10.000.1001]; National Institute of Mental Health [RO1 MG078075]; Psychiatric Genomics Consortium; Eli Lilly; Janssen Pharmaceutica; GlaxoSmithKline; Bristol-Myers Squibb; AstraZeneca Pharmaceuticals; Pfizer; Forest Pharmaceuticals; Novartis; Solvay; Generation Scotland; Genetics Health Initiative; Organon; Foundation for the National Institutes of Health; Shire; Forest; Merck; PGxHealth (a division of Clinical Data, Inc.); Roche Diagnostics; Vanda Pharmaceuticals; Eli Lilly Company; Golden Helix, Inc.; InforMed Insights; Janssen; EGIS; H. Lundbeck A/S; Richter; Schering-Plough; Johnson Johnson; Janssen-Cilag; Hospira (Mayne); Hospira; Janssen Cilag; Denmark-Aarhus group FX This work was supported by a Veni grant from Zorg Onderzoek Nederland, Medische Wetenschappen to SCB (the Dutch organization for health research and development, project number: 91686137), by a grant from the Dutch Brain Foundation to SCB [Grant 14F06(2)-34], and by Top Institute Pharma (project T5-203). The Genetic Risk and Outcome of Psychosis project was supported by a Grant from Zorg Onderzoek Nederland, Medische Wetenschappen, within the Mental Health program (project number: 10.000.1001). Genome-wide association study of this sample was funded by the National Institute of Mental Health (Grant RO1 MG078075 to RAO).; All individual authors on this paper declare no biomedical financial interests or potential conflicts of interest. The following are financial disclosures for the Psychiatric Genomics Consortium: Eli Lilly funded portions of the genotyping for the Clinical Antipsychotic Trials of Intervention Effectiveness Study and TOP. PFS received research funding from Eli Lilly in connection with the Clinical Antipsychotic Trials of Intervention Effectiveness Study. TSS received research funding from Eli Lilly and consulting fees from Janssen Pharmaceutica, GlaxoSmithKline, and Bristol-Myers Squibb. JAL received research funding from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmaceutica, and Pfizer and consulting and educational fees from AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Novartis, Pfizer, and Solvay. DStC received research funding from GlaxoSmithKline and Generation Scotland, Genetics Health Initiative. FA received funds from Pfizer, Organon, and the Foundation for the National Institutes of Health. DWB has received research support from Shire and Forest, has been on the speakers' bureau for Pfizer, and has received consulting honoraria from Forest and Jazz. TW has received consulting and lecture fees from H. Lundbeck A/S. OAA has received Speaker's honorarium from AstraZeneca, Janssen, Bristol-Myers Squibb, and GlaxoSmithKline. IM has received a Speaker's honorarium from Janssen and AstraZeneca. AKM has received consulting fees or honoraria from Eli Lilly & Company, Janssen Pharmaceutica, Merck, Bristol-Meyers Squibb, Pfizer, PGxHealth (a division of Clinical Data, Inc.), Roche Diagnostics, and Vanda Pharmaceuticals and has received research support from Eli Lilly & Company. TL has received consulting fees or honoraria from Merck, Eli Lilly & Company, Golden Helix, Inc., InforMed Insights, and PGxHealth (a division of Clinical Data, Inc.). IB has been an advisory board member, consultant, and lecturer for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, EGIS, Janssen, H. Lundbeck A/S, Novartis, Pfizer, Richter, and Schering-Plough and received a grant for an investigator-initiated study from H. Lundbeck A/S. JJM has received consulting and speaker's fees from Johnson & Johnson, Schering-Plough and Eli Lilly. CP has received grant support from Janssen-Cilag, Eli Lilly, Hospira (Mayne), and AstraZeneca; provided consultancy to Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, Pfizer, and Schering-Plough; and has undertaken investigator-initiated studies supported by Eli Lilly, Hospira, Janssen Cilag, and AstraZeneca. The Denmark-Aarhus group (The GEMSStud [Genetic and Phenotypic Architecture of Metabolic Syndrome-Associated Components in Dyslipidemic and Normolipidemic Subjects Study] with principal investigators ADB, OM, and PBM) received research funding from H. Lundbeck A/S. EGJ has served as an unpaid consultant for Eli Lilly. NR 32 TC 22 Z9 22 U1 1 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 15 PY 2013 VL 73 IS 6 BP 525 EP 531 DI 10.1016/j.biopsych.2012.08.017 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 093JA UT WOS:000315186700007 ER PT J AU Johnson, JR Tchesnokova, V Johnston, B Clabots, C Roberts, PL Billig, M Riddell, K Rogers, P Qin, X Butler-Wu, S Price, LB Aziz, M Nicolas-Chanoine, MH DebRoy, C Robicsek, A Hansen, G Urban, C Platell, J Trott, DJ Zhanel, G Weissman, SJ Cookson, BT Fang, FC Limaye, AP Scholes, D Chattopadhyay, S Hooper, DC Sokurenko, EV AF Johnson, James R. Tchesnokova, Veronika Johnston, Brian Clabots, Connie Roberts, Pacita L. Billig, Mariya Riddell, Kim Rogers, Peggy Qin, Xuan Butler-Wu, Susan Price, Lance B. Aziz, Maliha Nicolas-Chanoine, Marie-Helene DebRoy, Chitrita Robicsek, Ari Hansen, Glen Urban, Carl Platell, Joanne Trott, Darren J. Zhanel, George Weissman, Scott J. Cookson, Brad T. Fang, Ferric C. Limaye, Ajit P. Scholes, Delia Chattopadhyay, Sujay Hooper, David C. Sokurenko, Evgeni V. TI Abrupt Emergence of a Single Dominant Multidrug-Resistant Strain of Escherichia coli SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Escherichia coli infections; antimicrobial resistance; extended-spectrum beta-lactamase; CTX-M-15; fluoroquinolone resistance; multidrug resistance; sequence type ST131; multilocus sequence typing; molecular epidemiology; FimH ID SEQUENCE TYPE ST131; EXTRAINTESTINAL INFECTIONS; UNITED-STATES; MECHANISMS; ANIMALS; CLONE AB Background. Fluoroquinolone-resistant Escherichia coli are increasingly prevalent. Their clonal origins-potentially critical for control efforts-remain undefined. Methods. Antimicrobial resistance profiles and fine clonal structure were determined for 236 diverse-source historical (1967-2009) E. coli isolates representing sequence type ST131 and 853 recent (2010-2011) consecutive E. coli isolates from 5 clinical laboratories in Seattle, Washington, and Minneapolis, Minnesota. Clonal structure was resolved based on fimH sequence (fimbrial adhesin gene: H subclone assignments), multilocus sequence typing, gyrA and parC sequence (fluoroquinolone resistance-determining loci), and pulsed-field gel electrophoresis. Results. Of the recent fluoroquinolone-resistant clinical isolates, 52% represented a single ST131 subclonal lineage, H30, which expanded abruptly after 2000. This subclone had a unique and conserved gyrA/parC allele combination, supporting its tight clonality. Unlike other ST131 subclones, H30 was significantly associated with fluoroquinolone resistance and was the most prevalent subclone among current E. coli clinical isolates, overall (10.4%) and within every resistance category (11%-52%). Conclusions. Most current fluoroquinolone-resistant E. coli clinical isolates, and the largest share of multidrug-resistant isolates, represent a highly clonal subgroup that likely originated from a single rapidly expanded and disseminated ST131 strain. Focused attention to this strain will be required to control the fluoroquinolone and multidrug-resistant E. coli epidemic. C1 [Johnson, James R.; Johnston, Brian; Clabots, Connie] VA Med Ctr, Minneapolis, MN 55417 USA. [Johnson, James R.; Johnston, Brian; Clabots, Connie] Univ Minnesota, Minneapolis, MN USA. [Tchesnokova, Veronika; Billig, Mariya; Cookson, Brad T.; Fang, Ferric C.; Chattopadhyay, Sujay; Sokurenko, Evgeni V.] Univ Washington, Sch Med, Dept Microbiol, Seattle, WA 98195 USA. [Roberts, Pacita L.; Limaye, Ajit P.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Riddell, Kim; Rogers, Peggy] Grp Hlth Cooperat Puget Sound, Grp Hlth Clin Lab, Seattle, WA USA. [Qin, Xuan] Seattle Childrens Hosp, Dept Lab Med, Seattle, WA USA. [Butler-Wu, Susan; Cookson, Brad T.; Fang, Ferric C.] Univ Washington, Sch Med, Dept Lab Med, Seattle, WA 98195 USA. [Price, Lance B.; Aziz, Maliha] Translat Genom Res Inst TGen, Flagstaff, AZ USA. [Nicolas-Chanoine, Marie-Helene] Hop Beaujon, Clichy, France. [DebRoy, Chitrita] Penn State Univ, University Pk, PA 16802 USA. [Robicsek, Ari] NorthShore Univ HealthSyst, Evanston, IL USA. [Hansen, Glen] Hennepin Cty Med Ctr, Mineapolis, MN USA. [Urban, Carl] New York Hosp Queens, Flushing, NY USA. [Urban, Carl] NYU, Sch Med, New York, NY USA. [Platell, Joanne] Biosecur Queensland, Anim Dis Surveillance Lab, Toowoomba, Qld, Australia. [Trott, Darren J.] Univ Adelaide, Roseworthy, Australia. [Zhanel, George] Univ Manitoba, Winnipeg, MB, Canada. [Weissman, Scott J.] Seattle Childrens Res Inst, Seattle, WA USA. [Scholes, Delia] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Hooper, David C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hooper, David C.] Massachusetts Gen Hosp, Dept Infect Dis, Boston, MA 02114 USA. RP Johnson, JR (reprint author), VA Med Ctr, 1 Vet Dr, Minneapolis, MN 55417 USA. EM johns007@umn.edu OI Fang, Ferric/0000-0002-3243-110X FU Office of Research and Development, Medical Research Service, Department of Veterans Affairs, Merit Review grant [1 I01 CX000192 01]; NIH ARRA [1RC4AI092828]; Cepheid; Rib-X Pharmaceuticals; Merck; Rochester Medical; Syntiron; Direction de la Recherche Clinique AP-HP; Group Health; ARC Linkage; Achaogen; Cubist; Affinium; Sunovion; Pfizer FX This material is based upon work supported by Office of Research and Development, Medical Research Service, Department of Veterans Affairs, Merit Review grant 1 I01 CX000192 01 (J. R. J.), and NIH ARRA award 1RC4AI092828 (E. V. S.).; The following authors report these conflicts of interest: F. C. F.: Consultancy, research grants, and educational presentations with Cepheid. D. C. H.: Research grant from Rib-X Pharmaceuticals, consultancies with Fab Pharma and Pfizer, speakers bureau with Pfizer. J. R. J.: Research grants and contracts from Merck, Rochester Medical, and Syntiron; patent pending for detection of the H30 ST131 subclone. L. B. P.: Patent pending for detection of the H30 ST131 subclone. M.-H. N.-C.: Expert testimony for Region Wallon; research grant from Direction de la Recherche Clinique AP-HP; lectures for Novartis; travel reimbursement for 2012 ICAAC speaker. E. V. S.: Research grant from Group Health; patent pending for detection of the H30 ST131 subclone. D. T.: Research grant from ARC Linkage; consultancy from Pfizer and Bayer; speaker for Bayer Animal Health. C. U.: Consultancy with Pfizer, lecture/speaker for Forest Pharmaceuticals, Cubist, and Pfizer. G. Z.: Research grants from Achaogen, Merck, Pfizer, Cubist, Affinium, and Sunovion. All other authors report no potential conflicts. NR 26 TC 96 Z9 97 U1 1 U2 31 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2013 VL 207 IS 6 BP 919 EP 928 DI 10.1093/infdis/jis933 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 092XO UT WOS:000315156500008 PM 23288927 ER PT J AU Kim, AY Onofrey, S Church, DR AF Kim, Arthur Y. Onofrey, Shauna Church, Daniel R. TI An Epidemiologic Update on Hepatitis C Infection in Persons Living With or at Risk of HIV Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE sexual transmission; epidemiology; viral infection; incidence; prevalence; perinatal transmission; men who have sex with men ID VIRUS-INFECTION; UNITED-STATES; VIRAL-HEPATITIS; NATURAL-HISTORY; LIVER FIBROSIS; YOUNG-ADULTS; INDIVIDUALS; OUTBREAK; COHORT; MEN AB Due to shared routes of transmission, coinfection with both human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) is relatively common and results in accelerated liver disease, driving morbidity and mortality. Deaths related to HCV now exceed deaths related to HIV in the United States, and co-infected patients bear a significant proportion of that mortality. This burden may be addressed by novel antiviral therapies that promise increased rates of cure or by enhanced access to liver transplantation, but these are costly interventions. Ultimately, the future burden of coinfection is addressed by greater understanding of who is at risk for development of each infection, thus guiding preventive efforts. Key recent reports regarding the US burden of morbidity and mortality due to HCV and groups at risk for coinfection are reviewed, with a focus on recently described HCV occurring among young injection drug users and men who have sex with men. Given the lack of available vaccine against HCV, enhanced detection and surveillance is a vital component of our public health strategy to combat HCV. C1 [Kim, Arthur Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02115 USA. [Onofrey, Shauna; Church, Daniel R.] Massachusetts Dept Publ Hlth, Jamaica Plain, MA USA. RP Kim, AY (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02115 USA. EM akim1@partners.org FU National Institutes of Health [U19 AI066345, R01 DA 033541, R01 DA 031056, R01 DA 031059] FX A. Y. K. is supported by the National Institutes of Health, grants U19 AI066345, R01 DA 033541, R01 DA 031056, R01 DA 031059. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. NR 26 TC 35 Z9 35 U1 0 U2 23 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2013 VL 207 SU 1 BP S1 EP S6 DI 10.1093/infdis/jis927 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 089FG UT WOS:000314895000001 PM 23390299 ER PT J AU Lauer, GM AF Lauer, Georg M. TI Immune Responses to Hepatitis C Virus (HCV) Infection and the Prospects for an Effective HCV Vaccine or Immunotherapies SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE hepatitis C virus; acute infection; T cells; protective immunity; vaccine ID VIRAL PERSISTENCE; CELL RESPONSES; DRUG-USERS; B-VIRUS; CLEARANCE; RESOLUTION; DETERMINANTS; REINFECTION; CHALLENGE AB Infection with hepatitis C virus (HCV) typically leads to persistent infection, with > 170 million people estimated to be affected worldwide, putting them at risk for chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Importantly, 20%-30% of individuals are able to control the virus spontaneously, usually within 6 months of exposure. This suggests that HCV vaccines and immunotherapies are a distinct possibility. We discuss here the role of T cells in controlling HCV, the gaps in our understanding of protective HCV immunity, and the recent introduction of a HCV T-cell vaccine into clinical trials. C1 [Lauer, Georg M.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Lauer, Georg M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Lauer, GM (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM glauer@helix.mgh.harvard.edu RI Cheng, Yushao/E-6256-2011 FU National Institutes of Health [U19 AI082630, U19 AI066345] FX This work was supported by the National Institutes of Health (grants U19 AI082630 and U19 AI066345). NR 27 TC 21 Z9 23 U1 0 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2013 VL 207 SU 1 BP S7 EP S12 DI 10.1093/infdis/jis762 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 089FG UT WOS:000314895000002 PM 23390305 ER PT J AU Lin, WY Weinberg, EM Chung, RT AF Lin, Wenyu Weinberg, Ethan M. Chung, Raymond T. TI Pathogenesis of Accelerated Fibrosis in HIV/HCV Co-infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Hepatitis C Virus (HCV); Human Immunodeficiency Virus (HIV); Hepatic Fibrogenesis ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C VIRUS; LIVER FIBROSIS; STELLATE CELLS; MICROBIAL TRANSLOCATION; OXIDATIVE STRESS; HIV-INFECTION; PROGRESSION; FIBROGENESIS; ACTIVATION AB Human immunodeficiency virus (HIV) infection is a major cause of acceleration of hepatitis C virus-related liver disease, cirrhosis, and death. However, studies of liver disease pathogenesis in HIV/HCV coinfection have thus far been limited. Emerging data support multiple derangements attending HIV coinfection, including increases in profibrogenic cytokine expression and secretion, generation of enhanced oxidative stress, and increases in hepaotcyte apoptosis. These derangements may be further augmented in the presence of increased microbial translocation in the setting of HIV disease. New insight into the mechanisms of HIV/HCV pathogenesis causing accelerated liver fibrosis could lead to new therapeutic strategies designed to retard ths process. C1 [Lin, Wenyu; Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, Boston, MA USA. [Weinberg, Ethan M.] Weill Cornell Med Ctr, Div Gastroenterol & Hepatol, New York, NY USA. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Warren 1007, Boston, MA 02114 USA. EM rtchung@partners.org FU National Institutes of Health [AI069939, DK098079] FX This work was supported by the National Institutes of Health (grants AI069939 and DK098079). NR 28 TC 37 Z9 40 U1 1 U2 13 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2013 VL 207 SU 1 BP S13 EP S18 DI 10.1093/infdis/jis926 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 089FG UT WOS:000314895000003 PM 23390300 ER PT J AU Stock, S DeGruttola, V AF Stock, Shannon DeGruttola, Victor TI Recursive partitioning for monotone missing at random longitudinal markers SO STATISTICS IN MEDICINE LA English DT Article DE inverse probability weighting; recursive partitioning; U-statistics ID REGRESSION TREES; CLASSIFICATION; INFECTION; RESPONSES AB The development of HIV resistance mutations reduces the efficacy of specific antiretroviral drugs used to treat HIV infection and cross-resistance within classes of drugs is common. Recursive partitioning has been extensively used to identify resistance mutations associated with a reduced virologic response measured at a single time point; here we describe a statistical method that accommodates a large set of genetic or other covariates and a longitudinal response. This recursive partitioning approach for continuous longitudinal data uses the kernel of a U-statistic as the splitting criterion and avoids the need for parametric assumptions regarding the relationship between observed response trajectories and covariates. We propose an extension of this approach that allows longitudinal measurements to be monotone missing at random by making use of inverse probability weights. We assess the performance of our method using extensive simulation studies and apply them to data collected by the Forum for Collaborative HIV Research as part of an investigation of the viral genetic mutations associated with reduced clinical efficacy of the drug abacavir. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Stock, Shannon] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Stock, Shannon; DeGruttola, Victor] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Stock, S (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, CLS11007,450 Brookline Ave, Boston, MA 02215 USA. EM sstock@jimmy.harvard.edu FU NIH [AI R01 51164, AI T32 007358] FX The authors would like to thank Eric Tchetgen Tchetgen for his help with methods to accommodate missing data, as well as the reviewer and associate editor for their helpful suggestions and comments. This work was supported by NIH grants AI R01 51164 and AI T32 007358. NR 14 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAR 15 PY 2013 VL 32 IS 6 BP 978 EP 994 DI 10.1002/sim.5574 PG 17 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 092BT UT WOS:000315094500007 PM 22941582 ER PT J AU Rego, EM Kim, HT Ruiz-Arguelles, GJ Undurraga, MS Uriarte, MD Jacomo, RH Gutierrez-Aguirre, H Melo, RAM Bittencourt, R Pasquini, R Pagnano, K Fagundes, EM Chauffaille, MD Chiattone, CS Martinez, L Meillon, LA Gomez-Almaguer, D Kwaan, HC Garces-Eisele, J Gallagher, R Niemeyer, CM Schrier, SL Tallman, M Grimwade, D Ganser, A Berliner, N Ribeiro, RC Lo-Coco, F Lowenberg, B Sanz, MA AF Rego, Eduardo M. Kim, Haesook T. Ruiz-Argueelles, Guillermo J. Undurraga, Maria Soledad Uriarte, Maria del Rosario Jacomo, Rafael H. Gutierrez-Aguirre, Homero Melo, Raul A. M. Bittencourt, Rosane Pasquini, Ricardo Pagnano, Katia Fagundes, Evandro M. Chauffaille, Maria de Lourdes Chiattone, Carlos S. Martinez, Lem Meillon, Luis A. Gomez-Almaguer, David Kwaan, Hau C. Garces-Eisele, Javier Gallagher, Robert Niemeyer, Charlotte M. Schrier, Stanley L. Tallman, Martin Grimwade, David Ganser, Arnold Berliner, Nancy Ribeiro, Raul C. Lo-Coco, Francesco Loewenberg, Bob Sanz, Miguel A. TI Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL SO BLOOD LA English DT Article ID TRANS-RETINOIC ACID; AGENT ARSENIC TRIOXIDE; MINIMAL-RESIDUAL-DISEASE; RISK-ADAPTED TREATMENT; ALPHA FUSION GENE; EARLY DEATH RATE; RT-PCR ANALYSIS; ANTHRACYCLINE MONOCHEMOTHERAPY; REMISSION INDUCTION; CLINICAL-FEATURES AB Thanks to modern treatment with all-trans retinoic acid and chemotherapy, acute promyelocytic leukemia (APL) is now the most curable type of leukemia. However, this progress has not yielded equivalent benefit in developing countries. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) was established to create a network of institutions in developing countries that would exchange experience and data and receive support from well-established US and European cooperative groups. The IC-APL formulated expeditious diagnostic, treatment, and supportive guidelines that were adapted to local circumstances. APL was chosen as a model disease because of the potential impact on improved diagnosis and treatment. The project included 4 national coordinators and reference laboratories, common clinical record forms, 5 subcommittees, and laboratory and data management training programs. In addition, participating institutions held regular virtual and face-to-face meetings. Complete hematological remission was achieved in 153/180 (85%) patients and 27 (15%) died during induction. After a median follow-up of 28 months, the 2-year cumulative incidence of relapse, overall survival (OS), and disease-free survival (DFS) were 4.5%, 80%, and 91%, respectively. The establishment of the IC-APL network resulted in a decrease of almost 50% in early mortality and an improvement in OS of almost 30% compared with historical controls, resulting in OS and DFS similar to those reported in developed countries. C1 [Rego, Eduardo M.; Jacomo, Rafael H.] Univ Sao Paulo, Hematol Oncol Div, Dept Internal Med, Med Sch Ribeirao Preto, BR-14048900 Ribeirao Preto, Brazil. [Rego, Eduardo M.; Jacomo, Rafael H.] Univ Sao Paulo, Ctr Cell Based Therapy, BR-14048900 Ribeirao Preto, Brazil. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Ruiz-Argueelles, Guillermo J.; Garces-Eisele, Javier] Clin Ruiz Puebla, Puebla, Mexico. [Undurraga, Maria Soledad] Hosp Salvador, Dept Hematol, Santiago, Chile. [Uriarte, Maria del Rosario; Martinez, Lem] Asociac Espanola Primera Socorros Mutuos, Montevideo, Uruguay. [Gutierrez-Aguirre, Homero; Gomez-Almaguer, David] Hosp Univ Dr Jose E Gonzalez, Div Hematol, Monterrey, Mexico. [Melo, Raul A. M.] Fundacao HEMOPE, Recife, PE, Brazil. [Bittencourt, Rosane] Univ Fed Rio Grande do Sul, Div Hematol, Porto Alegre, RS, Brazil. [Pasquini, Ricardo] Univ Fed Parana, Div Hematol, BR-80060000 Curitiba, Parana, Brazil. [Pagnano, Katia] Univ Campinas UNICAMP, Hematol & Hemotherapy Ctr, Campinas, Brazil. [Fagundes, Evandro M.] Univ Fed Minas Gerais, Div Hematol, Belo Horizonte, MG, Brazil. [Chauffaille, Maria de Lourdes] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Chiattone, Carlos S.] Santa Casa Med Sch, Div Hematol, Sao Paulo, Brazil. [Meillon, Luis A.] Ctr Med Nacl Siglo XXI, Mexico City, DF, Mexico. [Kwaan, Hau C.] Northwestern Univ, Feinberg Sch Med, Hematol Oncol Div, Chicago, IL 60611 USA. [Gallagher, Robert] Albert Einstein Canc Ctr, New York, NY USA. [Niemeyer, Charlotte M.] Univ Med Ctr, Dept Pediat & Adolescent Med, Freiburg, Germany. [Schrier, Stanley L.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Tallman, Martin] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, Weill Cornell Med Coll, New York, NY 10021 USA. [Grimwade, David] Kings Coll London Sch Med, Dept Med & Mol Genet, London, England. [Ganser, Arnold] Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, Hannover, Germany. [Berliner, Nancy] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Ribeiro, Raul C.] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Lo-Coco, Francesco] Univ Roma Tor Vergata, Dept Biopathol, Rome, Italy. [Lo-Coco, Francesco] Santa Lucia Fdn, Rome, Italy. [Loewenberg, Bob] Erasmus MC, Dept Hematol, Rotterdam, Netherlands. [Sanz, Miguel A.] Valencia Univ Med Sch, Hosp Univ La Fe, Dept Hematol, Valencia, Spain. RP Rego, EM (reprint author), Univ Sao Paulo, Hematol Oncol Div, Dept Internal Med, Med Sch Ribeirao Preto, Av Bandeirantes 3900, BR-14048900 Ribeirao Preto, Brazil. EM emrego@hcrp.fmrp.usp.br RI UNICAMP, CCES - /J-7787-2015; Rego, Eduardo/A-1058-2012 OI Rego, Eduardo/0000-0003-1567-4086 FU American Society of Hematology; Fondazione Umberto Veronesi; Roche Saudi Arabia; Fundacao de Apoio a Pesquisa do Estado de Sao Paulo [1998/14247-6]; Fundacion Mexicana para la Salud; St. Jude Children's Research Hospital; Cephalon Europe FX This study was supported by the American Society of Hematology, Fondazione Umberto Veronesi, Roche Saudi Arabia, Fundacao de Apoio a Pesquisa do Estado de Sao Paulo (grant 1998/14247-6), Fundacion Mexicana para la Salud, St. Jude Children's Research Hospital, and Cephalon Europe. NR 44 TC 21 Z9 28 U1 2 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 14 PY 2013 VL 121 IS 11 BP 1935 EP 1943 DI 10.1182/blood-2012-08-449918 PG 9 WC Hematology SC Hematology GA 182PR UT WOS:000321756700009 PM 23319575 ER PT J AU Richardson, PG Siegel, D Baz, R Kelley, SL Munshi, NC Laubach, J Sullivan, D Alsina, M Schlossman, R Ghobrial, IM Doss, D Loughney, N McBride, L Bilotti, E Anand, P Nardelli, L Wear, S Larkins, G Chen, M Zaki, MH Jacques, C Anderson, KC AF Richardson, Paul G. Siegel, David Baz, Rachid Kelley, Susan L. Munshi, Nikhil C. Laubach, Jacob Sullivan, Daniel Alsina, Melissa Schlossman, Robert Ghobrial, Irene M. Doss, Deborah Loughney, Nora McBride, Laura Bilotti, Elizabeth Anand, Palka Nardelli, Lisa Wear, Sandra Larkins, Gail Chen, Min Zaki, Mohamad H. Jacques, Christian Anderson, Kenneth C. TI Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib SO BLOOD LA English DT Article ID PERIPHERAL NEUROPATHY; THALIDOMIDE ANALOGS; THERAPY; CELLS; IMMUNOMODULATION; REVERSIBILITY; SURVIVAL; INHIBIT; CC-4047; IMPACT AB This phase 1 dose-escalation study determined the maximum tolerated dose (MTD) of oral pomalidomide (4 dose levels) administered on days 1 to 21 of each 28-day cycle in patients with relapsed and refractory multiple myeloma (RRMM). After four cycles, patients who progressed or had not achieved minimal response (serum and urine M-protein reduction of >= 25% and >= 50%) could receive dexamethasone 40 mg per week. Safety and efficacy were evaluated. Thirty-eight patients who had received both bortezomib and lenalidomide (median 6 prior therapies) were enrolled; 63% were refractory to both lenalidomide and bortezomib. There were four dose-limiting toxicities (grade 4 neutropenia) at 5 mg per day and so the MTD was 4 mg per day. Rates of peripheral neuropathy and venous thromboembolism were low (<= 5%). Among the 38 patients enrolled (including 22 with added dexamethasone), 42% achieved minimal response or better, 21% achieved partial response or better, and 3% achieved complete response. Median duration of response, progression-free survival, and overall survival were 4.6, 4.6, and 18.3 months, respectively. Pomalidomide 4 mg per day on days 1 to 21 of each 28-day cycle, with or without dexamethasone (40 mg/week), has encouraging activity with manageable toxicity in RRMM, including those refractory to both lenalidomide and bortezomib. C1 [Richardson, Paul G.; Munshi, Nikhil C.; Laubach, Jacob; Schlossman, Robert; Ghobrial, Irene M.; Doss, Deborah; Loughney, Nora; Anderson, Kenneth C.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Siegel, David; McBride, Laura; Bilotti, Elizabeth; Anand, Palka] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Baz, Rachid; Sullivan, Daniel; Alsina, Melissa; Nardelli, Lisa] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Kelley, Susan L.; Wear, Sandra] Multiple Myeloma Res Consortium, Norwalk, CT USA. [Larkins, Gail; Chen, Min; Zaki, Mohamad H.; Jacques, Christian] Celgene Corp, Summit, NJ USA. RP Richardson, PG (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Div Hematol Malignancies, 450 Brookline Ave, Boston, MA 02215 USA. EM Paul_Richardson@dfci.harvard.edu FU Celgene Corporation; Dana-Farber Cancer Institute; John Theuer Cancer Center-Hackensack University Medical Center; H. Lee Moffitt Cancer and Research Institute; Massachusetts General Hospital; Mayo Clinic Arizona; Mayo Clinic Minnesota; Roswell Park Cancer Institute; Ohio State University-James Cancer Hospital; University of Michigan Comprehensive Cancer Center; Washington University-Siteman Cancer Center; St Vincent's Comprehensive Cancer Center; University of Pittsburgh Cancer Institute; Emory University; Princess Margaret Hospital-UHN; Cross Cancer Center; University of Calgary-Tom Baker Cancer Center; Vancouver General Hospital; Diamond Health Care Centre; Royal Victoria Hospital McGill University; Multiple Myeloma Research Consortium FX The authors received editorial support from Adriana Stan, PhD (Excerpta Medica) in the preparation of this manuscript, funded by Celgene Corporation.; We thank the following institutions, which collaborated and supported this study: Dana-Farber Cancer Institute, John Theuer Cancer Center-Hackensack University Medical Center, H. Lee Moffitt Cancer and Research Institute, Massachusetts General Hospital, Mayo Clinic Arizona, Mayo Clinic Minnesota, Roswell Park Cancer Institute, The Ohio State University-James Cancer Hospital, University of Michigan Comprehensive Cancer Center, Washington University-Siteman Cancer Center, St Vincent's Comprehensive Cancer Center, University of Pittsburgh Cancer Institute, Emory University, Princess Margaret Hospital-UHN, Cross Cancer Center, University of Calgary-Tom Baker Cancer Center, Vancouver General Hospital, Diamond Health Care Centre, Royal Victoria Hospital McGill University, Multiple Myeloma Research Consortium, Clinical Research Staff, Celgene Corporation. We also thank our patients and their families. NR 29 TC 85 Z9 89 U1 0 U2 15 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 14 PY 2013 VL 121 IS 11 BP 1961 EP 1967 DI 10.1182/blood-2012-08-450742 PG 7 WC Hematology SC Hematology GA 182PR UT WOS:000321756700012 PM 23243282 ER PT J AU Xu, L Hunter, ZR Yang, G Zhou, YS Cao, Y Liu, X Morra, E Trojani, A Greco, A Arcaini, L Varettoni, M Brown, JR Tai, YT Anderson, KC Munshi, NC Patterson, CJ Manning, RJ Tripsas, CK Lindeman, NI Treon, SP AF Xu, Lian Hunter, Zachary R. Yang, Guang Zhou, Yangsheng Cao, Yang Liu, Xia Morra, Enrica Trojani, Alessandra Greco, Antonino Arcaini, Luca Varettoni, Marzia Brown, Jennifer R. Tai, Yu-Tzu Anderson, Kenneth C. Munshi, Nikhil C. Patterson, Christopher J. Manning, Robert J. Tripsas, Christina K. Lindeman, Neal I. Treon, Steven P. TI MYD88 L265P in Waldenstrom macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction SO BLOOD LA English DT Article ID UNDETERMINED SIGNIFICANCE; FOLLICULAR LYMPHOMA; KAPPA-B; MUTATION; ESTABLISHMENT; EVOLUTION; COMPLEX; GENOME; IRAK1; LINE AB By whole-genome and/or Sanger sequencing, we recently identified a somatic mutation (MYD88 L265P) that stimulates nuclear factor kappa B activity and is present in >90% of Waldenstrom macroglobulinemia (WM) patients. MYD88 L265P was absent in 90% of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) patients. We therefore developed conventional and real-time allele-specific polymerase chain reaction (AS-PCR) assays for more sensitive detection and quantification of MYD88 L265P. Using either assay, MYD88 L265P was detected in 97 of 104 (93%) WM and 13 of 24 (54%) IgM MGUS patients and was either absent or rarely expressed in samples from splenic marginal zone lymphoma (2/20; 10%), CLL (1/26; 4%), multiple myeloma (including IgM cases, 0/14), and immunoglobulin G MGUS (0/9) patients as well as healthy donors (0/40; P < 1.5 x 10(-5) for WM vs other cohorts). Real-time AS-PCR identified IgM MGUS patients progressing to WM and showed a high rate of concordance between MYD88 L265P Delta C-T and BM disease involvement (r = 0.89, P = .008) in WM patients undergoing treatment. These studies identify MYD88 L265P as a widely present mutation in WM and IgM MGUS patients using highly sensitive and specific AS-PCR assays with potential use in diagnostic discrimination and/or response assessment. The finding of this mutation in many IgM MGUS patients suggests that MYD88 L265P may be an early oncogenic event in WM pathogenesis. C1 [Xu, Lian; Hunter, Zachary R.; Yang, Guang; Zhou, Yangsheng; Cao, Yang; Liu, Xia; Patterson, Christopher J.; Manning, Robert J.; Tripsas, Christina K.; Treon, Steven P.] Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02215 USA. [Xu, Lian; Hunter, Zachary R.; Yang, Guang; Zhou, Yangsheng; Cao, Yang; Liu, Xia; Tai, Yu-Tzu; Anderson, Kenneth C.; Munshi, Nikhil C.; Lindeman, Neal I.; Treon, Steven P.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Morra, Enrica; Trojani, Alessandra; Greco, Antonino] Osped Niguarda Ca Granda, Div Hematol, Milan, Italy. [Arcaini, Luca; Varettoni, Marzia] Univ Pavia, Sch Med, Dept Hematol Oncol, I-27100 Pavia, Italy. [Arcaini, Luca; Varettoni, Marzia] Policlin San Matteo, Fdn Ist Ricovero & Cura Carattere Sci, I-27100 Pavia, Italy. [Brown, Jennifer R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Tai, Yu-Tzu; Anderson, Kenneth C.; Munshi, Nikhil C.] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02215 USA. [Lindeman, Neal I.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Treon, SP (reprint author), Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, M547,45 Brookline Ave, Boston, MA 02215 USA. EM steven_treon@dfci.harvard.edu RI Arcaini, Luca/P-8913-2015; OI Arcaini, Luca/0000-0002-9504-991X; Hunter, Zachary/0000-0002-1689-1691 FU Peter and Helen Bing Foundation; Coyote Fund for WM; International Waldenstrom's Macroglobulinemia Foundation; Waldenstrom's Cancer Fund; Bailey Family Fund for WM; D'Amato Family Fund for Genomic Discovery; Edward and Linda Nelson Fund for WM Research; Bauman Family Trust; Tannenhauser Family Foundation FX This study was supported by the Peter and Helen Bing Foundation, the Coyote Fund for WM, the International Waldenstrom's Macroglobulinemia Foundation, the Waldenstrom's Cancer Fund, the Bailey Family Fund for WM, the D'Amato Family Fund for Genomic Discovery, the Edward and Linda Nelson Fund for WM Research, the Bauman Family Trust, and the Tannenhauser Family Foundation. NR 30 TC 106 Z9 110 U1 1 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 14 PY 2013 VL 121 IS 11 BP 2051 EP 2058 DI 10.1182/blood-2012-09-454355 PG 8 WC Hematology SC Hematology GA 182PR UT WOS:000321756700022 PM 23321251 ER PT J AU Qin, LL Zhao, DZ Xu, JF Ren, XH Terwilliger, EF Parangi, S Lawler, J Dvorak, HF Zeng, HY AF Qin, Liuliang Zhao, Dezheng Xu, Jianfeng Ren, Xianghui Terwilliger, Ernest F. Parangi, Sareh Lawler, Jack Dvorak, Harold F. Zeng, Huiyan TI The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through thrombospondin-1 SO BLOOD LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; NITRIC-OXIDE SYNTHASE; MAST-CELL HISTAMINE; TUMOR-GROWTH; VEGF-A; RECEPTOR; CANCER; INFLAMMATION; EXPRESSION; TISSUE AB Angiogenesis plays an important role in cancer and in many other human diseases. Vascular endothelial growth factor-A (VEGF-A), the best known angiogenic factor, was originally discovered as a potent vascular permeability factor (VPF), suggesting that other vascular permeabilizing agents, such as histamine and serotonin, might also have angiogenic activity. We recently demonstrated that, like VEGF-A, histamine and serotonin up-regulate the orphan nuclear receptor and transcription factor TR3 (mouse homolog Nur77) and that TR3/Nur77 is essential for their vascular permeabilizing activities. We now report that histamine and serotonin are also angiogenic factors that, at low micromolar concentrations, induce endothelial cell proliferation, migration and tube formation in vitro, and angiogenesis in vivo. All of these responses are mediated through specific histamine and serotonin receptors, are independent of VEGF-A, and are directly dependent on TR3/Nur77. Initially, the angiogenic response closely resembled that induced by VEGF-A, with generation of "mother" vessels. However, after similar to 10 days, mother vessels began to regress as histamine and serotonin, unlike VEGF-A, up-regulated the potent angiogenesis inhibitor thrombospondin-1, thereby triggering a negative feedback loop. Thus, histamine and serotonin induce an angiogenic response that fits the time scale of acute inflammation. C1 [Qin, Liuliang; Lawler, Jack; Dvorak, Harold F.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Zhao, Dezheng] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gastroenterol,Dept Med, Boston, MA 02215 USA. [Zhao, Dezheng; Lawler, Jack; Dvorak, Harold F.; Zeng, Huiyan] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Vasc Biol Res Ctr, Boston, MA 02215 USA. [Xu, Jianfeng; Ren, Xianghui; Terwilliger, Ernest F.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Expt Med,Dept Med, Boston, MA 02215 USA. [Parangi, Sareh] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Zeng, Huiyan] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Mol & Vasc Biol,Dept Med, Boston, MA 02215 USA. RP Zeng, HY (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Mol & Vasc Biol, 99 Brookline Ave RN 270F, Boston, MA 02215 USA. EM hzeng@caregroup.harvard.edu FU National Institutes of Health [K01 CA098581, R01CA133235, CA-142262, P01 CA-92644]; National Foundation for Cancer Research; [CA-130895]; [NS071197] FX This study was supported in part by research funding from National Institutes of Health grants K01 CA098581 and R01CA133235 (H.Z.); CA-142262, P01 CA-92644, and a contract from the National Foundation for Cancer Research (H. F. D.); and CA-130895 and NS071197 (J.L.). NR 42 TC 20 Z9 20 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 14 PY 2013 VL 121 IS 11 BP 2154 EP 2164 DI 10.1182/blood-2012-07-443903 PG 11 WC Hematology SC Hematology GA 182PR UT WOS:000321756700035 PM 23315169 ER PT J AU Bested, AC Logan, AC Selhub, EM AF Bested, Alison C. Logan, Alan C. Selhub, Eva M. TI Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part II - contemporary contextual research SO GUT PATHOGENS LA English DT Review DE Intestinal microbiota; Autointoxication; Depression; Anxiety; Probiotics; Microbial ecology; Lipopolysaccharide endotoxin; Diet; Intestinal permeability; Microbial ecosystems ID IRRITABLE-BOWEL-SYNDROME; CHRONIC-FATIGUE-SYNDROME; HIGH-FAT-DIET; LACTOBACILLUS-PLANTARUM 299V; JUNCTION PROTEIN EXPRESSION; AUTISM SPECTRUM DISORDERS; HUMAN FECAL MICROBIOTA; GUT MICROBIOTA; BACTERIAL OVERGROWTH; MAJOR DEPRESSION AB In recent years there has been a renewed interest concerning the ways in which the gastrointestinal tract - its functional integrity and microbial residents - might influence human mood (e.g. depression) and behavioral disorders. Once a hotbed of scientific interest in the early 20th century, this area lay dormant for decades, in part due to its association with the controversial term 'autointoxication'. Here we review contemporary findings related to intestinal permeability, small intestinal bacterial overgrowth, lipopolysaccharide endotoxin (LPS) exposure, D-lactic acid, propionic acid, and discuss their relevance to microbiota and mental health. In addition, we include the context of modern dietary habits as they relate to depression, anxiety and their potential interaction with intestinal microbiota. C1 [Bested, Alison C.] BC Womens Hosp & Hlth Ctr, Complex Chron Dis Program, Vancouver, BC V6H 3N1, Canada. [Logan, Alan C.] CAMNR, Mill Valley, CA 94941 USA. [Selhub, Eva M.] Harvard Univ, Sch Med, Waltham, MA 02453 USA. [Selhub, Eva M.] Massachusetts Gen Hosp, Waltham, MA 02453 USA. RP Logan, AC (reprint author), CAMNR, 775 Blithedale Ave,Suite 364, Mill Valley, CA 94941 USA. EM aclnd@cfs-fm.org FU Genuine Health, Toronto, Canada FX ACB and EMS have no competing interests. ACL has received consulting fees from Genuine Health, Toronto, Canada. NR 202 TC 21 Z9 22 U1 1 U2 75 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-4749 J9 GUT PATHOG JI Gut Pathogens PD MAR 14 PY 2013 VL 5 AR 3 DI 10.1186/1757-4749-5-3 PG 14 WC Gastroenterology & Hepatology; Microbiology SC Gastroenterology & Hepatology; Microbiology GA 118GP UT WOS:000317013100001 PM 23497633 ER PT J AU Morancho, B Parra-Palau, JL Ibrahim, YH Morales, CB Peg, V Bech-Serra, JJ Pandiella, A Canals, F Baselga, J Rubio, I Arribas, J AF Morancho, B. Parra-Palau, J. L. Ibrahim, Y. H. Bernado Morales, C. Peg, V. Bech-Serra, J. J. Pandiella, A. Canals, F. Baselga, J. Rubio, I. Arribas, J. TI A dominant-negative N-terminal fragment of HER2 frequently expressed in breast cancers SO ONCOGENE LA English DT Article DE HER2; ErbB2; breast cancer ID RECEPTOR; CLEAVAGE; ERBB-2; GELDANAMYCIN; IDENTIFICATION; TRASTUZUMAB; DEGRADATION; EFFECTOR; P95HER2; GROWTH AB The transmembrane tyrosine kinase HER2 (ErbB2, neu) is a prototypical biomarker for breast cancers and a therapeutic target. Although anti-HER2 therapies are remarkably effective, HER2-positive tumors are heterogeneous and some subtypes do not respond or develop resistance to these therapies. Here we show that H2NTF, a novel N-terminal fragment of HER2, is expressed at variable levels in 60% of the breast cancer samples analyzed. Characterization of H2NTF shows that it is devoid of the tyrosine kinase domain but it readily interacts with full-length HER2 and other HER receptors. As a consequence, H2NTF acts as a dominant-negative, attenuating the signaling triggered by full-length HER receptors. Expression of H2NTF results in resistance to the treatment with low concentrations of trastuzumab in vitro. However, cells expressing H2NTF and non-expressing cells have similar sensitivity to trastuzumab in vivo, indicating that H2NTF/trastuzumab complexes trigger antibody-dependent cell-mediated cytotoxicity. Oncogene (2013) 32, 1452-1459; doi:10.1038/onc.2012.152; published online 28 May 2012 C1 [Morancho, B.; Parra-Palau, J. L.; Ibrahim, Y. H.; Bernado Morales, C.; Bech-Serra, J. J.; Canals, F.; Baselga, J.; Arribas, J.] Vall dHebron Inst Oncol VHIO, Preclin Res Program, Barcelona 08035, Spain. [Peg, V.] Univ Autonoma Barcelona, Vall dHebron Univ Hosp, Dept Pathol, Bellaterra, Spain. [Peg, V.] Univ Autonoma Barcelona, Dept Morphol Sci, Bellaterra, Spain. [Pandiella, A.] Univ Salamanca, CSIC, Inst Biol Mol Celular & Celular Canc, E-37008 Salamanca, Spain. [Baselga, J.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. [Rubio, I.] Vall dHebron Univ Hosp, Breast Canc Ctr, Barcelona, Spain. [Arribas, J.] Univ Autonoma Barcelona, Dept Biochem & Mol Biol, Bellaterra, Spain. [Arribas, J.] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain. RP Arribas, J (reprint author), Vall dHebron Inst Oncol VHIO, Preclin Res Program, Psg Vall dHebron 119-129, Barcelona 08035, Spain. EM jarribas@vhio.net RI Arribas, Joaquin/M-4482-2014; Pandiella, Atanasio/O-5180-2014; OI Arribas, Joaquin/0000-0002-0504-0664; Pandiella, Atanasio/0000-0002-4704-8971; Peg, Vicente/0000-0002-5203-6166 FU Instituto de Salud Carlos III (Intrasalud) [PI081154, PI11/02496]; Instituto de Salud Carlos III (network of cooperative cancer research) [RTICC-RD06/0020/0022, RTICC-RD06/0020/0041]; GlaxoSmithKline; Breast Cancer Research Foundation (BCRF) FX This work was supported by Instituto de Salud Carlos III (Intrasalud PI081154, PI11/02496 and the network of cooperative cancer research (RTICC-RD06/0020/0022 and RTICC-RD06/0020/0041)), GlaxoSmithKline and the Breast Cancer Research Foundation (BCRF). NR 23 TC 4 Z9 4 U1 2 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 14 PY 2013 VL 32 IS 11 BP 1452 EP 1459 DI 10.1038/onc.2012.152 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 110OZ UT WOS:000316455600011 PM 22641219 ER PT J AU Suidan, GL Duerschmied, D Dillon, GM Vanderhorst, V Hampton, TG Wong, SL Voorhees, JR Wagner, DD AF Suidan, Georgette L. Duerschmied, Daniel Dillon, Gregory M. Vanderhorst, Veronique Hampton, Thomas G. Wong, Siu Ling Voorhees, Jaymie R. Wagner, Denisa D. TI Lack of Tryptophan Hydroxylase-1 in Mice Results in Gait Abnormalities SO PLOS ONE LA English DT Article ID SEROTONIN(1A) RECEPTOR; DEFICIENT MICE; NEONATAL-RAT; ANXIETY; DYNAMICS; BEHAVIOR; ATTENTION; DISORDER; MODEL; BRAIN AB The role of peripheral serotonin in nervous system development is poorly understood. Tryptophan hydroxylase-1 (TPH1) is expressed by non-neuronal cells including enterochromaffin cells of the gut, mast cells and the pineal gland and is the rate-limiting enzyme involved in the biosynthesis of peripheral serotonin. Serotonin released into circulation is taken up by platelets via the serotonin transporter and stored in dense granules. It has been previously reported that mouse embryos removed from Tph1-deficient mothers present abnormal nervous system morphology. The goal of this study was to assess whether Tph1-deficiency results in behavioral abnormalities. We did not find any differences between Tph1-deficient and wild-type mice in general motor behavior as tested by rotarod, grip-strength test, open field and beam walk. However, here we report that Tph1 (-/-) mice display altered gait dynamics and deficits in rearing behavior compared to wild-type (WT) suggesting that tryptophan hydroxylase-1 expression has an impact on the nervous system. C1 [Suidan, Georgette L.; Duerschmied, Daniel; Wong, Siu Ling; Voorhees, Jaymie R.; Wagner, Denisa D.] Immune Dis Inst, Boston, MA USA. [Suidan, Georgette L.; Duerschmied, Daniel; Wong, Siu Ling; Voorhees, Jaymie R.; Wagner, Denisa D.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Wagner, Denisa D.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Suidan, Georgette L.; Duerschmied, Daniel; Wong, Siu Ling; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Duerschmied, Daniel] Univ Heart Ctr Freiburg Bad Krozingen, Dept Cardiol & Angiol 1, Freiburg, Germany. [Dillon, Gregory M.] Harvard NeuroDiscovery Ctr, Neurobehav Lab, Boston, MA USA. [Dillon, Gregory M.; Vanderhorst, Veronique] Harvard Univ, Sch Med, Boston, MA USA. [Vanderhorst, Veronique] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Hampton, Thomas G.] Neurosci Discovery Core, Framingham, MA USA. RP Wagner, DD (reprint author), Immune Dis Inst, Boston, MA USA. EM Denisa.Wagner@childrens.harvard.edu FU National Heart, Lung and Blood Institute of the National Institutes of Health [R01 HL041002]; National Research Service Award from the National Institutes of Neurological Disease and Stroke of the National Institutes of Health [1F32NS073245] FX This work was generously supported by National Heart, Lung and Blood Institute of the National Institutes of Health grant R01 HL041002 (to DDW) and a National Research Service Award from the National Institutes of Neurological Disease and Stroke of the National Institutes of Health grant 1F32NS073245 (to GLS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 4 Z9 4 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 14 PY 2013 VL 8 IS 3 AR e59032 DI 10.1371/journal.pone.0059032 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109YM UT WOS:000316407400088 PM 23516593 ER PT J AU Lee, JT Bartolomei, MS AF Lee, Jeannie T. Bartolomei, Marisa S. TI X-Inactivation, Imprinting, and Long Noncoding RNAs in Health and Disease SO CELL LA English DT Review ID PLURIPOTENT STEM-CELLS; EARLY MOUSE EMBRYOS; FACULTATIVE HETEROCHROMATIN FORMATION; ASSISTED REPRODUCTIVE TECHNOLOGY; BECKWITH-WIEDEMANN-SYNDROME; CHROMOSOME INACTIVATION; XIST RNA; DOSAGE COMPENSATION; PREIMPLANTATION DEVELOPMENT; CHROMATIN-STRUCTURE AB X chromosome inactivation and genomic imprinting are classic epigenetic processes that cause disease when not appropriately regulated in mammals. Whereas X chromosome inactivation evolved to solve the problem of gene dosage, the purpose of genomic imprinting remains controversial. Nevertheless, the two phenomena are united by allelic control of large gene clusters, such that only one copy of a gene is expressed in every cell. Allelic regulation poses significant challenges because it requires coordinated long-range control in cis and stable propagation over time. Long noncoding RNAs have emerged as a common theme, and their contributions to diseases of imprinting and the X chromosome have become apparent. Here, we review recent advances in basic biology, the connections to disease, and preview potential therapeutic strategies for future development. C1 [Lee, Jeannie T.] Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, Boston, MA 02114 USA. [Lee, Jeannie T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Bartolomei, Marisa S.] Univ Penn, Perelman Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. RP Lee, JT (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, Boston, MA 02114 USA. EM lee@molbio.mgh.harvard.edu; bartolom@mail.med.upenn.edu FU National Institutes of Health; Howard Hughes Medical Institute FX We thank the Lee and Bartolomei labs for many inspirational discussions, and the National Institutes of Health and the Howard Hughes Medical Institute for supporting their research. NR 152 TC 232 Z9 243 U1 14 U2 117 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 MAR 14 PY 2013 VL 152 IS 6 BP 1308 EP 1323 DI 10.1016/j.cell.2013.02.016 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 107CO UT WOS:000316192500012 PM 23498939 ER PT J AU Price, BD D'Andrea, AD AF Price, Brendan D. D'Andrea, Alan D. TI Chromatin Remodeling at DNA Double-Strand Breaks SO CELL LA English DT Review ID HISTONE H2AX PHOSPHORYLATION; DAMAGE RESPONSE; HOMOLOGOUS RECOMBINATION; KAP-1 PHOSPHORYLATION; H4-K16 ACETYLATION; GENOME INTEGRITY; REPAIR PROTEINS; END RESECTION; FACTOR CHD4; NUCLEOSOME AB DNA double-strand breaks (DSBs) can arise from multiple sources, including exposure to ionizing radiation. The repair of DSBs involves both posttranslational modification of nucleosomes and concentration of DNA-repair proteins at the site of damage. Consequently, nucleosome packing and chromatin architecture surrounding the DSB may limit the ability of the DNA-damage response to access and repair the break. Here, we review early chromatin-based events that promote the formation of open, relaxed chromatin structures at DSBs and that allow the DNA-repair machinery to access the spatially confined region surrounding the DSB, thereby facilitating mammalian DSB repair. C1 [Price, Brendan D.; D'Andrea, Alan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol,Div Genom Stabil & DNA Repair, Boston, MA 02215 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol,Div Genom Stabil & DNA Repair, 450 Brookline Ave, Boston, MA 02215 USA. EM alan_dandrea@dfci.harvard.edu FU NIH [CA64585, CA93602, RO1-DK43889] FX This work was supported by NIH grants CA64585 and CA93602 to B.D.P. and grant RO1-DK43889 to A.D.D. NR 100 TC 146 Z9 149 U1 6 U2 97 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 MAR 14 PY 2013 VL 152 IS 6 BP 1344 EP 1354 DI 10.1016/j.cell.2013.02.011 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 107CO UT WOS:000316192500014 PM 23498941 ER PT J AU Morrow, M Winograd, JM Freer, PE Eichhorn, JH AF Morrow, Monica Winograd, Jonathan M. Freer, Phoebe E. Eichhorn, John H. TI Case 8-2013: A 48-Year-Old Woman with Carcinoma In Situ of the Breast Ductal carcinoma in situ of the breast SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACELLULAR DERMAL MATRIX; SKIN-SPARING MASTECTOMY; CONTRALATERAL PROPHYLACTIC MASTECTOMY; RANDOMIZED CONTROLLED-TRIAL; LOCAL RECURRENCE; CANCER; RECONSTRUCTION; TOMOSYNTHESIS; RADIOTHERAPY; WOMEN C1 [Morrow, Monica] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Morrow, Monica] Weill Cornell Med Coll, Dept Surg, New York, NY USA. [Winograd, Jonathan M.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Freer, Phoebe E.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Eichhorn, John H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Winograd, Jonathan M.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Freer, Phoebe E.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Eichhorn, John H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Morrow, M (reprint author), Mem Sloan Kettering Canc Ctr, Dept Surg, 1275 York Ave, New York, NY 10021 USA. NR 40 TC 2 Z9 2 U1 0 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 14 PY 2013 VL 368 IS 11 BP 1046 EP 1053 DI 10.1056/NEJMcpc1214221 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 104HF UT WOS:000315982100012 PM 23484832 ER PT J AU Moslehi, J AF Moslehi, Javid TI The Cardiovascular Perils of Cancer Survivorship SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID EARLY BREAST-CANCER; THERAPY C1 [Moslehi, Javid] Brigham & Womens Hosp, Watkins Clin, Dana Farber Canc Inst, Cardiooncol Program, Boston, MA 02115 USA. [Moslehi, Javid] Harvard Univ, Sch Med, Boston, MA USA. RP Moslehi, J (reprint author), Brigham & Womens Hosp, Watkins Clin, Dana Farber Canc Inst, Cardiooncol Program, 75 Francis St, Boston, MA 02115 USA. NR 10 TC 13 Z9 13 U1 0 U2 9 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 14 PY 2013 VL 368 IS 11 BP 1055 EP 1056 DI 10.1056/NEJMe1215300 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 104HF UT WOS:000315982100013 PM 23484833 ER PT J AU Mitnick, CD Franke, MF Rich, ML Viru, FAA Appleton, SC Atwood, SS Bayona, JN Bonilla, CA Chalco, K Fraser, HSF Furin, JJ Guerra, D Hurtado, RM Joseph, K Llaro, K Mestanza, L Mukherjee, JS Munoz, M Palacios, E Sanchez, E Seung, KJ Shin, SS Sloutsky, A Tolman, AW Becerra, MC AF Mitnick, Carole D. Franke, Molly F. Rich, Michael L. Alcantara Viru, Felix A. Appleton, Sasha C. Atwood, Sidney S. Bayona, Jaime N. Bonilla, Cesar A. Chalco, Katiuska Fraser, Hamish S. F. Furin, Jennifer J. Guerra, Dalia Hurtado, Rocio M. Joseph, Keith Llaro, Karim Mestanza, Lorena Mukherjee, Joia S. Munoz, Maribel Palacios, Eda Sanchez, Epifanio Seung, Kwonjune J. Shin, Sonya S. Sloutsky, Alexander Tolman, Arielle W. Becerra, Mercedes C. TI Aggressive Regimens for Multidrug-Resistant Tuberculosis Decrease All-Cause Mortality SO PLOS ONE LA English DT Article ID MDR-TB; MYCOBACTERIUM-TUBERCULOSIS; TREATMENT OUTCOMES; STANDARDIZED TREATMENT; THERAPY; PERU; TIME; LIMA; FLUOROQUINOLONES; METAANALYSIS AB Rationale: A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB) is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen. Objectives: This study assessed the impact of an aggressive regimen-one containing at least five likely effective drugs, including a fluoroquinolone and injectable-on treatment outcomes in a large MDR-TB patient cohort. Methods: This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death. Measurements and Main Results: In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7) drugs. Cure or completion was achieved in 66.1% (442) of patients; death occurred in 20.8% (139). Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89), compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93). Conclusions: The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB. C1 [Mitnick, Carole D.; Franke, Molly F.; Mukherjee, Joia S.; Tolman, Arielle W.; Becerra, Mercedes C.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA 02215 USA. [Mitnick, Carole D.; Franke, Molly F.; Rich, Michael L.; Appleton, Sasha C.; Bayona, Jaime N.; Fraser, Hamish S. F.; Joseph, Keith; Mukherjee, Joia S.; Seung, Kwonjune J.; Shin, Sonya S.; Becerra, Mercedes C.] Partners Hlth, Boston, MA USA. [Mitnick, Carole D.; Rich, Michael L.; Atwood, Sidney S.; Fraser, Hamish S. F.; Joseph, Keith; Mukherjee, Joia S.; Seung, Kwonjune J.; Shin, Sonya S.; Becerra, Mercedes C.] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. [Alcantara Viru, Felix A.; Bayona, Jaime N.; Chalco, Katiuska; Guerra, Dalia; Llaro, Karim; Mestanza, Lorena; Munoz, Maribel; Palacios, Eda] Socios Salud Sucursal Peru, Lima, Peru. [Bonilla, Cesar A.] Minist Hlth, Lima, Peru. [Furin, Jennifer J.] Case Western Reserve Univ, TB Res Unit, Cleveland, OH 44106 USA. [Hurtado, Rocio M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hurtado, Rocio M.] Global Hlth Comm, Boston, MA USA. [Sanchez, Epifanio] Hosp Nacl Sergio E Bernales, Lima, Peru. [Sloutsky, Alexander] Ctr Hlth Policy & Res, Massachusetts Supranat TB Reference Lab, Boston, MA USA. RP Mitnick, CD (reprint author), Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA 02215 USA. EM carole_mitnick@hms.harvard.edu RI Fraser, Hamish/E-3773-2013 FU National Institute of Allergy and Infectious Diseases [1 K01 AI065836-01] FX This work was supported by the National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov/Pages/default.aspx) (1 K01 AI065836-01 to CDM). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 30 Z9 30 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 13 PY 2013 VL 8 IS 3 AR e58664 DI 10.1371/journal.pone.0058664 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 115YY UT WOS:000316849200103 PM 23516529 ER PT J AU Wong, ES Liu, CF AF Wong, Edwin S. Liu, Chuan-Fen TI The relationship between local area labor market conditions and the use of Veterans Affairs health services SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Health services; Utilization; Veterans; Socioeconomic factors ID QUALITY-OF-CARE; BEHAVIORAL-MODEL; MEDICAL-CARE; SYSTEM; ACCESS; VA; ALCOHOL; TRENDS AB Background: In the U.S., economic conditions are intertwined with labor market decisions, access to health care, health care utilization and health outcomes. The Veterans Affairs (VA) health care system has served as a safety net provider by supplying free or reduced cost care to qualifying veterans. This study examines whether local area labor market conditions, measured using county-level unemployment rates, influence whether veterans obtain health care from the VA. Methods: We used survey data from the Behavioral Risk Factor Surveillance System in years 2000, 2003 and 2004 to construct a random sample of 73,964 respondents self-identified as veterans. VA health service utilization was defined as whether veterans received all, some or no care from the VA. Hierarchical ordered logistic regression was used to address unobserved state and county random effects while adjusting for individual characteristics. Local area labor market conditions were defined as the average 12-month unemployment rate in veterans' county of residence. Results: The mean unemployment rate for veterans receiving all, some and no care was 5.56%, 5.37% and 5.24%, respectively. After covariate adjustment, a one percentage point increase in the unemployment rate in a veteran's county of residence was associated with an increase in the probability of receiving all care (0.34%, p-value = 0.056) or some care (0.29%, p-value = 0.023) from the VA. Conclusions: Our findings suggest that the important role of the VA in providing health care services to veterans is magnified in locations with high unemployment. C1 [Wong, Edwin S.; Liu, Chuan-Fen] VA Puget Sound Hlth Care Syst, Northwest Ctr Outcomes Res Older Adults, Seattle, WA 98101 USA. [Wong, Edwin S.; Liu, Chuan-Fen] Univ Washington, Sch Publ Hlth & Community Med, Dept Hlth Serv, Seattle, WA 98195 USA. RP Wong, ES (reprint author), VA Puget Sound Hlth Care Syst, Northwest Ctr Outcomes Res Older Adults, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM edwin.wong@va.gov FU VA Health Services Research and Development Postdoctoral Fellowship [TPP 61-024] FX Dr. Wong is supported by VA Health Services Research and Development Postdoctoral Fellowship TPP 61-024. 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 and the University of Washington. NR 41 TC 0 Z9 0 U1 2 U2 4 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 MAR 13 PY 2013 VL 13 AR 96 DI 10.1186/1472-6963-13-96 PG 10 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 119QI UT WOS:000317112000001 ER PT J AU Cassol, E Cassetta, L Rizzi, C Gabuzda, D Alfano, M Poli, G AF Cassol, Edana Cassetta, Luca Rizzi, Chiara Gabuzda, Dana Alfano, Massimo Poli, Guido TI Dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin mediates HIV-1 infection of and transmission by M2a-polarized macrophages in vitro SO AIDS LA English DT Article DE dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin; HIV transmission; HIV-1; macrophage polarization; T cells ID HUMAN-IMMUNODEFICIENCY-VIRUS; MONOCYTE-DERIVED MACROPHAGES; DC-SIGN; VERTICAL TRANSMISSION; INDUCED EXPRESSION; GENE-EXPRESSION; TYPE-1 HIV-1; T-CELLS; POLARIZATION; TROPISM AB Objective: To assess in-vitro effects of monocyte-derived macrophage (MDM) polarization into M1 and M2a cells on HIV-1 replication and transmission and obtain new insights into the potential importance of macrophage polarization in vivo. Design: Human peripheral blood monocytes were differentiated into MDM for 7 days. Control and MDM polarized into M1 or M2a cells were exposed to different strains of HIV-1 and assessed for their ability to bind and transmit virus to CD4(+) T lymphocytes. Methods: MDM were incubated with either tumour necrosis factor-alpha (TNF-alpha) along with interferon-gamma (IFN-gamma) or with interleukin-4 (IL-4) for 18 h to obtain M1 or M2a cells, respectively. Expression of cell surface antigens, including CD4 and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN), was evaluated by flow cytometry. C-C chemokine receptor type 5 (CCR5)-dependent (R5) HIV-1 binding, DNA synthesis and viral replication were assessed in the presence or absence of anti-DC-SIGN blocking mAbs. Transmission of C-X-C chemokine receptor type 4 (CXCR4)-dependent (X4) and R5 HIV-1 from MDM to IL-2 activated CD4(+) T cells was also investigated. Results: DC-SIGN was strongly upregulated on M2a-MDM and downregulated on M1-MDM compared with control MDM. DC-SIGN facilitated HIV-1 entry and DNA synthesis in M2a-MDM, compensating for their low levels of CD4 cell expression. M2a-MDM efficiently transmitted both R5 and X4 HIV-1 to CD4(+) T cells in a DC-SIGN-dependent manner. Conclusion: DC-SIGN facilitates HIV-1 infection of M2a-MDM, and HIV-1 transfer from M2a-MDM to CD4(+) T cells. M2a-polarized tissue macrophages may play an important role in the capture and spread of HIV-1 in mucosal tissues and placenta. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins AIDS 2013, 27:707-716 C1 [Cassol, Edana; Cassetta, Luca; Rizzi, Chiara; Alfano, Massimo; Poli, Guido] Ist Sci San Raffaele, Div Immunol Transplantat & Infect Dis, AIDS Immunopathogenesis Unit, I-20132 Milan, Italy. [Cassol, Edana; Cassetta, Luca; Poli, Guido] Univ Vita Salute San Raffaele, Sch Med, Milan, Italy. [Cassol, Edana; Gabuzda, Dana] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Cassol, E (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. EM edana_cassol@dfci.harvard.edu FU Fondation Dormeur; Europrise [LSHP CT-2006-037611]; Italian Ministry of Health Grant Program of AIDS Research; CIHR fellowship; NIH [R01 MH83588] FX This study was supported in part by the Fondation Dormeur, by Europrise (grant no. LSHP CT-2006-037611 to G.P.) and by the Italian Ministry of Health Grant Program of AIDS Research 2009-2010 (to M.A. and G.P.). E.C. was supported in part by a CIHR fellowship. D.G. was supported by NIH R01 MH83588. NR 42 TC 5 Z9 6 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAR 13 PY 2013 VL 27 IS 5 BP 707 EP 716 DI 10.1097/QAD.0b013e32835cfc82 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 098CY UT WOS:000315524700004 PM 23211775 ER PT J AU Perederiy, JV Luikart, BW Washburn, EK Schnell, E Westbrook, GL AF Perederiy, Julia V. Luikart, Bryan W. Washburn, Eric K. Schnell, Eric Westbrook, Gary L. TI Neural Injury Alters Proliferation and Integration of Adult-Generated Neurons in the Dentate Gyrus SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ENTORHINAL CORTEX LESION; ELECTRON-MICROSCOPIC ANALYSIS; TRAUMATIC BRAIN-INJURY; CENTRAL-NERVOUS-SYSTEM; RAT FASCIA-DENTATA; GRANULE CELLS; HIPPOCAMPAL NEUROGENESIS; INDUCED SYNAPTOGENESIS; VESICULAR GLUTAMATE; RECEPTOR ACTIVATION AB Neural plasticity following brain injury illustrates the potential for regeneration in the central nervous system. Lesioning of the perforant path, which innervates the outer two-thirds of the molecular layer of the dentate gyrus, was one of the first models to demonstrate structural plasticity of mature granule cells (Parnavelas et al., 1974; Caceres and Steward, 1983; Diekmann et al., 1996). The dentate gyrus also harbors a continuously proliferating population of neuronal precursors that can integrate into functional circuits and show enhanced short-term plasticity (Schmidt-Hieber et al., 2004; Abrous et al., 2005). To examine the response of adult-generated granule cells to unilateral complete transection of the perforant path in vivo, we tracked these cells using transgenic POMC-EGFP mice or by retroviral expression of GFP. Lesioning triggered a marked proliferation of newborn neurons. Subsequently, the dendrites of newborn neurons showed reduced complexity within the denervated zone, but dendritic spines still formed in the absence of glutamatergic nerve terminals. Electron micrographs confirmed the lack of intact presynaptic terminals apposing spines on mature cells and on newborn neurons. Newborn neurons, but not mature granule cells, had a higher density of dendritic spines in the inner molecular layer postlesion accompanied by an increase in miniature EPSC amplitudes and rise times. Our results indicate that injury causes an increase in newborn neurons and lamina-specific synaptic reorganization indicative of enhanced plasticity. The presence of de novo dendritic spines in the denervated zone suggests that the postlesion environment provides the necessary signals for spine formation. C1 [Perederiy, Julia V.; Luikart, Bryan W.; Washburn, Eric K.; Westbrook, Gary L.] OHSU, Vollum Inst, Portland, OR 97239 USA. [Schnell, Eric] Portland VA Med Ctr, Portland, OR 97239 USA. [Schnell, Eric] OHSU Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. RP Perederiy, JV (reprint author), OHSU, Vollum Inst, L474,3181 Southwest Sam Jackson Pk Rd, Portland, OR 97239 USA. EM perederi@ohsu.edu OI Schnell, Eric/0000-0002-5623-5015 FU NIH [MH46613, P30 NS06180]; Oregon Partnership for Alzheimer's Research Tax Check-Off Grant FX This work was supported by NIH Grant MH46613 and by Oregon Partnership for Alzheimer's Research Tax Check-Off Grant. We thank Oswald Steward for training in the perforant path lesion procedure. We thank Stephanie Kaech-Petrie with the Jungers Center Microscopy Core for assistance with imaging parameters and Sue Aicher, Melissa Williams, Lisa Dirling, and Robert Kayton with the Electron Microscopy Core for tissue preparation and assistance with imaging equipment (supported by NIH Grant P30 NS06180). NR 82 TC 15 Z9 15 U1 0 U2 9 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 MAR 13 PY 2013 VL 33 IS 11 BP 4754 EP 4767 DI 10.1523/JNEUROSCI.4785-12.2013 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 106CO UT WOS:000316119200011 PM 23486947 ER PT J AU Clair, C Rigotti, NA Porneala, B Fox, CS D'Agostino, RB Pencina, MJ Meigs, JB AF Clair, Carole Rigotti, Nancy A. Porneala, Bianca Fox, Caroline S. D'Agostino, Ralph B., Sr. Pencina, Michael J. Meigs, James B. TI Association of Smoking Cessation and Weight Change With Cardiovascular Disease Among Adults With and Without Diabetes SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; CORONARY-HEART-DISEASE; CIGARETTE-SMOKING; UNITED-STATES; RISK-FACTORS; MORTALITY; MELLITUS; WOMEN; POPULATION; OUTCOMES AB Importance Smoking cessation reduces the risks of cardiovascular disease (CVD), but weight gain that follows quitting smoking may weaken the CVD benefit of quitting. Objective To test the hypothesis that weight gain following smoking cessation does not attenuate the benefits of smoking cessation among adults with and without diabetes. Design, Setting, and Participants Prospective community-based cohort study using data from the Framingham Offspring Study collected from 1984 through 2011. At each 4-year examination, self-reported smoking status was assessed and categorized as smoker, recent quitter (-4 years), long-term quitter (-4 years), and nonsmoker. Pooled Cox proportional hazards models were used to estimate the association between quitting smoking and 6-year CVD events and to test whether 4-year change in weight following smoking cessation modified the association between smoking cessation and CVD events. Main Outcome Measure Incidence over 6 years of total CVD events, comprising coronary heart disease, cerebrovascular events, peripheral artery disease, and congestive heart failure. Results After a mean follow-up of 25 (SD, 9.6) years, 631 CVD events occurred among 3251 participants. Median 4-year weight gain was greater for recent quitters without diabetes (2.7 kg [interquartile range {IQR}, -0.5 to 6.4]) and with diabetes (3.6 kg [IQR, -1.4 to 8.2]) than for long-term quitters (0.9 kg [IQR, -1.4 to 3.2] and 0.0 kg [IQR, -3.2 to 3.2], respectively, P < .001). Among participants without diabetes, age-and sex-adjusted incidence rate of CVD was 5.9 per 100 person-examinations (95% CI, 4.9-7.1) in smokers, 3.2 per 100 person-examinations (95% CI, 2.1-4.5) in recent quitters, 3.1 per 100 person-examinations (95% CI, 2.6-3.7) in long-term quitters, and 2.4 per 100 person-examinations (95% CI, 2.0-3.0) in nonsmokers. After adjustment for CVD risk factors, compared with smokers, recent quitters had a hazard ratio (HR) for CVD of 0.47 (95% CI, 0.23-0.94) and long-term quitters had an HR of 0.46 (95% CI, 0.34-0.63); these associations had only a minimal change after further adjustment for weight change. Among participants with diabetes, there were similar point estimates that did not reach statistical significance. Conclusions and Relevance In this community-based cohort, smoking cessation was associated with a lower risk of CVD events among participants without diabetes, and weight gain that occurred following smoking cessation did not modify this association. This supports a net cardiovascular benefit of smoking cessation, despite subsequent weight gain. JAMA. 2013;309(10):1014-1021 www.jama.com C1 [Clair, Carole; Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Clair, Carole; Rigotti, Nancy A.; Porneala, Bianca; Meigs, James B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Med, Boston, MA USA. [Fox, Caroline S.] NHLBI, NIH, Framingham Heart Study, Framingham, MA USA. [D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Pencina, Michael J.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Pencina, Michael J.] Harvard Clin Res Inst, Boston, MA USA. RP Clair, C (reprint author), Univ Lausanne, Dept Ambulatory Care & Community Med, 44 Bugnon Ave, CH-1011 Lausanne, Switzerland. EM carole.willi@gmail.com RI Clair, Carole/D-9786-2014 OI Clair, Carole/0000-0001-5281-0943 FU UpToDate Inc; Swiss National Science Foundation [PBLAP3-127728/1]; SICPA Foundation; National Heart, Lung, and Blood Institute (NHLBI) [5K24HL4440-10]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [K24 DK080140]; Swiss National Science Foundation; NHLBI Framingham Heart Study [N01-HC-25195] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rigotti reported serving as an unpaid consultant to Pfizer and Allere Wellbeing Inc; conducting research projects sponsored by Pfizer and Nabi Biopharmaceuticals; and receiving royalties from UpToDate Inc for chapters related to smoking cessation. Dr Pencina reported serving as a data and safety monitoring board member for Thoracos. No other authors reported disclosures.; Dr Clair was supported by a grant from the Swiss National Science Foundation (PBLAP3-127728/1) and by a grant from the SICPA Foundation. Dr Rigotti was supported by National Heart, Lung, and Blood Institute (NHLBI) grant 5K24HL4440-10. Dr Meigs was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant K24 DK080140.; The Swiss National Science Foundation, SICPA Foundation, and NIDDK had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. The Framingham Heart Study is supported by the NHLBI Framingham Heart Study (contract N01-HC-25195 [Drs D'Agostino and Pencina]). The NHLBI approved the manuscript. NR 26 TC 71 Z9 73 U1 3 U2 26 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 MAR 13 PY 2013 VL 309 IS 10 BP 1014 EP 1021 DI 10.1001/jama.2013.1644 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 103SH UT WOS:000315938700030 PM 23483176 ER PT J AU Chhatriwalla, AK Amin, AP Kennedy, KF House, JA Cohen, DJ Rao, SV Messenger, JC Marso, SP AF Chhatriwalla, Adnan K. Amin, Amit P. Kennedy, Kevin F. House, John A. Cohen, David J. Rao, Sunil V. Messenger, John C. Marso, Steven P. CA Natl Cardiovasc Data Registry TI Association Between Bleeding Events and In-hospital Mortality After Percutaneous Coronary Intervention SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID GLYCOPROTEIN IIB/IIIA INHIBITION; CARDIOVASCULAR DATA REGISTRY; MYOCARDIAL-INFARCTION; CLINICAL-OUTCOMES; ACUITY TRIAL; ANTITHROMBOTIC THERAPY; ECONOMIC-EVALUATION; PROGNOSTIC IMPACT; PROPENSITY SCORE; ISCHEMIC EVENTS AB Importance Bleeding is the most common complication after percutaneous coronary intervention (PCI) and is associated with increased morbidity and health care costs. The incidence of bleeding-related mortality after PCI has not been described in a nationally representative population. Furthermore, the relationships among bleeding risk, bleeding site, and mortality are unclear. Objectives To describe the association between bleeding events and in-hospital mortality after PCI and to estimate the adjusted population attributable risk (estimated as the proportion of mortality risk associated with bleeding events), risk difference, and number needed to harm (NNH) for bleeding-related in-hospital mortality after PCI. Design, Setting, and Patients Data from 3 386 688 procedures in the CathPCI Registry performed in the United States between 2004 and 2011 were analyzed. The population attributable risk was calculated after adjustment for baseline demographic, clinical, and procedural variables. To calculate the NNH for bleeding-related mortality, a propensity-matched analysis was performed. Main Outcome Measures In-hospital mortality. Results There were 57 246 bleeding events (1.7%) and 22 165 in-hospital deaths (0.65%) in 3 386 688 PCI procedures. The adjusted population attributable risk for mortality related to major bleeding was 12.1% (95% CI, 11.4%-12.7%) in the entire CathPCI cohort. The propensity-matched population consisted of 56 078 procedures with a major bleeding event and 224 312 controls. In this matched cohort, major bleeding was associated with increased in-hospital mortality (5.26% vs 1.87%; risk difference, 3.39% [95% CI, 3.20%-3.59%]; NNH=29 [95% CI, 28-31]; P < .001). The association between major bleeding and in-hospital mortality was observed in all strata of preprocedural bleeding risk (low: 1.62% vs 0.17%; risk difference, 1.45% [95% CI, 1.13%-1.77%], NNH=69 [95% CI, 57-88], P < .001; intermediate: 3.27% vs 0.71%; risk difference, 2.56% [95% CI, 2.33%-2.79%], NNH=39 [95% CI, 36-43], P < .001; and high: 8.16% vs 3.45%; risk difference, 4.71% [95% CI, 4.35%-5.07%], NNH=21 [95% CI, 20-23], P < .001). Although both access-site and non-access-site bleeding were associated with increased in-hospital mortality (2.73% vs 1.87%; risk difference, 0.86% [95% CI, 0.66%-1.05%], NNH=117 [95% CI, 95-151], P < .001; and 8.25% vs 1.87%; risk difference, 6.39% [95% CI, 6.04%-6.73%], NNH=16 [95% CI, 15-17], P < .001, respectively), the NNH was lower for nonaccess bleeding. Conclusions and Relevance In a large registry of patients undergoing PCI, post-procedural bleeding events were associated with increased risk of in-hospital mortality, with an estimated 12.1% of deaths related to bleeding complications. JAMA. 2013;309(10):1022-1029 www.jama.com C1 [Kennedy, Kevin F.; House, John A.] St Lukes Mid Amer Heart Inst, Dept Biostat, Kansas City, MO 64111 USA. [Chhatriwalla, Adnan K.; Cohen, David J.; Marso, Steven P.] St Lukes Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Chhatriwalla, Adnan K.; Cohen, David J.; Marso, Steven P.] Univ Missouri Kansas City, Sch Med, Dept Internal Med, Div Cardiol, Kansas City, MO USA. [Amin, Amit P.] Washington Univ, Sch Med, Dept Internal Med, Div Cardiol, St Louis, MO 63110 USA. [Rao, Sunil V.] Duke Clin Res Inst, Dept Internal Med, Div Cardiol, Durham, NC USA. [Messenger, John C.] Univ Colorado Denver, Dept Internal Med, Div Cardiol, Denver, CO USA. [Messenger, John C.] Denver VA Med Ctr, Denver, CO USA. RP Chhatriwalla, AK (reprint author), St Lukes Mid Amer Heart Inst, 4300 Wornall Rd,Ste 2000, Kansas City, MO 64111 USA. EM achhatri-walla@saint-lukes.org FU Medtronic; Edwards Lifesciences; Abbott Vascular; Boston Scientific; Eli Lilly; AstraZeneca; Biomet Inc; Daiichii Sankyo; Medicines Company; Novo Nordisk; Amylin Pharmaceuticals; Volcano Corporation; Terumo Medical; American College of Cardiology Foundation's National Cardiovascular Data Registry (NCDR) FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Chhatriwalla reports that he will be receiving speaking honoraria from Edwards Lifesciences to be paid directly to Saint Luke's Hospital Foundation of Kansas City. Mr House reports receiving consulting honoraria from Vita Solutions and KU Medical Center. Dr Cohen reports medical board membership for Medtronic and Abbott Vascular and reports receiving research support from Medtronic, Edwards Lifesciences, Abbott Vascular, Boston Scientific, Eli Lilly, AstraZeneca, Biomet Inc, and Daiichii Sankyo; consultant honoraria from AstraZeneca, Eli Lilly, Merck, and Janssen Pharmaceuticals; and speaking honoraria from St Jude Medical and Eli Lilly. Dr Rao reports receiving research support and consultant honoraria from The Medicines Company. Dr Marso reports that all compensation for research activities, including research grants and consulting fees from The Medicines Company, Novo Nordisk, Abbott Vascular, Amylin Pharmaceuticals, Boston Scientific, Volcano Corporation, and Terumo Medical, was paid directly to the Saint Luke's Hospital Foundation of Kansas City. No other disclosures were reported.; This research was supported by the American College of Cardiology Foundation's National Cardiovascular Data Registry (NCDR). NR 33 TC 87 Z9 91 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 13 PY 2013 VL 309 IS 10 BP 1022 EP 1029 DI 10.1001/jama.2013.1556 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 103SH UT WOS:000315938700031 PM 23483177 ER PT J AU Stamatakis, KA Norton, WE Stirman, SW Melvin, C Brownson, RC AF Stamatakis, Katherine A. Norton, Wynne E. Stirman, Shannon W. Melvin, Cathy Brownson, Ross C. TI Developing the next generation of dissemination and implementation researchers: insights from initial trainees SO IMPLEMENTATION SCIENCE LA English DT Article DE Dissemination and implementation research; Career development; Early-stage investigators ID KNOWLEDGE TRANSLATION; ACADEMIC MEDICINE; MENTORS; COMPETENCES; STRATEGIES; SCHOLARS; SCIENCE AB Background: Dissemination and implementation (D&I) research is a relatively young discipline, underscoring the importance of training and career development in building and sustaining the field. As such, D&I research faces several challenges in designing formal training programs and guidance for career development. A cohort of early-stage investigators (ESI) recently involved in an implementation research training program provided a resource for formative data in identifying needs and solutions around career development. Results: Responses outlined fellows' perspectives on the perceived usefulness and importance of, as well as barriers to, developing practice linkages, acquiring additional methods training, academic advancement, and identifying institutional supports. Mentorship was a cross-cutting issue and was further discussed in terms of ways it could foster career advancement in the context of D&I research. Conclusions: Advancing an emerging field while simultaneously developing an academic career offers a unique challenge to ESIs in D&I research. This article summarizes findings from the formative data that outlines some directions for ESIs and provides linkages to the literature and other resources on key points. C1 [Stamatakis, Katherine A.; Brownson, Ross C.] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO 63130 USA. [Stamatakis, Katherine A.; Brownson, Ross C.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO USA. [Norton, Wynne E.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Hlth Behav, Birmingham, AL 35294 USA. [Stirman, Shannon W.] VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA USA. [Stirman, Shannon W.] Boston Univ, Boston, MA 02215 USA. [Melvin, Cathy] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Melvin, Cathy] Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. [Brownson, Ross C.] Washington Univ, Brown Sch, Prevent Res Ctr St Louis, St Louis, MO USA. RP Stamatakis, KA (reprint author), Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO 63130 USA. EM stamatakisk@wustl.edu FU Washington University Institute of Clinical and Translational Sciences from the National Center for Advancing Translational Sciences [UL1 TR000448, KL2 TR000450]; Implementation Research Institute (IRI), at the George Warren Brown School of Social Work, Washington University in St. Louis; National Institute of Mental Health [R25 MH080916-01A2]; Department of Veterans Affairs, Health Services Research & Development Service, Quality Enhancement Research Initiative (QUERI) [R00 MH 080100]; Centers for Disease Control and Prevention (the Prevention Research Centers Program) [U48/DP001903] FX This publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1 TR000448 and KL2 TR000450 from the National Center for Advancing Translational Sciences. The preparation of this article was also supported in part by the Implementation Research Institute (IRI), at the George Warren Brown School of Social Work, Washington University in St. Louis; through an award from the National Institute of Mental Health (R25 MH080916-01A2) and the Department of Veterans Affairs, Health Services Research & Development Service, Quality Enhancement Research Initiative (QUERI), in part by R00 MH 080100, and in part by Cooperative Agreement Number U48/DP001903 from the Centers for Disease Control and Prevention (the Prevention Research Centers Program). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, VA, or CDC. NR 22 TC 8 Z9 8 U1 0 U2 9 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 MAR 12 PY 2013 VL 8 AR 29 DI 10.1186/1748-5908-8-29 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 137EM UT WOS:000318418300001 PM 23497462 ER PT J AU Leshchiner, ES Braun, CR Bird, GH Walensky, LD AF Leshchiner, Elizaveta S. Braun, Craig R. Bird, Gregory H. Walensky, Loren D. TI Direct activation of full-length proapoptotic BAK SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE apoptosis; BCL-2 family; SAHB; stapled peptide; photocrosslinking ID STABILIZED ALPHA-HELICES; BCL-2 HOMOLOG BAK; MITOCHONDRIAL APOPTOSIS; CYTOCHROME-C; BH3 DOMAIN; CELL-DEATH; MEMBRANE PERMEABILIZATION; X-RAY; PROTEIN; INHIBITOR AB Proapoptotic B-cell lymphoma 2 (BCL-2) antagonist/killer (BAK) and BCL-2-associated X (BAX) form toxic mitochondrial pores in response to cellular stress. Whereas BAX resides predominantly in the cytosol, BAK is constitutively localized to the outer mitochondrial membrane. Select BCL-2 homology domain 3 (BH3) helices activate BAX directly by engaging an alpha 1/alpha 6 trigger site. The inability to express full-length BAK has hampered full dissection of its activation mechanism. Here, we report the production of full-length, monomeric BAK by mutagenesis-based solubilization of its C-terminal alpha-helical surface. Recombinant BAK autotranslocates to mitochondria but only releases cytochrome c upon BH3 triggering. A direct activation mechanism was explicitly demonstrated using a liposomal system that recapitulates BAK-mediated release upon addition of BH3 ligands. Photoreactive BH3 helices mapped both triggering and autointeractions to the canonical BH3-binding pocket of BAK, whereas the same ligands crosslinked to the alpha 1/alpha 6 site of BAX. Thus, activation of both BAK and BAX is initiated by direct BH3-interaction but at distinct trigger sites. These structural and biochemical insights provide opportunities for developing proapoptotic agents that activate the death pathway through direct but differential engagement of BAK and BAX. C1 [Leshchiner, Elizaveta S.; Braun, Craig R.; Bird, Gregory H.; Walensky, Loren D.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Leshchiner, Elizaveta S.; Braun, Craig R.; Bird, Gregory H.; Walensky, Loren D.] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02215 USA. [Leshchiner, Elizaveta S.; Braun, Craig R.; Bird, Gregory H.; Walensky, Loren D.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Leshchiner, Elizaveta S.; Braun, Craig R.; Bird, Gregory H.; Walensky, Loren D.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Leshchiner, Elizaveta S.