FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Abhishek, F Heist, E Elmariah, S Passeri, J Palacios, I Inglessis, I Baker, J Vlahakes, G Ruskin, J Mansour, M AF Abhishek, Fnu Heist, Edwin Elmariah, Sammy Passeri, Jonathan Palacios, Igor Inglessis, Ignacio Baker, Joshua Vlahakes, Gus Ruskin, Jeremy Mansour, Moussa TI CLINICAL IMPACT OF PERSISTENT LEFT BUNDLE BRANCH BLOCK AND PERMANENT PACEMAKER IMPLANTATION AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT ON LEFT VENTICULAR FUNCTION SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1123-352 BP A1958 EP A1958 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102716 ER PT J AU Arora, P Reingold, J Baggish, A Guanaga, D Wu, C Ghorbani, A Chen-Tournoux, A Khan, A Tainsh, L Buys, E Williams, J Scherrer-Crosbie, M Newton-Cheh, C Kaplan, L Wang, T AF Arora, Pankaj Reingold, Jason Baggish, Aaron Guanaga, Derek Wu, Connie Ghorbani, Anahita Chen-Tournoux, Annabel Khan, Abigail Tainsh, Laurel Buys, Emmanuel Williams, Jonathan Scherrer-Crosbie, Marielle Newton-Cheh, Christopher Kaplan, Lee Wang, Thomas TI WEIGHT LOSS, SALINE LOADING, AND THE NATRIURETIC PEPTIDE SYSTEM SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Alabama Birmingham, Birmingham, AL 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1144-144 BP A1354 EP A1354 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102112 ER PT J AU Bertrand, PB Verhaert, D Smeets, CJ Verbrugge, FH Grieten, L Mullens, W Gutermann, H Dion, RA Levine, R Vandervoort, PM AF Bertrand, Philippe B. Verhaert, David Smeets, Christophe J. Verbrugge, Frederik H. Grieten, Lars Mullens, Wilfried Gutermann, Herbert Dion, Robert A. Levine, Robert Vandervoort, Pieter M. TI EXERCISE-INDUCED INCREASE IN EFFECTIVE MITRAL VALVE AREA AFTER RESTRICTIVE MITRAL VALVE ANNULOPLASTY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Hosp Oost Limburg, Genk, Belgium. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1243M-366B BP A1929 EP A1929 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102687 ER PT J AU Bui, A Cannon, C Steg, P Storey, R Husted, S Ren, F James, S Michelson, E Himmelmann, A Wallentin, L Scirica, B AF Bui, An Cannon, Christopher Steg, Philippe Storey, Robert Husted, Steen Ren, Fang James, Stefan Michelson, Eric Himmelmann, Anders Wallentin, Lars Scirica, Benjamin TI RISK OF CARDIOVASCULAR DEATH AND NON-SUSTAINED VENTRICULAR TACHYCARDIA DETECTED 30-DAYS AFTER ACUTE CORONARY SYNDROME IN THE PLATO (PLATELET INHIBITION AND PATIENT OUTCOMES) TRIAL SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 921-06 BP A298 EP A298 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579100299 ER PT J AU Chatterjee, N Singh, J Szymonifka, J Lavender, Z Smith, C Januzzi, J Truong, Q AF Chatterjee, Neal Singh, Jagmeet Szymonifka, Jackie Lavender, Zachary Smith, Chelsea Januzzi, James Quynh Truong TI INCREMENTAL VALUE OF CYSTATIN C BEYOND CONVENTIONAL MARKERS OF RENAL FUNCTION FOR PREDICTING CLINICAL RESPONSE IN PATIENTS RECEIVING CARDIAC RESYNCHRONIZATION THERAPY: THE BIOCRT STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Chatterjee, Neal; Singh, Jagmeet; Szymonifka, Jackie; Lavender, Zachary; Smith, Chelsea; Januzzi, James; Quynh Truong] 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1221-203 BP A916 EP A916 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579101574 ER PT J AU Cheezum, M Subramaniyam, PS Bittencourt, M Hulten, E Ghoshhajra, B Shah, N Forman, D Hainer, J Leavitt, M Padmanabhan, R Skali, H Dorbala, S Hoffmann, U Abbara, S Gewirtz, H Di Carli, M Blankstein, R AF Cheezum, Michael Subramaniyam, Prem Srinivas Bittencourt, Marcio Hulten, Edward Ghoshhajra, Brian Shah, Nishant Forman, Daniel Hainer, Jon Leavitt, Marcia Padmanabhan, Ram Skali, Hicham Dorbala, Sharmila Hoffmann, Udo Abbara, Suhny Gewirtz, Henry Di Carli, Marcelo Blankstein, Ron TI PROGNOSTIC VALUE OF CORONARY CTA VERSUS EXERCISE TREADMILL TESTING SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1239M-362B BP A983 EP A983 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579101641 ER PT J AU Elmariah, S Inglessis, I Baker, J Stewart, W Lindman, B Xu, K Alu, M Vlahakes, G Kodali, S Dal-Bianco, J Melnitchouk, S Leon, M Svensson, L Pibarot, P Douglas, P Weissman, N Hahn, R Palacios, I Passeri, J AF Elmariah, Sammy Inglessis, Ignacio Baker, Joshua Stewart, William Lindman, Brian Xu, Ke Alu, Maria Vlahakes, Gus Kodali, Susheel Dal-Bianco, Jacob Melnitchouk, Serguei Leon, Martin Svensson, Lars Pibarot, Philippe Douglas, Pamela Weissman, Neil Hahn, Rebecca Palacios, Igor Passeri, Jonathan TI PATTERNS OF LEFT VENTRICULAR REMODELING IN PATIENTS WITH SEVERE AORTIC STENOSIS IN THE PARTNER TRIAL SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Elmariah, Sammy; Inglessis, Ignacio; Baker, Joshua; Stewart, William; Lindman, Brian; Xu, Ke; Alu, Maria; Vlahakes, Gus; Kodali, Susheel; Dal-Bianco, Jacob; Melnitchouk, Serguei; Leon, Martin; Svensson, Lars; Pibarot, Philippe; Douglas, Pamela; Weissman, Neil; Hahn, Rebecca; Palacios, Igor; Passeri, Jonathan] 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 919-07 BP A1937 EP A1937 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102695 ER PT J AU Emami, H Singh, P MacNabb, M Figueroa, A Abdelbaky, A Nasir, K Hoffmann, U Nahrendorf, M Tawakol, A AF Emami, Hamed Singh, Parmanand MacNabb, Megan Figueroa, Amparo Abdelbaky, Amr Nasir, Khurram Hoffmann, Udo Nahrendorf, Matthias Tawakol, Ahmed TI INCREASED BONE MARROW METABOLIC ACTIVITY IS ASSOCIATED WITH INCREASED RISK OF FUTURE CARDIOVASCULAR EVENTS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Baptist Hlth Med Grp, Miami Beach, FL 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1165M-362A BP A976 EP A976 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579101634 ER PT J AU Ferencik, M Puchner, S Liu, T Mayrhofer, T Truong, Q Lee, H Fleg, J Nagurney, J Udelson, J Hoffmann, U AF Ferencik, Maros Puchner, Stefan Liu, Ting Mayrhofer, Thomas Truong, Quynh Lee, Hang Fleg, Jerome Nagurney, John Udelson, James Hoffmann, Udo TI HIGH-RISK PLAQUE PREDICTS ACUTE CORONARY SYNDROME INDEPENDENTLY OF SIGNIFICANT CAD IN PATIENTS WITH ACUTE CHEST PAIN: RESULTS FROM ROMICAT II SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 914-07 BP A1003 EP A1003 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579101661 ER PT J AU Gandhi, PU Motiwala, S Sheftel, AD Weiner, R Baggish, A Gaggin, H Liu, P Januzzi, J AF Gandhi, Parul U. Motiwala, Shweta Sheftel, Alex D. Weiner, Rory Baggish, Aaron Gaggin, Hanna Liu, Peter Januzzi, James TI INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN 7 IN HEART FAILURE PATIENTS: A NOVEL BIOMARKER OF MYOCARDIAL DIASTOLIC FUNCTION? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Ottawa, Inst Heart, Ottawa, ON, Canada. 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1114-192 BP A788 EP A788 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579101446 ER PT J AU Hariharan, P Dudzinski, D Okechukwu, I Takayesu, J Chang, YC Kabrhel, C AF Hariharan, Praveen Dudzinski, David Okechukwu, Ikenna Takayesu, James Chang, Yuchiao Kabrhel, Christopher TI ASSOCIATION BETWEEN ELECTROCARDIOGRAPHIC FINDINGS, RIGHT HEART STRAIN AND SHORT-TERM ADVERSE CLINICAL EVENTS IN PATIENTS WITH ACUTE PULMONARY EMBOLISM SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Hariharan, Praveen; Dudzinski, David; Okechukwu, Ikenna; Takayesu, James; Chang, Yuchiao; Kabrhel, Christopher] 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1188-213 BP A1492 EP A1492 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102250 ER PT J AU Jia, HB Dauerman, H Toma, C Samady, H Lee, S Vergallo, R Hu, SN Tian, JW Soeda, T Wang, Z Lee, H McNulty, I Yu, B Uemura, S Jang, IK AF Jia, Haibo Dauerman, Harold Toma, Catalin Samady, Habib Lee, Stephen Vergallo, Rocco Hu, Sining Tian, Jinwei Soeda, Tsunenari Wang, Zhao Lee, Hang McNulty, Iris Yu, Bo Uemura, Shiro Jang, Ik-Kyung TI MANAGEMENT AND CLINICAL OUTCOME OF PATIENTS WITH ACUTE CORONARY SYNDROME CAUSED BY PLAQUE RUPTURE AND PLAQUE EROSION: AN INTRAVASCULAR OPTICAL COHERENCE TOMOGRAPHY STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, Harbin, Peoples R China. NR 0 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1117-250 BP A72 EP A72 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579100073 ER PT J AU Kataoka, A Zeng, X Garcia, M Seybolt, M Sullivan, S Guerrero, J Muriuki, M Kozak, A Braithwaite, G Handschumacher, M Levine, R Hung, J AF Kataoka, Akihisa Zeng, Xin Garcia, Michael Seybolt, Margo Sullivan, Suzanne Guerrero, Jose Muriuki, Maryanne Kozak, Adam Braithwaite, Gavin Handschumacher, Mark Levine, Robert Hung, Judy TI DEVELOPMENT AND APPLICATION OF POLYMER-MATRIX DEVICE TO REMODEL LEFT VENTRICULAR - MITRAL VALVE APPARATUS IN ISCHEMIC MITRAL REGURGITATION SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kataoka, Akihisa; Zeng, Xin; Garcia, Michael; Seybolt, Margo; Sullivan, Suzanne; Guerrero, Jose; Muriuki, Maryanne; Kozak, Adam; Braithwaite, Gavin; Handschumacher, Mark; Levine, Robert; Hung, Judy] Cambridge Polymer Grp Inc, 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1196-353 BP A1993 EP A1993 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102751 ER PT J AU Kato, ET Bonaca, M Morrow, D Jarolim, P Sloan, S Solomon, S Braunwald, E Sabatine, M AF Kato, Eri Toda Bonaca, Marc Morrow, David Jarolim, Petr Sloan, Sarah Solomon, Scott Braunwald, Eugene Sabatine, Marc TI GROWTH DIFFERENTIATION FACTOR-15 (GDF-15) AND THE RISK OF CARDIOVASCULAR EVENTS IN PATIENTS WITH STABLE ISCHEMIC HEART DISEASE SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 TIMI Study Grp, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 908-06 BP A1525 EP A1525 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102283 ER PT J AU Kim, J Al Mheid, I Malekzadegan, M Sher, S Shoop, J Galante, A Williams, B Sperling, L Weiner, R Baggish, A Quyyumi, A AF Kim, Jonathan Al Mheid, Ibhar Malekzadegan, Mohammad Sher, Salman Shoop, Jay Galante, Angelo Williams, Byron Sperling, Laurence Weiner, Rory Baggish, Aaron Quyyumi, Arshed TI ARTERIAL STIFFNESS IN NATIONAL COLLEGIATE ATHLETIC ASSOCIATION DIVISION I AMERICAN-STYLE FOOTBAL PLAYERS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Emory Univ, Atlanta, GA 30322 USA. 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1132M-366B BP A1633 EP A1633 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102391 ER PT J AU Kostis, JB Liu, J Cabrera, J Cheng, JQ Kostis, WJ AF Kostis, John B. Liu, Jie Cabrera, Javier Cheng, Jerry Q. Kostis, William J. TI FACTORS ASSOCIATED WITH MORE WEIGHT LOSS AFTER INTENSIVE DIETARY INTERVENTION SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Rutgers Robert Wood Johnson Med Sch, New Brunswick, NJ USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1144-148 BP A1358 EP A1358 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102116 ER PT J AU Kumar, V Liao, K Cheng, C Yu, S Kartoun, U Brettman, A Gainer, V Cagan, A Murphy, S Savova, G Chen, P Szolovits, P Xia, ZQ Karlson, E Plenge, R Ananthakrishnan, A Churchill, S Cai, TX Kohane, I Shaw, S AF Kumar, Vishesh Liao, Katherine Cheng, Chun Yu, Sheng Kartoun, Uri Brettman, Ari Gainer, Vivian Cagan, Andrew Murphy, Shawn Savova, Guergana Chen, Pei Szolovits, Peter Xia, Zongqi Karlson, Elizabeth Plenge, Robert Ananthakrishnan, Ashwin Churchill, Susanne Cai, Tianxi Kohane, Isaac Shaw, Stanley TI NATURAL LANGUAGE PROCESSING IMPROVES PHENOTYPIC ACCURACY IN AN ELECTRONIC MEDICAL RECORD COHORT OF TYPE 2 DIABETES AND CARDIOVASCULAR DISEASE SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Kumar, Vishesh; Liao, Katherine; Cheng, Chun; Yu, Sheng; Kartoun, Uri; Brettman, Ari; Gainer, Vivian; Cagan, Andrew; Murphy, Shawn; Savova, Guergana; Chen, Pei; Szolovits, Peter; Xia, Zongqi; Karlson, Elizabeth; Plenge, Robert; Ananthakrishnan, Ashwin; Churchill, Susanne; Cai, Tianxi; Kohane, Isaac; Shaw, Stanley] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1144-149 BP A1359 EP A1359 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102117 ER PT J AU Le, DTE Wei, KV Zhao, Y Nugent, M Kaul, S AF Le, Dai-Trang Elizabeth Wei, Kevin Zhao, Yan Nugent, Matthew Kaul, Sanjiv TI RANOLAZINE RELIEVES ISCHEMIA BY DECREASING MYOCARDIAL WORK WITHOUT ALTERING MYOCARDIAL BLOOD FLOW: INSIGHTS FROM AN EXPERIMENTAL MODEL SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Portland VA Med Ctr, Portland, OR USA. Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97201 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1279M-365A BP A1519 EP A1519 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102277 ER PT J AU Lo, JC Ljubicic, S Leibiger, B Chatterjee-Bhowmick, D Kelly, ME Cohen, P Leibiger, I Banks, A Flier, J Bluher, M Danial, N Berggren, PO Spiegelman, BM AF Lo, James C. Ljubicic, Sanda Leibiger, Barbara Chatterjee-Bhowmick, Diti Kelly, Molly E. Cohen, Paul Leibiger, Ingo Banks, Alexander Flier, Jeffrey Bluher, Matthias Danial, Nika Berggren, Per-Olof Spiegelman, Bruce M. TI ADIPSIN IS AN ADIPOCYTOKINE DYSREGULATED IN OBESITY/METABOLIC SYNDROME THAT SUSTAINS CARDIOVASCULAR HEALTH SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Farber Canc Inst, Boston, MA USA. 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 918-03 BP A2144 EP A2144 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579103002 ER PT J AU Lu, LY Jackevicius, C de Leon, N Warner, A Chang, D Mody, F AF Lu, Lingyun Jackevicius, Cynthia de Leon, Noelle Warner, Alberta Chang, Donald Mody, Freny TI IMPACT OF A MULTI-DISCIPLINARY HEART FAILURE POST-DISCHARGE MANAGEMENT CLINIC ON MEDICATION ADHERENCE SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 VA Greater Los Angeles HealthCare Syst, Los Angeles, CA USA. Western Univ Hlth Sci, Pomona, 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1186-180 BP A539 EP A539 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579101197 ER PT J AU May, EAB Bonaca, M Scirica, B Kuder, J Murphy, S Jarolim, P Sabatine, M Morrow, D AF May, Erin Ann Bohula Bonaca, Marc Scirica, Benjamin Kuder, Julia Murphy, Sabina Jarolim, Petr Sabatine, Marc Morrow, David TI GROWTH DIFFERENTIATION FACTOR-15 LEVEL PREDICTS RECURRENT CARDIOVASCULAR EVENTS IN PATIENTS WITH AN ACUTE CORONARY SYNDROME IN MERLIN-TIMI 36 SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. TIMI Study Grp, 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 900-08 BP A20 EP A20 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579100021 ER PT J AU Mehta, HH Tan, T Flynn, A Jansen, K Cohen, I Hung, J Mehrotra, P AF Mehta, Hetal H. Tan, Timothy Flynn, Aidan Jansen, Katrijn Cohen, Ira Hung, Judy Mehrotra, Praveen TI GENDER DIFFERENCES IN PATIENTS WITH PRESERVED EJECTION FRACTION, LOW-FLOW, LOW-GRADIENT SEVERE AORTIC STENOSIS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Thomas Jefferson Univ, Philadelphia, PA 19107 USA. 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1270-349 BP A2023 EP A2023 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102781 ER PT J AU Natarajan, P Stitziel, N Ferencik, M Hildebrand, L Gupta, N Gabriel, S Hoffmann, U Kathiresan, S AF Natarajan, Pradeep Stitziel, Nathan Ferencik, Maros Hildebrand, Lindsey Gupta, Namrata Gabriel, Stacey Hoffmann, Udo Kathiresan, Sekar TI CORONARY COMPUTED TOMOGRAPHY ANGIOGRAPHY AND WHOLE GENOME SEQUENCING AS AN APROACH TO DISCOVER THE GENETIC BASIS OF DISEASE IN A FAMILY PRONE TO MYOCARDIAL INFARCTION SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Broad Inst, Cambridge, 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1156-327 BP A1560 EP A1560 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102318 ER PT J AU Niehaus, E Tabtabai, S Sarswat, N Stone, JR Gilstrap, L Maurer, M Witteles, R Estep, J Baran, D Zucker, M Feltrin, G Seldin, D Semigran, M AF Niehaus, Emily Tabtabai, Sara Sarswat, Nitasha Stone, James R. Gilstrap, Lauren Maurer, Mathew Witteles, Ronald Estep, Jerry Baran, David Zucker, Mark Feltrin, Guiseppe Seldin, David Semigran, Marc TI NEED FOR RENAL REPLACEMENT THERAPY AFTER CARDIAC TRANSPLANTATION IN PATIENTS WITH AL AMYLOIDOSIS IS ASOCIATED WITH POOR SURVIVAL SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Niehaus, Emily; Tabtabai, Sara; Sarswat, Nitasha; Stone, James R.; Gilstrap, Lauren; Maurer, Mathew; Witteles, Ronald; Estep, Jerry; Baran, David; Zucker, Mark; Feltrin, Guiseppe; Seldin, David; Semigran, Marc] 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1221-182 BP A895 EP A895 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579101553 ER PT J AU Perl, L Zemer-Wassercug, N Rechavia, E Vaduganathan, M Orvin, K Lerman-Shivek, H Kornowski, R Lev, E AF Perl, Leor Zemer-Wassercug, Noa Rechavia, Eldad Vaduganathan, Muthiah Orvin, Katia Lerman-Shivek, Hila Kornowski, Ran Lev, Eli TI VARIABILITY IN RESPONSE TO PRASUGREL AND TICAGRELOR OVER TIME IN PATIENTS WITH ACUTE CORONARY SYNDROME SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Rabin Med Ctr, Petah Tiqwa, Israel. 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 901-04 BP A23 EP A23 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579100024 ER PT J AU Pursnani, A Lee, A Mayrhofer, T Ahmed, W Uthamalingam, S Ferencik, M Bamberg, F Schlett, C Udelson, J Hoffmann, U Ghoshhajra, B AF Pursnani, Amit Lee, Ashley Mayrhofer, Thomas Ahmed, Waleed Uthamalingam, Shanmugam Ferencik, Maros Bamberg, Fabian Schlett, Christopher Udelson, James Hoffmann, Udo Ghoshhajra, Brian TI INCREMENTAL VALUE OF EARLY RESTING MYOCARDIAL CT PERFUSION ASSESSMENT TO CARDIAC CT ANGIOGRAPHY FOR PREDICTION OF ACUTE CORONARY SYNDROME IN THE EMERGENCY DEPARTMENT SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Pursnani, Amit; Lee, Ashley; Mayrhofer, Thomas; Ahmed, Waleed; Uthamalingam, Shanmugam; Ferencik, Maros; Bamberg, Fabian; Schlett, Christopher; Udelson, James; Hoffmann, Udo; Ghoshhajra, Brian] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1250-66 BP A1264 EP A1264 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102022 ER PT J AU Russell, DC Goodfriend, T Haworth, R AF Russell, Douglas C. Goodfriend, Theodore Haworth, Robert TI MECHANISM OF ARRHYTHMOGENESIS INDUCED BY FATTY ACIDS: A ROLE OF MODIFICATION OF MITOCHONDRIAL CREATINE KINASE AND CITRATE SYNTHASE? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. Univ Wisconsin, Madison, WI 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1180-91 BP A370 EP A370 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579101028 ER PT J AU Sarswat, N Niehaus, E Tabtabai, S Stone, J Gilstrap, L Maurer, M Witteles, R Estep, J Baran, D Zucker, M Seldin, D Semigran, M AF Sarswat, Nitasha Niehaus, Emily Tabtabai, Sara Stone, James Gilstrap, Lauren Maurer, Matthew Witteles, Ronald Estep, Jerry Baran, David Zucker, Mark Seldin, David Semigran, Marc TI PRE-TRANSPLANT CHEMOTHERAPY DOES NOT AFFECT POST TRANSPLANT OUTCOME IN PATIENTS UNDERGOING OHT FOR AL CARDIOMYOPATHY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Sarswat, Nitasha; Niehaus, Emily; Tabtabai, Sara; Stone, James; Gilstrap, Lauren; Maurer, Matthew; Witteles, Ronald; Estep, Jerry; Baran, David; Zucker, Mark; Seldin, David; Semigran, Marc] 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1220-171 BP A884 EP A884 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579101542 ER PT J AU Schwartzenberg, S Goland, S Sagie, A AF Schwartzenberg, Shmuel Goland, Sorel Sagie, Alik TI AN UNUSUAL CASE OF CARDIAC AMYLOIDOSIS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Rabin Med Ctr, Petah Tiqwa, Israel. 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1172-04 BP A668 EP A668 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579101326 ER PT J AU Singh, P Tawakol, A Vucic, E Emami, H Fayad, Z Narula, J Rudd, J Morss, A Swanson, J Fontanez, S Traves, P Tejedor, A Pimentel-Santillana, M Mojena, M Fernaandez-Velasco, M Bosca, L AF Singh, Parmanand Tawakol, Ahmed Vucic, Esad Emami, Hamed Fayad, Zahi Narula, Jagat Rudd, James Morss, Alex Swanson, Jeffrey Fontanez, Sara Traves, Paqui Tejedor, Alberto Pimentel-Santillana, Maria Mojena, Marina Fernandez-Velasco, Maria Bosca, Lisardo TI HYPOXIA-INDUCIBLE FACTOR 1-ALPHA REGULATES ATHEROSCLEROSIS VIA MACROPHAGE ACTIVATION AND METABOLIC PATHWAYS SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Singh, Parmanand; Tawakol, Ahmed; Vucic, Esad; Emami, Hamed; Fayad, Zahi; Narula, Jagat; Rudd, James; Morss, Alex; Swanson, Jeffrey; Fontanez, Sara; Traves, Paqui; Tejedor, Alberto; Pimentel-Santillana, Maria; Mojena, Marina; Fernandez-Velasco, Maria; Bosca, Lisardo] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Bosca, Lisardo/A-2059-2008 OI Bosca, Lisardo/0000-0002-0253-5469 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 918-04 BP A2145 EP A2145 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579103003 ER PT J AU Soeda, T Uemura, S Dauerman, H Lee, S Park, SJ Jang, YS Itoh, T Kuramitsu, S Domei, T Barlis, P Yu, B Jia, HB Tian, JW Vergallo, R Sining, H Saito, Y Jang, IK AF Soeda, Tsunenari Uemura, Shiro Dauerman, Harold Lee, Stephen Park, Seung-Jung Jang, Yang-Soo Itoh, Tomonori Kuramitsu, Shoichi Domei, Takenori Barlis, Peter Yu, Bo Jia, Haibo Tian, Jinwei Vergallo, Rocco Sining, Hu Saito, Yoshihiko Jang, Ik-Kyung TI FREQUENCY, PREDICTORS, AND NATURAL HISTORY OF STENT EDGE DISSECTION: AN OPTICAL COHERENCE TOMOGRAPHY STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 2103-309 BP A1793 EP A1793 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102551 ER PT J AU Strom, J Wimmer, N Wasfy, J Yeh, R AF Strom, Jordan Wimmer, Neil Wasfy, Jason Yeh, Robert TI RE-EXAMINING THE OPERATOR VOLUME-OUTCOMES RELATIONSHIP IN PERCUTANEOUS CORONARY INTERVENTION: A SYSTEMATIC REVIEW SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Strom, Jordan; Wimmer, Neil; Wasfy, Jason; Yeh, Robert] 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 2904-04 BP A1700 EP A1700 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102458 ER PT J AU Tabtabai, S Niehaus, E Sarswat, N Stone, JR Maurer, M Witteles, R Estep, J Baran, D Zucker, M Feltrin, G Seldin, D Semigran, M AF Tabtabai, Sara Niehaus, Emily Sarswat, Nitasha Stone, James R. Maurer, Mathew Witteles, Ronald Estep, Jerry Baran, David Zucker, Mark Feltrin, Guiseppe Seldin, David Semigran, Marc TI REDUCED SURVIVAL IN LAMBDA PREDOMINANT CARDIAC AL AMYLOIDOSIS PATIENTS AWAITING ORTHOTOPIC HEART TRANSPLANT SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Tabtabai, Sara; Niehaus, Emily; Sarswat, Nitasha; Stone, James R.; Maurer, Mathew; Witteles, Ronald; Estep, Jerry; Baran, David; Zucker, Mark; Feltrin, Guiseppe; Seldin, David; Semigran, Marc] 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1260-167 BP A930 EP A930 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579101588 ER PT J AU Tian, JW Dauerman, H Toma, C Samady, H Itoh, T Kuramitsu, S Domei, T Jia, HB Vergallo, R Soeda, T Hu, SN Lee, H Yu, B Jang, IK AF Tian, Jinwei Dauerman, Harold Toma, Catalin Samady, Habib Itoh, Tomonori Kuramitsu, Shoichi Domei, Takenori Jia, Haibo Vergallo, Rocco Soeda, Tsunenari Hu Sining Lee, Hang Yu, Bo Jang, Ik-Kyung TI PREVALENCE OF THIN-CAP FIBROATHEROMA AND DEGREE OF STENOSIS: AN OPTICAL COHERENCE TOMOGRAPHY, INTRAVASCULAR ULTRASOUND, AND ANGIOGRAPHIC STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract 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 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1265-252 BP A258 EP A258 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579100259 ER PT J AU Tian, JW Uemura, S Park, SJ Jang, Y Barlis, P Lee, S Jia, HB Vergallo, R Soeda, T Hu, SN Lee, H Yu, B Jang, IK AF Tian, Jinwei Uemura, Shiro Park, Seung-Jung Jang, Yangsoo Barlis, Peter Lee, Stephen Jia, Haibo Vergallo, Rocco Soeda, Tsunenari Hu, Sining Lee, Hang Yu, Bo Jang, Ik-Kyung TI DETAILED MORPHOLOGICAL CHARACTERISTICS OF PLAQUES WITH EROSION: A THREE-VESSEL OCT AND IVUS STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract 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 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1265-242 BP A248 EP A248 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579100249 ER PT J AU Tietjens, J Whooley, M Schiller, N Mishra, R AF Tietjens, Jeremy Whooley, Mary Schiller, Nelson Mishra, Rakesh TI THE PROGNOSTIC UTILITY OF AN ECHO-ESTIMATED LEFT VENTRICULAR END-DIASTOLIC PRESSURE-VOLUME RELATIONSHIP IN PATIENTS WITH STABLE CORONARY ARTERY DISEASE: THE HEART & SOUL STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1129M-363C BP A975 EP A975 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579101633 ER PT J AU Truong, QA Januzzi, J Szymonifka, J Thai, WE Wai, B Sharma, U Sandoval, R Grunau, Z Basnet, S Babatunde, A Ajijola, O Singh, J AF Truong, Quynh A. Januzzi, James Szymonifka, Jackie Thai, Wai-ee Wai, Bryan Sharma, Umesh Sandoval, Ryan Grunau, Zachary Basnet, Sandeep Babatunde, Adefolakemi Ajijola, Olujimi Singh, Jagmeet TI SUPERIORITY OF CORONARY SINUS CARDIAC BIOMARKER SAMPLING OVER PERIPHERAL VENOUS BLOOD FOR PROGNOSTICATION IN CARDIAC RESYNCHRONIZATION THERAPY: THE BIOCRT STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Calif Los Angeles, Los Angeles, 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1108-104 BP A314 EP A314 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579100315 ER PT J AU Udell, JA Scirica, B Cavender, MA Mosenzon, O Steg, P Davidson, J Hirshberg, B Im, KK Raz, I Bhatt, D AF Udell, Jacob A. Scirica, Benjamin Cavender, Matthew A. Mosenzon, Ofri Steg, Philippe Davidson, Jaime Hirshberg, Boaz Im, Kyungah (Kelly) Raz, Itamar Bhatt, Deepak TI BASELINE RENAL FUNCTION AND CARDIOVASCULAR RISK IN PATIENTS TREATED WITH SAXAGLIPTIN: OBSERVATIONS FROM THE SAVOR-TIMI 53 TRIAL SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp,Cardiovasc Div, Boston, MA 02115 USA. Hadassah Univ Hosp, Dept Internal Med, Diabet Unit, IL-91120 Jerusalem, Israel. 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 908-04 BP A1523 EP A1523 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102281 ER PT J AU Wang, Z Jia, HB Tian, JW Vergallo, R Soeda, T Aguirre, A Fujimoto, J Jang, IK AF Wang, Zhao Jia, Haibo Tian, Jinwei Vergallo, Rocco Soeda, Tsunenari Aguirre, Aaron Fujimoto, James Jang, Ik-Kyung TI COMPUTER AIDED IMAGE ANALYSIS TO ENHANCE IN VIVO DIAGNOSIS OF PLAQUE EROSION BY INTRAVASCULAR OPTICAL COHERENCE TOMOGRAPHY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 MIT, Cambridge, MA 02139 USA. 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1150-222 BP A91 EP A91 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579100092 ER PT J AU Wasfy, MM Weiner, R Deluca, J Wang, F Berkstresser, B Hutter, A Picard, M Baggish, A AF Wasfy, Meagan Murphy Weiner, Rory Deluca, James Wang, Francis Berkstresser, Brant Hutter, Adolph Picard, Michael Baggish, Aaron TI ENDURANCE EXERCISE-INDUCED CARDIAC REMODELING: NOT ALL SPORTS ARE CREATED EQUAL SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Wasfy, Meagan Murphy; Weiner, Rory; Deluca, James; Wang, Francis; Berkstresser, Brant; Hutter, Adolph; 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 927-05 BP A1649 EP A1649 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102407 ER PT J AU Weiner, RB Wang, F Hutter, A Stohr, E Shave, R Picard, M Baggish, A AF Weiner, Rory B. Wang, Francis Hutter, Adolph Stohr, Eric Shave, Rob Picard, Michael Baggish, Aaron TI ACUTE VERSUS CHRONIC EXERCISE-INDUCED LEFT VENTRICULAR REMODELING: A PREVIOUSLY UNRECOGNIZED BIPHASIC PHENOMENON SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Weiner, Rory B.; Wang, Francis; Hutter, Adolph; Stohr, Eric; Shave, Rob; 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1132M-366A BP A1632 EP A1632 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102390 ER PT J AU Yeh, RW Mauri, L Wolf, R Lovett, A Romm, I Normand, SL AF Yeh, Robert W. Mauri, Laura Wolf, Robert Lovett, Ann Romm, Iyah Normand, Sharon-Lise TI STEEP DECLINES IN POPULATION RATES OF CORONARY REVASCULARIZATION SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Yeh, Robert W.; Mauri, Laura; Wolf, Robert; Lovett, Ann; Romm, Iyah; Normand, Sharon-Lise] Massachusetts Gen Hosp, Boston, MA 02114 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 915-04 BP A1528 EP A1528 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102286 ER PT J AU Zilinski, JL Contursi, ME Isaacs, SK Lewis, G Hutter, A Troyanos, C D'Hemecourt, PA Dyer, KS Baggish, A AF Zilinski, Jodi L. Contursi, Miranda E. Isaacs, Stephanie K. Lewis, Gregory Hutter, Adolph Troyanos, Christopher D'Hemecourt, Pierre A. Dyer, K. Sophia Baggish, Aaron TI CARDIO-METABOLIC ADAPTATIONS TO MARATHON TRAINING SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract C1 [Zilinski, Jodi L.; Contursi, Miranda E.; Isaacs, Stephanie K.; Lewis, Gregory; Hutter, Adolph; Troyanos, Christopher; D'Hemecourt, Pierre A.; Dyer, K. Sophia; Baggish, Aaron] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 1 PY 2014 VL 63 IS 12 SU S MA 1197-356 BP A1659 EP A1659 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA CP0QC UT WOS:000359579102417 ER PT J AU Corominas, R Yang, XP Lin, GN Kang, SL Shen, Y Ghamsari, L Broly, M Rodriguez, M Tam, S Trigg, SA Fan, CY Yi, S Tasan, M Lemmens, I Kuang, XY Zhao, N Malhotra, D Michaelson, JJ Vacic, V Calderwood, MA Roth, FP Tavernier, J Horvath, S Salehi-Ashtiani, K Korkin, D Sebat, J Hill, DE Hao, T Vidal, M Iakoucheva, LM AF Corominas, Roser Yang, Xinping Lin, Guan Ning Kang, Shuli Shen, Yun Ghamsari, Lila Broly, Martin Rodriguez, Maria Tam, Stanley Trigg, Shelly A. Fan, Changyu Yi, Song Tasan, Murat Lemmens, Irma Kuang, Xingyan Zhao, Nan Malhotra, Dheeraj Michaelson, Jacob J. Vacic, Vladimir Calderwood, Michael A. Roth, Frederick P. Tavernier, Jan Horvath, Steve Salehi-Ashtiani, Kourosh Korkin, Dmitry Sebat, Jonathan Hill, David E. Hao, Tong Vidal, Marc Iakoucheva, Lilia M. TI Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism SO NATURE COMMUNICATIONS LA English DT Article ID DE-NOVO MUTATIONS; COPY-NUMBER VARIATION; GENOME-WIDE ANALYSIS; SPECTRUM DISORDERS; STRUCTURAL VARIATION; MENTAL-RETARDATION; COMMON VARIANTS; CONFERRING RISK; SCHIZOPHRENIA; DUPLICATIONS AB Increased risk for autism spectrum disorders (ASD) is attributed to hundreds of genetic loci. The convergence of ASD variants have been investigated using various approaches, including protein interactions extracted from the published literature. However, these datasets are frequently incomplete, carry biases and are limited to interactions of a single splicing isoform, which may not be expressed in the disease-relevant tissue. Here we introduce a new interactome mapping approach by experimentally identifying interactions between brain-expressed alternatively spliced variants of ASD risk factors. The Autism Spliceform Interaction Network reveals that almost half of the detected interactions and about 30% of the newly identified interacting partners represent contribution from splicing variants, emphasizing the importance of isoform networks. Isoform interactions greatly contribute to establishing direct physical connections between proteins from the de novo autism CNVs. Our findings demonstrate the critical role of spliceform networks for translating genetic knowledge into a better understanding of human diseases. C1 [Corominas, Roser; Lin, Guan Ning; Kang, Shuli; Iakoucheva, Lilia M.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Yang, Xinping; Shen, Yun; Ghamsari, Lila; Broly, Martin; Rodriguez, Maria; Tam, Stanley; Trigg, Shelly A.; Fan, Changyu; Yi, Song; Calderwood, Michael A.; Roth, Frederick P.; Salehi-Ashtiani, Kourosh; Hill, David E.; Hao, Tong; Vidal, Marc] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Yang, Xinping; Shen, Yun; Ghamsari, Lila; Broly, Martin; Rodriguez, Maria; Tam, Stanley; Trigg, Shelly A.; Fan, Changyu; Yi, Song; Calderwood, Michael A.; Roth, Frederick P.; Salehi-Ashtiani, Kourosh; Hill, David E.; Hao, Tong; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Yang, Xinping; Shen, Yun; Ghamsari, Lila; Broly, Martin; Rodriguez, Maria; Tam, Stanley; Trigg, Shelly A.; Fan, Changyu; Yi, Song; Calderwood, Michael A.; Roth, Frederick P.; Salehi-Ashtiani, Kourosh; Hill, David E.; Hao, Tong; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Tasan, Murat; Roth, Frederick P.] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. [Tasan, Murat; Roth, Frederick P.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada. [Tasan, Murat; Roth, Frederick P.] Univ Toronto, Dept Comp Sci, Toronto, ON M5S 3E1, Canada. [Tasan, Murat; Roth, Frederick P.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5S 3E1, Canada. [Lemmens, Irma; Tavernier, Jan] Univ Ghent VIB, Dept Med Prot Res, B-9000 Ghent, Belgium. [Lemmens, Irma; Tavernier, Jan] Univ Ghent, Fac Med & Hlth Sci, Dept Biochem, B-9000 Ghent, Belgium. [Kuang, Xingyan; Zhao, Nan; Korkin, Dmitry] Univ Missouri, Dept Comp Sci, Columbia, MO 65203 USA. [Kuang, Xingyan; Zhao, Nan; Korkin, Dmitry] Univ Missouri, Inst Informat, Columbia, MO 65203 USA. [Malhotra, Dheeraj; Michaelson, Jacob J.; Sebat, Jonathan] Univ Calif San Diego, Beyster Ctr Genom Psychiat Dis, La Jolla, CA 92093 USA. [Malhotra, Dheeraj; Michaelson, Jacob J.; Sebat, Jonathan] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Vacic, Vladimir] New York Genome Ctr, New York, NY 10013 USA. [Horvath, Steve] Univ Calif Los Angeles, Dept Human Genet & Biostat, Los Angeles, CA 90095 USA. RP Hao, T (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. EM tong_hao@dfci.harvard.edu; marc_vidal@dfci.harvard.edu; lilyak@ucsd.edu RI Calderwood, Mike/B-2475-2014; Zhao, Nan/K-4015-2015; Corominas, Roser/H-4163-2016; Roth, Frederick/H-6308-2011 OI Calderwood, Mike/0000-0001-6475-1418; Zhao, Nan/0000-0002-7897-2374; Corominas, Roser/0000-0001-8888-5402; FU NICHD [ARRA R01HD065288]; NIMH [R01MH091350]; NHGRI [R01HG001715]; Ellison Foundation, Boston; Dana-Farber Cancer Institute Strategic Initiative; NIH [MH076431]; Simons Foundation Autism Research Initiative [275724]; Canadian Institute for Advanced Research Fellowship; Canada Excellence Research Chairs Program; National Science Foundation [DBI-0845196, IOS-1126992]; Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWO); Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation, Belgium) FX We thank all members of the DFCI Center for Cancer Systems Biology (CCSB) for helpful discussions throughout the course of this project. We also thank Dr Joseph Gleeson for valuable comments on the manuscript, the members of Dr Sebat laboratory for helpful discussions and Abhishek Bhandari, Ashleigh Schaffer and Naiara Akizu for technical assistance. This work was supported by NIH grants ARRA R01HD065288 from NICHD to L. M. I and K. S.-A. and by R01MH091350 from NIMH to L. M. I. and T. H., R01HG001715 from NHGRI to M. V., D. E. H., F. P. R. and J.T.; by The Ellison Foundation, Boston, MA to M. V.; by Institute Sponsored Research funds from the Dana-Farber Cancer Institute Strategic Initiative to M. V.; by NIH (MH076431) and the Simons Foundation Autism Research Initiative (275724) to J.S.; by a Canadian Institute for Advanced Research Fellowship and the Canada Excellence Research Chairs Program to F. P. R. and by National Science Foundation grants DBI-0845196 and IOS-1126992 to D. K. I. L. is a postdoctoral fellow with the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWO). M. V. is a "Chercheur Qualifie Honoraire'' from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation, Belgium). NR 69 TC 39 Z9 48 U1 3 U2 31 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD APR PY 2014 VL 5 AR 3650 DI 10.1038/comms4650 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AG2BZ UT WOS:000335221700005 ER PT J AU Schmitz, S Ang, KK Vermorken, J Haddad, R Suarez, C Wolf, GT Hamoir, M Machiels, JP AF Schmitz, Sandra Ang, Kie Kian Vermorken, Jan Haddad, Robert Suarez, Carlos Wolf, Gregory T. Hamoir, Marc Machiels, Jean-Pascal TI Targeted therapies for squamous cell carcinoma of the head and neck: Current knowledge and future directions SO CANCER TREATMENT REVIEWS LA English DT Review DE Head & neck cancer; Squamous cell carcinoma; Targeted therapies; Treatment; Molecular biology ID GROWTH-FACTOR RECEPTOR; PHASE-II TRIAL; PLATINUM-BASED CHEMOTHERAPY; GENE COPY NUMBER; FACTOR-KAPPA-B; HISTONE DEACETYLASE INHIBITOR; COOPERATIVE-ONCOLOGY-GROUP; LYMPH-NODE METASTASIS; HUMAN-PAPILLOMAVIRUS; LUNG-CANCER AB Despite progress in the therapeutic management of patients with squamous cell carcinoma of the head and neck (SCCHN), the mortality rate of patients presenting with advanced disease remains high. One approach to improve treatment efficacy is to add novel molecular targeted agents to the classical treatment regimens. Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) have shown clinical benefits in palliative and curative settings. However, only a minority of patients presenting with recurrent or metastatic (RIM) SCCHN have meaningful tumor regression with these agents and virtually all who do develop acquired tumor resistance after a few months of treatment. For these reasons, other inhibitors of EGFR or molecules that interfere with known molecular pathways activated in SCCHN are of considerable interest, either as single agents or in combination with other treatment modalities. In this review, we discuss the different molecular therapeutic approaches explored in SCCHN. We also briefly outline new trial designs that could be used to accelerate the investigation of emerging therapeutic agents in this disease. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Schmitz, Sandra; Hamoir, Marc; Machiels, Jean-Pascal] Catholic Univ Louvain, Dept Med Oncol & Head & Neck Surg, Clin Univ St Luc, Ctr Canc, B-1200 Brussels, Belgium. [Schmitz, Sandra; Hamoir, Marc; Machiels, Jean-Pascal] Catholic Univ Louvain, Inst Rech Clin & Expt Pole MIRO, B-1200 Brussels, Belgium. [Ang, Kie Kian] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. [Vermorken, Jan] Univ Antwerp Hosp, Dept Med Oncol, B-2650 Edegem, Belgium. [Haddad, Robert] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Head & Neck Oncol Program, Boston, MA 02215 USA. [Suarez, Carlos] Hosp Univ Cent Asturias Oviedo, Dept Otolaryngol, Oviedo 33006, Asturias, Spain. [Wolf, Gregory T.] Univ Michigan Hlth Syst, Dept Otolaryngol Head & Neck Surg, Ann Arbor, MI 48109 USA. RP Machiels, JP (reprint author), Catholic Univ Louvain, Dept Med Oncol & Head & Neck Surg, Clin Univ St Luc, Ctr Canc, Ave Hippocrate 10, B-1200 Brussels, Belgium. EM Sandra.schmitz@uclouvain.be; kianang@mdanderson.org; jan.b.vermorken@uza.be; robert_haddad@dfci.harvard.edu; csuarezn@hcas.sespa.es; gregwolf@umich.edu; marc.hamoir@uclouvain.be; jean-pascal.machiels@uclouvain.be OI Hamoir, Marc/0000-0001-8547-2768 NR 184 TC 28 Z9 28 U1 2 U2 19 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0305-7372 EI 1532-1967 J9 CANCER TREAT REV JI Cancer Treat. Rev. PD APR PY 2014 VL 40 IS 3 BP 390 EP 404 DI 10.1016/j.ctrv.2013.09.007 PG 15 WC Oncology SC Oncology GA AB3JT UT WOS:000331687800006 PM 24176789 ER PT J AU Gershman, B Shui, IM Stampfer, M Platz, EA Gann, PH Sesso, HL DuPre, N Giovannucci, E Mucci, LA AF Gershman, Boris Shui, Irene M. Stampfer, Meir Platz, Elizabeth A. Gann, Peter H. Sesso, Howard L. DuPre, Natalie Giovannucci, Edward Mucci, Lorelei A. TI Prediagnostic Circulating Sex Hormones Are Not Associated with Mortality for Men with Prostate Cancer SO EUROPEAN UROLOGY LA English DT Article DE Prostate cancer; Testosterone; Androgens; Sex hormones; Mortality ID SERUM TESTOSTERONE LEVELS; RADICAL PROSTATECTOMY; INDEPENDENT PREDICTOR; PATHOLOGICAL STAGE; BINDING GLOBULIN; RISK; LEVEL; HYPOGONADISM; MARKER; INDEX AB Background: Sex hormones play an important role in the growth and development of the prostate, and low androgen levels have been suggested to carry an adverse prognosis for men with prostate cancer (PCa). Objective: To examine the association between prediagnostic circulating sex hormones and lethal PCa in two prospective cohort studies, the Physicians' Health Study (PHS) and the Health Professionals Follow-up Study (HPFS). Design, setting, and participants: We included 963 PCa cases (700 HPFS; 263 PHS) that provided prediagnostic blood samples, in 1982 for PHS and in 1993-1995 for HPFS, in which circulating sex hormone levels were assayed. Outcome measures and statistical analysis: The primary end point was lethal PCa (defined as cancer-specific mortality or development of metastases), and we also assessed total mortality through March 2011. We used Cox proportional hazards models to evaluate the association of prediagnostic sex hormone levels with time from diagnosis to development of lethal PCa or total mortality. Results and limitations: PCa cases were followed for a mean of 12.0 +/- 4.9 yr after diagnosis. We confirmed 148 cases of lethal PCa and 421 deaths overall. Using Cox proportional hazard models, we found no significant association between quartile of total testosterone, sex hormone binding globulin (SHBG), SHBG-adjusted testosterone, free testosterone, dihydrotestosterone, androstanediol glucuronide, or estradiol and lethal PCa or total mortality. In subset analyses stratified by Gleason score, TNM stage, age, and interval between blood draw and diagnosis, there was also no consistent association between lethal PCa and sex hormone quartile. Conclusions: We found no overall association between prediagnostic circulating sex hormones and lethal PCa or total mortality. Our null results suggest that reverse causation may be responsible in prior studies that noted adverse outcomes for men with low circulating androgens. (C) 2013 European Association of Urology. Published by Elsevier B. V. All rights reserved. C1 [Gershman, Boris] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Shui, Irene M.; Stampfer, Meir; DuPre, Natalie; Giovannucci, Edward; Mucci, Lorelei A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Stampfer, Meir; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Stampfer, Meir; Giovannucci, Edward; Mucci, Lorelei A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Stampfer, Meir; Sesso, Howard L.; Giovannucci, Edward; Mucci, Lorelei A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Gann, Peter H.] Univ Illinois, Dept Pathol, Chicago, IL USA. [Sesso, Howard L.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. RP Mucci, LA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM lmucci@hsph.harvard.edu FU National Institutes of Health/National Cancer Institute [RO1 CA136578, P01 CA055075, R01 CA133891, R01 CA141298]; DF/HCC SPORE in Prostate Cancer NIH/NCI [P50 CA90381]; National Cancer Institute NRSA [T32 CA09001]; US Army Prostate Cancer Postdoctoral Fellowship FX This study was funded in part by grants from the National Institutes of Health/National Cancer Institute (RO1 CA136578 PI: Mucci; P01 CA055075 PI: Willett; R01 CA133891 PI: Giovannucci; R01 CA141298 PI: Stampfer; DF/HCC SPORE in Prostate Cancer NIH/NCI P50 CA90381 PI: Kantoff). Lorelei A. Mucci was a Milken Young Investigator of the Prostate Cancer Foundation. Irene M. Shui is supported by the National Cancer Institute NRSA T32 CA09001 (PI: Stampfer) and a US Army Prostate Cancer Postdoctoral Fellowship. NR 29 TC 11 Z9 11 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2014 VL 65 IS 4 BP 683 EP 689 DI 10.1016/j.eururo.2013.01.003 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AB3UW UT WOS:000331716700007 PM 23340241 ER PT J AU Gershman, B Shui, IM Mucci, LA AF Gershman, Boris Shui, Irene M. Mucci, Lorelei A. TI Reply from Authors re: Andrea Salonia. Androgens and Prostate Cancer: We Are Still (Almost) Completely Ignorant. Eur Urol 2014;65:690-1 Androgens and Prostate Cancer: Clinical Implications and Future Directions SO EUROPEAN UROLOGY LA English DT Editorial Material ID RADICAL PROSTATECTOMY; TESTOSTERONE C1 [Gershman, Boris] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Shui, Irene M.; Mucci, Lorelei A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mucci, Lorelei A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Mucci, Lorelei A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Mucci, LA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM lmucci@hsph.harvard.edu NR 9 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2014 VL 65 IS 4 BP 691 EP 692 DI 10.1016/j.eururo.2013.03.028 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA AB3UW UT WOS:000331716700009 ER PT J AU Nguyen, PL AF Nguyen, Paul L. TI Androgen-deprivation Therapy and Cardiovascular Harm: Let's Not Throw Out the Baby with the Bathwater SO EUROPEAN UROLOGY LA English DT Editorial Material ID PROSTATE-CANCER; ASSOCIATION; SUPPRESSION; RADIATION; DISEASE; MEN C1 Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu NR 10 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2014 VL 65 IS 4 BP 710 EP 712 DI 10.1016/j.eururo.2013.03.002 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA AB3UW UT WOS:000331716700013 PM 23498063 ER PT J AU Schutz, FAB Xie, WL Donskov, F Sircar, M McDermott, DF Rini, BI Agarwal, N Pal, SK Srinivas, S Kollmannsberger, C North, SA Wood, LA Vaishampayan, U Tan, MH Mackenzie, MJ Lee, JL Rha, SY Yuasa, T Heng, DYC Choueiri, TK AF Schutz, Fabio A. B. Xie, Wanling Donskov, Frede Sircar, Monica McDermott, David F. Rini, Brian I. Agarwal, Neeraj Pal, Sumanta Kumar Srinivas, Sandy Kollmannsberger, Christian North, Scott A. Wood, Lori A. Vaishampayan, Ulka Tan, Min-Han Mackenzie, Mary J. Lee, Jae Lyun Rha, Sun-Young Yuasa, Takeshi Heng, Daniel Y. C. Choueiri, Toni K. TI The Impact of Low Serum Sodium on Treatment Outcome of Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Cancer Database Consortium SO EUROPEAN UROLOGY LA English DT Article DE Hyponatremia; Renal cell cancer; Anti-VEGF; Prognostic factors ID INAPPROPRIATE SECRETION; PROGNOSTIC-FACTORS; HYPONATREMIA; CIRRHOSIS; SURVIVAL; MORTALITY; FAILURE; ASCITES AB Background: Hyponatremia has been associated with poor survival in many solid tumors and more recently found to be of prognostic and predictive value in metastatic renal cell cancer (mRCC) patients treated with immunotherapy. Objective: To investigate the influence of baseline hyponatremia in mRCC patients treated with targeted therapy in the International Metastatic Renal Cell Carcinoma Database Consortium. Design, setting, and participants: Data on 1661 patients treated with first-line vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) targeted therapy for mRCC were available from 18 cancer centers to study the impact of hyponatremia (serum sodium level < 135 mmol/l) on clinical outcomes. Outcome measurements and statistical analysis: The primary objective was overall survival (OS) and secondary end points included time to treatment failure (TTF) and the disease control rate (DCR). The chi-square test was used to compare the DCR in patients with and without hyponatremia. OS and TTF were estimated with the Kaplan-Meier method and differences between groups were examined by the log-rank test. Multivariable logistic regression (for DCR) and Cox regression (for OS and TTF) were undertaken adjusted for prognostic risk factors. Results and limitations: Median OS after treatment initiation was 18.5 mo (95% confidence interval [CI], 17.5-19.8 mo), with 552 (33.2%) of patients remaining alive on a median follow-up of 22.1 mo. Median baseline serum sodium was 138 mmol/l (range: 122-159 mmol/l), and hyponatremia was found in 14.6% of patients. On univariate analysis, hyponatremia was associated with shorter OS (7.0 vs 20.9 mo), shorter TTF (2.9 vs 7.4 mo), and lower DCR rate (54.9% vs 78.8%) (p < 0.0001 for all comparisons). In multivariate analysis, these effects remain significant (hazard ratios: 1.51 [95% CI, 1.26-1.80] for OS, and 1.57 [95% CI, 1.34-1.83] for TTF; odds ratio: 0.50 [95% CI, 34-0.72] for DCR; adjusted p < 0.001). Results were similar if sodium was analyzed as a continuous variable (adjusted p < 0.0001 for OS, TTF, and DCR). Conclusions: This is the largest multi-institutional report to show that hyponatremia is independently associated with a worse outcome in mRCC patients treated with VEGF and mTOR-targeted agents. (C) 2013 Published by Elsevier B.V. on behalf of European Association of Urology. C1 [Schutz, Fabio A. B.; Xie, Wanling; Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Donskov, Frede] Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. [Sircar, Monica; Choueiri, Toni K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [McDermott, David F.