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. RP Walensky, LD (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM Loren_Walensky@dfci.harvard.edu OI Bird, Geoffrey/0000-0002-2310-0202 FU National Institutes of Health [5R01CA050239, 5R01GM090299]; Stand Up to Cancer Innovative Research Grant; Lander Fellowship in Cancer Chemical Biology; American Association of University Women International Fellowship FX We thank Eric D. Smith for graphical support, Marina Godes for technical assistance with mitochondrial isolation and purification, David Whitehead for protein production support, Eileen White for providing wild-type and Bax-/-Bak-/- iBMK cells, David Andrews for guidance on the liposomal assay system, and Steven Gygi and Wilhelm Haas for their advice and input on the MS analyses. This work was supported by National Institutes of Health Grants 5R01CA050239 and 5R01GM090299 and a Stand Up to Cancer Innovative Research Grant (to L.D.W.) and a Lander Fellowship in Cancer Chemical Biology and an American Association of University Women International Fellowship (to E.S.L.). NR 57 TC 59 Z9 61 U1 1 U2 20 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 12 PY 2013 VL 110 IS 11 BP E986 EP E995 DI 10.1073/pnas.1214313110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107RK UT WOS:000316238300069 PM 23404709 ER PT J AU Baik, A Olenchock, B Moslehi, J Kaelin, WG AF Baik, Alan Olenchock, Ben Moslehi, Javid Kaelin, William G., Jr. TI ACUTE HYPOXIA-INDUCIBLE FACTOR EGLN1 INACTIVATION PROTECTS AGAINST ISCHEMIA-REPERFUSION INJURY BY REGULATION OF GLUCOSE OXIDATION AND REACTIVE OXYGEN SPECIES GENERATION SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E28 EP E28 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200029 ER PT J AU Bhatia, RS Picard, M Weiner, R Milford, C AF Bhatia, Rajan Sacha Picard, Michael Weiner, Rory Milford, Creagh TI AN EDUCATIONAL INTERVENTION REDUCES THE RATE OF INAPPROPRIATE TRANSTHORACIC ECHOCARDIOGRAMS ON AN INPATIENT MEDICAL SERVICE SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Bhatia, Rajan Sacha; Picard, Michael; Weiner, Rory; Milford, Creagh] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E2122 EP E2122 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555202326 ER PT J AU Chandrashekhar, R Akers, S Vakilipour, A Shiva-Kumar, P Haines, P Jain, S Saif, H Witschey, W Ferrari, VA Chirinos, JA AF Chandrashekhar, Rahul Akers, Scott Vakilipour, Amin Shiva-Kumar, Prithvi Haines, Philip Jain, Snigdha Saif, Hassam Witschey, Walter Ferrari, Victor A. Chirinos, Julio A. TI TIME-RESOLVED LEFT VENTRICULAR MYOCARDIAL STRESS IN HEART FAILURE WITH REDUCED EJECTION FRACTION REVEALS A MARKED INCREASE IN LATE SYSTOLIC MYOCARDIAL LOAD SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Philadelphia VA Med Ctr, Philadelphia, PA USA. Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E613 EP E613 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200613 ER PT J AU Chirinos, JA Shiva-Kumar, P Chandrashekhar, R Haines, P Vakilipour, A Saif, H Witschey, W Pandya, N Segers, P Ferrari, V Akers, S AF Chirinos, Julio A. Shiva-Kumar, Prithvi Chandrashekhar, Rahul Haines, Philip Vakilipour, Amin Saif, Hassam Witschey, Walter Pandya, Nirzari Segers, Patrick Ferrari, Victor Akers, Scott TI RELATIONSHIP BETWEEN ARTERIAL LOAD AND LV CONCENTRIC HYPERTROPHY ASSESSED WITH MRI SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Philadelphia VA Med Ctr, Philadelphia, PA USA. Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1473 EP E1473 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201578 ER PT J AU Chou, ET Zakroysky, P Hayden, D Woodard, P Wiviott, S Nagurney, J Fleg, J Lee, H Schoenfeld, D Hoffmann, U Truong, Q AF Chou, Eric T. Zakroysky, Pearl Hayden, Doug Woodard, Pamela Wiviott, Stephen Nagurney, John Fleg, Jerome Lee, Hang Schoenfeld, David Hoffmann, Udo Quynh Truong TI UTILITY OF CORONARY ARTERY CALCIUM SCANNING IN EMERGENCY DEPARTMENT EVALUATION FOR ACUTE CHEST PAIN: THE ROMICAT II TRIAL SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Kaiser Permanente Fontana Med Ctr, Fontana, CA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1109 EP E1109 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201214 ER PT J AU Daniels, K Arena, R Zavin, A Allsup, K Lazzari, A Schulze, PC Forman, DE AF Daniels, Karla Arena, Ross Zavin, Alexandra Allsup, Kelly Lazzari, Antonio Schulze, P. Christian Forman, Daniel E. TI ADIPONECTIN RESISTANCE IN NON-CACHECTIC HEART FAILURE PATIENTS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 VA Boston Healthcare Syst, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RI Arena, Ross/A-3141-2008 OI Arena, Ross/0000-0002-6675-1996 NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E600 EP E600 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200600 ER PT J AU De Berardinis, B Magrini, L Gaggin, HK Belcker, A Zancla, B Femia, A Simon, M Motiwala, S Bhardwaj, A Parry, B Nagurney, TJ Di Somma, S Januzzi, JL AF De Berardinis, Benedetta Magrini, Laura Gaggin, Hanna K. Belcker, Arianna Zancla, Benedetta Femia, Alexandra Simon, Mandy Motiwala, Shweta Bhardwaj, Anju Parry, Blair Nagurney, Toby J. Di Somma, Salvatore Januzzi, James L. TI A PROSPECTIVE, BLINDED STUDY OF BIOIMPEDANCE VECTOR ANALYSIS AND BIOMARKER TESTING FOR THE PREDICTION OF WORSENING RENAL FUNCTION IN CONSECUTIVE PATIENTS WITH ACUTELY DECOMPENSATED HEART FAILURE: PRIMARY RESULTS OF THE BIOMONITORING AND CARDIORENAL SYNDROME IN HEART FAILURE (BIONICS-HF) TRIAL SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Univ Roma La Sapienza, Dep Med Surg Sci & Traslat Med, Rome, Italy. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Cardiol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E639 EP E639 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200639 ER PT J AU Elmariah, S Furlan, A Reisman, M Burke, D Vardi, M Ling, SQ Chen, XH Mauri, L AF Elmariah, Sammy Furlan, Anthony Reisman, Mark Burke, David Vardi, Moshe Ling, Shuqiong Chen, Xiaohua Mauri, Laura CA CLOSURE I Investigators TI PREDICTORS OF RECURRENT NEUROLOGIC EVENTS IN PATIENTS WITH PATENT FORAMEN OVALE: INSIGHTS FROM THE CLOSURE I TRIAL SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Clin Res Inst, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1749 EP E1749 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201854 ER PT J AU Emami, H Subramanian, S Vucic, E Vijayakumar, J Fifer, K Brady, TJ Rudd, JHF Fayad, ZA Van Dyke, TE Tawakol, A AF Emami, Hamed Subramanian, Sharath Vucic, Esad Vijayakumar, Jayanthi Fifer, Kenneth Brady, Thomas J. Rudd, James H. F. Fayad, Zahi A. Van Dyke, Thomas E. Tawakol, Ahmed TI HIGH DOSE ATORVASTATIN REDUCES PERIODONTAL ACTIVITY IN PROPORTION TO ATHEROSCLEROTIC INFLAMMATION: A POTENTIALLY NOVEL PLEIOTROPIC EFFECT OF STATINS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Sch Med, Forsyth Inst, Boston, MA USA. FU Academy of Medical Sciences (AMS) [AMS-SGCL1-Rudd] NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1055 EP E1055 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201160 ER PT J AU Falk, RH Laubach, JP Kruger, J Quarta, CC AF Falk, Rodney H. Laubach, Jacob P. Kruger, Jenna Quarta, Candida Cristina TI BORTEZOMIB/DEXAMETHASONE-BASED TREATMENT FOR LIGHT-CHAIN CARDIAC AMYLOIDOSIS RESULTS IN MARKEDLY PROLONGED SURVIVAL COMPARED TO PREVIOUSLY USED REGIMENS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E712 EP E712 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200712 ER PT J AU Gaggin, HK Motiwala, S Bhardwaj, A Szymonifka, J Parks, K Januzzi, J AF Gaggin, Hanna Kim Motiwala, Shweta Bhardwaj, Anju Szymonifka, Jackie Parks, Kimberly Januzzi, James TI CIRCULATING CONCENTRATIONS OF SOLUBLE ST2 IDENTIFY BENEFIT OF HIGH DOSE BETA BLOCKER IN CHRONIC HEART FAILURE: RESULTS FROM THE PROBNP OUTPATIENT TAILORED CHRONIC HEART FAILURE THERAPY (PROTECT) STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Gaggin, Hanna Kim; Motiwala, Shweta; Bhardwaj, Anju; Szymonifka, Jackie; Parks, Kimberly; Januzzi, James] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E746 EP E746 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200746 ER PT J AU Grinstein, J Bonaca, M Sabatine, M Jarolim, P Conrad, M Braunwald, E Giugliano, R Newby, LK Morrow, D AF Grinstein, Jonathan Bonaca, Marc Sabatine, Marc Jarolim, Petr Conrad, Michael Braunwald, Eugene Giugliano, Robert Newby, L. Kristin Morrow, David TI PROGNOSTIC IMPLICATIONS OF LOW-LEVEL CARDIAC TROPONIN ELEVATION USING THE HIGH-SENSITIVITY ASSAY FOR CARDIAC TROPONIN T: RESULTS FROM EARLY ACS & SEPIA-TIMI 42 SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 TIMI Study Grp, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E110 EP E110 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200111 ER PT J AU Hu, SN Jia, HB Hou, JB Lei, X Tian, JW Kato, K Yonetsu, T Vergallo, R Abtahian, F Han, ZG Meng, LB Yu, H Zhang, SS Yu, B Jang, IK AF Hu, Sining Jia, Haibo Hou, Jingbo Lei, Xing Tian, JinWei Kato, Koji Yonetsu, Taishi Vergallo, Rocco Abtahian, Farhad Han, Zhigang Meng, Lingbo Yu, Huai Zhang, Shaosong Yu, Bo Jang, Ik-Kyung TI ATTENUATED RESPONSE OF LIPID PLAQUE TO CHOLESTEROL LOWERING THERAPY IN DIABETIC PATIENT: AN OPTICAL COHERENCE TOMOGRAPHY STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, Harbin, Peoples R China. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E219 EP E219 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200220 ER PT J AU Hulten, E Bittencourt, M Singh, A O'Leary, D Patil, M Osmani, W Abbara, S Steigner, M Nasir, K Truong, Q Klein, J Hainer, J Rybicki, F Hoffmann, U Di Carli, M Ghoshhajra, B Blankstein, R AF Hulten, Edward Bittencourt, Marcio Singh, Avinainder O'Leary, Daniel Patil, Mitalee Osmani, Wafa Abbara, Suhny Steigner, Michael Nasir, Khurram Quynh Truong Klein, Josh Hainer, Jon Rybicki, Frank Hoffmann, Udo Di Carli, Marcelo Ghoshhajra, Brian Blankstein, Ron TI CHANGE IN STATIN THERAPY AFTER CCTA IS ASSOCIATED WITH LOWER LDL-CHOLESTEROL WITHOUT CHANGE IN THREE-YEAR PROGNOSIS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1106 EP E1106 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201211 ER PT J AU Januzzi, JL Zakroysky, P Truong, Q Woodard, P Pope, JH Hauser, T Nagurney, J Schoenfeld, D Peacock, WF Wiviott, S Pang, P Udelson, J Hoffmann, U AF Januzzi, James L. Zakroysky, Pearl Quynh Truong Woodard, Pamela Pope, James Hector Hauser, Thomas Nagurney, John Schoenfeld, David Peacock, W. Frank Wiviott, Stephen Pang, Peter Udelson, James Hoffmann, Udo TI PERFORMANCE OF TWO SENSITIVE TROPONIN I ASSAYS FOR THE EVALUATION OF SUSPECTED ACS : RESULTS FROM THE MULTICENTER RULE OUT MYOCARDIAL INFARCTION USING COMPUTER ASSISTED TOMOGRAPHY (ROMICAT) II BIOMARKER SUB-STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Januzzi, James L.; Zakroysky, Pearl; Quynh Truong; Woodard, Pamela; Pope, James Hector; Hauser, Thomas; Nagurney, John; Schoenfeld, David; Peacock, W. Frank; Wiviott, Stephen; Pang, Peter; Udelson, James; Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E229 EP E229 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200230 ER PT J AU Jia, HB Yonetsu, T Jang, YS Walters, D Prasad, A Chia, S Kato, K Abtahian, F Vergallo, R Tian, JW Hu, SN Lee, H Zhang, SS Yu, B Jang, IK AF Jia, Haibo Yonetsu, Taishi Jang, Yang-Soo Walters, Darren Prasad, Abhiram Chia, Stanley Kato, Koji Abtahian, Farhad Vergallo, Rocco Tian, JinWei Hu, Sining Lee, Hang Zhang, Shaosong Yu, Bo Jang, Ik-Kyung TI NEW INSIGHTS INTO DISTRIBUTION OF VARIOUS PLAQUE TYPES AROUND CORONARY ARTERY BIFURCATIONS: AN IN VIVO OPTICAL COHERENCE TOMOGRAPHY STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harbin Med Univ, Affiliated Hosp 2, Harbin, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1709 EP E1709 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201814 ER PT J AU Jia, HB Li, N Wang, XD Kato, K Yonetsu, T Hu, SN Tian, JW Zhang, SS Hou, JB Yu, B Jang, IK AF Jia, Haibo Li, Ning Wang, Xuedong Kato, Koji Yonetsu, Taishi Hu, Sining Tian, Jinwei Zhang, Shaosong Hou, Jingbo Yu, Bo Jang, Ik-Kyung TI CHRONIC TOTAL OCCLUSION: OPTICAL COHERENCE TOMOGRAPHY FINDINGS AT SIX MONTHS FOLLOWING TREATMENT WITH SIROLIMUS ELUTING STENTS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, Harbin, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1688 EP E1688 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201793 ER PT J AU Kato, K Yonetsu, T Jia, HB Abtahian, F Vergallo, R Kim, SJ Lee, H McNulty, I Lee, S Uemura, S Jang, YS Park, SJ Mizuno, K Yu, B Jang, IK AF Kato, Koji Yonetsu, Taishi Jia, Haibo Abtahian, Farhad Vergallo, Rocco Kim, Soo-Joong Lee, Hang McNulty, Iris Lee, Stephen Uemura, Shiro Jang, Yang Soo Park, Seung-Jung Mizuno, Kyoichi Yu, Bo Jang, Ik-Kyung TI NON-CULPRIT CORONARY PLAQUE CHARACTERISTICS OF CHRONIC KIDNEY DISEASE SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Kato, Koji; Yonetsu, Taishi; Jia, Haibo; Abtahian, Farhad; Vergallo, Rocco; Kim, Soo-Joong; Lee, Hang; McNulty, Iris; Lee, Stephen; Uemura, Shiro; Jang, Yang Soo; Park, Seung-Jung; Mizuno, Kyoichi; Yu, Bo; Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1730 EP E1730 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201835 ER PT J AU Le Elizabeth, DT Pascotto, M Leong-Poi, H Sari, I Micari, A Kaul, S AF Le Elizabeth, Dai-Trang Pascotto, Marco Leong-Poi, Howard Sari, Ibrahim Micari, Antonio Kaul, Sanjiv TI ANTI-INFLAMMATORY AND PRO-ANGIOGENIC EFFECTS OF BETA-BLOCKERS IN A CANINE MODEL OF CHRONIC ISCHEMIC CARDIOMYOPATHY: COMPARISON BETWEEN CARVEDILOL AND METOPROLOL SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Portland VA Med Ctr, Portland, OR USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1175 EP E1175 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201280 ER PT J AU Lin, EY Cohen, HW Johnson, J Stefanescu, A Bhatt, AB Lui, GK AF Lin, Elaine Y. Cohen, Hillel W. Johnson, Jacob Stefanescu, Ada Bhatt, Ami B. Lui, George K. TI PREDICTING OUTCOMES USING THE HEART FAILURE SURVIVAL SCORE IN ADULTS WITH CONGENITAL HEART DISEASE SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E507 EP E507 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200507 ER PT J AU MacNabb, MH Abdelbaky, A Lavender, ZR Kaplan, RS di Carli, M Taqueti, V Foster, C Mann, J Comley, R Weber, CIK Tawakol, A AF MacNabb, Megan H. Abdelbaky, Amr Lavender, Zachary R. Kaplan, Rebecca S. di Carli, Marcelo Taqueti, Viviany Foster, Courtney Mann, Jessica Comley, Robert Weber, Chek Ing Kiu Tawakol, Ahmed TI ARTERIAL INFLAMMATION IS HIGHER IN INDIVIDUALS WITH CHRONIC KIDNEY DISEASE AND LOW FRAMINGHAM RISK SCORES SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E838 EP E838 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200838 ER PT J AU May, EB Scirica, B Bonaca, M Murphy, S Braunwald, E Morrow, D AF May, Erin Bohula Scirica, Benjamin Bonaca, Marc Murphy, Sabina Braunwald, Eugene Morrow, David TI PROGNOSTIC VALUE OF HIGH-SENSITIVITY CRP FOR CARDIOVASCULAR OUTCOMES IN TRA 2 degrees P-TIMI 50 SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Brigham & Womens Hosp, Boston, MA 02115 USA. TIMI Study Grp, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1162 EP E1162 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201267 ER PT J AU Mehrotra, P Jansen, K Tan, T Flynn, A Elmariah, S Picard, M Hung, J AF Mehrotra, Praveen Jansen, Katrijn Tan, Timothy Flynn, Aidan Elmariah, Sammy Picard, Michael Hung, Judy TI PROGNOSIS OF PATIENTS WITH ISOLATED SEVERE AORTIC STENOSIS: ARE OUTCOMES SIMILAR FOR ALL PATIENTS WITH AN AORTIC VALVE AREA LESS THAN 1.0 CM2? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1937 EP E1937 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555202141 ER PT J AU Motiwala, S Szymonifka, J Belcher, A Weiner, R Baggish, A Sluss, P Gaggin, H Bhardwaj, A Januzzi, J AF Motiwala, Shweta Szymonifka, Jackie Belcher, Arianna Weiner, Rory Baggish, Aaron Sluss, Patrick Gaggin, Hanna Bhardwaj, Anju Januzzi, James TI SERIAL MEASUREMENT OF GALECTIN-3 PREDICTS CHRONIC HEART FAILURE OUTCOMES AND VENTRICULAR REMODELING: RESULTS FROM THE PROBNP OUTPATIENT TAILORED CHRONIC HEART FAILURE THERAPY (PROTECT) STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Motiwala, Shweta; Szymonifka, Jackie; Belcher, Arianna; Weiner, Rory; Baggish, Aaron; Sluss, Patrick; Gaggin, Hanna; Bhardwaj, Anju; Januzzi, James] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E745 EP E745 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200745 ER PT J AU Motiwala, S Bhardwaj, A Szymonifka, J Belcher, A Weiner, R Baggish, A Gaggin, H Januzzi, J AF Motiwala, Shweta Bhardwaj, Anju Szymonifka, Jackie Belcher, Arianna Weiner, Rory Baggish, Aaron Gaggin, Hanna Januzzi, James TI SERIAL MEASUREMENT OF INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 7 PREDICTS CHRONIC HEART FAILURE OUTCOMES AND VENTRICULAR REMODELING: RESULTS FROM THE PROBNP OUTPATIENT TAILORED CHRONIC HEART FAILURE THERAPY (PROTECT) STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Motiwala, Shweta; Bhardwaj, Anju; Szymonifka, Jackie; Belcher, Arianna; Weiner, Rory; Baggish, Aaron; Gaggin, Hanna; Januzzi, James] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E565 EP E565 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200565 ER PT J AU Niesor, EJ Schwartz, G Suchankova, G Benghozi, R Abt, M Kallend, D AF Niesor, Eric J. Schwartz, Gregory Suchankova, Gabriela Benghozi, Renee Abt, Markus Kallend, David TI STATIN-INDUCED DECREASE IN ABCA1 EXPRESSION VIA MIR33 INDUCTION MAY COUNTERACT CHOLESTEROL EFFLUX BY HIGH-DENSITY LIPOPROTEINS RAISED WITH THE CHOLESTERYL ESTER TRANSFER PROTEIN MODULATOR DALCETRAPIB SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 F Hoffmann La Roche Ltd, Basel, Switzerland. Denver VA Med Ctr, Denver, CO USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E2032 EP E2032 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555202236 ER PT J AU Nunes, MCP Tan, T Elmariah, S do Lago, R Inglessis, I Palacios, I Hung, J Levine, R AF Pereira Nunes, Maria Carmo Tan, Timothy Elmariah, Sammy do Lago, Rodrigo Inglessis, Ignacio Palacios, Igor Hung, Judy Levine, Robert TI NET ATRIOVENTRICULAR COMPLIANCE IS AN INDEPENDENT PREDICTOR OF MORTALITY IN MITRAL STENOSIS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA USA. Univ Fed Minas Gerais, Sch Med, Belo Horizonte, MG, Brazil. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1931 EP E1931 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555202135 ER PT J AU Rajabali, A Asrani, P Bhatt, A He, W Benavidez, O AF Rajabali, Alefiyah Asrani, Priyanka Bhatt, Ami He, Wei Benavidez, Oscar TI HIGH RESOURCE USE AMONG ADULT CONGENITAL HEART SURGERY ADMISSIONS IN ADULT HOSPITALS: RISK FACTORS AND ASSOCIATION WITH DEATH AND COMPLICATIONS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Rajabali, Alefiyah; Asrani, Priyanka; Bhatt, Ami; He, Wei; Benavidez, Oscar] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E534 EP E534 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200534 ER PT J AU Saha, S Beatty, A Mishra, R Whooley, M Schiller, N AF Saha, Sandeep Beatty, Alexis Mishra, Rakesh Whooley, Mary Schiller, Nelson TI AN ECHOCARDIOGRAPHIC COMPOSITE CARDIAC CALCIFICATION SCORE PREDICTS MAJOR CARDIOVASCULAR EVENTS IN PATIENTS WITH STABLE CORONARY ARTERY DISEASE: THE HEART AND SOUL STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. San Francisco VA Med Ctr, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1024 EP E1024 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201129 ER PT J AU Singh, P Tawakol, A Mojena, M Pimentel-Santillana, M Fayad, ZA Rudd, J Traves, PG Fernandez, M Tejedor, A Bosca, L AF Singh, Parmanand Tawakol, Ahmed Mojena, Marina Pimentel-Santillana, Maria Fayad, Zahi A. Rudd, James Traves, Paqui G. Fernandez, Maria Tejedor, Alberto Bosca, Lisardo TI GM-CSF ENHANCES GLYCOLYTIC ACTIVITY IN MACROPHAGES IN VITRO AND IMPROVES DETECTION OF ATHEROSCLEROTIC INFLAMMATION IN VIVO SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Inst Invest Biomed Alberto Sols, Madrid, Spain. RI G. Traves, Paqui/L-5693-2014; Pimentel-Santillana, Maria/L-9437-2014 OI G. Traves, Paqui/0000-0001-5749-8426; Pimentel-Santillana, Maria/0000-0003-1179-4259 NR 0 TC 0 Z9 0 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1153 EP E1153 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201258 ER PT J AU Tian, JW Hu, SN Jia, HB Abtahian, F Kato, K Yonetsu, T Vergallo, R McNulty, I Zhang, SS Yu, B Jang, IK AF Tian, JinWei Hu, Sining Jia, Haibo Abtahian, Farhad Kato, Koji Yonetsu, Taishi Vergallo, Rocco McNulty, Iris Zhang, Shaosong Yu, Bo Jang, Ik-Kyung TI GENDER DIFFERENCE IN CULPRIT LESION CHARACTERISTICS IN PATIENTS WITH ACS: AN OPTICAL COHERENCE TOMOGRAPHY STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, Harbin, Peoples R China. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E79 EP E79 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200080 ER PT J AU Truong, QA Thai, WE Wai, B Zhou, Q Brown, H Bennett, R Beaudoin, J Singh, J Barrett, C Danik, S AF Truong, Quynh A. Thai, Wai-ee Wai, Bryan Zhou, Qing Brown, Heather Bennett, Richard Beaudoin, Jonathan Singh, Jagmeet Barrett, Conor Danik, Stephan TI A NEW METHOD USING CARDIAC CT KINEMATICS TO REFLECT THE ACTIVATION PATTERN VISUALIZED WITH ELECTROANATOMICAL MAP: CARDIAC CT PHASE TIME VELOCITY ACTIVATION-ENCODED MAP (ACTIVATE) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. QI Imaging LLC, Redwood City, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E913 EP E913 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201018 ER PT J AU Truong, QA Thai, WE Szymonifka, J Basnet, S Wai, B Grunau, Z Beaudoin, J Smith, CL Babatunde, A Ajijola, O Singh, J Januzzi, J AF Truong, Quynh A. Thai, Wai-ee Szymonifka, Jackie Basnet, Sandeep Wai, Bryan Grunau, Zachary Beaudoin, Jonathan Smith, Chelsea L. Babatunde, Adefolakemi Ajijola, Olujimi Singh, Jagmeet Januzzi, James TI CORONARY SINUS LEVEL OF GALECTIN-3 IS A BETTER PREDICTOR THAN PERIPHERAL VENOUS LEVEL OF MAJOR ADVERSE CARDIAC EVENTS IN PATIENTS WITH CARDIAC RESYNCHRONIZATION THERAPY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Truong, Quynh A.; Thai, Wai-ee; Szymonifka, Jackie; Basnet, Sandeep; Wai, Bryan; Grunau, Zachary; Beaudoin, Jonathan; Smith, Chelsea L.; Babatunde, Adefolakemi; Ajijola, Olujimi; Singh, Jagmeet; Januzzi, James] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E248 EP E248 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200248 ER PT J AU Vergallo, R Yonetsu, T Lee, S Uemura, S Kato, K Jia, HB Abtahian, F Tian, JW Hu, SN Aguirre, A McNulty, I Lee, H Zhang, SS Yu, B Porto, I Biasucci, L Crea, F Jang, IK AF Vergallo, Rocco Yonetsu, Taishi Lee, Stephen Uemura, Shiro Kato, Koji Jia, Haibo Abtahian, Farhad Tian, Jinwei Hu, Sining Aguirre, Aaron McNulty, Iris Lee, Hang Zhang, Shaosong Yu, Bo Porto, Italo Biasucci, Luigi Crea, Filippo Jang, Ik-Kyung TI CORRELATION BETWEEN DEGREE OF NEOINTIMAL HYPERPLASIA AND INCIDENCE AND CHARACTERISTICS OF NEOATHEROSCLEROSIS AFTER STENT IMPLANTATION: AN OPTICAL COHERENCE TOMOGRAPHY STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Vergallo, Rocco; Yonetsu, Taishi; Lee, Stephen; Uemura, Shiro; Kato, Koji; Jia, Haibo; Abtahian, Farhad; Tian, Jinwei; Hu, Sining; Aguirre, Aaron; McNulty, Iris; Lee, Hang; Zhang, Shaosong; Yu, Bo; Porto, Italo; Biasucci, Luigi; Crea, Filippo; Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1800 EP E1800 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555202005 ER PT J AU Weinberg, I Rogers, K Halpern, E Jaff, M AF Weinberg, Ido Rogers, Kevin Halpern, Elkan Jaff, Michael TI PREDICTORS OF CLINICAL BENEFIT OF RENAL ARTERY STENTING IN 1,003 PATIENTS IN SIX PROSPECTIVE MULTICENTER TRIALS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Weinberg, Ido; Rogers, Kevin; Halpern, Elkan; Jaff, Michael] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E2058 EP E2058 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555202262 ER PT J AU Weiner, RB Isaacs, SK Wang, F Berkstresser, B Wang, T Hutter, A Lewis, G Picard, M Baggish, A AF Weiner, Rory B. Isaacs, Stephanie K. Wang, Francis Berkstresser, Brant Wang, Thomas Hutter, Adolph Lewis, Gregory Picard, Michael Baggish, Aaron TI FUNCTIONAL IMPLICATIONS OF THE ATHLETE'S HEART: MYOCARDIAL STRAIN AND TWIST PROVIDE A MECHANISM FOR THE ADAPTIVE RESPONSE TO INTRAVASCULAR VOLUME CHALLENGE SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Weiner, Rory B.; Isaacs, Stephanie K.; Wang, Francis; Berkstresser, Brant; Wang, Thomas; Hutter, Adolph; Lewis, Gregory; Picard, Michael; Baggish, Aaron] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1624 EP E1624 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201729 ER PT J AU Yonetsu, T Kato, K Yu, B Uemura, S Jia, HB Vergallo, R Abtahian, F Tian, JW Hu, SN Aguirre, A McNulty, I Zhang, SS Lee, H Jang, IK AF Yonetsu, Taishi Kato, Koji Yu, Bo Uemura, Shiro Jia, Haibo Vergallo, Rocco Abtahian, Farhad Tian, Jinwei Hu, Sining Aguirre, Aaron McNulty, Iris Zhang, Shaosong Lee, Hang Jang, Ik-Kyung TI COMPREHENSIVE THREE-VESSEL PLAQUE MAPPING BY OPTICAL COHERENCE TOMOGRAPHY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Yonetsu, Taishi; Kato, Koji; Yu, Bo; Uemura, Shiro; Jia, Haibo; Vergallo, Rocco; Abtahian, Farhad; Tian, Jinwei; Hu, Sining; Aguirre, Aaron; McNulty, Iris; Zhang, Shaosong; Lee, Hang; Jang, Ik-Kyung] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1783 EP E1783 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555201888 ER PT J AU Yonetsu, T Suh, W Abtahian, F Kato, K Vergallo, R Jia, HB Kim, SJ McNulty, I Lee, H Jang, IK AF Yonetsu, Taishi Suh, William Abtahian, Farhad Kato, Koji Vergallo, Rocco Jia, Haibo Kim, Soo-Joong McNulty, Iris Lee, Hang Jang, Ik-Kyung TI COMPARISON OF NEAR-INFRARED SPECTROSCOPY AND OPTICAL COHERENCE TOMOGRAPHY FOR DETECTION OF LIPID SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Yonetsu, Taishi; Suh, William; Abtahian, Farhad; Kato, Koji; Vergallo, Rocco; Jia, Haibo; Kim, Soo-Joong; McNulty, Iris; Lee, Hang; Jang, Ik-Kyung] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E1796 EP E1796 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555202001 ER PT J AU Zakroysky, P Basnet, S Thai, WE Onandia, ZG Gandhi, S Truong, Q AF Zakroysky, Pearl Basnet, Sandeep Thai, Wai-ee Onandia, Zurine Galvan Gandhi, Sachin Quynh Truong TI DRAMATIC REDUCTION IN ACUTE CORONARY SYNDROME WITH STEROID EXPOSURE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Zakroysky, Pearl; Basnet, Sandeep; Thai, Wai-ee; Onandia, Zurine Galvan; Gandhi, Sachin; Quynh Truong] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E180 EP E180 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200181 ER PT J AU Zeng, X Nunes, M Hung, J AF Zeng, Xin Nunes, Maria Hung, Judy TI ASYMMETRIC OR SYMMETRIC MITRAL LEAFLET TETHERING: PATTERN OF TETHERING AN IMPORTANT DETERMINANT OF ISCHEMIC MITRAL REGURGITATION SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 62nd Annual Scientific Session of the American-College-of-Cardiology CY MAR 09-11, 2013 CL San Francisco, CA SP Amer Coll Cardiol C1 [Zeng, Xin; Nunes, Maria; Hung, Judy] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 SU S BP E884 EP E884 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 111XO UT WOS:000316555200884 ER PT J AU Ghaffari, R Page, SL Farrahi, S Sellon, JB Freeman, DM AF Ghaffari, Roozbeh Page, Scott L. Farrahi, Shirin Sellon, Jonathan B. Freeman, Dennis M. TI Electrokinetic properties of the mammalian tectorial membrane SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cochlear amplification; cochlear mechanics; mechanoelectrical transduction; motility ID POLYELECTROLYTE GEL MODEL; HAIR CELL BUNDLES; INNER-EAR; EQUILIBRIUM BEHAVIOR; TRAVELING-WAVES; HEARING-LOSS; TRANSDUCTION; COCHLEA; ORGAN; CORTI AB The tectorial membrane (TM) clearly plays a mechanical role in stimulating cochlear sensory receptors, but the presence of fixed charge in TM constituents suggests that electromechanical properties also may be important. Here, we measure the fixed charge density of the TM and show that this density of fixed charge is sufficient to affect mechanical properties and to generate electrokinetic motions. In particular, alternating currents applied to the middle and marginal zones of isolated TM segments evoke motions at audio frequencies (1-1,000 Hz). Electrically evoked motions are nanometer scaled (similar to 5-900 nm), decrease with increasing stimulus frequency, and scale linearly over a broad range of electric field amplitudes (0.05-20 kV/m). These findings show that the mammalian TM is highly charged and suggest the importance of a unique TM electrokinetic mechanism. C1 [Ghaffari, Roozbeh; Page, Scott L.; Farrahi, Shirin; Sellon, Jonathan B.; Freeman, Dennis M.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Ghaffari, Roozbeh; Sellon, Jonathan B.; Freeman, Dennis M.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Page, Scott L.; Farrahi, Shirin; Freeman, Dennis M.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Freeman, Dennis M.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, Boston, MA 02114 USA. RP Freeman, DM (reprint author), MIT, Elect Res Lab, Cambridge, MA 02139 USA. EM freeman@mit.edu FU National Institutes of Health [R01-DC00238]; Harvard-MIT Division of Health Sciences and Technology FX We thank A. Grodzinsky and J. Guinan for helpful discussions about the manuscript. This research was supported by National Institutes of Health Grant R01-DC00238. R.G. was supported in part by a training grant from the National Institutes of Health to the Speech and Hearing Bioscience and Technology Program of the Harvard-MIT Division of Health Sciences and Technology. NR 61 TC 4 Z9 4 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 12 PY 2013 VL 110 IS 11 BP 4279 EP 4284 DI 10.1073/pnas.1214744110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107RK UT WOS:000316238300033 PM 23440188 ER PT J AU Haq, R Yokoyama, S Hawryluk, EB Jonssond, GB Frederick, DT McHenry, K Porter, D Tran, TN Love, KT Langer, R Anderson, DG Garraway, LA Duncan, LM Morton, DL Hoon, DSB Wargo, JA Song, JS Fisher, DE AF Haq, Rizwan Yokoyama, Satoru Hawryluk, Elena B. Jonssond, Goran B. Frederick, Dennie Tampers McHenry, Kevin Porter, Dale Tran, Thanh-Nga Love, Kevin T. Langer, Robert Anderson, Daniel G. Garraway, Levi A. Duncan, Lyn McDivitt Morton, Donald L. Hoon, Dave S. B. Wargo, Jennifer A. Song, Jun S. Fisher, David E. TI BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MALIGNANT-MELANOMA; METASTATIC MELANOMA; SURVIVAL ONCOGENE; CELL-LINES; IN-VIVO; B-RAF; CANCER; MUTATION; MITF; SENSITIVITY AB Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, "driver" oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in similar to 30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF-immortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy. C1 [Haq, Rizwan; Fisher, David E.] Massachusetts Gen Hosp, Dept Med, Div Med Oncol, Boston, MA 02115 USA. [Haq, Rizwan; Yokoyama, Satoru; Hawryluk, Elena B.; Tran, Thanh-Nga; Fisher, David E.] Massachusetts Gen Hosp, Dermatol & Cutaneous Biol Res Ctr, Boston, MA 02115 USA. [Frederick, Dennie Tampers; Wargo, Jennifer A.] Massachusetts Gen Hosp, Boston, MA 02115 USA. [Duncan, Lyn McDivitt] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02115 USA. [Yokoyama, Satoru] Toyama Univ, Inst Nat Med, Div Pathogen Biochem, Toyama 9300194, Japan. [Jonssond, Goran B.] Lund Univ, Dept Oncol, SE-22100 Lund, Sweden. [Love, Kevin T.; Langer, Robert] Oncol Drug Discovery, Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Love, Kevin T.; Langer, Robert; Anderson, Daniel G.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Langer, Robert; Anderson, Daniel G.] MIT, Harvard MIT Div Hlth Sci & Technol, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Garraway, Levi A.] Broad Inst Harvard, Cambridge, MA 02142 USA. [Garraway, Levi A.] MIT, Cambridge, MA 02142 USA. [Morton, Donald L.] John Wayne Canc Inst, Dept Mol Oncol, Santa Monica, CA 90404 USA. [Hoon, Dave S. B.; Song, Jun S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94107 USA. [Song, Jun S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94107 USA. RP Song, JS (reprint author), Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94107 USA. EM Songj@humgen.ucsf.edu; dfisher3@partners.org RI Jonsson, Goran/D-1212-2014; OI Hoon, Dave/0000-0003-1915-3683 FU American Skin Association; National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health (NIH); Melanoma Research Alliance; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Ministry of Education, Culture, Sports, Science, and Technology, Japan [24700971]; NIH [eb00244]; PhRMA Foundation; University of California at San Francisco (UCSF); Committee on Research; UCSF Research Allocation Program; National Cancer Institute [R01CA163336] FX We thank Meenhard Herlyn (Wistar Institute) for cell lines, Gideon Bollag and Plexxikon for PLX4720-containing chow, Hans Widlund (Brigham and Women's Hospital), and members of the Fisher laboratory for discussions and suggestions. We thank Juying Li for advice, Su-Jean Seo (Beth-Israel Deaconess Hospital) for help with microscopy, and Myung-Shin Sims (John Wayne Cancer Institute) for statistical help. This work was supported by the American Skin Association (R.H.); National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health (NIH); the Melanoma Research Alliance; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (D.L.M., D.S.B.H., and D.E.F.); and Grant-in-Aid 24700971 for Young Scientists (B) (to S.Y.) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. D.G.A. is supported by NIH Grant eb00244. J.S.S. acknowledges support from the PhRMA Foundation, University of California at San Francisco (UCSF), Committee on Research, UCSF Research Allocation Program, and National Cancer Institute Grant R01CA163336. D.E.F. is a Distinguished Clinical Scholar of the Doris Duke Medical Foundation. NR 43 TC 75 Z9 76 U1 0 U2 19 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 MAR 12 PY 2013 VL 110 IS 11 BP 4321 EP 4326 DI 10.1073/pnas.1205575110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107RK UT WOS:000316238300040 PM 23447565 ER PT J AU Chiyomaru, T Yamamura, S Fukuhara, S Hidaka, H Majid, S Saini, S Arora, S Deng, GR Shahryari, V Chang, I Tanaka, Y Tabatabai, ZL Enokida, H Seki, N Nakagawa, M Dahiya, R AF Chiyomaru, Takeshi Yamamura, Soichiro Fukuhara, Shinichiro Hidaka, Hideo Majid, Shahana Saini, Sharanjot Arora, Sumit Deng, Guoren Shahryari, Varahram Chang, Inik Tanaka, Yuichiro Tabatabai, Z. Laura Enokida, Hideki Seki, Naohiko Nakagawa, Masayuki Dahiya, Rajvir TI Genistein Up-Regulates Tumor Suppressor MicroRNA-574-3p in Prostate Cancer SO PLOS ONE LA English DT Article ID GROWTH-FACTOR RECEPTOR; MATRIX-METALLOPROTEINASE TYPE-2; INHIBITS CELL-PROLIFERATION; ANDROGEN-INDEPENDENCE; ENRICHMENT ANALYSIS; SIGNALING PATHWAY; INDUCED APOPTOSIS; GENE-EXPRESSION; BLADDER-CANCER; TARGETING EGFR AB Genistein has been shown to inhibit cancers both in vitro and in vivo, by altering the expression of several microRNAs (miRNAs). In this study, we focused on tumor suppressor miRNAs regulated by genistein and investigated their function in prostate cancer (PCa) and target pathways. Using miRNA microarray analysis and real-time RT-PCR we observed that miR-574-3p was significantly up-regulated in PCa cells treated with genistein compared with vehicle control. The expression of miR-574-3p was significantly lower in PCa cell lines and clinical PCa tissues compared with normal prostate cells (RWPE-1) and adjacent normal tissues. Low expression level of miR-574-3p was correlated with advanced tumor stage and higher Gleason score in PCa specimens. Re-expression of miR-574-3p in PCa cells significantly inhibited cell proliferation, migration and invasion in vitro and in vivo. miR-574-3p restoration induced apoptosis through reducing Bcl-xL and activating caspase-9 and caspase-3. Using GeneCodis software analysis, several pathways affected by miR-574-3p were identified, such as 'Pathways in cancer', 'Jak-STAT signaling pathway', and 'Wnt signaling pathway'. Luciferase reporter assays demonstrated that miR-574-3p directly binds to the 39 UTR of several target genes (such as RAC1, EGFR and EP300) that are components of 'Pathways in cancer'. Quantitative real-time PCR and Western analysis showed that the mRNA and protein expression levels of the three target genes in PCa cells were markedly down-regulated with miR-574-3p. Loss-of-function studies demonstrated that the three target genes significantly affect cell proliferation, migration and invasion in PCa cell lines. Our results show that genistein up-regulates tumor suppressor miR-574-3p expression targeting several cell signaling pathways. These findings enhance understanding of how genistein regulates with miRNA in PCa. C1 [Chiyomaru, Takeshi; Yamamura, Soichiro; Fukuhara, Shinichiro; Majid, Shahana; Saini, Sharanjot; Arora, Sumit; Deng, Guoren; Shahryari, Varahram; Chang, Inik; Tanaka, Yuichiro; Dahiya, Rajvir] San Francisco VA Med Ctr, Dept Urol, San Francisco, CA 94121 USA. [Chiyomaru, Takeshi; Yamamura, Soichiro; Fukuhara, Shinichiro; Majid, Shahana; Saini, Sharanjot; Arora, Sumit; Deng, Guoren; Shahryari, Varahram; Chang, Inik; Tanaka, Yuichiro; Tabatabai, Z. Laura; Dahiya, Rajvir] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hidaka, Hideo; Enokida, Hideki; Nakagawa, Masayuki] Kagoshima Univ, Dept Urol, Grad Sch Med & Dent Sci, Kagoshima 890, Japan. [Tabatabai, Z. Laura] San Francisco VA Med Ctr, Dept Pathol, San Francisco, CA USA. [Seki, Naohiko] Chiba Univ, Grad Sch Med, Dept Funct Genom, Chiba, Japan. RP Dahiya, R (reprint author), San Francisco VA Med Ctr, Dept Urol, San Francisco, CA 94121 USA. EM rdahiya@urology.ucsf.edu FU National Center for Research Resources of the National Institutes of Health [R01CA160079, R01CA138642, T32DK007790]; VA Merit Review; VA Program Project FX This research was supported by the National Center for Research Resources of the National Institutes of Health through Grant Numbers R01CA160079, R01CA138642, T32DK007790 and VA Merit Review and VA Program Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 49 Z9 52 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 12 PY 2013 VL 8 IS 3 AR e58929 DI 10.1371/journal.pone.0058929 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107WV UT WOS:000316252500058 PM 23554959 ER PT J AU Kamlet, AS Neumann, CN Lee, E Carlin, SM Moseley, CK Stephenson, N Hooker, JM Ritter, T AF Kamlet, Adam S. Neumann, Constanze N. Lee, Eunsung Carlin, Stephen M. Moseley, Christian K. Stephenson, Nickeisha Hooker, Jacob M. Ritter, Tobias TI Application of Palladium-Mediated F-18-Fluorination to PET Radiotracer Development: Overcoming Hurdles to Translation SO PLOS ONE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; RECEPTOR MESSENGER-RNA; REDUCTIVE ELIMINATION; CELLULAR-LOCALIZATION; TRANSPORTER BINDING; DRUG DEVELOPMENT; HUMAN BRAIN; FLUORINE; CHEMISTRY; LIGANDS AB New chemistry methods for the synthesis of radiolabeled small molecules have the potential to impact clinical positron emission tomography (PET) imaging, if they can be successfully translated. However, progression of modern reactions from the stage of synthetic chemistry development to the preparation of radiotracer doses ready for use in human PET imaging is challenging and rare. Here we describe the process of and the successful translation of a modern palladium-mediated fluorination reaction to non-human primate (NHP) baboon PET imaging-an important milestone on the path to human PET imaging. The method, which transforms [F-18]fluoride into an electrophilic fluorination reagent, provides access to aryl-F-18 bonds that would be challenging to synthesize via conventional radiochemistry methods. C1 [Kamlet, Adam S.; Neumann, Constanze N.; Lee, Eunsung; Stephenson, Nickeisha; Ritter, Tobias] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Carlin, Stephen M.; Moseley, Christian K.; Hooker, Jacob M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Carlin, Stephen M.; Moseley, Christian K.; Hooker, Jacob M.] Harvard Univ, Sch Med, Charlestown, MA USA. [Hooker, Jacob M.; Ritter, Tobias] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. RP Hooker, JM (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM hooker@nmr.mgh.harvard.edu; ritter@chemistry.harvard.edu RI Lee, Eunsung/F-5308-2013; OI Hooker, Jacob/0000-0002-9394-7708 FU National Institutes of Health (NIH) [GM088237, MH093874, EB013042, S10RR017208, S10RR022976] FX This work was supported by the National Institutes of Health (NIH) (GM088237, MH093874, EB013042, S10RR017208, and S10RR022976). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 27 Z9 27 U1 3 U2 64 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 MAR 12 PY 2013 VL 8 IS 3 AR e59187 DI 10.1371/journal.pone.0059187 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107WV UT WOS:000316252500072 PM 23554994 ER PT J AU Stipp, RN Boisvert, H Smith, DJ Hofling, JF Duncan, MJ Mattos-Graner, RO AF Stipp, Rafael N. Boisvert, Heike Smith, Daniel J. Hoefling, Jose F. Duncan, Margaret J. Mattos-Graner, Renata O. TI CovR and VicRK Regulate Cell Surface Biogenesis Genes Required for Biofilm Formation in Streptococcus mutans SO PLOS ONE LA English DT Article ID GLUCAN-BINDING-PROTEIN; GLUCOSYLTRANSFERASE GTFBC OPERON; SIGNAL-TRANSDUCTION PATHWAY; YYCF RESPONSE REGULATOR; GRAM-POSITIVE BACTERIA; STAPHYLOCOCCUS-AUREUS; ORAL STREPTOCOCCI; MUREIN HYDROLASE; PNEUMONIAE R6; IN-VIVO AB The two-component system VicRK and the orphan regulator CovR of Streptococcus mutans co-regulate a group of virulence genes associated with the synthesis of and interaction with extracellular polysaccharides of the biofilm matrix. Knockout mutants of vicK and covR display abnormal cell division and morphology phenotypes, although the gene function defects involved are as yet unknown. Using transcriptomic comparisons between parent strain UA159 with vicK (UAvic) or covR (UAcov) deletion mutants together with electrophoretic motility shift assays (EMSA), we identified genes directly regulated by both VicR and CovR with putative functions in cell wall/surface biogenesis, including gbpB, wapE, smaA, SMU.2146c, and lysM. Deletion mutants of genes regulated by VicR and CovR (wapE, lysM, smaA), or regulated only by VicR (SMU.2146c) or CovR (epsC) promoted significant alterations in biofilm initiation, including increased fragility, defects in microcolony formation, and atypical cell morphology and/or chaining. Significant reductions in mureinolytic activity and/or increases in DNA release during growth were observed in knockout mutants of smaA, wapE, lysM, SMU.2146c and epsC, implying roles in cell wall biogenesis. WapE and lysM mutations also affected cell hydrophobicity and sensitivity to osmotic or oxidative stress. Finally, vicR, covR and VicRK/CovR-targets (gbpB, wapE, smaA, SMU.2146c, lysM, epsC) are up-regulated in UA159 during biofilm initiation, in a sucrose-dependent manner. These data support a model in which VicRK and CovR coordinate cell division and surface biogenesis with the extracellular synthesis of polysaccharides, a process apparently required for formation of structurally stable biofilms in the presence of sucrose. C1 [Stipp, Rafael N.; Hoefling, Jose F.; Mattos-Graner, Renata O.] Univ Campinas UNICAMP, Dept Oral Diag, Piracicaba Dent Sch, Sao Paulo, Brazil. [Boisvert, Heike; Duncan, Margaret J.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Smith, Daniel J.] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. RP Mattos-Graner, RO (reprint author), Univ Campinas UNICAMP, Dept Oral Diag, Piracicaba Dent Sch, Sao Paulo, Brazil. EM rmgraner@fop.unicamp.br RI Mattos-Graner, Renata/C-9410-2012 OI Mattos-Graner, Renata/0000-0001-8309-8135 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [proc. 07/56100-2, 09/54182-7, proc. 06/55933-8]; National Institutes of Health (NIH) Fogarty award [R03-TW-06324]; CAPES (PNPD); [R01 DE15931]; [R37 DE06153] FX This study was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, proc. 07/56100-2 and 09/54182-7) and the National Institutes of Health (NIH) Fogarty award R03-TW-06324. RNS was supported by FAPESP (proc. 06/55933-8) and CAPES (PNPD, 2010). MJD was supported by R01 DE15931 and R37 DE06153. DJS was supported by R37 DE06153. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 15 Z9 16 U1 1 U2 23 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 12 PY 2013 VL 8 IS 3 AR e58271 DI 10.1371/journal.pone.0058271 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107WV UT WOS:000316252500019 PM 23554881 ER PT J AU Iskandrian, AE Hage, FG AF Iskandrian, Ami E. Hage, Fadi G. TI Declining Frequency of Ischemia Detection Using Stress Myocardial Perfusion Imaging SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE coronary artery disease risk factors; myocardial ischemia; perfusion; prognosis ID AMERICAN-HEART-ASSOCIATION; CORONARY-ARTERY-DISEASE; OPTIMAL MEDICAL THERAPY; COMPUTED-TOMOGRAPHY; NUCLEAR CARDIOLOGY; TRIAL; OUTCOMES; RISK C1 [Iskandrian, Ami E.] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Hage, Fadi G.] Birmingham Vet Affairs Med Ctr, Div Cardiol, Birmingham, AL USA. RP Iskandrian, AE (reprint author), Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, 318 LHRB,1900 Univ Blvd, Birmingham, AL 35294 USA. EM aiskand@uab.edu OI Hage, Fadi/0000-0002-1397-4942 NR 17 TC 10 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 12 PY 2013 VL 61 IS 10 BP 1066 EP 1068 DI 10.1016/j.jacc.2012.12.009 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 100HA UT WOS:000315687300006 PM 23473412 ER PT J AU Knight, SJ AF Knight, Sara J. TI Bridging the Gap at the Center of Patient Centeredness Individual Patient Preferences in Health Care Decision Making SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID MEN C1 [Knight, Sara J.] US Dept Vet Affairs, Hlth Serv Res & Dev Serv, Off Res & Dev, Vet Hlth Adm, Washington, DC 20420 USA. [Knight, Sara J.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Knight, Sara J.] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA. RP Knight, SJ (reprint author), US Dept Vet Affairs, Hlth Serv Res & Dev Serv, Off Res & Dev, Vet Hlth Adm, 180 Vermont Ave NW, Washington, DC 20420 USA. EM sara.knight@va.gov NR 9 TC 1 Z9 1 U1 2 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR 11 PY 2013 VL 173 IS 5 BP 369 EP 370 DI 10.1001/jamainternmed.2013.3370 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 153OY UT WOS:000319613100009 PM 23400376 ER PT J AU Prochazka, AV Caverly, T AF Prochazka, Allan V. Caverly, Tanner TI General Health Checks in Adults for Reducing Morbidity and Mortality From Disease Summary Review of Primary Findings and Conclusions SO JAMA INTERNAL MEDICINE LA English DT Editorial Material C1 [Prochazka, Allan V.] Denver VA Med Ctr, Dept Ambulatory Care, Denver, CO 80220 USA. Univ Colorado, Sch Med, Div Gen Internal Med, Denver, CO USA. RP Prochazka, AV (reprint author), Denver VA Med Ctr, Dept Ambulatory Care, 11B,1055 Clermont, Denver, CO 80220 USA. EM allan.prochazka@va.gov NR 8 TC 5 Z9 6 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR 11 PY 2013 VL 173 IS 5 BP 371 EP 372 DI 10.1001/jamainternmed.2013.3187 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 153OY UT WOS:000319613100010 PM 23318544 ER PT J AU Dodson, JA Fried, TR Van Ness, PH Goldstein, NE Lampert, R AF Dodson, John A. Fried, Terri R. Van Ness, Peter H. Goldstein, Nathan E. Lampert, Rachel TI Patient Preferences for Deactivation of Implantable Cardioverter-Defibrillators SO JAMA INTERNAL MEDICINE LA English DT Letter ID LIFE; END; MANAGEMENT C1 [Dodson, John A.; Lampert, Rachel] Yale Univ, Sch Med, Cardiol Sect, Dept Internal Med, New Haven, CT 06520 USA. [Dodson, John A.; Fried, Terri R.; Van Ness, Peter H.] Yale Univ, Sch Med, Sect Geriatr, Dept Internal Med, New Haven, CT 06520 USA. Mt Sinai Sch Med, Dept Geriatr & Palliat Care, New York, NY USA. [Goldstein, Nathan E.] James J Peters VA Med Ctr, Bronx, NY USA. RP Lampert, R (reprint author), Yale Univ, Sch Med, Cardiol Sect, 789 Howard Ave,Dana 3,Room 319, New Haven, CT 06520 USA. EM rachel.lampert@yale.edu FU NIA NIH HHS [T32 AG019134, P30 AG021342, P30AG021342, K24AG028443, K24 AG028443] NR 9 TC 18 Z9 18 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR 11 PY 2013 VL 173 IS 5 BP 377 EP 379 DI 10.1001/jamainternmed.2013.1883 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 153OY UT WOS:000319613100013 PM 23358714 ER PT J AU Steinman, MA AF Steinman, Michael A. TI Reaching Out to Patients to Identify Adverse Drug Reactions and Nonadherence: Necessary but Not Sufficient SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID MEDICATION; CARE C1 [Steinman, Michael A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Steinman, Michael A.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. RP Steinman, MA (reprint author), San Francisco VA Med Ctr, POB 181G,4150 Clement St, San Francisco, CA 94121 USA. EM mike.steinman@ucsf.edu FU NIA NIH HHS [K23 AG030999, 1K23-AG030999.] NR 8 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR 11 PY 2013 VL 173 IS 5 BP 384 EP 385 DI 10.1001/jamainternmed.2013.2965 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 153OY UT WOS:000319613100017 PM 23381677 ER PT J AU Chatterjee, P Joynt, KE Jha, AK AF Chatterjee, Paula Joynt, Karen E. Jha, Ashish K. TI Safety-Net Hospitals: Other Hospitals Score Similarly on Patient Experience reply SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Chatterjee, Paula; Joynt, Karen E.; Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy, Boston, MA 02115 USA. [Chatterjee, Paula; Joynt, Karen E.; Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Dept Management, Boston, MA 02115 USA. [Joynt, Karen E.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Jha, Ashish K.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. [Joynt, Karen E.; Jha, Ashish K.] VA Boston Healthcare Syst, Boston, MA USA. [Joynt, Karen E.] Harvard Univ, Div Cardiovasc Med, Sch Med, Boston, MA 02115 USA. [Jha, Ashish K.] Harvard Univ, Div Gen Internal Med, Sch Med, Boston, MA 02115 USA. [Chatterjee, Paula] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Jha, AK (reprint author), Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, 677 Huntington Ave, Boston, MA 02115 USA. EM ajha@hsph.harvard.edu NR 3 TC 0 Z9 0 U1 2 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD MAR 11 PY 2013 VL 173 IS 5 BP 390 EP 391 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 153OY UT WOS:000319613100022 ER PT J AU Naik, AD Martin, LA Karel, M Wachen, JS Mulligan, E Gosian, JS Herman, LI Moye, J AF Naik, Aanand D. Martin, Lindsey A. Karel, Michele Wachen, Jennifer Schuster Mulligan, Elizabeth Gosian, Jeffrey S. Herman, Levi Ian Moye, Jennifer TI Cancer survivor rehabilitation and recovery: Protocol for the Veterans Cancer Rehabilitation Study (Vet-CaRes) SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Cancer care; Cancer survivorship; Veterans; Aging; Psychosocial; Functional assessment; Quality of life ID QUALITY-OF-LIFE; BREAST-CANCER; QUESTIONNAIRE; HEALTH; OLDER; COMORBIDITY; RELIABILITY; PERSPECTIVE; DISTRESS; VALIDITY AB Background: Cancer survivors are a rapidly growing and aging population in the U. S., but there are many challenges associated with the survivorship experience such as functional disabilities and psychosocial distress. When viewed next to the general population, Veterans are especially at risk for these challenges as they are older and have a high incidence of co-morbid conditions. While the Institute of Medicine (IOM) has called for further cancer survivorship research to address these challenges, we still know little about this experience from the perspective of aging Veterans. Methods/design: We conducted a longitudinal, mixed-methods study over the course of three and a half years at the Boston and Houston VA Medical Centers. We recruited 170 Veterans diagnosed with head and neck, colorectal and esophageal/gastric cancers that were identified from the VA tumor registry. Veterans completed three in-depth interviews, conducted at 6, 12 and 18 months after pathology confirmation, measuring the physical, social and psychological factors related to cancer survivorship. The longitudinal design allowed us to assess any changes in cancer related disability and distress over time. Discussion: Weekly teleconference study team meetings were a key aspect to the research process. Issues related to recruitment, data management and analysis, and the dissemination of research results was discussed. Interviewers presented detailed case reports of completed interviews that allowed us to refine our interview protocols. We also discussed issues relevant to the Veteran population of which we were previously unaware and some of the challenges of the research process itself. This novel study produced a robust data set that documents the functional and psychosocial cancer survivorship experiences of aging Veterans. The longitudinal design will help us more fully understand the recovery patterns for this specific population, and identify the unique needs and gaps in health services. C1 [Naik, Aanand D.; Martin, Lindsey A.; Herman, Levi Ian] Michael E DeBakey VA Med Ctr, Houston VA Hlth Serv, Res & Dev Ctr Excellence, Houston, TX USA. [Naik, Aanand D.; Martin, Lindsey A.; Herman, Levi Ian] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Karel, Michele; Wachen, Jennifer Schuster; Mulligan, Elizabeth; Gosian, Jeffrey S.; Moye, Jennifer] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Karel, Michele; Mulligan, Elizabeth; Gosian, Jeffrey S.; Moye, Jennifer] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Wachen, Jennifer Schuster] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Martin, LA (reprint author), Michael E DeBakey VA Med Ctr, Houston VA Hlth Serv, Res & Dev Ctr Excellence, Houston, TX USA. EM Lindsey.Martin3@va.gov RI Moye, Jennifer/F-2240-2017 OI Moye, Jennifer/0000-0002-3434-347X FU Department of Veterans Affairs Rehabilitation Research and Development Service [5I01RX000104-02] FX Funding for this study was provided by the Department of Veterans Affairs Rehabilitation Research and Development Service (5I01RX000104-02). NR 45 TC 7 Z9 7 U1 1 U2 4 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 MAR 11 PY 2013 VL 13 AR 93 DI 10.1186/1472-6963-13-93 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 124KI UT WOS:000317461800001 PM 23497430 ER PT J AU Cleary, RT Sun, HY Huynh, T Manning, SM Li, YJ Rotenberg, A Talos, DM Kahle, KT Jackson, M Rakhade, SN Berry, G Jensen, FE AF Cleary, Ryan T. Sun, Hongyu Thanhthao Huynh Manning, Simon M. Li, Yijun Rotenberg, Alexander Talos, Delia M. Kahle, Kristopher T. Jackson, Michele Rakhade, Sanjay N. Berry, Gerard Jensen, Frances E. TI Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures SO PLOS ONE LA English DT Article ID NA-K-2CL COTRANSPORTER NKCC1; CRITICALLY ILL INFANTS; DEVELOPING BRAIN; ANTIEPILEPTIC DRUGS; APOPTOTIC NEURODEGENERATION; STATUS EPILEPTICUS; IMMATURE BRAIN; HIPPOCAMPUS; GABA; PHARMACOKINETICS AB Neonatal seizures can be refractory to conventional anticonvulsants, and this may in part be due to a developmental increase in expression of the neuronal Na+-K+-2 Cl- cotransporter, NKCC1, and consequent paradoxical excitatory actions of GABA(A) receptors in the perinatal period. The most common cause of neonatal seizures is hypoxic encephalopathy, and here we show in an established model of neonatal hypoxia-induced seizures that the NKCC1 inhibitor, bumetanide, in combination with phenobarbital is significantly more effective than phenobarbital alone. A sensitive mass spectrometry assay revealed that bumetanide concentrations in serum and brain were dose-dependent, and the expression of NKCC1 protein transiently increased in cortex and hippocampus after hypoxic seizures. Importantly, the low doses of phenobarbital and bumetanide used in the study did not increase constitutive apoptosis, alone or in combination. Perforated patch clamp recordings from ex vivo hippocampal slices removed following seizures revealed that phenobarbital and bumetanide largely reversed seizure-induced changes in E-GABA. Taken together, these data provide preclinical support for clinical trials of bumetanide in human neonates at risk for hypoxic encephalopathy and seizures. C1 [Cleary, Ryan T.; Sun, Hongyu; Thanhthao Huynh; Manning, Simon M.; Rotenberg, Alexander; Talos, Delia M.; Jackson, Michele; Rakhade, Sanjay N.; Jensen, Frances E.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Li, Yijun; Berry, Gerard] Childrens Hosp, Div Genet & Metab, Boston, MA 02115 USA. [Manning, Simon M.] Brigham & Womens Hosp, Div Newborn Med, Boston, MA 02115 USA. [Jensen, Frances E.] Harvard Univ, Sch Med, Program Neurobiol, Boston, MA USA. [Kahle, Kristopher T.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Kahle, Kristopher T.] Harvard Univ, Sch Med, Boston, MA USA. RP Jensen, FE (reprint author), Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. EM frances.jensen@uphs.upenn.edu OI Berry, Gerard/0000-0001-5299-3313 FU National Institutes of Health (NIH) [NS 31718, 1R21NS080268]; National Institutes of Health (NIH) (Office of the Director) [DPI OD003347]; Intellectual Developmental Disabilities Center [P30 HD18655] FX This work was supported by National Institutes of Health (NIH) Grants: NS 31718 (NINDS) (FEJ), DPI OD003347 (from the Office of the Director) (FEJ), 1R21NS080268 (FEJ), and Intellectual Developmental Disabilities Center Grant P30 HD18655 (NICHD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 39 Z9 40 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 11 PY 2013 VL 8 IS 3 AR e57148 DI 10.1371/journal.pone.0057148 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107WI UT WOS:000316251100007 PM 23536761 ER PT J AU Guo, YY Yuan, HS Cho, HS Kuruppu, D Jokivarsi, K Agarwal, A Shah, K Josephson, L AF Guo, Yanyan Yuan, Hushan Cho, Hoonsung Kuruppu, Darshini Jokivarsi, Kimmo Agarwal, Aayush Shah, Khalid Josephson, Lee TI High Efficiency Diffusion Molecular Retention Tumor Targeting SO PLOS ONE LA English DT Article ID BENIGN PROSTATIC HYPERPLASIA; RGD PEPTIDES; NEUROENDOCRINE TUMORS; THERAPY; DESIGN; CANCER; NANOPARTICLE; THERAPEUTICS; PROTEINS; ANALOGS AB Here we introduce diffusion molecular retention (DMR) tumor targeting, a technique that employs PEG-fluorochrome shielded probes that, after a peritumoral (PT) injection, undergo slow vascular uptake and extensive interstitial diffusion, with tumor retention only through integrin molecular recognition. To demonstrate DMR, RGD (integrin binding) and RAD (control) probes were synthesized bearing DOTA (for (111) In3+), a NIR fluorochrome, and 5 kDa PEG that endows probes with a protein-like volume of 25 kDa and decreases non-specific interactions. With a GFP-BT-20 breast carcinoma model, tumor targeting by the DMR or IV methods was assessed by surface fluorescence, biodistribution of [In-111] RGD and [In-111] RAD probes, and whole animal SPECT. After a PT injection, both probes rapidly diffused through the normal and tumor interstitium, with retention of the RGD probe due to integrin interactions. With PT injection and the [In-111] RGD probe, SPECT indicated a highly tumor specific uptake at 24 h post injection, with 352% ID/g tumor obtained by DMR (vs 4.14% ID/g by IV). The high efficiency molecular targeting of DMR employed low probe doses (e. g. 25 ng as RGD peptide), which minimizes toxicity risks and facilitates clinical translation. DMR applications include the delivery of fluorochromes for intraoperative tumor margin delineation, the delivery of radioisotopes (e. g. toxic, short range alpha emitters) for radiotherapy, or the delivery of photosensitizers to tumors accessible to light. C1 [Guo, Yanyan; Yuan, Hushan; Cho, Hoonsung; Kuruppu, Darshini; Josephson, Lee] Massachusetts Gen Hosp, Dept Radiol, Ctr Translat Nucl Med & Mol Imaging, Charlestown, MA 02129 USA. [Jokivarsi, Kimmo; Josephson, Lee] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Jokivarsi, Kimmo] Univ Eastern Finland, AI Virtanen Inst, Dept Neurobiol, Kuopio, Finland. [Agarwal, Aayush; Shah, Khalid] Massachusetts Gen Hosp, Mol Neurotherapy & Imaging Lab, Dept Radiol, Charlestown, MA USA. RP Josephson, L (reprint author), Massachusetts Gen Hosp, Dept Radiol, Ctr Translat Nucl Med & Mol Imaging, Charlestown, MA 02129 USA. EM ljosephson@mgh.harvard.edu FU National Institutes of Health [R01 EB 011996, R01 EB 009691] FX National Institutes of Health Grants to Josephson # R01 EB 011996 and # R01 EB 009691. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 7 Z9 7 U1 1 U2 23 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 11 PY 2013 VL 8 IS 3 AR e58290 DI 10.1371/journal.pone.0058290 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107WI UT WOS:000316251100041 PM 23505478 ER PT J AU Schwede, M Spentzos, D Bentink, S Hofmann, O Haibe-Kains, B Harrington, D Quackenbush, J Culhane, AC AF Schwede, Matthew Spentzos, Dimitrios Bentink, Stefan Hofmann, Oliver Haibe-Kains, Benjamin Harrington, David Quackenbush, John Culhane, Aedin C. TI Stem Cell-Like Gene Expression in Ovarian Cancer Predicts Type II Subtype and Prognosis SO PLOS ONE LA English DT Article ID NEGATIVE BREAST-CANCER; TO-MESENCHYMAL TRANSITION; GRADE SEROUS CARCINOMA; BRCA MUTATION CARRIERS; POLY(ADP-RIBOSE) POLYMERASE; MOLECULAR SUBTYPES; SET ENRICHMENT; P53 STATUS; TUMORS; METASTASIS AB Although ovarian cancer is often initially chemotherapy-sensitive, the vast majority of tumors eventually relapse and patients die of increasingly aggressive disease. Cancer stem cells are believed to have properties that allow them to survive therapy and may drive recurrent tumor growth. Cancer stem cells or cancer-initiating cells are a rare cell population and difficult to isolate experimentally. Genes that are expressed by stem cells may characterize a subset of less differentiated tumors and aid in prognostic classification of ovarian cancer. The purpose of this study was the genomic identification and characterization of a subtype of ovarian cancer that has stem cell-like gene expression. Using human and mouse gene signatures of embryonic, adult, or cancer stem cells, we performed an unsupervised bipartition class discovery on expression profiles from 145 serous ovarian tumors to identify a stem-like and more differentiated subgroup. Subtypes were reproducible and were further characterized in four independent, heterogeneous ovarian cancer datasets. We identified a stem-like subtype characterized by a 51-gene signature, which is significantly enriched in tumors with properties of Type II ovarian cancer; high grade, serous tumors, and poor survival. Conversely, the differentiated tumors share properties with Type I, including lower grade and mixed histological subtypes. The stem cell-like signature was prognostic within high-stage serous ovarian cancer, classifying a small subset of high-stage tumors with better prognosis, in the differentiated subtype. In multivariate models that adjusted for common clinical factors (including grade, stage, age), the subtype classification was still a significant predictor of relapse. The prognostic stem-like gene signature yields new insights into prognostic differences in ovarian cancer, provides a genomic context for defining Type I/II subtypes, and potential gene targets which following further validation may be valuable in the clinical management or treatment of ovarian cancer. C1 [Schwede, Matthew; Bentink, Stefan; Haibe-Kains, Benjamin; Harrington, David; Quackenbush, John; Culhane, Aedin C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hofmann, Oliver; Harrington, David; Quackenbush, John; Culhane, Aedin C.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Spentzos, Dimitrios] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Dept Med, Boston, MA 02215 USA. [Bentink, Stefan] Exosome Diagnost GmbH, Martinsried, Germany. [Haibe-Kains, Benjamin] Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada. RP Culhane, AC (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM aedin@jimmy.harvard.edu RI Haibe-Kains, Benjamin/D-3702-2011; OI Haibe-Kains, Benjamin/0000-0002-7684-0079; Hofmann, Oliver/0000-0002-7738-1513; Coppola, Vincenzo/0000-0001-6163-1779 FU National Institutes of Health [1U19CA148065]; Dana-Farber Cancer Institute Women's Cancers Program; Claudia Adams Barr foundation FX Funding for this work was provided by the National Institutes of Health 1U19CA148065 (J.Q., B.H.K.), Dana-Farber Cancer Institute Women's Cancers Program (awarded to A.C.C; M.S, A.C.C.) and the Claudia Adams Barr foundation (J.Q. and A.C.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 17 Z9 17 U1 1 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 MAR 11 PY 2013 VL 8 IS 3 AR e57799 DI 10.1371/journal.pone.0057799 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107WI UT WOS:000316251100016 PM 23536770 ER PT J AU Wright, AA Stieglitz, H Kupersztoch, YM Paulk, ME Kim, Y Katz, IT Munoz, F Jimenez, RB Mutchler, J Rivera, L Back, AL Prigerson, HG AF Wright, Alexi A. Stieglitz, Heather Kupersztoch, Yankel M. Paulk, M. Elizabeth Kim, Yookyung Katz, Ingrid T. Munoz, Francisco Jimenez, Rachel B. Mutchler, Jan Rivera, Lorna Back, Anthony L. Prigerson, Holly G. TI United States Acculturation and Cancer Patients' End-of-Life Care SO PLOS ONE LA English DT Article ID STAGE LUNG-CANCER; ETHNIC-DIFFERENCES; SOCIOECONOMIC-STATUS; RACIAL-DIFFERENCES; MEXICAN-AMERICANS; AFRICAN-AMERICAN; CLINICAL-TRIALS; CULTURAL ISSUES; PALLIATIVE CARE; THE-LITERATURE AB Background: Culture shapes how people understand illness and death, but few studies examine whether acculturation influences patients' end-of-life treatment preferences and medical care. Methods and Findings: In this multi-site, prospective, longitudinal cohort study of terminally-ill cancer patients and their caregivers (n = 171 dyads), trained interviewers administered the United States Acculturation Scale (USAS). The USAS is a 19-item scale developed to assess the degree of "Americanization" in first generation or non-US born caregivers of terminally-ill cancer patients. We evaluated the internal consistency, concurrent, criterion, and content validity of the USAS. We also examined whether caregivers' USAS scores predicted patients' communication, treatment preferences, and end-of-life medical care in multivariable models that corrected for significant confounding influences (e.g. education, country of origin, English proficiency). The USAS measure was internally consistent (Cronbach alpha = 0.98); and significantly associated with US birthplace (r = 0.66, P < 0.0001). USAS scores were predictive of patients' preferences for prognostic information (AOR = 1.31, 95% CI: 1.00-1.72), but not comfort asking physicians' questions about care (AOR 1.23, 95% CI: 0.87-1.73). They predicted patients' preferences for feeding tubes (AOR = 0.68, 95% CI: 0.49-0.99) and wish to avoid dying in an intensive care unit (AOR = 1.36, 95% CI: 1.05-1.76). Scores indicating greater acculturation were also associated with increased odds of patient participation in clinical trials (AOR = 2.20, 95% CI: 1.28-3.78), compared with lower USAS scores, and greater odds of patients receiving chemotherapy (AOR = 1.59, 95% CI: 1.20-2.12). Conclusion: The USAS is a reliable and valid measure of "Americanization" associated with advanced cancer patients' end-of-life preferences and care. USAS scores indicating greater caregiver acculturation were associated with increased odds of patient participation in cancer treatment (chemotherapy, clinical trials) compared with lower scores. Future studies should examine the effects of acculturation on end-of-life care to identify patient and provider factors that explain these effects and targets for future interventions to improve care (e.g., by designing more culturally-competent health education materials). C1 [Wright, Alexi A.; Prigerson, Holly G.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wright, Alexi A.; Jimenez, Rachel B.; Prigerson, Holly G.] Dana Farber Canc Inst, Ctr Psychosocial Epidemiol & Outcomes Res, Boston, MA 02115 USA. [Wright, Alexi A.; Katz, Ingrid T.; Jimenez, Rachel B.; Prigerson, Holly G.] Harvard Univ, Sch Med, Boston, MA USA. [Wright, Alexi A.; Prigerson, Holly G.] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. [Stieglitz, Heather] Parkland Ctr Clin Innovat, Dallas, TX USA. [Kupersztoch, Yankel M.; Paulk, M. Elizabeth] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Kim, Yookyung] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Katz, Ingrid T.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Munoz, Francisco] Pomona Valley Hosp Med Ctr, Pomona, CA USA. [Jimenez, Rachel B.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Mutchler, Jan; Rivera, Lorna] Univ Massachusetts, Boston, MA 02125 USA. [Back, Anthony L.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Prigerson, Holly G.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. RP Prigerson, HG (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM Holly_Prigerson@dfci.harvard.edu FU National Institute of Mental Health [MH63892]; National Cancer Institute [CA 106370, CA 156732]; Conquer Cancer Foundation of the American Society of Clinical Oncology; National Palliative Care Research Center; American Cancer Society; Center for Psychosocial Epidemiology and Outcomes Research, Dana-Farber Cancer Institute FX This research was supported in part by the following grants to Dr. Prigerson: MH63892 from the National Institute of Mental Health and CA 106370 and CA 156732 from the National Cancer Institute; by Career Development Awards sponsored by the Conquer Cancer Foundation of the American Society of Clinical Oncology, the National Palliative Care Research Center, and the American Cancer Society to Dr. Wright; and by the Center for Psychosocial Epidemiology and Outcomes Research, Dana-Farber Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 4 Z9 4 U1 4 U2 20 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 MAR 11 PY 2013 VL 8 IS 3 AR e58663 DI 10.1371/journal.pone.0058663 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 107WI UT WOS:000316251100076 PM 23536809 ER PT J AU Ohashi, K Maruvka, YE Michor, F Pao, W AF Ohashi, Kadoaki Maruvka, Yosef E. Michor, Franziska Pao, William TI Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-Resistant Disease SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID CELL LUNG-CANCER; CHRONIC MYELOID-LEUKEMIA; PREVIOUSLY TREATED PATIENTS; CISPLATIN PLUS GEMCITABINE; NERVOUS-SYSTEM METASTASES; DOSE WEEKLY ERLOTINIB; RANDOMIZED PHASE-III; ACQUIRED-RESISTANCE; EGFR MUTATIONS; NEVER-SMOKERS AB Purpose EGFR-mutant lung cancer was first described as a new clinical entity in 2004. Here, we present an update on new controversies and conclusions regarding the disease. Methods This article reviews the clinical implications of EGFR mutations in lung cancer with a focus on epidermal growth factor receptor tyrosine kinase inhibitor resistance. Results The discovery of EGFR mutations has altered the ways in which we consider and treat non-small-cell lung cancer (NSCLC). Patients whose metastatic tumors harbor EGFR mutations are expected to live longer than 2 years, more than double the previous survival rates for lung cancer. Conclusion The information presented in this review can guide practitioners and help them inform their patients about EGFR mutations and their impact on the treatment of NSCLC. Efforts should now concentrate on making EGFR-mutant lung cancer a chronic rather than fatal disease. J Clin Oncol 31:1070-1080. (C) 2013 by American Society of Clinical Oncology C1 [Ohashi, Kadoaki; Pao, William] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Maruvka, Yosef E.; Michor, Franziska] Dana Farber Canc Inst, Boston, MA 02115 USA. [Maruvka, Yosef E.; Michor, Franziska] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Pao, W (reprint author), Vanderbilt Ingram Canc Ctr, 2220 Pierce Ave,777 PRB, Nashville, TN 37232 USA. EM william.pao@vanderbilt.edu RI Mendez, Pedro /J-8955-2016 OI Mendez, Pedro /0000-0001-6713-7907 FU National Cancer Institute, National Institutes of Health [R01-CA121210, P01-CA129243, U54-CA143798, P30-CA68485]; AstraZeneca; Clovis; Bristol-Myers Squibb FX Supported by Grants No. R01-CA121210, P01-CA129243, U54-CA143798, and P30-CA68485 from the National Cancer Institute, National Institutes of Health.; William Pao, AstraZeneca, Clovis, Bristol-Myers Squibb NR 114 TC 161 Z9 168 U1 0 U2 41 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 MAR 10 PY 2013 VL 31 IS 8 BP 1070 EP 1080 DI 10.1200/JCO.2012.43.3912 PG 11 WC Oncology SC Oncology GA 104LL UT WOS:000315994300011 PM 23401451 ER PT J AU Oxnard, GR Binder, A Janne, PA AF Oxnard, Geoffrey R. Binder, Adam Jaenne, Pasi A. TI New Targetable Oncogenes in Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID GROWTH-FACTOR RECEPTOR; ANAPLASTIC LYMPHOMA KINASE; HARBORING BRAF MUTATIONS; PHASE-III TRIAL; THYROID-CANCER; SIGNALING PATHWAY; BREAST-CANCER; PIK3CA GENE; ADENOCARCINOMA; INHIBITOR AB The identification of oncogenic driver mutations underlying sensitivity to epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors has led to a surge of interest in identifying additional targetable oncogenes in non-small-cell lung cancer. A number of new potentially oncogenic gene alterations have been characterized in recent years, including BRAF mutations, HER2 insertions, PIK3CA mutations, FGFR1 amplifications, DDR2 mutations, ROS1 rearrangements, and RET rearrangements. In this review, we will discuss the techniques used to discover each of these candidate oncogenes, the prevalence of each in non-small-cell lung cancer, the preclinical data supporting their role in lung cancer, and data on small molecular inhibitors in development. J Clin Oncol 31:1097-1104. (C) 2013 by American Society of Clinical Oncology C1 [Oxnard, Geoffrey R.; Jaenne, Pasi A.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Oxnard, Geoffrey R.; Jaenne, Pasi A.] Harvard Univ, Sch Med, Boston, MA USA. [Binder, Adam] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, 450 Brookline Ave,HIM223, Boston, MA 02215 USA. EM pasi_janne@dfci.harvard.edu FU National Cancer Institute, National Institutes of Health [P50-CA090578] FX Supported in part by Grant No. P50-CA090578 from the National Cancer Institute, National Institutes of Health. NR 81 TC 132 Z9 135 U1 4 U2 42 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 MAR 10 PY 2013 VL 31 IS 8 BP 1097 EP 1104 DI 10.1200/JCO.2012.42.9829 PG 8 WC Oncology SC Oncology GA 104LL UT WOS:000315994300014 PM 23401445 ER PT J AU Shaw, AT Engelman, JA AF Shaw, Alice T. Engelman, Jeffrey A. TI ALK in Lung Cancer: Past, Present, and Future SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID ANAPLASTIC LYMPHOMA KINASE; EML4-ALK FUSION GENE; EGFR MUTATION; 1ST-LINE TREATMENT; OPEN-LABEL; RESISTANCE; CHEMOTHERAPY; GEFITINIB; CRIZOTINIB; INHIBITORS AB In 2007, scientists discovered that anaplastic lymphoma kinase (ALK) gene rearrangements are present in a small subset of non-small-cell lung cancers. ALK-positive cancers are highly sensitive to small-molecule ALK kinase inhibitors, such as crizotinib. Phase I and II studies of crizotinib in ALK-positive lung cancer demonstrated impressive activity and clinical benefit, leading to rapid US Food and Drug Administration approval in 2011. Although crizotinib induces remissions and extends the lives of patients, cures are not achieved as resistance to therapy develops. In this review, we will discuss the history of this field, current diagnostic and treatment practices, and future challenges and opportunities to advance outcomes for patients with ALK-positive lung cancers. J Clin Oncol 31:1105-1111. (C) 2013 by American Society of Clinical Oncology C1 [Shaw, Alice T.; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Shaw, Alice T.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. RP Shaw, AT (reprint author), Massachusetts Gen Hosp, Ctr Canc, Yawkey 7B,32 Fruit St, Boston, MA 02114 USA. EM ashaw1@partners.org FU Novartis; AstraZeneca; sanofi-aventis FX Alice T. Shaw, Novartis, AstraZeneca; Jeffrey A. Engelman, Novartis, AstraZeneca, sanofi-aventis NR 45 TC 130 Z9 136 U1 2 U2 33 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2013 VL 31 IS 8 BP 1105 EP 1111 DI 10.1200/JCO.2012.44.5353 PG 7 WC Oncology SC Oncology GA 104LL UT WOS:000315994300015 PM 23401436 ER PT J AU Barthelemy, O Limbourg, T Collet, JP Beygui, F Silvain, J Bellemain-Appaix, A Cayla, G Chastre, T Baumgartner, I Rother, J Zeymer, U Bhatt, DL Steg, G Montalescot, G AF Barthelemy, Olivier Limbourg, Tobias Collet, Jean Philippe Beygui, Farzin Silvain, Johanne Bellemain-Appaix, Anne Cayla, Guillaume Chastre, Thomas Baumgartner, Iris Roether, Joachim Zeymer, Uwe Bhatt, Deepak L. Steg, Gabriel Montalescot, Gilles CA REACH Registry Investigators TI Impact of non-steroidal anti-inflammatory drugs (NSAIDs) on cardiovascular outcomes in patients with stable atherothrombosis or multiple risk factors SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE NSAIDs; Cardiovascular outcomes; Myocardial infarction; Stroke; Bleeding; Atherothrombosis ID RANDOMIZED CONTROLLED-TRIAL; RHEUMATOID-ARTHRITIS; CYCLOOXYGENASE-2 INHIBITORS; GASTROINTESTINAL TOXICITY; MYOCARDIAL-INFARCTION; BLOOD-PRESSURE; STROKE; ROFECOXIB; CELECOXIB; NAPROXEN AB Background: We aimed to assess whether the use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of cardiovascular (CV) events in stable patients with established atherothrombosis or multiple risk factors. Methods: We analysed the 23,728 European patients of the REACH Registry; 20,588 (86.8%) had established atherothrombotic disease and 3140 (13.2%) had multiple risk factors only. Aspirin (ASA) and/or NSAIDs use was determined at enrolment and ischemic events were recorded over two years of follow-up. cMACCE was defined as the composite of CV death, MI or stroke. Bleeding was defined as any bleeding leading to both hospitalisation and transfusion. Results: The mean age of population was 67.2 +/- 9.8 years. At baseline, 1573 patients (6.6%) received NSAIDs and 15,395 (64.9%) received ASA. Four groups were defined: 1) no ASA/no NSAIDs, 2) ASA only, 3) NSAIDs only, 4) NSAIDs + ASA, with 7722 (32.5%), 14,433 (60.8%), 611 (2.6%) and 962 (4.1%) patients in these groups, respectively. Among the 22,028 (92.8%) with complete 2-year follow-up, 683 (3.2%) died from CV causes, while 395 (1.9%) had MI, 665 (3.1%) stroke, 1651 (7.6%) cMACCE and 199 (1.0%) bleeding. After adjustment, NSAID use was independently associated with an increased risk of stroke (OR 1.635; 95% CI 1.239-2.159, p<0.001), and a trend towards an increased bleeding rate (OR 1.554; CI 95% 0.960-2.51, p=0.07). No association was found between NSAID use and MI or MACCE. Conclusions: In stable atherothrombosis patients, the use of NSAIDs appears to be independently associated with an increased cerebrovascular event risk. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Barthelemy, Olivier; Collet, Jean Philippe; Beygui, Farzin; Silvain, Johanne; Bellemain-Appaix, Anne; Cayla, Guillaume; Chastre, Thomas; Montalescot, Gilles] APHP, Inst Cardiol, INSERM, CMR937, Paris, France. [Barthelemy, Olivier; Collet, Jean Philippe; Beygui, Farzin; Silvain, Johanne; Bellemain-Appaix, Anne; Cayla, Guillaume; Chastre, Thomas; Montalescot, Gilles] Univ Paris 06, Pitie Salpetriere Hosp, Paris, France. [Limbourg, Tobias; Zeymer, Uwe] Heidelberg Univ, Inst Herzinfarktforsch Ludwigshafen, Ludwigshafen, Germany. [Baumgartner, Iris] Univ Hosp Bern, Swiss Cardiovasc Ctr, Div Clin & Intervent Angiol, Inselspital, CH-3010 Bern, Switzerland. [Roether, Joachim] Hamburg Med Sch, Dept Neurol, Asklepios Klin Altona, Hamburg, Germany. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Steg, Gabriel] Univ Paris 07, INSERM, U698, Paris, France. [Steg, Gabriel] AP HP, Paris, France. RP Montalescot, G (reprint author), Ctr Hosp Univ Pitie Salpetriere, AP HP, Inst Cardiol, Bur 236, 47-83 Blvd Hop, F-75013 Paris, France. EM gilles.montalescot@psl.aphp.fr FU Sanofi-Aventis; Bristol-Myers Squibb; Waksman Foundation (Tokyo, Japan) FX The REACH Registry is sponsored by Sanofi-Aventis, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan). The REACH Registry is endorsed by the World Heart Federation. A complete list of REACH investigators is accessible online at www.reachregistry.org. The REACH Registry enforces a no ghost-writing policy. The first draught was written by Olivier Barthelemy. We thank Deborah Burrage, PhD, for her assistance with coordinating revisions and providing editorial help in preparing this manuscript including editing, checking content and language, formatting, referencing and preparing tables and figures, and Tobias Limbourg for his support with statistical analyses. NR 30 TC 8 Z9 8 U1 7 U2 27 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD MAR 10 PY 2013 VL 163 IS 3 BP 266 EP 271 DI 10.1016/j.ijcard.2011.06.015 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 092XJ UT WOS:000315156000013 PM 21719126 ER PT J AU Pride, YB Cutlip, DE AF Pride, Yuri B. Cutlip, Donald E. TI Disappearing stents-DREAMS of a sorcerer's apprentice? SO LANCET LA English DT Editorial Material ID PACLITAXEL-ELUTING STENTS; VASCULAR SCAFFOLD; CORONARY-ARTERIES; EVEROLIMUS; THROMBOSIS; OUTCOMES; 2ND-GENERATION; METAANALYSIS; HUMANS; TRIAL C1 [Pride, Yuri B.; Cutlip, Donald E.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Cardiovasc Med,Dept Med, Boston, MA 02215 USA. RP Cutlip, DE (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Cardiovasc Med,Dept Med, Boston, MA 02215 USA. EM dcutlip@bidmc.harvard.edu NR 16 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD MAR 9 PY 2013 VL 381 IS 9869 BP 787 EP 789 DI 10.1016/S0140-6736(12)62036-4 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 105IL UT WOS:000316060600009 PM 23332166 ER PT J AU He, YQ Cao, ZW De Groot, AS Brusic, V Schonbach, C Petrovsky, N AF He, Yongqun Cao, Zhiwei De Groot, Anne S. Brusic, Vladimir Schoenbach, Christian Petrovsky, Nikolai TI Computational vaccinology and the ICoVax 2012 workshop SO BMC BIOINFORMATICS LA English DT Editorial Material ID YELLOW-FEVER VACCINE; IMMUNOTHERAPY VACCINES; REVERSE VACCINOLOGY; EPITOPE PREDICTION; SYSTEMS BIOLOGY; UNITED-STATES; ASSOCIATION; DETERMINANTS; INFORMATICS; RESPONSES AB Computational vaccinology or vaccine informatics is an interdisciplinary field that addresses scientific and clinical questions in vaccinology using computational and informatics approaches. Computational vaccinology overlaps with many other fields such as immunoinformatics, reverse vaccinology, postlicensure vaccine research, vaccinomics, literature mining, and systems vaccinology. The second ISV Pre-conference Computational Vaccinology Workshop (ICoVax 2012) was held on October 13, 2013 in Shanghai, China. A number of topics were presented in the workshop, including allergen predictions, prediction of linear T cell epitopes and functional conformational epitopes, prediction of protein-ligand binding regions, vaccine design using reverse vaccinology, and case studies in computational vaccinology. Although a significant progress has been made to date, a number of challenges still exist in the field. This Editorial provides a list of major challenges for the future of computational vaccinology and identifies developing themes that will expand and evolve over the next few years. C1 [He, Yongqun] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Unit Lab Anim Med, Ann Arbor, MI 48109 USA. [He, Yongqun] Univ Michigan, Sch Med, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Cao, Zhiwei] Tongji Univ, Dept Biomed Engn, Coll Life Sci & Technol, Shanghai 200092, Peoples R China. [De Groot, Anne S.] EpiVax Inc, Providence, RI 02903 USA. [De Groot, Anne S.] Univ Rhode Isl, Inst Immunol & Informat, Providence, RI 02903 USA. [Brusic, Vladimir] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Schoenbach, Christian] Kyushu Inst Technol, Dept Biosci & Bioinformat, Fukuoka 8208502, Japan. [Schoenbach, Christian] Kyushu Inst Technol, Biomed Informat Res & Dev Ctr BMIRC, Fukuoka 8208502, Japan. [Petrovsky, Nikolai] Flinders Med Ctr, Bedford Pk, SA 5042, Australia. RP He, YQ (reprint author), Univ Michigan, Sch Med, Dept Microbiol & Immunol, Unit Lab Anim Med, Ann Arbor, MI 48109 USA. EM yongqunh@umich.edu RI De Groot, Anne/B-6221-2013; Schonbach, Christian/B-1998-2009; OI De Groot, Anne/0000-0001-5911-1459; Schonbach, Christian/0000-0002-0693-7617; He, Yongqun/0000-0001-9189-9661; Petrovsky, Nikolai/0000-0002-1580-5245 FU NIAID NIH HHS [1R01AI081062, U19AI082642] NR 48 TC 12 Z9 12 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAR 8 PY 2013 VL 14 SU 4 AR I1 DI 10.1186/1471-2105-14-S4-I1 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 142RR UT WOS:000318815300001 PM 23514034 ER PT J AU Bergwitz, C Wee, MJ Sinha, S Huang, JN DeRobertis, C Mensah, LB Cohen, J Friedman, A Kulkarni, M Hu, YH Vinayagam, A Schnall-Levin, M Berger, B Perkins, LA Mohr, SE Perrimon, N AF Bergwitz, Clemens Wee, Mark J. Sinha, Sumi Huang, Joanne DeRobertis, Charles Mensah, Lawrence B. Cohen, Jonathan Friedman, Adam Kulkarni, Meghana Hu, Yanhui Vinayagam, Arunachalam Schnall-Levin, Michael Berger, Bonnie Perkins, Lizabeth A. Mohr, Stephanie E. Perrimon, Norbert TI Genetic Determinants of Phosphate Response in Drosophila SO PLOS ONE LA English DT Article ID RECEPTOR TYROSINE KINASE; CHRONIC KIDNEY-DISEASE; VASCULAR CALCIFICATION; INORGANIC-PHOSPHATE; MINERAL METABOLISM; IN-VITRO; PROTEIN; EXPRESSION; MICE; BONE AB Phosphate is required for many important cellular processes and having too little phosphate or too much can cause disease and reduce life span in humans. However, the mechanisms underlying homeostatic control of extracellular phosphate levels and cellular effects of phosphate are poorly understood. Here, we establish Drosophila melanogaster as a model system for the study of phosphate effects. We found that Drosophila larval development depends on the availability of phosphate in the medium. Conversely, life span is reduced when adult flies are cultured on high phosphate medium or when hemolymph phosphate is increased in flies with impaired Malpighian tubules. In addition, RNAi-mediated inhibition of MAPK-signaling by knockdown of Ras85D, phl/D-Raf or Dsor1/MEK affects larval development, adult life span and hemolymph phosphate, suggesting that some in vivo effects involve activation of this signaling pathway by phosphate. To identify novel genetic determinants of phosphate responses, we used Drosophila hemocyte-like cultured cells (S2R+) to perform a genome-wide RNAi screen using MAPK activation as the readout. We identified a number of candidate genes potentially important for the cellular response to phosphate. Evaluation of 51 genes in live flies revealed some that affect larval development, adult life span and hemolymph phosphate levels. C1 [Bergwitz, Clemens; Wee, Mark J.; Sinha, Sumi; Huang, Joanne; DeRobertis, Charles; Mensah, Lawrence B.; Cohen, Jonathan] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Friedman, Adam; Kulkarni, Meghana; Hu, Yanhui; Vinayagam, Arunachalam; Perkins, Lizabeth A.; Mohr, Stephanie E.; Perrimon, Norbert] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, Boston, MA USA. [Schnall-Levin, Michael; Berger, Bonnie] MIT, Dept Math & Comp Sci, Cambridge, MA 02139 USA. [Schnall-Levin, Michael; Berger, Bonnie] MIT, Artificial Intelligence Lab, Cambridge, MA 02139 USA. RP Bergwitz, C (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. EM cwhb2002@yahoo.com OI arunachalam, vinayagam/0000-0003-0091-4497; Mohr, Stephanie/0000-0001-9639-7708 FU Harvard Catalyst; NIDDK [1K08 DK08361] FX CB received funding for this project by the Harvard Catalyst and NIDDK 1K08 DK08361. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 3 Z9 3 U1 0 U2 27 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 MAR 8 PY 2013 VL 8 IS 3 AR e56753 DI 10.1371/journal.pone.0056753 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 140TZ UT WOS:000318679900014 PM 23520455 ER PT J AU Dams, J Klotsche, J Bornschein, B Reese, JP Balzer-Geldsetzer, M Winter, Y Schrag, A Siderowf, A Oertel, WH Deuschl, G Siebert, U Dodel, R AF Dams, Judith Klotsche, Jens Bornschein, Bernhard Reese, Jens P. Balzer-Geldsetzer, Monika Winter, Yaroslav Schrag, Anette Siderowf, Andrew Oertel, Wolfgang H. Deuschl, Guenther Siebert, Uwe Dodel, Richard TI Mapping the EQ-5D index by UPDRS and PDQ-8 in patients with Parkinson's disease SO HEALTH AND QUALITY OF LIFE OUTCOMES LA English DT Article DE Parkinson's disease; Quality of life; EuroQoL/EQ-5D; UPDRS; PDQ-8; Prediction ID QUALITY-OF-LIFE AB Background: Clinical studies employ the Unified Parkinson's Disease Rating Scale (UPDRS) to measure the severity of Parkinson's disease. Evaluations often fail to consider the health-related quality of life (HrQoL) or apply disease-specific instruments. Health-economic studies normally use estimates of utilities to calculate quality-adjusted life years. We aimed to develop an estimation algorithm for EuroQol- 5 dimensions (EQ-5D)-based utilities from the clinical UPDRS or disease-specific HrQoL data in the absence of original utilities estimates. Methods: Linear and fractional polynomial regression analyses were performed with data from a study of Parkinson's disease patients (n=138) to predict the EQ-5D index values from UPDRS and Parkinson's disease questionnaire eight dimensions (PDQ-8) data. German and European weights were used to calculate the EQ-5D index. The models were compared by R-2, the root mean square error (RMS), the Bayesian information criterion, and Pregibon's link test. Three independent data sets validated the models. Results: The regression analyses resulted in a single best prediction model (R-2: 0.713 and 0.684, RMS: 0.139 and 13.78 for indices with German and European weights, respectively) consisting of UPDRS subscores II, III, IVa-c as predictors. When the PDQ-8 items were utilised as independent variables, the model resulted in an R-2 of 0.60 and 0.67. The independent data confirmed the prediction models. Conclusion: The best results were obtained from a model consisting of UPDRS subscores II, III, IVa-c. Although a good model fit was observed, primary EQ-5D data are always preferable. Further validation of the prediction algorithm within large, independent studies is necessary prior to its generalised use. C1 [Dams, Judith; Reese, Jens P.; Balzer-Geldsetzer, Monika; Winter, Yaroslav; Oertel, Wolfgang H.; Dodel, Richard] Philipps Univ, Dept Neurol, Marburg, Germany. [Klotsche, Jens] German Rheumatism Res Ctr, Leibniz Inst, Epidemiol Unit, Berlin, Germany. [Bornschein, Bernhard; Siebert, Uwe] UMIT Univ Hlth Sci, Dept Publ Hlth & Hlth Technol Assessment, Inst Publ Hlth, Hall It, Australia. [Schrag, Anette] Royal Free & Univ Coll Med Sch, Dept Clin Neurosci, London WC1E 6BT, England. [Siderowf, Andrew] Avid Radiopharmaceut, Philadelphia, PA USA. [Deuschl, Guenther] Univ Kiel, Dept Neurol, Kiel, Germany. [Siebert, Uwe] ONCOTYROL Ctr Personalized Canc Med, Div Publ Hlth Decis Modelling, Innsbruck, Austria. [Siebert, Uwe] Harvard Univ, Sch Med, Inst Technol Assessment, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Dodel, R (reprint author), Philipps Univ, Dept Neurol, Marburg, Germany. EM dodel@med.uni-marburg.de RI Deuschl, Gunther/A-7986-2010 FU German Federal Ministry of Education and Research/Parkinson Competence Network [01GI9901/1]; German Parkinson Association; COMET Center ONCOTYROL; Austrian Federal Ministries BMVIT/BMWFJ (via FFG); Tiroler Zukunftsstiftung/Standortagentur Tirol (SAT) FX This study was supported by a research grant from the German Federal Ministry of Education and Research/Parkinson Competence Network, 01GI9901/1 and the German Parkinson Association. Prof. Siebert's work was in part supported by the COMET Center ONCOTYROL, which is funded by the Austrian Federal Ministries BMVIT/BMWFJ (via FFG) and the Tiroler Zukunftsstiftung/Standortagentur Tirol (SAT). Andrew Siderowf is an employee of Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Co. No competing financial and non-financial interests exist which adversely affected the preparation of this manuscript. NR 16 TC 10 Z9 10 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7525 J9 HEALTH QUAL LIFE OUT JI Health Qual. Life Outcomes PD MAR 8 PY 2013 VL 11 AR 35 DI 10.1186/1477-7525-11-35 PG 7 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 126WE UT WOS:000317651900001 PM 23497005 ER PT J AU Arystarkhova, E Liu, YB Salazar, C Stanojevic, V Clifford, RJ Kaplan, JH Kidder, GM Sweadner, KJ AF Arystarkhova, Elena Liu, Yi B. Salazar, Cynthia Stanojevic, Violeta Clifford, Rebecca J. Kaplan, Jack H. Kidder, Gerald M. Sweadner, Kathleen J. TI Hyperplasia of Pancreatic Beta Cells and Improved Glucose Tolerance in Mice Deficient in the FXYD2 Subunit of Na, K-ATPase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SODIUM-POTASSIUM PUMP; GAMMA-SUBUNIT; RENAL NA,K-ATPASE; IMMUNOCYTOCHEMICAL LOCALIZATION; CRYSTAL-STRUCTURE; MAMMALIAN-CELLS; FUNCTIONAL-ROLE; CULTURED-CELLS; EXPRESSION; MASS AB Restoration of the functional potency of pancreatic islets either through enhanced proliferation (hyperplasia) or increase in size (hypertrophy) of beta cells is a major objective for intervention in diabetes. We have obtained experimental evidence that global knock-out of a small, single-span regulatory subunit of Na,K-ATPase, FXYD2, alters glucose control. Adult Fxyd2(-/-) mice showed significantly lower blood glucose levels, no signs of peripheral insulin resistance, and improved glucose tolerance compared with their littermate controls. Strikingly, there was a substantial hyperplasia in pancreatic beta cells from the Fxyd2(-/-) mice compared with the wild type littermates, compatible with an observed increase in the level of circulating insulin. No changes were seen in the exocrine compartment of the pancreas, and the mice had only a mild, well-adapted renal phenotype. Morphometric analysis revealed an increase in beta cell mass in KO compared with WT mice. This appears to explain a phenotype of hyperinsulinemia. By RT-PCR, Western blot, and immunocytochemistry we showed the FXYD2b splice variant in pancreatic beta cells from wild type mice. Phosphorylation of Akt kinase was significantly higher under basal conditions in freshly isolated islets from Fxyd2(-/-) mice compared with their WT littermates. Inducible expression of FXYD2 in INS 832/13 cells produced a reduction in the phosphorylation level of Akt, and phosphorylation was restored in parallel with degradation of FXYD2. Thus we suggest that in pancreatic beta cells FXYD2 plays a role in Akt signaling pathways associated with cell growth and proliferation. C1 [Arystarkhova, Elena; Liu, Yi B.; Salazar, Cynthia; Sweadner, Kathleen J.] Massachusetts Gen Hosp, Lab Membrane Biol, Boston, MA 02114 USA. [Stanojevic, Violeta] Massachusetts Gen Hosp, Mol Endocrinol Lab, Boston, MA 02114 USA. [Clifford, Rebecca J.; Kaplan, Jack H.] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. [Kidder, Gerald M.] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6C 2V5, Canada. [Kidder, Gerald M.] Childrens Hlth Res Inst, Div Genet & Dev, London, ON N6C 2V5, Canada. RP Arystarkhova, E (reprint author), Massachusetts Gen Hosp, Lab Membrane Biol, Edwards 410,55 Fruit St, Boston, MA 02114 USA. EM aristarkhova@helix.mgh.harvard.edu OI Kaplan, Jack/0000-0002-7048-6574 FU National Institutes of Health [HL036271, NS045083, NS050696]; Pilot Feasibility Grant [5P30DK057521-12]; American Recovery and Reinvestment Act supplement [NS050696] FX This work was supported, in whole or in part, by National Institutes of Health Grants HL036271, NS045083, and NS050696. This work was also supported by Pilot Feasibility Grant 5P30DK057521-12 (Boston Area Diabetes Endocrinology Research Center) and American Recovery and Reinvestment Act supplement to Grant NS050696. NR 37 TC 4 Z9 4 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 8 PY 2013 VL 288 IS 10 BP 7077 EP 7085 DI 10.1074/jbc.M112.401190 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 104NY UT WOS:000316002400029 PM 23344951 ER PT J AU Rass, E Chandramouly, G Zha, S Alt, FW Xie, AY AF Rass, Emilie Chandramouly, Gurushankar Zha, Shan Alt, Frederick W. Xie, Anyong TI Ataxia Telangiectasia Mutated (ATM) Is Dispensable for Endonuclease I-Scel-induced Homologous Recombination in Mouse Embryonic Stem Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; HISTONE H2AX; GENOMIC INSTABILITY; IONIZING-RADIATION; FUNCTIONAL SYNERGY; KINASE-ACTIVITY; REPAIR PATHWAY; MDC1; PHOSPHORYLATION AB Ataxia telangiectasia mutated (ATM) is activated upon DNA double strand breaks (DSBs) and phosphorylates numerous DSB response proteins, including histone H2AX on serine 139 (Ser-139) to form gamma-H2AX. Through interaction with MDC1, gamma-H2AX promotes DSB repair by homologous recombination (HR). H2AX Ser-139 can also be phosphorylated by DNA-dependent protein kinase catalytic subunit and ataxia telangiectasia- and Rad3-related kinase. Thus, we tested whether ATM functions in HR, particularly that controlled by gamma-H2AX, by comparing HR occurring at the euchromatic ROSA26 locus between mouse embryonic stem cells lacking either ATM, H2AX, or both. We show here that loss of ATM does not impair HR, including H2AX-dependent HR, but confers sensitivity to inhibition of poly(ADP-ribose) polymerases. Loss of ATM or H2AX has independent contributions to cellular sensitivity to ionizing radiation. The ATM-independent HR function of H2AX requires both Ser-139 phosphorylation and gamma-H2AX/MDC1 interaction. Our data suggest that ATM is dispensable for HR, including that controlled by H2AX, in the context of euchromatin, excluding the implication of such an HR function in genomic instability, hypersensitivity to DNA damage, and poly(ADP-ribose) polymerase inhibition associated with ATM deficiency. C1 [Rass, Emilie; Chandramouly, Gurushankar; Xie, Anyong] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Rass, Emilie; Chandramouly, Gurushankar; Xie, Anyong] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Zha, Shan; Alt, Frederick W.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Childrens Hosp,Immune Dis Inst, Boston, MA 02115 USA. [Zha, Shan; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Xie, AY (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol & Oncol, 330 Brookline Ave, Boston, MA 02215 USA. EM axie@bidmc.harvard.edu FU National Institutes of Health [R01GM073894] FX This work was supported, in whole or in part, by National Institutes of Health Grant R01GM073894. NR 54 TC 9 Z9 9 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 8 PY 2013 VL 288 IS 10 BP 7086 EP 7095 DI 10.1074/jbc.M112.445825 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 104NY UT WOS:000316002400030 PM 23355489 ER PT J AU Lim, JH Gerhart-Hines, Z Dominy, JE Lee, Y Kim, S Tabata, M Xiang, YK Puigserver, P AF Lim, Ji-Hong Gerhart-Hines, Zachary Dominy, John E. Lee, Yoonjin Kim, Sungjin Tabata, Mitsuhisa Xiang, Yang K. Puigserver, Pere TI Oleic Acid Stimulates Complete Oxidation of Fatty Acids through Protein Kinase A-dependent Activation of SIRT1-PGC1 alpha Complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INDUCED INSULIN-RESISTANCE; MITOCHONDRIAL BIOGENESIS; SKELETAL-MUSCLE; TRANSCRIPTIONAL COACTIVATOR; PGC-1-ALPHA EXPRESSION; METABOLIC REGULATOR; ENERGY-EXPENDITURE; LIPID-METABOLISM; SIRT1; AMPK AB Fatty acids are essential components of the dynamic lipid metabolism in cells. Fatty acids can also signal to intracellular pathways to trigger a broad range of cellular responses. Oleic acid is an abundant monounsaturated omega-9 fatty acid that impinges on different biological processes, but the mechanisms of action are not completely understood. Here, we report that oleic acid stimulates the cAMP/protein kinase A pathway and activates the SIRT1-PGC1 alpha transcriptional complex to modulate rates of fatty acid oxidation. In skeletal muscle cells, oleic acid treatment increased intracellular levels of cyclic adenosine monophosphate (cAMP) that turned on protein kinase A activity. This resulted in SIRT1 phosphorylation at Ser-434 and elevation of its catalytic deacetylase activity. A direct SIRT1 substrate is the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1 alpha), which became deacetylated and hyperactive after oleic acid treatment. Importantly, oleic acid, but not other long chain fatty acids such as palmitate, increased the expression of genes linked to fatty acid oxidation pathway in a SIRT1-PGC1 alpha-dependent mechanism. As a result, oleic acid potently accelerated rates of complete fatty acid oxidation in skeletal muscle cells. These results illustrate how a single long chain fatty acid specifically controls lipid oxidation through a signaling/transcriptional pathway. Pharmacological manipulation of this lipid signaling pathway might provide therapeutic possibilities to treat metabolic diseases associated with lipid dysregulation. C1 [Lim, Ji-Hong; Gerhart-Hines, Zachary; Dominy, John E.; Lee, Yoonjin; Tabata, Mitsuhisa; Puigserver, Pere] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Lim, Ji-Hong; Gerhart-Hines, Zachary; Dominy, John E.; Lee, Yoonjin; Tabata, Mitsuhisa; Puigserver, Pere] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Kim, Sungjin; Xiang, Yang K.] Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA. RP Puigserver, P (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,CLSB-11144, Boston, MA 02215 USA. EM pere_puigserver@dfci.harvard.edu FU Dana-Farber Cancer Institute; American Diabetes Association; Department of Defense; National Institutes of Health/NIDDK [RO1 069966]; National Institutes of Health [RO1-HL82846]; American Heart Association [12EIA841007] FX This work was supported by the Dana-Farber Cancer Institute, the American Diabetes Association, the Department of Defense, National Institutes of Health/NIDDK Grant RO1 069966 (to P. P.) as well as National Institutes of Health Grant RO1-HL82846 and American Heart Association Grant 12EIA841007 (to Y. K. X.).; Supported by an American Diabetes Association mentor supported post-doctoral fellowship.; Supported in part by a fellowship from the American Heart Association.; Supported in part by an National Research Service Award Kirschstein fellowship from the National Institutes of Health. NR 40 TC 24 Z9 29 U1 0 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 8 PY 2013 VL 288 IS 10 BP 7117 EP 7126 DI 10.1074/jbc.M112.415729 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 104NY UT WOS:000316002400033 PM 23329830 ER PT J AU Bass, AJ Wang, TC AF Bass, Adam J. Wang, Timothy C. TI An Inflammatory Situation: SOX2 and STAT3 Cooperate in Squamous Cell Carcinoma Initiation SO CELL STEM CELL LA English DT Editorial Material ID SURVIVAL; ROLES; MICE; STEM AB Although SOX2 has been identified as a squamous cell carcinoma oncogene, mechanisms of SOX2-induce oncogenesis have remained elusive. In this issue of Cell Stem Cell, Li et al. (2013) show that SOX2 synergizes with inflammation-induced STAT3 activation to transform basal progenitors and initiate squamous cell carcinoma. C1 [Bass, Adam J.] Dana Farber Canc Inst, Div Mol & Cellular Oncol, Boston, MA 02215 USA. [Bass, Adam J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bass, Adam J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Bass, Adam J.] Broad Inst, Cambridge, MA 02142 USA. [Wang, Timothy C.] Columbia Univ Coll Phys & Surg, Div Digest & Liver Dis, New York, NY 10032 USA. [Wang, Timothy C.] Columbia Univ Coll Phys & Surg, Herbert Irving Canc Res Ctr, New York, NY 10032 USA. RP Wang, TC (reprint author), Columbia Univ Coll Phys & Surg, Div Digest & Liver Dis, New York, NY 10032 USA. EM tcw21@columbia.edu NR 9 TC 4 Z9 6 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD MAR 7 PY 2013 VL 12 IS 3 BP 266 EP 268 DI 10.1016/j.stem.2013.02.004 PG 4 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 287VC UT WOS:000329569400002 PM 23472866 ER PT J AU Hogdal, LJ Letai, A AF Hogdal, Leah J. Letai, Anthony TI BCL-2 Inhibition: Stemming the Tide of Myeloid Malignancies SO CELL STEM CELL LA English DT Editorial Material ID BH3 MIMETIC ABT-737; LEUKEMIA; SENSITIVITY; APOPTOSIS AB Leukemia stem cells (LSCs) are likely to be the source for both therapeutic resistance and relapse in myeloid malignancies. As reported in this issue of Cell Stem Cell, Lagadinou et al. (2013) and Goff et al. (2013) support selective targeting of LSCs by small molecule antagonists of anti-apoptotic BCL-2 family proteins. C1 [Hogdal, Leah J.; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Letai, A (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM anthony_letai@dfci.harvard.edu FU NCI NIH HHS [R01 CA129974] NR 10 TC 3 Z9 4 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD MAR 7 PY 2013 VL 12 IS 3 BP 269 EP 270 DI 10.1016/j.stem.2013.02.006 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 287VC UT WOS:000329569400003 PM 23472867 ER PT J AU McMurry, AJ Murphy, SN MacFadden, D Weber, G Simons, WW Orechia, J Bickel, J Wattanasin, N Gilbert, C Trevvett, P Churchill, S Kohane, IS AF McMurry, Andrew J. Murphy, Shawn N. MacFadden, Douglas Weber, Griffin Simons, William W. Orechia, John Bickel, Jonathan Wattanasin, Nich Gilbert, Clint Trevvett, Philip Churchill, Susanne Kohane, Isaac S. TI SHRINE: Enabling Nationally Scalable Multi-Site Disease Studies SO PLOS ONE LA English DT Article ID ELECTRONIC MEDICAL-RECORDS; INTEGRATING BIOLOGY; CLINICAL-RESEARCH; MYOCARDIAL-INFARCTION; DISCOVERY RESEARCH; DIABETES-MELLITUS; PUBLIC-HEALTH; CARE; INFORMATICS; SYSTEM AB Results of medical research studies are often contradictory or cannot be reproduced. One reason is that there may not be enough patient subjects available for observation for a long enough time period. Another reason is that patient populations may vary considerably with respect to geographic and demographic boundaries thus limiting how broadly the results apply. Even when similar patient populations are pooled together from multiple locations, differences in medical treatment and record systems can limit which outcome measures can be commonly analyzed. In total, these differences in medical research settings can lead to differing conclusions or can even prevent some studies from starting. We thus sought to create a patient research system that could aggregate as many patient observations as possible from a large number of hospitals in a uniform way. We call this system the 'Shared Health Research Information Network', with the following properties: (1) reuse electronic health data from everyday clinical care for research purposes, (2) respect patient privacy and hospital autonomy, (3) aggregate patient populations across many hospitals to achieve statistically significant sample sizes that can be validated independently of a single research setting, (4) harmonize the observation facts recorded at each institution such that queries can be made across many hospitals in parallel, (5) scale to regional and national collaborations. The purpose of this report is to provide open source software for multi-site clinical studies and to report on early uses of this application. At this time SHRINE implementations have been used for multi-site studies of autism co-morbidity, juvenile idiopathic arthritis, peripartum cardiomyopathy, colorectal cancer, diabetes, and others. The wide range of study objectives and growing adoption suggest that SHRINE may be applicable beyond the research uses and participating hospitals named in this report. C1 [McMurry, Andrew J.; MacFadden, Douglas; Simons, William W.; Gilbert, Clint; Trevvett, Philip; Kohane, Isaac S.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [McMurry, Andrew J.; Bickel, Jonathan; Kohane, Isaac S.] Childrens Hosp, Childrens Hosp Informat Program, Boston, MA 02115 USA. [McMurry, Andrew J.; Murphy, Shawn N.; Weber, Griffin; Churchill, Susanne; Kohane, Isaac S.] Brigham & Womens Hosp, Natl Ctr Biomed Comp I2b2, Boston, MA 02115 USA. [McMurry, Andrew J.] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Murphy, Shawn N.; Wattanasin, Nich; Churchill, Susanne] Res Comp, Partners Healthcare Syst, Boston, MA 02215 USA. [Murphy, Shawn N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Weber, Griffin] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Weber, Griffin] Harvard Univ, Med Sch Informat Technol, Boston, MA 02115 USA. [Orechia, John] Dana Farber Canc Inst, Clin Res Informat Technol, Boston, MA 02115 USA. [Bickel, Jonathan] Childrens Hosp, Dept Informat Syst, Boston, MA 02115 USA. RP McMurry, AJ (reprint author), Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. EM Andrew_McMurry@hms.harvard.edu OI Weber, Griffin/0000-0002-2597-881X FU CTSA award (National Institutes of Health/National Center for Research Resources NIH/NCRR) [1UL1RR025758-01]; i2b2 National Center for Biomedical Computing [NIH/NLM U54 LM008748] FX This work was funded in part by the CTSA award (National Institutes of Health/National Center for Research Resources NIH/NCRR 1UL1RR025758-01) and the i2b2 National Center for Biomedical Computing (NIH/NLM U54 LM008748). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 35 Z9 35 U1 2 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 7 PY 2013 VL 8 IS 3 AR e55811 DI 10.1371/journal.pone.0055811 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136BN UT WOS:000318334500004 PM 23533569 ER PT J AU Rice, WL Van Hoek, AN Paunescu, TG Huynh, C Goetze, B Singh, B Scipioni, L Stern, LA Brown, D AF Rice, William L. Van Hoek, Alfred N. Paunescu, Teodor G. Huynh, Chuong Goetze, Bernhard Singh, Bipin Scipioni, Larry Stern, Lewis A. Brown, Dennis TI High Resolution Helium Ion Scanning Microscopy of the Rat Kidney SO PLOS ONE LA English DT Article ID ACUTE RESPIRATORY-ACIDOSIS; ELECTRON-MICROSCOPY; INTERCALATED CELLS; HEYMANN NEPHRITIS; COLLECTING DUCT; EPITHELIAL-CELLS; BRUSH-BORDER; COATED PITS; ULTRASTRUCTURE; IDENTIFICATION AB Helium ion scanning microscopy is a novel imaging technology with the potential to provide sub-nanometer resolution images of uncoated biological tissues. So far, however, it has been used mainly in materials science applications. Here, we took advantage of helium ion microscopy to explore the epithelium of the rat kidney with unsurpassed image quality and detail. In addition, we evaluated different tissue preparation methods for their ability to preserve tissue architecture. We found that high contrast, high resolution imaging of the renal tubule surface is possible with a relatively simple processing procedure that consists of transcardial perfusion with aldehyde fixatives, vibratome tissue sectioning, tissue dehydration with graded methanol solutions and careful critical point drying. Coupled with the helium ion system, fine details such as membrane texture and membranous nanoprojections on the glomerular podocytes were visualized, and pores within the filtration slit diaphragm could be seen in much greater detail than in previous scanning EM studies. In the collecting duct, the extensive and striking apical microplicae of the intercalated cells were imaged without the shrunken or distorted appearance that is typical with conventional sample processing and scanning electron microscopy. Membrane depressions visible on principal cells suggest possible endo- or exocytotic events, and central cilia on these cells were imaged with remarkable preservation and clarity. We also demonstrate the use of colloidal gold probes for highlighting specific cell-surface proteins and find that 15 nm gold labels are practical and easily distinguishable, indicating that external labels of various sizes can be used to detect multiple targets in the same tissue. We conclude that this technology represents a technical breakthrough in imaging the topographical ultrastructure of animal tissues. Its use in future studies should allow the study of fine cellular details and provide significant advances in our understanding of cell surface structures and membrane organization. C1 [Rice, William L.; Van Hoek, Alfred N.; Paunescu, Teodor G.; Brown, Dennis] Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. [Rice, William L.; Van Hoek, Alfred N.; Paunescu, Teodor G.; Brown, Dennis] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Rice, William L.; Van Hoek, Alfred N.; Paunescu, Teodor G.; Brown, Dennis] Harvard Univ, Sch Med, Boston, MA USA. [Huynh, Chuong; Goetze, Bernhard; Singh, Bipin; Scipioni, Larry; Stern, Lewis A.] Carl Zeiss Microscopy, Peabody, MA USA. RP Brown, D (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. EM brown.dennis@mgh.harvard.edu FU NIH [DK42956]; Zeiss Corporation; Massachusetts General Hospital FX Funding was in part from an NIH grant to D. Brown to examine the role of renal intercalated cell cells in kidney function (DK42956). Additional funding was provided by a sponsored research agreement to Dr. Brown from the Zeiss Corporation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors have read the journal's policy and have the following conflicts. The work was performed partially with a sponsored research agreement between the Massachusetts General Hospital and the Zeiss Corporation. Four of the authors are employed by the Zeiss Corporation in the Helium Ion Microscopy Facility in Peabody, MA. The corresponding author D. Brown is the PI of the sponsored research agreement from the Zeiss Corporation. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. NR 37 TC 17 Z9 17 U1 1 U2 21 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 MAR 7 PY 2013 VL 8 IS 3 AR e57051 DI 10.1371/journal.pone.0057051 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136BN UT WOS:000318334500010 PM 23505418 ER PT J AU Wanic, K Krolewski, B Ju, WJ Placha, G Niewczas, MA Walker, W Warram, JH Kretzler, M Krolewski, AS AF Wanic, Krzysztof Krolewski, Bozena Ju, Wenjun Placha, Grzegorz Niewczas, Monika A. Walker, William Warram, James H. Kretzler, Matthias Krolewski, Andrzej S. TI Transcriptome Analysis of Proximal Tubular Cells (HK-2) Exposed to Urines of Type 1 Diabetes Patients at Risk of Early Progressive Renal Function Decline SO PLOS ONE LA English DT Article ID TNF RECEPTORS 1; NEPHROTIC SYNDROME; URINARY PROTEINS; EPITHELIAL-CELLS; NECROSIS-FACTOR; NEPHROPATHY; MICROALBUMINURIA; EXPRESSION; DISEASE; VEGF AB Background: In patients with Type 1 Diabetes (T1D) who develop microalbuminuria, progressive decline in glomerular filtration rate (GFR) may be initiated by leakage into the urine of toxic proteins (txUPs). This study tested this hypothesis. Methods: After archiving baseline urine, we followed T1D patients with microalbuminuria for 8-12 years to distinguish those in whom GFR declined (Decliners) and those in whom it remained stable (Non-decliners). Human proximal tubular cells (HK-2 cells) were grown in serum-free medium enriched with pooled urines from Decliners or Non-decliners. We determined genome-wide expression profiles in extracted mRNA. Results: The two pooled urines induced differential expression of 312 genes. In terms of gene ontology, molecular functions of the 119 up-regulated genes were enriched for protein binding and peptidase inhibitor activities. Their biologic processes were enriched for defense response, responses to other organisms, regulation of cellular processes, or response to stress or stimulus, and programmed cell death. The 195 down-regulated genes were disproportionately represented in molecular functions of cation binding, hydrolase activity, and DNA binding. They were disproportionately represented in biological processes for regulation of metabolic processes, nucleic acid metabolic processes, cellular response to stress and macromolecule biosynthesis. The set of up-regulated genes in HK-2 cells overlaps significantly with sets of over-expressed genes in tubular and interstitial compartments of kidney biopsies from patients with advanced DN (33 genes in one study and 25 in the other compared with 10.3 expected by chance, p<10(-9) and p<10(-4), respectively). The overlap included genes encoding chemokines and cytokines. Overlap of down-regulated genes was no more than expected by chance. Conclusions: Molecular processes in tubules and interstitium seen in advanced diabetic nephropathy can be induced in vitro by exposure to urine from patients with minimal microalbuminuria who subsequently developed progressive renal function decline, presumably due to putative txUPs. C1 [Wanic, Krzysztof; Krolewski, Bozena; Placha, Grzegorz; Niewczas, Monika A.; Walker, William; Warram, James H.; Krolewski, Andrzej S.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. [Wanic, Krzysztof; Krolewski, Bozena; Placha, Grzegorz; Niewczas, Monika A.; Krolewski, Andrzej S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Wanic, Krzysztof] Jagiellonian Univ, Dept Metab Dis, Krakow, Poland. [Ju, Wenjun; Kretzler, Matthias] Univ Michigan, Dept Internal Med, Div Nephrol, Ann Arbor, MI 48109 USA. [Placha, Grzegorz] Warsaw Med Univ, Dept Hypertens, Warsaw, Poland. RP Krolewski, AS (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. EM Andrzej.Krolewski@joslin.harvard.edu FU NIH [DK41526, DK67638]; JDRF [JDRF 3-2005-908, JDRF 3-2004-631] FX This research was supported by NIH grants DK41526 & DK67638 (to ASK); KW and GP were supported by the JDRF fellowships (JDRF 3-2005-908, & JDRF 3-2004-631). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 2 Z9 2 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 7 PY 2013 VL 8 IS 3 AR e57751 DI 10.1371/journal.pone.0057751 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136BN UT WOS:000318334500030 PM 23505438 ER PT J AU Kampa-Schittenhelm, KM Heinrich, MC Akmut, F Dohner, H Dohner, K Schittenhelm, MM AF Kampa-Schittenhelm, Kerstin Maria Heinrich, Michael Charles Akmut, Figen Doehner, Hartmut Doehner, Konstanze Schittenhelm, Marcus Matthias TI Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA and -KIT isoforms SO MOLECULAR CANCER LA English DT Article DE AC220; Quizartinib; Leukemia; KIT; FLT3; PDGFR ID ACUTE MYELOID-LEUKEMIA; GASTROINTESTINAL STROMAL TUMOR; INTERNAL TANDEM DUPLICATIONS; LIGAND-INDEPENDENT ACTIVATION; MAST-CELL LEUKEMIA; C-KIT; MYELODYSPLASTIC SYNDROME; FLT3 GENE; WILD-TYPE; SYSTEMIC MASTOCYTOSIS AB Background: Activating mutations of class III receptor tyrosine kinases (RTK) FLT3, PDGFR and KIT are associated with multiple human neoplasms including hematologic malignancies, for example: systemic mast cell disorders (KIT), non-CML myeloproliferative neoplasms (PDGFR) and subsets of acute leukemias (FLT3 and KIT). First generation tyrosine kinase inhibitors (TKI) are rapidly being integrated into routine cancer care. However, the expanding spectrum of TK-mutations, bioavailability issues and the emerging problem of primary or secondary TKI-therapy resistance have lead to the search for novel second generation TKIs to improve target potency and to overcome resistant clones. Quizartinib was recently demonstrated to be a selective FLT3 inhibitor with excellent pharmacokinetics and promising in vivo activity in a phase II study for FLT3 ITD + AML patients. In vitro kinase assays have suggested that in addition to FLT3, quizartinib also targets related class III RTK isoforms. Methods: Various FLT3 or KIT leukemia cell lines and native blasts were used to determine the antiproliferative and proapoptotic efficacy of quizartinib. To better compare differences between the mutant kinase isoforms, we generated an isogenic BaF3 cell line expressing different FLT3, KIT or BCR/ABL isoforms. Using immunoblotting, we examined the effects of quizartinib on activation of mutant KIT or FLT3 isoforms. Results: Kinase inhibition of (mutant) KIT, PDGFR and FLT3 isoforms by quizartinib leads to potent inhibition of cellular proliferation and induction of apoptosis in in vitro leukemia models as well as in native leukemia blasts treated ex vivo. However, the sensitivity patterns vary widely depending on the underlying (mutant)-kinase isoform, with some isoforms being relatively insensitive to this agent (e. g. FLT3 D835V and KIT codon D816 mutations). Evaluation of sensitivities in an isogenic cellular background confirms a direct association with the underlying mutant-TK isoform - which is further validated by immunoblotting experiments demonstrating kinase inhibition consistent with the cellular sensitivity/resistance to quizartinib. Conclusion: Quizartinib is a potent second-generation class III receptor TK-inhibitor - but specific, mutation restricted spectrum of activity may require mutation screening prior to therapy. C1 [Kampa-Schittenhelm, Kerstin Maria; Akmut, Figen; Schittenhelm, Marcus Matthias] Univ Tubingen Hosp, Dept Hematol Oncol Rheumatol Immunol & Pulmol, Tubingen, Germany. [Heinrich, Michael Charles] Portland VA Med Ctr, Dept Med, Div Hematol & Med Oncol, Portland, OR USA. [Heinrich, Michael Charles] OHSU Knight Canc Inst, Portland, OR USA. [Doehner, Hartmut; Doehner, Konstanze] Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany. RP Kampa-Schittenhelm, KM (reprint author), Univ Tubingen Hosp, Dept Hematol Oncol Rheumatol Immunol & Pulmol, Tubingen, Germany. EM kerstin.kampa-schittenhelm@med.uni-tuebingen.de FU Deutsche Krebshilfe Foundation; IZKF Program of the Medical Faculty Tubingen; Carreras Scholarship Program; Leukemia and Lymphoma Society; Department of Veterans Affairs; Deutsche Forschungsgemeinschaft; Open Access Publishing Fund of Tubingen University FX Grant support in part by the Deutsche Krebshilfe Foundation (MMS, KKS), the IZKF Program of the Medical Faculty Tubingen (MMS) and the Carreras Scholarship Program (KKS), a grant from the Leukemia and Lymphoma Society (MCH) and a Merit Review Grant from the Department of Veterans Affairs (MCH). We acknowledge support by Deutsche Forschungsgemeinschaft and Open Access Publishing Fund of Tubingen University. NR 52 TC 26 Z9 27 U1 0 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD MAR 7 PY 2013 VL 12 AR 19 DI 10.1186/1476-4598-12-19 PG 15 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 133BS UT WOS:000318113000001 PM 23497317 ER PT J AU Chen, XL Shen, YP Zhang, F Chiang, C Pillalamarri, V Blumenthal, I Talkowski, M Wu, BL Gusella, JF AF Chen, Xiaoli Shen, Yiping Zhang, Feng Chiang, Colby Pillalamarri, Vamsee Blumenthal, Ian Talkowski, Michael Wu, Bai-Lin Gusella, James F. TI Molecular Analysis of a Deletion Hotspot in the NRXN1 Region Reveals the Involvement of Short Inverted Repeats in Deletion CNVs SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID COPY-NUMBER VARIATION; AUTISM SPECTRUM DISORDERS; HUMAN GENOME; STRUCTURAL VARIANTS; SEGMENTAL DUPLICATIONS; COMPLEX REARRANGEMENTS; GENETIC INSTABILITY; SCHIZOPHRENIA; PALINDROME; RISK AB NRXN1 microdeletions occur at a relatively high frequency and confer increased risk for neurodevelopmental and neurobehavioral abnormalities. The mechanism that makes NRXN1 a deletion hotspot is unknown. Here, we identified deletions of the NRXN1 region in affected cohorts, confirming a strong association with the autism spectrum and other neurodevelopmental disorders. Interestingly, deletions in both affected and control individuals were clustered in the 5' portion of NRXN1 and its immediate upstream region. To explore the mechanism of deletion, we mapped and analyzed the breakpoints of 32 deletions. At the deletion breakpoints, frequent microhomology (68.8%, 2-19 bp) suggested predominant mechanisms of DNA replication error and/or microhomology-mediated end-joining. Long terminal repeat (LTR) elements, unique non-B-DNA structures, and MEME-defined sequence motifs were significantly enriched, but Alu and LINE sequences were not. Importantly, small-size inverted repeats (minus self chains, minus sequence motifs, and partial complementary sequences) were significantly overrepresented in the vicinity of NRXN1 region deletion breakpoints, suggesting that, although they are not interrupted by the deletion process, such inverted repeats can predispose a region to genomic instability by mediating single-strand DNA looping via the annealing of partially reverse complementary strands and the promoting of DNA replication fork stalling and DNA replication error. Our observations highlight the potential importance of inverted repeats of variable sizes in generating a rearrangement hotspot in which individual breakpoints are not recurrent. Mechanisms that involve short inverted repeats in initiating deletion may also apply to other deletion hotspots in the human genome. C1 [Chen, Xiaoli] Capital Inst Pediat, Beijing 100020, Peoples R China. [Chen, Xiaoli; Shen, Yiping; Chiang, Colby; Pillalamarri, Vamsee; Blumenthal, Ian; Talkowski, Michael; Gusella, James F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Chen, Xiaoli; Shen, Yiping; Wu, Bai-Lin] Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. [Shen, Yiping] Shanghai Jiao Tong Univ, Shanghai Childrens Med Ctr, Sch Med, Shanghai 200127, Peoples R China. [Shen, Yiping; Wu, Bai-Lin] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Zhang, Feng] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Zhang, Feng] Fudan Univ, Sch Life Sci, Minist Educ, Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Talkowski, Michael] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Talkowski, Michael; Gusella, James F.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Wu, Bai-Lin] Fudan Univ, Childrens Hosp, Shanghai 200032, Peoples R China. [Wu, Bai-Lin] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China. [Gusella, James F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Wu, BL (reprint author), Childrens Hosp, Dept Lab Med, 300 Longwood Ave, Boston, MA 02115 USA. EM bai-lin.wu@childrens.harvard.edu; gusella@helix.mgh.harvard.edu RI Zhang, Feng/C-7735-2009; OI Chiang, Colby/0000-0002-4113-6065 FU Natural Science Foundation of China [81100841]; Beijing Science and Technology Fund for Chinese Returned Oversea Scientist; Shanghai Science and Technology Commission [11dz1950300]; National Basic Research Program of China [2011CBA00401, 2012CB944600]; Ministry-of Science and Technology of China for the National 973 Program on Population and Health [2010CB529601]; Nature Science Fund of Shanghai [09JC1402400, 09ZR1404500]; NIH [GM061354, HD065286]; Autism Speaks grant [2042]; National Institute of Mental Health (NIMH) National Research Service Award [MH087123]; Mass General Hospital Executive Committee on Research Fund for Medical Discovery award FX This work was supported by the Natural Science Foundation of China (grant 81100841) and the Beijing Science and Technology Fund for Chinese Returned Oversea Scientist (to X.L.C.); a Shanghai Science and Technology Commission major issue grant (11dz1950300) to Y.S.; the National Basic Research Program of China (grants 2011CBA00401 and 2012CB944600 to F.Z.); the Ministry-of Science and Technology of China for the National 973 Program on Population and Health (grant 2010CB529601 to B.L.W.) and the Nature Science Fund of Shanghai (09JC1402400 and 09ZR1404500 to B.L.W.), and NIH grants GM061354 and HD065286 and Autism Speaks grant 2042 to J.F.G. M.T. was supported by a National Institute of Mental Health (NIMH) National Research Service Award (grant MH087123) and a Mass General Hospital Executive Committee on Research Fund for Medical Discovery award. NR 78 TC 20 Z9 23 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR 7 PY 2013 VL 92 IS 3 BP 375 EP 386 DI 10.1016/j.ajhg.2013.02.006 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 106RF UT WOS:000316161700010 PM 23472757 ER PT J AU Simon, JA Kingston, RE AF Simon, Jeffrey A. Kingston, Robert E. TI Occupying Chromatin: Polycomb Mechanisms for Getting to Genomic Targets, Stopping Transcriptional Traffic, and Staying Put SO MOLECULAR CELL LA English DT Review ID RNA-POLYMERASE-II; H3 LYSINE 27; HISTONE METHYLTRANSFERASE ACTIVITY; EMBRYONIC STEM-CELLS; REPRESSIVE COMPLEX 1; GROUP PROTEIN COMPLEXES; REPLICATION IN-VITRO; LONG NONCODING RNA; GROUP CBX FAMILY; GENE-EXPRESSION AB Chromatin modification by Polycomb proteins provides an essential strategy for gene silencing in higher eukaryotes. Polycomb repressive complexes (PRCs) silence key developmental regulators and are centrally integrated in the transcriptional circuitry of stem cells. PRC2 trimethylates histone H3 on lysine 27 (H3K27me3), and PRC1-type complexes ubiquitylate histone H2A and compact polynucleosomes. How PRCs are deployed to select and silence genomic targets is the subject of intense investigation. We review advances on targeting, modulation, and functions of PRC1 and PRC2 and progress on defining the transcriptional steps they impact. Recent findings emphasize PRC1 targeting independent of H3K27me3, nonenzymatic PRC1-mediated compaction, and connections between PRCs and noncoding RNAs. Systematic analyses of Polycomb complexes and associated histone modifications during DNA replication and mitosis have also emerged. The stage is now set to reveal fundamental epigenetic mechanisms that determine how Polycomb target genes are silenced and how Polycomb silence is preserved through cell-cycle progression. C1 [Simon, Jeffrey A.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. [Kingston, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. [Kingston, Robert E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Simon, JA (reprint author), Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. EM simon004@umn.edu; kingston@molbio.mgh.harvard.edu FU NIGMS NIH HHS [R01 GM043901, R01 GM049850] NR 157 TC 266 Z9 272 U1 11 U2 97 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 MAR 7 PY 2013 VL 49 IS 5 BP 808 EP 824 DI 10.1016/j.molcel.2013.02.013 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 106TQ UT WOS:000316168000004 PM 23473600 ER PT J AU Staber, PB Zhang, P Ye, M Welner, RS Nombela-Arrieta, C Bach, C Kerenyi, M Bartholdy, BA Zhang, H Alberich-Jorda, M Lee, S Yang, H Ng, F Zhang, JY Leddin, M Silberstein, LE Hoefler, G Orkin, SH Gottgens, B Rosenbauer, F Huang, G Tenen, DG AF Staber, Philipp B. Zhang, Pu Ye, Min Welner, Robert S. Nombela-Arrieta, Cesar Bach, Christian Kerenyi, Marc Bartholdy, Boris A. Zhang, Hong Alberich-Jorda, Meritxell Lee, Sanghoon Yang, Henry Ng, Felicia Zhang, Junyan Leddin, Mathias Silberstein, Leslie E. Hoefler, Gerald Orkin, Stuart H. Goettgens, Berthold Rosenbauer, Frank Huang, Gang Tenen, Daniel G. TI Sustained PU.1 Levels Balance Cell-Cycle Regulators to Prevent Exhaustion of Adult Hematopoietic Stem Cells SO MOLECULAR CELL LA English DT Article ID TRANSCRIPTION FACTOR PU.1; SELF-RENEWAL; PROGENITOR CELLS; GENE; ELEMENTS; DIFFERENTIATION; PROLIFERATION; MAINTENANCE; ACTIVATION; MACROPHAGE AB To provide a lifelong supply of blood cells, hematopoietic stem cells (HSCs) need to carefully balance both self-renewing cell divisions and quiescence. Although several regulators that control this mechanism have been identified, we demonstrate that the transcription factor PU.1 acts upstream of these regulators. So far, attempts to uncover PU.1's role in HSC biology have failed because of the technical limitations of complete loss-of-function models. With the use of hypomorphic mice with decreased PU.1 levels specifically in phenotypic HSCs, we found reduced HSC long-term repopulation potential that could be rescued completely by restoring PU.1 levels. PU.1 prevented excessive HSC division and exhaustion by controlling the transcription of multiple cell-cycle regulators. Levels of PU.1 were sustained through autoregulatory PU.1 binding to an upstream enhancer that formed an active looped chromosome architecture in HSCs. These results establish that PU.1 mediates chromosome looping and functions as a master regulator of HSC proliferation. C1 [Staber, Philipp B.; Zhang, Pu; Ye, Min; Welner, Robert S.; Bach, Christian; Kerenyi, Marc; Bartholdy, Boris A.; Zhang, Hong; Alberich-Jorda, Meritxell; Zhang, Junyan; Silberstein, Leslie E.; Orkin, Stuart H.; Tenen, Daniel G.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Nombela-Arrieta, Cesar; Silberstein, Leslie E.] Harvard Univ, Sch Med, Boston Childrens Hosp, Joint Program Transfus Med, Boston, MA 02115 USA. [Kerenyi, Marc; Orkin, Stuart H.] Harvard Univ, Sch Med, Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Kerenyi, Marc; Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Staber, Philipp B.] Med Univ Graz, Div Hematol, A-8036 Graz, Austria. [Hoefler, Gerald] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria. [Staber, Philipp B.] Med Univ Vienna, Comprehens Canc Ctr Vienna, Div Hematol & Hemostaseol, A-1090 Vienna, Austria. [Lee, Sanghoon; Yang, Henry; Tenen, Daniel G.] Natl Univ Singapore, Canc Sci Inst, Singapore 119615, Singapore. [Ng, Felicia; Goettgens, Berthold] Cambridge Inst Med Res, Cambridge CB2 0XY, England. [Ng, Felicia; Goettgens, Berthold] Wellcome Trust Res Labs, Cambridge CB2 0XY, England. [Ng, Felicia; Goettgens, Berthold] MRC Stem Cell Inst, Cambridge CB2 0XY, England. [Leddin, Mathias; Rosenbauer, Frank] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Rosenbauer, Frank] Univ Munster, Inst Mol Tumor Biol, D-48149 Munster, Germany. [Huang, Gang] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. RP Staber, PB (reprint author), Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA 02115 USA. EM pstaber@bidmc.harvard.edu; csidgt@nus.edu.sg RI Alberich Jorda, Meritxell/G-3137-2014; Hoefler, Gerald/H-1796-2016; OI Bach, Christian/0000-0003-4675-7896; Nombela-Arrieta, Cesar/0000-0003-0415-259X; Gottgens, Berthold/0000-0001-6302-5705; Hoefler, Gerald/0000-0002-9056-3063; Rosenbauer, Frank/0000-0001-7977-9421; Tenen, Daniel/0000-0002-6423-3888 FU NIH [R01HL112719]; Austrian Research Foundation [J2876-B12]; Austrian Academy of Science [11379]; European Union [P10E-254486]; German Research Foundation (DFG fellowship) [BA 4186/1-1]; Yousef Jameel scholarship FX We thank Christopher Hetherington and Alexander Ebralidze for expert assistance with quantitative 3C analysis, the Dartmouth Transgenic Facility directed by Steven Fiering, and the BIDMC Flow Cytometry Facility. We thank Dr. Wenyi Wei and Dr. Peter Sicinski for providing reagents (the anti-Cdc25a antibody and the Cdk1 expression construct, respectively). We are grateful to the members of the Tenen laboratory for helpful discussions, especially Annalisa Di Ruscio, Elena Levantini, and Deepak Bararia. This work was supported by NIH grant R01HL112719 to D.G.T. and by fellowships from the Austrian Research Foundation (Erwin Schrodinger Stipendium: J2876-B12) and the Austrian Academy of Science (APART Stipendium: 11379) to P.B.S. Starting in January, 2012, P.B.S. has received a Marie Curie International Outgoing Fellowship from the European Union (P10E-254486). C.B. was supported by the German Research Foundation (DFG fellowship BA 4186/1-1). F.N. is the recipient of a Yousef Jameel scholarship administered by the Cambridge Commonwealth and Overseas Trust. NR 44 TC 34 Z9 35 U1 2 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD MAR 7 PY 2013 VL 49 IS 5 BP 934 EP 946 DI 10.1016/j.molcel.2013.01.007 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 106TQ UT WOS:000316168000015 PM 23395001 ER PT J AU Chatzaki, E Anton, PA Million, M Lambropoulou, M Constantinidis, T Kolios, G Tache, Y Grigoriadis, DE AF Chatzaki, Ekaterini Anton, Peter A. Million, Mulugeta Lambropoulou, Maria Constantinidis, Theodoros Kolios, George Tache, Yvette Grigoriadis, Dimitri E. TI Corticotropin-releasing factor receptor subtype 2 in human colonic mucosa: Down-regulation in ulcerative colitis SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Colonic mucosa; Corticotropin-releasing factor; Corticotropin-releasing factor receptor; Human immunodeficiency virus; Ulcerative colitis; Urocortin ID INFLAMMATORY-BOWEL-DISEASE; STRESS-RELATED ALTERATIONS; ENTERIC NERVOUS-SYSTEM; FACTOR CRF RECEPTOR; GUT MOTOR FUNCTION; GASTROINTESTINAL-TRACT; RHEUMATOID-ARTHRITIS; PSYCHOLOGICAL STRESS; RAT-BRAIN; UROCORTIN AB AIM: To assess corticotropin-releasing factor receptor 2 (CRF2) expression in the colon of healthy subjects and patients with ulcerative colitis (UC). METHODS: We examined CRF2 gene and protein expression in the distal/sigmoid colonic mucosal biopsies from healthy subjects and patients with UC (active or disease in remission), human immunodeficiency virus (HIV) and functional bowel disease (FBD) by reverse transcription-polymerase chain reaction and immunofluorescence. RESULTS: Gene expression of CRF2 was demonstrated in the normal human colonic biopsies, but not in the human colorectal adenocarcinoma cell line Caco2. Receptor protein localization showed immunoreactive CRF2 receptors in the lamina propria and in the epithelial cells of the distal/sigmoid biopsy samples. Interestingly, CRF2 immunoreactivity was no longer observed in epithelial cells of patients with mild-moderately active UC and disease in remission, while receptor protein expression did not change in the lamina propria. No differences in CRF2 expression profile were observed in distal/sigmoid intestinal biopsies from HIV infection and FBD patients, showing no signs of inflammation. CONCLUSION: The down-regulation of the CRF2 receptor in the distal/sigmoid biopsies of UC patients is indicative of change in CRF2 signalling associated with the process of inflammation. (C) 2013 Baishideng. All rights reserved. C1 [Chatzaki, Ekaterini; Grigoriadis, Dimitri E.] Neurocrine Biosci Inc, San Diego, CA 92121 USA. [Chatzaki, Ekaterini; Kolios, George] Democritus Univ Thrace, Pharmacol Lab, Fac Med, Dragana 68100, Alexandroupolis, Greece. [Anton, Peter A.] Univ Calif Los Angeles, Ctr HIV Prevent Res, Div Digest Dis, Los Angeles, CA 90073 USA. [Anton, Peter A.; Million, Mulugeta; Tache, Yvette] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Anton, Peter A.; Million, Mulugeta; Tache, Yvette] Univ Calif Los Angeles, Digest Dis Res Ctr, Los Angeles, CA 90073 USA. [Anton, Peter A.; Million, Mulugeta; Tache, Yvette] Univ Calif Los Angeles, Ctr Neurobiol Stress, Div Digest Dis, Los Angeles, CA 90073 USA. [Lambropoulou, Maria] Democritus Univ Thrace, Lab Histol Embryol, Fac Med, Dragana 68100, Alexandroupolis, Greece. [Constantinidis, Theodoros] Democritus Univ Thrace, Lab Hyg & Environm Protect, Fac Med, Dragana 68100, Alexandroupolis, Greece. RP Chatzaki, E (reprint author), Democritus Univ Thrace, Pharmacol Lab, Fac Med, Dragana 68100, Alexandroupolis, Greece. EM achatzak@med.duth.gr RI Kolios, George/N-6641-2013; OI Kolios, George/0000-0002-2066-4782 FU National Institute of Diabetes and Digestive and Kidney Diseases R01 grant [DK-57238]; Veteran Administration Research Career Scientist Award; NIH [DK-78676]; [DK-41301] FX Supported by The National Institute of Diabetes and Digestive and Kidney Diseases R01 grant DK-57238; Center Grant DK-41301 (Clinical core); Veteran Administration Research Career Scientist Award (YT); and NIH DK-78676 (MM) NR 55 TC 9 Z9 9 U1 0 U2 1 PU BAISHIDENG PUBL GRP CO LTD PI WANCHAI PA ROOM 1701, 17-F, HENAN BUILDING, NO. 90, JAFFE RD, WANCHAI, HONG KONG 100025, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD MAR 7 PY 2013 VL 19 IS 9 BP 1416 EP 1423 DI 10.3748/wjg.v19.i9.1416 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 104NT UT WOS:000316001700012 PM 23539366 ER PT J AU Kidwell, CS Jahan, R Gornbein, J Alger, JR Nenov, V Ajani, Z Feng, L Meyer, BC Olson, S Schwamm, LH Yoo, AJ Marshall, RS Meyers, PM Yavagal, DR Wintermark, M Guzy, J Starkman, S Saver, JL AF Kidwell, Chelsea S. Jahan, Reza Gornbein, Jeffrey Alger, Jeffry R. Nenov, Val Ajani, Zahra Feng, Lei Meyer, Brett C. Olson, Scott Schwamm, Lee H. Yoo, Albert J. Marshall, Randolph S. Meyers, Philip M. Yavagal, Dileep R. Wintermark, Max Guzy, Judy Starkman, Sidney Saver, Jeffrey L. CA MR RESCUE Investigators TI A Trial of Imaging Selection and Endovascular Treatment for Ischemic Stroke SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED-TRIAL; MERCI TRIAL; THROMBECTOMY; ALTEPLASE; SAFETY; MRI; REVASCULARIZATION; REPERFUSION; MANAGEMENT; DIFFUSION AB BACKGROUND Whether brain imaging can identify patients who are most likely to benefit from therapies for acute ischemic stroke and whether endovascular thrombectomy improves clinical outcomes in such patients remains unclear. METHODS In this study, we randomly assigned patients within 8 hours after the onset of large-vessel, anterior-circulation strokes to undergo mechanical embolectomy (Merci Retriever or Penumbra System) or receive standard care. All patients underwent pretreatment computed tomography or magnetic resonance imaging of the brain. Randomization was stratified according to whether the patient had a favorable penumbral pattern (substantial salvageable tissue and small infarct core) or a nonpenumbral pattern (large core or small or absent penumbra). We assessed outcomes using the 90-day modified Rankin scale, ranging from 0 (no symptoms) to 6 (dead). RESULTS Among 118 eligible patients, the mean age was 65.5 years, the mean time to enrollment was 5.5 hours, and 58% had a favorable penumbral pattern. Revascularization in the embolectomy group was achieved in 67% of the patients. Ninety-day mortality was 21%, and the rate of symptomatic intracranial hemorrhage was 4%; neither rate differed across groups. Among all patients, mean scores on the modified Rankin scale did not differ between embolectomy and standard care (3.9 vs. 3.9, P = 0.99). Embolectomy was not superior to standard care in patients with either a favorable penumbral pattern (mean score, 3.9 vs. 3.4; P = 0.23) or a nonpenumbral pattern (mean score, 4.0 vs. 4.4; P = 0.32). In the primary analysis of scores on the 90-day modified Rankin scale, there was no interaction between the pretreatment imaging pattern and treatment assignment (P = 0.14). CONCLUSIONS A favorable penumbral pattern on neuroimaging did not identify patients who would differentially benefit from endovascular therapy for acute ischemic stroke, nor was embolectomy shown to be superior to standard care. (Funded by the National Institute of Neurological Disorders and Stroke; MR RESCUE ClinicalTrials.gov number, NCT00389467.) C1 [Kidwell, Chelsea S.] Georgetown Univ, Dept Neurol, Washington, DC 20007 USA. [Kidwell, Chelsea S.] Georgetown Univ, Stroke Ctr, Washington, DC 20007 USA. [Jahan, Reza] Univ Calif Los Angeles, Dept Radiol & Neurosurg, Los Angeles, CA USA. [Gornbein, Jeffrey] Univ Calif Los Angeles, Dept Biomath, Los Angeles, CA USA. [Alger, Jeffry R.; Saver, Jeffrey L.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Nenov, Val] Univ Calif Los Angeles, Dept Neurosurg, Los Angeles, CA USA. [Guzy, Judy; Starkman, Sidney] Univ Calif Los Angeles, Dept Emergency Med & Neurol, Los Angeles, CA USA. [Jahan, Reza; Alger, Jeffry R.; Guzy, Judy; Starkman, Sidney; Saver, Jeffrey L.] Univ Calif Los Angeles, Stroke Ctr, Los Angeles, CA USA. [Ajani, Zahra] Kaiser Permanente, Dept Neurol, Los Angeles, CA USA. [Feng, Lei] Kaiser Permanente, Dept Radiol, Los Angeles, CA USA. [Meyer, Brett C.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Olson, Scott] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. [Meyer, Brett C.] Univ Calif San Diego, Stroke Ctr, San Diego, CA 92103 USA. [Olson, Scott] Scripps Clin, Div Neurosurg, La Jolla, CA 92037 USA. [Schwamm, Lee H.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Yoo, Albert J.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. [Marshall, Randolph S.] Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. [Meyers, Philip M.] Columbia Univ Coll Phys & Surg, Dept Neurol Surg & Radiol, New York, NY 10032 USA. [Yavagal, Dileep R.] Univ Miami, Jackson Mem Hosp, Dept Neurol, Miami, FL 33136 USA. [Yavagal, Dileep R.] Univ Miami, Jackson Mem Hosp, Dept Neurosurg, Miami, FL 33136 USA. [Wintermark, Max] Univ Virginia, Dept Radiol, Neuroradiol Div, Charlottesville, VA USA. RP Kidwell, CS (reprint author), Georgetown Univ, Bldg D,Suite 150,4000 Reservoir Rd NW, Washington, DC 20007 USA. EM ck256@georgetown.edu RI Buck, Brian/B-8482-2009; Demchuk, Andrew/E-1103-2012; OI Buck, Brian/0000-0002-7984-6062; Demchuk, Andrew/0000-0002-4930-7789; Kummer, Terrance/0000-0001-8938-8280; Ajani, Zahra/0000-0001-6187-5204; Molyneaux, Bradley/0000-0002-3377-1229; Gonzalez, Nestor/0000-0002-8277-6317; Saver, Jeffrey/0000-0001-9141-2251; Wintermark, Max/0000-0002-6726-3951; Schwamm, Lee/0000-0003-0592-9145 FU National Institute of Neurological Disorders and Stroke; NINDS [P50 NS044378] FX Funded by the National Institute of Neurological Disorders and Stroke; MR RESCUE ClinicalTrials.gov number, NCT00389467.); Supported by a grant (P50 NS044378) from NINDS. Concentric Medical provided study catheters and devices from the initiation of the study until August 2007; thereafter, costs for all study catheters and devices were covered by study funds or third-party payers. NR 22 TC 602 Z9 622 U1 3 U2 73 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 7 PY 2013 VL 368 IS 10 BP 914 EP 923 DI 10.1056/NEJMoa1212793 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 100BG UT WOS:000315669100007 PM 23394476 ER PT J AU Tarter, L Yazdany, J Moyers, B Barnett, C Dhaliwal, G AF Tarter, Laura Yazdany, Jinoos Moyers, Brian Barnett, Christopher Dhaliwal, Gurpreet TI The Heart of the Matter SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; LIBMAN-SACKS ENDOCARDITIS; ANTIPHOSPHOLIPID ANTIBODIES; VALVE REPLACEMENT; DISEASE; INVOLVEMENT C1 [Tarter, Laura] Stanford Univ, Med Ctr, Dept Med, Div Rheumatol & Immunol, Palo Alto, CA 94304 USA. [Yazdany, Jinoos] Univ Calif San Francisco, Div Rheumatol, San Francisco, CA USA. [Moyers, Brian; Barnett, Christopher] Univ Calif San Francisco, Div Cardiol, San Francisco, CA USA. [Dhaliwal, Gurpreet] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Barnett, Christopher] San Francisco Gen Hosp, San Francisco, CA 94110 USA. [Dhaliwal, Gurpreet] San Francisco VA Med Ctr, San Francisco, CA USA. RP Tarter, L (reprint author), Stanford Univ, Med Ctr, Dept Med, Div Rheumatol & Immunol, 1000 Welch Rd,Suite 203, Palo Alto, CA 94304 USA. EM tarter@gmail.com NR 15 TC 1 Z9 2 U1 0 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 7 PY 2013 VL 368 IS 10 BP 944 EP 950 DI 10.1056/NEJMcps1114207 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 100BG UT WOS:000315669100012 PM 23465105 ER PT J AU Rosenbaum, L AF Rosenbaum, Lisa TI The Whole Ball Game - Overcoming the Blind Spots in Health Care Reform SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID LOW-BACK-PAIN; TRIAL C1 [Rosenbaum, Lisa] Univ Penn, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Rosenbaum, Lisa] Univ Penn, Robert Wood Johnson Fdn Clin Scholars Program, Philadelphia, PA 19104 USA. RP Rosenbaum, L (reprint author), Univ Penn, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. NR 11 TC 10 Z9 10 U1 0 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 7 PY 2013 VL 368 IS 10 BP 959 EP 962 DI 10.1056/NEJMms1301576 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 100BG UT WOS:000315669100015 PM 23465107 ER PT J AU Schaefferkoetter, J Casey, M Townsend, D El Fakhri, G AF Schaefferkoetter, Joshua Casey, Michael Townsend, David El Fakhri, Georges TI Clinical impact of time-of-flight and point response modeling in PET reconstructions: a lesion detection study SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID HUMAN-OBSERVER; IMAGE-RECONSTRUCTION; NOISE; PERFORMANCE; LROC AB Time-of-flight (TOF) and point spread function (PSF) modeling have been shown to improve PET reconstructions, but the impact on physicians in the clinical setting has not been thoroughly investigated. A lesion detection and localization study was performed using simulated lesions in real patient images. Four reconstruction schemes were considered: ordinary Poisson OSEM (OP) alone and combined with TOF, PSF, and TOF + PSF. The images were presented to physicians experienced in reading PET images, and the performance of each was quantified using localization receiver operating characteristic. Numerical observers (non-prewhitening and Hotelling) were used to identify optimal reconstruction parameters, and observer SNR was compared to the performance of the physicians. The numerical models showed good agreement with human performance, and best performance was achieved by both when using TOF + PSF. These findings suggest a large potential benefit of TOF + PSF for oncology PET studies, especially in the detection of small, low-intensity, focal disease in larger patients. C1 [Schaefferkoetter, Joshua] Univ Tennessee, Med Ctr, Knoxville, TN 37920 USA. [Casey, Michael] Siemens Med Solut, Knoxville, TN 37919 USA. [Townsend, David] A STAR NUS Clin Imaging Res Ctr, Singapore 117599, Singapore. [El Fakhri, Georges] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Radiol Dept,Ctr Adv Med Imaging Sci, Boston, MA 02114 USA. RP Schaefferkoetter, J (reprint author), Univ Tennessee, Med Ctr, Knoxville, TN 37920 USA. EM jschaefferkoetter@utmck.edu; elfakhri@pet.mgh.harvard.edu FU National Institutes of Health [R01HL110241, R01CA165221] FX The authors wish to thank the three physicians who assisted with this study, Drs Yitong Fu, Karen Wells and Yong Bradley, of the University of Tennessee Medical Center, Knoxville, TN, and also Harold Rothfuss, Jim Hamill, and Judson Jones of Siemens Medical Solutions, Knoxville, TN for many helpful discussions. The assistance of Nathalie AbiHatem and Jinsong Oyang in selecting possible lesion locations is also acknowledged. One of the authors (GEF) acknowledges support, in part, from the National Institutes of Health grant R01HL110241 and R01CA165221. NR 28 TC 29 Z9 29 U1 0 U2 16 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 MAR 7 PY 2013 VL 58 IS 5 BP 1465 EP 1478 DI 10.1088/0031-9155/58/5/1465 PG 14 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 093KS UT WOS:000315191400019 PM 23403399 ER PT J AU Singh, JA Lewallen, DG AF Singh, Jasvinder A. Lewallen, David G. TI Income and patient-reported outcomes (PROs) after primary total knee arthroplasty SO BMC MEDICINE LA English DT Article DE arthroplasty; income; joint replacement; patient-reported outcomes; risk factor; total knee replacement ID TOTAL HIP-ARTHROPLASTY; SEVERE FUNCTIONAL LIMITATION; TOTAL JOINT ARTHROPLASTY; CLINICAL RATING SYSTEM; SOCIOECONOMIC-STATUS; REPLACEMENT SURGERY; HEALTH-CARE; PAIN; PREDICTORS; EXPECTATIONS AB Background: To assess whether income is associated with patient-reported outcomes (PROs) after primary total knee arthroplasty (TKA). Methods: We used prospectively collected data from the Mayo Clinic Total Joint Registry to assess the association of income with index knee functional improvement, moderate to severe pain and moderate to severe activity limitation at 2-year and 5-year follow-up after primary TKA using multivariable-adjusted logistic regression analyses. Results: There were 7, 139 primary TKAs at 2 years and 4, 234 at 5 years. In multivariable-adjusted analyses, at 2-year follow-up, compared to income > US$45, 000, lower incomes of <= US$35, 000 and > US$35, 000 to 45, 000 were associated (1) significantly with moderate to severe pain with an odds ratio (OR) 0.61 (95% CI 0.40 to 0.94) (P = 0.02) and 0.68 (95% CI 0.49 to 0.94) (P = 0.02); and (2) trended towards significance for moderate to severe activity limitation with OR 0.78 (95% CI 0.60 to 1.02) (P = 0.07) and no significant association with OR 0.96 (95% CI 0.78 to 1.20) (P = 0.75), respectively. At 5 years, odds were not statistically significantly different by income, although numerically they favored lower income. In multivariable-adjusted analyses, overall improvement in knee function was rated as 'better' slightly more often at 2 years by patients with income in the <= US$35, 000 range compared to patients with income > US$45, 000, with an OR 1.9 (95% CI 1.0 to 3.6) (P = 0.06). Conclusions: We found that patients with lower income had better pain outcomes compared to patients with higher income. There was more improvement in knee function, and a trend towards less overall activity limitation after primary TKA in lower income patients compared to those with higher incomes. Insights into mediators of these relationships need to be investigated to understand how income influences outcomes after TKA. C1 [Singh, Jasvinder A.] Birmingham VA Med Ctr, Med Serv, Birmingham, AL 35233 USA. [Singh, Jasvinder A.] Birmingham VA Med Ctr, C SMART, Birmingham, AL 35233 USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Sch Med, Dept Med, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Sch Publ Hlth, Div Epidemiol, Birmingham, AL 35294 USA. [Singh, Jasvinder A.; Lewallen, David G.] Mayo Clin, Coll Med, Dept Orthoped Surg, Rochester, MN 55905 USA. RP Singh, JA (reprint author), Birmingham VA Med Ctr, Med Serv, 700 19th St S, Birmingham, AL 35233 USA. EM jasvinder.md@gmail.com OI singh, jasvinder/0000-0003-3485-0006 FU Takeda; Savient; URL pharmaceuticals; Regeneron; Allergan; Ardea; Novartis; Zimmer; Orthosonic; Osteotech; Pipeline Biomedical; DePuy; Stryker; Biomet; Mayo Clinic Orthopedic Surgery research funds; Agency for Health Quality and Research Center for Education and Research on Therapeutics (CERTs); National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS); National Institute of Aging (NIA); National Cancer Institute (NCI) FX The authors report no financial conflicts related directly to this study. JAS has received research grants from Takeda and Savient; and consultant fees from URL pharmaceuticals, Savient, Takeda, Regeneron, Allergan, Ardea and Novartis. DGL has received royalties/speaker fees from Zimmer, Orthosonic and Osteotech, has been a paid consultant to and owns stock in Pipeline Biomedical and has received institutional research funds from DePuy, Stryker, Biomet and Zimmer.; This material is the result of work supported by Mayo Clinic Orthopedic Surgery research funds and the resources and use of facilities at the Birmingham VA Medical Center, Alabama, USA. JAS is also supported by grants from the Agency for Health Quality and Research Center for Education and Research on Therapeutics (CERTs), National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institute of Aging (NIA) and National Cancer Institute (NCI). NR 53 TC 4 Z9 4 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD MAR 6 PY 2013 VL 11 AR 62 DI 10.1186/1741-7015-11-62 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 137LE UT WOS:000318436600001 PM 23497272 ER PT J AU Warner, ET Glasgow, RE Emmons, KM Bennett, GG Askew, S Rosner, B Colditz, GA AF Warner, Erica T. Glasgow, Russell E. Emmons, Karen M. Bennett, Gary G. Askew, Sandy Rosner, Bernard Colditz, Graham A. TI Recruitment and retention of participants in a pragmatic randomized intervention trial at three community health clinics: Results and lessons learned SO BMC PUBLIC HEALTH LA English DT Article DE Health disparities; Weight-loss; Obesity; Hypertension; Pragmatic trial; Recruitment; Retention ID TERM WEIGHT-LOSS; AFRICAN-AMERICANS; MEDICAL-RESEARCH; FOLLOW-UP; OBESITY; PROGRAM; COHORT; WOMEN; HYPERTENSION; PREVALENCE AB Background: Obesity and hypertension and their associated health complications disproportionately affect communities of color and people of lower socioeconomic status. Recruitment and retention of these populations in research trials, and retention in weight loss trials has been an ongoing challenge. Methods: Be Fit, Be Well was a pragmatic randomized weight loss and hypertension management trial of patients attending one of three community health centers in Boston, Massachusetts. Participants were asked to complete follow-up assessments every 6-months for two years. We describe challenges encountered and strategies implemented to recruit and retain trial participants over the 24-month intervention. We also identify baseline participant characteristics associated with retention status. Retention strategies included financial incentives, contact between assessment visits, building relationships with health center primary care providers (PCPs) and staff, and putting participant convenience first. Results: Active refusal rates were low with 130 of 2,631 patients refusing participation (4.9%). Of 474 eligible persons completing telephone screening, 365 (77.0%) completed their baseline visit and were randomized into the study. The study population was predominantly non-Hispanic Black (71.2%), female (68.5%) and reported annual household income of less than $35,000 (70.1%). Recruitment strategies included use of passive approval of potential participants by PCPs, use of part-time staff, and outsourcing calls to a call center. A total of 314 (86.0%) people completed the 24-month visit. Retention levels varied across study visits and intervention condition. Most participants completed three or more visits (69.6%), with 205 (56.2%) completing all four. At 24-months, lower retention was observed for males and the intervention condition. Retention strategies included building strong relationships with clinic staff, flexibility in overcoming participant barriers through use of taxi vouchers, night and weekend appointments, and keeping participants engaged via newsletters and social gatherings. Conclusion: We were able to retain 86.0% of participants at 24-months. Recruitment and retention of high percentages of racial/ethnic minorities and lower income samples is possible with planning, coordination with a trusted community setting and staff (e.g. community health centers and RAs), adaptability and building strong relationships. C1 [Warner, Erica T.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Warner, Erica T.; Emmons, Karen M.; Bennett, Gary G.] Dana Farber Canc Inst, Ctr Community Based Res, Div Populat Sci, Boston, MA 02115 USA. [Warner, Erica T.; Rosner, Bernard] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Bennett, Gary G.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Bennett, Gary G.; Askew, Sandy] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Rosner, Bernard] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Rosner, Bernard] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Colditz, Graham A.] Washington Univ, Sch Med, Dept Surg, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. RP Warner, ET (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM ewarner@hsph.harvard.edu RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU National Heart, Lung, and Blood Institute [U01-HL087071, K22CA126992, K05CA124415-04, 5T32CA009001-36, 5R25GM055353-14] FX This work was supported in part by grant U01-HL087071 from the National Heart, Lung, and Blood Institute and grants K22CA126992 (Dr. Bennett), K05CA124415-04 (Dr. Emmons), 5T32CA009001-36 (Dr. Warner), and 5R25GM055353-14 (Dr. Warner). NR 36 TC 13 Z9 13 U1 3 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD MAR 6 PY 2013 VL 13 AR 192 DI 10.1186/1471-2458-13-192 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 119UH UT WOS:000317123500002 PM 23496916 ER PT J AU Shao, LJ Zhou, ZS Cai, Y Castro, P Dakhov, O Shi, P Bai, YX Ji, HX Shen, WH Wang, JH AF Shao, Longjiang Zhou, Zhansong Cai, Yi Castro, Patricia Dakhov, Olga Shi, Ping Bai, Yaoxia Ji, Huixiang Shen, Wenhao Wang, Jianghua TI Celastrol Suppresses Tumor Cell Growth through Targeting an AR-ERG-NF-kappa B Pathway in TMPRSS2/ERG Fusion Gene Expressing Prostate Cancer SO PLOS ONE LA English DT Article ID TRANSCRIPTIONAL ACTIVITY; SIGNALING PATHWAYS; IKK-EPSILON; P65 SUBUNIT; NUDE-MICE; GOD VINE; PHOSPHORYLATION; PROGRESSION; ACTIVATION; KINASE AB The TMPRSS2/ERG (T/E) fusion gene is present in the majority of all prostate cancers (PCa). We have shown previously that NF-kappa B signaling is highly activated in these T/E fusion expressing cells via phosphorylation of NF-kB p65 Ser536 (p536). We therefore hypothesize that targeting NF-kB signaling may be an efficacious approach for the subgroup of PCas that carry T/E fusions. Celastrol is a well known NF-kB inhibitor, and thus may inhibit T/E fusion expressing PCa cell growth. We therefore evaluated Celastrol's effects in vitro and in vivo in VCaP cells, which express the T/E fusion gene. VCaP cells were treated with different concentrations of Celastrol and growth inhibition and target expression were evaluated. To test its ability to inhibit growth in vivo, 0.5 mg/kg Celastrol was used to treat mice bearing subcutaneous VCaP xenograft tumors. Our results show Celastrol can significantly inhibit the growth of T/E fusion expressing PCa cells both in vitro and in vivo through targeting three critical signaling pathways: AR, ERG and NF-kB in these cells. When mice received 0.5 mg/kg Celastrol for 4 times/week, significant growth inhibition was seen with no obvious toxicity or significant weight loss. Therefore, Celastrol is a promising candidate drug for T/E fusion expressing PCa. Our findings provide a novel strategy for the targeted therapy which may benefit the more than half of PCa patients who have T/E fusion expressing PCas. C1 [Shao, Longjiang; Cai, Yi; Castro, Patricia; Dakhov, Olga; Wang, Jianghua] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Shao, Longjiang; Cai, Yi; Castro, Patricia; Dakhov, Olga; Wang, Jianghua] Michael E DeBakey Dept Vet Affairs Med Ctr, Houston, TX USA. [Zhou, Zhansong; Shi, Ping; Bai, Yaoxia; Ji, Huixiang; Shen, Wenhao] South West Hosp, Dept Urol, Chongqing, Peoples R China. RP Wang, JH (reprint author), Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. EM jwang1@bcm.edu FU Department of Defense Prostate Cancer Research program [DOD W81XWH-08-1-0055]; NCI; Duncan Cancer Center Human Tissue and Pathology Core [NCI: P30CA125123] FX This work was supported by the Department of Defense Prostate Cancer Research program (DOD W81XWH-08-1-0055; JW) and the NCI to the Dan L. Duncan Cancer Center Human Tissue and Pathology Core (NCI: P30CA125123). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 18 Z9 19 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 6 PY 2013 VL 8 IS 3 AR e58391 DI 10.1371/journal.pone.0058391 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 117EP UT WOS:000316936100115 PM 23554889 ER PT J AU Huang, HW Chen, ZX Huang, XD AF Huang, Hanwen Chen, Zhongxue Huang, Xudong TI Age-adjusted nonparametric detection of differential DNA methylation with case-control designs SO BMC BIOINFORMATICS LA English DT Article DE Nonparametric method; One-sided test; Combining p-value ID GENOME-WIDE ASSOCIATION; EXPRESSED GENES; ARRAY DATA; CANCER; LOCI; PROBABILITIES; TESTS AB Background: DNA methylation profiles differ among disease types and, therefore, can be used in disease diagnosis. In addition, large-scale whole genome DNA methylation data offer tremendous potential in understanding the role of DNA methylation in normal development and function. However, due to the unique feature of the methylation data, powerful and robust statistical methods are very limited in this area. Results: In this paper, we proposed and examined a new statistical method to detect differentially methylated loci for case control designs that is fully nonparametric and does not depend on any assumption for the underlying distribution of the data. Moreover, the proposed method adjusts for the age effect that has been shown to be highly correlated with DNA methylation profiles. Using simulation studies and a real data application, we have demonstrated the advantages of our method over existing commonly used methods. Conclusions: Compared to existing methods, our method improved the detection power for differentially methylated loci for case control designs and controlled the type I error well. Its applications are not limited to methylation data; it can be extended to many other case-control studies. C1 [Huang, Hanwen] Univ Georgia, Dept Epidemiol & Biostat, Athens, GA 30605 USA. [Chen, Zhongxue] Indiana Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Bloomington, IN 47405 USA. [Huang, Xudong] Massachusetts Gen Hosp, Neurochem Lab, Dept Psychiat, Charlestown, MA 02129 USA. [Huang, Xudong] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Chen, ZX (reprint author), Indiana Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, 1025 E 7th St, Bloomington, IN 47405 USA. EM zc3@indiana.edu RI Chen, Zhongxue/K-1372-2013 OI Chen, Zhongxue/0000-0003-2537-7843 FU School of Public Health at the Indiana University Bloomington FX The authors would like to thank Ms. Kim Lawson for her professional editorial assistance, which highly improved the presentation of this paper. ZC also thanks the support from the faculty research funds awarded by the School of Public Health at the Indiana University Bloomington. NR 32 TC 9 Z9 9 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAR 6 PY 2013 VL 14 AR 86 DI 10.1186/1471-2105-14-86 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 106ZV UT WOS:000316185300001 PM 23497201 ER PT J AU Wojno, AP Pierce, EA Bennett, J AF Wojno, Adam P. Pierce, Eric A. Bennett, Jean TI Seeing the Light SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material ID LEBER CONGENITAL AMAUROSIS; GENE-THERAPY; CHILDHOOD BLINDNESS; RPE65 MUTATIONS; CANINE MODEL; VISION; ROD AB One-time gene therapy resulted in multiyear visual improvement, and new approaches were used to evaluate effects on retinal structure. C1 [Wojno, Adam P.; Bennett, Jean] Univ Penn, Sch Med, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA. [Pierce, Eric A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Genom Inst,Dept Ophthalmol, Boston, MA 02114 USA. RP Bennett, J (reprint author), Univ Penn, Sch Med, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA. EM jebennet@mail.med.upenn.edu OI Pierce, Eric/0000-0002-2354-4102 NR 7 TC 3 Z9 3 U1 0 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAR 6 PY 2013 VL 5 IS 175 AR 175fs8 DI 10.1126/scitranslmed.3005798 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 103MY UT WOS:000315922500002 PM 23467559 ER PT J AU Ruchelsman, DE Christoforou, D Jupiter, JB AF Ruchelsman, David E. Christoforou, Dimitrios Jupiter, Jesse B. TI Fractures of the Radial Head and Neck SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Review ID PARTIAL ARTICULAR FRACTURES; MEDIAL COLLATERAL LIGAMENT; ESSEX-LOPRESTI INJURY; TERM-FOLLOW-UP; MASON TYPE-III; INTERNAL-FIXATION; OPEN REDUCTION; INTEROSSEOUS MEMBRANE; ELBOW DISLOCATION; MORPHOMETRIC PARAMETERS C1 [Ruchelsman, David E.; Christoforou, Dimitrios; Jupiter, Jesse B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg,Hand & Upper Extrem Serv, Boston, MA 02114 USA. Tufts Univ, Sch Med, Newton Wellesley Hosp, Boston, MA 02111 USA. RP Ruchelsman, DE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg,Hand & Upper Extrem Serv, 55 Fruit St,Yawkey Ctr,Suite 2100, Boston, MA 02114 USA. EM druchelsman@partners.org; jjupiter1@partners.org NR 93 TC 13 Z9 16 U1 0 U2 6 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD MAR 6 PY 2013 VL 95A IS 5 BP 469 EP 478 DI 10.2106/JBJS.J.01989 PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AF8MV UT WOS:000334971200012 PM 23467871 ER PT J AU Berg, AH Drechsler, C Wenger, J Buccafusca, R Hod, T Kalim, S Ramma, W Parikh, SM Steen, H Friedman, DJ Danziger, J Wanner, C Thadhani, R Karumanchi, SA AF Berg, Anders H. Drechsler, Christiane Wenger, Julia Buccafusca, Roberto Hod, Tammy Kalim, Sahir Ramma, Wenda Parikh, Samir M. Steen, Hanno Friedman, David J. Danziger, John Wanner, Christoph Thadhani, Ravi Karumanchi, S. Ananth TI Carbamylation of Serum Albumin as a Risk Factor for Mortality in Patients with Kidney Failure SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID HEMODIALYSIS-PATIENTS; AMINO-ACIDS; FUNCTIONAL GROUPS; RENAL-FAILURE; MAINTENANCE HEMODIALYSIS; PERITONEAL-DIALYSIS; ENDOTHELIAL-CELLS; PROTEIN; CYANATE; UREA AB Urea, the toxic end product of protein catabolism, is elevated in end-stage renal disease (ESRD), although it is unclear whether or how it contributes to disease. Urea can promote the carbamylation of proteins on multiple lysine side chains, including human albumin, which has a predominant carbamylation site on Lys(549). The proportion of serum albumin carbamylated on Lys(549) (% C-Alb) correlated with time-averaged blood urea concentrations and was twice as high in ESRD patients than in non-uremic subjects (0.90% versus 0.42%). Baseline %C-Alb was higher in ESRD subjects who died within 1 year than in those who survived longer than 1 year (1.01% versus 0.77%) and was associated with an increased risk of death within 1 year (hazard ratio, 3.76). These findings were validated in an independent cohort of diabetic ESRD subjects (hazard ratio, 3.73). Decreased concentrations of serum amino acids correlated with higher %C-Alb in ESRD patients, and mice with diet-induced amino acid deficiencies exhibited greater susceptibility to albumin carbamylation than did chow-fed mice. In vitro studies showed that amino acids such as cysteine, histidine, arginine, and lysine, as well as other nucleophiles such as taurine, inhibited cyanate-induced C-Alb formation at physiologic pH and temperature. Together, these results suggest that chronically elevated urea promotes carbamylation of proteins in ESRD and that serum amino acid concentrations may modulate this protein modification. In summary, we have identified serum % C-Alb as a risk factor for mortality in patients with ESRD and propose that this risk factor may be modifiable with supplemental amino acid therapy. C1 [Berg, Anders H.; Ramma, Wenda] Beth Israel Deaconess Med Ctr, Dept Pathol, Div Clin Chem, Boston, MA 02215 USA. [Drechsler, Christiane; Wanner, Christoph] Univ Wurzburg, Dept Internal Med, Div Nephrol, D-97074 Wurzburg, Germany. [Wenger, Julia; Kalim, Sahir; Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Wenger, Julia; Kalim, Sahir; Thadhani, Ravi] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Buccafusca, Roberto; Hod, Tammy; Parikh, Samir M.; Friedman, David J.; Danziger, John; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA 02215 USA. [Buccafusca, Roberto; Hod, Tammy; Parikh, Samir M.; Friedman, David J.; Danziger, John; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Dept Med, Boston, MA 02215 USA. [Buccafusca, Roberto; Hod, Tammy; Parikh, Samir M.; Friedman, David J.; Danziger, John; Karumanchi, S. Ananth] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Buccafusca, Roberto; Steen, Hanno] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Buccafusca, Roberto; Steen, Hanno] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Karumanchi, S. Ananth] Howard Hughes Med Inst, Boston, MA 02215 USA. RP Berg, AH (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, Div Clin Chem, 330 Brookline Ave, Boston, MA 02215 USA. EM ahberg@bidmc.harvard.edu FU Beth Israel Deaconess Medical Center Department of Pathology; Howard Hughes Medical Institute; University Hospital Wuerzberg "Gundausstattung" grant program; [K24 DK094872] FX Supported by the Beth Israel Deaconess Medical Center Department of Pathology (to A.H.B.); the Howard Hughes Medical Institute (to S.A.K.); K24 DK094872 (to R.T.); and the University Hospital Wuerzberg "Gundausstattung" grant program (to C.D. and C.W.). NR 54 TC 23 Z9 24 U1 2 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD MAR 6 PY 2013 VL 5 IS 175 AR 175ra29 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 103MY UT WOS:000315922500004 PM 23467560 ER PT J AU Chen, CY Garcia-Santos, D Ishikawa, Y Seguin, A Li, LT Fegan, KH Hildick-Smith, GJ Shah, DI Cooney, JD Chen, W King, MJ Yien, YY Schultz, IJ Anderson, H Dalton, AJ Freedman, ML Kingsley, PD Palis, J Hattangadi, SM Lodish, HF Ward, DM Kaplan, J Maeda, T Ponka, P Paw, BH AF Chen, Caiyong Garcia-Santos, Daniel Ishikawa, Yuichi Seguin, Alexandra Li, Liangtao Fegan, Katherine H. Hildick-Smith, Gordon J. Shah, Dhvanit I. Cooney, Jeffrey D. Chen, Wen King, Matthew J. Yien, Yvette Y. Schultz, Iman J. Anderson, Heidi Dalton, Arthur J. Freedman, Matthew L. Kingsley, Paul D. Palis, James Hattangadi, Shilpa M. Lodish, Harvey F. Ward, Diane M. Kaplan, Jerry Maeda, Takahiro Ponka, Prem Paw, Barry H. TI Snx3 Regulates Recycling of the Transferrin Receptor and Iron Assimilation SO CELL METABOLISM LA English DT Article ID ERYTHROID-DIFFERENTIATION; PROTEIN TRAFFICKING; RESPONSIVE ELEMENTS; SORTING NEXINS; HBD MICE; CELLS; METABOLISM; GENE; TRANSPORT; LOCI AB Sorting of endocytic ligands and receptors is critical for diverse cellular processes. The physiological significance of endosomal sorting proteins in vertebrates, however, remains largely unknown. Here we report that sorting nexin 3 (Snx3) facilitates the recycling of transferrin receptor (Tfrc) and thus is required for the proper delivery of iron to erythroid progenitors. Snx3 is highly expressed in vertebrate hematopoietic tissues. Silencing of Snx3 results in anemia and hemoglobin defects in vertebrates due to impaired transferrin (Tf)-mediated iron uptake and its accumulation in early endosomes. This impaired iron assimilation can be complemented with non-Tf iron chelates. We show that Snx3 and Vps35, a component of the retromer, interact with Tfrc to sort it to the recycling endosomes. Our findings uncover a role of Snx3 in regulating Tfrc recycling, iron homeostasis, and erythropoiesis. Thus, the identification of Snx3 provides a genetic tool for exploring erythropoiesis and disorders of iron metabolism. C1 [Chen, Caiyong; Ishikawa, Yuichi; Hildick-Smith, Gordon J.; Shah, Dhvanit I.; Cooney, Jeffrey D.; Chen, Wen; King, Matthew J.; Yien, Yvette Y.; Schultz, Iman J.; Anderson, Heidi; Dalton, Arthur J.; Hattangadi, Shilpa M.; Maeda, Takahiro; Paw, Barry H.] Harvard Univ, Sch Med, Dept Med, Div Hematol,Brigham & Womens Hosp, Boston, MA 02115 USA. [Garcia-Santos, Daniel; Ponka, Prem] McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3G 1Y6, Canada. [Garcia-Santos, Daniel; Ponka, Prem] McGill Univ, Dept Physiol, Montreal, PQ H3G 1Y6, Canada. [Seguin, Alexandra; Li, Liangtao; Ward, Diane M.; Kaplan, Jerry] Univ Utah, Dept Pathol, Sch Med, Salt Lake City, UT 84312 USA. [Fegan, Katherine H.; Kingsley, Paul D.; Palis, James] Univ Rochester, Sch Med & Dent, Dept Pediat, Ctr Pediat Biomed Res, Rochester, NY 14642 USA. [Freedman, Matthew L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hattangadi, Shilpa M.; Paw, Barry H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Hattangadi, Shilpa M.; Paw, Barry H.] Harvard Univ, Sch Med, Dept Med, Div Hematol Oncol,Boston Childrens Hosp, Boston, MA 02115 USA. [Hattangadi, Shilpa M.; Lodish, Harvey F.