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Rini, Brian I.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Agarwal, Neeraj] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Pal, Sumanta Kumar] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Srinivas, Sandy] Stanford Med Ctr, Stanford, CA USA. [Kollmannsberger, Christian] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [North, Scott A.] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Wood, Lori A.] Dalhousie Univ, Halifax, NS, Canada. [Vaishampayan, Ulka] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Tan, Min-Han] Natl Canc Ctr Singapore, Singapore, Singapore. [Mackenzie, Mary J.] London Reg Canc Program, London, ON, Canada. [Lee, Jae Lyun] Univ Ulsan, Coll Med, Asan Med Ctr, Seoul, South Korea. [Rha, Sun-Young] Yonsei Univ, Coll Med, Yonsei Canc Ctr, Seoul, South Korea. [Yuasa, Takeshi] Japanese Fdn Canc Res, Canc Inst Hosp, Tokyo, Japan. [Heng, Daniel Y. C.] Tom Baker Canc Clin, Calgary, AB, Canada. RP Choueiri, TK (reprint author), 450 Brookline Ave, Boston, MA 02115 USA. EM toni_choueiri@dfci.harvard.edu OI Donskov, Frede/0000-0002-8449-863X FU Novartis; Pfizer; GlaxoSmithKline; Bayer Korea FX Toni K. Choueiri 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: Daniel Y.C. Heng has advisory roles at Aveo, Pfizer, Novartis, and Bayer. Mary J. Mackenzie has advisory roles at Novartis and Pfizer, and has received research funding from both. Lori A. Wood has advisory roles at Pfizer and Novartis, and has received research funding from Pfizer, Novartis, and GlaxoSmithKline. Ulka Vaishampayan has received honoraria and research funding from Pfizer, Novartis, and GlaxoSmithKline. Sun-Young Rha has advisory roles at Novartis, Pfizer, and GlaxoSmithKline, and has received research funding from Novartis and Bayer Korea. Frede Donskov has received research funding from Novartis. Christian Kollmannsberger has advisory roles at Pfizer, Novartis, and GlaxoSmithKline, and has received honoraria and research funding from Pfizer, Novartis, and GlaxoSmithKline. Brian I. Rini has advisory role at Pfizer, GlaxoSmithKline, Aveo, Bayer, Onyx, and has received research funding from GlaxoSmithKline and Pfizer. Sandy Srinivas has advisory roles at Pfizer, Novartis, and Genentech. Scott A. North has an advisory role Pfizer, Novartis, Bayer, and GlaxoSmithKline. Toni K. Choueiri has received research funding from Pfizer and has advisory roles at Aveo, Pfizer, Novartis, GlaxoSmithKline, Genentech, Bayer, and Onyx. The other authors declare that they have no conflicts of interest. NR 28 TC 14 Z9 14 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2014 VL 65 IS 4 BP 723 EP 730 DI 10.1016/j.eururo.2013.10.013 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA AB3UW UT WOS:000331716700016 PM 24184025 ER PT J AU Bellmunt, J Leow, JJ AF Bellmunt, Joaquim Leow, Jeffrey J. TI Hyponatremia Associated with Worse Outcomes in Metastatic Renal Cell Cancer: A Potential Target for Intervention? SO EUROPEAN UROLOGY LA English DT Editorial Material ID CARCINOMA; SURVIVAL; VALIDATION C1 [Bellmunt, Joaquim; Leow, Jeffrey J.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Bladder Canc Ctr, Boston, MA USA. RP Bellmunt, J (reprint author), Dana Farber Canc Inst, 450 Brookline Ave DANA 1230, Boston, MA 02215 USA. EM Joaquim_bellmunt@dfci.harvard.edu NR 10 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2014 VL 65 IS 4 BP 731 EP 732 DI 10.1016/j.eururo.2013.10.057 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA AB3UW UT WOS:000331716700017 PM 24262101 ER PT J AU Keating, NL Liu, PH O'Malley, AJ Freedland, SJ Smith, MR AF Keating, Nancy L. Liu, Pang-Hsiang O'Malley, A. James Freedland, Stephen J. Smith, Matthew R. TI Androgen-deprivation Therapy and Diabetes Control Among Diabetic Men with Prostate Cancer SO EUROPEAN UROLOGY LA English DT Article DE Prostate cancer; Androgen-deprivation therapy; Diabetes ID CARDIOVASCULAR-DISEASE; ARTERIAL STIFFNESS; BODY-COMPOSITION; ASSOCIATION; RISK; CARE; MANAGEMENT; VETERANS; MELLITUS; INSULIN AB Background: Androgen-deprivation therapy (ADT) for prostate cancer (PCa) is associated with decreased insulin sensitivity and increased diabetes risk among nondiabetic men. Few data are available about the effects of ADT on diabetes control among men with diabetes. Objective: We examined care for men who had diabetes at the time of PCa diagnosis to assess the effect of ADT on diabetes control, as measured by hemoglobin A1c (HbA1c) levels and the intensification of diabetes pharmacotherapy. Design, setting, and participants: This was an observational cohort study using US Department of Veterans Affairs registry data and administrative data to assess HbA1c levels and intensification of diabetes pharmacotherapy among 2237 pairs of propensitymatched men with PCa and diabetes who were or were not treated with ADT. Outcome measurements and statistical analysis: We calculated the difference in difference of HbA1c levels at baseline and at 1 and 2 yr in the two groups, compared using a paired Student t test. We used a Cox proportional hazards model to estimate time to intensification of diabetes pharmacotherapy. Results and limitations: The mean HbA1c at baseline was 7.24 (standard error [SE]: 0.05) for the ADT group and 7.24 (SE: 0.04) for the no-ADT group. HbA1c increased at 1 yr for men treated with ADT to 7.38 (SE: 0.04) and decreased among men not treated with ADT to 7.14 (SE: 0.04), for a difference in differences of +0.24 (p = 0.008). Results were similar at 2 yr (p = 0.03). The worsening HbA1c control occurred despite ADT being associated with an increased hazard of addition of diabetes medication (adjusted hazard ratio: 1.20; 95% confidence interval, 1.09-1.32). The limitation of this study was that it was observational and relied on administrative data. Conclusions: ADT is associated with worsening of diabetes control and increases in HbA1c levels despite the use of additional diabetes medications. (C) 2013 Published by Elsevier B.V. on behalf of European Association of Urology. C1 [Keating, Nancy L.] Brigham & Womens Hosp, Dept Med, Div Gen Internal Med, Boston, MA 02115 USA. [Keating, Nancy L.; Liu, Pang-Hsiang; O'Malley, A. James] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Freedland, Stephen J.] Duke Univ, Sch Med, Div Urol, Dept Surg, Durham, NC USA. [Freedland, Stephen J.] Durham Vet Affairs Med Ctr, Durham, NC USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. RP Keating, NL (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM keating@hcp.med.harvard.edu RI Liu, Michael Pang-Hsiang/B-9903-2015 OI Liu, Michael Pang-Hsiang/0000-0001-8842-2264 FU Prostate Cancer Foundation FX This study was funded by the Prostate Cancer Foundation. The data were obtained from the US Department of Veterans Affairs (VA) through the Office of Policy and Planning as part of a larger evaluation of oncology care. Neither the sponsor nor the VA had any role in the design and conduct of the study or the collection, management, analysis, interpretation of the data, preparation of the manuscript, or decision to submit the manuscript for publication. NR 29 TC 14 Z9 14 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 EI 1873-7560 J9 EUR UROL JI Eur. Urol. PD APR PY 2014 VL 65 IS 4 BP 816 EP 824 DI 10.1016/j.eururo.2013.02.023 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA AB3UW UT WOS:000331716700027 PM 23453420 ER PT J AU Mosse, YP Deyell, RJ Berthold, F Nagakawara, A Ambros, PF Monclair, T Cohn, SL Pearson, AD London, WB Matthay, KK AF Mosse, Yael P. Deyell, Rebecca J. Berthold, Frank Nagakawara, Akira Ambros, Peter F. Monclair, Tom Cohn, Susan L. Pearson, Andrew D. London, Wendy B. Matthay, Katherine K. TI Neuroblastoma in Older Children, Adolescents and Young Adults: A Report From the International Neuroblastoma Risk Group Project SO PEDIATRIC BLOOD & CANCER LA English DT Article DE adolescents; autologous hematopoietic cell transplant; neuroblastoma; young adults ID INDOLENT COURSE; ONCOLOGY-GROUP; N-MYC; AGE; AMPLIFICATION; EXPERIENCE; DIAGNOSIS; SURVIVAL; CLASSIFICATION; CHEMOTHERAPY AB BackgroundNeuroblastoma in older children and adolescents has a distinctive, indolent phenotype, but little is known about the clinical and biological characteristics that distinguish this rare subgroup. Our goal was to determine if an optimal age cut-off exists that defines indolent disease and if accepted prognostic factors and treatment approaches are applicable to older children. ProcedureUsing data from the International Neuroblastoma Risk Group, among patients 18 months old (n=4,027), monthly age cut-offs were tested to determine the effect of age on survival. The prognostic effect of baseline characteristics and autologous hematopoietic cell transplant (AHCT) for advanced disease was assessed within two age cohorts; 5 to <10 years (n=730) and 10 years (n=200). ResultsOlder age was prognostic of poor survival, with outcome gradually worsening with increasing age at diagnosis, without statistical evidence for an optimal age cut-off beyond 18 months. Among patients 5 years, factors significantly prognostic of lower event-free survival (EFS) and overall survival (OS) in multivariable analyses were INSS stage 4, MYCN amplification and unfavorable INPC histology classification. Among stage 4 patients, AHCT provided a significant EFS and OS benefit. Following relapse, patients in both older cohorts had prolonged OS compared to those 18 months to <5 years (P<0.0001). ConclusionsDespite indolent disease and infrequent MYCN amplification, older children with advanced disease have poor survival, without evidence for a specific age cut-off. Our data suggest that AHCT may provide a survival benefit in older children with advanced disease. Novel therapeutic approaches are required to more effectively treat these patients. Pediatr Blood Cancer 2014;61:627-635. (c) 2013 Wiley Periodicals, Inc. C1 [Mosse, Yael P.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Mosse, Yael P.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Deyell, Rebecca J.] Univ British Columbia, British Columbia Childrens Hosp, Div Pediat Hematol & Oncol, Vancouver, BC V5Z 1M9, Canada. [Berthold, Frank] Univ Cologne, Dept Pediat Hematol & Oncol, D-50931 Cologne, Germany. [Nagakawara, Akira] Chiba Canc Ctr, Res Inst, Chiba 2608717, Japan. [Ambros, Peter F.] St Anna Childrens Hosp, Childrens Canc Res Inst, Vienna, Austria. [Monclair, Tom] Univ Oslo, Rikshosp, Natl Hosp, Dept Surg, N-0027 Oslo, Norway. [Cohn, Susan L.] Univ Chicago, Sch Med, Chicago, IL 60637 USA. [Pearson, Andrew D.] Royal Marsden Hosp, Inst Canc Res, Sutton, Surrey, England. [London, Wendy B.] Boston Childrens Hosp, Boston, MA USA. [London, Wendy B.] Harvard Univ, Sch Med, Dana Farber Harvard Canc Ctr, Boston, MA USA. [London, Wendy B.] Childrens Oncol Grp Stat & Data Ctr, Boston, MA USA. [Matthay, Katherine K.] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA. RP Mosse, YP (reprint author), Childrens Hosp Philadelphia, Colket Translat Res Bldg,3501 Civ Ctr Blvd,Off 30, Philadelphia, PA 19104 USA. EM mosse@email.chop.edu OI Cohn, Susan/0000-0001-5749-7650; Ambros, Peter F./0000-0002-5507-7211 FU St. Baldrick's Foundation; Carly Hillman Foundation; Little Heroes Pediatric Cancer Foundation; Forbeck Foundation; Campini, Conner, and Dougherty Foundation; UBC Clinician Investigator Program FX Grant sponsor: St. Baldrick's Foundation; Grant sponsor: Carly Hillman Foundation; Grant sponsor: Little Heroes Pediatric Cancer Foundation; Grant sponsor: Forbeck Foundation; Grant sponsor: Campini, Conner, and Dougherty Foundation; Grant sponsor: UBC Clinician Investigator Program NR 27 TC 12 Z9 14 U1 0 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD APR PY 2014 VL 61 IS 4 BP 627 EP 635 DI 10.1002/pbc.24777 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 303OL UT WOS:000330683700009 PM 24038992 ER PT J AU Robison, NJ Campigotto, F Chi, SN Manley, PE Turner, CD Zimmerman, MA Chordas, CA Werger, AM Allen, JC Goldman, S Rubin, JB Isakoff, MS Pan, WJ Khatib, ZA Comito, MA Bendel, AE Pietrantonio, JB Kondrat, L Hubbs, SM Neuberg, DS Kieran, MW AF Robison, Nathan J. Campigotto, Federico Chi, Susan N. Manley, Peter E. Turner, Christopher D. Zimmerman, Mary Ann Chordas, Christine A. Werger, Annette M. Allen, Jeffrey C. Goldman, Stewart Rubin, Joshua B. Isakoff, Michael S. Pan, Wilbur J. Khatib, Ziad A. Comito, Melanie A. Bendel, Anne E. Pietrantonio, Jay B. Kondrat, Laura Hubbs, Shannon M. Neuberg, Donna S. Kieran, Mark W. TI A Phase II Trial of a Multi-Agent Oral Antiangiogenic (Metronomic) Regimen in Children With Recurrent or Progressive Cancer SO PEDIATRIC BLOOD & CANCER LA English DT Article DE angiogenesis; drug resistance; pediatric oncology; phase II clinical trials ID LOW-GRADE GLIOMA; TUMOR ANGIOGENESIS; CHEMOTHERAPY; THERAPY; VINBLASTINE; INHIBITION; GROWTH; THROMBOSPONDIN-1; ETOPOSIDE AB BackgroundPreclinical models show that an antiangiogenic regimen at low-dose daily (metronomic) dosing may be effective against chemotherapy-resistant tumors. We undertook a prospective, open-label, single-arm, multi-institutional phase II study to evaluate the efficacy of a 5-drug oral regimen in children with recurrent or progressive cancer. ProcedurePatients 21 years old with recurrent or progressive tumors were eligible. Treatment consisted of continuous oral celecoxib, thalidomide, and fenofibrate, with alternating 21-day cycles of low-dose cyclophosphamide and etoposide. Primary endpoint was to assess, within eight disease strata, activity of the 5-drug regimen over 27 weeks. Blood and urine angiogenesis markers were assessed. ResultsOne hundred one patients were enrolled; 97 began treatment. Median age was 10 years (range: 191 days-21 years); 47 (49%) were female. Disease strata included high-grade glioma (HGG, 21 patients), ependymoma (19), low-grade glioma (LGG, 12), bone tumors (12), medulloblastoma/primitive neuroectodermal tumor (PNET, 8), leukemia (4), neuroblastoma (3), and miscellaneous tumors (18). Treatment was generally well tolerated; most common toxicities were hematologic. Twenty-four (25%) patients completed 27 weeks therapy without progression, including HGG: 1 (5%), ependymoma: 7 (37%), LGG: 7 (58%), medulloblastoma/PNET: 1, neuroblastoma: 1, and miscellaneous tumors: 7 (39%). Best response was complete response (one patient with medulloblastoma), partial response (12), stable disease (36), progressive disease (47), and inevaluable (1). Baseline serum thrombospondin levels were significantly higher in patients successfully completing therapy than in those who progressed (P=0.009). ConclusionThe 5-drug regimen was well tolerated. Clinical activity was demonstrated in some but not all tumor strata. Pediatric Blood Cancer 2014;61:636-642. (c) 2013 The Authors Pediatric Blood & Cancer Published by Wiley Periodicals, Inc. C1 [Robison, Nathan J.; Chi, Susan N.; Manley, Peter E.; Turner, Christopher D.; Zimmerman, Mary Ann; Chordas, Christine A.; Werger, Annette M.; Pietrantonio, Jay B.; Kondrat, Laura; Hubbs, Shannon M.; Kieran, Mark W.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Robison, Nathan J.; Chi, Susan N.; Manley, Peter E.; Turner, Christopher D.; Zimmerman, Mary Ann; Chordas, Christine A.; Werger, Annette M.; Pietrantonio, Jay B.; Kondrat, Laura; Hubbs, Shannon M.; Kieran, Mark W.] Boston Childrens Hosp, Div Pediat Hematol Oncol, Dept Pediat, Boston, MA USA. [Campigotto, Federico; Neuberg, Donna S.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Allen, Jeffrey C.] NYU, Langone Med Ctr, New York, NY USA. [Goldman, Stewart] Northwestern Univ, Feinberg Sch Med, Lurie Childrens Hosp, Chicago, IL 60611 USA. [Rubin, Joshua B.] Washington Univ, St Louis Childrens Hosp, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Isakoff, Michael S.] Connecticut Childrens Med Ctr, Div Hematol Oncol, Hartford, CT USA. [Pan, Wilbur J.] UMDNJ Robert Wood Johnson Med Sch, New Brunswick, NJ USA. [Khatib, Ziad A.] Florida Int Univ, Dept Pediat, Miami Childrens Hosp, Miami, FL 33199 USA. [Comito, Melanie A.] Penn State Hershey Childrens Hosp, Hershey, PA USA. [Bendel, Anne E.] Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. [Bendel, Anne E.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Los Angeles, CA 90033 USA. RP Kieran, MW (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Pediat Neurooncol Program, 450 Brookline Ave,SW331, Boston, MA 02215 USA. EM mark_kieran@dfci.harvard.edu OI Kieran, Mark/0000-0003-2184-7692 FU Alex's Lemonade Stand Foundation for Childhood Cancer; Stop & Shop Pediatric Brain Tumor Research Fund; Celgene Pharmaceutical Corporation FX Grant sponsor: Alex's Lemonade Stand Foundation for Childhood Cancer; Grant sponsor: Stop & Shop Pediatric Brain Tumor Research Fund; Grant sponsor: Pediatric Brain Tumor Research and Clinical Fund Support for data management was provided by Celgene Pharmaceutical Corporation NR 31 TC 26 Z9 26 U1 0 U2 30 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD APR PY 2014 VL 61 IS 4 BP 636 EP 642 DI 10.1002/pbc.24794 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 303OL UT WOS:000330683700010 PM 24123865 ER PT J AU Borinstein, SC Barkauskas, DA Bernstein, M Goorin, A Gorlick, R Krailo, M Schwartz, CL Wexler, LH Toretsky, JA AF Borinstein, Scott C. Barkauskas, Donald A. Bernstein, Mark Goorin, Allen Gorlick, Richard Krailo, Mark Schwartz, Cindy L. Wexler, Leonard H. Toretsky, Jeffrey A. TI Analysis of Serum Insulin Growth Factor-1 Concentrations in Localized Osteosarcoma: A Children's Oncology Group Study SO PEDIATRIC BLOOD & CANCER LA English DT Article DE cancer biology; clinical trials; osteosarcoma ID METASTATIC OSTEOSARCOMA; EWING SARCOMA; CELL-LINES; IGF-I; RECEPTOR; EXPRESSION; MALIGNANCIES; PATHWAY; CANCER AB To investigate the role of insulin-like growth factor-1 (IGF-1), in localized osteosarcoma, serum levels of IGF-1, IGFBP-2, and IGFBP-3 were measured in 224 similarly treated, newly diagnosed patients. We demonstrated that younger patients had lower concentrations of IGF-1 and IGFBP-3 compared to older (P<0.001) along with lower IGFBP-3:IGF-1 and IGFBP-2:IGF-1 ratios (P<0.001). IGFBP-2 did not correlate with age (P=0.16), yet IGFBP-2:IGF-1 ratios were higher in the younger population (P<0.001). These findings show that older patients have higher concentrations of free IGF-1. None of IGF-1, IGFBP-2, nor IGFBP-3 concentrations were associated with event-free nor overall survival. Pediatr Blood Cancer 2014;61:749-752. (c) 2013 Wiley Periodicals, Inc. C1 [Borinstein, Scott C.] Vanderbilt Univ, Dept Pediat, Div Pediat Hematol Oncol, Nashville, TN 37232 USA. [Barkauskas, Donald A.; Krailo, Mark] Childrens Oncol Grp, Monrovia, CA USA. [Barkauskas, Donald A.; Krailo, Mark] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Bernstein, Mark] Dalhousie Univ, Dept Pediat, Div Hematol Oncol, IWK Hlth Ctr, Halifax, NS, Canada. [Goorin, Allen] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. [Gorlick, Richard] Childrens Hosp Montefiore, Dept Pediat, Div Pediat Hematol Oncol, Bronx, NY USA. [Schwartz, Cindy L.] Brown Univ, Dept Pediat, Div Pediat Hematol Oncol, Providence, RI 02912 USA. [Wexler, Leonard H.] Cornell Univ, Dept Pediat, Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Toretsky, Jeffrey A.] Georgetown Univ, Dept Oncol, Washington, DC USA. [Toretsky, Jeffrey A.] Georgetown Univ, Dept Pediat, Washington, DC 20057 USA. RP Borinstein, SC (reprint author), Vanderbilt Univ, Dept Pediat, Div Pediat Hematol Oncol, 390 PRB,2200 Pierce Ave, Nashville, TN 37232 USA. EM scott.c.borinstein@vanderbilt.edu FU Chair's Grant [U10 CA98543]; NCI, NIH, Bethesda, MD, USA [U24 CA114766]; QuadW Foundaton; AFLAC; Children's Cancer Foundation (Baltimore MD); Go4theGoal; Dani's Foundation; Alex's Lemonade Stand Foundation; Liddy Shriver Sarcoma Initiative, Burroughs Wellcome Clinical Scientist Award in Translational Research; NIH [R01CA88004, R01CA133662, R01CA138212, RC4CA156509] FX Grant sponsor: Chair's Grant; Grant number: U10 CA98543; Grant sponsor: NCI, NIH, Bethesda, MD, USA; Grant number: U24 CA114766; Grant sponsor: QuadW Foundaton; Grant sponsor: AFLAC; Grant sponsor: Children's Cancer Foundation (Baltimore MD); Grant sponsor: Go4theGoal; Grant sponsor: Dani's Foundation; Grant sponsor: Alex's Lemonade Stand Foundation; Grant sponsor: Liddy Shriver Sarcoma Initiative, Burroughs Wellcome Clinical Scientist Award in Translational Research; Grant sponsor: NIH; Grant numbers: R01CA88004; R01CA133662; R01CA138212; RC4CA156509 NR 20 TC 3 Z9 5 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD APR PY 2014 VL 61 IS 4 BP 749 EP 752 DI 10.1002/pbc.24778 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 303OL UT WOS:000330683700031 PM 24178953 ER PT J AU Birdsill, AC Koscik, RL Jonaitis, EM Johnson, SC Okonkwo, OC Hermann, BP Larue, A Sager, MA Bendlin, BB AF Birdsill, Alex C. Koscik, Rebecca L. Jonaitis, Erin M. Johnson, Sterling C. Okonkwo, Ozioma C. Hermann, Bruce P. Larue, Asenath Sager, Mark A. Bendlin, Barbara B. TI Regional white matter hyperintensities: aging, Alzheimer's disease risk, and cognitive function SO NEUROBIOLOGY OF AGING LA English DT Article DE White matter hyperintensities; Aging; Processing speed; Cognition; MRI ID EXECUTIVE FUNCTION; EPISODIC MEMORY; OLDER-ADULTS; ROTTERDAM SCAN; LESIONS; MRI; AGE; BRAIN; APOE; HYPERTENSION AB White matter hyperintensities (WMH) of presumed vascular origin, as seen on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging, are known to increase with age and are elevated in Alzheimer's disease (AD). The cognitive implications of these common markers are not well understood. Previous research has primarily focused on global measures of WMH burden and broad localizations that contain multiple white matter tracts. The aims of this study were to determine the pattern of WMH accumulation with age, risk for AD, and the relationship with cognitive function utilizing a voxel-wise analysis capable of identifying specific white matter regions. A total of 349 participants underwent T1-weighted and high-resolution T2-weighted fluid attenuated inversion recovery magnetic resonance imaging and neuropsychological testing. Increasing age and lower cognitive speed and flexibility (a component of executive function), were both significantly associated with regional WMH throughout the brain. When age was controlled, lower cognitive speed and flexibility was independently associated with WMH in the superior corona radiata. Apolipoprotein E epsilon 4 and parental family history of AD were not associated with higher burden of WMH. The results contribute to a larger body of literature suggesting that white matter measures are linked with processing speed, and illustrate the utility of voxel-wise analysis in understanding the effect of lesion location on cognitive function. (C) 2014 Elsevier Inc. All rights reserved. C1 [Birdsill, Alex C.; Johnson, Sterling C.; Okonkwo, Ozioma C.; Bendlin, Barbara B.] William S Middleton Mem Vet Adm Med Ctr, GRECC, Madison, WI USA. [Birdsill, Alex C.; Johnson, Sterling C.; Okonkwo, Ozioma C.; Sager, Mark A.; Bendlin, Barbara B.] Univ Wisconsin, Wisconsin Alzheimers Dis Res Ctr, Dept Med, Madison, WI 53792 USA. [Koscik, Rebecca L.; Jonaitis, Erin M.; Hermann, Bruce P.; Larue, Asenath; Sager, Mark A.] Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Alzheimers Inst, Madison, WI 53792 USA. RP Bendlin, BB (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Ctr Clin Sci J5 1M, 600 Highland Ave, Madison, WI 53792 USA. EM bbb@medicine.wisc.edu OI Bendlin, Barbara/0000-0002-0580-9875 FU Alzheimer's Association [NIRG-09-132626]; National Institute on Aging [R01 AG027161, ADRC P50 AG033514, R01 AG021155, R01 AG037639]; Veteran's Administration Merit Review award [I01CX000165] FX This project was supported by the Alzheimer's Association, NIRG-09-132626, the National Institute on Aging (R01 AG027161 [MAS], ADRC P50 AG033514 [SA], R01 AG021155 [SCJ], R01 AG037639 [BBB]), and by the Veteran's Administration Merit Review award I01CX000165. The project was also facilitated by the facilities and resources at the Geriatric Research, Education, and Clinical Center (GRECC) of the William S. Middleton Memorial Veterans Hospital, Madison, WI, USA. GRECC MS # 2013-03. The authors gratefully acknowledge Nancy Davenport-Sis, Amy Hawley, Jennifer Bond, Caitlin Cleary, Jennifer Oh, Chuck Illingworth, and the support of researchers and staff at the Waisman Center, University of Wisconsin-Madison, for their assistance in recruitment, data collection, and data analysis. Above all, the authors wish to thank our dedicated volunteers for their participation in this research. NR 61 TC 17 Z9 17 U1 1 U2 39 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD APR PY 2014 VL 35 IS 4 BP 769 EP 776 DI 10.1016/j.neurobiolaging.2013.10.072 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 297VN UT WOS:000330283300007 PM 24199958 ER PT J AU Ghosh, SK Yigit, MV Uchida, M Ross, AW Barteneva, N Moore, A Medarova, Z AF Ghosh, Subrata K. Yigit, Mehmet V. Uchida, Masashi Ross, Alana W. Barteneva, Natalie Moore, Anna Medarova, Zdravka TI Sequence-dependent combination therapy with doxorubicin and a survivin-specific small interfering RNA nanodrug demonstrates efficacy in models of adenocarcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE small interfering RNA; nanodrug; breast cancer; pancreatic cancer; doxorubicin ID BREAST-CANCER CELLS; IN-VIVO; TUMOR RESPONSE; APOPTOSIS; EXPRESSION; DELIVERY; SIRNA; RESISTANCE; STRATEGY; AGENTS AB The clinical management of cancer reflects a balance between treatment efficacy and toxicity. While typically, combination therapy improves response rate and time to progression compared with sequential monotherapy, it causes increased toxicity. Consequently, in cases of advanced cancer, emerging guidelines recommend sequential monotherapy, as a means to enhance quality of life. An alternative approach that could overcome nonspecific toxicity while retaining therapeutic efficacy, involves the combination of chemotherapy with targeted therapy. In the current study, we tested the hypothesis that combination therapy targeting survivin (BIRC5) and low-dose doxorubicin (Dox) will show enhanced therapeutic potential in the treatment of cancer, as compared to monotherapy with Dox. We demonstrate in both in vitro and in vivo models of breast cancer that combination therapy with a low dose of Dox and an anti-survivin siRNA nanodrug (MN-siBIRC5) is superior to mono-therapy with either low- or high-dose Dox alone. Importantly, therapeutic efficacy showed prominent sequence dependence. Induction of apoptosis was observed only when the cells were treated with Dox followed by MN-siBIRC5, whereas the reverse sequence abrogated the benefit of the drug combination. In vivo, confirmation of successful sequence dependent combination therapy was demonstrated in a murine xenograft model of breast cancer. Finally, to determine if the observed effect is not limited to breast cancer, we extended our studies to a murine xenograft model of pancreatic adenocarcinoma and found similar outcomes as shown for breast cancer. What's new? Standard combination chemotherapy can overcome drug resistance and delay cancer progression, but it is also more toxic than the use of single drugs alone. This study suggests, however, that combination therapy involving a chemotherapeutic agent and molecularly targeted therapy may have the ability to both retain therapeutic efficacy and preserve quality of life. In vitro and in vivo experiments reveal that sequence-dependent therapy with low-dose doxorubicin and an anti-survivin siRNA nanodrug can have profound effects on primary tumor growth and circumvent the issues of toxicity and morbidity associated with standard chemotherapy. C1 [Ghosh, Subrata K.; Yigit, Mehmet V.; Uchida, Masashi; Ross, Alana W.; Moore, Anna; Medarova, Zdravka] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Mol Imaging Lab, MGH HST Athinoula A Martinos Ctr Biomed Imaging,D, Boston, MA USA. RP Medarova, Z (reprint author), Massachusetts Gen Hosp, Dept Radiol, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Rm 1-424,Bldg 75,13th St, Charlestown, MA 02129 USA. EM zmedarova@partners.org FU National Cancer Institute [R00CA129070, R01CA16346101A1]; Breast Cancer Alliance FX Grant sponsor: National Cancer Institute; Grant numbers: R00CA129070, R01CA16346101A1; Grant sponsor: Breast Cancer Alliance NR 28 TC 10 Z9 11 U1 1 U2 54 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 2014 VL 134 IS 7 BP 1758 EP 1766 DI 10.1002/ijc.28499 PG 9 WC Oncology SC Oncology GA 287YW UT WOS:000329579500024 PM 24114765 ER PT J AU Shenoy, ES Paras, ML Noubary, F Walensky, RP Hooper, DC AF Shenoy, Erica S. Paras, Molly L. Noubary, Farzad Walensky, Rochelle P. Hooper, David C. TI Natural history of colonization with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE): a systematic review SO BMC INFECTIOUS DISEASES LA English DT Review DE MRSA; VRE; Colonization; Carrier; Contact precautions ID RANDOMIZED CONTROLLED-TRIAL; CHRONIC-HEMODIALYSIS PATIENTS; POLYMERASE-CHAIN-REACTION; HEALTH-CARE SETTINGS; CONTACT PRECAUTIONS; RISK-FACTORS; ANTIBIOTIC-THERAPY; UNITED-STATES; NOSOCOMIAL TRANSMISSION; INTRANASAL MUPIROCIN AB Background: No published systematic reviews have assessed the natural history of colonization with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE). Time to clearance of colonization has important implications for patient care and infection control policy. Methods: We performed parallel searches in OVID Medline for studies that reported the time to documented clearance of MRSA and VRE colonization in the absence of treatment, published between January 1990 and July 2012. Results: For MRSA, we screened 982 articles, identified 16 eligible studies (13 observational studies and 3 randomized controlled trials), for a total of 1,804 non-duplicated subjects. For VRE, we screened 284 articles, identified 13 eligible studies (12 observational studies and 1 randomized controlled trial), for a total of 1,936 non-duplicated subjects. Studies reported varying definitions of clearance of colonization; no study reported time of initial colonization. Studies varied in the frequency of sampling, assays used for sampling, and follow-up period. The median duration of total follow-up was 38 weeks for MRSA and 25 weeks for VRE. Based on pooled analyses, the model-estimated median time to clearance was 88 weeks after documented colonization for MRSA-colonized patients and 26 weeks for VRE-colonized patients. In a secondary analysis, clearance rates for MRSA and VRE were compared by restricting the duration of follow-up for the MRSA studies to the maximum observed time point for VRE studies (43 weeks). With this restriction, the model-fitted median time to documented clearance for MRSA would occur at 41 weeks after documented colonization, demonstrating the sensitivity of the pooled estimate to length of study follow-up. Conclusions: Few available studies report the natural history of MRSA and VRE colonization. Lack of a consistent definition of clearance, uncertainty regarding the time of initial colonization, variation in frequency of sampling for persistent colonization, assays employed and variation in duration of follow-up are limitations of the existing published literature. The heterogeneity of study characteristics limits interpretation of pooled estimates of time to clearance, however, studies included in this review suggest an increase in documented clearance over time, a result which is sensitive to duration of follow-up. C1 [Shenoy, Erica S.] Massachusetts Gen Hosp, Div Infect Dis, Infect Control Unit, Boston, MA 02114 USA. [Shenoy, Erica S.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Shenoy, Erica S.; Paras, Molly L.; Walensky, Rochelle P.; Hooper, David C.] Harvard Univ, Sch Med, Boston, MA USA. [Paras, Molly L.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Noubary, Farzad] Tufts Clin & Translat Sci Inst, Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. [Noubary, Farzad] Tufts Univ, Boston, MA 02111 USA. [Walensky, Rochelle P.] Massachusetts Gen & Brigham & Womens Hosp, Div Infect Dis, Boston, MA USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Hooper, David C.] Massachusetts Gen Hosp, Infect Control Unit, Div Infect Dis, Boston, MA 02114 USA. RP Shenoy, ES (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Infect Control Unit, Boston, MA 02114 USA. EM eshenoy@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X FU The Institute for Health Technology Studies; NIH [T32 A107061]; MGH Clinical Innovation Award; CFAR [NIH P30 AI060354]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Research Resources, National Institutes of Health) [8UL1TR000170-05, 1 UL1 RR02578]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [8UL1TR000170-05, 1 UL1 RR02578] FX Support for this work provided by: The Institute for Health Technology Studies; NIH T32 A107061; 2010 MGH Clinical Innovation Award; Departmental Funds; CFAR (NIH P30 AI060354) and the Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Awards 8UL1TR000170-05 and 1 UL1 RR02578). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 15 Z9 17 U1 4 U2 24 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD MAR 31 PY 2014 VL 14 AR 177 DI 10.1186/1471-2334-14-177 PG 13 WC Infectious Diseases SC Infectious Diseases GA AG5PD UT WOS:000335470000003 PM 24678646 ER PT J AU Tache, Y AF Tache, Yvette TI HANS SELYE AND THE STRESS RESPONSE: FROM "THE FIRST MEDIATOR" TO THE IDENTIFICATION OF THE HYPOTHALAMIC CORTICOTROPIN-RELEASING FACTOR SO IDEGGYOGYASZATI SZEMLE-CLINICAL NEUROSCIENCE LA English DT Article DE corticotropin releasing factor; hypothalamus; Selye; stress ID RECEPTORS; CRF AB Selye pioneered the stress concept that is ingrained in the vocabulary of daily life. This was originally build on experimental observations that divers noxious agents can trigger a similar triad of endocrine (adrenal enlargement), immune (involution of thymus) and gut (gastric erosion formation) responses as reported in a letter to Nature in 1936. Subsequently, he articulated the underlying mechanisms and hypothesized the existence of a "first mediator" in the hypothalamus able to orchestrate this bodily changes. However he took two generations to identify this mediator. The Nobel Laureate, Roger Guillemin, alpha former Selye's PhD student, demonstrated in 1955 the existence of a hypothalamic factor that elicited adrenocorticotropic hormone release from the rat pituitary and named it corticotropin releasing factor (CRF). In 1981, Wylie Vale, a former Guillemin's Ph Student, characterized CRF as 41 amino acid and cloned the CRF1 and CRF2 receptors. This paves the way to experimental studies establishing that the activation of the CRF signaling pathways in the brain plays a key role in mediating the stress-related endocrine, behavioral, autonomic and visceral responses. The unraveling of the biochemical coding of stress is rooted in Selye legacy continues to have increasing impact on the scientific community. C1 [Tache, Yvette] Univ Calif Los Angeles, Dept Med, CURE Digest Dis Res Ctr, Ctr Neurobiol Stress,Digest Dis Div, Los Angeles, CA 90024 USA. [Tache, Yvette] VA Greater Angeles Healthcare Syst, Los Angeles, CA USA. RP Tache, Y (reprint author), Univ Calif Los Angeles, Dept Med, CURE Digest Dis Res Ctr, Ctr Neurobiol Stress,Digest Dis Div, Los Angeles, CA 90024 USA. EM yvette.tache@va.gov NR 13 TC 0 Z9 0 U1 4 U2 8 PU LITERATURA MEDICA PI BUDAPEST PA MARGIT KRT 31-33, BUDAPEST, 1024, HUNGARY SN 0019-1442 J9 IDEGGYOGY SZEMLE JI Ideggyogy. Szle. PD MAR 30 PY 2014 VL 67 IS 3-4 BP 95 EP 98 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AX1BU UT WOS:000346684200007 PM 26118248 ER PT J AU Black, AC McMahon, TJ Rosenheck, RA Ball, SA Ries, RK Ames, D Rosen, MI AF Black, Anne C. McMahon, Thomas J. Rosenheck, Robert A. Ball, Samuel A. Ries, Richard K. Ames, Donna Rosen, Marc I. TI Development of the Clinician Assessment of Financial Incapability (CAFI) SO PSYCHIATRY RESEARCH LA English DT Article DE Assessment; Financial capability; Representative payee; Social Security; Psychiatric; Income ID REPRESENTATIVE PAYEE PROGRAM; SEVERE MENTAL-ILLNESS; SUBSTANCE USE DISORDERS; MONEY MANAGEMENT; BENEFICIARIES; ADDICTION; LEVERAGE; THERAPY; CLIENTS; ADULTS AB The Social Security Administration (SSA) provides financial support to adults disabled by psychiatric conditions to provide for their basic needs. For beneficiaries identified as incapable of managing their funds, representative payee assignment is mandated: However, studies indicate that the current SSA method of determining capability leads to idiosyncratic payee assignment, with a tendency to under-identify beneficiaries needing payees. Over two phases with data from 78 mental health clinicians treating 134 patient-beneficiaries, we describe the development of a new assessment, the Clinician Assessment of Financial Incapability (CAFI). Item generation, subscale construction, and preliminary assessments of validity are described. We also describe the simultaneous development of a criterion measure of capability, a comprehensive review of all data. Experts identified four subscales mapping to four criteria of incapability; factor analysis provided support for this item structure. Close to one-half of patients were determined to be incapable by review of all data. CAFI and SSA methods correctly classified 73% of cases, but errors with CAFI were more evenly distributed between false negatives and false positives. The implications of classification error are considered, and advantages of CAFI over the SSA method are enumerated. Plans for future instrument revision are briefly described. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Black, Anne C.; McMahon, Thomas J.; Rosenheck, Robert A.; Ball, Samuel A.; Rosen, Marc I.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Black, Anne C.; Rosen, Marc I.] VA Connecticut Healthcare Syst, West Haven, CT 06516 USA. [Ries, Richard K.] Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. [Ames, Donna] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Ames, Donna] Greater Los Angeles VA Healthcare Syst, Los Angeles, CA USA. RP Black, AC (reprint author), VA Connecticut Healthcare Syst, 950 Campbell Ave 116A-4, West Haven, CT 06516 USA. EM anne.black@yale.edu FU National Institute on Drug Abuse [R01 DA025613] FX This study was funded by the National Institute on Drug Abuse R01 DA025613 (MIR). NR 30 TC 4 Z9 4 U1 3 U2 12 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 2014 VL 215 IS 3 BP 784 EP 789 DI 10.1016/j.psychres.2014.01.021 PG 6 WC Psychiatry SC Psychiatry GA AE2AU UT WOS:000333776500045 PM 24495575 ER PT J AU Noel, PH Parchman, ML Palmer, RF Romero, RL Leykum, LK Lanham, HJ Zeber, JE Bowers, KW AF Noel, Polly H. Parchman, Michael L. Palmer, Ray F. Romero, Raquel L. Leykum, Luci K. Lanham, Holly J. Zeber, John E. Bowers, Krista W. TI Alignment of patient and primary care practice member perspectives of chronic illness care: a cross-sectional analysis SO BMC FAMILY PRACTICE LA English DT Article DE Chronic care; Primary care; Patient surveys ID PREVENTIVE SERVICE DELIVERY; SELF-MANAGEMENT; UNDERSTANDING PRACTICE; RANDOMIZED-TRIAL; CLINICAL-TRIAL; QUALITY; MODEL; OUTCOMES; SATISFACTION; BEHAVIORS AB Background: Little is known as to whether primary care teams' perceptions of how well they have implemented the Chronic Care Model (CCM) corresponds with their patients' own experience of chronic illness care. We examined the extent to which practice members' perceptions of how well they organized to deliver care consistent with the CCM were associated with their patients' perceptions of the chronic illness care they have received. Methods: Analysis of baseline measures from a cluster randomized controlled trial testing a practice facilitation intervention to implement the CCM in small, community-based primary care practices. All practice "members" (i.e., physician providers, non-physician providers, and staff) completed the Assessment of Chronic Illness Care(ACIC) survey and adult patients with 1 or more chronic illnesses completed the Patient Assessment of Chronic Illness Care (PACIC) questionnaire. Results: Two sets of hierarchical linear regression models accounting for nesting of practice members (N = 283) and patients (N = 1,769) within 39 practices assessed the association between practice member perspectives of CCM implementation (ACIC scores) and patients' perspectives of CCM (PACIC). ACIC summary score was not significantly associated with PACIC summary score or most of PACIC subscale scores, but four of the ACIC subscales [Self- management Support (p < 0.05); Community Linkages (p < 0.02), Delivery System Design (p < 0.02), and Organizational Support (p < 0.02)] were consistently associated with PACIC summary score and the majority of PACIC subscale scores after controlling for patient characteristics. The magnitude of the coefficients, however, indicates that the level of association is weak. Conclusions: The ACIC and PACIC scales appear to provide complementary and relatively unique assessments of how well clinical services are aligned with the CCM. Our findings underscore the importance of assessing both patient and practice member perspectives when evaluating quality of chronic illness care. Trial registration: NCT00482768 C1 [Noel, Polly H.; Leykum, Luci K.] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Noel, Polly H.; Palmer, Ray F.; Romero, Raquel L.; Leykum, Luci K.; Lanham, Holly J.; Bowers, Krista W.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Parchman, Michael L.] MacColl Ctr Healthcare Innovat, Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA. [Lanham, Holly J.] Univ Texas Austin, McCombs Sch Business, Austin, TX 78712 USA. [Zeber, John E.] Cent Texas Vet Hlth Care Syst, Temple, TX 76504 USA. [Zeber, John E.] Scott & White Healthcare Ctr Appl Hlth Res, Temple, TX 76508 USA. RP Noel, PH (reprint author), South Texas Vet Hlth Care Syst, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM noelp@uthscsa.edu OI Parchman, Michael/0000-0001-7129-2889 FU National Institute of Health (NIDDK) [R18DK075692]; Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service; South Texas Veterans Health Care System FX The research reported here was supported by the National Institute of Health (NIDDK Grant R18DK075692) and the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service. Investigator salary support was also provided through the South Texas Veterans Health Care System. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. The study team would like to acknowledge technical assistance from Poomachand Veerapaneni, Janet Hendricks, and Paul Hartman, and the assistance of Amr Mazen Arar, Brendan Nadeau, and Alan B. Romero in collecting patient surveys, as well as the primary care practices and their anonymous patients who participated in the project. We would also like to posthumously acknowledge the overall contributions of Dr. Nedal H. Arar, who was an integral member of the study team. NR 39 TC 5 Z9 5 U1 1 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2296 J9 BMC FAM PRACT JI BMC Fam. Pract. PD MAR 29 PY 2014 VL 15 AR 57 DI 10.1186/1471-2296-15-57 PG 8 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA AF4TJ UT WOS:000334706700001 PM 24678983 ER PT J AU Jehle, K Cato, L Neeb, A Muhle-Goll, C Jung, N Smith, EW Buzon, V Carbo, LR Estebanez-Perpina, E Schmitz, K Fruk, L Luy, B Chen, Y Cox, MB Brase, S Brown, M Cato, ACB AF Jehle, Katja Cato, Laura Neeb, Antje Muhle-Goll, Claudia Jung, Nicole Smith, Emmanuel W. Buzon, Victor Carbo, Laia R. Estebanez-Perpina, Eva Schmitz, Katja Fruk, Ljiljana Luy, Burkhard Chen, Yu Cox, Marc B. Braese, Stefan Brown, Myles Cato, Andrew C. B. TI Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-binding Motif SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Androgen Receptor; Chromatin Immunoprecipitation (ChiP); Gene Expression; Ligand-binding Protein; Prostate Cancer; Activation Function-2 (AF-2); Androgen Receptor Ligand-binding Domain (AR-LBD); Bag-1L; Binding Function-3 (BF-3); Nuclear Receptors ID RESISTANT PROSTATE-CANCER; HEAT-SHOCK-PROTEIN; VITAMIN-D-RECEPTOR; LIGAND-BINDING; TRANSACTIVATION FUNCTION; COACTIVATOR INTERACTIONS; GLUCOCORTICOID-RECEPTOR; NUCLEOTIDE EXCHANGE; GENE-EXPRESSION; IN-VIVO AB Background: The interaction surface of coactivators and the androgen receptor (AR) is an important target for prostate cancer therapeutics. Results: A new interface formed by binding of the sequence (GARRPR) and the allosteric pocket (BF-3) of the AR has been identified. Conclusion: GARRPR binding modulates AR activity. Significance: The GARRPR/BF-3 interaction is a novel regulatory hub for AR activity. The androgen receptor (AR) is a ligand-activated transcription factor that is essential for prostate cancer development. It is activated by androgens through its ligand-binding domain (LBD), which consists predominantly of 11 -helices. Upon ligand binding, the last helix is reorganized to an agonist conformation termed activator function-2 (AF-2) for coactivator binding. Several coactivators bind to the AF-2 pocket through conserved LXXLL or FXXLF sequences to enhance the activity of the receptor. Recently, a small compound-binding surface adjacent to AF-2 has been identified as an allosteric modulator of the AF-2 activity and is termed binding function-3 (BF-3). However, the role of BF-3 in vivo is currently unknown, and little is understood about what proteins can bind to it. Here we demonstrate that a duplicated GARRPR motif at the N terminus of the cochaperone Bag-1L functions through the BF-3 pocket. These findings are supported by the fact that a selective BF-3 inhibitor or mutations within the BF-3 pocket abolish the interaction between the GARRPR motif(s) and the BF-3. Conversely, amino acid exchanges in the two GARRPR motifs of Bag-1L can impair the interaction between Bag-1L and AR without altering the ability of Bag-1L to bind to chromatin. Furthermore, the mutant Bag-1L increases androgen-dependent activation of a subset of AR targets in a genome-wide transcriptome analysis, demonstrating a repressive function of the GARRPR/BF-3 interaction. We have therefore identified GARRPR as a novel BF-3 regulatory sequence important for fine-tuning the activity of the AR. C1 [Jehle, Katja; Neeb, Antje; Braese, Stefan; Cato, Andrew C. B.] Karlsruhe Inst Technol, Inst Toxicol & Genet, D-76344 Eggenstein Leopoldshafen, Germany. [Cato, Laura; Brown, Myles] Harvard Univ, Sch Med, Div Mol & Cellular Oncol, Dept Med Oncol, Boston, MA 02215 USA. [Cato, Laura; Brown, Myles] Harvard Univ, Sch Med, Ctr Funct Canc Epigenet, Dana Farber Canc Inst, Boston, MA 02215 USA. [Muhle-Goll, Claudia; Jung, Nicole; Luy, Burkhard; Braese, Stefan] Karlsruhe Inst Technol, Inst Organ Chem, D-76131 Karlsruhe, Germany. [Smith, Emmanuel W.; Chen, Yu] Univ S Florida, Coll Med, Dept Mol Med, Tampa, FL 33612 USA. [Buzon, Victor; Carbo, Laia R.; Estebanez-Perpina, Eva] Univ Barcelona, Inst Biomed, Dept Biochem & Mol Biol, Barcelona 08028, Spain. [Schmitz, Katja] Tech Univ Darmstadt, Clemens Schopf Inst Organ Chem & Biochem, D-64287 Darmstadt, Germany. [Fruk, Ljiljana] Karlsruhe Inst Technol, Deutsch Forschungsgemeinschaft Ctr Nanostruct, D-76131 Karlsruhe, Germany. [Cox, Marc B.] Univ Texas El Paso, Border Biomed Res Ctr, El Paso, TX 79968 USA. [Cox, Marc B.] Univ Texas El Paso, Dept Biol Sci, El Paso, TX 79968 USA. RP Cato, ACB (reprint author), Karlsruhe Inst Technol, Inst Toxicol & Genet, D-76344 Eggenstein Leopoldshafen, Germany. EM andrew.cato@kit.edu RI Braese, Stefan/B-9057-2008; Cato, Andrew/H-2071-2013; Schmitz, Katja/B-9342-2008; OI Braese, Stefan/0000-0003-4845-3191; Cato, Andrew/0000-0001-8508-3834; Schmitz, Katja/0000-0001-9023-318X; Fruk, Ljiljana/0000-0003-2104-5817; Brown, Myles/0000-0002-8213-1658 FU National Institutes of Health from the National Center for Research Resources [5 G12 RR008124]; National Institutes of Health from the National Institute on Minority Health and Health Disparities [8 G12 MD007592]; National Institutes of Health [1P01CA163227-01A1, P50CA090381]; KIT start-up funds; Deutsche Krebshilfe [110237]; Cancer Prevention and Research Institute of Texas [RP110444-P2] FX This work was supported, in whole or in part, by National Institutes of Health Grants 5 G12 RR008124 (from the National Center for Research Resources) and 8 G12 MD007592 (from the National Institute on Minority Health and Health Disparities) (to M. B. C.) and 1P01CA163227-01A1 (Androgen Receptor Action in Castration Resistant Prostate Cancer) and P50CA090381 (Prostate Cancer SPORE) (to M. B.). This work was also supported by grants from the KIT start-up funds and Deutsche Krebshilfe Grant 110237 (to A. C. B. C.) and Cancer Prevention and Research Institute of Texas Grant RP110444-P2 (to M. B. C.). NR 71 TC 18 Z9 18 U1 1 U2 15 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 28 PY 2014 VL 289 IS 13 BP 8839 EP 8851 DI 10.1074/jbc.M113.534859 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AD7UJ UT WOS:000333472100010 PM 24523409 ER PT J AU Baek, JI Choi, SY Chacon-Heszele, MF Zuo, XF Lipschutz, JH AF Baek, Jeong-In Choi, Soo Young Chacon-Heszele, Maria F. Zuo, Xiaofeng Lipschutz, Joshua H. TI Expression of Drosophila forkhead transcription factors during kidney development SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Drosophila forkhead; Transcription factor; Nephrogenesis ID DISRUPTION; FAMILY; BF-2 AB The Drosophila forkhead (Dfkh) family of transcription factors has over 40 family members. One Dfkh family member, BF2 (aka FoxD1), has been shown, by targeted disruption, to be essential for kidney development. In order to determine if other Dfkh family members were involved in kidney development and to search for new members of this family, reverse transcriptase polymerase chain reaction (RT-PCR) was performed using degenerate primers of the consensus sequence of the DNA binding domain of this family and developing rat kidney RNA. The RT-PCR product was used to probe RNA from a developing rat kidney (neonatal), from a 20-day old kidney, and from an adult kidney. The RT-PCR product hybridized only to a developing kidney RNA transcript of similar to 2.3 kb (the size of BF2). A lambda gt10 mouse neonatal kidney library was then screened, using the above-described RT-PCR product as a probe. Three lambda phage clones were isolated that strongly hybridized to the RT-PCR probe. Sequencing of the RT-PCR product and the lambda phage clones isolated from the developing kidney library revealed Dfkh BF2. In summary, only MI6 family member BF2, which has already been shown to be essential for nephrogenesis, was identified in our screen and no other candidate Dfkh family members were identified. Published by Elsevier Inc. C1 [Baek, Jeong-In; Choi, Soo Young; Chacon-Heszele, Maria F.; Zuo, Xiaofeng; Lipschutz, Joshua H.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Baek, Jeong-In; Choi, Soo Young; Chacon-Heszele, Maria F.; Zuo, Xiaofeng; Lipschutz, Joshua H.] VAMC, Philadelphia, PA 19104 USA. [Lipschutz, Joshua H.] Philadelphia Vet Affairs Med Ctr, Dept Med, Philadelphia, PA 19104 USA. RP Lipschutz, JH (reprint author), Room 405C,Clin Res Bldg,415 Curie Blvd, Philadelphia, PA 19104 USA. EM jhlipsch@mail.med.upenn.edu FU Veteran Affairs; NIH [RO1 DK069909, DK047757]; NephHope Foundation FX This work was supported in part by the Veteran Affairs (Merit Award to J.H.L.), the NIH (RO1 DK069909 and DK047757 to J.H.L.), and the NephHope Foundation (Fellowship award to M.F.C.H.). NR 7 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 28 PY 2014 VL 446 IS 1 BP 15 EP 17 DI 10.1016/j.bbrc.2014.01.135 PG 3 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AF4AX UT WOS:000334654900003 PM 24491558 ER PT J AU Tjokro, NO Rocco, CJ Priyadarshini, R Davey, ME Goodman, SD AF Tjokro, Natalia O. Rocco, Christopher J. Priyadarshini, Richa Davey, Mary E. Goodman, Steven D. TI A Biochemical Analysis of the Interaction of Porphyromonas gingivalis HU PG0121 Protein with DNA SO PLOS ONE LA English DT Article ID 6 CAPSULAR SEROTYPES; ESCHERICHIA-COLI HU; BINDING PROTEIN; CRUCIFORM DNA; HIGH-AFFINITY; BACILLUS-SUBTILIS; STRANDED-DNA; TRANSCRIPTION; GENE; BACTERIA AB K-antigen capsule, a key virulence determinant of the oral pathogen Porphyromonas gingivalis, is synthesized by proteins encoded in a series of genes transcribed as a large polycistronic message. Previously, we identified a 77-base pair inverted repeat region with the potential to form a large stem-loop structure at the 5' end of this locus. PG0121, one of two genes flanking the capsule operon, was found to be co-transcribed with the operon and to share high similarity to the DNA binding protein HU from Escherichia coli. A null mutation in PG0121 results in down-regulation of transcription of the capsule synthesis genes and production of capsule. Furthermore, we have also shown that PG0121 gene can complement multiple deficiencies in a strain of E. coli that is deficient for both the alpha and beta subunits of HU. Here, we examined the biochemical properties of the interaction of PG0121 to DNA with the emphasis on the kinds of nucleic acid architectures that may be encountered at the 77-bp inverted repeat. We have concluded that although some DNA binding characteristics are shared with E. coli HU, HU PG0121 also shows some distinct characteristics that set it apart from other HU-like proteins tested to date. We discuss our results in the context of how PG0121 may affect the regulation of the K-antigen capsule expression. C1 [Tjokro, Natalia O.] Univ So Calif, Dept Mol & Computat Biol, Los Angeles, CA USA. [Priyadarshini, Richa; Davey, Mary E.] Forsyth Inst, Dept Mol Genet, Boston, MA USA. [Rocco, Christopher J.; Goodman, Steven D.] Nationwide Childrens Hosp, Ctr Microbial Pathogenesis, Res Inst, Columbus, OH USA. RP Davey, ME (reprint author), Univ Florida, Coll Dent, Dept Oral Biol, Gainesville, FL 32610 USA. EM mdavey@dental.ufl.edu; steven.goodman@nationwidechildrens.org RI Goodman, Steven/C-5732-2013 FU National Institutes of Health [5R01DE019117-06] FX This work was supported by National Institutes of Health grant 5R01DE019117-06 (NIH; www.nih.gov) to MED and SDG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 4 Z9 4 U1 2 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 28 PY 2014 VL 9 IS 3 AR e93266 DI 10.1371/journal.pone.0093266 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE0TC UT WOS:000333678100037 PM 24681691 ER PT J AU Lee, S Vinegoni, C Sebas, M Weissleder, R AF Lee, Sungon Vinegoni, Claudio Sebas, Matthew Weissleder, Ralph TI Automated motion artifact removal for intravital microscopy, without a priori information SO SCIENTIFIC REPORTS LA English DT Article ID VIVO; RESOLUTION; ANIMALS; HEART AB Intravital fluorescence microscopy, through extended penetration depth and imaging resolution, provides the ability to image at cellular and subcellular resolution in live animals, presenting an opportunity for new insights into in vivo biology. Unfortunately, physiological induced motion components due to respiration and cardiac activity are major sources of image artifacts and impose severe limitations on the effective imaging resolution that can be ultimately achieved in vivo. Here we present a novel imaging methodology capable of automatically removing motion artifacts during intravital microscopy imaging of organs and orthotopic tumors. The method is universally applicable to different laser scanning modalities including confocal and multiphoton microscopy, and offers artifact free reconstructions independent of the physiological motion source and imaged organ. The methodology, which is based on raw data acquisition followed by image processing, is here demonstrated for both cardiac and respiratory motion compensation in mice heart, kidney, liver, pancreas and dorsal window chamber. C1 [Lee, Sungon; Vinegoni, Claudio; Sebas, Matthew; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Lee, Sungon; Vinegoni, Claudio; Sebas, Matthew; Weissleder, Ralph] Harvard Univ, Sch Med, Richard B Simches Res Ctr, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Lee, Sungon] Korea Inst Sci & Technol, Interact & Robot Res Ctr, Seoul, South Korea. RP Vinegoni, C (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. EM cvinegoni@mgh.harvard.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services [HHSN268201000044C]; Institute of Biomedical Engineering [R01EB006432]; NIH HHS/United States [P01 CA139980/CA/NCI, 1R01CA164448/CA/NCI]; KIST Institutional Program [2Z04010] FX This project was funded in part by Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (under Contract No. HHSN268201000044C), and from the Institute of Biomedical Engineering (under R01EB006432), P01 CA139980/CA/NCI NIH HHS/United States, 1R01CA164448/CA/NCI NIH HHS/United States and the KIST Institutional Program (Project No. 2Z04010). NR 23 TC 8 Z9 8 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 28 PY 2014 VL 4 AR 4507 DI 10.1038/srep04507 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD8KU UT WOS:000333515700014 PM 24676021 ER PT J AU Hayano, K Fuentes-Orrego, JM Sahani, DV AF Hayano, Koichi Fuentes-Orrego, Jorge M. Sahani, Dushyant V. TI New approaches for precise response evaluation in hepatocellular carcinoma SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Hepatocellular carcinoma; World Health Organization criteria; Response Evaluation Criteria in Solid Tumors; European Association for the Study of Liver; Computed tomography perfusion; Dynamic contrast-enhanced-magnetic resonance imaging; Diffusion-weighted imaging; Positron emission tomography ID POSITRON-EMISSION-TOMOGRAPHY; APPARENT DIFFUSION-COEFFICIENT; TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION; RESONANCE-IMAGING BIOMARKERS; SOLID TUMORS RECIST; CELL LUNG-CANCER; COMPUTED-TOMOGRAPHY; EVALUATION CRITERIA; LIVER-TUMORS; COLORECTAL-CANCER AB With the increasing clinical use of cytostatic and novel biologic targeted agents, conventional morphologic tumor burden assessments, including World Health Organization criteria and Response Evaluation Criteria in Solid Tumors, are confronting limitations because of their difficulties in distinguishing viable tumor from necrotic or fibrotic tissue. Therefore, the investigation for reliable quantitative biomarkers of therapeutic response such as metabolic imaging or functional imaging has been desired. In this review, we will discuss the conventional and new approaches to assess tumor burden. Since targeted therapy or locoregional therapies can induce biological changes much earlier than morphological changes, these functional tumor burden analyses are very promising. However, some of them have not gone thorough all steps for standardization and validation. Nevertheless, these new techniques and criteria will play an important role in the cancer management, and provide each patient more tailored therapy. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved. C1 [Hayano, Koichi; Fuentes-Orrego, Jorge M.; Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. RP Sahani, DV (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, 55 Fruit St,White 270, Boston, MA 02114 USA. EM dsahani@partners.org OI Fuentes-Orrego, Jorge/0000-0002-9254-0746 NR 80 TC 2 Z9 2 U1 1 U2 6 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 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD MAR 28 PY 2014 VL 20 IS 12 BP 3059 EP 3068 DI 10.3748/wjg.v20.i12.3059 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AE0PH UT WOS:000333667700001 PM 24696594 ER PT J AU Bhagwat, N Koppikar, P Keller, M Marubayashi, S Shank, K Rampal, R Qi, J Kleppe, M Patel, HJ Shah, SK Taldone, T Bradner, JE Chiosis, G Levine, RL AF Bhagwat, Neha Koppikar, Priya Keller, Matthew Marubayashi, Sachie Shank, Kaitlyn Rampal, Raajit Qi, Jun Kleppe, Maria Patel, Hardik J. Shah, Smit K. Taldone, Tony Bradner, James E. Chiosis, Gabriela Levine, Ross L. TI Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms SO BLOOD LA English DT Article ID TYROSINE KINASE JAK2; ACTIVATING MUTATION; MYELOID METAPLASIA; POLYCYTHEMIA-VERA; MYELOFIBROSIS; RESISTANCE; INHIBITORS; DISORDERS; JAK2V617F; DOMAIN AB The discovery of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) led to clinical development of Janus kinase (JAK) inhibitors for treatment of MPN. These inhibitors improve constitutional symptoms and splenomegaly but do not significantly reduce mutant allele burden in patients. We recently showed that chronic exposure to JAK inhibitors results in inhibitor persistence via JAK2 transactivation and persistent JAK-signal transducer and activator of transcription signaling. We performed genetic and pharmacologic studies to determine whether improved JAK2 inhibition would show increased efficacy in MPN models and primary samples. Jak2 deletion in vivo led to profound reduction in disease burden not seen with JAK inhibitors, and deletion of Jak2 following chronic ruxolitinib therapy markedly reduced mutant allele burden. This demonstrates that JAK2 remains an essential target in MPN cells that survive in the setting of chronic JAK inhibition. Combination therapy with the heat shock protein 90 (HSP90) inhibitor PU-H71 and ruxolitinib reduced total and phospho-JAK2 and achieved more potent inhibition of downstream signaling than ruxolitinib monotherapy. Combination treatment improved blood counts, spleen weights, and reduced bone marrow fibrosis compared with ruxolitinib alone. These data suggest alternate approaches that increase JAK2 targeting, including combination JAK/HSP90 inhibitor therapy, are warranted in the clinical setting. C1 [Bhagwat, Neha; Koppikar, Priya; Keller, Matthew; Marubayashi, Sachie; Shank, Kaitlyn; Rampal, Raajit; Kleppe, Maria; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Bhagwat, Neha; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Gerstner Sloan Kettering Grad Sch Biomed Sci, New York, NY 10065 USA. [Rampal, Raajit] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Qi, Jun; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Patel, Hardik J.; Shah, Smit K.; Taldone, Tony; Chiosis, Gabriela] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA. [Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY 10065 USA. RP Levine, RL (reprint author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave,Box 20, New York, NY 10065 USA. EM leviner@mskcc.org FU Leukemia & Lymphoma Society Translational Research Program grant; National Cancer Institute at the National Institutes of Health [1R01CA151949-01]; Geoffrey Beene Cancer Research Center; EMBO FX This work was supported by a Leukemia & Lymphoma Society Translational Research Program grant (R. L. L. and G. C.) and by National Cancer Institute at the National Institutes of Health grants 1R01CA151949-01 (R. L. L.). R. L. L. and R. R. are also supported by grants from the Geoffrey Beene Cancer Research Center.; M. Kleppe is a fellow of the Leukemia & Lymphoma Society and was previously supported by an EMBO Postdoctoral Fellowship. R. L. L. is a Leukemia & Lymphoma Society Scholar. NR 22 TC 29 Z9 29 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 27 PY 2014 VL 123 IS 13 BP 2075 EP 2083 DI 10.1182/blood-2014-01-547760 PG 9 WC Hematology SC Hematology GA AH1AP UT WOS:000335852200020 PM 24470592 ER PT J AU Scadden, DT AF Scadden, David T. TI Nice Neighborhood: Emerging Concepts of the Stem Cell Niche SO CELL LA English DT Review ID BONE-MARROW MICROENVIRONMENT; HEMATOPOIETIC STEM; IN-VIVO; PROGENITOR CELLS; ENDOTHELIAL-CELLS; MAINTENANCE; REGENERATION; FATE; ENGRAFTMENT; DROSOPHILA AB No metazoan cell survives on its own, absent the signals and support of its milieu. For multicellular life with specialized tissues to persist, organization is everything and so defining the association of position with cell state is critical to understanding how tissues function, maintain, and repair. This review focuses specifically on place for progenitor and stem cells. Especially emphasized are hematopoietic cells that balance free movement and stable position and where concepts of regulatory interrelationships have been shown with some precision. It reviews classical and emerging concepts of the niche, particularly considering how niche functions may participate in neoplastic disease. C1 [Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Scadden, DT (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. EM david_scadden@harvard.edu FU Gerald and Darlene Jordan Chair; [HL096372]; [CA148180] FX The contributions of Elizabeth Scadden, Jay Rajagopal, Rushdia Yusuf, Vionnie Yu, Borja Saez, and Jonathon Hoggatt are gratefully acknowledged for their thoughtful input, editing, and help with figures. Members of the Scadden lab have been invaluable in shaping this work and being the best partners in discovery a lab chief could ever imagine. There is much outstanding work in the field that is not included in this piece for reasons of space, and I ask the forbearance of my colleagues for omissions of their contributions. This work was funded by: HL096372, CA148180, and the Gerald and Darlene Jordan Chair. NR 70 TC 79 Z9 82 U1 6 U2 40 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 27 PY 2014 VL 157 IS 1 BP 41 EP 50 DI 10.1016/j.cell.2014.02.013 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AE4QW UT WOS:000333968900006 PM 24679525 ER PT J AU Rajabi, H Alam, M Takahashi, H Kharbanda, A Guha, M Ahmad, R Kufe, D AF Rajabi, H. Alam, M. Takahashi, H. Kharbanda, A. Guha, M. Ahmad, R. Kufe, D. TI MUC1-C oncoprotein activates the ZEB1/miR-200c regulatory loop and epithelial-mesenchymal transition SO ONCOGENE LA English DT Article DE MUC1-C; ZEB1; miR-200c; breast cancer; EMT ID BREAST-CANCER CELLS; FACTOR-KAPPA-B; TRANSCRIPTION FACTOR; DOWN-REGULATION; FEEDBACK LOOP; STEM-CELLS; E-CADHERIN; ZEB1; METASTASIS; FAMILY AB The epithelial-mesenchymal transition (EMT) is activated in cancer cells by ZEB1, a member of the zinc finger/homeodomain family of transcriptional repressors. The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed in human carcinoma cells. The present studies in breast cancer cells demonstrate that the oncogenic MUC1-C subunit induces expression of ZEB1 by a NF-kappa B (nuclear factor kappa B) p65-dependent mechanism. MUC1-C occupies the ZEB1 promoter with NF-kappa B p65 and thereby promotes ZEB1 transcription. In turn, ZEB1 associates with MUC1-C and the ZEB1/MUC1-C complex contributes to the transcriptional suppression of miR-200c, an inducer of epithelial differentiation. The co-ordinate upregulation of ZEB1 and suppression of miR-200c has been linked to the induction of EMT. In concert with the effects of MUC1-C on ZEB1 and miR-200c, we show that MUC1-C induces EMT and cellular invasion by a ZEB1-mediated mechanism. These findings indicate that (i) MUC1-C activates ZEB1 and suppresses miR-200c with the induction of EMT and (ii) targeting MUC1-C could be an effective approach for the treatment of breast and possibly other types of cancers that develop EMT properties. C1 [Rajabi, H.; Alam, M.; Takahashi, H.; Kharbanda, A.; Guha, M.; Ahmad, R.; Kufe, D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 450 Brookline Ave,Dana 830, Boston, MA 02215 USA. EM donald_kufe@dfci.harvard.edu FU National Cancer Institute of the National Institutes of Health [CA97098, CA166480] FX Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers CA97098 and CA166480. NR 37 TC 21 Z9 22 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD MAR 27 PY 2014 VL 33 IS 13 BP 1680 EP 1689 DI 10.1038/onc.2013.114 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AE9QY UT WOS:000334344700008 PM 23584475 ER PT J AU Grayson, AR Walsh, EM Cameron, MJ Godec, J Ashworth, T Ambrose, JM Aserlind, AB Wang, H Evan, GI Kluk, MJ Bradner, JE Aster, JC French, CA AF Grayson, A. R. Walsh, E. M. Cameron, M. J. Godec, J. Ashworth, T. Ambrose, J. M. Aserlind, A. B. Wang, H. Evan, G. I. Kluk, M. J. Bradner, J. E. Aster, J. C. French, C. A. TI MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma SO ONCOGENE LA English DT Article DE BRD4; NUT; MYC; epigenetic; differentiation; fusion oncogene ID SQUAMOUS-CELL CARCINOMA; SET ENRICHMENT ANALYSIS; C-MYC; POOR-PROGNOSIS; IN-VIVO; INDUCED APOPTOSIS; BET BROMODOMAINS; STEM-CELLS; GENE; REARRANGEMENT AB NUT midline carcinoma (NMC) is an aggressive type of squamous cell carcinoma that is defined by the presence of BRD-NUT fusion oncogenes, which encode chimeric proteins that block differentiation and maintain tumor growth. BRD-NUT oncoproteins contain two bromodomains whose binding to acetylated histones is required for the blockade of differentiation in NMC, but the mechanisms by which BRD-NUT act remain uncertain. Here, we provide evidence that MYC is a key downstream target of BRD4-NUT. Expression profiling of NMCs shows that the set of genes whose expression is maintained by BRD4-NUT is highly enriched for MYC upregulated genes, and MYC and BRD4-NUT protein expression is strongly correlated in primary NMCs. More directly, we find that BRD4-NUT associates with the MYC promoter and is required to maintain MYC expression in NMC cell lines. Moreover, both siRNA knockdown of MYC and a dominant-negative form of MYC, omomyc, induce differentiation of NMC cells. Conversely, differentiation of NMC cells induced by knockdown of BRD4-NUT is abrogated by enforced expression of MYC. Together, these findings suggest that MYC is a downstream target of BRD4-NUT that is required for maintenance of NMC cells in an undifferentiated, proliferative state. Our findings support a model in which dysregulation of MYC by BRD-NUT fusion proteins has a central role in the pathogenesis of NMC. C1 [Grayson, A. R.; Walsh, E. M.; Cameron, M. J.; Ashworth, T.; Ambrose, J. M.; Aserlind, A. B.; Wang, H.; Kluk, M. J.; Aster, J. C.; French, C. A.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Grayson, A. R.; Walsh, E. M.; Cameron, M. J.; Ashworth, T.; Ambrose, J. M.; Aserlind, A. B.; Wang, H.; Kluk, M. J.; Bradner, J. E.; Aster, J. C.; French, C. A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Godec, J.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Godec, J.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Evan, G. I.] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England. [Bradner, J. E.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP French, CA (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM cfrench@partners.org FU Samuel Waxman Cancer Research Foundation; US National Institutes of Health [1R01CA124633]; Adolescent and Young Adult Gap Fund; American Association for Cancer Research [10-20-03-FREN] FX This work was supported by the Samuel Waxman Cancer Research Foundation (CAF and JEB), the US National Institutes of Health grant 1R01CA124633 (CAF), the Adolescent and Young Adult Gap Fund (CAF and JEB), and the American Association for Cancer Research grant 10-20-03-FREN. We would like to thank Dr Nicholas Haining for assistance with GSEA. Many thanks to Dr Paola Dal Cin for providing fluorescent in situ hybridization probes, and to Mr Dan Shea for his assistance with fluorescent in situ hybridization photomicrographs. High-throughput siRNA assays were performed at the Institute of Chemistry and Cell Biology, Longwood Campus (ICCB-L, http://iccb.med.harvard.edu/). NR 45 TC 30 Z9 30 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD MAR 27 PY 2014 VL 33 IS 13 BP 1736 EP 1742 DI 10.1038/onc.2013.126 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AE9QY UT WOS:000334344700013 PM 23604113 ER PT J AU Cranmer, HH Biddinger, PD AF Cranmer, Hilarie H. Biddinger, Paul D. TI Typhoon Haiyan and the Professionalization of Disaster Response SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material AB When international medical response teams landed in the Philippines after Typhoon Haiyan, they had to act as professional humanitarian responders. Medical responders to disasters can help best when they are well prepared and function as part of a coordinated effort. When international medical response teams landed in the Philippines last November in the days and weeks after Super Typhoon Haiyan hit, it was immediately apparent that they needed to act as professional humanitarian responders. The top priority was not that they deploy their medical skills but that they support the plans that were already in place. Although there were posters directing foreign medical response teams to register with the Philippine government, the trucks loaded with bags of rice from the World Food Program being delivered to the Department of Social Welfare and Development should have tipped off the response teams ... C1 [Cranmer, Hilarie H.; Biddinger, Paul D.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Cranmer, Hilarie H.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Biddinger, Paul D.] Harvard Univ, Sch Publ Hlth, Div Policy Translat & Leadership Dev, Boston, MA 02115 USA. RP Cranmer, HH (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. NR 4 TC 6 Z9 6 U1 4 U2 25 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 27 PY 2014 VL 370 IS 13 BP 1185 EP 1187 DI 10.1056/NEJMp1401820 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AD7EW UT WOS:000333426000005 PM 24552286 ER PT J AU Shaw, AT Kim, DW Mehra, R Tan, DSW Felip, E Chow, LQM Camidge, DR Vansteenkiste, J Sharma, S De Pas, T Riely, GJ Solomon, BJ Wolf, J Thomas, M Schuler, M Liu, G Santoro, A Lau, YY Goldwasser, M Boral, AL Engelman, JA AF Shaw, Alice T. Kim, Dong-Wan Mehra, Ranee Tan, Daniel S. W. Felip, Enriqueta Chow, Laura Q. M. Camidge, D. Ross Vansteenkiste, Johan Sharma, Sunil De Pas, Tommaso Riely, Gregory J. Solomon, Benjamin J. Wolf, Juergen Thomas, Michael Schuler, Martin Liu, Geoffrey Santoro, Armando Lau, Yvonne Y. Goldwasser, Meredith Boral, Anthony L. Engelman, Jeffrey A. TI Ceritinib in ALK-Rearranged Non-Small-Cell Lung Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID EML4-ALK FUSION GENE; KINASE INHIBITOR; ACQUIRED-RESISTANCE; CLINICAL RESISTANCE; MUTATION; EGFR; CRIZOTINIB; GEFITINIB; STI-571; TRIALS AB BackgroundNon-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. MethodsIn this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib. ResultsA total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5). ConclusionsCeritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.) Ceritinib is 20 times as potent as crizotinib at inhibiting anaplastic lymphoma kinase (ALK) in vitro. In patients, ceritinib produced antitumor responses in 56% of those who had resistance to crizotinib. Genetic alterations in the anaplastic lymphoma kinase gene (ALK) are implicated in the pathogenesis of several human cancers.(1) ALK can be aberrantly activated by mutation, gene amplification, or chromosomal rearrangement, leading to the expression of a potent oncogenic driver. In non-small-cell lung cancer (NSCLC), ALK rearrangement occurs in approximately 5% of cases.(2)-(8)ALK-rearranged tumors depend on ALK for growth and survival and show marked sensitivity to ALK inhibitors such as crizotinib. Among patients with advanced, ALK-rearranged NSCLC, crizotinib has been associated with response rates of approximately 60% across multiple studies and a median progression-free survival ... C1 [Shaw, Alice T.; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kim, Dong-Wan] Seoul Natl Univ Hosp, Seoul 110744, South Korea. [Mehra, Ranee] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Tan, Daniel S. W.] Natl Canc Ctr, Singapore, Singapore. [Tan, Daniel S. W.] Genome Inst Singapore, Singapore, Singapore. [Felip, Enriqueta] Vall dHebron Univ, Barcelona, Spain. [Chow, Laura Q. M.] Univ Washington, Seattle, WA 98195 USA. [Camidge, D. Ross] Univ Colorado, Denver, CO 80202 USA. [Vansteenkiste, Johan] Univ Hosp KU Leuven, Louvain, Belgium. [Sharma, Sunil] Huntsman Canc Inst, Salt Lake City, UT USA. [De Pas, Tommaso] Ist Europeo Oncol, Milan, Italy. [Santoro, Armando] Ist Clin Humanitas, Ist Ricovero & Cura Carattere Sci, Milan, Italy. [Riely, Gregory J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Solomon, Benjamin J.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Wolf, Juergen] Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany. [Thomas, Michael] Heidelberg Univ, Thoraxklin, Translat Lung Res Ctr Heidelberg, German Ctr Lung Res, Heidelberg, Germany. [Schuler, Martin] German Canc Consortium, Heidelberg, Germany. [Schuler, Martin] Univ Duisburg Essen, Essen, Germany. [Liu, Geoffrey] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Lau, Yvonne Y.; Goldwasser, Meredith; Boral, Anthony L.] Novartis Inst BioMed Res, Cambridge, MA USA. RP Shaw, AT (reprint author), Massachusetts Gen Hosp, Ctr Canc, Yawkey 7B,32 Fruit St, Boston, MA 02114 USA. EM ashaw1@mgh.harvard.edu FU Novartis Pharmaceuticals; National Cancer Institute [5R01CA164273]; V Foundation Translational Research Grant; Be a Piece of the Solution; Evan Spirito Memorial Foundation FX Supported by Novartis Pharmaceuticals, by a grant from the National Cancer Institute (5R01CA164273, to Drs. Shaw and Engelman), by a V Foundation Translational Research Grant (to Drs. Shaw and Engelman), by Be a Piece of the Solution, and by the Evan Spirito Memorial Foundation. NR 28 TC 462 Z9 494 U1 8 U2 95 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 27 PY 2014 VL 370 IS 13 BP 1189 EP 1197 DI 10.1056/NEJMoa1311107 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AD7EW UT WOS:000333426000006 PM 24670165 ER PT J AU Chiappa, V Chang, CY Sellas, MI Pierce, VM Kradin, RL AF Chiappa, Victor Chang, Connie Y. Sellas, Monique I. Pierce, Virginia M. Kradin, Richard L. TI Case 10-2014: A 45-Year- Old Man with a Rash SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article AB A 45-year-old man was admitted to the hospital because of diffuse, purple, blanching livedo and signs of severe sepsis. Three days earlier, he had been bitten by a dog. A diagnostic test result was received. Presentation of CaseDr. Douglas S. Micalizzi (Medicine): A 45-year-old man was admitted to this hospital because of a new rash. The patient had been well until 2 p.m. on the day before admission, when nausea, epigastric pain, and vomiting developed. The next morning, he was seen at another hospital, where he reported increasing asthma and right-sided back pain, which he rated at 10 on a scale of 0 to 10 (with 10 indicating the most severe pain). On examination, he was in moderate distress. The temperature was 36.5 degrees C, the blood pressure 112/69 mm Hg, the pulse 125 beats per ... C1 [Chiappa, Victor] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Chang, Connie Y.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sellas, Monique I.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Pierce, Virginia M.; Kradin, Richard L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Chiappa, Victor] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Chang, Connie Y.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Sellas, Monique I.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Pierce, Virginia M.; Kradin, Richard L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Chiappa, V (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 4 TC 4 Z9 4 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 27 PY 2014 VL 370 IS 13 BP 1238 EP 1248 DI 10.1056/NEJMcpc1304162 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AD7EW UT WOS:000333426000012 PM 24670171 ER PT J AU Greka, A Weins, A Mundel, P AF Greka, Anna Weins, Astrid Mundel, Peter TI Abatacept in B7-1-Positive Proteinuric Kidney Disease Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Greka, Anna; Mundel, Peter] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Weins, Astrid] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Greka, A (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM mundel.peter@mgh.harvard.edu FU NHLBI NIH HHS [R01 HL109582]; NIDDK NIH HHS [R01 DK062472, K01 DK068253, K08 DK083511, K08 DK093783, P30 DK057521, R01 DK057683, R01 DK090316, R01 DK095045, R01 DK099465, R56 DK093746] NR 1 TC 2 Z9 2 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 27 PY 2014 VL 370 IS 13 BP 1263 EP 1266 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AD7EW UT WOS:000333426000021 PM 24670178 ER PT J AU Salado, IG Redondo, M Bello, ML Perez, C Liachko, NF Kraemer, BC Miguel, L Lecourtois, M Gil, C Martinez, A Perez, DI AF Salado, Irene G. Redondo, Miriam Bello, Murilo L. Perez, Concepcion Liachko, Nicole F. Kraemer, Brian C. Miguel, Laetitia Lecourtois, Magalie Gil, Carmen Martinez, Ana Perez, Daniel I. TI Protein Kinase CK-1 Inhibitors As New Potential Drugs for Amyotrophic Lateral Sclerosis SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID FRONTOTEMPORAL LOBAR DEGENERATION; BLOOD-BRAIN-BARRIER; TDP-43 PROTEINOPATHIES; HEXANUCLEOTIDE REPEAT; MUTATIONS; ALS; PHOSPHORYLATION; MODEL; OPTIMIZATION; EXPRESSION AB Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons in cortex, brain stem, and spinal cord die progressively, resulting in muscle wasting, paralysis, and death. Currently, effective therapies for ALS are lacking; however, identification of pathological TAR DNA-binding protein 43 (TDP-43) as the hallmark lesion in sporadic ALS suggests new therapeutic targets for pharmacological intervention. Pathological TDP-43 phosphorylation appears to drive the onset and progression of ALS and may result from upregulation of the protein kinase CK-1 in affected neurons, resulting in postranslational TDP-43 modification. Consequently, brain penetrant specific CK-1 inhibitors may provide a new therapeutic strategy for treating ALS and other TDP-43 proteinopathies. Using a chemical genetic approach, we report the discovery and further optimization of a number of potent CK-1 delta inhibitors. Moreover, these small heterocyclic molecules are able to prevent TDP-43 phosphorylation in cell cultures, to increase Drosophila lifespan by reduction of TDP-43 neurotoxicity, and are predicted to cross the blood brain barrier. Thus, N-(benzothiazolyl)-2-phenyl-acetamides are valuable drug candidates for further studies and may be a new therapeutic approach for ALS and others pathologies in which TDP-43 is involved. C1 [Salado, Irene G.; Redondo, Miriam; Bello, Murilo L.; Perez, Concepcion; Gil, Carmen; Martinez, Ana; Perez, Daniel I.] CSIC, Inst Quim Med, E-28006 Madrid, Spain. [Bello, Murilo L.] Univ Fed Rio de Janeiro, Fac Farm, BR-21949900 Rio De Janeiro, Brazil. [Liachko, Nicole F.; Kraemer, Brian C.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Liachko, Nicole F.; Kraemer, Brian C.] Univ Washington, Gerontol Div, Dept Med, Seattle, WA 98104 USA. [Kraemer, Brian C.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Miguel, Laetitia; Lecourtois, Magalie] INSERM, U1079, F-76183 Rouen, France. [Miguel, Laetitia; Lecourtois, Magalie] Univ Rouen, Normandie Univ, IRIB, F-76183 Rouen, France. RP Martinez, A (reprint author), CSIC, Inst Quim Med, Juan Cierva 3, E-28006 Madrid, Spain. EM amartinez@iqm.csic.es; dperez@iqm.csic.es RI Gil, Carmen/J-8932-2014; Perez Fernandez, Daniel Ignacio/L-6245-2014; Martinez, Ana/L-6414-2014; Perez, Concepcion/K-3684-2014 OI Gil, Carmen/0000-0002-3882-6081; Perez Fernandez, Daniel Ignacio/0000-0003-1774-4471; Martinez, Ana/0000-0002-2707-8110; FU MINECO [SAF2012-37979-C03-01]; Association Francaise contre les Myopathies [AFM-16169]; Department of Veterans Affairs [1147891]; CDA2 [I01BX007080]; Ligue Europeenne Contre la Maladie d'Alzheimer (LECMA); National Institutes of Health [R01NS064131]; MICINN (FPI program); CSIC (JAE program); Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) FX This work was supported by grants from MINECO (SAF2012-37979-C03-01 to A.M.), Association Francaise contre les Myopathies (AFM-16169 to D.I.P.), the Department of Veterans Affairs (Merit Review grant no. 1147891 to B.K.) and CDA2 no. I01BX007080 to N.L.), Ligue Europeenne Contre la Maladie d'Alzheimer (LECMA to M.L.), and National Institutes of Health (R01NS064131 to B.K.). I.G.S. and D.I.P. acknowledge a pre- and postdoctoral fellowship from MICINN (FPI program) and CSIC (JAE program), respectively. M.L.B. acknowledges a travel grant from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES). We thank Elaine Loomis for outstanding technical assistance with immunoblotting NR 48 TC 9 Z9 9 U1 0 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD MAR 27 PY 2014 VL 57 IS 6 BP 2755 EP 2772 DI 10.1021/jm500065f PG 18 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AD9IK UT WOS:000333578400046 PM 24592867 ER PT J AU Lu, T Aron, L Zullo, J Pan, Y Kim, H Chen, YW Yang, TH Kim, HM Drake, D Liu, XS Bennett, DA Colaiacovo, MP Yankner, BA AF Lu, Tao Aron, Liviu Zullo, Joseph Pan, Ying Kim, Haeyoung Chen, Yiwen Yang, Tun-Hsiang Kim, Hyun-Min Drake, Derek Liu, X. Shirley Bennett, David A. Colaiacovo, Monica P. Yankner, Bruce A. TI REST and stress resistance in ageing and Alzheimer's disease SO NATURE LA English DT Article ID MILD COGNITIVE IMPAIRMENT; GENOME-WIDE ANALYSIS; CAENORHABDITIS-ELEGANS; SEL-12 PRESENILIN; C. ELEGANS; LIFE-SPAN; PROTEIN; REPRESSOR; CHROMATIN; NEURONS AB Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid beta-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid beta-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain. C1 [Lu, Tao; Aron, Liviu; Zullo, Joseph; Pan, Ying; Kim, Haeyoung; Yang, Tun-Hsiang; Kim, Hyun-Min; Drake, Derek; Colaiacovo, Monica P.; Yankner, Bruce A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Chen, Yiwen; Liu, X. Shirley] Dana Faber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Kim, Haeyoung; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. RP Yankner, BA (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM Bruce_Yankner@hms.harvard.edu RI Kim, Haeyoung/C-3069-2008 FU NIH [DP1OD006849, PO1AG27916, RO1AG26651, RO1GM072551, P30AG10161, R01AG15819, R01AG17917]; Glenn Foundation for Medical Research FX We thank members of the Yankner laboratory for suggestions and discussion, Monlan Yuan, Allison Harwick, Kelly Dakin and Gregory Klein for assistance, and Cheng Li and Dana Gabuzda for helpful discussion. We also acknowledge the Rush Alzheimer's Disease Center, the Brigham and Women's Hospital Brain Bank, the Massachusetts General Hospital ADRC Brain Bank, and the Kathleen Price Bryan Brain Bank at Duke University for providing tissue samples. This work was supported by an NIH Director's Pioneer Award (DP1OD006849) and NIH grants PO1AG27916 and RO1AG26651 to B.A.Y., RO1GM072551 to M. P. C., P30AG10161, R01AG15819 and R01AG17917 to D. A. B., and a grant from the Glenn Foundation for Medical Research to B.A.Y. J.Z. is a Molecular Biology of Neurodegeneration fellow at Harvard Medical School. NR 55 TC 140 Z9 144 U1 19 U2 159 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 27 PY 2014 VL 507 IS 7493 BP 448 EP + DI 10.1038/nature13163 PG 21 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD6WN UT WOS:000333402000031 PM 24670762 ER PT J AU Forrest, ARR Kawaji, H Rehli, M Baillie, JK de Hoon, MJL Haberle, V Lassmann, T Kulakovskiy, IV Lizio, M Itoh, M Andersson, R Mungall, CJ Meehan, TF Schmeier, S Bertin, N Jorgensen, M Dimont, E Arner, E Schmidl, C Schaefer, U Medvedeva, YA Plessy, C Vitezic, M Severin, J Semple, CA Ishizu, Y Young, RS Francescatto, M Alam, I Albanese, D Altschuler, GM Arakawa, T Archer, JAC Arner, P Babina, M Rennie, S Balwierz, PJ Beckhouse, AG Pradhan-Bhatt, S Blake, JA Blumenthal, A Bodega, B Bonetti, A Briggs, J Brombacher, F Burroughs, AM Califano, A Cannistraci, CV Carbajo, D Chen, Y Chierici, M Ciani, Y Clevers, HC Dalla, E Davis, CA Detmar, M Diehl, AD Dohi, T Drablos, F Edge, ASB Edinger, M Ekwall, K Endoh, M Enomoto, H Fagiolini, M Fairbairn, L Fang, H Farach-Carson, MC Faulkner, GJ Favorov, AV Fisher, ME Frith, MC Fujita, R Fukuda, S Furlanello, C Furuno, M Furusawa, J Geijtenbeek, TB Gibson, AP Gingeras, T Goldowitz, D Gough, J Guhl, S Guler, R Gustincich, S Ha, TJ Hamaguchi, M Hara, M Harbers, M Harshbarger, J Hasegawa, A Hasegawa, Y Hashimoto, T Herlyn, M Hitchens, KJ Sui, SJH Hofmann, OM Hoof, I Hori, F Huminiecki, L Iida, K Ikawa, T Jankovic, BR Jia, H Joshi, A Jurman, G Kaczkowski, B Kai, C Kaida, K Kaiho, A Kajiyama, K Kanamori-Katayama, M Kasianov, A Kasukawa, T Katayama, S Kato, S Kawaguchi, S Kawamoto, H Kawamura, YI Kawashima, T Kempfle, JS Kenna, TJ Kere, J Khachigian, LM Kitamura, T Klinken, SP Knox, AJ Kojima, M Kojima, S Kondo, N Koseki, H Koyasu, S Krampitz, S Kubosaki, A Kwon, AT Laros, JFJ Lee, W Lennartsson, A Li, K Lilje, B Lipovich, L Mackay-sim, A Manabe, R Mar, JC Marchand, B Mathelier, A Mejhert, N Meynert, A Mizuno, Y Morais, DAD Morikawa, H Morimoto, M Moro, K Motakis, E Motohashi, H Mummery, CL Murata, M Nagao-Sato, S Nakachi, Y Nakahara, F Nakamura, T Nakamura, Y Nakazato, K Van Nimwegen, E Ninomiya, N Nishiyori, H Noma, S Nozaki, T Ogishima, S Ohkura, N Ohmiya, H Ohno, H Ohshima, M Okada-Hatakeyama, M Okazaki, Y Orlando, V Ovchinnikov, DA Pain, A Passier, R Patrikakis, M Persson, H Piazza, S Prendergast, JGD Rackham, OJL Ramilowski, JA Rashid, M Ravasi, T Rizzu, P Roncador, M Roy, S Rye, MB Saijyo, E Sajantila, A Saka, A Sakaguchi, S Sakai, M Sato, H Satoh, H Savvi, S Saxena, A Schneider, C Schultes, EA Schulze-Tanzil, GG Schwegmann, A Sengstag, T Sheng, GJ Shimoji, H Shimoni, Y Shin, JW Simon, C Sugiyama, D Sugiyama, T Suzuki, M Suzuki, N Swoboda, RK 't Hoen, PAC Tagami, M Takahashi, N Takai, J Tanaka, H Tatsukawa, H Tatum, Z Thompson, M Toyoda, H Toyoda, T Valen, E van de Wetering, M van den Berg, LM Verardo, R Vijayan, D Vorontsov, IE Wasserman, WW Watanabe, S Wells, CA Winteringham, LN Wolvetang, E Wood, EJ Yamaguchi, Y Yamamoto, M Yoneda, M Yonekura, Y Yoshida, S Zabierowski, SE Zhang, PG Zhao, XB Zucchelli, S Summers, KM Suzuki, H Daub, CO Kawai, J Heutink, P Hide, W Freeman, TC Lenhard, B Bajic, VB Taylor, MS Makeev, VJ Sandelin, A Hume, DA Carninci, P Hayashizaki, Y AF Forrest, Alistair R. R. Kawaji, Hideya Rehli, Michael Baillie, J. Kenneth de Hoon, Michiel J. L. Haberle, Vanja Lassmann, Timo Kulakovskiy, Ivan V. Lizio, Marina Itoh, Masayoshi Andersson, Robin Mungall, Christopher J. Meehan, Terrence F. Schmeier, Sebastian Bertin, Nicolas Jorgensen, Mette Dimont, Emmanuel Arner, Erik Schmidl, Christian Schaefer, Ulf Medvedeva, Yulia A. Plessy, Charles Vitezic, Morana Severin, Jessica Semple, Colin A. Ishizu, Yuri Young, Robert S. Francescatto, Margherita Alam, Intikhab Albanese, Davide Altschuler, Gabriel M. Arakawa, Takahiro Archer, John A. C. Arner, Peter Babina, Magda Rennie, Sarah Balwierz, Piotr J. Beckhouse, Anthony G. Pradhan-Bhatt, Swati Blake, Judith A. Blumenthal, Antje Bodega, Beatrice Bonetti, Alessandro Briggs, James Brombacher, Frank Burroughs, A. Maxwell Califano, Andrea Cannistraci, Carlo V. Carbajo, Daniel Chen, Yun Chierici, Marco Ciani, Yari Clevers, Hans C. Dalla, Emiliano Davis, Carrie A. Detmar, Michael Diehl, Alexander D. Dohi, Taeko Drablos, Finn Edge, Albert S. B. Edinger, Matthias Ekwall, Karl Endoh, Mitsuhiro Enomoto, Hideki Fagiolini, Michela Fairbairn, Lynsey Fang, Hai Farach-Carson, Mary C. Faulkner, Geoffrey J. Favorov, Alexander V. Fisher, Malcolm E. Frith, Martin C. Fujita, Rie Fukuda, Shiro Furlanello, Cesare Furuno, Masaaki Furusawa, Jun-ichi Geijtenbeek, Teunis B. Gibson, Andrew P. Gingeras, Thomas Goldowitz, Daniel Gough, Julian Guhl, Sven Guler, Reto Gustincich, Stefano Ha, Thomas J. Hamaguchi, Masahide Hara, Mitsuko Harbers, Matthias Harshbarger, Jayson Hasegawa, Akira Hasegawa, Yuki Hashimoto, Takehiro Herlyn, Meenhard Hitchens, Kelly J. Sui, Shannan J. Ho Hofmann, Oliver M. Hoof, Ilka Hori, Fumi Huminiecki, Lukasz Iida, Kei Ikawa, Tomokatsu Jankovic, Boris R. Jia, Hui Joshi, Anagha Jurman, Giuseppe Kaczkowski, Bogumil Kai, Chieko Kaida, Kaoru Kaiho, Ai Kajiyama, Kazuhiro Kanamori-Katayama, Mutsumi Kasianov, ArtemS. Kasukawa, Takeya Katayama, Shintaro Kato, Sachi Kawaguchi, Shuji Kawamoto, Hiroshi Kawamura, Yuki I. Kawashima, Tsugumi Kempfle, Judith S. Kenna, Tony J. Kere, Juha Khachigian, Levon M. Kitamura, Toshio Klinken, S. Peter Knox, Alan J. Kojima, Miki Kojima, Soichi Kondo, Naoto Koseki, Haruhiko Koyasu, Shigeo Krampitz, Sarah Kubosaki, Atsutaka Kwon, Andrew T. Laros, Jeroen F. J. Lee, Weonju Lennartsson, Andreas Li, Kang Lilje, Berit Lipovich, Leonard Mackay-sim, Alan Manabe, Ri-ichiroh Mar, Jessica C. Marchand, Benoit Mathelier, Anthony Mejhert, Niklas Meynert, Alison Mizuno, Yosuke Morais, David A. de Lima Morikawa, Hiromasa Morimoto, Mitsuru Moro, Kazuyo Motakis, Efthymios Motohashi, Hozumi Mummery, Christine L. Murata, Mitsuyoshi Nagao-Sato, Sayaka Nakachi, Yutaka Nakahara, Fumio Nakamura, Toshiyuki Nakamura, Yukio Nakazato, Kenichi Van Nimwegen, Erik Ninomiya, Noriko Nishiyori, Hiromi Noma, Shohei Nozaki, Tadasuke Ogishima, Soichi Ohkura, Naganari Ohmiya, Hiroko Ohno, Hiroshi Ohshima, Mitsuhiro Okada-Hatakeyama, Mariko Okazaki, Yasushi Orlando, Valerio Ovchinnikov, Dmitry A. Pain, Arnab Passier, Robert Patrikakis, Margaret Persson, Helena Piazza, Silvano Prendergast, James G. D. Rackham, Owen J. L. Ramilowski, Jordan A. Rashid, Mamoon Ravasi, Timothy Rizzu, Patrizia Roncador, Marco Roy, Sugata Rye, Morten B. Saijyo, Eri Sajantila, Antti Saka, Akiko Sakaguchi, Shimon Sakai, Mizuho Sato, Hiroki Satoh, Hironori Savvi, Suzana Saxena, Alka Schneider, Claudio Schultes, Erik A. Schulze-Tanzil, Gundula G. Schwegmann, Anita Sengstag, Thierry Sheng, Guojun Shimoji, Hisashi Shimoni, Yishai Shin, Jay W. Simon, Christophe Sugiyama, Daisuke Sugiyama, Takaaki Suzuki, Masanori Suzuki, Naoko Swoboda, Rolf K. 't Hoen, Peter A. C. Tagami, Michihira Takahashi, Naoko Takai, Jun Tanaka, Hiroshi Tatsukawa, Hideki Tatum, Zuotian Thompson, Mark Toyoda, Hiroo Toyoda, Tetsuro Valen, Eivind van de Wetering, Marc van den Berg, Linda M. Verardo, Roberto Vijayan, Dipti Vorontsov, Ilya E. Wasserman, Wyeth W. Watanabe, Shoko Wells, Christine A. Winteringham, Louise N. Wolvetang, Ernst Wood, Emily J. Yamaguchi, Yoko Yamamoto, Masayuki Yoneda, Misako Yonekura, Yohei Yoshida, Shigehiro Zabierowski, Susan E. Zhang, Peter G. Zhao, Xiaobei Zucchelli, Silvia Summers, Kim M. Suzuki, Harukazu Daub, Carsten O. Kawai, Jun Heutink, Peter Hide, Winston Freeman, Tom C. Lenhard, Boris Bajic, Vladimir B. Taylor, Martin S. Makeev, Vsevolod J. Sandelin, Albin Hume, David A. Carninci, Piero Hayashizaki, Yoshihide CA FANTOM Consortium RIKEN PMI CLST DGT TI A promoter-level mammalian expression atlas SO NATURE LA English DT Article ID HUMAN TRANSCRIPTION FACTORS; GENE-EXPRESSION; HOMEOBOX GENE; MICE LACKING; HUMAN GENOME; INNER-EAR; DIFFERENTIATION; EVOLUTION; ONTOLOGY; CELLS AB Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis revealskey transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research. C1 [Forrest, Alistair R. R.; Kawaji, Hideya; de Hoon, Michiel J. L.; Lassmann, Timo; Lizio, Marina; Itoh, Masayoshi; Bertin, Nicolas; Arner, Erik; Plessy, Charles; Vitezic, Morana; Severin, Jessica; Ishizu, Yuri; Arakawa, Takahiro; Bonetti, Alessandro; Burroughs, A. Maxwell; Fukuda, Shiro; Furuno, Masaaki; Harbers, Matthias; Harshbarger, Jayson; Hasegawa, Akira; Hasegawa, Yuki; Hashimoto, Takehiro; Hori, Fumi; Kaczkowski, Bogumil; Kaida, Kaoru; Kaiho, Ai; Kajiyama, Kazuhiro; Kanamori-Katayama, Mutsumi; Katayama, Shintaro; Kato, Sachi; Kawashima, Tsugumi; Kojima, Miki; Kondo, Naoto; Kubosaki, Atsutaka; Kwon, Andrew T.; Manabe, Ri-ichiroh; Motakis, Efthymios; Murata, Mitsuyoshi; Nagao-Sato, Sayaka; Nakazato, Kenichi; Ninomiya, Noriko; Nishiyori, Hiromi; Noma, Shohei; Ohmiya, Hiroko; Ramilowski, Jordan A.; Roy, Sugata; Saijyo, Eri; Saka, Akiko; Sakai, Mizuho; Saxena, Alka; Sengstag, Thierry; Shimoji, Hisashi; Shin, Jay W.; Simon, Christophe; Suzuki, Masanori; Suzuki, Naoko; Tagami, Michihira; Takahashi, Naoko; Watanabe, Shoko; Yoshida, Shigehiro; Suzuki, Harukazu; Daub, Carsten O.; Kawai, Jun; Carninci, Piero; Hayashizaki, Yoshihide] RIKEN, OSC, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Forrest, Alistair R. R.; Kawaji, Hideya; de Hoon, Michiel J. L.; Lassmann, Timo; Lizio, Marina; Itoh, Masayoshi; Bertin, Nicolas; Arner, Erik; Plessy, Charles; Severin, Jessica; Ishizu, Yuri; Arakawa, Takahiro; Bonetti, Alessandro; Furuno, Masaaki; Harshbarger, Jayson; Hasegawa, Akira; Hasegawa, Yuki; Hori, Fumi; Kaczkowski, Bogumil; Kaida, Kaoru; Kajiyama, Kazuhiro; Kasukawa, Takeya; Kato, Sachi; Kawashima, Tsugumi; Kojima, Miki; Kondo, Naoto; Kwon, Andrew T.; Manabe, Ri-ichiroh; Motakis, Efthymios; Murata, Mitsuyoshi; Nishiyori, Hiromi; Noma, Shohei; Ohmiya, Hiroko; Ramilowski, Jordan A.; Roy, Sugata; Sakai, Mizuho; Shin, Jay W.; Simon, Christophe; Suzuki, Naoko; Tagami, Michihira; Takahashi, Naoko; Yoshida, Shigehiro; Suzuki, Harukazu; Carninci, Piero] RIKEN, CLST, DGT, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Kawaji, Hideya; Itoh, Masayoshi; Kawai, Jun; Hayashizaki, Yoshihide] RIKEN, Prevent Med & Diag Innovat Program PMI, Wako, Saitama 3510198, Japan. [Rehli, Michael; Schmidl, Christian; Edinger, Matthias] Univ Hosp Regensburg, Dept Internal Med 3, D-93042 Regensburg, Germany. [Rehli, Michael; Edinger, Matthias] Regensburg Ctr Intervent Immunol RCI, D-93042 Regensburg, Germany. [Baillie, J. Kenneth; Fairbairn, Lynsey; Fisher, Malcolm E.; Joshi, Anagha; Summers, Kim M.; Freeman, Tom C.; Hume, David A.] Univ Edinburgh, Roslin Inst, Edinburgh EH25 9RG, Midlothian, Scotland. [Baillie, J. Kenneth; Fairbairn, Lynsey; Fisher, Malcolm E.; Joshi, Anagha; Summers, Kim M.; Freeman, Tom C.; Hume, David A.] Univ Edinburgh, Royal Dick Sch Vet Studies, Edinburgh EH25 9RG, Midlothian, Scotland. [Haberle, Vanja] Univ Bergen, Dept Biol, NO-5006 Bergen, Norway. [Haberle, Vanja; Lenhard, Boris] Univ London Imperial Coll Sci Technol & Med, Fac Med, Inst Clin Sci, MRC Clin Sci Ctr, London W12 0NN, England. [Kulakovskiy, Ivan V.; Makeev, Vsevolod J.] Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 119991, Russia. [Kulakovskiy, Ivan V.; Medvedeva, Yulia A.; Favorov, Alexander V.; Kasianov, ArtemS.; Vorontsov, Ilya E.; Makeev, Vsevolod J.] Russian Acad Sci, Vavilov Inst Gen Genet, Moscow 119991, Russia. [Andersson, Robin; Jorgensen, Mette; Chen, Yun; Hoof, Ilka; Li, Kang; Lilje, Berit; Zhao, Xiaobei; Sandelin, Albin] Univ Copenhagen, Bioinformat Ctr, Dept Biol, DK-2200 Copenhagen, Denmark. [Andersson, Robin; Jorgensen, Mette; Chen, Yun; Hoof, Ilka; Li, Kang; Lilje, Berit; Zhao, Xiaobei; Sandelin, Albin] Univ Copenhagen, BRIC, DK-2200 Copenhagen, Denmark. [Mungall, Christopher J.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Genom Div, Berkeley, CA 94720 USA. [Meehan, Terrence F.] European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England. [Schmeier, Sebastian; Schaefer, Ulf; Medvedeva, Yulia A.; Alam, Intikhab; Archer, John A. C.; Jankovic, Boris R.; Marchand, Benoit; Pain, Arnab; Rashid, Mamoon; Bajic, Vladimir B.] KAUST, Computat Biosci Res Ctr, Thuwal 239556900, Saudi Arabia. [Schmeier, Sebastian] Massey Univ, North Shore Mail Ctr, Inst Nat & Math Sci, Auckland 0745, New Zealand. [Dimont, Emmanuel; Altschuler, Gabriel M.; Sui, Shannan J. Ho; Hofmann, Oliver M.; Hide, Winston] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Vitezic, Morana; Huminiecki, Lukasz] Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden. [Semple, Colin A.; Young, Robert S.; Rennie, Sarah; Meynert, Alison; Prendergast, James G. D.; Taylor, Martin S.] Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, MRC IGMM, Edinburgh EH4 2XU, Midlothian, Scotland. [Francescatto, Margherita; Rizzu, Patrizia; Heutink, Peter] Vrije Univ Amsterdam, Dept Clin Genet, Med Ctr Amsterdam, NL-1081 BT Amsterdam, Netherlands. [Francescatto, Margherita] Univ Porto, Grad Program Areas Basic & Appl Biol, Abel Salazar Biomed Sci Inst, P-4050313 Oporto, Portugal. [Albanese, Davide; Chierici, Marco; Furlanello, Cesare; Jurman, Giuseppe; Roncador, Marco] Fdn Bruno Kessler, I-38123 Trento, Italy. [Arner, Peter; Mejhert, Niklas] Karolinska Inst, Dept Med, Karolinska Univ Hosp, SE-14186 Huddinge, Sweden. [Babina, Magda; Guhl, Sven] Univ Med Berlin, Dept Dermatol & Allergy, D-10117 Berlin, Germany. [Balwierz, Piotr J.; Van Nimwegen, Erik] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland. [Beckhouse, Anthony G.; Briggs, James; Hitchens, Kelly J.; Ovchinnikov, Dmitry A.; Vijayan, Dipti; Wells, Christine A.; Wolvetang, Ernst] Univ Queensland, AIBN, St Lucia, Qld 4072, Australia. [Beckhouse, Anthony G.; Blumenthal, Antje; Hitchens, Kelly J.; Vijayan, Dipti; Wells, Christine A.] Univ Queensland, Australian Infect Dis Res Ctr AID, St Lucia, Qld 4072, Australia. [Pradhan-Bhatt, Swati] Univ Delaware, Dept Biol Sci, Newark, DE 19713 USA. [Blake, Judith A.] Jackson Lab, Bar Harbor, ME 04609 USA. [Blumenthal, Antje; Kenna, Tony J.] Univ Queensland, Diamantina Inst, St Lucia, Qld 4072, Australia. [Bodega, Beatrice; Orlando, Valerio] IRCCS Fdn Santa Lucia, I-00143 Rome, Italy. [Brombacher, Frank; Guler, Reto; Savvi, Suzana; Schwegmann, Anita] Int Ctr Genet Engn & Biotechnol ICGEB Cape Town C, ZA-7925 Cape Town, South Africa. [Brombacher, Frank; Guler, Reto; Savvi, Suzana; Schwegmann, Anita] Univ Cape Town, Div Immunol, Inst Infect Dis & Mol Med IDM, ZA-7925 Cape Town, South Africa. [Califano, Andrea] Columbia Univ, Med Ctr, Dept Syst Biol, New York, NY 10032 USA. [Califano, Andrea] Columbia Univ, Med Ctr, Dept Biochem & Mol Biophys, New York, NY 10032 USA. [Califano, Andrea] Columbia Univ, Med Ctr, Dept Biomed Informat, New York, NY 10032 USA. [Califano, Andrea; Shimoni, Yishai] Columbia Univ, Med Ctr, Herbert Irving Comprehens Canc Ctr, Inst Canc Genet, New York, NY 10032 USA. [Cannistraci, Carlo V.; Orlando, Valerio; Pain, Arnab; Rashid, Mamoon; Ravasi, Timothy] KAUST, Biol & Environm Sci & Engn Div, Thuwal 239556900, Saudi Arabia. [Cannistraci, Carlo V.; Ravasi, Timothy] KAUST, Appl Math & Computat Sci Program, Thuwal 239556900, Saudi Arabia. [Carbajo, Daniel; Mar, Jessica C.] Albert Einstein Coll Med, Dept Syst & Computat Biol, Bronx, NY 10461 USA. [Ciani, Yari; Dalla, Emiliano; Piazza, Silvano; Schneider, Claudio; Verardo, Roberto] LNCIB, I-34149 Trieste, Italy. [Clevers, Hans C.; van de Wetering, Marc] Hubrecht Inst, NL-3584 CT Utrecht, Netherlands. [Clevers, Hans C.] Royal Netherlands Acad Arts & Sci, NL-1000 GC Amsterdam, Netherlands. [Clevers, Hans C.] Univ Med Ctr Utrecht, NL-3508 GA Utrecht, Netherlands. [Davis, Carrie A.; Gingeras, Thomas] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11797 USA. [Detmar, Michael; Krampitz, Sarah] ETH, Inst Pharmaceut Sci, CH-8093 Zurich, Switzerland. [Diehl, Alexander D.] SUNY Buffalo, Dept Neurol, Sch Med & Biomed Sci, New York State Ctr Excellence Bioinformat & Life, Buffalo, NY 14203 USA. [Dohi, Taeko; Kawamura, Yuki I.] Natl Ctr Global Hlth & Med, Res Ctr Hepatitis & Immunol Res Inst, Ichikawa, Chiba 2728516, Japan. [Drablos, Finn; Rye, Morten B.] Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, NO-7491 Trondheim, Norway. [Edge, Albert S. B.; Kempfle, Judith S.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. [Ekwall, Karl; Kere, Juha; Lennartsson, Andreas; Persson, Helena] Karolinska Inst, Dept Biosci & Nutr, Ctr Biosci, SE-14183 Huddinge, Sweden. [Endoh, Mitsuhiro; Furusawa, Jun-ichi; Ikawa, Tomokatsu; Kawamoto, Hiroshi; Koseki, Haruhiko; Koyasu, Shigeo; Moro, Kazuyo; Ohno, Hiroshi; Okada-Hatakeyama, Mariko] RIKEN, RCAI, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Endoh, Mitsuhiro; Furusawa, Jun-ichi; Ikawa, Tomokatsu; Koseki, Haruhiko; Koyasu, Shigeo; Moro, Kazuyo; Ohno, Hiroshi; Okada-Hatakeyama, Mariko] RIKEN, Ctr Integrat Med Sci, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. [Enomoto, Hideki; Morimoto, Mitsuru; Sheng, Guojun; Yonekura, Yohei] RIKEN, CDB, Chuo Ku, Kobe, Hyogo 6500047, Japan. [Fagiolini, Michela] Harvard Univ, Sch Med, FM Kirby Neurobiol Ctr, Childrens Hosp Boston, Boston, MA 02115 USA. [Fang, Hai; Gough, Julian; Rackham, Owen J. L.] Univ Bristol, Dept Comp Sci, Bristol BS8 1UB, Avon, England. [Farach-Carson, Mary C.] Rice Univ, Dept Biochem & Cell Biol, Houston, TX 77251 USA. [Faulkner, Geoffrey J.] Mater Med Res Inst, Cancer Biol Program, South Brisbane, Qld 4101, Australia. [Favorov, Alexander V.] Johns Hopkins Univ, Sch Med, Dept Oncol, Div Oncol Biostat & Bioinformat, Baltimore, MD 21205 USA. [Favorov, Alexander V.] State Res Inst Genet & Select Ind Microorganisms, Moscow 117545, Russia. [Frith, Martin C.] Natl Inst Adv Ind Sci & Technol, Computat Biol Res Ctr, Koto Ku, Tokyo 1350064, Japan. [Fujita, Rie; Satoh, Hironori; Takai, Jun; Yamamoto, Masayuki] Tohoku Univ, Dept Med Biochem, Grad Sch Med, Aoba Ku, Sendai, Miyagi 9808575, Japan. [Furusawa, Jun-ichi; Koyasu, Shigeo; Moro, Kazuyo] Keio Univ, Sch Med, Dept Microbiol & Immunol, Shinjuku Ku, Tokyo 1608582, Japan. [Geijtenbeek, Teunis B.; van den Berg, Linda M.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Gibson, Andrew P.; Laros, Jeroen F. J.; Schultes, Erik A.; 't Hoen, Peter A. C.; Tatum, Zuotian; Thompson, Mark] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands. [Goldowitz, Daniel; Ha, Thomas J.; Mathelier, Anthony; Wasserman, Wyeth W.; Zhang, Peter G.] Univ British Columbia, Dept Med Genet, Ctr Mol Med & Therapeut, Child & Family Res Inst, Vancouver, BC V5Z 4H4, Canada. [Gustincich, Stefano; Zucchelli, Silvia] SISSA, I-34136 Trieste, Italy. [Hamaguchi, Masahide; Morikawa, Hiromasa; Ohkura, Naganari; Sakaguchi, Shimon] Osaka Univ, Immunol Frontier Res Ctr, Suita, Osaka 5650871, Japan. [Hara, Mitsuko; Kojima, Soichi] RIKEN, ASI, Wako, Saitama 3510198, Japan. [Herlyn, Meenhard; Swoboda, Rolf K.; Zabierowski, Susan E.] Wistar Inst Anat & Biol, Melanoma Res Ctr, Philadelphia, PA 19104 USA. [Iida, Kei; Kawaguchi, Shuji; Toyoda, Tetsuro] RIKEN, Bioinformat & Syst Engn Div BASE, Yokohama, Kanagawa 2300045, Japan. [Jia, Hui; Lipovich, Leonard; Wood, Emily J.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Kai, Chieko; Nakamura, Toshiyuki; Sato, Hiroki; Sugiyama, Takaaki; Yoneda, Misako] Univ Tokyo, Lab Anim Res Ctr, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan. [Kere, Juha] Sci Life Lab, SE-17121 Solna, Sweden. [Khachigian, Levon M.; Patrikakis, Margaret] Univ New S Wales, Ctr Vasc Res, Sydney, NSW 2052, Australia. [Kitamura, Toshio; Nakahara, Fumio] Univ Tokyo, Div Cellular Therapy, Inst Med Sci, Tokyo 1088639, Japan. [Kitamura, Toshio; Nakahara, Fumio] Univ Tokyo, Div Stem Cell Signaling, Inst Med Sci, Tokyo 1088639, Japan. [Klinken, S. Peter; Winteringham, Louise N.] Univ Western Australia, Harry Perkins Inst Med Res, QEII Med Ctr, Perth, WA 6009, Australia. [Klinken, S. Peter; Winteringham, Louise N.] Univ Western Australia, Med Res Ctr, QEII Med Ctr, Perth, WA 6009, Australia. [Knox, Alan J.] Univ Nottingham, City Hosp, Nottingham NG5 1PB, England. [Lee, Weonju] Kyungpook Natl Univ, Sch Med, Dept Dermatol, Taegu 700721, South Korea. [Mackay-sim, Alan] Griffith Univ, Natl Ctr Adult Stem Cell Res, Eskitis Inst Cell & Mol Therapies, Brisbane, Qld 4111, Australia. [Mizuno, Yosuke; Nakachi, Yutaka; Okazaki, Yasushi] Saitama Med Univ, Div Funct Genom & Syst Med, Res Ctr Genom Med, Hidaka, Saitama 3501241, Japan. [Morais, David A. de Lima] Univ Bristol, Fac Engn, Clifton BS81UB, England. [Moro, Kazuyo] Japanese Sci & Technol Agcy JST, PRESTO, Tokyo 1020076, Japan. [Motohashi, Hozumi] Tohoku Univ, Ctr Radioisotope Sci, Grad Sch Med, Aoba Ku, Sendai, Miyagi 9808575, Japan. [Mummery, Christine L.; Passier, Robert] Leiden Univ, Med Ctr, NL-2300 RC Leiden, Netherlands. [Nakachi, Yutaka; Okazaki, Yasushi] Saitama Med Univ, Div Translat Res, Res Ctr Genom Med, Hidaka, Saitama 3501241, Japan. [Nakamura, Yukio] RIKEN, BioResource Ctr BRC, Tsukuba, Ibaraki 3050074, Japan. [Nozaki, Tadasuke; Toyoda, Hiroo] Tokyo Univ Pharm & Life Sci, Dept Clin Mol Genet, Sch Pharm, Hachioji, Tokyo 1920392, Japan. [Ogishima, Soichi; Tanaka, Hiroshi] Tokyo Med & Dent Univ, Dept Bioinformat, Med Res Inst, Bunkyo Ku, Tokyo 1138510, Japan. [Ohshima, Mitsuhiro] Ohu Univ, Dept Biochem, Sch Pharmaceut Sci, Koriyama, Fukushima 9638611, Japan. [Sajantila, Antti] Univ Helsinki, Dept Forens Med, Hjelt Inst, Helsinki 003000, Finland. [Schneider, Claudio] Univ Udine, DSMB, I-33100 Udine, Italy. [Schulze-Tanzil, Gundula G.] Charite, Dept Orthoped Trauma & Reconstruct Surg, D-14195 Berlin, Germany. [Sugiyama, Daisuke] Kyushu Univ Hosp, Ctr Clin & Translat Reseach, Higashi Ku, Fukuoka 8128582, Japan. [Tatsukawa, Hideki] Nagoya Univ, Grad Sch Pharmaceut Sci, Chikusa Ku, Nagoya, Aichi 4648601, Japan. [Valen, Eivind] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Yamaguchi, Yoko] Nihon Univ, Dept Biochem, Sch Dent, Chiyoda Ku, Tokyo 1018310, Japan. [Lenhard, Boris] Univ Bergen, Dept Informat, NO-5008 Bergen, Norway. [Makeev, Vsevolod J.] MIPT, Dept Biol & Med Phys, Dolgoprudnyi 141700, Moscow Region, Russia. RP Forrest, ARR (reprint author), RIKEN, OSC, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan. EM alistair.forrest@gmail.com; carninci@riken.jp; yosihide@gsc.riken.jp RI Daub, Carsten/A-7436-2010; Lassmann, Timo/A-8271-2008; Carninci, Piero/K-1568-2014; Sandelin, Albin/G-2881-2011; Kere, Juha/A-9179-2008; Sakaguchi, Shimon/C-9535-2009; Hide, Winston Hide/C-7217-2009; Kenna, Tony/A-6035-2011; Cannistraci, Carlo Vittorio/G-1710-2014; Zhao, Xiaobei/G-3567-2014; Sheng, Guojun/G-4116-2014; Andersson, Robin/B-5311-2009; Koseki, Haruhiko/I-3825-2014; de Hoon, Michiel/N-8006-2015; Suzuki, Harukazu/N-9553-2015; Kojima, Soichi/N-7104-2015; Nakamura, Yukio/A-5263-2016; KONDO, NAOTO/A-5829-2016; Moro, Kazuyo/A-5987-2016; Kawai, Jun/A-6451-2016; Koyasu, Shigeo/J-5583-2015; Semple, Colin/A-5613-2009; U-ID, Kyushu/C-5291-2016; Vorontsov, Ilya/C-6333-2014; Diehl, Alexander/G-9883-2016; Mackay-Sim, Alan/C-3431-2008; Ovchinnikov, Dmitry/J-7963-2014; Vitezic, Morana/A-6165-2013; Ravasi, Timothy/B-8777-2008; Rehli, Michael/E-9093-2011; Ohno, Hiroshi/L-7899-2014; Wasserman, Wyeth/I-4866-2015; Sheng, Guojun/I-4900-2015; Pain, Arnab/L-5766-2015; Beckhouse, Anthony/A-2601-2010; Summers, Kim/M-4086-2015; Arner, Erik/A-1895-2010; Kasukawa, Takeya/N-5070-2015; Plessy, Charles/N-5054-2015; Itoh, Masayoshi/N-5363-2015; Schmeier, Sebastian/D-4731-2011; Kawaji, Hideya/N-5116-2015; Wolvetang, Ernst/D-6644-2017; Kwon, Andrew/D-4625-2017; Kaczkowski, Bogumil/D-5336-2017; Bertin, Nicolas/C-3025-2008; Archer, John/D-5200-2012; Bajic, Vladimir/D-2810-2009; Katayama, Shintaro/F-2958-2010; OI Daub, Carsten/0000-0002-3295-8729; Lassmann, Timo/0000-0002-0138-2691; Carninci, Piero/0000-0001-7202-7243; Sandelin, Albin/0000-0002-7109-7378; Kere, Juha/0000-0003-1974-0271; Hide, Winston Hide/0000-0002-8621-3271; Cannistraci, Carlo Vittorio/0000-0003-0100-8410; Zhao, Xiaobei/0000-0002-5277-0846; Andersson, Robin/0000-0003-1516-879X; Koseki, Haruhiko/0000-0001-8424-5854; Suzuki, Harukazu/0000-0002-8087-0836; Kojima, Soichi/0000-0002-5252-1612; KONDO, NAOTO/0000-0001-9576-7615; Koyasu, Shigeo/0000-0001-9585-3038; Semple, Colin/0000-0003-1765-4118; Vorontsov, Ilya/0000-0001-8888-0804; Diehl, Alexander/0000-0001-9990-8331; Mackay-Sim, Alan/0000-0003-4446-5371; Ovchinnikov, Dmitry/0000-0001-9603-8385; Vitezic, Morana/0000-0002-7994-9600; Rehli, Michael/0000-0003-3992-932X; Ohno, Hiroshi/0000-0001-8776-9661; Pain, Arnab/0000-0002-1755-2819; Beckhouse, Anthony/0000-0002-5141-8250; Summers, Kim/0000-0002-7084-4386; Arner, Erik/0000-0003-1225-4908; Kasukawa, Takeya/0000-0001-5085-0802; Plessy, Charles/0000-0001-7410-6295; Itoh, Masayoshi/0000-0002-1772-318X; Schmeier, Sebastian/0000-0002-3947-8226; Kawaji, Hideya/0000-0002-0575-0308; Kwon, Andrew/0000-0001-5019-8156; Kaczkowski, Bogumil/0000-0001-6554-5608; Bertin, Nicolas/0000-0002-9835-9606; Bajic, Vladimir/0000-0001-5435-4750; Katayama, Shintaro/0000-0001-7581-5157; Harbers, Matthias/0000-0002-5613-7220; Kenna, Tony/0000-0001-6844-3463; Gingeras, Thomas/0000-0001-9106-3573; Alam, Intikhab/0000-0001-5306-847X; Taylor, Martin/0000-0001-7656-330X; Chierici, Marco/0000-0001-9791-9301; Persson, Helena/0000-0002-5187-6446; van Nimwegen, Erik/0000-0001-6338-1312; Fang, Hai/0000-0003-3961-8572; Morikawa, Hiromasa/0000-0002-6793-5885; Hamaguchi, Masahide/0000-0002-8651-4445; Ravasi, Timothy/0000-0002-9950-465X; Lenhard, Boris/0000-0002-1114-1509; Lennartsson, Andreas/0000-0002-3272-2505; Rackham, Owen/0000-0002-4390-0872; Furlanello, Cesare/0000-0002-5384-3605; Hofmann, Oliver/0000-0002-7738-1513; Fisher, Malcolm/0000-0003-1074-8103; Frith, Martin/0000-0003-0998-2859; Rashid, Mamoon/0000-0003-4851-4994; Jurman, Giuseppe/0000-0002-2705-5728; Valen, Eivind/0000-0003-1840-6108; Meehan, Terrence/0000-0003-1980-3228; Prendergast, James/0000-0001-8916-018X; Wells, Christine/0000-0003-3133-3628; Forrest, Alistair/0000-0003-4543-1675; Ciani, Yari/0000-0002-9635-2830 FU MEXT; MEXT, Japan; Research Grants for RIKEN Preventive Medicine and Diagnosis Innovation Program(RIKEN PMI); RIKEN Centre for Life Science Technologies, Division of Genomic Technologies (RIKEN CLST (DGT)) from the MEXT, Japan FX FANTOM5 was made possible by a Research Grant for RIKEN Omics Science Center from MEXT to Y. Hayashizaki and a grant of the Innovative Cell Biology by Innovative Technology (Cell Innovation Program) from the MEXT, Japan to Y. Hayashizaki. It was also supported by Research Grants for RIKEN Preventive Medicine and Diagnosis Innovation Program(RIKEN PMI) to Y. Hayashizaki and RIKEN Centre for Life Science Technologies, Division of Genomic Technologies (RIKEN CLST (DGT)) from the MEXT, Japan. Extended acknowledgements are provided in the Supplementary Information. NR 54 TC 313 Z9 315 U1 16 U2 140 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 27 PY 2014 VL 507 IS 7493 BP 462 EP + DI 10.1038/nature13182 PG 22 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD6WN UT WOS:000333402000033 ER PT J AU Liu, HP Moynihan, KD Zheng, YR Szeto, GL Li, AV Huang, B Van Egeren, DS Park, C Irvine, DJ AF Liu, Haipeng Moynihan, Kelly D. Zheng, Yiran Szeto, Gregory L. Li, Adrienne V. Huang, Bonnie Van Egeren, Debra S. Park, Clara Irvine, Darrell J. TI Structure-based programming of lymph-node targeting in molecular vaccines SO NATURE LA English DT Article ID IMMUNE-RESPONSE; DELIVERY; CELLS; OLIGONUCLEOTIDES; VACCINATION; ANTIGEN AB In cancer patients, visual identification of sentinel lymph nodes (LNs) is achieved by the injection of dyes that bind avidly to endogenous albumin, targeting these compounds to LNs, where they are efficiently filtered by resident phagocytes(1,2). Here we translate this 'albumin hitchhiking' approach to molecular vaccines, through the synthesis of amphiphiles (amph-vaccines) comprising an antigen or adjuvant cargo linked to a lipophilic albumin-binding tail by a solubility-promoting polar polymer chain. Administration of structurally optimized CpG-DNA/peptide amph-vaccines in mice resulted in marked increases in LN accumulation and decreased systemic dissemination relative to their parent compounds, leading to 30-fold increases in T-cell priming and enhanced anti-tumour efficacy while greatly reducing systemic toxicity. Amph-vaccines provide a simple, broadly applicable strategy to simultaneously increase the potency and safety of subunit vaccines. C1 [Liu, Haipeng; Irvine, Darrell J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Liu, Haipeng; Moynihan, Kelly D.; Zheng, Yiran; Szeto, Gregory L.; Li, Adrienne V.; Huang, Bonnie; Park, Clara; Irvine, Darrell J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Liu, Haipeng; Moynihan, Kelly D.; Zheng, Yiran; Szeto, Gregory L.; Li, Adrienne V.; Huang, Bonnie; Irvine, Darrell J.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Van Egeren, Debra S.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Irvine, Darrell J.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA. [Irvine, Darrell J.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Irvine, DJ (reprint author), MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. EM djirvine@mit.edu OI Van Egeren, Debra/0000-0002-4017-0413; Szeto, Gregory/0000-0001-7604-1333 FU Koch Institute from the National Cancer Institute [P30-CA14051]; National Institutes of Health [AI091693, AI104715, AI095109]; Department of Defense [W911NF-13-D-0001, W911NF-07-D-0004, T.O. 8]; Ragon Institute of Massachusetts General Hospital; Massachusetts Institute of Technology and Harvard FX This work was supported in part by the Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, the National Institutes of Health (grants AI091693, AI104715 and AI095109), the Department of Defense (W911NF-13-D-0001 and W911NF-07-D-0004, T.O. 8) and the Ragon Institute of Massachusetts General Hospital, the Massachusetts Institute of Technology and Harvard. D.J.I. is an investigator of the Howard Hughes Medical Institute. We thank T. C. Wu for kindly providing the TC-1 tumour cells. We thank the Koch Institute Swanson Biotechnology Center for technical support, specifically the applied therapeutics and whole animal imaging core facility, histology and flow cytometry core facility. The authors acknowledge the service to the MIT community of the late Sean Collier. NR 28 TC 113 Z9 114 U1 8 U2 125 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 27 PY 2014 VL 507 IS 7493 BP 519 EP + DI 10.1038/nature12978 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD6WN UT WOS:000333402000045 PM 24531764 ER PT J AU Liu, S An, J Lin, JH Liu, YL Bao, LD Zhang, W Zhao, JJ AF Liu, Shuang An, Jie Lin, Jianhong Liu, Yanli Bao, Lidao Zhang, Wen Zhao, Jian-Jun TI Single Nucleotide Polymorphisms of MicroRNA Processing Machinery Genes and Outcome of Hepatocellular Carcinoma SO PLOS ONE LA English DT Article ID NUCLEAR EXPORT; CANCER; EPIDEMIOLOGY; PRECURSORS; CHINA; RISK AB MicroRNA (miRNA)-related single nucleotide polymorphisms (miR-SNPs) can affect cancer development, treatment efficacy and patients prognosis. We examined 6 miR-SNPs in miRNA processing machinery genes including exportin 5 (XPO5) (rs11077), Ran-GTPase (RAN) (rs14035), Dicer (rs3742330), Trinucleotide Repeat Containing 6B (TNRC6B) (rs9623117), GEMIN3 (rs197412), GEMIN4 (rs2740348) in 108 surgically resected HCC patients and evaluated the impact of these miR-SNPs on HCC outcome. Among the 6 SNPs, only the A/A genotype of rs11077 located in XPO5 3'UTR was identified to associated independently with worse survival in HCC patients by multivariate analysis with relative risk, 0.395; 95% CI, 0.167-0.933; p = 0.034. This is the first study reporting that polymorphisms related to miRSNPs have prognostic value in hepatocellular carcinoma and identify the A/A genotype of rs11077 SNP site located in XPO5 3'UTR can help to predict worse prognosis in patients. C1 [Liu, Shuang; An, Jie; Liu, Yanli; Zhang, Wen] Bethune Int Peace Hosp, Dept Pathol, Shijiazhuang, Peoples R China. [Lin, Jianhong; Bao, Lidao; Zhao, Jian-Jun] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Liu, S (reprint author), Bethune Int Peace Hosp, Dept Pathol, Shijiazhuang, Peoples R China. EM Liu_Shuang11@hotmail.com; Jianjun_zhao@dfci.harvard.edu FU Bethune International Peace Hospital (BIPH) research grant; SPORE career development award from Dana-Farber Cancer Institute (DFCI); Multiple Myeloma Research Foundation (MMRF) award FX SL is supported by Bethune International Peace Hospital (BIPH) research grant. JL is supported by SPORE career development award from Dana-Farber Cancer Institute (DFCI). JJZ is supported by Multiple Myeloma Research Foundation (MMRF) award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 15 Z9 17 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 27 PY 2014 VL 9 IS 3 AR e92791 DI 10.1371/journal.pone.0092791 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE0SW UT WOS:000333677500039 PM 24676133 ER PT J AU Sharma, RK Makino, CL Hicks, D Duda, T AF Sharma, Rameshwar K. Makino, Clint L. Hicks, David Duda, Teresa TI ROS-GC interlocked Ca2+-sensor S100B protein signaling in cone photoreceptors: review SO FRONTIERS IN MOLECULAR NEUROSCIENCE LA English DT Review DE ROS-GC guanylate cyclase; cyclic GMP; phototransduction; cones; S100B ID MEMBRANE GUANYLATE-CYCLASE; NATRIURETIC-FACTOR RECEPTOR; OUTER SEGMENT; ACTIVATING PROTEIN; FUNCTIONAL-CHARACTERIZATION; CA2+ SENSOR; MOLECULAR CHARACTERIZATION; PEPTIDE RECEPTOR; RHODOPSIN KINASE; WILD-TYPE AB Photoreceptor rod outer segment membrane guanylate cyclase (ROS-GC) is central to visual transduction; it generates cyclic GMP the second messenger of the photon signal. Photoexcited rhodopsin initiates a biochemical cascade that leads to a drop in the intracellular level of cyclic GMP and closure of cyclic nucleotide gated ion channels. Recovery of the photoresponse requires resynthesis of cyclic GMP typically by a pair of ROS-GCs, 1 and 2. In rods, ROS-GCs exist as complexes with guanylate cyclase activating proteins (GCAPs), which are Ca2+-sensing elements. There is a light-induced fall in intracellular Ca2+. As Ca2+ dissociates from GCAPs in the 20-200 nM range, ROS-GC activity rises to quicken the photoresponse recovery. GCAPs then progressively turn down ROS-GC activity as Ca2+ and cyclic G MP levels return to baseline. To date, GCAPs mediate the only known mechanism of ROS-GC regulation in the photoreceptors. However, in mammalian cone outer segments, cone synapses and ON bipolar cells, another Ca2+ sensor protein, S100B, complexes with ROS-GC1 and senses the Ca2+ signal with a K-1/2 of 400 nM. Unlike GCAPs, S100B stimulates ROS-GC activity when Ca2+ is bound. Thus, the ROS-GC system in cones functions as a Ca2+ bimodal switch; with rising intracellular Ca2+, its activity is first turned down by GCAPs and then turned up by S100B. This presentation provides a historical perspective on the role of S100B in the photoreceptors, offers a pictorial model for the "bimodal" operation of the ROS-GC switch and projects future tasks that are needed to understand its operation. Some accounts of this review have been adopted from the original publications of these authors. C1 [Sharma, Rameshwar K.; Duda, Teresa] Salus Univ, Res Div Biochem & Mol Biol, Unit Regulatory & Mol Biol, Elkins Pk, PA 19207 USA. [Makino, Clint L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Hicks, David] CNRS, Inst Cellular & Integrat Neurosci, Dept Neurobiol Rhythms, CNRSUPR3212, Strasbourg, France. RP Sharma, RK (reprint author), Salus Univ, Res Div Biochem & Mol Biol, Unit Regulatory & Mol Biol, 8360 Old York Rd, Elkins Pk, PA 19207 USA. EM rsharma@salus.edu; Clint_Makino@meei.harvard.edu; tduda@salus.edu OI Makino, Clint/0000-0002-6005-9069 FU National Institutes of Health; National Science Foundation; Damon Runyon Walter Winchell Cancer Fund; Howe Laboratory Endowment of the Massachusetts Eye and Ear Infirmary FX The authors gratefuily acknowledge the continuous past support by the numerous USPHS award from the National Institutes of Health, the beginning award from the National Science Foundation and the Damon Runyon Walter Winchell Cancer Fund and the Howe Laboratory Endowment of the Massachusetts Eye and Ear Infirmary. NR 66 TC 7 Z9 7 U1 0 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5099 J9 FRONT MOL NEUROSCI JI Front. Molec. Neurosci. PD MAR 26 PY 2014 VL 7 AR 21 DI 10.3389/fnmol.2014.00021 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AZ0WT UT WOS:000347963500001 PM 24723847 ER PT J AU Bang, A Bellad, R Gisore, P Hibberd, P Patel, A Goudar, S Esamai, F Goco, N Meleth, S Derman, RJ Liechty, EA McClure, E Carlo, WA Wright, LL AF Bang, Akash Bellad, Roopa Gisore, Peter Hibberd, Patricia Patel, Archana Goudar, Shivaprasad Esamai, Fabian Goco, Norman Meleth, Sreelatha Derman, Richard J. Liechty, Edward A. McClure, Elizabeth Carlo, Waldemar A. Wright, Linda L. TI Implementation and evaluation of the Helping Babies Breathe curriculum in three resource limited settings: does Helping Babies Breathe save lives? A study protocol SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article DE Neonatal mortality; Perinatal mortality; Asphyxia; Stillbirth; Helping Babies Breathe; Resuscitation; Bag and mask ventilation; >= 1500 grams ID NEONATAL RESUSCITATION; PERINATAL-MORTALITY; DEVELOPING-COUNTRY AB Background: Neonatal deaths account for over 40% of all under-5 year deaths; their reduction is increasingly critical for achieving Millennium Development Goal 4. An estimated 3 million newborns die annually during their first month of life; half of these deaths occur during delivery or within 24 hours. Every year, 6 million babies require help to breathe immediately after birth. Resuscitation training to help babies breathe and prevent/manage birth asphyxia is not routine in low-middle income facility settings. Helping Babies Breathe (HBB), a simulation-training program for babies wherever they are born, was developed for use in low-middle income countries. We evaluated whether HBB training of facility birth attendants reduces perinatal mortality in the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Global Network research sites. Methods/design: We hypothesize that a two-year prospective pre-post study to evaluate the impact of a facility-based training package, including HBB and essential newborn care, will reduce all perinatal mortality (fresh stillbirth or neonatal death prior to 7 days) among the Global Network's Maternal Neonatal Health Registry births >= 1500 grams in the study clusters served by the facilities. We will also evaluate the effectiveness of the HBB training program changing on facility-based perinatal mortality and resuscitation practices. Seventy-one health facilities serving 52 geographically-defined study clusters in Belgaum and Nagpur, India, and Eldoret, Kenya, and 30,000 women will be included. Primary outcome data will be collected by staff not involved in the HBB intervention. Additional data on resuscitations, resuscitation debriefings, death audits, quality monitoring and improvement will be collected. HBB training will include training of MTs, facility level birth attendants, and quality monitoring and improvement activities. Discussion: Our study will evaluate the effect of a HBB/ENC training and quality monitoring and improvement package on perinatal mortality using a large multicenter design and approach in 71 resource-limited health facilities, leveraging an existing birth registry to provide neonatal outcomes through day 7. The study will provide the evidence base, lessons learned, and best practices that will be essential to guiding future policy and investment in neonatal resuscitation. C1 [Bang, Akash] Mahatma Gandhi Inst Med Sci, Sevagram, India. [Bellad, Roopa; Goudar, Shivaprasad] KLEs Jawaharlal Nehru Med Coll, Belgaum, India. [Gisore, Peter; Esamai, Fabian] Moi Univ, Eldoret, Kenya. [Hibberd, Patricia] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Patel, Archana] Lata Med Res Fdn, Nagpur, Maharashtra, India. [Goco, Norman; Meleth, Sreelatha; McClure, Elizabeth] RTI Int, Durham, NC USA. [Derman, Richard J.] Christiana Care, Newark, DE USA. [Liechty, Edward A.] Indiana Univ, Indianapolis, IN 46204 USA. [Carlo, Waldemar A.] Univ Alabama Birmingham, Birmingham, AL USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Bang, A (reprint author), Mahatma Gandhi Inst Med Sci, Sevagram, India. EM drakashbang@gmail.com OI GOUDAR, SHIVAPRASAD/0000-0002-8680-7053 FU Laerdal Foundation; Norad; NICHD [U01 HD040636, U01 HD058322, U01 HD042372, U01 HD058326] FX We thank the Scientific Advisory Board members, Alan H Jobe, MD, PhD; William J Keenan, MD and Petter Andreas Steen, MD for their oversight and guidance. This study was funded with grants from the Laerdal Foundation, Norad, and the NICHD (grant numbers U01 HD040636; U01 HD058322; U01 HD042372; U01 HD058326). NR 18 TC 18 Z9 18 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD MAR 26 PY 2014 VL 14 AR 116 DI 10.1186/1471-2393-14-116 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AF8CK UT WOS:000334942700001 PM 24670013 ER PT J AU Pitroda, SP Pashtan, IM Logan, HL Budke, B Darga, TE Weichselbaum, RR Connell, PP AF Pitroda, Sean P. Pashtan, Itai M. Logan, Hillary L. Budke, Brian Darga, Thomas E. Weichselbaum, Ralph R. Connell, Philip P. TI DNA Repair Pathway Gene Expression Score Correlates with Repair Proficiency and Tumor Sensitivity to Chemotherapy SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID STRAND BREAK REPAIR; CELL LUNG-CANCER; HOMOLOGOUS RECOMBINATION; MAMMALIAN-CELLS; ADJUVANT CHEMOTHERAPY; END RESECTION; RAD51; OVEREXPRESSION; INSTABILITY; PROTEIN AB Mutagenesis is a hallmark of malignancy, and many oncologic treatments function by generating additional DNA damage. Therefore, DNA damage repair is centrally important in both carcinogenesis and cancer treatment. Homologous recombination (HR) and nonhomologous end joining are alternative pathways of double-strand DNA break repair. We developed a method to quantify the efficiency of DNA repair pathways in the context of cancer therapy. The recombination proficiency score (RPS) is based on the expression levels for four genes involved in DNA repair pathway preference (Rif1, PARI, RAD51, and Ku80), such that high expression of these genes yields a low RPS. Carcinoma cells with low RPS exhibit HR suppression and frequent DNA copy number alterations, which are characteristic of error-prone repair processes that arise in HR-deficient backgrounds. The RPS system was clinically validated in patients with breast or non-small cell lung carcinomas (NSCLCs). Tumors with low RPS were associated with greater mutagenesis, adverse clinical features, and inferior patient survival rates, suggesting that HR suppression contributes to the genomic instability that fuels malignant progression. This adverse prognosis associated with low RPS was diminished if NSCLC patients received adjuvant chemotherapy, suggesting that HR suppression and associated sensitivity to platinum-based drugs counteract the adverse prognosis associated with low RPS. Therefore, RPS may help oncologists select which therapies will be effective for individual patients, thereby enabling more personalized care. C1 [Pitroda, Sean P.; Logan, Hillary L.; Budke, Brian; Darga, Thomas E.; Weichselbaum, Ralph R.; Connell, Philip P.] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60647 USA. [Pashtan, Itai M.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. [Pashtan, Itai M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02215 USA. [Weichselbaum, Ralph R.] Univ Chicago, Ludwig Ctr Metastasis Res, Chicago, IL 60647 USA. RP Connell, PP (reprint author), Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60647 USA. EM pconnell@radonc.uchicago.edu OI Darga, Thomas/0000-0002-8968-6701 FU NIH [CA142642-02]; Ludwig Foundation for Cancer Research; Lung Cancer Research Foundation FX Funding: This work was supported by funding from the NIH (CA142642-02 2010-2015 to P. P. C.), Ludwig Foundation for Cancer Research (to R. R. W.), and the Lung Cancer Research Foundation (to R.R.W.). NR 61 TC 13 Z9 13 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 26 PY 2014 VL 6 IS 229 AR 229ra42 DI 10.1126/scitranslmed.3008291 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AE3UR UT WOS:000333904300007 PM 24670686 ER PT J AU Hiraki, LT Joshi, AD Ng, K Fuchs, CS Ma, J Hazra, A Peters, U Karlson, EW Giovannucci, E Kraft, P Chan, AT AF Hiraki, Linda T. Joshi, Amit D. Ng, Kimmie Fuchs, Charles S. Ma, Jing Hazra, Aditi Peters, Ulrike Karlson, Elizabeth W. Giovannucci, Edward Kraft, Peter Chan, Andrew T. TI Joint Effects of Colorectal Cancer Susceptibility Loci, Circulating 25-Hydroxyvitamin D Risk of Colorectal Cancer SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; VITAMIN-D; COLON-CANCER; PHYSICIANS HEALTH; METAANALYSIS; WOMEN; CALCIUM; DISEASE; MEN; SCAN AB Background: Genome wide association studies (GWAS) have identified several SNPs associated with colorectal cancer (CRC) susceptibility. Vitamin D is also inversely associated with CRC risk. Methods: We examined main and joint effects of previously GWAS identified genetic markers of CRC and plasma 25-hydroxyvitamin D (25(OH)D) on CRC risk in three prospective cohorts: the Nurses' Health Study (NHS), the Health Professionals Follow-up Study (HPFS), and the Physicians' Health Study (PHS). We included 1895 CRC cases and 2806 controls with genomic DNA. We calculated odds ratios and 95% confidence intervals for CRC associated with additive genetic risk scores (GRSs) comprised of all CRC SNPs and subsets of these SNPs based on proximity to regions of increased vitamin D receptor binding to vitamin D response elements (VDREs), based on published ChiP-seq data. Among a subset of subjects with additional prediagnostic 25(OH)D we tested multiplicative interactions between plasma 25(OH)D and GRS's. We used fixed effects models to meta-analyze the three cohorts. Results: The per allele multivariate OR was 1.12 (95% CI, 1.06-1.19) for GRS-proximalVDRE; and 1.10 (95% Cl, 1.06-1.14) for GRS-nonproxVDRE. The lowest quartile of plasma 25(OH)D compared with the highest, had a multivariate OR of 0.63 (95% Cl, 0.48-0.82) for CRC. We did not observe any significant interactions between any GRSs and plasma 25(OH)D. Conclusions: We did not observe evidence for the modification of genetic susceptibility for CRC according to vitamin D status, or evidence that the effect of common CRC risk alleles differed according to their proximity to putative VDR binding sites. C1 [Hiraki, Linda T.; Joshi, Amit D.; Hazra, Aditi; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Ng, Kimmie; Fuchs, Charles S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Fuchs, Charles S.; Ma, Jing; Hazra, Aditi; Giovannucci, Edward; Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Fuchs, Charles S.; Ma, Jing; Hazra, Aditi; Karlson, Elizabeth W.; Giovannucci, Edward; Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA USA. [Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Karlson, Elizabeth W.] Brigham & Womens Hosp, Dept Med, Div Rheumatol, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Dept Med, Div Gastroenterol, Boston, MA 02114 USA. RP Chan, AT (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. EM ACHAN@partners.org FU National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services [U01 CA137088, R01 CA059045, RO1 CA137178, K24 DK098311]; Canadian Institute of Health Research (CIHR) Fellowship Award; NIH [5K07CA148894] FX Support was provided by National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045; RO1 CA137178; K24 DK098311). Dr. Hiraki was supported by a Canadian Institute of Health Research (CIHR) Fellowship Award, Dr. Ng was supported by an NIH 5K07CA148894 award. Dr. Chan is a Damon Runyon Clinical Investigator. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 3 Z9 3 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 26 PY 2014 VL 9 IS 3 AR e92212 DI 10.1371/journal.pone.0092212 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE0SR UT WOS:000333677000036 PM 24670869 ER PT J AU Muller, LPD Sargoy, A Rodriguez, AR Brecha, NC AF Mueller, Luis Perez de Sevilla Sargoy, Allison Rodriguez, Allen R. Brecha, Nicholas C. TI Melanopsin Ganglion Cells Are the Most Resistant Retinal Ganglion Cell Type to Axonal Injury in the Rat Retina SO PLOS ONE LA English DT Article ID OPTIC-NERVE SECTION; MOUSE RETINA; ADULT-RATS; SURVIVAL; PROTEIN; NEURONS; MICE; AKT; MORPHOLOGY; APOPTOSIS AB We report that the most common retinal ganglion cell type that remains after optic nerve transection is the M1 melanopsin ganglion cell. M1 ganglion cells are members of the intrinsically photosensitive retinal ganglion cell population that mediates non-image-forming vision, comprising similar to 2.5% of all ganglion cells in the rat retina. In the present study, M1 ganglion cells comprised 1.7 +/- 1%, 28 +/- 14%, 55 +/- 13% and 82 +/- 8% of the surviving ganglion cells 7, 14, 21 and 60 days after optic nerve transection, respectively. Average M1 ganglion cell somal diameter and overall morphological appearance remained unchanged in non-injured and injured retinas, suggesting a lack of injury-induced degeneration. Average M1 dendritic field size increased at 7 and 60 days following optic nerve transection, while average dendritic field size remained similar in non-injured retinas and in retinas at 14 and 21 days after optic nerve transection. These findings demonstrate that M1 ganglion cells are more resistant to injury than other ganglion cell types following optic nerve injury, and provide an opportunity to develop pharmacological or genetic therapeutic approaches to mitigate ganglion cell death and save vision following optic nerve injury. C1 [Mueller, Luis Perez de Sevilla; Sargoy, Allison; Rodriguez, Allen R.; Brecha, Nicholas C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Brecha, Nicholas C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Sargoy, Allison; Brecha, Nicholas C.] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. [Brecha, Nicholas C.] Univ Calif Los Angeles, David Geffen Sch Med, CURE Digest Dis Res Ctr, Los Angeles, CA 90095 USA. [Brecha, Nicholas C.] Vet Adm Greater Los Angeles Hlth Syst, Los Angeles, CA USA. RP Muller, LPD (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. EM luisperez@mednet.ucla.edu FU Telemedicine & Advanced Technology Research Center (TATRC), at Fort Detrick, MD [W81XWH-10-2-0077]; NIH [EY04067]; NIDDK [P30 DK41301]; VA Merit Review; VA Career Research Scientist FX This research and development project was conducted by the authors at the David Geffen School of Medicine at UCLA and is made possible by a contract agreement that was awarded and administered by the U.S. Army Medical Research & Materiel Command (USAMRMC) and the Telemedicine & Advanced Technology Research Center (TATRC), at Fort Detrick, MD under Contract Number: W81XWH-10-2-0077. Support for these studies also came from NIH EY04067, NIDDK P30 DK41301 (UCLA Cure Center Core) and a VA Merit Review (NB). NCB is a VA Career Research Scientist. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 17 Z9 17 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 26 PY 2014 VL 9 IS 3 AR e93274 DI 10.1371/journal.pone.0093274 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE0SR UT WOS:000333677000130 ER PT J AU Nettiksimmons, J Simonsick, EM Harris, T Satterfield, S Rosano, C Yaffe, K AF Nettiksimmons, Jasmine Simonsick, Eleanor M. Harris, Tamara Satterfield, Suzanne Rosano, Caterina Yaffe, Kristine CA Hlth ABC Study TI The Associations between Serum Brain-Derived Neurotrophic Factor, Potential Confounders, and Cognitive Decline: A Longitudinal Study SO PLOS ONE LA English DT Article ID BDNF MESSENGER-RNA; ALZHEIMERS-DISEASE; CARDIORESPIRATORY FITNESS; DECREASED-LEVELS; BLOOD-BRAIN; IMPAIRMENT; DEPRESSION; SURVIVAL; NEURONS; MEN AB Brain-derived neurotrophic factor (BDNF) plays a role in the maintenance and function of neurons. Although persons with Alzheimer's disease have lower cortical levels of BDNF, evidence regarding the association between circulating BDNF and cognitive function is conflicting. We sought to determine the correlates of BDNF level and whether BDNF level was prospectively associated with cognitive decline in healthy older adults. We measured serum BDNF near baseline in 912 individuals. Cognitive status was assessed repeatedly with the modified Mini-Mental Status Examination and the Digit Symbol Substitution test over the next 10 years. We evaluated the association between BDNF and cognitive decline with longitudinal models. We also assessed the association between BDNF level and demographics, comorbidities and health behaviors. We found an association between serum BDNF and several characteristics that are also associated with dementia (race and depression), suggesting that future studies should control for these potential confounders. We did not find evidence of a longitudinal association between serum BDNF and subsequent cognitive test trajectories in older adults, although we did identify a potential trend toward a cross-sectional association. Our results suggest that serum BDNF may have limited utility as a biomarker of prospective cognitive decline. C1 [Nettiksimmons, Jasmine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Harris, Tamara] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Rosano, Caterina] Univ Pittsburgh, Dept Epidemiol, Ctr Aging & Populat Hlth, Pittsburgh, PA 15261 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. RP Nettiksimmons, J (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. EM Jasmine.nettiksimmons@ucsf.edu OI Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010 FU NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; NINR [R01-NR012459]; Intramural Research Program of the NIH, National Institute of Aging; American Health Assistance Foundation [A201-0029]; National Institute of Aging [K24AG031155] FX This research was supported by the following: NIA contract numbers: N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant numbers: R01-AG028050, NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Aging and by a grant from the American Health Assistance Foundation, grant number A201-0029. Dr. Yaffe is supported in part by a National Institute of Aging Grant (K24AG031155). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 16 Z9 17 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 26 PY 2014 VL 9 IS 3 AR e91339 DI 10.1371/journal.pone.0091339 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE0SR UT WOS:000333677000018 PM 24670553 ER PT J AU Wang, J Land, D Ono, K Galvez, J Zhao, W Vempati, P Steele, JW Cheng, A Yamada, M Levine, S Mazzola, P Pasinetti, GM AF Wang, Jun Land, David Ono, Kenjiro Galvez, Jorge Zhao, Wei Vempati, Prashant Steele, John W. Cheng, Alice Yamada, Masahito Levine, Samara Mazzola, Paolo Pasinetti, Giulio M. TI Molecular Topology as Novel Strategy for Discovery of Drugs with A beta Lowering and Anti-Aggregation Dual Activities for Alzheimer's Disease SO PLOS ONE LA English DT Article ID MOUSE MODEL; PROTEIN; OLIGOMERS; NEUROPATHOLOGY; TOXICITY; PATHWAY; DESIGN; MEMORY AB Background and Purpose: In this study, we demonstrate the use of Molecular topology (MT) in an Alzheimer's disease (AD) drug discovery program. MT uses and expands upon the principles governing the molecular connectivity theory of numerically characterizing molecular structures, in the present case, active anti-AD drugs/agents, using topological descriptors to build models. Topological characterization has been shown to embody sufficient molecular information to provide strong correlation to therapeutic efficacy. Experimental Approach: We used MT to include multiple bioactive properties that allows for the identification of multifunctional single agent compounds, in this case, the dual functions of beta-amyloid (A beta) -lowering and anti-oligomerization. Using this technology, we identified and designed novel compounds in chemical classes unrelated to current anti-AD agents that exert dual A beta lowering and anti-A beta oligomerization activities in animal models of AD. AD is a multifaceted disease with different pathological features. Conclusion and Implications: Our study, for the first time, demonstrated that MT can provide novel strategy for discovering drugs with A beta lowering and anti-aggregation dual activities for AD. C1 [Wang, Jun; Zhao, Wei; Vempati, Prashant; Steele, John W.; Cheng, Alice; Levine, Samara; Mazzola, Paolo; Pasinetti, Giulio M.] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. [Land, David] Medisyn Technol Inc, Minnetonka, MN USA. [Ono, Kenjiro; Yamada, Masahito] Kanazawa Univ, Dept Neurol & Neurobiol Aging, Kanazawa, Ishikawa, Japan. [Galvez, Jorge] Univ Valencia, Mol Topol & Drug Design Unit, Valencia, Spain. [Wang, Jun; Pasinetti, Giulio M.] James J Peters Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. RP Pasinetti, GM (reprint author), Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. EM giulio.pasinetti@mssm.edu FU Altschul Foundation; Icahn School of Medicine at Mount Sinai FX This study is supported in part by the Altschul Foundation and by Discretionary Funds to Giulio Maria Pasinetti from the Icahn School of Medicine at Mount Sinai. NR 33 TC 0 Z9 0 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 26 PY 2014 VL 9 IS 3 AR e92750 DI 10.1371/journal.pone.0092750 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE0SR UT WOS:000333677000072 PM 24671215 ER PT J AU Goldberg, DS French, B Forde, KA Groeneveld, PW Bittermann, T Backus, L Halpern, SD Kaplan, DE AF Goldberg, David S. French, Benjamin Forde, Kimberly A. Groeneveld, Peter W. Bittermann, Therese Backus, Lisa Halpern, Scott D. Kaplan, David E. TI Association of Distance From a Transplant Center With Access to Waitlist Placement, Receipt of Liver Transplantation, and Survival Among US Veterans SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HEPATITIS-C VIRUS; BARIATRIC SURGERY; UNITED-STATES; PRIMARY-CARE; SERVICES; POLICY; MODEL; IMPLEMENTATION; EXCELLENCE; GUIDELINES AB IMPORTANCE Centralization of specialized health care services such as organ transplantation and bariatric surgery is advocated to improve quality, increase efficiency, and reduce cost. The effect of increased travel on access and outcomes from these services is not fully understood. OBJECTIVE To evaluate the association between distance from a Veterans Affairs (VA) transplant center (VATC) and access to being waitlisted for liver transplantation, actually having a liver transplant, and mortality. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of veterans meeting liver transplantation eligibility criteria from January 1, 2003, until December 31, 2010, using data from the Veterans Health Administration's integrated, national, electronic medical record linked to Organ Procurement and Transplantation Network data. MAIN OUTCOMES AND MEASURES The primary outcome was being waitlisted for transplantation at a VATC. Secondary outcomes included being waitlisted at any transplant center, undergoing a transplantation, and survival. RESULTS From 2003-2010, 50 637 veterans were classified as potentially eligible for transplant; 2895 (6%) were waitlisted and 1418 of those were waitlisted (49%) at 1 of the 5 VATCs. Of 3417 veterans receiving care at a VA hospital located within 100 miles from a VATC, 244 (7.1%) were waitlisted at a VATC and 372 (10.9%) at any transplant center (VATC and non-VATCs). Of 47 219 veterans receiving care at a VA hospital located more than 100 miles from a VATC, 1174 (2.5%) were waitlisted at a VATC and 2523 (5.3%) at any transplant center (VATC and non-VATCs). In multivariable models, increasing distance to closest VATC was associated with significantly lower odds of being waitlisted at a VATC (odds ratio [OR], 0.91 [95% CI, 0.89-0.93] for each doubling in distance) or any transplant center (OR, 0.94 [95% CI, 0.92-0.96] for each doubling in distance). For example, a veteran living 25 miles from a VATC would have a 7.4%(95% CI, 6.6%-8.1%) adjusted probability of being waitlisted, whereas a veteran 100 miles from a VATC would have a 6.2%(95% CI, 5.7%-6.6%) adjusted probability. In adjusted models, increasing distance from a VATC was associated with significantly lower transplantation rates (subhazard ratio, 0.97; 95% CI, 0.95-0.98 for each doubling in distance). There was significantly increased mortality among waitlisted veterans from the time of first hepatic decompensation event in multivariable survival models (hazard ratio, 1.03; 95% CI, 1.01-1.04 for each doubling in distance). For example, a waitlisted veteran living 25 miles from a VATC would have a 62.9% (95% CI, 59.1%-66.1%) 5-year adjusted probability of survival from first hepatic decompensation event compared with a 59.8%(95% CI, 56.3%-63.1%) 5-year adjusted probability of survival for a veteran living 100 miles from a VATC. CONCLUSIONS AND RELEVANCE Among VA patients meeting eligibility criteria for liver transplantation, greater distance from a VATC or any transplant center was associated with lower likelihood of being waitlisted, receiving a liver transplant, and greater likelihood of death. The relationship between these findings and centralizing specialized care deserves further investigation. C1 [Goldberg, David S.; Forde, Kimberly A.; Kaplan, David E.] Univ Penn, Dept Med, Div Gastroenterol, Philadelphia, PA 19104 USA. [Goldberg, David S.; French, Benjamin; Forde, Kimberly A.; Halpern, Scott D.] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Goldberg, David S.; French, Benjamin; Groeneveld, Peter W.; Halpern, Scott D.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Groeneveld, Peter W.] Univ Penn, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Groeneveld, Peter W.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Bittermann, Therese] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Backus, Lisa] Dept Vet Affairs, Off Publ Hlth, Philadelphia, PA USA. [Halpern, Scott D.] Univ Penn, Dept Med, Div Pulm Allergy & Crit Care, Philadelphia, PA 19104 USA. [Kaplan, David E.] Philadelphia VA Med Ctr, Gastroenterol Sect, Philadelphia, PA USA. RP Goldberg, DS (reprint author), Hosp Univ Penn, 3400 Civ Ctr Blvd,9 Penn Tower, Philadelphia, PA 19104 USA. EM david.goldberg@uphs.upenn.edu FU Health Resources and Services Administration [234-2005-37011C] FX This work was supported in part by Health Resources and Services Administration contract 234-2005-37011C. NR 40 TC 24 Z9 24 U1 3 U2 4 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 26 PY 2014 VL 311 IS 12 BP 1234 EP 1243 DI 10.1001/jama.2014.2520 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AD6CE UT WOS:000333340500027 PM 24668105 ER PT J AU McNulty, EJ Hung, YY Almers, LM Go, AS Yeh, RW AF McNulty, Edward J. Hung, Yun-Yi Almers, Lucy M. Go, Alan S. Yeh, Robert W. TI Population Trends From 2000-2011 in Nuclear Myocardial Perfusion Imaging Use SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID UNITED-STATES C1 [McNulty, Edward J.] Kaiser Permanente Med Ctr, Div Cardiol, San Francisco, CA 94115 USA. [Hung, Yun-Yi; Almers, Lucy M.; Go, Alan S.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Yeh, Robert W.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP McNulty, EJ (reprint author), Kaiser Permanente Med Ctr, 2200 OFarrell Blvd, San Francisco, CA 94115 USA. EM edward.j.mcnulty@kp.org NR 5 TC 12 Z9 12 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 26 PY 2014 VL 311 IS 12 BP 1248 EP 1249 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AD6CE UT WOS:000333340500030 PM 24668108 ER PT J AU Liberman, MC Liberman, LD Maison, SF AF Liberman, M. Charles Liberman, Leslie D. Maison, Stephane F. TI Efferent Feedback Slows Cochlear Aging SO JOURNAL OF NEUROSCIENCE LA English DT Article DE auditory neuropathy; feedback; hair cells; hearing conservation ID AUDITORY-NERVE FIBERS; CROSSED OLIVOCOCHLEAR BUNDLE; GUINEA-PIG COCHLEA; ELECTRICAL-STIMULATION; MAMMALIAN COCHLEA; ACOUSTIC INJURY; HEARING-LOSS; BRAIN-STEM; OTOACOUSTIC EMISSIONS; SYNAPTIC RIBBONS AB The inner ear receives two types of efferent feedback from the brainstem: one pathway provides gain control on outer hair cells' contribution to cochlear amplification, and the other modulates the excitability of the cochlear nerve. Although efferent feedback can protect hair cells from acoustic injury and thereby minimize noise-induced permanent threshold shifts, most prior studies focused on high-intensity exposures (> 100 dB SPL). Here, we show that efferents are essential for long-term maintenance of cochlear function in mice aged 1 year post-de-efferentation without purposeful acoustic overexposure. Cochlear de-efferentation was achieved by surgical lesion of efferent pathways in the brainstem and was assessed by quantitative analysis of immunostained efferent terminals in outer and inner hair cell areas. The resultant loss of efferent feedback accelerated the age-related amplitude reduction in cochlear neural responses, as seen in auditory brainstem responses, and increased the loss of synapses between hair cells and the terminals of cochlear nerve fibers, as seen in confocal analysis of the organ of Corti immunostained for presynaptic and postsynaptic markers. This type of neuropathy, also seen after moderate noise exposure, has been termed "hidden hearing loss", because it does not affect thresholds, but can be seen in the suprathreshold amplitudes of cochlear neural responses, and likely causes problems with hearing in a noisy environment, a classic symptom of age-related hearing loss in humans. Since efferent reflex strength varies among individuals and can be measured noninvasively, a weak reflex may be an important risk factor, and prognostic indicator, for age-related hearing impairment. C1 [Liberman, M. Charles; Maison, Stephane F.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Liberman, M. Charles; Liberman, Leslie D.; Maison, Stephane F.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Liberman, M. Charles; Maison, Stephane F.] 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 Research was supported by National Institute on Deafness and Other Communication Disorders Grants R01 DC 0188 and P30 DC 05209. NR 59 TC 33 Z9 34 U1 2 U2 25 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 26 PY 2014 VL 34 IS 13 BP 4599 EP 4607 DI 10.1523/JNEUROSCI.4923-13.2014 PG 9 WC Neurosciences SC Neurosciences & Neurology GA AE0RP UT WOS:000333674200016 PM 24672005 ER PT J AU Fang, MC Go, AS Chang, YC Borowsky, LH Pomernacki, NK Udaltsova, N Singer, DE AF Fang, Margaret C. Go, Alan S. Chang, Yuchiao Borowsky, Leila H. Pomernacki, Niela K. Udaltsova, Natalia Singer, Daniel E. TI Long-term survival after ischemic stroke in patients with atrial fibrillation SO NEUROLOGY LA English DT Article ID ANTICOAGULATION THERAPY; ANTITHROMBOTIC THERAPY; RISK-FACTORS; MORTALITY; WARFARIN; REGISTRY; POPULATION; PREVENTION; SEVERITY; PROJECT AB Objectives:While the short-term impact of atrial fibrillation-related stroke has been well studied, surprisingly little is known about its long-term effect on survival.Methods:We followed 13,559 patients with atrial fibrillation for a median of 6 years, identifying ischemic strokes through computerized databases and validating 1,025 events. Stroke severity was determined from hospital records. We compared survival of stroke patients with comparator nonstroke patients (matched for age, sex, race, comorbid conditions, and time of entry into the cohort) using proportional hazard models controlling for warfarin use and compared survival by degree of discharge deficit.Results:Median survival after stroke was 1.8 years compared with 5.7 years for matched nonstroke comparators (hazard ratio [HR] 2.8, 95% confidence interval [CI] 2.5-3.2). This increased risk of all-cause death persisted even after restricting the analysis to the 576 stroke patients who survived 6 months after the initial stroke event (HR 2.0, 95% CI 1.7-2.5, adjusting for warfarin use). Risk of death was strongly associated with stroke severity: HR 2.9 (95% CI 2.3-3.5) for strokes resulting in major deficits and HR 8.3 (95% CI 5.2-13.2) for strokes resulting in severe deficits compared with matched comparators without stroke.Conclusions:Ischemic stroke approximately triples the mortality rate in patients with atrial fibrillation. This effect persists well beyond the immediate period poststroke and is strongly associated with disability after stroke. Stroke prevention by anticoagulation has even greater beneficial effects on survival than usually considered when focusing solely on 30-day mortality rates. C1 [Fang, Margaret C.; Go, Alan S.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Go, Alan S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Go, Alan S.; Pomernacki, Niela K.; Udaltsova, Natalia] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Chang, Yuchiao; Borowsky, Leila H.; Singer, Daniel E.] Massachusetts Gen Hosp, Clin Epidemiol Unit, Div Gen Med, Boston, MA 02114 USA. RP Fang, MC (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM mfang@medicine.ucsf.edu FU National Institute on Aging [R01 AG15478, K23 AG028978]; National Heart, Lung, and Blood Institute [U19 HL91179, RC2HL101589]; Eliot B. and Edith C. Shoolman fund of the Massachusetts General Hospital (Boston) FX Supported by the National Institute on Aging (R01 AG15478 and K23 AG028978), the National Heart, Lung, and Blood Institute (U19 HL91179 and RC2HL101589), and the Eliot B. and Edith C. Shoolman fund of the Massachusetts General Hospital (Boston). The funding sources had no role in study design, data collection, data analysis, data interpretation, or preparation of the manuscript. Dr. Fang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 26 TC 8 Z9 8 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 25 PY 2014 VL 82 IS 12 BP 1033 EP 1037 DI 10.1212/WNL.0000000000000248 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA AH9XW UT WOS:000336500100010 PM 24532273 ER PT J AU James, BD Leurgans, SE Hebert, LE Scherr, PA Yaffe, K Bennett, DA AF James, Bryan D. Leurgans, Sue E. Hebert, Liesi E. Scherr, Paul A. Yaffe, Kristine Bennett, David A. TI Contribution of Alzheimer disease to mortality in the United States SO NEUROLOGY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; COMMUNITY-BASED COHORT; CLINICAL-DIAGNOSIS; AGING PROJECT; OLDER PERSONS; RUSH MEMORY; DEMENTIA; SURVIVAL; DEATH; POPULATION AB Objective:To assess the burden of mortality attributable to Alzheimer disease (AD) dementia in the United States.Methods:Data came from 2,566 persons aged 65 years and older (mean 78.1 years) without dementia at baseline from 2 cohort studies of aging with identical annual diagnostic assessments of dementia. Because both studies require organ donation, ascertainment of mortality was complete and dates of death accurate. Mortality hazard ratios (HRs) after incident AD dementia were estimated per 10-year age strata from proportional hazards models. Population attributable risk percentage was derived to estimate excess mortality after a diagnosis of AD dementia. The number of excess deaths attributable to AD dementia in the United States was then estimated.Results:Over an average of 8 years, 559 participants (21.8%) without dementia at baseline developed AD dementia and 1,090 (42.4%) died. Median time from AD dementia diagnosis to death was 3.8 years. The mortality HR for AD dementia was 4.30 (confidence interval = 3.33, 5.58) for ages 75-84 years and 2.77 (confidence interval = 2.37, 3.23) for ages 85 years and older (too few deaths after AD dementia in ages 65-74 were available to estimate HR). Population attributable risk percentage was 37.0% for ages 75-84 and 35.8% for ages 85 and older. An estimated 503,400 deaths in Americans aged 75 years and older were attributable to AD dementia in 2010.Conclusions:A larger number of deaths are attributable to AD dementia in the United States each year than the number (<84,000 in 2010) reported on death certificates. C1 [James, Bryan D.; Leurgans, Sue E.; Bennett, David A.] Rush Univ, Rush Alzheimers Dis Ctr, Med Ctr, Chicago, IL 60612 USA. [James, Bryan D.] Rush Univ, Dept Internal Med, Med Ctr, Chicago, IL 60612 USA. [Leurgans, Sue E.; Bennett, David A.] Rush Univ, Dept Neurol Sci, Med Ctr, Chicago, IL 60612 USA. [Hebert, Liesi E.; Scherr, Paul A.] Rush Univ, Rush Inst Hlth Aging, Med Ctr, Chicago, IL 60612 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] San Francisco VA Med Ctr, San Francisco, CA USA. RP James, BD (reprint author), Rush Univ, Rush Alzheimers Dis Ctr, Med Ctr, Chicago, IL 60612 USA. EM Bryan_James@rush.edu FU National Institute on Aging [P30 AG10161, R01AG15819, R01AG17917, K24AG031155]; Illinois Department of Public Health [23282007] FX Directly supported by the National Institute on Aging (P30 AG10161, R01AG15819, R01AG17917, K24AG031155), and the Illinois Department of Public Health (contract 23282007). NR 35 TC 50 Z9 51 U1 1 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 25 PY 2014 VL 82 IS 12 BP 1045 EP 1050 DI 10.1212/WNL.0000000000000240 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA AH9XW UT WOS:000336500100012 PM 24598707 ER PT J AU Lu, L Barfejani, AH Qin, T Dong, Q Ayata, C Waeber, C AF Lu, Lei Barfejani, Arnavaz Hajizadeh Qin, Tao Dong, Qiang Ayata, Cenk Waeber, Christian TI Fingolimod exerts neuroprotective effects in a mouse model of intracerebral hemorrhage SO BRAIN RESEARCH LA English DT Article DE Intracerebral hemorrhage; Stroke; FTY720; Sphingosine 1-phosphate; Neuroprotection ID CEREBRAL-ARTERY OCCLUSION; SPHINGOSINE 1-PHOSPHATE RECEPTOR-1; TRAUMATIC BRAIN-INJURY; MULTIPLE-SCLEROSIS; FTY720 FINGOLIMOD; IN-VIVO; RATS; STROKE; REMYELINATION; APOPTOSIS AB Recent studies have shown that fingolimod (FTY720) is neuroprotective in CNS injury models of cerebral ischemia and spinal cord injury. The purpose of the study was to examine the effect of fingolimod in a mouse model of intracerebral hemorrhage. ICH was produced in adult CD1 mice by injecting collagenase VII-S (0.5 mu L, 0.06 U) into the basal ganglia. Fingolimod (or saline) was given 30 min after surgery and once daily for two days. Three days after intracerebral hemorrhage, brain edema, hematoma volume and the number of apoptotic cells were quantified. In another cohort of mice, brain atrophy was evaluated two weeks following intracerebral hemorrhage. Neurobehavioral tests were performed on the 3rd, the 7th and the 14th day. Fingolimod significantly decreased edema, apoptosis and brain atrophy. More importantly, fingolimod enhanced neurobehavioral recovery. Preliminary experiments showed no difference in the number of inflammatory (CD68-positive) cells between the two groups. In conclusion, fingolimod exerts protective effects in a mouse model of intracerebral hemorrhage; the mechanisms underlying these neuroprotective effects deserve further study. (c) 2014 Elsevier B.V. All rights reserved. C1 [Lu, Lei; Barfejani, Arnavaz Hajizadeh; Qin, Tao; Waeber, Christian] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Barfejani, Arnavaz Hajizadeh] Northeastern Univ, Sch Pharm, Bouve Coll Hlth Sci, Boston, MA 02115 USA. [Dong, Qiang] Fudan Univ, Huashan Hosp, Dept Neurol, State Key Lab Med Neurobiol, Shanghai 200040, Peoples R China. [Ayata, Cenk] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. RP Waeber, C (reprint author), Natl Univ Ireland Univ Coll Cork, Sch Pharm, Cavanagh Bldg,Room 1-26,Coll Rd, Cork, Ireland. EM c.waeber@ucc.ie RI Waeber, Christian/A-8333-2009 OI Waeber, Christian/0000-0001-6078-0027 FU NIH [NS049263, NS055104]; Boehringer Ingelheim Pharma GmbH Co. KG FX Funding for this study was provided by NIH Grant nos. (NS049263 and NS055104 to Dr. Christian Waeber). We thank Prof. Wolfgang Eisert and Boehringer Ingelheim Pharma GmbH & Co. KG for providing the BI Stroke Award fellowship to Dr. Lei Lu. We thank Prof. Eng H. Lo for his critical advice and support during the study. NR 40 TC 18 Z9 18 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 EI 1872-6240 J9 BRAIN RES JI Brain Res. PD MAR 25 PY 2014 VL 1555 BP 89 EP 96 DI 10.1016/j.brainres.2014.01.048 PG 8 WC Neurosciences SC Neurosciences & Neurology GA AF1LS UT WOS:000334476000009 PM 24502984 ER PT J AU Brown, ST Tate, JP Kyriakides, TC Kirkwood, KA Holodniy, M Goulet, JL Angus, BJ Cameron, DW Justice, AC AF Brown, Sheldon T. Tate, Janet P. Kyriakides, Tassos C. Kirkwood, Katherine A. Holodniy, Mark Goulet, Joseph L. Angus, Brian J. Cameron, D. William Justice, Amy C. CA OPTIMA Team TI The VACS Index Accurately Predicts Mortality and Treatment Response among Multi-Drug Resistant HIV Infected Patients Participating in the Options in Management with Antiretrovirals (OPTIMA) Study SO PLOS ONE LA English DT Article ID VETERANS AGING COHORT; NON-AIDS EVENTS; NONFATAL AIDS; RISK; THERAPY; PROGRESSION; EFFICACY; DISEASE; TRIALS; SAFETY AB Objectives: The VACS Index is highly predictive of all-cause mortality among HIV infected individuals within the first few years of combination antiretroviral therapy (cART). However, its accuracy among highly treatment experienced individuals and its responsiveness to treatment interventions have yet to be evaluated. We compared the accuracy and responsiveness of the VACS Index with a Restricted Index of age and traditional HIV biomarkers among patients enrolled in the OPTIMA study. Methods: Using data from 324/339 (96%) patients in OPTIMA, we evaluated associations between indices and mortality using Kaplan-Meier estimates, proportional hazards models, Harrel's C-statistic and net reclassification improvement (NRI). We also determined the association between study interventions and risk scores over time, and change in score and mortality. Results: Both the Restricted Index (c = 0.70) and VACS Index (c = 0.74) predicted mortality from baseline, but discrimination was improved with the VACS Index (NRI = 23%). Change in score from baseline to 48 weeks was more strongly associated with survival for the VACS Index than the Restricted Index with respective hazard ratios of 0.26 (95% CI 0.14-0.49) and 0.39(95% CI 0.22-0.70) among the 25% most improved scores, and 2.08 (95% CI 1.27-3.38) and 1.51 (95% CI 0.90-2.53) for the 25% least improved scores. Conclusions: The VACS Index predicts all-cause mortality more accurately among multi-drug resistant, treatment experienced individuals and is more responsive to changes in risk associated with treatment intervention than an index restricted to age and HIV biomarkers. The VACS Index holds promise as an intermediate outcome for intervention research. C1 [Brown, Sheldon T.] James J Peters VA Med Ctr, Bronx, NY 10468 USA. [Brown, Sheldon T.] Icahn Sch Med Mt Sinai, Dept Med, New York, NY USA. [Tate, Janet P.; Goulet, Joseph L.; Justice, Amy C.] VA Connecticut Healthcare Syst, Gen Internal Med Sect, West Haven, CT USA. [Tate, Janet P.; Goulet, Joseph L.; Justice, Amy C.] Yale Univ, Sch Med, New Haven, CT USA. [Tate, Janet P.; Goulet, Joseph L.; Justice, Amy C.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Kyriakides, Tassos C.; Kirkwood, Katherine A.] VA Connecticut Healthcare Syst, VA Cooperat Studies Program, Coordinating Ctr, West Haven, CT USA. [Holodniy, Mark] VA Palo Alto Healthcare Syst, Palo Alto, CA USA. [Holodniy, Mark] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [Angus, Brian J.] Univ Oxford, Nuffield Dept Med, Oxford, England. [Cameron, D. William] Univ Ottawa, Ottawa Hosp, Res Inst, Ottawa, ON, Canada. RP Brown, ST (reprint author), James J Peters VA Med Ctr, Bronx, NY 10468 USA. EM sheldon.brown@va.gov OI Cameron, Bill/0000-0002-0090-3539; Goulet, Joseph/0000-0002-0842-804X FU Office of Research and Development (Cooperative Studies Program), US Department of Veterans Affairs; US National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism [U01-13566]; Canadian Institutes for Health Research; United Kingdom Medical Research Council; Ontario HIV Treatment Network/Ministry of Health, Canada FX This work was supported by the Office of Research and Development (Cooperative Studies Program), US Department of Veterans Affairs; US National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism [U01-13566]; Canadian Institutes for Health Research; and United Kingdom Medical Research Council. DWC is a Career Scientist supported by the Ontario HIV Treatment Network/Ministry of Health, Canada. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 5 Z9 5 U1 2 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 25 PY 2014 VL 9 IS 3 AR e92606 DI 10.1371/journal.pone.0092606 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE0SD UT WOS:000333675600053 PM 24667813 ER PT J AU Codeluppi, S Fernandez-Zafra, T Sandor, K Kjell, J Liu, QS Abrams, M Olson, L Gray, NS Svensson, CI Uhlen, P AF Codeluppi, Simone Fernandez-Zafra, Teresa Sandor, Katalin Kjell, Jacob Liu, Qingsong Abrams, Mathew Olson, Lars Gray, Nathanael S. Svensson, Camilla I. Uhlen, Per TI Interleukin-6 Secretion by Astrocytes Is Dynamically Regulated by PI3K-mTOR-Calcium Signaling SO PLOS ONE LA English DT Article ID SPINAL-CORD-INJURY; GENE-EXPRESSION; MESSENGER-RNA; IMMUNE-RESPONSES; SMOOTH-MUSCLE; CNS REPAIR; GLIAL SCAR; MTOR; REGENERATION; RAPAMYCIN AB After contusion spinal cord injury (SCI), astrocytes become reactive and form a glial scar. While this reduces spreading of the damage by containing the area of injury, it inhibits regeneration. One strategy to improve the recovery after SCI is therefore to reduce the inhibitory effect of the scar, once the acute phase of the injury has passed. The pleiotropic cytokine interleukin-6 (IL-6) is secreted immediately after injury and regulates scar formation; however, little is known about the role of IL-6 in the sub-acute phases of SCI. Interestingly, IL-6 also promotes axon regeneration, and therefore its induction in reactive astrocytes may improve regeneration after SCI. We found that IL-6 is expressed by astrocytes and neurons one week post-injury and then declines. Using primary cultures of rat astrocytes we delineated the molecular mechanisms that regulate IL-6 expression and secretion. IL-6 expression requires activation of p38 and depends on NF-kappa B transcriptional activity. Activation of these pathways in astrocytes occurs when the PI3K-mTOR-AKT pathway is inhibited. Furthermore, we found that an increase in cytosolic calcium concentration was necessary for IL-6 secretion. To induce IL-6 secretion in astrocytes, we used torin2 and rapamycin to block the PI3K-mTOR pathway and increase cytosolic calcium, respectively. Treating injured animals with torin2 and rapamycin for two weeks, starting two weeks after injury when the scar has been formed, lead to a modest effect on mechanical hypersensitivity, limited to the period of treatment. These data, taken together, suggest that treatment with torin2 and rapamycin induces IL-6 secretion by astrocytes and may contribute to the reduction of mechanical hypersensitivity after SCI. C1 [Codeluppi, Simone; Fernandez-Zafra, Teresa; Uhlen, Per] Karolinska Inst, Mol Neurobiol Lab, Dept Med Biochem & Biophys, Stockholm, Sweden. [Sandor, Katalin; Svensson, Camilla I.] Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. [Kjell, Jacob; Abrams, Mathew; Olson, Lars] Karolinska Inst, Dept Neurosci, Stockholm, Sweden. [Liu, Qingsong; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Liu, Qingsong; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Codeluppi, S (reprint author), Karolinska Inst, Mol Neurobiol Lab, Dept Med Biochem & Biophys, Stockholm, Sweden. EM simone.codeluppi@ki.se RI codeluppi, simone/I-4143-2012; OI codeluppi, simone/0000-0002-7053-0520; Kjell, Jacob/0000-0002-8335-0780; Uhlen, Per/0000-0003-1446-1062 FU Wenner-Gren foundation; Svenska Sallskapet for Medicinsk Forskning; Becas Talentia; Hjarnfonden; Swedish Research Council; Linnaeus Center in Developmental Biology for Regenerative Medicine; Knut and Alice Wallenberg Foundation; Royal Swedish Academy of Sciences; Wings for Life; Vinnova; Karolinska Distinguished Professor Award; Karolinska StratNeuro program FX This work was supported by: Wenner-Gren foundation (SC, KS), Svenska Sallskapet for Medicinsk Forskning (SC), Becas Talentia (TFZ), Hjarnfonden (SC, PU), Swedish Research Council (CS, PU, LO), Linnaeus Center in Developmental Biology for Regenerative Medicine (PU), the Knut and Alice Wallenberg Foundation Grant to Center of Live Imaging of Cells at Karolinska Institutet (PU), the Royal Swedish Academy of Sciences (PU), Wings for Life (LO, MA), Vinnova (LO), Karolinska Distinguished Professor Award (LO), Karolinska StratNeuro program (LO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 3 Z9 5 U1 2 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 25 PY 2014 VL 9 IS 3 AR e92649 DI 10.1371/journal.pone.0092649 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE0SD UT WOS:000333675600061 PM 24667246 ER PT J AU Jamin, Y Glass, L Hallsworth, A George, R Koh, DM Pearson, ADJ Chesler, L Robinson, SP AF Jamin, Yann Glass, Laura Hallsworth, Albert George, Rani Koh, Dow-Mu Pearson, Andrew D. J. Chesler, Louis Robinson, Simon P. TI Intrinsic Susceptibility MRI Identifies Tumors with ALK(F1174L) Mutation in Genetically-Engineered Murine Models of High-Risk Neuroblastoma SO PLOS ONE LA English DT Article ID VASCULAR ARCHITECTURE; ACTIVATING MUTATIONS; ALK KINASE; CANCER; MYCN; ANGIOGENESIS; HYPOXIA; IMMUNOHISTOCHEMISTRY; AMPLIFICATION; RECRUITMENT AB The early identification of children presenting ALK(F1174L)-mutated neuroblastoma, which are associated with resistance to the promising ALK inhibitor crizotinib and a marked poorer prognosis, has become a clinical priority. In comparing the radiology of the novel Th-ALK(F1174L)/Th-MYCN and the well-established Th-MYCN genetically-engineered murine models of neuroblastoma using MRI, we have identified a marked ALK(F1174L)-driven vascular phenotype. We demonstrate that quantitation of the transverse relaxation rate R-2* (s(-1)) using intrinsic susceptibility-MRI under baseline conditions and during hyperoxia, can robustly discriminate this differential vascular phenotype, and identify MYCN-driven tumors harboring the ALK(F1174L) mutation with high specificity and selectivity. Intrinsic susceptibility-MRI could thus potentially provide a non-invasive and clinically-exploitable method to help identifying children with MYCN-driven neuroblastoma harboring the ALK(F1174L) mutation at the time of diagnosis. C1 [Jamin, Yann; Glass, Laura; Koh, Dow-Mu; Chesler, Louis; Robinson, Simon P.] Inst Canc Res, Div Radiotherapy & Imaging, London SW3 6JB, England. [Jamin, Yann; Glass, Laura; Koh, Dow-Mu; Chesler, Louis; Robinson, Simon P.] Royal Marsden NHS Fdn Trust, London, England. [Glass, Laura; Hallsworth, Albert; Chesler, Louis] Inst Canc Res, Div Canc Therapeut, London SW3 6JB, England. [Glass, Laura; Chesler, Louis] Inst Canc Res, Div Mol Pathol, London SW3 6JB, England. [Glass, Laura; Pearson, Andrew D. J.; Chesler, Louis] Inst Canc Res, Div Clin Studies, London SW3 6JB, England. [George, Rani] Dana Farber Canc Inst, Dept Pediat Haematol & Oncol, Boston, MA 02115 USA. [George, Rani] Harvard Univ, Childrens Hosp, Sch Med, Boston, MA 02115 USA. RP Jamin, Y (reprint author), Inst Canc Res, Div Radiotherapy & Imaging, London SW3 6JB, England. EM yann.jamin@icr.ac.uk FU Institute of Cancer Research CR-UK; EPSRC Cancer Imaging Centre; MRC; Department of Health (England) [C1060/A10334]; NHS; Cancer Research-UK project grants [C16412/A6269]; Wellcome Trust [091763Z/10/Z]; Medical Research Council [G1000391]; Neuroblastoma Society; SPARKS charity; Medical Research Council NC3R [G1000121/94513]; National Institutes of Health [R01 CA148688] FX The authors acknowledge support received for The Institute of Cancer Research CR-UK (http://www.cancerresearchuk.org/) and EPSRC (http://www.epsrc.ac.uk) Cancer Imaging Centre, in association with the MRC (http://www.epsrc.ac.uk) and Department of Health (England) (https://www.gov.uk/government/organisations/department-of-health) grant C1060/A10334, and NHS funding to the NIHR Biomedical Research Centre. This work was supported by Cancer Research-UK project grants C16412/A6269, The Wellcome Trust (grant #091763Z/10/Z) (http://www.wellcome.ac.uk), and the Medical Research Council (grant #G1000391). Pre-clinical development of the TH-ALKF1174L/TH-MYCN model was funded by grants from The Neuroblastoma Society (http://www.nsoc.co.uk), the SPARKS charity (http://www.sparks.org.uk), Medical Research Council NC3R (grant #G1000121/94513)(http://www.nc3rs.org.uk/), and the National Institutes of Health (R01 CA148688) (http://www.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 4 Z9 4 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 25 PY 2014 VL 9 IS 3 AR e92886 DI 10.1371/journal.pone.0092886 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE0SD UT WOS:000333675600099 PM 24667968 ER PT J AU Kiwanuka, J Mulogo, E Haberer, JE AF Kiwanuka, Julius Mulogo, Edgar Haberer, Jessica E. TI Caregiver Perceptions and Motivation for Disclosing or Concealing the Diagnosis of HIV Infection to Children Receiving HIV Care in Mbarara, Uganda: A Qualitative Study SO PLOS ONE LA English DT Article ID SCHOOL-AGE-CHILDREN; SOUTH-AFRICA; ADOLESCENTS; HIV/AIDS; MORTALITY; MOTHERS; HEALTH AB Background: Disclosure of the diagnosis of HIV to HIV-infected children is challenging for caregivers. Despite current recommendations, data suggest that levels of disclosure of HIV status to HIV-infected children receiving care in resource-limited settings are very low. Few studies describe the disclosure process for children in these settings, particularly the motivators, antecedent goals, and immediate outcomes of disclosure to HIV-infected children. This study examined caregivers' perception of the disclosure concept prior to disclosure, their motivation towards or away from disclosure, and their short-and long-term intentions for disclosure to their HIV-infected children. Methods: In-depth interviews were conducted with primary caregivers of 40 HIV-infected children (ages 5-15 years) who were receiving HIV care but did not know their HIV status. Results: Caregivers of HIV-infected children mainly perceived disclosure as a single event rather than a process of gradual delivery of information about the child's illness. They viewed disclosure as potentially beneficial both to children and themselves, as well as an opportunity to explain the parents' role in the transmission of HIV to the children. Caregivers desired to personally conduct the disclosure; however, most reported being over-whelmed with fear of negative outcomes and revealed a lack of self-efficacy towards managing the disclosure process. Consequently, most cope by deception to avoid or delay disclosure until they perceive their own readiness to disclose. Conclusions: Interventions for HIV disclosure should consider that caregivers may desire to be directly responsible for disclosure to children under their care. They, however, need to be empowered with practical skills to recognize opportunities to initiate the disclosure process early, as well as supported to manage it in a phased, developmentally appropriate manner. The potential role for peer counselors in the disclosure process deserves further study. C1 [Kiwanuka, Julius] Mbarara Univ Sci & Technol, Dept Paediat & Child Hlth, Mbarara, Uganda. [Mulogo, Edgar] Mbarara Univ Sci & Technol, Dept Community Hlth, Mbarara, Uganda. [Haberer, Jessica E.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Haberer, Jessica E.] Harvard Univ, Sch Med, Boston, MA USA. RP Kiwanuka, J (reprint author), Mbarara Univ Sci & Technol, Dept Paediat & Child Hlth, Mbarara, Uganda. EM jpkiwanuka@gmail.com FU Canada-Africa Prevention Trials (CAPT) Network; US National Institutes of Health [K23MH087228] FX The study was funded by a mentorship grant from the Canada-Africa Prevention Trials (CAPT) Network (captnetwork.org). Dr. Haberer was supported by the US National Institutes of Health (K23MH087228). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 8 Z9 8 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 25 PY 2014 VL 9 IS 3 AR e93276 DI 10.1371/journal.pone.0093276 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE0SD UT WOS:000333675600161 PM 24667407 ER PT J AU Ferraro, A D'Alise, AM Raj, T Asinovski, N Phillips, R Ergun, A Replogle, JM Bernier, A Laffel, L Stranger, BE De Jager, PL Mathis, D Benoist, C AF Ferraro, Alessandra D'Alise, Anna Morena Raj, Towfique Asinovski, Natasha Phillips, Roxanne Ergun, Ayla Replogle, Joseph M. Bernier, Angelina Laffel, Lori Stranger, Barbara E. De Jager, Philip L. Mathis, Diane Benoist, Christophe TI Interindividual variation in human T regulatory cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunoregulation; suppression ID TRANSCRIPTION FACTOR FOXP3; GENE-EXPRESSION; LINEAGE SPECIFICATION; IMMUNE SUPPRESSION; FUNCTIONAL DEFECTS; REG CELLS; HOMEOSTASIS; DIFFERENTIATION; INFLAMMATION; SIGNATURE AB FOXP3(+) regulatory T (Treg) cells enforce immune self-tolerance and homeostasis, and variation in some aspects of Treg function may contribute to human autoimmune diseases. Here, we analyzed population-level Treg variability by performing genomewide expression profiling of CD4(+) Treg and conventional CD4(+) T (Tconv) cells from 168 donors, healthy or with established type-1 diabetes (T1D) or type-2 diabetes (T2D), in relation to genetic and immunologic screening. There was a range of variability in Treg signature transcripts, some almost invariant, others more variable, with more extensive variability for genes that control effector function (ENTPD1, FCRL1) than for lineage-specification factors like FOXP3 or IKZF2. Network analysis of Treg signature genes identified coregulated clusters that respond similarly to genetic and environmental variation in Treg and Tconv cells, denoting qualitative differences in otherwise shared regulatory circuits whereas other clusters are coregulated in Treg, but not Tconv, cells, suggesting Treg-specific regulation of genes like CTLA4 or DUSP4. Dense genotyping identified 110 local genetic variants (cis-expression quantitative trait loci), some of which are specifically active in Treg, but not Tconv, cells. The Treg signature became sharper with age and with increasing body-mass index, suggesting a tuning of Treg function with repertoire selection and/or chronic inflammation. Some Treg signature transcripts correlated with FOXP3 mRNA and/or protein, suggesting transcriptional or posttranslational regulatory relationships. Although no single transcript showed significant association to diabetes, overall expression of the Treg signature was subtly perturbed in T1D, but not T2D, patients. C1 [Ferraro, Alessandra; D'Alise, Anna Morena; Asinovski, Natasha; Ergun, Ayla; Mathis, Diane; Benoist, Christophe] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA. [Raj, Towfique; Replogle, Joseph M.; Stranger, Barbara E.; De Jager, Philip L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genom, Dept Neurol, Boston, MA 02115 USA. [Raj, Towfique; Replogle, Joseph M.; Stranger, Barbara E.; De Jager, Philip L.] Brigham & Womens Hosp, Div Genet, Dept Med, Boston, MA 02115 USA. [Raj, Towfique; Replogle, Joseph M.; Stranger, Barbara E.; De Jager, Philip L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Raj, Towfique; Replogle, Joseph M.; Stranger, Barbara E.; De Jager, Philip L.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02139 USA. [Phillips, Roxanne; Bernier, Angelina; Laffel, Lori] Joslin Diabet Ctr, Dept Pediat Immunol, Boston, MA 02215 USA. [Stranger, Barbara E.] Univ Chicago, Sect Genet Med, Dept Med, Chicago, IL 60637 USA. RP Mathis, D (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA. EM cbdm@hms.harvard.edu OI Replogle, Joseph/0000-0003-1832-919X; Stranger, Barbara/0000-0001-9021-7331 FU Juvenile Diabetes Research Foundation [4-2007-1057]; National Institutes of Health [RC2 GM09308] FX We thank Dr. D. Koller for helpful discussion; Katie Rothamel, Joyce LaVecchio, and Girijesh Buruzula for help with flow cytometry and RNA preparations; and Jeff Ericson, Scott Davis, and Henry Paik for help with bioinformatics analyses. This work was supported by Juvenile Diabetes Research Foundation Grant 4-2007-1057 (to D. M., C. B., and L. L.) and National Institutes of Health Grant RC2 GM09308 (to D. M. and C. B.). NR 60 TC 26 Z9 26 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 25 PY 2014 VL 111 IS 12 BP E1111 EP E1120 DI 10.1073/pnas.1401343111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD6CK UT WOS:000333341100009 PM 24610777 ER PT J AU Tao, JJ Castel, P Radosevic-Robin, N Elkabets, M Auricchio, N Aceto, N Weitsman, G Barber, P Vojnovic, B Ellis, H Morse, N Viola-Villegas, NT Bosch, A Juric, D Hazra, S Singh, S Kim, P Bergamaschi, A Maheswaran, S Ng, T Penault-Llorca, F Lewis, JS Carey, LA Perou, CM Baselga, J Scaltriti, M AF Tao, Jessica J. Castel, Pau Radosevic-Robin, Nina Elkabets, Moshe Auricchio, Neil Aceto, Nicola Weitsman, Gregory Barber, Paul Vojnovic, Borivoj Ellis, Haley Morse, Natasha Viola-Villegas, Nerissa Therese Bosch, Ana Juric, Dejan Hazra, Saswati Singh, Sharat Kim, Phillip Bergamaschi, Anna Maheswaran, Shyamala Ng, Tony Penault-Llorca, Frederique Lewis, Jason S. Carey, Lisa A. Perou, Charles M. Baselga, Jose Scaltriti, Maurizio TI Antagonism of EGFR and HER3 Enhances the Response to Inhibitors of the PI3K-Akt Pathway in Triple-Negative Breast Cancer SO SCIENCE SIGNALING LA English DT Article ID CIRCULATING TUMOR-CELLS; INDUCTION CHEMOTHERAPY; TYROSINE KINASE; THERAPY; COMBINATION; ACTIVATION; CARCINOMA; CETUXIMAB; ONCOLOGY; SUPERIOR AB Both abundant epidermal growth factor receptor (EGFR or ErbB1) and high activity of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway are common and therapeutically targeted in triple-negative breast cancer (TNBC). However, activation of another EGFR family member [human epidermal growth factor receptor 3 (HER3) (or ErbB3)] may limit the antitumor effects of these drugs. We found that TNBC cell lines cultured with the EGFR or HER3 ligand EGF or heregulin, respectively, and treated with either an Akt inhibitor (GDC0068) or a PI3K inhibitor (GDC-0941) had increased abundance and phosphorylation of HER3. The phosphorylation of HER3 and EGFR in response to these treatments was reduced by the addition of a dual EGFR and HER3 inhibitor (MEHD7945A). MEHD7945A also decreased the phosphorylation (and activation) of EGFR and HER3 and the phosphorylation of downstream targets that occurred in response to the combination of EGFR ligands and PI3K-Akt pathway inhibitors. In culture, inhibition of the PI3K-Akt pathway combined with either MEHD7945A or knockdown of HER3 decreased cell proliferation compared with inhibition of the PI3K-Akt pathway alone. Combining either GDC-0068 or GDC-0941 with MEHD7945A inhibited the growth of xenografts derived from TNBC cell lines or from TNBC patient tumors, and this combination treatment was also more effective than combining either GDC-0068 or GDC-0941 with cetuximab, an EGFR-targeted antibody. After therapy with EGFR-targeted antibodies, some patients had residual tumors with increased HER3 abundance and EGFR/HER3 dimerization (an activating interaction). Thus, we propose that concomitant blockade of EGFR, HER3, and the PI3K-Akt pathway in TNBC should be investigated in the clinical setting. C1 [Tao, Jessica J.; Auricchio, Neil; Aceto, Nicola; Juric, Dejan; Maheswaran, Shyamala] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Tao, Jessica J.; Auricchio, Neil; Aceto, Nicola; Juric, Dejan; Maheswaran, Shyamala] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Castel, Pau; Elkabets, Moshe; Ellis, Haley; Morse, Natasha; Bosch, Ana; Baselga, Jose; Scaltriti, Maurizio] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Radosevic-Robin, Nina; Penault-Llorca, Frederique] Ctr Jean Perrin, Dept Biopathol, F-63011 Clermont Ferrand, France. [Radosevic-Robin, Nina; Penault-Llorca, Frederique] Univ Auvergne, ERTICA EA4677, F-63000 Clermont Ferrand, France. [Weitsman, Gregory; Ng, Tony] Kings Coll London, Randall Div Cell & Mol Biophys, Richard Dimbleby Dept Canc Res, London SE1 1UL, England. [Weitsman, Gregory; Ng, Tony] Kings Coll London, Div Canc Studies, London SE1 1UL, England. [Barber, Paul; Vojnovic, Borivoj] Univ Oxford, Dept Oncol, Gray Inst Radiat Oncol & Biol, Oxford OX3 7DQ, England. [Barber, Paul] Kings Coll London, Inst Math & Mol Biomed, London SE1 1UL, England. [Vojnovic, Borivoj] Kings Coll London, Randall Div Cell & Mol Biophys, London SE1 1UL, England. [Viola-Villegas, Nerissa Therese; Lewis, Jason S.