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Hattangadi, Shilpa M.; Lodish, Harvey F.] MIT, Cambridge, MA 02142 USA. RP Paw, BH (reprint author), Harvard Univ, Sch Med, Dept Med, Div Hematol,Brigham & Womens Hosp, Boston, MA 02115 USA. EM bpaw@rics.bwh.harvard.edu RI Ponka, Prem/A-4123-2011; OI Garcia dos Santos, Daniel/0000-0003-3894-427X FU Cooley's Anemia Foundation; American Heart Association; American Society of Hematology; Dutch National Science Fund-NWO; Finnish Sigrid Juselius Foundation; March of Dimes Foundation [6-FY09-289]; Canadian Institutes of Health Research; National Institutes of Health [T32 HL007574, K01 DK085217, K08 DK076848, R01 DK09361, P01 HL032262, R01 HL026922, R01 DK052380, R01 DK070838] FX We thank members of our lab (Jacky Chung, Diana Branco, Adrianne Kolpak) and Dr. Elizabeth Leibold for critical discussion and reading of the manuscript, Dr. Yan Zhang for help with the enzymatic assays, Dr. Rebecca Wingert for the zebrafish tfr1a cDNA clone, Dr. Leonard Zon for the Tg(globin LCR: eGFP) transgenic line, Dr. Karin Hoffmeister for use of the FACS machine, and Christian Lawrence and his team for the zebrafish husbandry. This work was supported by grants from the Cooley's Anemia Foundation (C. C., D. I. S.), the American Heart Association (J. D. C., M. J. K., A. J. D.), the American Society of Hematology (M. J. K.), the Dutch National Science Fund-NWO (I. J. S.), the Finnish Sigrid Juselius Foundation (H. A.), the March of Dimes Foundation (6-FY09-289, B. H. P.), the Canadian Institutes of Health Research (D. G.-S. and P. P.), and the National Institutes of Health (T32 HL007574, Y. Y. Y.; K01 DK085217, D. I. S.; K08 DK076848, S. M. H.; R01 DK09361, J. P.; P01 HL032262, H. F. L.; R01 HL026922, D. M. W.; R01 DK052380, J. K.; R01 DK070838 and P01 HL032262, B. H. P.). C. C. and B. H. P. designed studies, performed experiments, analyzed data, and wrote the manuscript. D. G.-S. and P. P. measured the uptake of 59 Fe-Tf. Y. I. and T. M. measured the surface-bound Tfrc level and the recycling of internalized Tf-Alexa 647. A. S., L. L., D. M. W., and J. K. analyzed the subcellular localization of Tf-Alexa 488 and performed the enzymatic assays. K. H. F., P. D. K., and J. P. performed the in situ hybridization studies in mouse embryos. G. J. H.-S. and J. D. C. performed flow cytometry experiments on Tg(globin-LCR: eGFP) line. D. I. S. performed the qRT-PCR analysis. W. C. constructed Tfrc-FLAG and Abcb10-FLAG constructs and generated the MEL clones stably expressing these constructs. M. J. K., Y. Y. Y., I. J. S., H. A., and A. J. D. helped with RNA-seq data analysis and zebrafish colony maintenance. M. L. F. analyzed the GWAS database for potential interesting SNPs in Snx3. S. M. H. and H. F. L. provided gene expression data from the RNA-seq experiment and knocked down Snx3 in mouse primary fetal liver cells. NR 53 TC 22 Z9 25 U1 3 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD MAR 5 PY 2013 VL 17 IS 3 BP 343 EP 352 DI 10.1016/j.cmet.2013.01.013 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242TP UT WOS:000326265400007 PM 23416069 ER PT J AU Gameiro, PA Yang, JJ Metelo, AM Perez-Carro, R Baker, R Wang, ZW Arreola, A Rathmell, WK Olumi, A Lopez-Larrubia, P Stephanopoulos, G Iliopoulos, O AF Gameiro, Paulo A. Yang, Juanjuan Metelo, Ana M. Perez-Carro, Rocio Baker, Rania Wang, Zongwei Arreola, Alexandra Rathmell, W. Kimryn Olumi, Aria Lopez-Larrubia, Pilar Stephanopoulos, Gregory Iliopoulos, Othon TI In Vivo HIF-Mediated Reductive Carboxylation Is Regulated by Citrate Levels and Sensitizes VHL-Deficient Cells to Glutamine Deprivation SO CELL METABOLISM LA English DT Article ID ADENINE DINUCLEOTIDE PHOSPHATE; HYPOXIA-INDUCIBLE FACTOR-1; TUMOR-SUPPRESSOR PROTEIN; ISOCITRATE DEHYDROGENASE; OXIDATIVE STRESS; BINDING SITES; METABOLISM; CANCER; LIPOGENESIS; SUBSTRATE AB Hypoxic and VHL-deficient cells use glutamine to generate citrate and lipids through reductive carboxylation (RC) of alpha-ketoglutarate. To gain insights into the role of HIF and the molecular mechanisms underlying RC, we took advantage of a panel of disease-associated VHL mutants and showed that HIF expression is necessary and sufficient for the induction of RC in human renal cell carcinoma (RCC) cells. HIF expression drastically reduced intracellular citrate levels. Feeding VHL-deficient RCC cells with acetate or citrate or knocking down PDK-1 and ACLY restored citrate levels and suppressed RC. These data suggest that HIF-induced low intracellular citrate levels promote the reductive flux by mass action to maintain lipogenesis. Using [C1-13] glutamine, we demonstrated in vivo RC activity in VHL-deficient tumors growing as xenografts in mice. Lastly, HIF rendered VHL-deficient cells sensitive to glutamine deprivation in vitro, and systemic administration of glutaminase inhibitors suppressed the growth of RCC cells as mice xenografts. C1 [Gameiro, Paulo A.; Yang, Juanjuan; Metelo, Ana M.; Baker, Rania; Iliopoulos, Othon] Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Res, Charlestown, MA 02129 USA. [Gameiro, Paulo A.; Yang, Juanjuan; Metelo, Ana M.; Baker, Rania; Iliopoulos, Othon] Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. [Wang, Zongwei; Olumi, Aria] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Gameiro, Paulo A.; Stephanopoulos, Gregory] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Gameiro, Paulo A.] Univ Coimbra, Dept Life Sci, P-3004517 Coimbra, Portugal. [Arreola, Alexandra; Rathmell, W. Kimryn] Univ N Carolina, Dept Med, UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Arreola, Alexandra; Rathmell, W. Kimryn] Univ N Carolina, Dept Genet, UNC Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. [Perez-Carro, Rocio; Lopez-Larrubia, Pilar] CSIC UAM, Inst Invest Biomed Alberto Sols, Madrid 28029, Spain. RP Iliopoulos, O (reprint author), Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Res, Charlestown, MA 02129 USA. EM oiliopoulos@partners.org RI Lopez-Larrubia, Pilar/B-3902-2013 OI Lopez-Larrubia, Pilar/0000-0002-5141-8736 FU NIH [R01 CA122591]; MGH Proton Beam Federal Share Project; Astra-Zeneca; Foundation for Science and Technology (FCT), Portugal; MICINN [CTQ-2010-20960-CO2-02]; [NIHR01 DK075850] FX The authors declare no conflict of interest. This work was supported by NIH R01 CA122591, the MGH Proton Beam Federal Share Project, and an Astra-Zeneca Award (all to O.I.); funding from the Foundation for Science and Technology (FCT), Portugal (to P. A. G.); MICINN CTQ-2010-20960-CO2-02 (to P. L-L.); and NIHR01 DK075850 (to G. S.). We would like to thank Konstantia Angelidou (Harvard School of Public Health) for advice on statistical methods and Dr. Ralph DeBerardinis for helpful suggestions on the in vivo labeling experiments. NR 45 TC 77 Z9 78 U1 2 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD MAR 5 PY 2013 VL 17 IS 3 BP 372 EP 385 DI 10.1016/j.cmet.2013.02.002 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 242TP UT WOS:000326265400009 PM 23473032 ER PT J AU Nathan, DM Russell, S AF Nathan, David M. Russell, Steven TI The future of care for type 1 diabetes SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Editorial Material ID INSULIN DELIVERY; COMPLICATIONS; PANCREAS; MELLITUS C1 [Nathan, David M.; Russell, Steven] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Nathan, DM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. EM dnathan@partners.org NR 10 TC 0 Z9 0 U1 0 U2 2 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 5W8, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD MAR 5 PY 2013 VL 185 IS 4 BP 285 EP 286 DI 10.1503/cmaj.130011 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 180VM UT WOS:000321626900016 PM 23359043 ER PT J AU Degeling, MH Bovenberg, MSS Lewandrowski, GK de Gooijer, MC Vleggeert-Lankamp, CLA Tannous, M Maguire, CA Tannous, BA AF Degeling, M. Hannah Bovenberg, M. Sarah S. Lewandrowski, Grant K. de Gooijer, Mark C. Vleggeert-Lankamp, Carmen L. A. Tannous, Marie Maguire, Casey A. Tannous, Bakhos A. TI Directed Molecular Evolution Reveals Gaussia Luciferase Variants with Enhanced Light Output Stability SO ANALYTICAL CHEMISTRY LA English DT Article ID REPORTER GENE-EXPRESSION; IN-VIVO; BIOLUMINESCENCE; APOPTOSIS; PRINCEPS; CELLS AB Gaussia Luciferase (Gluc) has proven to be a powerful mammalian cell reporter for monitoring numerous biological processes in immunology, virology, oncology, and neuroscience. Current limitations of Gluc as a reporter include its emission of blue light, which is absorbed by mammalian tissues, limiting its use in vivo, and a flash-type bioluminescence reaction, making it unsuited for high-throughput applications. To overcome these limitations, a library of Gluc variants was generated using directed molecular evolution and screened for relative light: output, a shift in emission spectrum, and glow-type light emission kinetics. Several variants with a 10-15 nm shift in their light emission peak were found. Further, a Gluc variant that catalyzes a glow-type bioluminescence reaction, suited for high-throughput applications, was also identified. These results indicate that molecular evolution could be used to modulate Gluc bioluminescence reaction characteristics. C1 [Degeling, M. Hannah; Bovenberg, M. Sarah S.; Lewandrowski, Grant K.; de Gooijer, Mark C.; Maguire, Casey A.; Tannous, Bakhos A.] Massachusetts Gen Hosp, Ctr Neurosci, Expt Therapeut & Mol Imaging Lab, Dept Neurol, Charlestown, MA 02129 USA. [Degeling, M. Hannah; Bovenberg, M. Sarah S.; Lewandrowski, Grant K.; de Gooijer, Mark C.; Maguire, Casey A.; Tannous, Bakhos A.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02114 USA. [Degeling, M. Hannah; Bovenberg, M. Sarah S.; Vleggeert-Lankamp, Carmen L. A.] Leiden Univ, Med Ctr, Dept Neurosurg, Leiden, Netherlands. [de Gooijer, Mark C.] Canc Ctr Amsterdam, VU Med Ctr, Dept Neurosurg, Neurooncol Res Grp, NL-1007 MB Amsterdam, Netherlands. [Tannous, Marie] Notre Dame Univ, Fac Nat & Appl Sci, Barsa, Lebanon. RP Tannous, BA (reprint author), Massachusetts Gen Hosp, Ctr Neurosci, Bldg 149,13th St, Charlestown, MA 02129 USA. EM btannous@hms.harvard.edu FU NIH/NINDS [P30NS045776, 1R01NS064983]; American Brain Tumor Association; Fulbright scholarship; Saal van Zwanenberg Foundation; VSB fonds; Dr. Hendrik Muller Vaderlandschfonds; Dutch Cancer Foundation (KWF Kankerbestrijding); Hersenstichting brain fund; Huygens Scholarship Program FX This work was supported by grants from NIH/NINDS P30NS045776 and 1R01NS064983 (BAT). C.M. is supported by a Fellowship from the American Brain Tumor Association. M.H.D. is supported by a Fulbright scholarship, the Saal van Zwanenberg Foundation, VSB fonds, Dr. Hendrik Muller Vaderlandschfonds, the Dutch Cancer Foundation (KWF Kankerbestrijding), the Hersenstichting brain fund, and the Jo Keur (Leiden hospital). M.S.B. was supported by a Fulbright scholarship, the Huygens Scholarship Program, VSB fonds, and the Saal van Zwanenberg Foundation. M.C.d.G. is supported by a Fulbright scholarship. We thank John Darga of the Center for Computational and Integrative Biology, Massachusetts General Hospital, for performing the bacteria colony picking and growth of the Gluc plasmid library.tbl1. NR 23 TC 14 Z9 15 U1 0 U2 25 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD MAR 5 PY 2013 VL 85 IS 5 BP 3006 EP 3012 DI 10.1021/ac4003134 PG 7 WC Chemistry, Analytical SC Chemistry GA 118NG UT WOS:000317031600064 PM 23425213 ER PT J AU Chapman, JW O'Callaghan, CJ Hu, N Ding, K Yothers, GA Catalano, PJ Shi, Q Gray, RG O'Connell, MJ Sargent, DJ AF Chapman, J. W. O'Callaghan, C. J. Hu, N. Ding, K. Yothers, G. A. Catalano, P. J. Shi, Q. Gray, R. G. O'Connell, M. J. Sargent, D. J. CA ACCENT Collaborative Grp TI Innovative estimation of survival using log-normal survival modelling on ACCENT database SO BRITISH JOURNAL OF CANCER LA English DT Article DE colon cancer; survival; log-normal; Cox; Kaplan-Meier; ACCENT database ID INDIVIDUAL PATIENT DATA; 18 RANDOMIZED-TRIALS; COLORECTAL-CANCER; COLON-CANCER; PROPORTIONAL-HAZARDS; BREAST-CANCER; CETUXIMAB; THERAPY AB Background: The ACCENT database, with individual patient data for 20 898 patients from 18 colon cancer clinical trials, was used to support Food and Drug Administration (FDA) approval of 3-year disease-free survival as a surrogate for 5-year overall survival. We hypothesised substantive differences in survival estimation with log-normal modelling rather than standard Kaplan-Meier or Cox approaches. Methods: Time to relapse, disease-free survival, and overall survival were estimated using Kaplan-Meier, Cox, and log-normal approaches for male subjects aged 60-65 years, with stage III colon cancer, treated with 5-fluorouracil-based chemotherapy regimens (with 5FU), or with surgery alone (without 5FU). Results: Absolute differences between Cox and log-normal estimates with (without) 5FU varied by end point. The log-normal model had 5.8 (6.3)% higher estimated 3-year time to relapse than the Cox model; 4.8 (5.1)% higher 3-year disease-free survival; and 3.2 (2.2)% higher 5-year overall survival. Model checking indicated greater data support for the log-normal than the Cox model, with Cox and Kaplan Meier estimates being more similar. All three model types indicate consistent evidence of treatment benefit on both 3-year disease-free survival and 5-year overall survival; patients allocated to 5FU had 5.0-6.7% higher 3-year disease-free survival and 5.3-6.8% higher 5-year overall survival. Conclusion: Substantive absolute differences between estimates of 3-year disease-free survival and 5-year overall survival with log-normal and Cox models were large enough to be clinically relevant, and warrant further consideration. C1 [Chapman, J. W.; O'Callaghan, C. J.; Hu, N.; Ding, K.] Queens Univ, NCIC Clin Trials Grp, Kingston, ON, Canada. [Yothers, G. A.] Univ Pittsburgh, NSABP Biostat Ctr, Pittsburgh, PA USA. [Yothers, G. A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Catalano, P. J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Shi, Q.; Sargent, D. J.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Gray, R. G.] Univ Birmingham, Birmingham, W Midlands, England. [Yothers, G. A.; O'Connell, M. J.] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. RP Chapman, JW (reprint author), Queens Univ, NCIC Clin Trials Grp, 10 Stuart St, Kingston, ON, Canada. EM jchapman@ctg.queensu.ca OI Sargent, Daniel/0000-0002-2684-4741; Yothers, Greg/0000-0002-7965-7333 FU Canadian Cancer Society Research Institute; NCCTG grant from the National Cancer Institute at the National Institutes of Health [CA25224]; Canadian National Sciences and Engineering Research Council; Queen's University Department of Community Health and Epidemiology FX This work was supported by a Canadian Cancer Society Research Institute grant to the NCIC Clinical Trials Group (CTG) for NCIC CTG Faculty; the ACCENT group is supported by the NCCTG grant from the National Cancer Institute at the National Institutes of Health (Grant CA25224); and N Hu was supported by a Canadian National Sciences and Engineering Research Council grant to K Ding and by Queen's University Department of Community Health and Epidemiology graduate student support. NR 19 TC 3 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAR 5 PY 2013 VL 108 IS 4 BP 784 EP 790 DI 10.1038/bjc.2013.34 PG 7 WC Oncology SC Oncology GA 114XI UT WOS:000316775900008 PM 23385733 ER PT J AU Shekelle, PG Pronovost, PJ Wachter, RM McDonald, KM Schoelles, K Dy, SM Shojania, K Reston, JT Adams, AS Angood, PB Bates, DW Bickman, L Carayon, P Donaldson, L Duan, NH Farley, DO Greenhalgh, T Haughom, JL Lake, E Lilford, R Lohr, KN Meyer, GS Miller, MR Neuhauser, DV Ryan, G Saint, S Shortell, SM Stevens, DP Walshe, K AF Shekelle, Paul G. Pronovost, Peter J. Wachter, Robert M. McDonald, Kathryn M. Schoelles, Karen Dy, Sydney M. Shojania, Kaveh Reston, James T. Adams, Alyce S. Angood, Peter B. Bates, David W. Bickman, Leonard Carayon, Pascale Donaldson, Liam Duan, Naihua Farley, Donna O. Greenhalgh, Trisha Haughom, John L. Lake, Eileen Lilford, Richard Lohr, Kathleen N. Meyer, Gregg S. Miller, Marlene R. Neuhauser, Duncan V. Ryan, Gery Saint, Sanjay Shortell, Stephen M. Stevens, David P. Walshe, Kieran TI The Top Patient Safety Strategies That Can Be Encouraged for Adoption Now SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID SYSTEMATIC REVIEWS C1 [Shekelle, Paul G.] RAND Corp, Santa Monica, CA 90401 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Stanford Ctr Hlth Policy, Stanford, CA USA. Ctr Primary Care & Outcomes Res, Stanford, CA USA. Kaiser Permanente, Oakland, CA 94612 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. Johns Hopkins Univ, Baltimore, MD 21231 USA. Johns Hopkins Childrens Ctr, Baltimore, MD 21287 USA. ECRI Inst, Plymouth Meeting, PA 19462 USA. RAND Corp, Pittsburgh, PA 15213 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Toronto, Ottawa, ON, Canada. Natl Qual Forum, Washington, DC USA. Harvard Univ, Brigham & Womens Hosp, Boston, MA 02115 USA. Vanderbilt Univ, Peabody Coll, Nashville, TN 37203 USA. Univ Wisconsin, Madison, WI 53706 USA. Univ London Imperial Coll Sci Technol & Med, London W2 1NY, England. Univ London, London, England. Univ Birmingham, Birmingham B15 2TT, W Midlands, England. Univ Manchester, Manchester Business Sch, Manchester M15 6PB, Lancs, England. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. PeaceHlth Med Grp, Eugene, OR USA. Res Triangle Inst Int, Res Triangle Pk, NC 27709 USA. Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH 03766 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Vet Affairs Ann Arbor Healthcare Syst, Ann Arbor, MI 48105 USA. Univ Michigan, Ann Arbor, MI 48109 USA. RP Shekelle, PG (reprint author), RAND Corp, 1776 Main St, Santa Monica, CA 90401 USA. EM shekelle@rand.org RI Greenhalgh, Trisha/B-1825-2015; OI Greenhalgh, Trisha/0000-0003-2369-8088; Bickman, Leonard/0000-0002-0746-3791 FU PHS HHS [HHSA-290-2007-10062I] NR 10 TC 97 Z9 98 U1 1 U2 15 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 MAR 5 PY 2013 VL 158 IS 5 BP 365 EP + DI 10.7326/0003-4819-158-5-201303051-00001 PN 2 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 105HX UT WOS:000316058600001 PM 23460091 ER PT J AU Miake-Lye, IM Hempel, S Ganz, DA Shekelle, PG AF Miake-Lye, Isomi M. Hempel, Susanne Ganz, David A. Shekelle, Paul G. TI Inpatient Fall Prevention Programs as a Patient Safety Strategy A Systematic Review SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; ACUTE-CARE; MULTIFACTORIAL INTERVENTION; METHODOLOGICAL QUALITY; RISK-ASSESSMENT; ADVERSE EVENTS; HOSPITALS; INJURIES; MULTIDISCIPLINARY; IMPLEMENTATION AB Falls are common among inpatients. Several reviews, including 4 meta-analyses involving 19 studies, show that multicomponent programs to prevent falls among inpatients reduce relative risk for falls by as much as 30%. The purpose of this updated review is to reassess the benefits and harms of fall prevention programs in acute care settings and to identify factors associated with successful implementation of these programs. We searched for new evidence using PubMed from 2005 to September 2012. Two new, large, randomized, controlled trials supported the conclusions of the existing meta-analyses. An optimal bundle of components was not identified. Harms were not systematically examined, but potential harms included increased use of restraints and sedating drugs and decreased efforts to mobilize patients. Eleven studies showed that the following themes were associated with successful implementation: leadership support, engagement of front-line staff in program design, guidance of the prevention program by a multidisciplinary committee, pilot-testing interventions, use of information technology systems to provide data about falls, staff education and training, and changes in nihilistic attitudes about fall prevention. Future research would advance knowledge by identifying optimal bundles of component interventions for particular patients and by determining whether effectiveness relies more on the mix of the components or use of certain implementation strategies. Ann Intern Med. 2013;158:390-396. www.annals.org C1 Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Shekelle, Paul G.] RAND Corp, Santa Monica, CA 90401 USA. RP Shekelle, PG (reprint author), RAND Corp, Santa Monica, CA 90401 USA. EM shekelle@rand.org FU AHRQ, U.S. Department of Health and Human Services [HHSA-290-2007-10062I, HHSA-290-2010-00017I, HHSA-290-32001T]; Veterans Affairs Health Services Research & Development Service, Veterans Health Administration, U.S. Department of Veterans Affairs through the Veterans Affairs Greater Los Angeles Health Services Research & Development Center of Excellence [VA CD2 08-012-1]; AHRQ; AHRQ, Veterans Affairs Health Services Research and Development Service; Veterans Affairs; Centers for Medicare & Medicaid Services; National Institute of Nursing Research; Office of the National Coordinator FX Financial Support: From the AHRQ, U.S. Department of Health and Human Services (contracts HHSA-290-2007-10062I, HHSA-290-2010-00017I, and HHSA-290-32001T). Dr. Ganz was supported by a Career Development Award from the Veterans Affairs Health Services Research & Development Service, Veterans Health Administration, U.S. Department of Veterans Affairs through the Veterans Affairs Greater Los Angeles Health Services Research & Development Center of Excellence (project VA CD2 08-012-1).; Potential Conflicts of Interest: Dr. Hempel: Grant (money to institution): AHRQ. Dr. Ganz: Grant (money to institution): AHRQ, Veterans Affairs Health Services Research and Development Service. Dr. Shekelle: Consultancy: ECRI Institute; Employment: Veterans Affairs; Grants/grants pending: AHRQ, Veterans Affairs, Centers for Medicare & Medicaid Services, National Institute of Nursing Research, Office of the National Coordinator; Royalties: UpToDate. Ms. Miake-Lye: None disclosed. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum = M12-2569. NR 57 TC 49 Z9 52 U1 0 U2 26 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 MAR 5 PY 2013 VL 158 IS 5 BP 390 EP + DI 10.7326/0003-4819-158-5-201303051-00005 PN 2 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 105HX UT WOS:000316058600005 PM 23460095 ER PT J AU Shekelle, PG AF Shekelle, Paul G. TI Nurse-Patient Ratios as a Patient Safety Strategy A Systematic Review SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID INTENSIVE-CARE-UNIT; STAFFING LEVELS; HOSPITAL MORTALITY; JOB DISSATISFACTION; OUTCOMES EVIDENCE; 30-DAY MORTALITY; HEALTH-CARE; QUALITY; COST; ASSOCIATION AB A small percentage of patients die during hospitalization or shortly thereafter, and it is widely believed that more or better nursing care could prevent some of these deaths. The author systematically reviewed the evidence about nurse staffing ratios and in-hospital death through September 2012. From 550 titles, 87 articles were reviewed and 15 new studies that augmented the 2 existing reviews were selected. The strongest evidence supporting a causal relationship between higher nurse staffing levels and decreased inpatient mortality comes from a longitudinal study in a single hospital that carefully accounted for nurse staffing and patient comorbid conditions and a meta-analysis that found a "dose-response relationship" in observational studies of nurse staffing and death. No studies reported any serious harms associated with an increase in nurse staffing. Limiting any stronger conclusions is the lack of an evaluation of an intervention to increase nurse staffing ratios. The formal costs of increasing the nurse-patient ratio cannot be calculated because there has been no evaluation of an intentional change in nurse staffing to improve patient outcomes. Ann Intern Med. 2013;158:404-409. www.annals.org C1 [Shekelle, Paul G.] RAND Corp, Santa Monica, CA 90401 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Shekelle, PG (reprint author), RAND Corp, 1776 Main St, Santa Monica, CA 90401 USA. EM shekelle@rand.org FU Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services [HHSA-290-2007-10062I]; Agency for Healthcare Research and Quality; Veterans Affairs; Centers for Medicare & Medicaid Services; National Institute of Nursing Research; Office of the National Coordinator FX Financial Support: From the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services (contract HHSA-290-2007-10062I).; Potential Conflicts of Interest: Consultancy: ECRI Institute; Employment: Veterans Affairs; Grants/grants pending: Agency for Healthcare Research and Quality, Veterans Affairs, Centers for Medicare & Medicaid Services, National Institute of Nursing Research, Office of the National Coordinator; Royalties: UpToDate. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-257 4. NR 46 TC 26 Z9 26 U1 4 U2 42 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 MAR 5 PY 2013 VL 158 IS 5 BP 404 EP + DI 10.7326/0003-4819-158-5-201303051-00007 PN 2 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 105HX UT WOS:000316058600007 PM 23460097 ER PT J AU Bromley, SK Larson, RP Ziegler, SF Luster, AD AF Bromley, Shannon K. Larson, Ryan P. Ziegler, Steven F. Luster, Andrew D. TI IL-23 Induces Atopic Dermatitis-Like Inflammation Instead of Psoriasis-Like Inflammation in CCR2-Deficient Mice SO PLOS ONE LA English DT Article ID THYMIC STROMAL LYMPHOPOIETIN; INTERLEUKIN-12/23 MONOCLONAL-ANTIBODY; HUMAN TH17 CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CHEMOKINE RECEPTOR (CCR)2; CHRONIC PLAQUE PSORIASIS; HUMAN EPITHELIAL-CELLS; T-CELLS; DENDRITIC CELLS; AIRWAY INFLAMMATION AB Psoriasis is an immune-mediated chronic inflammatory skin disease, characterized by epidermal hyperplasia and infiltration of leukocytes into the dermis and epidermis. IL-23 is expressed in psoriatic skin, and IL-23 injected into the skin of mice produces IL-22-dependent dermal inflammation and acanthosis. The chemokine receptor CCR2 has been implicated in the pathogenesis of several inflammatory diseases, including psoriasis. CCR2-positive cells and the CCR2 ligand, CCL2 are abundant in psoriatic lesions. To examine the requirement of CCR2 in the development of IL-23-induced cutaneous inflammation, we injected the ears of wild-type (WT) and CCR2-deficient (CCR2(-)/(-)) mice with IL-23. CCR2(-)/(-) mice had increased ear swelling and epidermal thickening, which was correlated with increased cutaneous IL-4 levels and increased numbers of eosinophils within the skin. In addition, TSLP, a cytokine known to promote and amplify T helper cell type 2 (Th2) immune responses, was also increased within the inflamed skin of CCR2(-)/(-) mice. Our data suggest that increased levels of TSLP in CCR2(-)/(-) mice may contribute to the propensity of these mice to develop increased Th2-type immune responses. C1 [Bromley, Shannon K.; Luster, Andrew D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02115 USA. [Larson, Ryan P.; Ziegler, Steven F.] Univ Washington, Dept Immunol, Sch Med, Seattle, WA 98195 USA. [Larson, Ryan P.; Ziegler, Steven F.] Virginia Mason, Program Immunol, Benaroya Res Inst, Seattle, WA USA. RP Bromley, SK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02115 USA. EM sbromley@helix.mgh.harvard.edu; aluster@mgh.harvard.edu FU National Institutes of Health [R37-AI040618, R01-AR056113, K01-AR053715]; Claflin Distinguished Scholar Award FX Supported by the National Institutes of Health grant R37-AI040618 to ADL, R01-AR056113 to SFZ, and K01-AR053715 to SKB and a Claflin Distinguished Scholar Award to SKB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 7 Z9 8 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 MAR 5 PY 2013 VL 8 IS 3 AR e58196 DI 10.1371/journal.pone.0058196 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 099RC UT WOS:000315637900104 PM 23472158 ER PT J AU Matthews, LT Sibeko, S Mansoor, LE Yende-Zuma, N Bangsberg, DR Karim, QA AF Matthews, Lynn T. Sibeko, Sengeziwe Mansoor, Leila E. Yende-Zuma, Nonhlanhla Bangsberg, David R. Karim, Quarraisha Abdool TI Women with Pregnancies Had Lower Adherence to 1% Tenofovir Vaginal Gel as HIV Preexposure Prophylaxis in CAPRISA 004, a Phase IIB Randomized-Controlled Trial SO PLOS ONE LA English DT Article ID PLACEBO-CONTROLLED TRIAL; SOUTH-AFRICA; ANTIRETROVIRAL THERAPY; CONTRACEPTIVE USE; MALE CIRCUMCISION; SERODISCORDANT COUPLES; HORMONAL CONTRACEPTION; DOUBLE-BLIND; PREVENTION; INFECTION AB Background: Antiretroviral prophylaxis may be a critical strategy to reduce periconception HIV transmission. Maximizing the benefit of periconception pharmacologic HIV risk-reduction requires an understanding of the links between pregnancy and adherence to this prevention strategy. Methods: We assessed study gel adherence among women with pregnancies compared to women without pregnancies enrolled in the CAPRISA 004 phase IIB trial of 1% vaginal tenofovir gel. Pregnancy was assessed with monthly urine tests. Adherence was measured monthly and defined as proportion of sex acts covered by two returned, used applicators based on pre- and post-coital dosing. High adherence was defined as a median adherence score of >80%, that is, more than 80% of sex acts were covered by two applications of study gel. A multivariate generalized estimating equations (GEE) model with a binomial distribution was used to assess covariates associated with high adherence (>80%) over time. Median adherence before and after pregnancy was compared using Wilcoxon signed rank test. Results: Among 868 women, 53 had at least 1 pregnancy (4.06 per 100 woman years, 95% CI: 3.04, 5.31). Women with pregnancies had lower median adherence compared to women without pregnancies (50% [IQR: 45-83] vs. 60% [IQR: 50-100], p = 0.02). Women with pregnancies also had a 48% lower odds of high adherence compared to women without pregnancies when adjusting for confounders (aOR 0.52, 95% CI: 0.41-0.66, p<0.0001). Among women with pregnancies, adherence before and after pregnancy was not different (50% [IQR: 46-83] vs. 55% [IQR: 20-100], p = 0.68). Conclusions: Women with pregnancies were less likely to have high adherence to study gel compared to women without pregnancies. Understanding these differences may inform findings from HIV prevention trials and future implementation of antiretroviral prophylaxis for at-risk women who choose to conceive. The protocol for the parent trial is registered on ClinicalTrials.gov, NCT00441298, http://www.clinicaltrials.gov/ct2/show/NCT00441298. C1 [Matthews, Lynn T.; Bangsberg, David R.] Massachusetts Gen Hosp, Div Infect Dis, Ctr Global Hlth, Boston, MA 02114 USA. [Matthews, Lynn T.] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Matthews, Lynn T.; Bangsberg, David R.] Harvard Univ, Sch Med, Boston, MA USA. [Sibeko, Sengeziwe; Mansoor, Leila E.; Yende-Zuma, Nonhlanhla; Karim, Quarraisha Abdool] Ctr AIDS Program Res South Africa CAPRISA, Durban, Kwazulu Natal, South Africa. [Bangsberg, David R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Karim, Quarraisha Abdool] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. RP Matthews, LT (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Ctr Global Hlth, Boston, MA 02114 USA. EM ltmatthews@partners.org FU United States Agency for International Development (USAID) [FHI360, GPO-A-00-05-00022-00, 132119]; Technology Innovation Agency (LIFElab) of the South African government's Department of Science Technology; Burroughs Wellcome Fund; American Society for Tropical Medicine and Hygiene; [NIMH MH095655]; [NIMH MH087227] FX The parent trial (CAPRISA 004) was supported by the United States Agency for International Development (USAID), FHI360 [ USAID co-operative agreement # GPO-A-00-05-00022-00, contract # 132119], and the Technology Innovation Agency (LIFElab) of the South African government's Department of Science & Technology. Tenofovir was provided by Gilead Sciences and the gel was manufactured and supplied for the CAPRISA 004 trial by CONRAD. Dr. Matthews is supported by a postdoctoral fellowship in infectious diseases from the Burroughs Wellcome Fund and the American Society for Tropical Medicine and Hygiene, and by a K23 award (NIMH MH095655). Dr. Bangsberg was supported by a K24 award (NIMH MH087227). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 4 Z9 4 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 5 PY 2013 VL 8 IS 3 AR e56400 DI 10.1371/journal.pone.0056400 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 099RC UT WOS:000315637900009 PM 23472071 ER PT J AU Kalantarian, S Stern, TA Mansour, M Ruskin, JN AF Kalantarian, Shadi Stern, Theodore A. Mansour, Moussa Ruskin, Jeremy N. TI Cognitive Impairment Associated With Atrial Fibrillation A Meta-analysis SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID C-REACTIVE PROTEIN; RISK-FACTORS; POSTSTROKE DEMENTIA; CEREBRAL INFARCTION; ALZHEIMER-DISEASE; ISCHEMIC-STROKE; HEART-FAILURE; UNITED-STATES; POPULATION; DECLINE AB Background: Atrial fibrillation (AF) has been linked with an increased risk for cognitive impairment and dementia. Purpose: To complete a meta-analysis of studies examining the association between AF and cognitive impairment. Data Sources: Search of MEDLINE, PsycINFO, Cochrane Library, CINAHL, and EMBASE databases and hand search of article references. Study Selection: Prospective and nonprospective studies reporting adjusted risk estimates for the association between AF and cognitive impairment. Data Extraction: Two abstracters independently extracted data on study characteristics, risk estimates, methods of AF and outcome ascertainment, and methodological quality. Data Synthesis: Twenty-one studies were included in the meta-analysis. Atrial fibrillation was significantly associated with a higher risk for cognitive impairment in patients with first-ever or recurrent stroke (relative risk [RR], 2.70 [95% CI, 1.82 to 4.00]) and in a broader population including patients with or without a history of stroke (RR, 1.40 [CI, 1.19 to 1.64]). The association in the latter group remained significant independent proof of clinical stroke history (RR, 1.34 [CI, 1.13 to 1.58]). However, there was significant heterogeneity among studies of the broader population (I-2 = 69.4%). Limiting the analysis to prospective studies yielded similar results (RR, 1.36 [CI, 1.12 to 1.65]). Restricting the analysis to studies of dementia eliminated the significant heterogeneity (P = 0.137) but did not alter the pooled estimate substantially (RR, 1.38 [CI, 1.22 to 1.56]). Limitations: There is an inherent bias because of confounding variables in observational studies. There was significant heterogeneity among included studies. Conclusion: Evidence suggests that AF is associated with a higher risk for cognitive impairment and dementia, with or without a history of clinical stroke. Further studies are required to elucidate the association between AF and subtypes of dementia as well as the cause of cognitive impairment. C1 [Ruskin, Jeremy N.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Inst Heart Vasc & Stroke Care, Boston, MA 02114 USA. RP Ruskin, JN (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St,GRB 109, Boston, MA 02114 USA. EM jruskin@partners.org FU Deane Institute for Integrative Research in Atrial Fibrillation and Stroke at Massachusetts General Hospital; Harvard Catalyst; Harvard Clinical and Translational Science Center (National Institutes of Health) [UL1 RR 025758]; Harvard University FX Grant Support: By the Deane Institute for Integrative Research in Atrial Fibrillation and Stroke at Massachusetts General Hospital. This work was conducted with support from Harvard Catalyst and the Harvard Clinical and Translational Science Center (National Institutes of Health Award UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers). NR 51 TC 70 Z9 74 U1 2 U2 18 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 MAR 5 PY 2013 VL 158 IS 5 BP 338 EP + DI 10.7326/0003-4819-158-5-201303050-00007 PN 1 PG 20 WC Medicine, General & Internal SC General & Internal Medicine GA 105HP UT WOS:000316057700005 PM 23460057 ER PT J AU Wachter, RM Pronovost, PJ Shekelle, PG AF Wachter, Robert M. Pronovost, Peter J. Shekelle, Paul G. TI Strategies to Improve Patient Safety: The Evidence Base Matures SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Wachter, Robert M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Pronovost, Peter J.] Johns Hopkins Med Patient Safety & Qual, Baltimore, MD USA. [Shekelle, Paul G.] W Los Angeles Vet Affairs Med Ctr, Santa Monica, CA USA. [Shekelle, Paul G.] RAND Corp, Santa Monica, CA USA. RP Wachter, RM (reprint author), Univ Calif San Francisco, Room M-994,505 Parnassus Ave, San Francisco, CA 94143 USA. EM bobw@medicine.ucsf.edu NR 25 TC 12 Z9 14 U1 0 U2 13 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 MAR 5 PY 2013 VL 158 IS 5 BP 350 EP + DI 10.7326/0003-4819-158-5-201303050-00010 PN 1 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 105HP UT WOS:000316057700008 PM 23460060 ER PT J AU Chan, HH Wang, EM Sun, MS Hsu, PI Tsai, WL Tsai, TJ Wang, KM Chen, WC Wang, HM Liang, HL Lai, KH Brugge, WR AF Chan, Hoi-Hung Wang, E-Ming Sun, Meng-Shun Hsu, Ping-I Tsai, Wei-Lun Tsai, Tzung-Jiun Wang, Kai-Ming Chen, Wen-Chi Wang, Huay-Min Liang, Huei-Lung Lai, Kwok-Hung Brugge, William Robert TI Linear echoendoscope-guided ERCP for the diagnosis of occult common bile duct stones SO BMC GASTROENTEROLOGY LA English DT Article DE Linear echoendoscope; Occult common bile duct stones ID ENDOSCOPIC RETROGRADE CHOLANGIOGRAPHY; PROSPECTIVE MULTICENTER; LAPAROSCOPIC CHOLECYSTECTOMY; THERAPEUTIC ERCP; COMPLICATIONS; CHOLEDOCHOLITHIASIS; MANAGEMENT; ULTRASONOGRAPHY; SPHINCTEROTOMY; PANCREATITIS AB Background: Less than 67% of patients with intermediate risk for common bile duct (CBD) stones require therapeutic intervention. It is important to have an accurate, safe, and reliable method for the definitive diagnosis of CBD stones before initiating therapeutic endoscopic retrograde cholangiopancreatography (ERCP). Few publications detail the diagnostic efficacy of linear echoendoscopy (EUS) for CBD stones. Methods: 30 patients with biliary colic, pancreatitis, unexplained derangement of liver function tests, and/or dilated CBD without an identifiable cause were enrolled in the study. When a CBD stone was disclosed by linear EUS, ERCP with stone extraction was performed. Patients who failed ERCP were referred for surgical intervention. If no stone was found by EUS, ERCP would not be performed and patients were followed-up for possible biliary symptoms for up to three months. Results: The major reason for enrollment was acute pancreatitis. The mean predicted risk for CBD stones was 47% (28-61). Of the 12 patients who were positive for CBD stones by EUS, nine had successful ERCP, one failed ERCP (later treated successfully by surgical intervention) and two were false-positive cases. No procedure-related adverse events were noted. For those 18 patients without evidence of CBD stones by EUS, no false-negative case was noted during the three-month follow-up period. Linear EUS had sensitivity, specificity, positive and negative predicted values for the detection of CBD stones of 1, 0.9, 0.8 and 1, respectively. Conclusion: Linear EUS is safe and efficacious for the diagnosis of occult CBD stones in patients with intermediate risk for the disease. C1 [Chan, Hoi-Hung; Wang, E-Ming; Hsu, Ping-I; Tsai, Wei-Lun; Tsai, Tzung-Jiun; Wang, Kai-Ming; Chen, Wen-Chi; Wang, Huay-Min; Lai, Kwok-Hung] Kaohsiung Vet Gen Hosp, Dept Internal Med, Div Gastroenterol, Kaohsiung 81362, Taiwan. [Chan, Hoi-Hung; Wang, E-Ming] Natl Sun Yat Sen Univ, Dept Biol Sci, Kaohsiung 80424, Taiwan. [Chan, Hoi-Hung] Tajen Univ, Coll Pharm & & Hlth Care, Yanpu Township 907, Pingtung County, Taiwan. [Chan, Hoi-Hung; Hsu, Ping-I; Tsai, Wei-Lun; Chen, Wen-Chi; Liang, Huei-Lung; Lai, Kwok-Hung] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan. [Sun, Meng-Shun] Yuans Gen Hosp, Dept Gastroenterol & Hepatol, Kaohsiung 80249, Taiwan. [Liang, Huei-Lung] Kaohsiung Vet Gen Hosp, Dept Radiol, Kaohsiung 81362, Taiwan. [Brugge, William Robert] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. RP Lai, KH (reprint author), Kaohsiung Vet Gen Hosp, Dept Internal Med, Div Gastroenterol, 386 Ta Chung 1st Rd, Kaohsiung 81362, Taiwan. EM khlai@vghks.gov.tw; wbrugge@partners.org NR 17 TC 5 Z9 5 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-230X J9 BMC GASTROENTEROL JI BMC Gastroenterol. PD MAR 5 PY 2013 VL 13 AR 44 DI 10.1186/1471-230X-13-44 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 107FA UT WOS:000316199000001 PM 23497328 ER PT J AU Ganda, A Magnusson, M Yvan-Charvet, L Hedblad, B Engstrom, G Ai, D Wang, TJ Gerszten, RE Melander, O Tall, AR AF Ganda, Anjali Magnusson, Martin Yvan-Charvet, Laurent Hedblad, Bo Engstrom, Gunnar Ai, Ding Wang, Thomas J. Gerszten, Robert E. Melander, Olle Tall, Alan R. TI Mild Renal Dysfunction and Metabolites Tied to Low HDL Cholesterol Are Associated With Monocytosis and Atherosclerosis SO CIRCULATION LA English DT Article DE atherosclerosis; immunology; kidney; metabolomics; risk factors ID CHRONIC KIDNEY-DISEASE; INTIMA-MEDIA THICKNESS; SERUM CYSTATIN-C; GLOMERULAR-FILTRATION-RATE; ISCHEMIC-HEART-DISEASE; CARDIOVASCULAR EVENTS; CAROTID ATHEROSCLEROSIS; FUNCTION DECLINE; ELDERLY PERSONS; CELL COUNT AB Background-The number of circulating blood monocytes impacts atherosclerotic lesion size, and in mouse models, elevated levels of high-density lipoprotein cholesterol suppress blood monocyte counts and atherosclerosis. We hypothesized that individuals with mild renal dysfunction at increased cardiovascular risk would have reduced high-density lipoprotein levels, high blood monocyte counts, and accelerated atherosclerosis. Methods and Results-To test whether mild renal dysfunction is associated with an increase in a leukocyte subpopulation rich in monocytes that has a known association with future coronary events, we divided individuals from the Malmo Diet and Cancer study (MDC) into baseline cystatin C quintiles (n=4757). Lower levels of renal function were accompanied by higher monocyte counts, and monocytes were independently associated with carotid bulb intima-media thickness cross-sectionally (P=0.02). Cystatin C levels were positively and plasma high-density lipoprotein cholesterol levels negatively associated with monocyte counts at baseline, after adjustment for traditional risk factors. Several amino acid metabolites tied to low levels of high-density lipoprotein cholesterol and insulin resistance measured in a subset of individuals (n=752) by use of liquid chromatography-mass spectrometry were independently associated with a 22% to 34% increased risk of being in the top quartile of monocytes (P<0.05). Conclusions-A low high-density lipoprotein cholesterol, insulin resistance phenotype occurs in subjects with mild renal dysfunction and is associated with elevated monocytes and atherosclerosis. High blood monocyte counts may represent a previously unrecognized mechanism underlying the strong relationship between cystatin C and cardiovascular risk. (Circulation. 