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA. [Viola-Villegas, Nerissa Therese; Lewis, Jason S.] Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol & Chem, New York, NY 10065 USA. [Hazra, Saswati; Singh, Sharat; Kim, Phillip] Prometheus Therapeut & Diagnost, San Diego, CA 92121 USA. [Bergamaschi, Anna] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. [Ng, Tony] UCL, UCL Canc Inst, London WC1E 6DD, England. [Carey, Lisa A.] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Perou, Charles M.] Univ N Carolina, Dept Genet, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Baselga, J (reprint author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave,Box 20, New York, NY 10065 USA. EM baselgaj@mskcc.org; scaltrim@mskcc.org RI Aceto, Nicola/O-2484-2014; OI Vojnovic, Borivoj/0000-0001-9013-3816; Aceto, Nicola/0000-0001-9579-6918; Castel, Pau/0000-0002-4972-4347; Perou, Charles/0000-0001-9827-2247 FU Amgen and the Jean Perrin Comprehensive Cancer Center; Susan G. Komen for the Cure [SAC110046]; Breast Cancer Research Foundation; CRUK; Engineering and Physical Sciences Research Council in association with the Medical Research Council and Department of Health (England) [C1519/A10331]; European Union grant [259881]; Spanish Society of Medical Oncology (SEOM); National Cancer Institute Breast SPORE (Specialized Program of Research Excellence) program [P50-CA58223-09A1]; Swiss Foundation; Swiss National Science Foundation FX The clinical panitumumab study conducted in France was sponsored by Amgen and the Jean Perrin Comprehensive Cancer Center. Preclinical work was funded by Susan G. Komen for the Cure (SAC110046) and the Breast Cancer Research Foundation. King's College London-University College London Comprehensive Cancer Imaging Centre funding was provided by CRUK and the Engineering and Physical Sciences Research Council in association with the Medical Research Council and Department of Health (England; C1519/A10331) and an FP7-HEALTH-2010 European Union grant entitled "IMAGINT" (grant number 259881). M.E. is an International Sephardic Education Foundation postdoctoral fellow; A.B. holds a Translational Research Fellowship from the Spanish Society of Medical Oncology (SEOM); C.M.P. is funded by the National Cancer Institute Breast SPORE (Specialized Program of Research Excellence) program (P50-CA58223-09A1) and the Breast Cancer Research Foundation; and N. Aceto is a fellow of the Human Frontiers Science Program, the Swiss National Science Foundation, and the Swiss Foundation for Grants in Biology and Medicine. NR 43 TC 40 Z9 41 U1 2 U2 12 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAR 25 PY 2014 VL 7 IS 318 AR ra29 DI 10.1126/scisignal.2005125 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AD9BD UT WOS:000333558600004 PM 24667376 ER PT J AU Corcoran, C Rani, S Breslin, S Gogarty, M Ghobrial, IM Crown, J O'Driscoll, L AF Corcoran, Claire Rani, Sweta Breslin, Susan Gogarty, Martina Ghobrial, Irene M. Crown, John O'Driscoll, Lorraine TI miR-630 targets IGF1R to regulate response to HER-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer SO MOLECULAR CANCER LA English DT Article DE MicroRNA-630; IGF1R; Biomarker; Breast cancer; Drug resistance; Cancer cell aggression ID FACTOR-I RECEPTOR; TYROSINE KINASE INHIBITOR; GROWTH-FACTOR RECEPTOR; TUMOR-CELLS; EXTRACELLULAR MICRORNAS; TRASTUZUMAB RESISTANCE; LAPATINIB; LINES; ACTIVATION; INVASION AB Background: While the treatment of HER2 over-expressing breast cancer with recent HER-targeted drugs has been highly effective for some patients, primary (also known as innate) or acquired resistance limits the success of these drugs. microRNAs have potential as diagnostic, prognostic and predictive biomarkers, as well as replacement therapies. Here we investigated the role of microRNA-630 (miR-630) in breast cancer progression and as a predictive biomarker for response to HER-targeting drugs, ultimately yielding potential as a therapeutic approach to add value to these drugs. Methods: We investigated the levels of intra-and extracellular miR-630 in cells and conditioned media from breast cancer cell lines with either innate-or acquired-resistance to HER-targeting lapatinib and neratinib, compared to their corresponding drug sensitive cell lines, using qPCR. To support the role of miR-630 in breast cancer, we examined the clinical relevance of this miRNA in breast cancer tumours versus matched peritumours. Transfection of miR-630 mimics and inhibitors was used to manipulate the expression of miR-630 to assess effects on response to HER-targeting drugs (lapatinib, neratinib and afatinib). Other phenotypic changes associated with cellular aggressiveness were evaluated by motility, invasion and anoikis assays. TargetScan prediction software, qPCR, immunoblotting and ELISAs, were used to assess miR-630's regulation of mRNA, proteins and their phosphorylated forms. Results: We established that introducing miR-630 into cells with innate-or acquired-resistance to HER-drugs significantly restored the efficacy of lapatinib, neratinib and afatinib; through a mechanism which we have determined to, at least partly, involve miR-630's regulation of IGF1R. Conversely, we demonstrated that blocking miR-630 induced resistance/insensitivity to these drugs. Cellular motility, invasion, and anoikis were also observed as significantly altered by miR-630 manipulation, whereby introducing miR-630 into cells reduced cellular aggression while inhibition of miR-630 induced a more aggressive cellular phenotype. Conclusions: Taken together, our findings suggest miR-630 as a key regulator of cancer cell progression in HER2 over-expressing breast cancer, through targeting of IGF1R. This study supports miR-630 as a diagnostic and a predictive biomarker for response to HER-targeted drugs and indicates that the therapeutic addition of miR-630 may enhance and improve patients' response to HER-targeting drugs. C1 [Corcoran, Claire; Rani, Sweta; Breslin, Susan; Gogarty, Martina; O'Driscoll, Lorraine] Univ Dublin Trinity Coll, Sch Pharm & Pharmaceut Sci, Dublin 2, Ireland. [Corcoran, Claire; Rani, Sweta; Breslin, Susan; Gogarty, Martina; O'Driscoll, Lorraine] Univ Dublin Trinity Coll, Trinity Biomed Sci Inst, Dublin 2, Ireland. [Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Crown, John] St Vincents Univ Hosp, Dept Oncol, Dublin 4, Ireland. RP O'Driscoll, L (reprint author), Univ Dublin Trinity Coll, Sch Pharm & Pharmaceut Sci, Dublin 2, Ireland. EM lodrisc@tcd.ie OI O'Driscoll, Lorraine/0000-0002-9860-8262 FU Science Foundation Ireland's funding of MTCI [08/SRC/B1410]; SFGamma's Short Term Travel Fellowship [STTGamma-11]; Marie Keating Foundation; TBSI; Irish Cancer Society; Breast-PREDICT [CCRC13GAL]; Health Research Board [HRA_ POR/2013/342]; EU COST Action ME-HaD [BM1202] FX This work was supported by Science Foundation Ireland's funding of MTCI [08/SRC/B1410]; SF Gamma's Short Term Travel Fellowship [ST Gamma-11]; Marie Keating Foundation; the Higher Education Authority's PRTLI Cycle 5 support of TBSI; Irish Cancer Society's support of Breast-PREDICT [CCRC13GAL]; and the Health Research Board [HRA_ POR/2013/342]; and EU COST Action ME-HaD (BM1202). NR 43 TC 29 Z9 31 U1 1 U2 7 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 24 PY 2014 VL 13 AR 71 DI 10.1186/1476-4598-13-71 PG 12 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AF2NY UT WOS:000334550000001 PM 24655723 ER PT J AU Hajjarian, Z Nadkarni, SK AF Hajjarian, Zeinab Nadkarni, Seemantini K. TI Correction of optical absorption and scattering variations in laser speckle rheology measurements SO OPTICS EXPRESS LA English DT Article ID DIFFUSING-WAVE-SPECTROSCOPY; SPATIAL-FREQUENCY DOMAIN; DYNAMIC LIGHT-SCATTERING; COMPLEX FLUIDS; VISCOELASTIC MODULI; TISSUE; MIXTURES; EQUATION; LIMIT; MILK AB Laser Speckle Rheology (LSR) is an optical technique to evaluate the viscoelastic properties by analyzing the temporal fluctuations of backscattered speckle patterns. Variations of optical absorption and reduced scattering coefficients further modulate speckle fluctuations, posing a critical challenge for quantitative evaluation of viscoelasticity. We compare and contrast two different approaches applicable for correcting and isolating the collective influence of absorption and scattering, to accurately measure mechanical properties. Our results indicate that the numerical approach of Monte-Carlo ray tracing (MCRT) reliably compensates for any arbitrary optical variations. When scattering dominates absorption, yet absorption is non-negligible, diffusing wave spectroscopy (DWS) formalisms perform similar to MCRT, superseding other analytical compensation approaches such as Telegrapher equation. The computational convenience of DWS greatly simplifies the extraction of viscoelastic properties from LSR measurements in a number of chemical, industrial, and biomedical applications. (C) 2014 Optical Society of America C1 [Hajjarian, Zeinab; Nadkarni, Seemantini K.] Harvard Univ, Sch Med, Wellman Ctr Photomed, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Nadkarni, SK (reprint author), Harvard Univ, Sch Med, Wellman Ctr Photomed, Massachusetts Gen Hosp, 40 Blossom St, Boston, MA 02114 USA. EM snadkarni@partners.org FU NIH [R21 HL 088306, U54 EB015408-01]; ARRA [R21 HL 088306-02S1] FX This study was funded by the NIH grant No. R21 HL 088306 (S.N), NIH grant No. U54 EB015408-01 (S.N), and the ARRA grant No. R21 HL 088306-02S1 (S.N). NR 37 TC 5 Z9 5 U1 2 U2 14 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD MAR 24 PY 2014 VL 22 IS 6 BP 6349 EP 6361 DI 10.1364/OE.22.006349 PG 13 WC Optics SC Optics GA AD9IT UT WOS:000333579300016 PM 24663983 ER PT J AU Baac, HW Uribe-Patarroyo, N Bouma, BE AF Baac, Hyoung Won Uribe-Patarroyo, Nestor Bouma, Brett E. TI High-energy pulsed Raman fiber laser for biological tissue coagulation SO OPTICS EXPRESS LA English DT Article ID MU-M; POWER; IMPACT; NM AB We demonstrate a high-energy pulsed Raman fiber laser (RFL) with an emission wavelength of 1.44 mu m, corresponding to an absorption peak of water. Microsecond pulses with > 20 mJ/pulse and > 40 W peak power were generated, well above the threshold for tissue coagulation and ablation. Here, we focus on the optical characterization and optimization of high-energy and high-power RFLs excited by an ytterbium fiber laser, comparing three configurations that use different Raman gain fibers, but all of which were prepared with a one-side opened, free-run mode without output mirrors. We show that the free-run configuration can generate sufficiently high energy without requiring a closed cavity design. Experimental RFL characteristics corresponded well with numerical simulations. We discuss the Stokes beam generation process in our system and loss mechanisms mainly associated with fiber Bragg gratings. (C)2014 Optical Society of America C1 [Baac, Hyoung Won] Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Baac, HW (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM baac.hyoungwon@mgh.harvard.edu FU National Institutes of Health [P41 EB015903]; NinePoint Medical FX Research reported in this publication was supported in part by the National Institutes of Health, grant P41 EB015903 and NinePoint Medical. The authors thank nLight Photonics for providing access to and technical support for the ytterbium fiber laser used in this work. NR 24 TC 7 Z9 7 U1 2 U2 9 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD MAR 24 PY 2014 VL 22 IS 6 BP 7113 EP 7123 DI 10.1364/OE.22.007113 PG 11 WC Optics SC Optics GA AD9IT UT WOS:000333579300090 PM 24664059 ER PT J AU Dimant, H Zhu, LY Kibuuka, LN Fan, Z Hyman, BT McLean, PJ AF Dimant, Hemi Zhu, Liya Kibuuka, Laura N. Fan, Zhanyun Hyman, Bradley T. McLean, Pamela J. TI Direct Visualization of CHIP-Mediated Degradation of Alpha-Synuclein In Vivo: Implications for PD Therapeutics SO PLOS ONE LA English DT Article ID PARKINSONS-DISEASE; LEWY BODIES; C-TERMINUS; AGGREGATION; OLIGOMERS; TOXICITY; APOPTOSIS; PROTEINS; TARGETS AB Parkinson's disease is a neurodegenerative disorder characterized by Lewy bodies, a pathological hallmark comprised mostly of aggregated alpha synuclein. Accumulating evidence demonstrates the association of smaller oligomeric aggregates to disease etiology and many therapeutic approaches are aimed at inhibiting and reducing the aggregation process. Molecular chaperones and co-chaperones play a key role in protein homeostasis and have potential as therapeutics to inhibit alpha synuclein associated toxicity. Here we use a gene therapy approach to evaluate the applicability of the Hsp70 co-chaperone CHIP (C-terminal Hsp70 interacting protein) as a therapeutic candidate and examine its direct effect on alpha synuclein aggregates in vivo. Utilizing a novel viral vector mediated rat model to directly detect alpha synuclein aggregates, we show that CHIP can mediate the degradation of alpha synuclein aggregates in vivo. However, our studies also reveal that CHIP may potentially degrade tyrosine hydroxylase which would compromise the applicability of CHIP as a therapeutic approach for Parkinson's disease. C1 [Dimant, Hemi; Zhu, Liya; Kibuuka, Laura N.; Fan, Zhanyun; Hyman, Bradley T.; McLean, Pamela J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGeneral Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. [McLean, Pamela J.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. RP McLean, PJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGeneral Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. EM mclean.pamela@mayo.edu FU NIH [NS063963]; Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grants (T32) FX PM is supported by NIH NS063963. HD is supported by Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grants (T32). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 2 Z9 2 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 24 PY 2014 VL 9 IS 3 AR e92098 DI 10.1371/journal.pone.0092098 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD7QO UT WOS:000333459900040 PM 24664141 ER PT J AU Mukherjee, A Larson, EA Klein, RF Rotwein, P AF Mukherjee, Aditi Larson, Emily A. Klein, Robert F. Rotwein, Peter TI Distinct Actions of Akt1 on Skeletal Architecture and Function SO PLOS ONE LA English DT Article ID MICE LACKING; OSTEOBLAST DIFFERENTIATION; CELL-SURVIVAL; PHOSPHATIDYLINOSITOL 3-KINASE; GLUCOSE-HOMEOSTASIS; BONE; GROWTH; KINASE; OSTEOPOROSIS; OSTEOCLAST AB Skeletal integrity is dependent on the coordinated actions of bone-forming osteoblasts and bone-resorbing osteoclasts, which recognize and respond to multiple environmental inputs. Here we have studied the roles in bone development and growth of Akt1 and Akt2, two closely related signaling proteins, by evaluating mice lacking either of these enzymes. Global deficiency of Akt1 but not Akt2 caused a reduction in whole body and femoral bone mineral density, in femoral cortical thickness and volume, and in trabecular thickness in both males and females when measured at 20-weeks of age, which was reflected in diminished femoral resistance to fracture. Haplo-deficiency of Akt1 in male mice also decreased femoral cortical and trabecular skeletal parameters, and reduced bone strength. Cell-based studies showed that genetic Akt1 deficiency diminished the rate of proliferation of osteoblast progenitors and impaired osteoclast differentiation in primary culture but that loss of Akt2 did not. Our results demonstrate differential effects of Akt1 and Akt2 on skeletal maturation and architecture through actions on both osteoblast and osteoclast precursors. C1 [Mukherjee, Aditi; Rotwein, Peter] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97201 USA. [Larson, Emily A.; Klein, Robert F.] Oregon Hlth & Sci Univ, Dept Med, Bone & Mineral Res Unit, Portland, OR 97201 USA. [Klein, Robert F.] Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, Portland, OR 97201 USA. RP Rotwein, P (reprint author), Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97201 USA. EM rotweinp@ohsu.edu FU NIH [R01 DK42748]; VA Medical Research Service; OHSU Medical Research Foundation FX These studies were supported in part by NIH grant R01 DK42748 (to P. R.), by the VA Medical Research Service (R. F. K.), and by an OHSU Medical Research Foundation new investigator grant (to A. M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 2 Z9 2 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 24 PY 2014 VL 9 IS 3 AR e93040 DI 10.1371/journal.pone.0093040 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD7QO UT WOS:000333459900147 PM 24663486 ER PT J AU Kahn, SE Cooper, ME Del Prato, S AF Kahn, Steven E. Cooper, Mark E. Del Prato, Stefano TI Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future SO LANCET LA English DT Review ID BETA-CELL FUNCTION; GLUCAGON-LIKE PEPTIDE-1; IMPAIRED GLUCOSE-TOLERANCE; LIFE-STYLE INTERVENTION; TODAY CLINICAL-TRIAL; 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; DIPEPTIDYL PEPTIDASE-4 INHIBITORS; PREVENTION PROGRAM OUTCOMES; FIBROBLAST GROWTH-FACTORS; INSULIN-TREATED PATIENTS AB Glucose metabolism is normally regulated by a feedback loop including islet beta cells and insulin-sensitive tissues, in which tissue sensitivity to insulin affects magnitude of beta-cell response. If insulin resistance is present, beta cells maintain normal glucose tolerance by increasing insulin output. Only when beta cells cannot release sufficient insulin in the presence of insulin resistance do glucose concentrations rise. Although beta-cell dysfunction has a clear genetic component, environmental changes play an essential part. Modern research approaches have helped to establish the important role that hexoses, aminoacids, and fatty acids have in insulin resistance and beta-cell dysfunction, and the potential role of changes in the microbiome. Several new approaches for treatment have been developed, but more effective therapies to slow progressive loss of beta-cell function are needed. Recent findings from clinical trials provide important information about methods to prevent and treat type 2 diabetes and some of the adverse effects of these interventions. However, additional long-term studies of drugs and bariatric surgery are needed to identify new ways to prevent and treat type 2 diabetes and thereby reduce the harmful effects of this disease. C1 [Kahn, Steven E.] Univ Washington, VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. [Cooper, Mark E.] Baker IDI Heart & Diabet Inst, Diabet Div, Melbourne, Vic, Australia. [Del Prato, Stefano] Univ Pisa, Sch Med, Dept Clin & Expt Med, I-56100 Pisa, Italy. RP Kahn, SE (reprint author), VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. EM skahn@uw.edu RI Del Prato, Stefano/K-3405-2016; OI Del Prato, Stefano/0000-0002-5388-0270; Kahn, Steven/0000-0001-7307-9002 FU US Department of Veterans Affairs; NIH [DK-017047]; National Health and Medical Research Council of Australia; Italian Ministry of Education and Research [2010YK7Z5K_006] FX SEK is supported partly by the US Department of Veterans Affairs and NIH grant DK-017047. MEC is supported by an Australia Fellowship from the National Health and Medical Research Council of Australia. SDP was supported by grant 2010YK7Z5K_006 from the Italian Ministry of Education and Research. NR 202 TC 203 Z9 213 U1 24 U2 151 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAR 22 PY 2014 VL 383 IS 9922 BP 1068 EP 1083 DI 10.1016/S0140-6736(13)62154-6 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA AD8MV UT WOS:000333521200033 PM 24315620 ER PT J AU He, LZ Marneros, AG AF He, Lizhi Marneros, Alexander G. TI Doxycycline Inhibits Polarization of Macrophages to the Proangiogenic M2-type and Subsequent Neovascularization SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Angiogenesis; Antibiotics; Inflammation; Innate Immunity; Macrophages; Wound Healing; Macular Degeneration ID CHOROIDAL NEOVASCULARIZATION; MACULAR DEGENERATION; MEDIATED INHIBITION; ANGIOGENESIS; PREVENTS; RANIBIZUMAB; BEVACIZUMAB; PROGRESSION; MECHANISM AB Background: M2-type macrophages are proangiogenic and protumorigenic, whereas M1-type macrophages are antiangiogenic. Results: Doxycycline is a potent inhibitor of M2-type macrophage polarization in both human and mouse macrophages in vitro and in vivo. Conclusion: Preventing M2-type macrophage polarization correlates with inhibition of pathological angiogenesis. Significance: Doxycycline may be used to enhance current antiangiogenic treatment approaches in neovascular age-related macular degeneration and in certain cancers. Macrophages occur along a continuum of functional states between M1-type polarized macrophages with antiangiogenic and antitumor activity and M2-type polarized macrophages, which have been implicated to promote angiogenesis and tumor growth. Proangiogenic M2-type macrophages promote various pathologic conditions, including choroidal neovascularization in models of neovascular age-related macular degeneration, or certain cancers, such as glioblastoma multiforme. Thus, a potential novel therapeutic approach to target pathological angiogenesis in these conditions would be to inhibit the polarization of macrophages toward the proangiogenic M2-type. However, no pharmacological inhibitors of M2-type macrophage polarization have been identified yet. Here we performed an unbiased pharmacological and small chemical screen to identify drugs that inhibit proangiogenic M2-type macrophage polarization and block pathologic macrophage-driven neovascularization. We identified the well tolerated and commonly used antibiotic doxycycline as a potent inhibitor of M2-type polarization of macrophages. Doxycycline inhibited, in a dose-dependent manner, M2-type polarization of human and bone marrow-derived mouse macrophages without affecting cell viability. Furthermore, doxycycline inhibited M2-type macrophage polarization and subsequent neovascularization in vivo in a laser injury model of choroidal neovascularization. Thus, doxycycline could be used to enhance current antiangiogenic treatment approaches in various conditions that are promoted by proangiogenic M2-type macrophages, including neovascular age-related macular degeneration and certain cancers. C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Dermatol, Charlestown, MA 02129 USA. RP Marneros, AG (reprint author), CBRC, MGH East, CNY-149,Rm 3-216,13th St, Charlestown, MA 02129 USA. EM amarneros@mgh.harvard.edu FU NEI, National Institutes of Health [NEI R01-EY019297]; Shiseido research grant; Dermatology Foundation FX This study was supported, in whole or in part, by NEI, National Institutes of Health Grant NEI R01-EY019297 (to A. G. M.). This work was also supported by a Shiseido research grant (to A. G. M.) and by a Dermatology Foundation research grant (to L. H.). NR 18 TC 13 Z9 16 U1 2 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 21 PY 2014 VL 289 IS 12 BP 8019 EP 8028 DI 10.1074/jbc.M113.535765 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AD3PG UT WOS:000333157500002 PM 24505138 ER PT J AU Ghatak, S Misra, S Norris, RA Moreno-Rodriguez, RA Hoffman, S Levine, RA Hascall, VC Markwald, RR AF Ghatak, Shibnath Misra, Suniti Norris, Russell A. Moreno-Rodriguez, Ricardo A. Hoffman, Stanley Levine, Robert A. Hascall, Vincent C. Markwald, Roger R. TI Periostin Induces Intracellular Cross-talk between Kinases and Hyaluronan in Atrioventricular Valvulogenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Cd44; Cell Adhesion; Cell Migration; Collagen; Hyaluronate; Integrins; Atrioventricular Valve; Intracellular Kinase Signaling; Periostin; Prevalvular Cushion Cells ID FOCAL ADHESION KINASE; CONSTITUTIVELY REGULATES ACTIVATION; CARDIAC VALVULAR DYSTROPHY; HUMAN MESANGIAL CELLS; CANCER-CELLS; CARCINOMA-CELLS; PROTEIN-KINASE; FILAMIN-A; VALVE DEVELOPMENT; GROWTH-FACTOR AB Background: Periostin-null mice exhibit a myxomatous atrioventricular valve phenotype. We propose two mechanisms as follows: periostin binds to collagen and links it to cell-surface receptors; periostin/-INTEGRIN signaling promotes valve morphogenesis. Results: Periostin/-INTEGRINs/focal adhesion kinase/PI3K/ERK signals promote hyaluronan synthase-2 activation, matrix remodeling, and valve progenitor cell survival/differentiation. Conclusion: The phenotype of periostin-null valves is consistent with a role for PN cell signaling through INTEGRIN receptors. Significance: Periostin is a valvulogenic signaling morphogen. Periostin (PN), a novel fasciclin-related matricellular protein, has been implicated in cardiac development and postnatal remodeling, but the mechanism remains unknown. We examined the role of PN in mediating intracellular kinase activation for atrioventricular valve morphogenesis using well defined explant cultures, gene transfection systems, and Western blotting. The results show that valve progenitor (cushion) cells secrete PN into the extracellular matrix, where it can bind to INTEGRINs and activate INTEGRIN/focal adhesion kinase signaling pathways and downstream kinases, PI3K/AKT and ERK. Functional assays with prevalvular progenitor cells showed that activating these signaling pathways promoted adhesion, migration, and anti-apoptosis. Through activation of PI3K/ERK, PN directly enhanced collagen expression. Comparing PN-null to WT mice also revealed that expression of hyaluronan (HA) and activation of hyaluronan synthase-2 (Has2) are also enhanced upon PN/INTEGRIN/focal adhesion kinase-mediated activation of PI3K and/or ERK, an effect confirmed by the reduction of HA synthase-2 in PN-null mice. We also identified in valve progenitor cells a potential autocrine signaling feedback loop between PN and HA through PI3K and/or ERK. Finally, in a three-dimensional assay to simulate normal valve maturation in vitro, PN promoted collagen compaction in a kinase-dependent fashion. In summary, this study provides the first direct evidence that PN can act to stimulate a valvulogenic signaling pathway. C1 [Ghatak, Shibnath; Misra, Suniti; Norris, Russell A.; Moreno-Rodriguez, Ricardo A.; Markwald, Roger R.] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. [Hoffman, Stanley] Med Univ S Carolina, Dept Med, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Levine, Robert A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hascall, Vincent C.] Cleveland Clin, Dept Biomed Engn ND20, Cleveland, OH 44195 USA. RP Markwald, RR (reprint author), Med Univ S Carolina, Dept Regenerat Med & Cell Biol, 173 Ashley Ave, Charleston, SC 29425 USA. EM markwald@musc.edu FU National Institutes of Health [1R03CA167722-01A1, P20RR021949, P20RR016434, P20RR16461-05, RO1-HL033756-24, P01HL107147, 1P30AR050953]; EPS [0903795]; MCRC [39919]; COBRE [IP30-GM103342, 8P20 GM103444]; Fondation Leducq (Paris, France) Transatlantic Network of Excellence [07CDV04]; American Heart Association [11SDG5270006] FX This work was supported, in whole or in part, by National Institutes of Health Grants 1R03CA167722-01A1 (to S. M. and S. G.), P20RR021949 (to S. G.), P20RR016434 (to S. M., S. G., and R. R. M.), P20RR16461-05 (to S. G. and R. R. M), RO1-HL033756-24 and (to S. M., S. G., and R. R. M.), P01HL107147 and 1P30AR050953 (to V. C. H.), EPS 0903795 (to S. M.), MCRC 39919 (to S. G. and S. M.), COBRE IP30-GM103342 (to R. R. M. and R. A. N.), and 8P20 GM103444 (to R. R. M. and R. A. N.). This work was also supported by Fondation Leducq (Paris, France) Transatlantic Network of Excellence Grant 07CDV04 (to R. A. L.) and American Heart Association Grant 11SDG5270006 (to R. A. N.). NR 72 TC 11 Z9 11 U1 2 U2 11 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 21 PY 2014 VL 289 IS 12 BP 8545 EP 8561 DI 10.1074/jbc.M113.539882 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AD3PG UT WOS:000333157500045 PM 24469446 ER PT J AU Vecchio, D Bhayana, B Huang, LY Carrasco, E Evans, CL Hamblin, MR AF Vecchio, Daniela Bhayana, Brijesh Huang, Liyi Carrasco, Elisa Evans, Conor L. Hamblin, Michael R. TI Structure-function relationships of Nile blue (EtNBS) derivatives as antimicrobial photosensitizers SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Structure-activity relationships; Benzophenothiazinium dye; Nile blue derivatives, antimicrobial; photodynamic inactivation; Gram-positive bacteria; Gram-negative bacteria; Electron withdrawing/donating substituents ID PHOTODYNAMIC THERAPY; CLINICAL-APPLICATIONS; IN-VITRO; BENZOPHENOTHIAZINE; PHOTOTOXICITY; RESISTANCE; BACTERIA; EFFICACY; ANALOGS; MODELS AB The benzophenothiazinium dye EtNBS has previously been tested as a photosensitizer to mediate photodynamic therapy (PDT). It has been employed to kill cancer cells and microbial cells in vitro and to treat tumors and infections in vivo. We synthesized a panel of derivatives substituted at the 1-position of the benzene ring with electron donating or electron withdrawing groups (amino, acetamido and nitro) and tested their production of reactive oxygen species (ROS) and light-mediated killing of two species of Gram-positive and two species of Gram-negative bacteria. All three compounds showed lower fluorescence, lower yield of ROS and less microbial killing than parent EtNBS, while the order of activity (nitro > amino > acetamido) showed that an electron withdrawing substituent was better than electron donating. To test the hypothesis that 1-substitution distorts the planar structure of the conjugated rings we compared two compounds substituted with N-ethylpropylsulfonamido either at the 1-position or at the 4-position. The 4-isomer was significantly more photoactive than the 1-isomer. We also prepared an EtNBS derivative with a guanidinium group attached to the 5-amino group. This compound had high activity against Gram-negative bacteria due to the extra positive charge. Cellular uptake of the compounds by the four bacterial species was also measured and broadly correlated with activity. These results provided three separate pieces of structure activity relationship data for antimicrobial photosensitizers based on the EtNBS backbone. (C) 2014 Elsevier Masson SAS. All rights reserved. C1 [Vecchio, Daniela; Bhayana, Brijesh; Huang, Liyi; Carrasco, Elisa; Evans, Conor L.; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Vecchio, Daniela; Huang, Liyi; Evans, Conor L.; 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 530021, Peoples R China. [Carrasco, Elisa] Univ Autonoma Madrid, Fac Ciencias, Dept Biol, E-28049 Madrid, Spain. [Carrasco, Elisa] Univ Autonoma Madrid, Fac Med, CSIC, Inst Invest Biomed Alberto Sols,Dept Bioquim, E-28029 Madrid, Spain. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), BAR414,40 Blossom St, Boston, MA 02114 USA. EM Hamblin@helix.mgh.harvard.edu RI Carrasco, Elisa/G-7746-2015; OI Carrasco, Elisa/0000-0002-0817-1627; Hamblin, Michael/0000-0001-6431-4605 FU US NIH [R01AI050875, DP2OD007096] FX This work was supported by US NIH grant R01AI050875 to MRH and US NIH Director's New Innovator Award, grant number DP2OD007096 to CLE. Information on the New Innovator Award Program is at http://nihroadmap.nih.gov/newinnovator/. The funding sources had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. NR 29 TC 8 Z9 8 U1 0 U2 13 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 EI 1768-3254 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD MAR 21 PY 2014 VL 75 BP 479 EP 491 DI 10.1016/j.ejmech.2014.01.064 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AE2AL UT WOS:000333775600046 PM 24561676 ER PT J AU Hsieh, LC Chen, JW Wang, LY Tsang, YM Shueng, PW Liao, LJ Lo, WC Lin, YC Tseng, CF Kuo, YS Jhuang, JY Tien, HJ Juan, HF Hsieh, CH AF Hsieh, Li-Chun Chen, John W. Wang, Li-Ying Tsang, Yuk-Ming Shueng, Pei-Wei Liao, Li-Jen Lo, Wu-Chia Lin, Yu-Chin Tseng, Chien-Fu Kuo, Ying-Shiung Jhuang, Jie-Yang Tien, Hui-Ju Juan, Hsueh-Fen Hsieh, Chen-Hsi TI Predicting the Severity and Prognosis of Trismus after Intensity-Modulated Radiation Therapy for Oral Cancer Patients by Magnetic Resonance Imaging SO PLOS ONE LA English DT Article ID NASOPHARYNGEAL CARCINOMA; POSTOPERATIVE TREATMENT; NECK RADIOTHERAPY; CAVITY CANCER; HEAD; EXPERIENCE; SEQUELAE; TERMS AB To develop magnetic resonance imaging (MRI) indicators to predict trismus outcome for post-operative oral cavity cancer patients who received adjuvant intensity-modulated radiation therapy (IMRT), 22 patients with oral cancer treated with IMRT were studied over a two-year period. Signal abnormality scores (SA scores) were computed from Likert-type ratings of the abnormalities of nine masticator structures and compared with the Mann-Whitney U-test and Kruskal-Wallis one-way ANOVA test between groups. Seventeen patients (77.3%) experienced different degrees of trismus during the two-year follow-up period. The SA score correlated with the trismus grade (r = 0.52, p < 0.005). Patients having progressive trismus had higher mean doses of radiation to multiple structures, including the masticator and lateral pterygoid muscles, and the parotid gland (p < 0.05). In addition, this group also had higher SA-masticator muscle dose product at 6 months and SA scores at 12 months (p < 0.05). At the optimum cut-off points of 0.38 for the propensity score, the sensitivity was 100% and the specificity was 93% for predicting the prognosis of the trismus patients. The SA score, as determined using MRI, can reflect the radiation injury and correlate to trismus severity. Together with the radiation dose, it could serve as a useful biomarker to predict the outcome and guide the management of trismus following radiation therapy. C1 [Hsieh, Li-Chun; Tsang, Yuk-Ming] Far Eastern Mem Hosp, Dept Radiol, Div Med Imaging, Taipei, Taiwan. [Shueng, Pei-Wei; Tien, Hui-Ju; Hsieh, Chen-Hsi] Far Eastern Mem Hosp, Dept Radiol, Div Radiat Oncol, Taipei, Taiwan. [Liao, Li-Jen; Lo, Wu-Chia] Far Eastern Mem Hosp, Dept Otolaryngol, Taipei, Taiwan. [Lin, Yu-Chin] Far Eastern Mem Hosp, Dept Internal Med, Div Med Oncol & Hematol, Taipei, Taiwan. [Tseng, Chien-Fu; Kuo, Ying-Shiung] Far Eastern Mem Hosp, Dept Dent & Oral Surg, Taipei, Taiwan. [Jhuang, Jie-Yang] Far Eastern Mem Hosp, Dept Anat Pathol, Taipei, Taiwan. [Hsieh, Chen-Hsi] Natl Yang Ming Univ, Sch Med, Dept Med, Taipei 112, Taiwan. [Hsieh, Chen-Hsi] Natl Yang Ming Univ, Sch Med, Inst Tradit Med, Taipei 112, Taiwan. [Wang, Li-Ying] Natl Taiwan Univ, Coll Med, Sch & Grad Inst Phys Therapy, Taipei 10764, Taiwan. [Shueng, Pei-Wei] Natl Def Med Ctr, Dept Radiat Oncol, Taipei, Taiwan. [Chen, John W.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Cambridge, MA 02138 USA. [Chen, John W.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Cambridge, MA 02138 USA. [Hsieh, Li-Chun] Natl Taiwan Univ, Ctr Syst Biol, Inst Mol & Cellular Biol, Dept Life Sci, Taipei 10764, Taiwan. [Juan, Hsueh-Fen] Natl Taiwan Univ, Grad Inst Biomed Elect & Bioinformat, Taipei 10764, Taiwan. [Hsieh, Li-Chun; Juan, Hsueh-Fen] Taipei Med Univ Hosp, Med Imaging Ctr, Taipei, Taiwan. RP Hsieh, CH (reprint author), Far Eastern Mem Hosp, Dept Radiol, Div Radiat Oncol, Taipei, Taiwan. EM chenciab@gmail.com OI WANG, LI-YING/0000-0003-3075-6872; JUAN, HSUEH-FEN/0000-0003-4876-3309 FU Far Eastern Memorial Hospital [FEMH-2012-C-055, FEMH 101-2314-B-418-010-MY3] FX This work was supported by the Far Eastern Memorial Hospital grants (FEMH-2012-C-055; FEMH 101-2314-B-418-010-MY3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 6 Z9 6 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 21 PY 2014 VL 9 IS 3 AR e92561 DI 10.1371/journal.pone.0092561 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD6GL UT WOS:000333355300098 PM 24658376 ER PT J AU Subudhi, AW Bourdillon, N Bucher, J Davis, C Elliott, JE Eutermoster, M Evero, O Fan, JL Houten, SJV Julian, CG Kark, J Kark, S Kayser, B Kern, JP Kim, SE Lathan, C Laurie, SS Lovering, AT Paterson, R Polaner, DM Ryan, BJ Spira, JL Tsao, JW Wachsmuth, NB Roach, RC AF Subudhi, Andrew W. Bourdillon, Nicolas Bucher, Jenna Davis, Christopher Elliott, Jonathan E. Eutermoster, Morgan Evero, Oghenero Fan, Jui-Lin Jameson-Van Houten, Sonja Julian, Colleen G. Kark, Jonathan Kark, Sherri Kayser, Bengt Kern, Julia P. Kim, See Eun Lathan, Corinna Laurie, Steven S. Lovering, Andrew T. Paterson, Ryan Polaner, David M. Ryan, Benjamin J. Spira, James L. Tsao, Jack W. Wachsmuth, Nadine B. Roach, Robert C. TI AltitudeOmics: The Integrative Physiology of Human Acclimatization to Hypobaric Hypoxia and Its Retention upon Reascent SO PLOS ONE LA English DT Article ID ACUTE MOUNTAIN-SICKNESS; OPERATION EVEREST-II; PULMONARY GAS-EXCHANGE; PLASMA-VOLUME EXPANSION; RED-CELL MASS; COGNITIVE PERFORMANCE; EXTREME ALTITUDE; OXYGEN-TRANSPORT; SIMULATED ASCENT; CARDIAC-OUTPUT AB An understanding of human responses to hypoxia is important for the health of millions of people worldwide who visit, live, or work in the hypoxic environment encountered at high altitudes. In spite of dozens of studies over the last 100 years, the basic mechanisms controlling acclimatization to hypoxia remain largely unknown. The AltitudeOmics project aimed to bridge this gap. Our goals were 1) to describe a phenotype for successful acclimatization and assess its retention and 2) use these findings as a foundation for companion mechanistic studies. Our approach was to characterize acclimatization by measuring changes in arterial oxygenation and hemoglobin concentration [Hb], acute mountain sickness (AMS), cognitive function, and exercise performance in 21 subjects as they acclimatized to 5260 m over 16 days. We then focused on the retention of acclimatization by having subjects reascend to 5260 m after either 7 (n = 14) or 21 (n = 7) days at 1525 m. At 16 days at 5260 m we observed: 1) increases in arterial oxygenation and [Hb] (compared to acute hypoxia: PaO2 rose 964 mmHg to 45 +/- 4 while PaCO2 dropped a further 6 +/- 3 mmHg to 21 +/- 3, and [Hb] rose 1.8 +/- 0.7 g/dL to 16 +/- 2 g/dL; 2) no AMS; 3) improved cognitive function; and 4) improved exercise performance by 8 +/- 8% (all changes p<0.01). Upon reascent, we observed retention of arterial oxygenation but not [Hb], protection from AMS, retention of exercise performance, less retention of cognitive function; and noted that some of these effects lasted for 21 days. Taken together, these findings reveal new information about retention of acclimatization, and can be used as a physiological foundation to explore the molecular mechanisms of acclimatization and its retention. C1 [Subudhi, Andrew W.; Davis, Christopher; Eutermoster, Morgan; Evero, Oghenero; Jameson-Van Houten, Sonja; Julian, Colleen G.; Kark, Jonathan; Kark, Sherri; Paterson, Ryan; Roach, Robert C.] Univ Colorado, Altitude Res Ctr, Dept Emergency Med, Aurora, CO 80045 USA. [Subudhi, Andrew W.] Univ Colorado, Dept Biol, Colorado Springs, CO 80907 USA. [Bourdillon, Nicolas; Fan, Jui-Lin; Kayser, Bengt] Univ Lausanne, Fac Biol & Med, Inst Sports Sci, Lausanne, Switzerland. [Bourdillon, Nicolas; Fan, Jui-Lin] Univ Lausanne, Fac Biol & Med, Dept Physiol, Lausanne, Switzerland. [Bucher, Jenna; Elliott, Jonathan E.; Kern, Julia P.; Kim, See Eun; Laurie, Steven S.; Lovering, Andrew T.] Univ Oregon, Dept Human Physiol, Eugene, OR 97403 USA. [Fan, Jui-Lin] Univ Lausanne, Leman Doctoral Sch Neurosci, Lausanne, Switzerland. [Lathan, Corinna] AnthroTronix Inc, Silver Spring, MD USA. [Polaner, David M.] Univ Colorado, Sch Med, Dept Anesthesiol, Aurora, CO USA. [Polaner, David M.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO USA. [Polaner, David M.] Childrens Hosp Colorado, Aurora, CO USA. [Ryan, Benjamin J.] Univ Colorado, Dept Integrat Physiol, Boulder, CO USA. [Spira, James L.] Univ Hawaii, US Dept Vet Affairs, Pacific Islands Hlth Care Syst, Natl Ctr PTSD, Honolulu, HI 96822 USA. [Spira, James L.] Univ Hawaii, John A Burns Sch Med, Dept Psychiat, Honolulu, HI 96822 USA. [Tsao, Jack W.] US Navy Bur Med & Surg, Wounded Ill & Injured Directorate M9, Falls Church, VA USA. [Wachsmuth, Nadine B.] Univ Bayreuth, Dept Sports Med Sports Physiol, Bayreuth, Germany. RP Roach, RC (reprint author), Univ Colorado, Altitude Res Ctr, Dept Emergency Med, Anschutz Med Campus, Aurora, CO 80045 USA. EM Robert.Roach@ucdenver.edu RI Kayser, Bengt/M-8643-2013; OI Kayser, Bengt/0000-0002-9776-7501; Polaner, David/0000-0001-8716-6289; Elliott, Jonathan/0000-0002-6992-6851 FU United States Department of Defense [W81XWH-11-2-0040 TATRC, W81XWH-10-2-0114]; National Institutes of Health (NIH)/National Center for Advancing Translational Sciences Colorado CTSI [UL1 TR000154]; Cardiopulmonary & Respiratory Physiology Laboratory, University of Oregon; Altitude Research Center; Charles S. Houston Endowed Professorship, Department of Emergency Medicine, School of Medicine, University of Colorado Denver FX The overall AltitudeOmics study was funded, in part, by grants from the United States Department of Defense (W81XWH-11-2-0040 TATRC to RCR and W81XWH-10-2-0114 to ATL). The project was also supported, in part, by National Institutes of Health (NIH)/National Center for Advancing Translational Sciences Colorado CTSI Grant Number UL1 TR000154. Contents are the author's sole responsibility and do not necessarily represent official NIH views. Major additional support came from the Cardiopulmonary & Respiratory Physiology Laboratory, University of Oregon; the Altitude Research Center and the Charles S. Houston Endowed Professorship, Department of Emergency Medicine, School of Medicine, University of Colorado Denver. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 16 Z9 16 U1 0 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 21 PY 2014 VL 9 IS 3 AR e92191 DI 10.1371/journal.pone.0092191 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD6GL UT WOS:000333355300059 PM 24658407 ER PT J AU Saukkonen, K Tan, TC Sharma, A Channick, RN Murali, MR Zukerberg, LR AF Saukkonen, Kai Tan, Timothy C. Sharma, Amita Channick, Richard N. Murali, Mandakolathur R. Zukerberg, Lawrence R. TI Case 9-2014: A 34-Year-Old Woman with Increasing Dyspnea SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CONNECTIVE-TISSUE DISEASE; SYSTEMIC-LUPUS-ERYTHEMATOSUS; PULMONARY-HYPERTENSION; CLASSIFICATION; CRITERIA C1 [Saukkonen, Kai; Tan, Timothy C.; Channick, Richard N.; Murali, Mandakolathur R.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Sharma, Amita] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Zukerberg, Lawrence R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Saukkonen, Kai; Tan, Timothy C.; Channick, Richard N.; Murali, Mandakolathur R.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Sharma, Amita] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Zukerberg, Lawrence R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Saukkonen, K (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. FU Actelion Pharmaceuticals; Bayer; United Therapeutics FX Dr. Channick reports receiving consulting fees and grant support from Actelion Pharmaceuticals, Bayer, and United Therapeutics. No other potential conflict of interest relevant to this article was reported. NR 14 TC 3 Z9 3 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 20 PY 2014 VL 370 IS 12 BP 1149 EP 1157 DI 10.1056/NEJMcpc1305992 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AD2HA UT WOS:000333054000012 PM 24645948 ER PT J AU Weinstein, JN Akbani, R Broom, BM Wang, WY Verhaak, RGW McConkey, D Lerner, S Morgan, M Creighton, CJ Smith, C Kwiatkowski, DJ Cherniack, AD Kim, J Pedamallu, CS Noble, MS Al-Ahmadie, HA Reuter, VE Rosenberg, JE Bajorin, DF Bochner, BH Solit, DB Koppie, T Robinson, B Gordenin, DA Fargo, D Klimczak, LJ Roberts, SA Au, J Laird, PW Hinoue, T Schultz, N Ramirez, R Hansel, D Hoadley, KA Kim, WY Damrauer, JS Baylin, SB Mungall, AJ Robertson, AG Chu, A Kwiatkowski, DJ Sougnez, C Cibulskis, K Lichtenstein, L Sivachenko, A Stewart, C Lawrence, MS Getz, G Lander, E Gabriel, SB Creighton, CJ Donehower, L Cherniack, AD Kim, J Carter, SL Saksena, G Schumacher, SE Sougnez, C Freeman, SS Jung, J Pedamallu, CS Bhatt, AS Pugh, T Getz, G Beroukhim, R Gabriel, SB Meyerson, M Mungall, AJ Robertson, AG Chu, A Ally, A Balasundaram, M Butterfield, YSN Dhalla, N Hirst, C Holt, RA Jones, SJM Lee, D Li, HYI Marra, MA Mayo, M Moore, RA Schein, JE Sipahimalani, P Tam, A Thiessen, N Wong, T Wye, N Bowlby, R Chuah, E Guin, R Jones, SJM Marra, MA Hinoue, T Shen, H Bootwalla, MS Triche, T Lai, PH Van den Berg, DJ Weisenberger, DJ Laird, PW Hansel, D Hoadley, KA Balu, S Bodenheimer, T Damrauer, JS Hoyle, AP Jefferys, SR Meng, SW Mose, LE Simons, JV Soloway, MG Wu, JY Kim, WY Parker, JS Hayes, DN Roach, J Buda, E Jones, CD Mieczkowski, PA Tan, DH Veluvolu, U Waring, S Auman, JT Perou, CM Wilkerson, MD Santoso, N Parfenov, M Ren, XJ Pantazi, A Hadjipanayis, A Seidman, J Kucherlapati, R Lee, S Yang, LX Park, PJ Baylin, SB Xu, AW Protopopov, A Zhang, JH Bristow, C Mahadeshwar, HS Seth, S Song, XZ Tang, JB Zeng, D Chin, LD Guo, C Weinstein, JN Akbani, R Broom, BM McConkey, D Casasent, TD Liu, WB Ju, ZL Motter, T Peng, B Ryan, M Wang, WY Verhaak, RGW Su, XP Yang, JY Lorenzi, PL Yao, H Zhang, NX Zhang, JX Mills, GB Kim, J Noble, MS Cho, J DiCara, D Frazer, S Gehlenborg, N Heiman, DI Lin, P Liu, YC Stojanov, P Voet, D Zhang, HL Zou, LH Chin, LD Getz, G Bernard, B Kreisberg, D Reynolds, S Rovira, H Shmulevich, I Ramirez, R Schultz, N Gao, JJ Jacobsen, A Aksoy, BA Antipin, Y Ciriello, G Dresdner, G Gross, B Lee, W Reva, B Shen, RL Sinha, R Sumer, SO Weinhold, N Ladanyi, M Sander, C Benz, C Carlin, D Haussler, D Ng, S Paull, EO Stuart, J Zhu, J Liu, YX Zhang, W Taylor, BS Lichtenberg, TM Zmuda, E Barr, T Black, AD George, M Hanf, B Helsel, C McAllister, C Ramirez, NC Tabler, TR Weaver, S Wise, L Bowen, J Gastier-Foster, JM Weinstein, JN Lerner, S Jian, WG Tello, S Ittman, M Castro, P McClenden, WD Morgan, M Gibbs, R Liu, YC Saller, C Tarvin, K DiPiero, JM Owens, J Bollag, R Li, Q Weinberger, P Czerwinski, C Huelsenbeck-Dill, L Iacocca, M Petrelli, N Rabeno, B Swanson, P Shelton, T Curley, E Gardner, J Mallery, D Penny, R Bang, NV Hanh, PT Kohl, B Le, XV Phu, BD Thorp, R Tien, NV Vinh, LQ Sandusky, G Burks, E Christ, K Gee, J Holway, A Moinzadeh, A Sorcini, A Sullivan, T Al-Ahmadie, HA Bajorin, DF Bochner, BH Garcia-Grossman, IR Regazzi, AM Solit, DB Rosenberg, JE Reuter, VE Koppie, T Boice, L Rathmell, WK Thorne, L Bastacky, S Davies, B Dhir, R Gingrich, J Hrebinko, R Maranchie, J Nelson, J Parwani, A Bshara, W Gaudioso, C Morrison, C Alexopoulou, V Bartlett, J Engel, J Kodeeswaran, S Antic, T O'Donnell, PH Smith, ND Steinberg, GD Egea, S Gomez-Fernandez, C Herbert, L Jorda, M Soloway, M Beaver, A Carter, S Kapur, P Lewis, C Lotan, Y Robinson, B Hansel, D Guo, C Bondaruk, J Czerniak, B Akbani, R Broom, BM Liu, YX Zhang, W Weinstein, JN Lerner, S Morgan, M Kim, J Cherniack, AD Freeman, SS Pedamallu, CS Noble, MS Kwiatkowski, DJ Al-Ahmadie, HA Bajorin, DF Bochner, BH Solit, DB Rosenberg, JE Reuter, VE Koppie, T Robinson, B Skinner, E Ramirez, R Schultz, N Hansel, D Kim, WY Guo, C Bondaruk, J Aldape, K Czerniak, B Jensen, MA Kahn, AB Pihl, TD Pot, DA Srinivasan, D Wan, YH Ferguson, ML Zenklusen, JC Davidsen, T Demchok, JA Shaw, KRM Sheth, M Tarnuzzer, R Wang, ZN Yang, LM Hutter, C Ozenberger, BA Sofia, HJ Eley, G AF Weinstein, John N. Akbani, Rehan Broom, Bradley M. Wang, Wenyi Verhaak, Roeland G. W. McConkey, David Lerner, Seth Morgan, Margaret Creighton, Chad J. Smith, Carolyn Kwiatkowski, David J. Cherniack, Andrew D. Kim, Jaegil Pedamallu, Chandra Sekhar Noble, Michael S. Al-Ahmadie, Hikmat A. Reuter, Victor E. Rosenberg, Jonathan E. Bajorin, Dean F. Bochner, Bernard H. Solit, David B. Koppie, Theresa Robinson, Brian Gordenin, Dmitry A. Fargo, David Klimczak, Leszek J. Roberts, Steven A. Au, Jessie Laird, Peter W. Hinoue, Toshinori Schultz, Nikolaus Ramirez, Ricardo Hansel, Donna Hoadley, Katherine A. Kim, William Y. Damrauer, Jeffrey S. Baylin, Stephen B. Mungall, Andrew J. Robertson, A. Gordon Chu, Andy Kwiatkowski, David J. Sougnez, Carrie Cibulskis, Kristian Lichtenstein, Lee Sivachenko, Andrey Stewart, Chip Lawrence, Michael S. Getz, Gad Lander, Eric Gabriel, Stacey B. Creighton, Chad J. Donehower, Lawrence Cherniack, Andrew D. Kim, Jaegil Carter, Scott L. Saksena, Gordon Schumacher, Steven E. Sougnez, Carrie Freeman, Samuel S. Jung, Joonil Pedamallu, Chandra Sekhar Bhatt, Ami S. Pugh, Trevor Getz, Gad Beroukhim, Rameen Gabriel, Stacey B. Meyerson, Matthew Mungall, Andrew J. Robertson, A. Gordon Chu, Andy Ally, Adrian Balasundaram, Miruna Butterfield, Yaron S. N. Dhalla, Noreen Hirst, Carrie Holt, Robert A. Jones, Steven J. M. Lee, Darlene Li, Haiyan I. Marra, Marco A. Mayo, Michael Moore, Richard A. Schein, Jacqueline E. Sipahimalani, Payal Tam, Angela Thiessen, Nina Wong, Tina Wye, Natasja Bowlby, Reanne Chuah, Eric Guin, Ranabir Jones, Steven J. M. Marra, Marco A. Hinoue, Toshinori Shen, Hui Bootwalla, Moiz S. Triche, Timothy, Jr. Lai, Phillip H. Van den Berg, David J. Weisenberger, Daniel J. Laird, Peter W. Hansel, Donna Hoadley, Katherine A. Balu, Saianand Bodenheimer, Tom Damrauer, Jeffrey S. Hoyle, Alan P. Jefferys, Stuart R. Meng, Shaowu Mose, Lisle E. Simons, Janae V. Soloway, Mathew G. Wu, Junyuan Kim, William Y. Parker, Joel S. Hayes, D. Neil Roach, Jeffrey Buda, Elizabeth Jones, Corbin D. Mieczkowski, Piotr A. Tan, Donghui Veluvolu, Umadevi Waring, Scot Auman, J. Todd Perou, Charles M. Wilkerson, Matthew D. Santoso, Netty Parfenov, Michael Ren, Xiaojia Pantazi, Angeliki Hadjipanayis, Angela Seidman, Jonathan Kucherlapati, Raju Lee, Semin Yang, Lixing Park, Peter J. Baylin, Stephen B. Xu, Andrew Wei Protopopov, Alexei Zhang, Jianhua Bristow, Christopher Mahadeshwar, Harshad S. Seth, Sahil Song, Xingzhi Tang, Jiabin Zeng, Dong Chin, Lynda Guo, Charles Weinstein, John N. Akbani, Rehan Broom, Bradley M. McConkey, David Casasent, Tod D. Liu, Wenbin Ju, Zhenlin Motter, Thomas Peng, Bo Ryan, Michael Wang, Wenyi Verhaak, Roeland G. W. Su, Xiaoping Yang, Ji-Yeon Lorenzi, Philip L. Yao, Hui Zhang, Nianxiang Zhang, Jiexin Mills, Gordon B. Kim, Jaegil Noble, Michael S. Cho, Juok DiCara, Daniel Frazer, Scott Gehlenborg, Nils Heiman, David I. Lin, Pei Liu, Yingchun Stojanov, Petar Voet, Doug Zhang, Hailei Zou, Lihua Chin, Lynda Getz, Gad Bernard, Brady Kreisberg, Dick Reynolds, Sheila Rovira, Hector Shmulevich, Ilya Ramirez, Ricardo Schultz, Nikolaus Gao, Jianjiong Jacobsen, Anders Aksoy, B. Arman Antipin, Yevgeniy Ciriello, Giovanni Dresdner, Gideon Gross, Benjamin Lee, William Reva, Boris Shen, Ronglai Sinha, Rileen Sumer, S. Onur Weinhold, Nils Ladanyi, Marc Sander, Chris Benz, Christopher Carlin, Daniel Haussler, David Ng, Sam Paull, Evan O. Stuart, Joshua Zhu, Jing Liu, Yuexin Zhang, Wei Taylor, Barry S. Lichtenberg, Tara M. Zmuda, Erik Barr, Thomas Black, Aaron D. George, Myra Hanf, Benjamin Helsel, Carmen McAllister, Cynthia Ramirez, Nilsa C. Tabler, Teresa R. Weaver, Stephanie Wise, Lisa Bowen, Jay Gastier-Foster, Julie M. Weinstein, John N. Lerner, Seth Jian, Weiguo Tello, Sebrina Ittman, Michael Castro, Patricia McClenden, Whitney D. Morgan, Margaret Gibbs, Richard Liu, Yingchun Saller, Charles Tarvin, Katherine DiPiero, Jennifer M. Owens, Jennifer Bollag, Roni Li, Qiang Weinberger, Paul Czerwinski, Christine Huelsenbeck-Dill, Lori Iacocca, Mary Petrelli, Nicholas Rabeno, Brenda Swanson, Pat Shelton, Troy Curley, Erin Gardner, Johanna Mallery, David Penny, Robert Nguyen Van Bang Phan Thi Hanh Kohl, Bernard Xuan Van Le Bui Duc Phu Thorp, Richard Nguyen Viet Tien Le Quang Vinh Sandusky, George Burks, Eric Christ, Kimberly Gee, Jason Holway, Antonia Moinzadeh, Alireza Sorcini, Andrea Sullivan, Travis Al-Ahmadie, Hikmat A. Bajorin, Dean F. Bochner, Bernard H. Garcia-Grossman, Ilana R. Regazzi, Ashley M. Solit, David B. Rosenberg, Jonathan E. Reuter, Victor E. Koppie, Theresa Boice, Lori Rathmell, Wendy Kimryn Thorne, Leigh Bastacky, Sheldon Davies, Benjamin Dhir, Rajiv Gingrich, Jeffrey Hrebinko, Ronald Maranchie, Jodi Nelson, Joel Parwani, Anil Bshara, Wiam Gaudioso, Carmelo Morrison, Carl Alexopoulou, Vina Bartlett, John Engel, Jay Kodeeswaran, Sugy Antic, Tatjana O'Donnell, Peter H. Smith, Norm D. Steinberg, Gary D. Egea, Sophie Gomez-Fernandez, Carmen Herbert, Lynn Jorda, Merce Soloway, Mark Beaver, Allison Carter, Suzie Kapur, Payal Lewis, Cheryl Lotan, Yair Robinson, Brian Hansel, Donna Guo, Charles Bondaruk, Jolanta Czerniak, Bogdan Akbani, Rehan Broom, Bradley M. Liu, Yuexin Zhang, Wei Weinstein, John N. Lerner, Seth Morgan, Margaret Kim, Jaegil Cherniack, Andrew D. Freeman, Samuel S. Pedamallu, Chandra Sekhar Noble, Michael S. Kwiatkowski, David J. Al-Ahmadie, Hikmat A. Bajorin, Dean F. Bochner, Bernard H. Solit, David B. Rosenberg, Jonathan E. Reuter, Victor E. Koppie, Theresa Robinson, Brian Skinner, Eila Ramirez, Ricardo Schultz, Nikolaus Hansel, Donna Kim, William Y. Guo, Charles Bondaruk, Jolanta Aldape, Kenneth Czerniak, Bogdan Jensen, Mark A. Kahn, Ari B. Pihl, Todd D. Pot, David A. Srinivasan, Deepak Wan, Yunhu Ferguson, Martin L. Zenklusen, Jean Claude Davidsen, Tanja Demchok, John A. Shaw, Kenna R. Mills Sheth, Margi Tarnuzzer, Roy Wang, Zhining Yang, Liming Hutter, Carolyn Ozenberger, Bradley A. Sofia, Heidi J. Eley, Greg CA Canc Genome Atlas Res Network TI Comprehensive molecular characterization of urothelial bladder carcinoma SO NATURE LA English DT Article ID HUMAN CANCERS; GENE FUSIONS; TUMOR-GROWTH; MUTATIONS; GENOMES; KINASE; FGFR AB Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomasto provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities. C1 [Weinstein, John N.; Akbani, Rehan; Broom, Bradley M.; Wang, Wenyi; Verhaak, Roeland G. W.; Liu, Wenbin; Ju, Zhenlin; Motter, Thomas; Peng, Bo; Ryan, Michael; Su, Xiaoping; Yang, Ji-Yeon; Lorenzi, Philip L.; Yao, Hui; Zhang, Nianxiang; Zhang, Jiexin] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Liu, Wenbin; Ju, Zhenlin; Yang, Ji-Yeon; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [McConkey, David; Shaw, Kenna R. Mills] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Lerner, Seth; Jian, Weiguo; Tello, Sebrina] Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA. [Morgan, Margaret; Jian, Weiguo; Tello, Sebrina; Ittman, Michael; Castro, Patricia; McClenden, Whitney D.; Gibbs, Richard] Baylor Coll Med, TCRB, Houston, TX 77030 USA. [Gibbs, Richard] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Creighton, Chad J.; Donehower, Lawrence] Baylor Coll Med, Human Genome Sequencing Ctr, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Smith, Carolyn] Baylor Coll Med, Houston, TX 77030 USA. [Kwiatkowski, David J.; Kwiatkowski, David J.; Cibulskis, Kristian; Lichtenstein, Lee; Sivachenko, Andrey; Stewart, Chip; Lawrence, Michael S.; Getz, Gad; Lander, Eric; Gabriel, Stacey B.; Carter, Scott L.; Saksena, Gordon; Schumacher, Steven E.; Freeman, Samuel S.; Jung, Joonil; Bhatt, Ami S.; Pugh, Trevor; Beroukhim, Rameen; Meyerson, Matthew; Chin, Lynda; Cho, Juok; DiCara, Daniel; Frazer, Scott; Gehlenborg, Nils; Heiman, David I.; Lin, Pei; Liu, Yingchun; Stojanov, Petar; Voet, Doug; Zhang, Hailei; Zou, Lihua] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Kwiatkowski, David J.; Casasent, Tod D.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kwiatkowski, David J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Bhatt, Ami S.; Pugh, Trevor; Beroukhim, Rameen; Meyerson, Matthew; Stojanov, Petar] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Garcia-Grossman, Ilana R.; Regazzi, Ashley M.] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA. [Koppie, Theresa] Oregon Hlth & Sci Univ, Dept Urol, Portland, OR 97239 USA. Cornell Univ, Weill Med Coll, New York, NY 10065 USA. [Gordenin, Dmitry A.; Fargo, David; Klimczak, Leszek J.; Roberts, Steven A.] NIEHS, Res Triangle Pk, NC 27709 USA. [Au, Jessie] OptimumTherapeutics LLC, San Diego, CA 92121 USA. [Shen, Hui; Bootwalla, Moiz S.; Triche, Timothy, Jr.; Lai, Phillip H.; Van den Berg, David J.; Weisenberger, Daniel J.] Univ So Calif, Epigenome Ctr, Los Angeles, CA 90033 USA. [Schultz, Nikolaus; Ramirez, Ricardo; Gao, Jianjiong; Jacobsen, Anders; Aksoy, B. Arman; Antipin, Yevgeniy; Ciriello, Giovanni; Dresdner, Gideon; Gross, Benjamin; Lee, William; Reva, Boris; Shen, Ronglai; Sinha, Rileen; Sumer, S. Onur; Weinhold, Nils; Ladanyi, Marc; Sander, Chris] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA. [Hansel, Donna] UCSD Dept Pathol, La Jolla, CA 92093 USA. [Hoadley, Katherine A.; Balu, Saianand; Bodenheimer, Tom; Hoyle, Alan P.; Jefferys, Stuart R.; Meng, Shaowu; Mose, Lisle E.; Simons, Janae V.; Soloway, Mathew G.; Wu, Junyuan; Parker, Joel S.; Hayes, D. Neil] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Parker, Joel S.; Perou, Charles M.; Wilkerson, Matthew D.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Baylin, Stephen B.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Canc Biol Div, Baltimore, MD 21231 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Donehower, Lawrence] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. [Schumacher, Steven E.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Mungall, Andrew J.; Chu, Andy; Ally, Adrian; Balasundaram, Miruna; Butterfield, Yaron S. N.; Dhalla, Noreen; Hirst, Carrie; Holt, Robert A.; Jones, Steven J. M.; Lee, Darlene; Li, Haiyan I.; Marra, Marco A.; Mayo, Michael; Moore, Richard A.; Schein, Jacqueline E.; Sipahimalani, Payal; Tam, Angela; Thiessen, Nina; Wong, Tina; Wye, Natasja; Bowlby, Reanne; Chuah, Eric; Guin, Ranabir] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Hayes, D. Neil] Univ N Carolina, Dept Internal Med, Div Med Oncol, Chapel Hill, NC 27599 USA. [Roach, Jeffrey] Univ N Carolina, Res Comp Ctr, Chapel Hill, NC 27599 USA. [Buda, Elizabeth; Jones, Corbin D.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Jones, Corbin D.; Mieczkowski, Piotr A.; Tan, Donghui; Veluvolu, Umadevi; Waring, Scot] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Auman, J. Todd] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Santoso, Netty; Parfenov, Michael; Ren, Xiaojia; Pantazi, Angeliki; Hadjipanayis, Angela; Seidman, Jonathan; Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Hadjipanayis, Angela; Kucherlapati, Raju; Park, Peter J.; Xu, Andrew Wei] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Lee, Semin; Yang, Lixing; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Park, Peter J.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Protopopov, Alexei; Zhang, Jianhua; Bristow, Christopher; Mahadeshwar, Harshad S.; Seth, Sahil; Song, Xingzhi; Tang, Jiabin; Zeng, Dong] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Inst Appl Canc Sci, Houston, TX 77030 USA. [Guo, Charles; Bondaruk, Jolanta; Czerniak, Bogdan; Aldape, Kenneth] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Bernard, Brady; Kreisberg, Dick; Reynolds, Sheila; Rovira, Hector; Shmulevich, Ilya] Inst Syst Biol, Seattle, WA 98109 USA. [Benz, Christopher] Buck Inst Res Aging, Novato, CA 94945 USA. [Carlin, Daniel; Haussler, David; Ng, Sam; Paull, Evan O.; Stuart, Joshua; Zhu, Jing] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. [Liu, Yuexin; Zhang, Wei] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Taylor, Barry S.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA. [Lichtenberg, Tara M.; Zmuda, Erik; Barr, Thomas; Black, Aaron D.; George, Myra; Hanf, Benjamin; Helsel, Carmen; McAllister, Cynthia; Ramirez, Nilsa C.; Tabler, Teresa R.; Weaver, Stephanie; Wise, Lisa; Bowen, Jay; Gastier-Foster, Julie M.] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA. [Ramirez, Nilsa C.; Gastier-Foster, Julie M.] Ohio State Univ, Columbus, OH 43210 USA. [Ittman, Michael; Castro, Patricia] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. [Saller, Charles; Tarvin, Katherine] Analyt Biol Serv Inc, Wilmington, DE 19801 USA. [DiPiero, Jennifer M.; Owens, Jennifer] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Bollag, Roni; Li, Qiang; Weinberger, Paul] Georgia Regents Univ, Canc Ctr, Augusta, GA 30912 USA. [Czerwinski, Christine; Huelsenbeck-Dill, Lori; Iacocca, Mary; Petrelli, Nicholas; Rabeno, Brenda; Swanson, Pat] Christiana Care, Helen F Graham Canc Ctr, Newark, DE 19713 USA. [Shelton, Troy; Curley, Erin; Gardner, Johanna; Mallery, David; Penny, Robert] Int Genom Consortium, Phoenix, AZ 85004 USA. [Nguyen Van Bang; Phan Thi Hanh; Kohl, Bernard; Xuan Van Le; Bui Duc Phu; Thorp, Richard; Nguyen Viet Tien; Le Quang Vinh] ILSbio LLC, Chestertown, MD 21620 USA. Hue Cent Hosp, Hue City, Vietnam. [Sandusky, George] IU Sch Med, Indianapolis, IN 46202 USA. [Burks, Eric; Christ, Kimberly; Gee, Jason; Holway, Antonia; Moinzadeh, Alireza; Sorcini, Andrea; Sullivan, Travis] Lahey Hosp & Med Ctr, Burlington, MA 01805 USA. [Boice, Lori; Rathmell, Wendy Kimryn; Thorne, Leigh] Univ N Carolina, Lineberger Canc Ctr, Chapel Hill, NC 27599 USA. [Bastacky, Sheldon; Davies, Benjamin; Dhir, Rajiv; Gingrich, Jeffrey; Hrebinko, Ronald; Maranchie, Jodi; Nelson, Joel; Parwani, Anil] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Bshara, Wiam; Gaudioso, Carmelo; Morrison, Carl] Roswell Pk Canc Inst, Buffalo, NY 14063 USA. [Alexopoulou, Vina; Bartlett, John; Engel, Jay; Kodeeswaran, Sugy] St Josephs Healthcare Hamilton, Ontario Tumour Bank, Hamilton, ON L8N 3Z5, Canada. [Antic, Tatjana; O'Donnell, Peter H.; Smith, Norm D.; Steinberg, Gary D.] Univ Chicago, Chicago, IL 60637 USA. [Egea, Sophie; Gomez-Fernandez, Carmen; Herbert, Lynn; Jorda, Merce; Soloway, Mark] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. [Beaver, Allison; Carter, Suzie; Kapur, Payal; Lewis, Cheryl; Lotan, Yair] UT Southwestern Med Ctr, Dallas, TX 75390 USA. [Skinner, Eila] Stanford Univ, Dept Urol, Stanford, CA 94305 USA. [Jensen, Mark A.; Kahn, Ari B.; Pihl, Todd D.; Pot, David A.; Srinivasan, Deepak; Wan, Yunhu] SRA Int, Fairfax, VA 22033 USA. [Ferguson, Martin L.] MLF Consulting, Arlington, MA 02474 USA. [Zenklusen, Jean Claude; Davidsen, Tanja; Demchok, John A.; Shaw, Kenna R. Mills; Sheth, Margi; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming] NCI, Bethesda, MD 20892 USA. [Hutter, Carolyn; Ozenberger, Bradley A.; Sofia, Heidi J.] NHGRI, Rockville, MD 20852 USA. [Eley, Greg] Scimentis LLC, Atlanta, GA 30666 USA. RP Weinstein, JN (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. EM jweinste@mdanderson.org; slerner@bcm.edu; dk@rics.bwh.harvard.edu RI Laird, Peter/G-8683-2012; Jacobsen, Anders/K-1081-2013; Schein, Jacquie/G-3674-2015; Weinberger, Paul/B-7007-2008; Jones, Steven/C-3621-2009; Lee, Semin/S-2629-2016; Marra, Marco/B-5987-2008; Holt, Robert/C-3303-2009; OI Gordenin, Dmitry/0000-0002-8399-1836; Maranchie, Jodi/0000-0002-8534-9468; Seth, Sahil/0000-0003-4579-3959; Pot, David/0000-0002-1480-9826; Sinha, Rileen/0000-0001-5497-5055; Perou, Charles/0000-0001-9827-2247; Gehlenborg, Nils/0000-0003-0327-8297; Rosenberg, Jonathan/0000-0003-2637-4249; Triche, Tim/0000-0001-5665-946X; Jacobsen, Anders/0000-0001-6847-4980; Weinberger, Paul/0000-0002-5885-2631; Lee, Semin/0000-0002-9015-6046; Kohl, Bernard/0000-0002-4610-0934; Schultz, Nikolaus/0000-0002-0131-4904; Al-Ahmadie, Hikmat/0000-0002-2938-6627 FU United States National Institutes of Health [U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025, P01 CA120964] FX We are grateful to all of the patients and families who contributed to this study, as well as C. Gunter and L. Chastain for scientific editing and M. Sheth, J. Zhang and C. Ron Bouchard for administrative support. This work was supported by the following grants from the United States National Institutes of Health: U54 HG003273, U54 HG003067, U54 HG003079, U24 CA143799, U24 CA143835, U24 CA143840, U24 CA143843, U24 CA143845, U24 CA143848, U24 CA143858, U24 CA143866, U24 CA143867, U24 CA143882, U24 CA143883, U24 CA144025 and P01 CA120964. Additional personnel and funding sources are acknowledged in the Supplementary Information. NR 39 TC 379 Z9 383 U1 15 U2 126 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 20 PY 2014 VL 507 IS 7492 BP 315 EP 322 DI 10.1038/nature12965 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD1YG UT WOS:000333029000025 ER PT J AU DePeralta, DK Hoang, MP Tanabe, KK AF DePeralta, Danielle K. Hoang, Mai P. Tanabe, Kenneth K. TI Approaches to Regional Nodes in Patients With Melanoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SENTINEL LYMPH-NODES; RANDOMIZED SURGICAL TRIAL; EARLY-STAGE MELANOMA; POSITIVE MELANOMA; MALIGNANT-MELANOMA; CUTANEOUS MELANOMA; MULTICENTER TRIAL; NODAL OBSERVATION; EXCISION MARGINS; SCORING SYSTEM C1 [DePeralta, Danielle K.; Tanabe, Kenneth K.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [DePeralta, Danielle K.; Hoang, Mai P.; Tanabe, Kenneth K.] Harvard Univ, Sch Med, Boston, MA USA. [Hoang, Mai P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP DePeralta, DK (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM ktanabe@partners.org NR 28 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2014 VL 32 IS 9 BP 881 EP 885 DI 10.1200/JCO.2013.52.3571 PG 5 WC Oncology SC Oncology GA AG0XA UT WOS:000335137900017 PM 24516017 ER PT J AU Vaz-Luis, I Keating, NL Lin, NU Lii, HC Winer, EP Freedman, RA AF Vaz-Luis, Ines Keating, Nancy L. Lin, Nancy U. Lii, Huichuan Winer, Eric P. Freedman, Rachel A. TI Duration and Toxicity of Adjuvant Trastuzumab in Older Patients With Early-Stage Breast Cancer: A Population-Based Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SEER-MEDICARE DATA; HEART-FAILURE; COMORBIDITY INDEX; NSABP B-31; FOLLOW-UP; CHEMOTHERAPY; VALIDATION; ONCOGENE; THERAPY; TRIAL AB Purpose Few data are available regarding adjuvant trastuzumab use in older women with early-stage breast cancer. We examined rates and predictors of adjuvant trastuzumab completion and cardiac events in this population. Patients and Methods We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data to identify patients age 66 years with stage I to III breast cancer diagnosed between 2005 and 2009 who received trastuzumab. Completion of trastuzumab was defined as receipt of more than 270 days of therapy. We used multivariable logistic regression to examine patient, clinical, and geographic characteristics associated with trastuzumab completion. We also examined rates of hospital admissions for cardiac events. Results Among 2,028 women, most (71.2%) were younger than age 76 years and had a comorbidity score of 0 (66.8%); 85.2% received trastuzumab with chemotherapy. Overall, 1,656 women (81.7%) completed trastuzumab. Older patients and those with more comorbidity had lower odds of treatment completion (odds ratio [OR], 0.40 [95% CI, 0.30 to 0.55] for age 80 years v age 66 to 70 years; OR, 0.65 [95% CI, 0.49 to 0.88] for comorbidity score of 2 v 0). During treatment, 73 patients (3.6%) were hospitalized for cardiac events (2.6% of those who completed trastuzumab v 8.1% of those who did not; P < .001). Conclusion Most older patients who initiated adjuvant trastuzumab completed therapy. Age and comorbidity were among factors that were associated with treatment completion, and rates of significant cardiac events were higher in those who did not complete therapy. Further exploration of toxicities and optimal treatments for older women with human epidermal growth factor receptor 2-positive breast cancer are warranted. C1 [Vaz-Luis, Ines; Lin, Nancy U.; Winer, Eric P.; Freedman, Rachel A.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Keating, Nancy L.] Harvard Univ, Sch Med, Boston, MA USA. [Keating, Nancy L.; Lii, Huichuan] Brigham & Womens Hosp, Boston, MA 02115 USA. [Vaz-Luis, Ines] Inst Mol Med, Lisbon, Portugal. RP Freedman, RA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Rachel_Freedman@dfci.harvard.edu FU NCI NIH HHS [N01PC35139, P50 CA089393, N01PC35136, N02 PC015105] NR 22 TC 25 Z9 25 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2014 VL 32 IS 9 BP 927 EP + DI 10.1200/JCO.2013.51.1261 PG 9 WC Oncology SC Oncology GA AG0XA UT WOS:000335137900020 PM 24516021 ER PT J AU Zhou, YF Springer, TA AF Zhou, Yan-Feng Springer, Timothy A. TI Highly reinforced structure of a C-terminal dimerization domain in von Willebrand factor SO BLOOD LA English DT Article ID GROWTH-FACTOR; DENSITY MODIFICATION; PROTEINS; ALIGNMENT; ADHESION; SEQUENCE; DATABASE; QUALITY; SYSTEM; FAMILY AB The C-terminal cystine knot (CK) (CTCK) domain in von Willebrand factor (VWF) mediates dimerization of proVWF in the endoplasmic reticulum and is essential for long multimers required for hemostatic function. The CTCK dimer crystal structure reveals highly elongated monomers with 2 beta-ribbons and 4 intra-chain disulfides, including 3 in the CK. Dimerization buries an extensive interface of 1500 A(2) corresponding to 32% of the surface of each monomer and forms a super beta-sheet and 3 inter-chain disulfides. The shape, dimensions, and N-terminal connections of the crystal structure agree perfectly with previous electron microscopic images of VWF dimeric bouquets with the CTCK dimer forming a down-curved base. The dimer interface is suited to resist hydrodynamic force and disulfide reduction. CKs in each monomer flank the 3 inter-chain disulfides, and their presence in beta-structures with dense backbone hydrogen bonds creates a rigid, highly crosslinked interface. The structure reveals the basis for von Willebrand disease phenotypes and the fold and disulfide linkages for CTCK domains in diverse protein families involved in barrier function, eye and inner ear development, insect coagulation and innate immunity, axon guidance, and signaling in extracellular matrices. C1 [Springer, Timothy A.] Harvard Univ, Sch Med, Program Cellular & Mol Med, Childrens Hosp Boston, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Program Cellular & Mol Med, Childrens Hosp Boston, Boston, MA 02115 USA. EM timothy.springer@childrens.harvard.edu NR 40 TC 12 Z9 12 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 20 PY 2014 VL 123 IS 12 BP 1785 EP 1793 DI 10.1182/blood-2013-11-523639 PG 9 WC Hematology SC Hematology GA AH0ZH UT WOS:000335848800011 PM 24394662 ER PT J AU Richardson, PG Siegel, DS Vij, R Hofmeister, CC Baz, R Jagannath, S Chen, C Lonial, S Jakubowiak, A Bahlis, N Song, K Belch, A Raje, N Shustik, C Lentzsch, S Lacy, M Mikhael, J Matous, J Vesole, D Chen, M Zaki, MH Jacques, C Yu, ZN Anderson, KC AF Richardson, Paul G. Siegel, David S. Vij, Ravi Hofmeister, Craig C. Baz, Rachid Jagannath, Sundar Chen, Christine Lonial, Sagar Jakubowiak, Andrzej Bahlis, Nizar Song, Kevin Belch, Andrew Raje, Noopur Shustik, Chaim Lentzsch, Suzanne Lacy, Martha Mikhael, Joseph Matous, Jeffrey Vesole, David Chen, Min Zaki, Mohamed H. Jacques, Christian Yu, Zhinuan Anderson, Kenneth C. TI Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study SO BLOOD LA English DT Article ID LENALIDOMIDE PLUS DEXAMETHASONE; THALIDOMIDE ANALOGS; II TRIALS; BORTEZOMIB; THERAPY; CC-4047; DRUGS; IMIDS; CELLS AB This multicenter, open-label, randomized phase 2 study assessed the efficacy and safety of pomalidomide (POM) with/without low-dose dexamethasone (LoDEX) in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received >= 2 prior therapies (including lenalidomide [LEN] and bortezomib [BORT]) and had progressed within 60 days of their last therapy were randomized to POM (4 mg/day on days 1-21 of each 28-day cycle) with/without LoDEX (40 mg/week). The primary end point was progression-free survival (PFS). In total, 221 patients (median 5 prior therapies, range 1-13) received POM+LoDEX(n = 113) or POM(n = 108). With a median follow-up of 14.2 months, median PFS was 4.2 and 2.7 months (hazard ratio = 0.68, P = .003), overall response rates (ORRs) were 33% and 18% (P = .013), median response duration was 8.3 and 10.7 months, and median overall survival (OS) was 16.5 and 13.6 months, respectively. Refractoriness to LEN, or resistance to both LEN and BORT, did not affect outcomes with POM+LoDEX (median PFS 3.8 months for both; ORRs 30% and 31%; and median OS 16 and 13.4 months). Grade 3-4 neutropenia occurred in 41% (POM+LoDEX) and 48% (POM); no grade 3-4 peripheral neuropathy was reported. POM+LoDEX was effective and generally well tolerated and provides an important new treatment option for RRMM patients who have received multiple prior therapies. This trial was registered at www.clinicaltrials.gov as #NCT00833833. C1 [Richardson, Paul G.; Anderson, Kenneth C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Siegel, David S.; Vesole, David] John Theurer Canc Ctr, Hackensack, NJ USA. [Vij, Ravi] Washington Univ, Sch Med, St Louis, MO USA. [Hofmeister, Craig C.] Ohio State Univ, Columbus, OH 43210 USA. [Baz, Rachid] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Jagannath, Sundar] Mt Sinai Med Ctr, New York, NY 10029 USA. [Chen, Christine] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Lonial, Sagar] Emory Univ, Sch Med, Atlanta, GA USA. [Jakubowiak, Andrzej] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Bahlis, Nizar] Univ Calgary, Calgary, AB, Canada. [Song, Kevin] Vancouver Gen Hosp, Vancouver, BC, Canada. [Belch, Andrew] Univ Alberta, Edmonton, AB T6G 2M7, Canada. [Raje, Noopur] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Shustik, Chaim] Royal Victoria Hosp, Montreal, PQ H3A 1A1, Canada. [Lentzsch, Suzanne] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Lacy, Martha] Mayo Clin, Rochester, MN USA. [Mikhael, Joseph] Mayo Clinic Scottsdale, Scottsdale, AZ USA. [Matous, Jeffrey] Colorado Blood Canc Inst, Denver, CO USA. [Chen, Min; Zaki, Mohamed H.; Jacques, Christian; Yu, Zhinuan] Celgene Corp, Summit, NJ USA. RP Richardson, PG (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM paul_richardson@dfci.harvard.edu FU Celgene Corporation FX This study was funded by Celgene Corporation. The authors are fully responsible for all content and editorial decisions for this manuscript. NR 40 TC 106 Z9 110 U1 1 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 20 PY 2014 VL 123 IS 12 BP 1826 EP 1832 DI 10.1182/blood-2013-11-538835 PG 7 WC Hematology SC Hematology GA AH0ZH UT WOS:000335848800016 PM 24421329 ER PT J AU Martinez-Andrade, GO Cespedes, EM Rifas-Shiman, SL Romero-Quechol, G Gonzalez-Unzaga, MA Benitez-Trejo, MA Flores-Huerta, S Horan, C Haines, J Taveras, EM Perez-Cuevas, R Gillman, MW AF Oliva Martinez-Andrade, Gloria Cespedes, Elizabeth M. Rifas-Shiman, Sheryl L. Romero-Quechol, Guillermina Aurelio Gonazlez-Unzaga, Marco Amalia Benitez-Trejo, Maria Flores-Huerta, Samuel Horan, Chrissy Haines, Jess Taveras, Elsie M. Perez-Cuevas, Ricardo Gillman, Matthew W. TI Feasibility and impact of Creciendo Sanos, a clinic-based pilot intervention to prevent obesity among preschool children in Mexico City SO BMC PEDIATRICS LA English DT Article DE Obesity prevention; Intervention; Trial; Pediatrics; Primary care; Mexico; Preschool ID RANDOMIZED CONTROLLED-TRIAL; CHILDHOOD OBESITY; PRIMARY-CARE; YOUNG-CHILDREN; OVERWEIGHT; PERCEPTIONS; COMPONENTS; BEHAVIORS; SETTINGS; PROGRAMS AB Background: Mexico has the highest adult overweight and obesity prevalence in the Americas; 23.8% of children < 5 years old are at risk for overweight and 9.7% are already overweight or obese. Creciendo Sanos was a pilot intervention to prevent obesity among preschoolers in Instituto Mexicano del Seguro Social (IMSS) clinics. Methods: We randomized 4 IMSS primary care clinics to either 6 weekly educational sessions promoting healthful nutrition and physical activity or usual care. We recruited 306 parent-child pairs: 168 intervention, 138 usual care. Children were 2 5 years old with WHO body mass index (BMI) z score 0 3. We measured children's height and weight and parents reported children's diet and physical activity at baseline and 3 and 6-month follow-up. We analyzed behavioral and BMI outcomes with generalized mixed models incorporating multiple imputation for missing values. Results: 93 (55%) intervention and 96 (70%) usual care families completed 3 and 6-month follow-up. At 3 months, intervention v. usual care children increased vegetables by 6.3 servings/week (95% CI, 1.8, 10.8). In stratified analyses, intervention participants with high program adherence (5-6 sessions) decreased snacks and screen time and increased vegetables v. usual care. No further effects on behavioral outcomes or BMI were observed. Transportation time and expenses were barriers to adherence. 90% of parents who completed the post-intervention survey were satisfied with the program. Conclusions: Although satisfaction was high among participants, barriers to participation and retention included transportation cost and time. In intention to treat analyses, we found intervention effects on vegetable intake, but not other behaviors or BMI. C1 [Oliva Martinez-Andrade, Gloria; Romero-Quechol, Guillermina; Aurelio Gonazlez-Unzaga, Marco] Inst Mexicano Seguro Social, Unidad Invest Epidemiol & Serv Salud, Mexico City 06720, DF, Mexico. [Cespedes, Elizabeth M.; Rifas-Shiman, Sheryl L.; Horan, Chrissy; Gillman, Matthew W.] Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Obes Prevent Program,Dept Populat Med, Boston, MA 02215 USA. [Cespedes, Elizabeth M.; Taveras, Elsie M.; Gillman, Matthew W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Amalia Benitez-Trejo, Maria; Flores-Huerta, Samuel] Hosp Infantil Mexico Dr Federico Gomez, Secretaria Salud, Commun Hlth Dept, Mexico City 06720, DF, Mexico. [Haines, Jess] Univ Guelph, Dept Family Relat & Appl Nutr, Guelph, ON N1G 2W1, Canada. [Taveras, Elsie M.] MassGen Hosp Children, Div Gen Pediat, Boston, MA 02114 USA. [Perez-Cuevas, Ricardo] Banco Inter Amer Desarrollo, Div Protecc Social & Salud, Mexico City 6600, DF, Mexico. RP Cespedes, EM (reprint author), Harvard Univ, Sch Med, Harvard Pilgrim Hlth Care Inst, Obes Prevent Program,Dept Populat Med, 133 Brookline Ave,3rd Floor, Boston, MA 02215 USA. EM emc611@mail.harvard.edu OI Cespedes Feliciano, Elizabeth/0000-0003-1192-4017 FU NIDDK NIH HHS [T32 DK007703] NR 34 TC 5 Z9 5 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2431 J9 BMC PEDIATR JI BMC Pediatr. PD MAR 20 PY 2014 VL 14 AR 77 DI 10.1186/1471-2431-14-77 PG 15 WC Pediatrics SC Pediatrics GA AG4UD UT WOS:000335414900002 PM 24649831 ER PT J AU Cao, HJ Wu, SL Li, SQ Zhao, HY Ruan, CY Wu, YT Xing, AJ Li, KB Chen, J Yang, XC Cai, J AF Cao Huijun Wu Shouling Li Shuqiang Zhao Haiyan Ruan Chunyu Wu Yuntao Xing Aijun Li Kuibao Chen Jin Yang Xinchun Cai Jun TI Characterization and influencing factors of visit-to-visit blood pressure variability of the population in a northern Chinese industrial city SO CHINESE MEDICAL JOURNAL LA English DT Article DE blood pressure variability; age; influencing factors ID DIAGNOSED HYPERTENSION; EPISODIC HYPERTENSION; CARDIOVASCULAR RISK; ORGAN DAMAGE AB Background Blood pressure variability (BPV) is a reliable prognostic factor for cardiovascular events. Currently there is a worldwide lack of large sample size studies in visit-to-visit BPV. Based on the Kailuan Study, we analyzed the visit-to-visit BPV of patients to investigate the range and influencing factors of BPV. Methods In 11 hospitals in the Kailuan Company, 4 441 patients received routine health checkups. Physical examination measured blood pressure (BP), body height, body weight, and waist circumference, and body mass index was calculated. Blood samples were analyzed for plasma total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), and high-sensitivity c-reactive protein (hs-CRP). Results The effect of gender on systolic BPV was investigated. The average systolic BPV was 10.35 mmHg (1 mmHg= 0.133 kPa) overall, 10.54 mmHg in males and 10.06 mmHg in females. Multivariate Logistic regression analysis revealed that the age (RR=1.022), systolic BP (SBP, RR=1.007), LDL-C (RR=1.098), and history of hypertension (RR=1.273) were significant risk factors for higher systolic BPV. We found that aging (RR=1.022), increased SBP (RR=1.007), and a history of hypertension (RR=1.394) were determinants of systolic BPV in males. The risk factors for systolic BPV of females were aging (RR=1.017), increased SBP (RR=1.009), increased LDL (RR=1.136), and increased TG (RR= 1.157). Conclusion Our findings indicated that the systolic BPV is closely associated with age, SBP and history of hypertension. C1 [Cao Huijun; Li Kuibao; Chen Jin; Yang Xinchun; Cai Jun] Capital Med Univ, Chaoyang Hosp, Dept Cardiol, Beijing 100020, Peoples R China. [Wu Shouling; Zhao Haiyan; Ruan Chunyu; Wu Yuntao; Xing Aijun] Hebei United Univ, Kailuan Hosp, Dept Cardiol, Tangshan 063000, Hebei, Peoples R China. [Li Shuqiang] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Yang, XC (reprint author), Capital Med Univ, Chaoyang Hosp, Dept Cardiol, 8th Gongtinanlu Rd, Beijing 100020, Peoples R China. EM yangxc2010@hotmail.com FU National Natural Science Foundation of China [81170244]; Beijing Nova Program [2009B39]; Beijing Natural Science Foundation [7102057] FX This work is supported by grants from the National Natural Science Foundation of China (No. 81170244), Beijing Nova Program (No. 2009B39) and Beijing Natural Science Foundation (No. 7102057). NR 23 TC 1 Z9 1 U1 0 U2 1 PU CHINESE MEDICAL ASSOC PI BEIJING PA 42 DONGSI XIDAJIE, BEIJING 100710, PEOPLES R CHINA SN 0366-6999 J9 CHINESE MED J-PEKING JI Chin. Med. J. PD MAR 20 PY 2014 VL 127 IS 6 BP 1022 EP 1026 DI 10.3760/cma.j.issn.0366-6999.20132954 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA AE9JW UT WOS:000334325100005 PM 24622428 ER PT J AU Vassy, JL Lautenbach, DM McLaughlin, HM Kong, SW Christensen, KD Krier, J Kohane, IS Feuerman, LZ Blumenthal-Barby, J Roberts, JS Lehmann, LS Ho, CY Ubel, PA MacRae, CA Seidman, CE Murray, MF McGuire, AL Rehm, HL Green, RC AF Vassy, Jason L. Lautenbach, Denise M. McLaughlin, Heather M. Kong, Sek Won Christensen, Kurt D. Krier, Joel Kohane, Isaac S. Feuerman, Lindsay Z. Blumenthal-Barby, Jennifer Roberts, J. Scott Lehmann, Lisa Soleymani Ho, Carolyn Y. Ubel, Peter A. MacRae, Calum A. Seidman, Christine E. Murray, Michael F. McGuire, Amy L. Rehm, Heidi L. Green, Robert C. CA MedSeq Project TI The MedSeq Project: a randomized trial of integrating whole genome sequencing into clinical medicine SO TRIALS LA English DT Article DE Whole genome sequencing; Genome report; Genomic medicine; Translational genomics; Primary care; Cardiomyopathy genetics ID PERSONALIZED MEDICINE; INFORMED-CONSENT; DIAGNOSIS; EXOME; SCALE; VALIDATION; GENETICIST; STATEMENT; DISEASES; OUTBREAK AB Background: Whole genome sequencing (WGS) is already being used in certain clinical and research settings, but its impact on patient well-being, health-care utilization, and clinical decision-making remains largely unstudied. It is also unknown how best to communicate sequencing results to physicians and patients to improve health. We describe the design of the MedSeq Project: the first randomized trials of WGS in clinical care. Methods/Design: This pair of randomized controlled trials compares WGS to standard of care in two clinical contexts: (a) disease-specific genomic medicine in a cardiomyopathy clinic and (b) general genomic medicine in primary care. We are recruiting 8 to 12 cardiologists, 8 to 12 primary care physicians, and approximately 200 of their patients. Patient participants in both the cardiology and primary care trials are randomly assigned to receive a family history assessment with or without WGS. Our laboratory delivers a genome report to physician participants that balances the needs to enhance understandability of genomic information and to convey its complexity. We provide an educational curriculum for physician participants and offer them a hotline to genetics professionals for guidance in interpreting and managing their patients' genome reports. Using varied data sources, including surveys, semi-structured interviews, and review of clinical data, we measure the attitudes, behaviors and outcomes of physician and patient participants at multiple time points before and after the disclosure of these results. Discussion: The impact of emerging sequencing technologies on patient care is unclear. We have designed a process of interpreting WGS results and delivering them to physicians in a way that anticipates how we envision genomic medicine will evolve in the near future. That is, our WGS report provides clinically relevant information while communicating the complexity and uncertainty of WGS results to physicians and, through physicians, to their patients. This project will not only illuminate the impact of integrating genomic medicine into the clinical care of patients but also inform the design of future studies. C1 [Vassy, Jason L.] VA Boston Healthcare Syst, Gen Internal Med Sect, Boston, MA 02130 USA. [Christensen, Kurt D.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02130 USA. [Vassy, Jason L.; Lautenbach, Denise M.; Christensen, Kurt D.; Krier, Joel; MacRae, Calum A.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [McLaughlin, Heather M.; Rehm, Heidi L.] Partners Healthcare Ctr Personalized Genet Med, Mol Med Lab, Cambridge, MA 02139 USA. [McLaughlin, Heather M.; Rehm, Heidi L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [McLaughlin, Heather M.; Rehm, Heidi L.; Green, Robert C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kong, Sek Won] Boston Childrens Hosp, Dept Med, Boston, MA 02115 USA. [Kong, Sek Won; Krier, Joel; Kohane, Isaac S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Kohane, Isaac S.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Feuerman, Lindsay Z.; Blumenthal-Barby, Jennifer; McGuire, Amy L.] Baylor Coll Med, BCM Jewish Inst Res, Ctr Med Eth & Hlth Policy, Houston, TX 77030 USA. [Roberts, J. Scott] Univ Michigan, Sch Publ Hlth, Dept Hlth Behav & Hlth Educ, Ann Arbor, MI 48109 USA. [Lehmann, Lisa Soleymani] Brigham & Womens Hosp, Dept Med, Div Gen Internal Med & Primary Care, Ctr Bioeth, Boston, MA 02120 USA. [Lehmann, Lisa Soleymani] Harvard Univ, Sch Med, Boston, MA 02120 USA. [Ho, Carolyn Y.; MacRae, Calum A.; Seidman, Christine E.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Ubel, Peter A.] Duke Univ, Fuqua Sch Business, Durham, NC 27708 USA. [Seidman, Christine E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Murray, Michael F.] Geisinger Hlth Syst, Genom Med Inst, Wilkes Barre, PA 18711 USA. [Green, Robert C.] Genomes2People, Boston, MA 02115 USA. [Green, Robert C.] Brigham & Womens Hosp, Div Genet, Dept Med, Boston, MA 02115 USA. RP Green, RC (reprint author), Genomes2People, 41 Ave Louis Pasteur, Boston, MA 02115 USA. EM rcgreen@genetics.med.harvard.edu OI Ho, Carolyn/0000-0002-7334-7924; Christensen, Kurt/0000-0003-4068-776X; Lebo, Matthew/0000-0002-9733-5207 FU National Institutes of Health (NIH) National Human Genome Research Institute [U01-HG006500]; NIH [L30 DK089597, F32 HG006993, T32 GM007748-34]; Clinical Translational Science Award [UL1RR025758]; Brigham and Women's Hospital from the National Center for Research Resources FX The MedSeq Project is supported by the National Institutes of Health (NIH) National Human Genome Research Institute (U01-HG006500). JLV is supported by NIH L30 DK089597. KDC is supported by NIH F32 HG006993. JK is supported by NIH T32 GM007748-34. The project described was supported by Clinical Translational Science Award UL1RR025758 to Harvard University and Brigham and Women's Hospital from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. The authors thank 5AM Solutions, Inc. (Rockville, MD, USA), for their help in customizing the workflow of the "My Family Health Portrait" web tool for this study. NR 56 TC 43 Z9 44 U1 11 U2 21 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD MAR 20 PY 2014 VL 15 AR 85 DI 10.1186/1745-6215-15-85 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AF7AX UT WOS:000334866900001 PM 24645908 ER PT J AU Cornejo-Olivas, MR Yu, CE Mazzetti, P Mata, IF Meza, M Lindo-Samanamud, S Leverenz, JB Bird, TD AF Cornejo-Olivas, Mario R. Yu, Chang-En Mazzetti, Pilar Mata, Ignacio F. Meza, Maria Lindo-Samanamud, Saul Leverenz, James B. Bird, Thomas D. TI Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a Peruvian family with early-onset Alzheimer's disease SO NEUROSCIENCE LETTERS LA English DT Article DE Presenilin-1; Peruvian; Early-onset Alzheimer's disease ID PRECURSOR PROTEIN; PRESENILIN; GENETICS; FREQUENCY; GENES AB Presenilin 1 (PSEN1) gene mutations are found in 30-70% of familial early-onset Alzheimer disease (EOAD) cases (onset <60 years). Prevalence of these mutations is highly variable including ethnic differences worldwide. No Peruvian kindred with familial AD (FAD) have been described. Standardized clinical evaluation and cognitive assessment were completed in a Peruvian family with severe EOAD. Clinical course was characterized by very early onset (before age 35 years), progressive cognitive impairment with early memory loss, spatial disorientation and executive dysfunction. We sequenced all exons of PSEN1 in the proband and identified a c.475C>G DNA change resulting in a p.L153V missense mutation in the transmembrane domain 2 of the gene. This mutation is also present in the three additional affected siblings but not in a non-affected family member consistent with segregation of this mutation with the disease. This is the first report of a Peruvian family affected with EOAD associated with a PSEN1 mutation. This same mutation has been reported previously in English and French families, but a novel variants very close to the mutation and ancestry informative markers analysis suggests the mutation might be of Amerindian or African origin in this Peruvian family. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Cornejo-Olivas, Mario R.; Mazzetti, Pilar; Lindo-Samanamud, Saul] Inst Nacl Ciencias Neurol, Neurogenet Res Ctr, Lima 01, Peru. [Cornejo-Olivas, Mario R.] Northern Pacific Global Hlth Res Fellows Training, Bethesda, MD USA. [Mazzetti, Pilar; Meza, Maria] Univ Nacl Mayor San Marcos, Sch Med, Lima 14, Peru. [Yu, Chang-En; Leverenz, James B.; Bird, Thomas D.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Leverenz, James B.] VA Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. [Mata, Ignacio F.; Leverenz, James B.; Bird, Thomas D.] VA Puget Sound Hlth Care Syst, Parkinsons Res Educ & Clin Ctr, Seattle, WA USA. [Mata, Ignacio F.; Leverenz, James B.; Bird, Thomas D.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Leverenz, James B.; Bird, Thomas D.