2013; 127: 988-996.) C1 [Ganda, Anjali] Columbia Univ, Coll Phys & Surg, Div Nephrol, New York, NY 10032 USA. [Ganda, Anjali; Yvan-Charvet, Laurent; Ai, Ding; Tall, Alan R.] Columbia Univ, Coll Phys & Surg, Div Mol Med, New York, NY 10032 USA. [Magnusson, Martin] Skane Univ Hosp, Dept Cardiol, Malmo, Sweden. [Hedblad, Bo; Melander, Olle] Skane Univ Hosp, Ctr Emergency Med, Malmo, Sweden. [Magnusson, Martin; Hedblad, Bo; Engstrom, Gunnar; Melander, Olle] Lund Univ, Dept Clin Sci, Malmo, Sweden. [Wang, Thomas J.; Gerszten, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Wang, Thomas J.; Gerszten, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Gerszten, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Gerszten, Robert E.] Broad Inst MIT & Harvard Univ, Cambridge, MA USA. RP Ganda, A (reprint author), Columbia Univ, Coll Phys & Surg, Div Nephrol, PH4-124,622 W 168th St, New York, NY 10032 USA. EM ag355@columbia.edu OI Yvan-Charvet, Laurent/0000-0002-7748-4942; Engstrom, Gunnar/0000-0002-8618-9152; Magnusson, Martin/0000-0003-1710-5936 FU National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR000040, UL1 RR024156]; Leducq Foundation; Swedish Medical Research Council; Swedish Heart and Lung Foundation; Medical Faculty of Lund University; Skane University Hospital; Albert Pahlsson Research Foundation; Crafoord Foundation; Ernhold Lundstroms Research Foundation; Region Skane; Hulda and Conrad Mossfelt Foundation; Southwest Skanes Diabetes Foundation; King Gustaf V and Queen Victoria Foundation; Lennart Hanssons Memorial Fund; Knut and Alice Wallenberg Foundation; Marianne and Marcus Wallenberg Foundation; National Institutes of Health [HL 98280, DK 081572] FX Dr Ganda was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1 TR000040, formerly the National Center for Research Resources, grant number UL1 RR024156. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This research was additionally supported by the Leducq Foundation. Drs Magnusson and Melander were supported by grants from the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Medical Faculty of Lund University, Skane University Hospital, the Albert Pahlsson Research Foundation, the Crafoord Foundation, the Ernhold Lundstroms Research Foundation, the Region Skane, the Hulda and Conrad Mossfelt Foundation, the Southwest Skanes Diabetes Foundation, the King Gustaf V and Queen Victoria Foundation, the Lennart Hanssons Memorial Fund, Knut and Alice Wallenberg Foundation, and the Marianne and Marcus Wallenberg Foundation. Dr Gerszten was supported by National Institutes of Health R01 grants HL 98280 and DK 081572. NR 50 TC 19 Z9 23 U1 1 U2 20 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 MAR 5 PY 2013 VL 127 IS 9 BP 988 EP + DI 10.1161/CIRCULATIONAHA.112.000682 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 101WJ UT WOS:000315804800013 PM 23378299 ER PT J AU Dec, GW AF Dec, G. William TI Steroid Therapy Effectively Delays Duchenne's Cardiomyopathy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE cardiomyopathy; Duchenne muscular dystrophy; mortality; steroids ID MUSCULAR-DYSTROPHY C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dec, GW (reprint author), Massachusetts Gen Hosp, Bigelow 810,55 Fruit St, Boston, MA 02114 USA. EM gdec@partners.org NR 9 TC 9 Z9 9 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 5 PY 2013 VL 61 IS 9 BP 955 EP 956 DI 10.1016/j.jacc.2012.12.011 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 094VZ UT WOS:000315294100011 PM 23352780 ER PT J AU Maguen, S Madden, E Bosch, J Galatzer-Levy, I Knight, SJ Litz, BT Marmar, CR McCaslin, SE AF Maguen, Shira Madden, Erin Bosch, Jeane Galatzer-Levy, Isaac Knight, Sara J. Litz, Brett T. Marmar, Charles R. McCaslin, Shannon E. TI Killing and latent classes of PTSD symptoms in Iraq and Afghanistan veterans SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Veterans; Killing; Trauma; Posttraumatic stress disorder ID POSTTRAUMATIC-STRESS-DISORDER; MENTAL-HEALTH SYMPTOMS; WAR VETERANS; IMPACT; MODEL; HETEROGENEITY; SUBTHRESHOLD; IMPAIRMENT; NUMBER AB Background: Our goal was to better understand distinct PTSD symptom presentations in Iraq and Afghanistan Veterans (N=227) and to determine whether those who killed in war were at risk for being in the most symptomatic class. Methods: We used latent class analysis of responses to the PTSD checklist and logistic regression of most symptomatic class. Results: We found that a four-class solution best fit the data, with the following profiles emerging: High Symptom (34% of participants), Intermediate Symptom (41%), Intermediate Symptom with Low Emotional Numbing (10%), and Low Symptom (15%). The largest group of individuals who reported killing (45%) was in the High Symptom class, and those who killed had twice the odds of being in the most symptomatic PTSD class, compared to those who did not kill. Those who endorsed killing a non-combatant (OR=4.56, 95% CI [1.77, 11.7], p < 0.01) or killing in the context of anger or revenge (OR=4.63, 95% CI=[1.89, 11.4], p < 0.001) were more likely to belong to the most symptomatic PTSD class, compared to those who did not kill. Limitations: The study was retrospective and cross-sectional. The results may not generalize to veterans of other wars. Conclusions: Killing in war may be an important indicator of risk for developing frequent and severe PTSD symptoms. This has implications for the mental healthcare of veterans, providing evidence that a comprehensive evaluation of returning veterans should include an assessment of killing experiences and reactions to killing. Published by Elsevier B.V. C1 [Maguen, Shira; Madden, Erin; Bosch, Jeane; Knight, Sara J.; McCaslin, Shannon E.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Maguen, Shira; Madden, Erin; Bosch, Jeane; Knight, Sara J.; McCaslin, Shannon E.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Galatzer-Levy, Isaac; Marmar, Charles R.] NYU, Langone Med Ctr, New York, NY USA. [Litz, Brett T.] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Litz, Brett T.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Maguen, S (reprint author), San Francisco VA Med Ctr, PTSD Program P 116, 4150 Clement St, San Francisco, CA 94121 USA. EM Shira.Maguen@va.gov OI Galatzer-Levy, Isaac/0000-0003-1864-064X FU VA Clinical Science Research and Development Career Development Award [CDA-2-032-06 F]; VA Health Services Research and Development Career Development Award [RCD 06-042] FX This research was supported by VA Clinical Science Research and Development Career Development Award (CDA-2-032-06 F: McCaslin) and VA Health Services Research and Development Career Development Award (RCD 06-042: Maguen). The authors would like to thank Gary Tarasovsky, Tom Metzler, Thomas Neylan and John McQuaid for their contributions to this manuscript. We would also like to thank the veterans for their time and participation. NR 25 TC 24 Z9 25 U1 2 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAR 5 PY 2013 VL 145 IS 3 BP 344 EP 348 DI 10.1016/j.jad.2012.08.021 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 086LX UT WOS:000314686600011 PM 22959679 ER PT J AU Topor, DR Swenson, L Hunt, JI Birmaher, B Strober, M Yen, S Hoeppner, BB Case, BG Hower, H Weinstock, LM Ryan, N Goldstein, B Goldstein, T Gill, MK Axelson, D Keller, M AF Topor, David R. Swenson, Lance Hunt, Jeffrey I. Birmaher, Boris Strober, Michael Yen, Shirley Hoeppner, Bettina B. Case, Brady G. Hower, Heather Weinstock, Lauren M. Ryan, Neal Goldstein, Benjamin Goldstein, Tina Gill, Mary Kay Axelson, David Keller, Martin TI Manic symptoms in youth with bipolar disorder: Factor analysis by age of symptom onset and current age SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Pediatric bipolar disorder; Course; Onset ID SPECTRUM DISORDERS; RATING-SCALE; STEP-BD; NUMBER; ADOLESCENTS; QUESTIONNAIRE; INSTRUMENTS; PREDICTORS; COMPONENTS; CHILDREN AB Background: Factor analysis has been used to identify potential clinical subtypes of mania in pediatric bipolar disorder. Results vary in the number of factors retained. The present study used a formal diagnostic instrument to examine how symptoms of mania in young people are expressed, depending on age of symptom onset and current age. Methods: Trained clinicians completed the Schedule of Affective Disorders and Schizophrenia for School-Age Children (K-SADS) Mania Rating Scale (MRS) with parents of 163 children with child-onset of symptoms (before age 12), 94 adolescents with child-onset of symptoms, and 90 adolescents with adolescent-onset of symptoms (after age 12). Factor analysis of symptom ratings during the most severe lifetime manic episode was performed for each age group. Results: Symptom factor structures were established for each age group. Two factors were evident for children with child-onset of symptoms ("activated/pleasure seeking" and "labile/disorganized"), one factor was present for adolescents with child-onset of symptoms ("activated/pleasure seeking/disorganized") and two factors were evident for adolescents with adolescent-onset of symptoms ("activated/pleasure seeking" and "disorganized/psychotic"). The factor structures for children with child-onset and adolescents with adolescent-onset of symptoms were highly similar, with the latter factor structure including psychotic symptoms. Limitations: Limitations include reliance on retrospective parent report and potential issues with generalizability. Conclusions: Findings suggest mania symptomatology is largely similar when examined by both age of onset and current age, with some notable differences. Specifically, psychotic symptoms begin emerging as a distinct factor in adolescents with adolescent-onset of symptoms. (c) 2012 Elsevier B.V. All rights reserved. C1 [Topor, David R.] VA Boston Healthcare Syst, Boston, MA USA. [Topor, David R.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Swenson, Lance] Suffolk Univ, Dept Psychol, Boston, MA 02114 USA. [Hunt, Jeffrey I.; Yen, Shirley; Case, Brady G.; Hower, Heather; Weinstock, Lauren M.; Keller, Martin] Brown Univ, Dept Psychiat, Warren Alpert Med Sch, Providence, RI 02912 USA. [Birmaher, Boris; Ryan, Neal; Goldstein, Tina; Gill, Mary Kay; Axelson, David] Univ Pittsburgh, Western Psychiat Inst & Clin, Dept Psychiat, Med Ctr, Pittsburgh, PA 15213 USA. [Strober, Michael] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Goldstein, Benjamin] Univ Toronto, Fac Med, Dept Psychiat, Sunnybrook Hlth Serv Ctr, Toronto, ON M5S 1A1, Canada. [Hoeppner, Bettina B.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Addict Med, Boston, MA 02114 USA. RP Hunt, JI (reprint author), Brown Univ, Dept Psychiat, Warren Alpert Med Sch, Providence, RI 02912 USA. EM Jeffrey_Hunt@Brown.edu RI Case, Brady/M-1879-2015; OI Case, Brady/0000-0001-9512-0416; Weinstock, Lauren/0000-0001-9970-235X FU National Institute of Mental Health [MH59929, MH59977, MH59691]; Leon Levy Foundation; American Academy of Child and Adolescent Psychiatry Eli lily Pilot Research Award; American Psychiatric Association AstraZeneca Young Minds in Psychiatry Award; Pfizer; NIMH; NIDA; NICHD; The Pittsburgh Foundation Emmerling Fun; Ryan Licht Sang Bipolar Foundation FX This work was supported by grants MH59929 (Dr. Birmaher), MH59977 (Dr. Strober) and MH59691 (Dr. Keller) from the National Institute of Mental Health.; Potential conflicts of interest include being an editor of a Wiley Publishers newsletter (Dr. Hunt), being a consultant for Schering Plough (Dr. Birmaher), receiving royalties from publications from Random House, Inc. and Lippincott, Williams, 82 Wilkins (Dr. Birmaher), receiving past support from the Leon Levy Foundation, American Academy of Child and Adolescent Psychiatry Eli lily Pilot Research Award, and the American Psychiatric Association AstraZeneca Young Minds in Psychiatry Award (Dr. Case), receiving an investigator-initiated grant from Pfizer (Dr. Benjamin Goldstein), receiving a speaker's honoraria from Purdue Pharmaceuticals (Dr. Benjamin Goldstein) receiving travel support as a Bristol-Myers Squibb consultant (Dr. Benjamin Goldstein), receiving past grant funding from NIMH, NIDA, NICHD, The Pittsburgh Foundation Emmerling Fun, and the Ryan Licht Sang Bipolar Foundation (Dr. Tina Goldstein), receiving royalties from Guilford Press (Dr. Tina Goldstein), serving as a consultant to Cenerex, Medtronic, and Sierra Neuropharmaceuticals (Dr. Keller), receiving grant funding from Pfizer (Dr. Keller), and serving on the Cenerex Advisory Board (Dr. Keller). NR 22 TC 8 Z9 8 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD MAR 5 PY 2013 VL 145 IS 3 BP 409 EP 412 DI 10.1016/j.jad.2012.06.024 PG 4 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 086LX UT WOS:000314686600021 PM 23021377 ER PT J AU Gao, AQ Kantarci, A Herrera, BS Gao, HW Van Dyke, TE AF Gao, Anqi Kantarci, Alpdogan Herrera, Bruno Schneider Gao, Hongwei Van Dyke, Thomas E. TI A critical role for suppressors of cytokine signaling 3 in regulating LPS-induced transcriptional activation of matrix metalloproteinase-13 in osteoblasts SO PEERJ LA English DT Article DE Inflammation; Periodontitis; Cytokine; Osteoblasts AB Suppressor of cytokine signaling 3 (SOCS3) is a key regulator of cytokine signaling in macrophages and T cells. Although SOCS3 seems to contribute to the balance between the pro-inflammatory actions of IL-6 family of cytokines and anti-inflammatory signaling of IL-10 by negatively regulating gp130/Jak/Stat3 signal transduction, how and the molecular mechanisms whereby SOCS3 controls the downstream impact of TLR4 are largely unknown and current data are controversial. Furthermore, very little is known regarding SOCS3 function in cells other than myeloid cells and T cells. Our previous study demonstrates that SOCS3 is expressed in osteoblasts and functions as a critical inhibitor of LPS-induced IL-6 expression. However, the function of SOCS3 in osteoblasts remains largely unknown. In the current study, we report for the first time that LPS stimulation of osteoblasts induces the transcriptional activation of matrix metalloproteinase (MMP)-13, a central regulator of bone resorption. Importantly, we demonstrate that SOCS3 overexpression leads to a significant decrease of LPS-induced MMP-13 expression in both primary murine calvariae osteoblasts and a mouse osteoblast-like cell line, MC3T3-E1. Our findings implicate SOCS3 as an important regulatory mediator in bone inflammatory diseases by targetingMMP-13. C1 [Gao, Anqi; Kantarci, Alpdogan; Herrera, Bruno Schneider; Van Dyke, Thomas E.] Forsyth Inst, Dept Periodontol, Cambridge, MA 02142 USA. [Gao, Hongwei] Harvard Univ, Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med,Med Sch, Boston, MA 02115 USA. RP Van Dyke, TE (reprint author), Forsyth Inst, Dept Periodontol, Cambridge, MA 02142 USA. EM tvandyke@forsyth.org FU National Institutes of Health [DE15566, DE19938] FX This work was supported in part by National Institutes of Health Grants DE15566 and DE19938. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 9 Z9 10 U1 0 U2 3 PU PEERJ INC PI LONDON PA 341-345 OLD ST, THIRD FLR, LONDON, EC1V 9LL, ENGLAND SN 2167-8359 J9 PEERJ JI PeerJ PD MAR 5 PY 2013 VL 1 AR UNSP e51 DI 10.7717/peerj.51 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36AK UT WOS:000209185800005 PM 23638389 ER PT J AU Greenberg, CC Wind, JK Chang, GJ Chen, RC Schrag, D AF Greenberg, Caprice C. Wind, Jennifer K. Chang, George J. Chen, Ronald C. Schrag, Deborah TI Stakeholder engagement for comparative effectiveness research in cancer care: experience of the DEcIDE Cancer Consortium SO JOURNAL OF COMPARATIVE EFFECTIVENESS RESEARCH LA English DT Article DE cancer; CER; comparative effectiveness research; stakeholder AB Stakeholder input is a critical component of comparative effectiveness research. To ensure that the research activities of the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Network, supported by the Agency for Healthcare Research and Quality, translate into the greatest impact for everyday practice and policy-making in cancer, we were tasked with soliciting stakeholder input regarding priority areas in cancer-related comparative effectiveness research for the DEcIDE Cancer Consortium. Given the increasing emphasis on stakeholder engagement in research, many investigators are facing a similar task, yet there is limited literature to guide such efforts, particularly in cancer care. To help fill this gap, we present our approach to operationalizing stakeholder engagement and discuss it in the context of other recent developments in the area. We describe challenges encountered in convening stakeholders from multiple vantage points to prioritize topics and strategies used to mitigate these barriers. We offer several recommendations regarding how to best solicit stakeholder input to inform comparative effectiveness research in cancer care. These recommendations can inform other initiatives currently facing the challenges of engaging stakeholders in priority setting for cancer. C1 [Greenberg, Caprice C.; Wind, Jennifer K.; Schrag, Deborah] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Dept Med Oncol, Boston, MA 02115 USA. [Greenberg, Caprice C.] Univ Wisconsin, Dept Surg, Wisconsin Surg Outcomes Res Program, Madison, WI USA. [Chang, George J.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Chen, Ronald C.] Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC USA. RP Greenberg, CC (reprint author), Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Dept Med Oncol, Boston, MA 02115 USA. EM greenberg@surgery.wisc.edu FU Agency for Healthcare Research and Quality, US Department of Health and Human Services as part of the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) program [HHSA290201000006I] FX This project was funded under Contract number HHSA290201000006I from the Agency for Healthcare Research and Quality, US Department of Health and Human Services as part of the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) program. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 14 TC 3 Z9 3 U1 1 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 2042-6305 EI 2042-6313 J9 J COMP EFFECT RES JI J. Comp. Eff. Res. PD MAR PY 2013 VL 2 IS 2 BP 117 EP 125 DI 10.2217/CER.12.80 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 299CN UT WOS:000330372700010 PM 24236554 ER PT J AU Raffetto, JD AF Raffetto, J. D. TI Inflammation in chronic venous ulcers SO PHLEBOLOGY LA English DT Review DE Inflammation; leukocytes; macrophages; venous ulcer; cytokines; growth factors; matrix metalloproteinases; wound fluid; extracellular matrix; collagen ID CHRONIC LEG ULCERS; MATRIX METALLOPROTEINASE INDUCER; ELEVATED EXPRESSION; CYTOKINE LEVELS; DISEASE; LIPODERMATOSCLEROSIS; MICROCIRCULATION; INSUFFICIENCY; ULCERATION; ACTIVATION AB Chronic venous ulcers (CVUs) occur in approximately 1% of the general population. Risk factors for chronic venous disease (CVD) include heredity, age, female sex and obesity. Although not restricted to the elderly, the prevalence of CVD, especially leg ulcers, increases with age. 1 CVD has a considerable impact on health-care resources. It has been estimated that venous ulcers cause the loss of approximately two million working days and incur treatment costs of approximately $3 billion per year in the USA. 2 Overall, CVD has been estimated to account for 1-3% of the total health-care budgets in countries with developed health-care systems. 1 The pathophysiology of dermal abnormalities in CVU is reflective of a complex interplay that involves sustained venous hypertension, inflammation, changes in microcirculation, cytokine and matrix metalloproteinase (MMP) activation, resulting in altered cellular function and delayed wound healing.(3,4) C1 [Raffetto, J. D.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, West Roxbury, MA 02135 USA. [Raffetto, J. D.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Raffetto, JD (reprint author), VA Boston Healthcare Syst, 1400 VFW Pkwy,Surg 112, West Roxbury, MA 02135 USA. EM joseph.raffetto@med.va.gov NR 21 TC 23 Z9 24 U1 1 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0268-3555 EI 1758-1125 J9 PHLEBOLOGY JI Phlebology PD MAR PY 2013 VL 28 SU 1 BP 61 EP 67 DI 10.1177/0268355513476844 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 298CY UT WOS:000330302800013 PM 23482537 ER PT J AU Achildi, O Leong, SH Maust, DT Streim, JE Oslin, DW AF Achildi, Olga Leong, Shirley H. Maust, Donovan T. Streim, Joel E. Oslin, David W. TI Patterns of Newly-Prescribed Benzodiazepines in Late Life SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Achildi, Olga; Leong, Shirley H.; Maust, Donovan T.; Streim, Joel E.; Oslin, David W.] Univ Penn, Philadelphia, PA 19104 USA. [Achildi, Olga; Leong, Shirley H.; Maust, Donovan T.; Streim, Joel E.; Oslin, David W.] Philadelphia VA Med Ctr, Philadelphia, PA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S90 EP S91 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400089 ER PT J AU Asbury, M Helstrom, A Benson, A Leong, SH Zimmerman, J Streim, JE Oslin, DW AF Asbury, Melanie Helstrom, Amy Benson, Amy Leong, Shirley H. Zimmerman, Jacob Streim, Joel E. Oslin, David W. TI Experience of Pain in the Elderly in Relation to Mood, Anxiety and Physical Quality of Life in a PACE/BHL Program SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Asbury, Melanie; Helstrom, Amy; Benson, Amy; Zimmerman, Jacob; Streim, Joel E.; Oslin, David W.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Helstrom, Amy; Benson, Amy; Leong, Shirley H.; Streim, Joel E.; Oslin, David W.] Philadelphia VA Med Ctr, VISN Mental Illness Res Educ & Clin Ctr 4, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S109 EP S110 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400118 ER PT J AU Beristianos, M Yaffe, K Neylan, T Covinsky, K Byers, AL AF Beristianos, Matthew Yaffe, Kristine Neylan, Thomas Covinsky, Kenneth Byers, Amy L. TI Late-Life PTSD, Comorbid Psychiatric and Behavioral Disorders and Risk of Mortality among Veterans SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Beristianos, Matthew; Yaffe, Kristine; Neylan, Thomas; Covinsky, Kenneth; Byers, Amy L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Beristianos, Matthew; Yaffe, Kristine; Neylan, Thomas; Covinsky, Kenneth; Byers, Amy L.] San Francisco VA Med Ctr, San Francisco, CA USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S89 EP S90 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400088 ER PT J AU Byers, AL Barry, LC Okereke, OI Yaffe, K AF Byers, Amy L. Barry, Lisa C. Okereke, Olivia I. Yaffe, Kristine TI NEW EPIDEMIOLOGICAL EVIDENCE FOR MENTAL HEALTH PREDICTING LATE-LIFE COGNITIVE AND FUNCTIONAL DECLINE SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Byers, Amy L.; Yaffe, Kristine] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Byers, Amy L.; Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Barry, Lisa C.] Univ Connecticut, Ctr Hlth, Ctr Aging, Farmington, CT USA. [Okereke, Olivia I.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Okereke, Olivia I.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RI Okereke, Olivia/R-9934-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S25 EP S26 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400032 ER PT J AU Cohen, CI Kasckow, J Rajji, T Vahia, I AF Cohen, Carl I. Kasckow, John Rajji, Tarek Vahia, Ipsit TI ADVANCES IN LATE LIFE SCHIZOPHRENIA RESEARCH SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Rajji, Tarek] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Rajji, Tarek] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Kasckow, John] Suny Downstate Med Ctr, New York, NY USA. [Cohen, Carl I.] Univ Toronto, Toronto, ON, Canada. [Vahia, Ipsit] Univ Calif San Diego, San Diego, CA 92103 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S5 EP S6 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400003 ER PT J AU DeWitt, MA Barnes, DE Kunik, ME Gordon, SM AF DeWitt, Marie A. Barnes, Deborah E. Kunik, Mark E. Gordon, Sharon M. TI VA SYMPOSIUM: LINKS TO DEMENTIA SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [DeWitt, Marie A.; Kunik, Mark E.] Michael E DeBakey VAMC, Houston, TX USA. [Barnes, Deborah E.] San Francisco VA Med Ctr, San Francisco, CA USA. [Gordon, Sharon M.] VA Tennessee Valley Hlth Care Syst, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S40 EP S41 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400053 ER PT J AU Ege, MA Messias, E Krain, L Thapa, PB AF Ege, Margaret A. Messias, Erick Krain, Lewis Thapa, Puru B. TI AAGP Annual Meeting 2013 SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Ege, Margaret A.; Messias, Erick; Krain, Lewis; Thapa, Puru B.] Univ Arkansas Med Sci, Dept Psychiat, Little Rock, AR 72205 USA. [Krain, Lewis] US Dept Vet Affairs, Dept Psychiat, North Little Rock, AR USA. [Thapa, Puru B.] Arkansas Mental Hlth Res & Training Inst, Little Rock, AR USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S63 EP S63 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400054 ER PT J AU Fischer, C Sweet, RA Ismail, Z AF Fischer, Corinne Sweet, Robert A. Ismail, Zahinoor TI FITTING A SQUARE PEG INTO A ROUND HOLE: UNDERSTANDING PSYCHOTIC SYMPTOMS IN ALZHEIMER'S DISEASE SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Fischer, Corinne] St Michaels Hosp, Toronto, ON M5B 1W8, Canada. [Ismail, Zahinoor] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Fischer, Corinne; Ismail, Zahinoor] Univ Toronto, Toronto, ON, Canada. [Sweet, Robert A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Sweet, Robert A.] VA Pittsburgh Healthcare Syst, Mental Illness Res Educ & Clin Ctr, Pittsburgh, PA USA. OI Fischer, Corinne/0000-0002-1047-0167 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S16 EP S16 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400018 ER PT J AU Hochstetler, H Doraiswamy, PM Sperling, RA Johnson, KA Reiman, E Sabbagh, MN Sadowsky, CH Joshi, AD Lu, M Mintun, MA Pontecorvo, MJ Skovronsky, DM AF Hochstetler, Helen Doraiswamy, P. Murali Sperling, Reisa A. Johnson, Keith A. Reiman, Eric Sabbagh, Marwan N. Sadowsky, Carl H. Joshi, Abhinay D. Lu, Ming Mintun, Mark A. Pontecorvo, Michael J. Skovronsky, Daniel M. TI Relationship of Florbetapir F18 PET Amyloid Plaque Neuroimaging with Future Cognitive Decline over 36 Months SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Hochstetler, Helen] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Doraiswamy, P. Murali] Duke Univ, Med Ctr, Durham, NC USA. [Sperling, Reisa A.; Johnson, Keith A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Reiman, Eric] Banner Alzheimers Inst, Phoenix, AZ USA. [Sabbagh, Marwan N.] Banner Sun Hlth Res Inst, Sun City, AZ USA. [Sadowsky, Carl H.] Nova SE Univ, Ft Lauderdale, FL 33314 USA. [Joshi, Abhinay D.; Lu, Ming; Mintun, Mark A.; Pontecorvo, Michael J.; Skovronsky, Daniel M.] Avid Radiopharmaceut, Philadelphia, PA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S136 EP S136 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400150 ER PT J AU Lanctot, K Chau, S Herrmann, N Drye, L Rosenberg, P Scherer, RW Vaidya, V Black, S Mintzer, J AF Lanctot, Krista Chau, Sarah Herrmann, Nathan Drye, Lea Rosenberg, Paul Scherer, Roberta W. Vaidya, Vijay Black, Sandra Mintzer, Jacobo TI Effects of Methylphenidate on Attention and Association with Apathy in AD patients SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Lanctot, Krista; Chau, Sarah; Herrmann, Nathan; Black, Sandra] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Drye, Lea; Rosenberg, Paul; Scherer, Roberta W.; Vaidya, Vijay] Johns Hopkins Univ, Baltimore, MD USA. [Mintzer, Jacobo] Med Univ S Carolina, Charleston, SC 29425 USA. [Mintzer, Jacobo] Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S158 EP S159 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400179 ER PT J AU Maust, DT Oslin, DW Marcus, S AF Maust, Donovan T. Oslin, David W. Marcus, Steven TI The Association of Age and Clinical Factors in Psychotropic Prescribing Nationwide SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Maust, Donovan T.; Oslin, David W.; Marcus, Steven] Univ Penn, Philadelphia, PA 19104 USA. [Oslin, David W.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S114 EP S116 PG 4 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400124 ER PT J AU Sasaki, DA Takahashi, NY Feil, D AF Sasaki, Dean A. Takahashi, Nancy Y. Feil, Denise TI A Qualitative Study of Medical Student Attitudes About Individualizing Diabetes Care in Vulnerable Elders SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Sasaki, Dean A.] UCSF, San Francisco, CA USA. [Sasaki, Dean A.; Takahashi, Nancy Y.; Feil, Denise] Univ Calif Los Angeles, Los Angeles, CA USA. [Takahashi, Nancy Y.; Feil, Denise] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S110 EP S110 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400119 ER PT J AU Streim, JE Oslin, DW Liptzin, B Moak, GS AF Streim, Joel E. Oslin, David W. Liptzin, Benjamin Moak, Gary S. TI EVOLVING ROLES FOR GERIATRIC MENTAL HEALTH PROVIDERS IN THE 21ST CENTURY HEALTHCARE SYSTEM SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Streim, Joel E.; Oslin, David W.] Univ Penn, Philadelphia, PA 19104 USA. [Streim, Joel E.; Oslin, David W.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Liptzin, Benjamin] Baystate Med Ctr, Springfield, MA USA. [Liptzin, Benjamin] Tufts Univ, Boston, MA 02111 USA. [Moak, Gary S.] Moak Ctr Hlth Aging, Westborough, MA USA. [Moak, Gary S.] Univ Massachusetts, Worcester, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S14 EP S15 PG 4 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400016 ER PT J AU Streim, JE Oslin, DW Maust, DT Mavandadi, S AF Streim, Joel E. Oslin, David W. Maust, Donovan T. Mavandadi, Shahrzad TI A STATE-WIDE PROGRAM OF COLLABORATIVE CARE: WORKING TOWARDS GERIATRIC MENTAL HEALTHCARE REFORM SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Streim, Joel E.; Oslin, David W.; Maust, Donovan T.; Mavandadi, Shahrzad] Univ Penn, Philadelphia, PA 19104 USA. [Streim, Joel E.; Oslin, David W.; Maust, Donovan T.; Mavandadi, Shahrzad] Philadelphia VA Med Ctr, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S5 EP S5 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400002 ER PT J AU Sultzer, DL Leskin, LP Jacobs, ZM Melrose, RJ Harwood, DG Narvaez, TA Ando, TK Mandelkern, MA AF Sultzer, David L. Leskin, Lorraine P. Jacobs, Zachary M. Melrose, Rebecca J. Harwood, Dylan G. Narvaez, Theresa A. Ando, Timothy K. Mandelkern, Mark A. TI Cognitive, behavioral, and emotional domains of apathy in Alzheimer's disease: clinical and neurobiological features SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Sultzer, David L.; Leskin, Lorraine P.; Jacobs, Zachary M.; Melrose, Rebecca J.; Harwood, Dylan G.; Narvaez, Theresa A.; Ando, Timothy K.] VA Greater Los Angeles Healthcare Syst, Brain Behav & Aging Res Ctr, Los Angeles, CA USA. [Sultzer, David L.; Melrose, Rebecca J.; Harwood, Dylan G.] UCLA Dept Psychiat & Biobehav Sci, Los Angeles, CA USA. [Mandelkern, Mark A.] VA Greater Los Angeles Healthcare Syst, Nucl Med Serv, Los Angeles, CA USA. [Mandelkern, Mark A.] UC Irvine, Dept Phys, Irvine, CA USA. NR 0 TC 3 Z9 3 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S144 EP S145 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400160 ER PT J AU Yoder, M Kasckow, J Thorp, SR Magruder, KM AF Yoder, Matthew Kasckow, John Thorp, Steven R. Magruder, Kathryn M. TI PSYCHOSOCIAL INTERVENTIONS FOR OLDER PATIENTS WITH POST TRAUMATIC STRESS DISORDER SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry CY MAR 14-17, 2013 CL Los Angeles, CA SP Amer Assoc Geriatr Psychiat C1 [Kasckow, John] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Kasckow, John] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Yoder, Matthew; Magruder, Kathryn M.] Med Univ S Carolina, Charleston, SC 29425 USA. [Thorp, Steven R.] Univ Calif San Diego, San Diego, CA 92103 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2013 VL 21 IS 3 SU S BP S29 EP S30 PG 3 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 298XQ UT WOS:000330358400038 ER PT J AU Tellechea, A Kafanas, A Leal, EC Tecilazich, F Kuchibhotla, S Auster, ME Kontoes, I Paolino, J Carvalho, E Nabzdyk, LP Veves, A AF Tellechea, Ana Kafanas, Antonios Leal, Ermelindo C. Tecilazich, Francesco Kuchibhotla, Sarada Auster, Michael E. Kontoes, Iraklis Paolino, Jacqueline Carvalho, Eugenia Nabzdyk, Leena Pradhan Veves, Aristidis TI Increased Skin Inflammation and Blood Vessel Density in Human and Experimental Diabetes SO INTERNATIONAL JOURNAL OF LOWER EXTREMITY WOUNDS LA English DT Article DE diabetes; wound healing; skin changes; skin inflammation; skin blood vessels ID INSULIN-RESISTANCE; METABOLIC SYNDROME; FOOT ULCERATION; DYSFUNCTION; CYTOKINES; OBESITY; INTERLEUKIN-6; REACTIVITY; NEUROPATHY; MECHANISMS AB Systemic inflammation is associated with impaired wound healing in diabetes mellitus (DM) patients. Using immunohistochemistry techniques, the authors investigated changes in skin inflammation and skin blood vessels in human and experimental diabetes. Comparing to the non-DM human subjects, the total number of inflammatory cells per biopsy and the number of inflammatory cells around blood vessels, a strong indication of inflammation, were higher in DM subjects irrespective of their risk for developing diabetic foot ulcer. Inflammatory cell infiltration was robustly increased in all DM animal models compared with their non-DM controls. The number and density of blood vessels and CD31 positive proliferating endothelial cells around preexisting skin vessels was also higher in the DM patients. However, there were no differences in the skin blood flow between the non-DM and DM subjects. The number of skin blood vessels was also increased in the DM animals; however, these differences were less obvious than the ones observed for inflammatory cells. We conclude that skin inflammation and skin blood vessel density is increased in diabetic human subjects and in rodent and rabbit models of diabetes. C1 [Tellechea, Ana; Kafanas, Antonios; Leal, Ermelindo C.; Tecilazich, Francesco; Kuchibhotla, Sarada; Auster, Michael E.; Kontoes, Iraklis; Paolino, Jacqueline; Nabzdyk, Leena Pradhan; Veves, Aristidis] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Tellechea, Ana; Leal, Ermelindo C.; Carvalho, Eugenia] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal. [Paolino, Jacqueline] Mt Sinai Sch Med, New York, NY USA. RP Veves, A (reprint author), Microcirculat Lab, Palmer 321A,BIDMC West,One Deaconess Rd, Boston, MA 02215 USA. EM aveves@bidmc.harvard.edu RI Leal, Ermelindo/G-3051-2010; OI Leal, Ermelindo/0000-0003-1748-9861; Tellechea, Ana/0000-0001-9387-7706; Carvalho, Eugenia/0000-0001-6264-3632 FU National Institutes of Health [R01-DK076937, R01 NS066205]; National Center for Research Resources [UL1RR025758]; Portuguese Foundation for Science and Technology (FCT) [SFRH/BD/48624/2008, SFRH/BPD/46341/2008] 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 National Institutes of Health Grants R01-DK076937 and R01 NS066205 to AV. The project described was supported by the Clinical Translational Science Award UL1RR025758 to Harvard University and Beth Israel Deaconess Medical Center from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institute of Health. AT was supported by the SFRH/BD/48624/2008 grant and EL by the SFRH/BPD/46341/2008 grant from the Portuguese Foundation for Science and Technology (FCT). NR 21 TC 16 Z9 16 U1 2 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1534-7346 EI 1552-6941 J9 INT J LOW EXTR WOUND JI Int. J. Low. Extrem. Wounds PD MAR PY 2013 VL 12 IS 1 BP 4 EP 11 DI 10.1177/1534734612474303 PG 8 WC Dermatology; Surgery SC Dermatology; Surgery GA 298AR UT WOS:000330296800002 PM 23446362 ER PT J AU Garibyan, L Avashia, N AF Garibyan, Lilit Avashia, Nidhi TI Polymerase Chain Reaction SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID QUANTITATIVE PCR; CELL C1 [Garibyan, Lilit] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA USA. [Garibyan, Lilit] Harvard Med Sch, Boston, MA USA. [Avashia, Nidhi] Boston Univ, Dept Dermatol, Boston, MA USA. [Avashia, Nidhi] Boston Med Ctr, Boston, MA USA. RP Garibyan, L (reprint author), Wellman Ctr Photomed, 50 Blossom St, Tier 2, Boston, MA 02114 USA. EM lgaribyan@partners.org FU NIAMS NIH HHS [T32 AR007098] NR 10 TC 17 Z9 17 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAR PY 2013 VL 133 IS 3 BP E1 EP E4 DI 10.1038/jid.2013.1 PG 4 WC Dermatology SC Dermatology GA 090VQ UT WOS:000315008500047 PM 23399825 ER PT J AU Desikan, RS McEvoy, LK Holland, D Thompson, WK Brewer, JB Aisen, PS Andreassen, OA Hyman, BT Sperling, RA Dale, AM AF Desikan, R. S. McEvoy, L. K. Holland, D. Thompson, W. K. Brewer, J. B. Aisen, P. S. Andreassen, O. A. Hyman, B. T. Sperling, R. A. Dale, A. M. CA Alzheimer's Dis Neuroimaging Initi TI Apolipoprotein E epsilon 4 Does Not Modulate Amyloid-beta-Associated Neurodegeneration in Preclinical Alzheimer Disease SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID ENTORHINAL CORTEX NEURONS; NORMAL OLDER-ADULTS; MOUSE MODEL; CEREBRAL-CORTEX; VOLUME LOSS; TAU; DEPOSITION; BRAIN; ATROPHY; OCCURS AB These authors investigated the relationship between amyloid-, phosphorylated tau, and apolipoprotein E in preclinical Alzheimer disease in 170 patients and controls who had serial imaging up to 3.5 years after the initial study. Global volumes as well as volumes in brain regions known to be involved in the chronic stages of the disease were assessed. Their results led them to propose that atrophy rates are primarily influenced by apolipoprotein E via amyloid- mechanisms and that amyloid- -associated neurodegeneration occurs only in the presence of phosphorylated tau. BACKGROUND AND PURPOSE: Among cognitively healthy older individuals, the relationship among the 2 hallmark proteins of AD (A and APOE epsilon 4) and neurodegeneration is not well-understood. Here, we investigated the relationship between A, p-, and APOE epsilon 4 on longitudinal brain atrophy in preclinical AD. MATERIALS AND METHODS: We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed-effects model, we concurrently investigated main and interactive effects between the APOE epsilon 4 genotype and CSF A(1-42), CSF p- and CSF A(1-42), and the APOE epsilon 4 genotype and CSF p- on entorhinal cortex atrophy rate. We also examined the relationship of APOE epsilon 4, CSF p-, and CSF A(1-42) on the atrophy rate of other AD-vulnerable neuroanatomic regions. RESULTS: The full model with main and interactive effects demonstrated a significant interaction only between CSF p- and CSF A(1-42) on entorhinal cortex atrophy rate, indicating elevated atrophy with time in individuals with increased CSF p- and decreased CSF A(1-42). The APOE epsilon 4 genotype was significantly and specifically associated with CSF A(1-42). However, the interaction between the APOE epsilon 4 genotype and either CSF A(1-42) or CSF p- on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions. CONCLUSIONS: On the basis of our findings and building on prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD in which APOE epsilon 4 primarily influences the pathology of Alzheimer disease via A-related mechanisms, and in turn, A-associated neurodegeneration occurs only in the presence of p-. C1 [Desikan, R. S.; McEvoy, L. K.; Brewer, J. B.; Dale, A. M.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92037 USA. [Holland, D.; Brewer, J. B.; Aisen, P. S.; Dale, A. M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Thompson, W. K.; Andreassen, O. A.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Andreassen, O. A.] Univ Oslo, Inst Clin Med, Oslo, Norway. [Andreassen, O. A.] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway. [Hyman, B. T.; Sperling, R. A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sperling, R. A.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. RP Desikan, RS (reprint author), Univ Calif San Diego, Dept Radiol, 8950 Villa La Jolla Dr,Suite C101, La Jolla, CA 92037 USA. EM rdesikan@ucsd.edu RI Saykin, Andrew/A-1318-2007 OI Saykin, Andrew/0000-0002-1376-8532 FU National Institutes of Health [R01AG031224, K01AG029218, K02 NS067427, T32 EB005970, P30 AG010129, K01 AG030514]; Alzheimer Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research FX This research was supported by grants from the National Institutes of Health (R01AG031224, K01AG029218, K02 NS067427, T32 EB005970). Data collection and sharing for this project were funded by the Alzheimer Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Amorfix Life Sciences Ltd, AstraZeneca, Bayer HealthCare, BioClinica Inc, Biogen Idec Inc, Bristol-Myers Squibb Company, Eisai Inc, Elan Pharmaceuticals Inc, Eli Lilly and Company, F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc, GE Healthcare, Innogenetics, N.V., IXICO Ltd, Janssen Alzheimer Immunotherapy Research & Development LLC, Johnson & Johnson Pharmaceutical Research & Development LLC, Medpace Inc, Merck & Co Inc, Meso Scale Diagnostics LLC, Novartis Pharmaceuticals Corporation, Pfizer Inc, Servier, Synarc Inc, and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by National Institutes of Health grants P30 AG010129 and K01 AG030514. NR 31 TC 12 Z9 12 U1 0 U2 2 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD MAR PY 2013 VL 34 IS 3 BP 505 EP 510 DI 10.3174/ajnr.A3267 PG 6 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 291RN UT WOS:000329846900010 PM 22976236 ER EF