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Cornejo-Olivas, MR (reprint author), Inst Nacl Ciencias Neurol, Neurogenet Res Ctr, 1271 Ancash St Lima, Lima 01, Peru. EM mario.cornejo.o@incngen.org.pe OI Cornejo-Olivas, Mario /0000-0001-6313-5680 FU NIH [R25 TW009345]; Fogarty International Center; National Institute of Mental Health; NIH Office of the Director Office of Research on Women's Health; NIH Office of AIDS Research FX We want to thank the Latin American Research Consortium on the Genetics of Parkinson's disease (LARGE PD) for providing healthy control samples from Peru. This project was supported by NIH Research Training Grant # R25 TW009345 funded by the Fogarty International Center, the National Institute of Mental Health, and the NIH Office of the Director Office of Research on Women's Health and the Office of AIDS Research. NR 18 TC 1 Z9 3 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 20 PY 2014 VL 563 BP 140 EP 143 DI 10.1016/j.neulet.2014.01.016 PG 4 WC Neurosciences SC Neurosciences & Neurology GA AE5CR UT WOS:000334005900029 PM 24495933 ER PT J AU Wang, Y Godec, J Ben-Aissa, K Cui, KR Zhao, KJ Pucsek, AB Lee, YK Weaver, CT Yagi, R Lazarevic, V AF Wang, Yan Godec, Jernej Ben-Aissa, Khadija Cui, Kairong Zhao, Keji Pucsek, Alexandra B. Lee, Yun Kyung Weaver, Casey T. Yagi, Ryoji Lazarevic, Vanja TI The Transcription Factors T-bet and Runx Are Required for the Ontogeny of Pathogenic Interferon-gamma-Producing T Helper 17 Cells SO IMMUNITY LA English DT Article ID IFNG GENE-EXPRESSION; HUMAN TH17 CELLS; ROR-GAMMA; T(H)17 CELLS; LINEAGE; DIFFERENTIATION; PLASTICITY; CYTOKINE; FOXP3; ENCEPHALOMYELITIS AB T helper 17 (Th17) cells can give rise to interleukin-17A (IL-17A)- and interferon (IFN)-gamma-double-producing cells that are implicated in development of autoimmune diseases. However, the molecular mechanisms that govern generation of IFN-gamma-producing Th17 cells are unclear. We found that coexpression of the Th1 and Th17 cell master transcription factors, T-bet and retinoid-related orphan receptor gamma-t (ROR gamma t), respectively, did not generate Th cells with robust IL-17 and IFN-gamma expression. Instead, development of IFN-gamma-producing Th17 cells required T-bet and Runx1 or Runx3. IL-12-stimulated Th17 cells upregulated Runx1, which bound to the Ifng locus in a T-bet-dependent manner. Reciprocally, T-bet or Runx1 deficiency or inhibition of Runx transcriptional activity impaired the development of IFN-gamma-producing Th17 cells during experimental autoimmune encephalomyelitis, which correlated with substantially ameliorated disease course. Thus, our studies identify a critical role for T-bet and Runx transcription factors in the generation of pathogenic IFN-gamma-producing Th17 cells. C1 [Wang, Yan; Ben-Aissa, Khadija; Lazarevic, Vanja] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Godec, Jernej] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Godec, Jernej] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Cui, Kairong; Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Pucsek, Alexandra B.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21231 USA. [Lee, Yun Kyung; Weaver, Casey T.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Yagi, Ryoji] Chiba Univ, Grad Sch Med, Dept Immunol, Chiba 2608670, Japan. RP Lazarevic, V (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM lazarevicv@mail.nih.gov OI Weaver, Casey/0000-0002-2180-1793 FU Intramural NIH HHS [ZIA BC011431-02]; NCI NIH HHS [P30 CA013148]; NIAMS NIH HHS [P30 AR048311]; NIDDK NIH HHS [P01 DK071176] NR 39 TC 46 Z9 46 U1 2 U2 10 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 20 PY 2014 VL 40 IS 3 BP 355 EP 366 DI 10.1016/j.immuni.2014.01.002 PG 12 WC Immunology SC Immunology GA AD7DQ UT WOS:000333422300009 PM 24530058 ER PT J AU Lee, REC Walker, SR Savery, K Frank, DA Gaudet, S AF Lee, Robin E. C. Walker, Sarah R. Savery, Kate Frank, David A. Gaudet, Suzanne TI Fold Change of Nuclear NF-kappa B Determines TNF-Induced Transcription in Single Cells SO MOLECULAR CELL LA English DT Article ID RESPONSE ELEMENTS; GENE-EXPRESSION; ACTIVATION; P50; INFLAMMATION; SPECIFICITY; MACROPHAGES; VARIABILITY; APOPTOSIS; PROMOTER AB In response to tumor necrosis factor (TNF), NF-kappa B enters the nucleus and promotes inflammatory and stress-responsive gene transcription. Because NF-kappa B deregulation is associated with disease, one might expect strict control of NF-kappa B localization. However, nuclear NF-kappa B levels exhibit considerable cell-to-cell variability, even in unstimulated cells. To resolve this paradox and determine how transcription-inducing signals are encoded, we quantified single-cell NF-kappa B translocation dynamics and transcription in the same cells. We show that TNF-induced transcription correlates best with fold change in nuclear NF-kappa B, not absolute nuclear NF-kappa B abundance. Using computational modeling, we find that an incoherent feedforward loop, from competition for binding to kappa B motifs, could provide memory of the preligand state necessary for fold-change detection. Experimentally, we observed three gene-specific transcriptional patterns that our model recapitulates by modulating competition strength alone. Fold-change detection buffers against stochastic variation in signaling molecules and explains how cells tolerate variability in NF-kappa B abundance and localization. C1 [Lee, Robin E. C.; Savery, Kate; Gaudet, Suzanne] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Lee, Robin E. C.; Savery, Kate; Gaudet, Suzanne] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Lee, Robin E. C.; Gaudet, Suzanne] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Walker, Sarah R.; Frank, David A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Walker, Sarah R.; Frank, David A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Walker, Sarah R.; Frank, David A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Gaudet, S (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM suzanne_gaudet@dfci.harvard.edu FU NIH [CA139980, R01-GM104247]; Barr investigator award; NCI [R01-CA160979]; DeGregorio Family Foundation FX We thank B. B. Aldridge, W. W. Chen, M. S. Owen, X. Xia, and A. Aref for advice on the manuscript and many helpful discussions and L. Hill for technical assistance. We also thank Dr. Max Heiman for the use of his microscope. This work was funded by NIH grant CA139980, R01-GM104247 and a Barr investigator award to S. G., and NCI grant R01-CA160979 and funding from the DeGregorio Family Foundation to D. A. F. S. G. is a Kimmel Scholar, and R. E. C. L is a CIHR research fellow. NR 50 TC 39 Z9 40 U1 0 U2 17 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 20 PY 2014 VL 53 IS 6 BP 867 EP 879 DI 10.1016/j.molcel.2014.01.026 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AD5YM UT WOS:000333329400004 PM 24530305 ER PT J AU Manning, AL Yazinski, SA Nicolay, B Bryll, A Zou, L Dyson, NJ AF Manning, Amity L. Yazinski, Stephanie A. Nicolay, Brandon Bryll, Alysia Zou, Lee Dyson, Nicholas J. TI Suppression of Genome Instability in pRB-Deficient Cells by Enhancement of Chromosome Cohesion SO MOLECULAR CELL LA English DT Article ID CONDENSIN-II; CLONAL EVOLUTION; DNA-REPLICATION; CONSTITUTIVE HETEROCHROMATIN; PERICENTRIC HETEROCHROMATIN; RETINOBLASTOMA PROTEIN; MICROARRAY ANALYSIS; COLORECTAL CANCERS; CYCLE PROGRESSION; RB AB Chromosome instability (CIN), a common feature of solid tumors, promotes tumor evolution and increases drug resistance during therapy. We previously demonstrated that loss of the retinoblastoma protein (pRB) tumor suppressor causes changes in centromere structure and generates CIN. However, the mechanism and significance of this change was unclear. Here, we show that defects in cohesion are key to the pRB loss phenotype. pRB loss alters H4K20 methylation, a prerequisite for efficient establishment of cohesion at centromeres. Changes in cohesin regulation are evident during S phase, where they compromise replication and increase DNA damage. Ultimately, such changes compromise mitotic fidelity following pRB loss. Remarkably, increasing cohesion suppressed all of these phenotypes and dramatically reduced CIN in cancer cells lacking functional pRB. These data explain how loss of pRB undermines genomic integrity. Given the frequent functional inactivation of pRB in cancer, conditions that increase cohesion may provide a general strategy to suppress CIN. C1 [Manning, Amity L.; Yazinski, Stephanie A.; Nicolay, Brandon; Bryll, Alysia; Zou, Lee; Dyson, Nicholas J.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Manning, Amity L.; Yazinski, Stephanie A.; Nicolay, Brandon; Bryll, Alysia; Zou, Lee; Dyson, Nicholas J.] Harvard Univ, Sch Med, Dept Med, Charlestown, MA 02129 USA. RP Dyson, NJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM dyson@helix.mgh.harvard.edu FU MGH ECOR Tosteson postdoctoral fellowship; Department of Defense [BC120504]; NIH [CA155202, GM076388] FX We thank Katsuhiko Shirahige for the generous gift of AcSMC3 antibodies, Duane Compton for sharing the mCherry Mad2 construct, and Andreas Heilman for technical support. A. L. M. is supported by an MGH ECOR Tosteson postdoctoral fellowship; S.A.Y. is supported by a fellowship from the Department of Defense (BC120504); L.Z. is a Jim and Ann Orr MGH Research Scholar; and N.J.D. is a James and Shirley Curvey MGH Research Scholar. This work was supported by NIH grants to N.J.D. (CA155202) and L.Z. (GM076388). NR 63 TC 21 Z9 21 U1 1 U2 7 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 20 PY 2014 VL 53 IS 6 BP 993 EP 1004 DI 10.1016/j.molcel.2014.01.032 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AD5YM UT WOS:000333329400014 PM 24613344 ER PT J AU Ducker, GS Atreya, CE Simko, JP Hom, YK Matli, MR Benes, CH Hann, B Nakakura, EK Bergsland, EK Donner, DB Settleman, J Shokat, KM Warren, RS AF Ducker, G. S. Atreya, C. E. Simko, J. P. Hom, Y. K. Matli, M. R. Benes, C. H. Hann, B. Nakakura, E. K. Bergsland, E. K. Donner, D. B. Settleman, J. Shokat, K. M. Warren, R. S. TI Incomplete inhibition of phosphorylation of 4E-BP1 as a mechanism of primary resistance to ATP-competitive mTOR inhibitors SO ONCOGENE LA English DT Article DE mTOR; colon cancer; PIK3CA; KRAS; xenograft; PP242 ID RENAL-CELL CARCINOMA; COLORECTAL-CANCER; KINASE INHIBITORS; BINDING PARTNER; PIK3CA MUTATION; GROWTH-CONTROL; COLON-CANCER; LUNG-CANCER; IN-VITRO; RAPAMYCIN AB The mammalian target of rapamycin (mTOR) regulates cell growth by integrating nutrient and growth factor signaling and is strongly implicated in cancer. But mTOR is not an oncogene, and which tumors will be resistant or sensitive to new adenosine triphosphate (ATP) competitive mTOR inhibitors now in clinical trials remains unknown. We screened a panel of over 600 human cancer cell lines to identify markers of resistance and sensitivity to the mTOR inhibitor PP242. RAS and phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutations were the most significant genetic markers for resistance and sensitivity to PP242, respectively; colon origin was the most significant marker for resistance based on tissue type. Among colon cancer cell lines, those with KRAS mutations were most resistant to PP242, whereas those without KRAS mutations most sensitive. Surprisingly, cell lines with co-mutation of PIK3CA and KRAS had intermediate sensitivity. Immunoblot analysis of the signaling targets downstream of mTOR revealed that the degree of cellular growth inhibition induced by PP242 was correlated with inhibition of phosphorylation of the translational repressor eIF4E-binding protein 1 (4E-BP1), but not ribosomal protein S6 (rpS6). In a tumor growth inhibition trial of PP242 in patient-derived colon cancer xenografts, resistance to PP242-induced inhibition of 4E-BP1 phosphorylation and xenograft growth was again observed in KRAS mutant tumors without PIK3CA co-mutation, compared with KRAS wild-type controls. We show that, in the absence of PIK3CA co-mutation, KRAS mutations are associated with resistance to PP242 and that this is specifically linked to changes in the level of phosphorylation of 4E-BP1. C1 [Ducker, G. S.; Shokat, K. M.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. [Atreya, C. E.; Bergsland, E. K.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Simko, J. P.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA. [Hom, Y. K.; Hann, B.] Univ Calif San Francisco, Preclin Therapeut Core, San Francisco, CA 94143 USA. [Hom, Y. K.; Matli, M. R.; Hann, B.; Nakakura, E. K.; Donner, D. B.; Shokat, K. M.; Warren, R. S.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Matli, M. R.; Nakakura, E. K.; Donner, D. B.; Warren, R. S.] Univ Calif San Francisco, Dept Surg, Sect Surg Oncol, San Francisco, CA 94115 USA. [Benes, C. H.; Settleman, J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. [Shokat, K. M.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA USA. [Shokat, K. M.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. RP Shokat, KM (reprint author), Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, 600 E 16th St,MC 2280, San Francisco, CA 94158 USA. EM shokat@cmp.ucsf.edu; robert.warren@ucsfmedctr.org OI Ducker, Gregory/0000-0002-8651-6846 FU American Cancer Society Postdoctoral Fellowship [11-183-TBG]; Millennium Pharmaceuticals provided through the Alliance for Clinical Trials in Oncology Foundation; Littlefield Trust; Howard Hughes Medical Institute; Waxman Foundation FX We thank Dan Moore for his critical assistance in the statistical analysis, Sandy Devries for FISH analysis, Katherine Pogue-Guile for permission to use the ColoCarta oligonucleotide primer design files and Morris Feldman, Jon Ostrem and Iana Serafimova for reagents. CEA is supported in part by American Cancer Society Postdoctoral Fellowship 11-183-TBG; she also acknowledges support Millennium Pharmaceuticals provided through the Alliance for Clinical Trials in Oncology Foundation. RSW is supported in part by a charitable donation from the Littlefield 2000 Trust. KMS is supported by the Howard Hughes Medical Institute and the Waxman Foundation. NR 56 TC 23 Z9 23 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD MAR 20 PY 2014 VL 33 IS 12 BP 1590 EP 1600 DI 10.1038/onc.2013.92 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AD4TS UT WOS:000333244200012 PM 23542178 ER PT J AU Chung, AW Ghebremichael, M Robinson, H Brown, E Choi, I Lane, S Dugast, AS Schoen, MK Rolland, M Suscovich, TJ Mahan, AE Liao, L Streeck, H Andrews, C Rerks-Ngarm, S Nitayaphan, S de Souza, MS Kaewkungwal, J Pitisuttithum, P Francis, D Michael, NL Kim, JH Bailey-Kellogg, C Ackerman, ME Alter, G AF Chung, Amy W. Ghebremichael, Musie Robinson, Hannah Brown, Eric Choi, Ickwon Lane, Sophie Dugast, Anne-Sophie Schoen, Matthew K. Rolland, Morgane Suscovich, Todd J. Mahan, Alison E. Liao, Larry Streeck, Hendrik Andrews, Charla Rerks-Ngarm, Supachai Nitayaphan, Sorachai de Souza, Mark S. Kaewkungwal, Jaranit Pitisuttithum, Punnee Francis, Donald Michael, Nelson L. Kim, Jerome H. Bailey-Kellogg, Chris Ackerman, Margaret E. Alter, Galit TI Polyfunctional Fc-Effector Profiles Mediated by IgG Subclass Selection Distinguish RV144 and VAX003 Vaccines SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID NEUTRALIZING ANTIBODY-RESPONSE; HIV-SPECIFIC ANTIBODIES; B-CELL RESPONSES; EFFICACY TRIAL; HIV-1-INFECTED INDIVIDUALS; PLASMODIUM-FALCIPARUM; GLYCOFORM SELECTION; TETANUS VACCINATION; HIGH-THROUGHPUT; INFECTION AB The human phase 2B RV144 ALVAC-HIV vCP1521/AIDSVAX B/E vaccine trial, held in Thailand, resulted in an estimated 31.2% efficacy against HIV infection. By contrast, vaccination with VAX003 (consisting of only AIDSVAX B/E) was not protective. Because protection within RV144 was observed in the absence of neutralizing antibody activity or cytotoxic T cell responses, we speculated that the specificity or qualitative differences in Fc-effector profiles of nonneutralizing antibodies may have accounted for the efficacy differences observed between the two trials. We show that the RV144 regimen elicited nonneutralizing antibodies with highly coordinated Fc-mediated effector responses through the selective induction of highly functional immunoglobulin G3 (IgG3). By contrast, VAX003 elicited monofunctional antibody responses influenced by IgG4 selection, which was promoted by repeated AIDSVAX B/E protein boosts. Moreover, only RV144 induced IgG1 and IgG3 antibodies targeting the crown of the HIV envelope V2 loop, albeit with limited coverage of breakthrough viral sequences. These data suggest that subclass selection differences associated with coordinated humoral functional responses targeting strain-specific protective V2 loop epitopes may underlie differences in vaccine efficacy observed between these two vaccine trials. C1 [Chung, Amy W.; Ghebremichael, Musie; Robinson, Hannah; Lane, Sophie; Dugast, Anne-Sophie; Schoen, Matthew K.; Suscovich, Todd J.; Mahan, Alison E.; Alter, Galit] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA 02139 USA. [Brown, Eric; Ackerman, Margaret E.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Choi, Ickwon; Bailey-Kellogg, Chris] Dartmouth Coll, Dept Comp Sci, Hanover, NH 03755 USA. [Rolland, Morgane; Streeck, Hendrik; Andrews, Charla; Michael, Nelson L.; Kim, Jerome H.] US Mil HIV Res Program, Walter Reed Army Inst Res, Dept Mol Virol & Pathogenesis, Silver Spring, MD 20910 USA. [Liao, Larry] Duke Univ, Human Vaccine Inst, Durham, NC 27710 USA. [Liao, Larry] Ctr HIV AIDS Vaccine Immunol, Durham, NC 27710 USA. [Rerks-Ngarm, Supachai] Minist Publ Hlth, Dept Dis Control, Nonthaburi 11000, Thailand. [Nitayaphan, Sorachai; de Souza, Mark S.] Armed Forces Res Inst Med Sci, Bangkok 10400, Thailand. [Kaewkungwal, Jaranit; Pitisuttithum, Punnee] Mahidol Univ, Fac Trop Med, Bangkok 10400, Thailand. [Francis, Donald] Global Solut Infect Dis, Brisbane, CA 94005 USA. RP Alter, G (reprint author), Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA 02139 USA. EM galter@partners.org RI Dugast, AnneSophie/L-9541-2015 FU US Military HIV Research Program (MHRP); NIH [R01 AI080289]; American Australian Association (Amgen Fellowship); National Health and Medical Research Center [APP1036470]; Bill and Melinda Gates Foundation Collaboration; NIH Harvard Center for AIDS Research [P30 AI060354-02] FX This work was supported by the US Military HIV Research Program (MHRP) (A.W.C. and G.A.), NIH (R01 AI080289) (G.A.), American Australian Association (Amgen Fellowship) (A.W.C.), National Health and Medical Research Center (APP1036470) (A.W.C.), Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (A.W.C., E.B., I.C., A.-S.D., A.E.M., C.B.-K., M.E.A., and G.A.), and NIH Harvard Center for AIDS Research (P30 AI060354-02) (G.A.). NR 41 TC 24 Z9 24 U1 3 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 19 PY 2014 VL 6 IS 228 AR 228ra8 PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AD4XV UT WOS:000333256000002 ER PT J AU Olfson, M Marcus, SC Bridge, JA AF Olfson, Mark Marcus, Steven C. Bridge, Jeffrey A. TI Focusing Suicide Prevention on Periods of High Risk SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID DELIBERATE SELF-HARM; CARE C1 [Olfson, Mark] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Olfson, Mark] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Marcus, Steven C.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Marcus, Steven C.] Univ Penn, Sch Social Policy & Practice, Philadelphia, PA 19104 USA. [Bridge, Jeffrey A.] Nationwide Childrens Hosp, Res Inst, Ctr Innovat Pediat Practice, Columbus, OH USA. [Bridge, Jeffrey A.] Ohio State Univ, Columbus, OH 43210 USA. RP Olfson, M (reprint author), Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York State Psychiat Inst, 1051 Riverside Dr, New York, NY 10032 USA. EM mo49@columbia.edu FU AHRQ HHS [U19 HS021112] NR 10 TC 27 Z9 28 U1 2 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 19 PY 2014 VL 311 IS 11 BP 1107 EP 1108 DI 10.1001/jama.2014.501 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AD1RC UT WOS:000333010100011 PM 24515285 ER PT J AU Hayes, JH Barry, MJ AF Hayes, Julia H. Barry, Michael J. TI Screening for Prostate Cancer With the Prostate-Specific Antigen Test A Review of Current Evidence SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; SERVICES TASK-FORCE; FOLLOW-UP; RADICAL PROSTATECTOMY; MORTALITY; MEN; STATEMENT; OUTCOMES; RISK; RECOMMENDATION AB IMPORTANCE Prostate cancer screening with the prostate-specific antigen (PSA) test remains controversial. OBJECTIVE To review evidence from randomized trials and related modeling studies examining the effect of PSA screening vs no screening on prostate cancer-specific mortality and to suggest an approach balancing potential benefits and harms. EVIDENCE ACQUISITION MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials were searched from January 1, 2010, to April 3, 2013, for PSA screening trials to update a previous systematic review. Another search was performed in EMBASE and MEDLINE to identify modeling studies extending the results of the 2 large randomized trials identified. The American Heart Association Evidence-Based Scoring System was used to rate level of evidence. RESULTS Two trials-the Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC)-dominate the evidence regarding PSA screening. The former trial demonstrated an increase in cancer incidence in the screening group (relative risk [RR], 1.12; 95% CI, 1.07-1.17) but no cancer-specific mortality benefit to PSA screening after 13-year follow-up (RR, 1.09; 95% CI, 0.87-1.36). The ERSPC demonstrated an increase in cancer incidence with screening (RR, 1.63; 95% CI, 1.57-1.69) and an improvement in the risk of prostate cancer-specific death after 11 years (RR, 0.79; 95% CI, 0.68-0.91). The ERSPC documented that 37 additional men needed to receive a diagnosis through screening for every 1 fewer prostate cancer death after 11 years of follow-up among men aged 55 to 69 years (level B evidence for prostate cancer mortality reduction). Harms associated with screening include false-positive results and complications of biopsy and treatment. Modeling studies suggest that this high ratio of additional men receiving diagnoses to prostate cancer deaths prevented will decrease during a longer follow-up (level B evidence). CONCLUSIONS AND RELEVANCE Available evidence favors clinician discussion of the pros and cons of PSA screening with average-risk men aged 55 to 69 years. Only men who express a definite preference for screening should have PSA testing. Other strategies to mitigate the potential harms of screening include considering biennial screening, a higher PSA threshold for biopsy, and conservative therapy for men receiving a new diagnosis of prostate cancer. C1 [Hayes, Julia H.] Harvard Univ, Sch Med, Inst Canc, Boston, MA USA. [Hayes, Julia H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA USA. [Barry, Michael J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gen Internal Med, Boston, MA USA. RP Hayes, JH (reprint author), 450 Brookline Ave,Dana 1230, Boston, MA 02115 USA. EM julia_hayes@dfci.harvard.edu NR 54 TC 75 Z9 75 U1 5 U2 40 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 19 PY 2014 VL 311 IS 11 BP 1143 EP 1149 DI 10.1001/jama.2014.2085 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AD1RC UT WOS:000333010100019 PM 24643604 ER PT J AU Holt, DJ Cassidy, BS Yue, XM Rauch, SL Boeke, EA Nasr, S Tootell, RBH Coombs, G AF Holt, Daphne J. Cassidy, Brittany S. Yue, Xiaomin Rauch, Scott L. Boeke, Emily A. Nasr, Shahin Tootell, Roger B. H. Coombs, Garth, III TI Neural Correlates of Personal Space Intrusion SO JOURNAL OF NEUROSCIENCE LA English DT Article DE connectivity; fMRI; intraparietal sulcus; personal space; premotor cortex; social behavior ID VENTRAL INTRAPARIETAL AREA; INTRINSIC FUNCTIONAL CONNECTIVITY; HUMAN CEREBRAL-CORTEX; SOCIAL NETWORK SIZE; PREMOTOR CORTEX; INTERPERSONAL DISTANCE; DEPENDENT PLASTICITY; RESPONSE PROPERTIES; PERIPERSONAL SPACE; HUMAN BRAIN AB A parietal-frontal network in primates is thought to support many behaviors occurring in the space around the body, including interpersonal interactions and maintenance of a particular "comfort zone" or distance from other people ("personal space"). To better understand this network in humans, we used functionalMRIto measure the responses to moving objects (faces, cars, simple spheres) and the functional connectivity of two regions in this network, the dorsal intraparietal sulcus (DIPS) and the ventral premotor cortex (PMv). We found that both areas responded more strongly to faces that were moving toward (vs away from) subjects, but did not show this bias in response to comparable motion in control stimuli (cars or spheres). Moreover, these two regions were functionally interconnected. Tests of activity-behavior associations revealed that the strength of DIPS-PMv connectivity was correlated with the preferred distance that subjects chose to stand from an unfamiliar person (personal space size). In addition, the magnitude of DIPS and PMv responses was correlated with the preferred level of social activity. Together, these findings suggest that this parietal-frontal network plays a role in everyday interactions with others. C1 [Holt, Daphne J.; Boeke, Emily A.; Coombs, Garth, III] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Holt, Daphne J.; Rauch, Scott L.; Tootell, Roger B. H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Holt, Daphne J.; Boeke, Emily A.; Nasr, Shahin; Tootell, Roger B. H.; Coombs, Garth, III] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Cassidy, Brittany S.] Brandeis Univ, Dept Psychol, Waltham, MA 02453 USA. [Yue, Xiaomin] NIMH, Bethesda, MD 20892 USA. [Rauch, Scott L.] McLean Hosp, Belmont, MA 02478 USA. [Nasr, Shahin; Tootell, Roger B. H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Holt, DJ (reprint author), 149 13th St, Charlestown, MA 02129 USA. EM dholt@partners.org FU National Institute of Mental Health [K23MH076054] FX This study was supported by the National Institute of Mental Health K23MH076054 (DH). NR 50 TC 15 Z9 15 U1 2 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 19 PY 2014 VL 34 IS 12 BP 4123 EP 4134 DI 10.1523/JNEUROSCI.0686-13.2014 PG 12 WC Neurosciences SC Neurosciences & Neurology GA AD4WX UT WOS:000333253300002 PM 24647934 ER PT J AU Sperling, RA Rentz, DM Johnson, KA Karlawish, J Donohue, M Salmon, DP Aisen, P AF Sperling, Reisa A. Rentz, Dorene M. Johnson, Keith A. Karlawish, Jason Donohue, Michael Salmon, David P. Aisen, Paul TI The A4 Study: Stopping AD Before Symptoms Begin? SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Editorial Material ID PRECLINICAL ALZHEIMERS-DISEASE; RISK AB A new secondary prevention trial in older people with amyloid accumulation at high risk for Alzheimer's disease dementia should provide insights into whether anti-amyloid therapy can delay cognitive decline. C1 [Sperling, Reisa A.; Rentz, Dorene M.; Johnson, Keith A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Alzheimer Res & Treatment,Dept Neurol, Boston, MA 02115 USA. [Sperling, Reisa A.; Rentz, Dorene M.; Johnson, Keith A.] Harvard Aging Brain Study, Dept Neurol, Boston, MA 02114 USA. [Johnson, Keith A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Karlawish, Jason] Univ Penn, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. [Donohue, Michael; Salmon, David P.; Aisen, Paul] Univ Calif San Diego, Alzheimer Dis Cooperat Study, La Jolla, CA 92093 USA. RP Sperling, RA (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Alzheimer Res & Treatment,Dept Neurol, Boston, MA 02115 USA. EM reisa@rics.bwh.harvard.edu FU NIA NIH HHS [K24 AG035007, P30 AG010124, U19 AG010483] NR 10 TC 93 Z9 94 U1 3 U2 12 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 19 PY 2014 VL 6 IS 228 AR 228fs13 DI 10.1126/scitranslmed.3007941 PG 3 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AD4XV UT WOS:000333256000006 PM 24648338 ER PT J AU Qi, QB Chu, AY Kang, JH Huang, JY Rose, LM Jensen, MK Liang, LM Curhan, GC Pasquale, LR Wiggs, JL De Vivo, I Chan, AT Choi, HK Tamimi, RM Ridker, PM Hunter, DJ Willett, WC Rimm, EB Chasman, DI Hu, FB Qi, L AF Qi, Qibin Chu, Audrey Y. Kang, Jae H. Huang, Jinyan Rose, Lynda M. Jensen, Majken K. Liang, Liming Curhan, Gary C. Pasquale, Louis R. Wiggs, Janey L. De Vivo, Immaculata Chan, Andrew T. Choi, Hyon K. Tamimi, Rulla M. Ridker, Paul M. Hunter, David J. Willett, Walter C. Rimm, Eric B. Chasman, Daniel I. Hu, Frank B. Qi, Lu TI Fried food consumption, genetic risk, and body mass index: gene-diet interaction analysis in three US cohort studies SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID GENOME-WIDE ASSOCIATION; FREQUENCY QUESTIONNAIRE; PHYSICAL-ACTIVITY; ENVIRONMENT INTERACTION; ALCOHOL-CONSUMPTION; BREAST-CANCER; OBESITY; WOMEN; REPRODUCIBILITY; VALIDITY AB Objective To examine the interactions between genetic predisposition and consumption of fried food in relation to body mass index (BMI) and obesity. Design Prospective cohort study. Setting Health professionals in the United States. Participants 9623 women from the Nurses' Health Study, 6379 men from the Health Professionals Follow-up Study, and a replication cohort of 21 421 women from the Women's Genome Health Study. Main outcome measure Repeated measurement of BMI over follow-up. Results There was an interaction between fried food consumption and a genetic risk score based on 32 BMI-associated variants on BMI in both the Nurses' Health Study and Health Professionals Follow-up Study (P <= 0.001 for interaction). Among participants in the highest third of the genetic risk score, the differences in BMI between individuals who consumed fried foods four or more times a week and those who consumed fried foods less than once a week amounted to 1.0 (SE 0.2) in women and 0.7 (SE 0.2) in men, whereas the corresponding differences were 0.5 (SE 0.2) and 0.4 (SE 0.2) in the lowest third of the genetic risk score. The gene-diet interaction was replicated in the Women's Genome Health Study (P<0.001 for interaction). Viewed differently, the genetic association with adiposity was strengthened with higher consumption of fried foods. In the combined three cohorts, the differences in BMI per 10 risk alleles were 1.1 (SE 0.2), 1.6 (SE 0.3), and 2.2 (SE 0.6) for fried food consumption less than once, one to three times, and four or more times a week (P<0.001 for interaction); and the odds ratios (95% confidence intervals) for obesity per 10 risk alleles were 1.61 (1.40 to 1.87), 2.12 (1.73 to 2.59), and 2.72 (2.12 to 3.48) across the three categories of consumption (P=0.002 for interaction). In addition, the variants in or near genes highly expressed or known to act in the central nervous system showed significant interactions with fried food consumption, with the FTO (fat mass and obesity associated) variant showing the strongest result (P<0.001 for interaction). Conclusion Our findings suggest that consumption of fried food could interact with genetic background in relation to obesity, highlighting the particular importance of reducing fried food consumption in individuals genetically predisposed to obesity. C1 [Qi, Qibin; Jensen, Majken K.; Hunter, David J.; Willett, Walter C.; Rimm, Eric B.; Hu, Frank B.; Qi, Lu] Harvard Univ, Dept Nutr, Sch Publ Hlth, Boston, MA 02115 USA. [Qi, Qibin] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Chu, Audrey Y.; Rose, Lynda M.; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Chu, Audrey Y.; Kang, Jae H.; Rose, Lynda M.; Curhan, Gary C.; Pasquale, Louis R.; De Vivo, Immaculata; Chan, Andrew T.; Choi, Hyon K.; Tamimi, Rulla M.; Ridker, Paul M.; Hunter, David J.; Willett, Walter C.; Rimm, Eric B.; Chasman, Daniel I.; Hu, Frank B.; Qi, Lu] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kang, Jae H.; Curhan, Gary C.; Pasquale, Louis R.; De Vivo, Immaculata; Chan, Andrew T.; Choi, Hyon K.; Tamimi, Rulla M.; Hunter, David J.; Willett, Walter C.; Rimm, Eric B.; Hu, Frank B.; Qi, Lu] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Huang, Jinyan; Liang, Liming; Curhan, Gary C.; De Vivo, Immaculata; Tamimi, Rulla M.; Hunter, David J.; Willett, Walter C.; Rimm, Eric B.; Hu, Frank B.] Harvard Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02115 USA. [Pasquale, Louis R.; Wiggs, Janey L.] Harvard Univ, Dept Ophthalmol, Sch Med, Mass Eye & Ear Infirm, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Choi, Hyon K.] Boston Univ, Sch Med, Sect Rheumatol, Boston, MA 02118 USA. [Choi, Hyon K.] Boston Univ, Sch Med, Clin Epidemiol Unit, Boston, MA 02118 USA. [Ridker, Paul M.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Dis, Boston, MA 02115 USA. [Chasman, Daniel I.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. RP Qi, L (reprint author), Harvard Univ, Dept Nutr, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM nhlqi@channing.harvard.edu FU National Institutes of Health [DK091718, HL071981, HL073168, CA87969, CA49449, CA055075, HL34594, HL088521, U01HG004399, DK080140, P30DK46200, U01CA137088, U54CA155626, DK58845, DK098311, U01HG004728, EY015473, CA134958, DK70756, DK46200, HL043851, HL080467, CA047988]; Merck Research Laboratories, North Wales, PA; Amgen; American Heart Association Scientist Development Award [0730094N]; Arthur Ashley Williams Foundation; Harvard Ophthalmology Scholar Award (Harvard Medical School) from the Harvard Glaucoma Center of Excellence FX This study was supported by grants DK091718, HL071981, HL073168, CA87969, CA49449, CA055075, HL34594, HL088521, U01HG004399, DK080140, P30DK46200, U01CA137088, U54CA155626, DK58845, DK098311, U01HG004728, EY015473, CA134958, DK70756 and DK46200 from the National Institutes of Health, with additional support for genotyping from Merck Research Laboratories, North Wales, PA. The Women's Genome Health Study is supported by HL043851, HL080467 and CA047988 from the National Institutes of Health, with collaborative scientific support and funding for genotyping provided by Amgen. LQ is a recipient of the American Heart Association Scientist Development Award (0730094N). LRP is supported by the Arthur Ashley Williams Foundation and a Harvard Ophthalmology Scholar Award (Harvard Medical School) from the Harvard Glaucoma Center of Excellence. ATC is a Damon Runyon Cancer Foundation Clinical Investigator. The funding sources had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. NR 56 TC 45 Z9 45 U1 1 U2 21 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 2014 VL 348 AR g1610 DI 10.1136/bmj.g1610 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA AD7AZ UT WOS:000333414500002 PM 24646652 ER PT J AU Helmerhorst, GTT Vranceanu, AM Vrahas, M Smith, M Ring, D AF Helmerhorst, Gijs T. T. Vranceanu, Ana-Maria Vrahas, Mark Smith, Malcolm Ring, David TI Risk Factors for Continued Opioid Use One to Two Months After Surgery for Musculoskeletal Trauma SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID CHRONIC NONCANCER PAIN; LOW-BACK-PAIN; OPERATIVE TREATMENT; POSTOPERATIVE PAIN; UNITED-STATES; PRESCRIPTION; ASSOCIATION; MANAGEMENT; DEPENDENCE; ABUSE AB Background: The aim of this study was to determine factors associated with self-reported ongoing use of opioid medication one to two months after operative treatment of musculoskeletal trauma. Methods: Operatively treated patients (n = 145) with musculoskeletal trauma were evaluated one to two months after surgery. Patients indicated if they were taking opioid pain medication and completed several psychological questionnaires: the Center for Epidemiologic Studies Depression Scale, the Pain Catastrophizing Scale, the Pain Anxiety Symptoms Scale, and the Posttraumatic Stress Disorder Checklist, civilian version. The Numeric Rating Scale was used to measure pain intensity. Disability was measured with use of the Short Musculoskeletal Function Assessment Questionnaire and injury severity was measured with use of the Abbreviated Injury Scale. Results: Patients who scored higher on the catastrophic thinking, anxiety, posttraumatic stress disorder, and depression questionnaires were significantly more likely (p < 0.001) to report taking opioid pain medications one to two months after surgery, regardless of injury severity, fracture site, or treating surgeon. The magnitude of disability as measured by the Short Musculoskeletal Function Assessment score was significantly higher (p < 0.001) in the patients who reported using opioids (40 points) compared with those who reported not using opioids (24 points). A logistic regression model not including pain intensity found that the single best predictor of reported opioid use was catastrophic thinking (odds ratio, 1.12 [95% confidence interval, 1.07 to 1.18]), which explained 23% of the variance (p < 0.001). Conclusions: Patients who continue to use opioid pain medication one to two months after surgery for musculoskeletal trauma have more psychological distress, less effective coping strategies, and greater symptoms and disability than patients who do not take opioids, irrespective of injury, surgical procedure, or surgeon. C1 [Helmerhorst, Gijs T. T.; Vranceanu, Ana-Maria; Vrahas, Mark; Smith, Malcolm; Ring, David] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Helmerhorst, GTT (reprint author), Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, 55 Fruit St, Boston, MA 02114 USA. EM ghelmerhorst@gmail.com; avranceanu@partners.org; mvrahas@partners.org; rmsmith1@partners.org; dring@partners.org NR 44 TC 29 Z9 29 U1 1 U2 8 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD MAR 19 PY 2014 VL 96A IS 6 BP 495 EP 499 DI 10.2106/JBJS.L.01406 PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AD2NP UT WOS:000333072700009 PM 24647506 ER PT J AU Takeuchi, K Yanai, R Kumase, F Morizane, Y Suzuki, J Kayama, M Brodowska, K Nakazawa, M Miller, JW Connor, KM Vavvas, DG AF Takeuchi, Kimio Yanai, Ryoji Kumase, Fumiaki Morizane, Yuki Suzuki, Jun Kayama, Maki Brodowska, Katarzyna Nakazawa, Mitsuru Miller, Joan W. Connor, Kip M. Vavvas, Demetrios G. TI EGF-Like-Domain-7 Is Required for VEGF-Induced Akt/ERK Activation and Vascular Tube Formation in an Ex Vivo Angiogenesis Assay SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MICRORNA MIR-126; EGFL7; MECHANISMS; CELLS; NOTCH; NEUROPILIN-1; RETINOPATHY; INTEGRITY; MIGRATION AB EGFL7 is a secreted angiogenic factor, which in contrast to the well-known secreted angiogenic molecules VEGF and FGF-2, is almost exclusively expressed by endothelial cells and may act in an autocrine fashion. Prior studies have shown EGFL7 to mediate its angiogenic effects by interfering with the Notch pathway and/or via the intronic miR126. Less is known about its effects on VEGF signaling. We wanted to investigate the role of epidermal growth factor-like domain 7 (EGFL7) in VEGF-driven angiogenesis using an ex vivo Matrigel-embedded mouse eye cup assay and siRNA mediated knockdown of EGFL7 by siRNA. Our results suggested that VEGF-induced vascular tube formation was significantly impaired after siRNA downregulation of EGFL7. In addition, knockdown of EGFL7 suppressed VEGF upregulation of phospho-Akt and phospho-Erk(1/2) in endothelial cells, but did not alter VEGFR phosphorylation and neuropilin-1 protein expression or miR126 expression. Thus, in conclusion, EGFL7 is required for VEGF upregulation of the Akt/Erk (1/2) pathway during angiogenesis, and may represent a new therapeutic target in diseases of pathological neovascularization. C1 [Takeuchi, Kimio; Yanai, Ryoji; Kumase, Fumiaki; Morizane, Yuki; Suzuki, Jun; Kayama, Maki; Brodowska, Katarzyna; Miller, Joan W.; Connor, Kip M.; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Angiogenesis Lab,Dept Ophthalmol, Boston, MA 02114 USA. [Kumase, Fumiaki; Morizane, Yuki] Okayama Univ, Dept Ophthalmol, Grad Sch Med Dent & Pharmaceut Sci, Okayama, Japan. [Takeuchi, Kimio; Nakazawa, Mitsuru] Hirosaki Univ, Grad Sch Med, Dept Ophthalmol, Aomori, Japan. RP Vavvas, DG (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Angiogenesis Lab,Dept Ophthalmol, Boston, MA 02114 USA. EM vavvas@meei.harvard.edu OI Nakazawa, Mitsuru/0000-0001-6095-5712; Connor, Kip/0000-0002-2048-9080; Vavvas, Demetrios/0000-0002-8622-6478 FU Research to Prevent Blindness Physician Scientist Award; NIH NEI [R21EY023079-01A1]; Foundation Lions Eye Research Fund; Yeatts Family Foundation; Macula Society Research Grant award; Research to Prevent Blindness Foundation; National Institutes of Health Grant [EY014104, R01EY022084-01/S1]; Fight for Sight Grant in Aid; Bausch and Lomb Japan Vitreoretinal fellowship FX This work was supported, in whole or in part, by Research to Prevent Blindness Physician Scientist Award (DGV), NIH NEI R21EY023079-01A1 (DGV), Foundation Lions Eye Research Fund (DGV), The Yeatts Family Foundation (JWM, DGV), 2013 Macula Society Research Grant award (DGV), unrestricted grant to Massachusetts Eye and Ear Infirmary from the Research to Prevent Blindness Foundation (to D. G. V. and J.W.M.), National Institutes of Health Grant EY014104 core grant and R01EY022084-01/S1 (KMC), the Fight for Sight Grant in Aid (DGV), and a Bausch and Lomb Japan Vitreoretinal fellowship (KT, YM, JS, and MK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 8 Z9 8 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 19 PY 2014 VL 9 IS 3 AR e91849 DI 10.1371/journal.pone.0091849 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD6ER UT WOS:000333348500056 PM 24647208 ER PT J AU Kuo, P Hartzell, TL Eberlin, KR Miao, D Zurakowski, D Winograd, JM Day, CS AF Kuo, Phoebe Hartzell, Tristan L. Eberlin, Kyle R. Miao, Diana Zurakowski, David Winograd, Jonathan M. Day, Charles S. TI The Characteristics of Referring Facilities and Transferred Hand Surgery Patients SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID ON-CALL COVERAGE; CALIFORNIA; LEVEL; TRANSPLANTATION; COMPLICATIONS AB Background: As emergency departments (EDs) become increasingly overwhelmed and specialist coverage in some EDs decreases, patients may be transferred to tertiary or quaternary facilities for specialized care to decrease patient load at transferring facilities. Our objective was to determine whether facilities that transferred patients for hand surgery had hand surgery coverage and to evaluate any nonmedical factors that might have been associated with transfer. Methods: A retrospective review was conducted for 1167 visits of hand and wrist patients seen in the EDs of two urban level-I trauma centers. The hand surgery capacity of referring facilities was determined by phone calls to the EDs. Univariate and multivariable analyses were conducted to identify nonmedical factors that could potentially affect the decision to transfer. Results: A total of 155 (13.3%) of 1167 patients arrived from other facilities for specialized hand care. These patients were significantly more likely to be male (p = 0.02), have noncommercial insurance (p = 0.04), require an interpreter (p = 0.01), and arrive between 6: 00 P.M. and midnight (p = 0.03). In a multivariable analysis, sex and insurance status were significantly associated with transfer (p < 0.05). The subset of ninety-five patients who were transferred from other EDs was significantly more likely to be male (p < 0.01) and arrive on weekends (p < 0.01) or between 6: 00 P.M. and midnight (p < 0.01). Of these patients, seventy-seven (81%) were transferred from an ED that reported partial or full hand surgery coverage. However, only eight (10.4%) received a hand surgery evaluation prior to transfer. Conclusions: The low percentage of patients receiving hand surgery evaluations prior to transfer suggests that referring hospitals are not using their own hand surgeon resources. Nonmedical factors, including noncommercial insurance and off-hour time of initial arrival, may be associated with the decision to transfer patients. C1 [Kuo, Phoebe; Miao, Diana; Day, Charles S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Orthoped Surg, Boston, MA 02215 USA. [Hartzell, Tristan L.] Faith Reg Hlth Serv, Norfolk, NE 68701 USA. [Eberlin, Kyle R.; Winograd, Jonathan M.] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, WACC, Boston, MA 02114 USA. [Zurakowski, David] Childrens Hosp Boston, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. RP Kuo, P (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Orthoped Surg, 330 Brookline Ave,Stoneman 10, Boston, MA 02215 USA. EM cday1@bidmc.harvard.edu NR 15 TC 4 Z9 4 U1 0 U2 0 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD MAR 19 PY 2014 VL 96A IS 6 DI 10.2106/JBJS.L.01213 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA CF1QF UT WOS:000352322000005 PM 24647515 ER PT J AU Stengel, A Tache, Y AF Stengel, Andreas Tache, Yvette TI CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress SO FRONTIERS IN NEUROSCIENCE LA English DT Review DE body weight; CRF; food intake; stress; urocortin ID CORTICOTROPIN-RELEASING-FACTOR; CONDITIONED TASTE-AVERSION; FACTOR-RECEPTOR EXPRESSION; ENTERIC NERVOUS-SYSTEM; FASTED PLASMA GHRELIN; REDUCES FOOD-INTAKE; C-FOS EXPRESSION; RAT-BRAIN; INDUCED ANOREXIA; SIGNALING PATHWAYS AB Early on, corticotropin-releasing factor (CRF), a hallmark brain peptide mediating many components of the stress response, was shown to affect food intake inducing a robust anorexigenic response when injected into the rodent brain. Subsequently, other members of the CRF signaling family have been identified, namely urocortin (Ucn) 1, Ucn 2, and Ucn 3 which were also shown to decrease food intake upon central or peripheral injection. However, the kinetics of feeding suppression was different with an early decrease following intracerebroventricular injection of CRF and a delayed action of Ucns contrasting with the early onset after systemic injection. CRF and Ucns bind to two distinct G-protein coupled membrane receptors, the CRF1 and CRF2. New pharmacological tools such as highly selective peptide CRF1 or CRF2 agonists or antagonists along with genetic knock-in or knock-out models have allowed delineating the primary role of CRF2 involved in the anorexic response to exogenous administration of CRF and Ucns. Several stressors trigger behavioral changes including suppression of feeding behavior which are mediated by brain CRF receptor activation. The present review will highlight the state-of-knowledge on the effects and mechanisms of action of CRF/Ucns-CRF112 signaling under basal conditions and the role in the alterations of food intake in response to stress. C1 [Stengel, Andreas] Charite, Charite Ctr Internal Med & Dermatol, Div Gen Internal & Psychosomat Med, D-12200 Berlin, Germany. [Tache, Yvette] Univ Calif Los Angeles, Dept Med, CURE Digest Dis Res Ctr, Ctr Neurobiol Stress & Womens Hlth,Digest Dis Div, Los Angeles, CA 90024 USA. [Tache, Yvette] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90073 USA. RP Stengel, A (reprint author), Charite, Charite Ctr Internal Med & Dermatol, Div Gen Internal & Psychosomat Med, Campus Benjamin Franklin,Hindenburgdamm 30, D-12200 Berlin, Germany. EM andreas.stengel@charite.de; ytache@mednet.ucla.edu FU NIH (Animal Core) [RO1 DK-33061, DK-41301]; VA Research Career Scientist (Yvette Tache), German Research Foundation STE [1765/3-1]; Charite University Funding UFF [89-441176] FX This work was supported by NIH RO1 DK-33061, NIH Center Grant DK-41301 (Animal Core), VA Research Career Scientist (Yvette Tache), German Research Foundation STE 1765/3-1 (Andreas Stengel) and Charite University Funding UFF 89-441176 (Andreas Stengel). NR 154 TC 21 Z9 22 U1 4 U2 13 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-453X J9 FRONT NEUROSCI-SWITZ JI Front. Neurosci. PD MAR 18 PY 2014 VL 8 AR 52 DI 10.3389/fnins.2014.00052 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AW7HO UT WOS:000346435500003 PM 24672423 ER PT J AU Lo Re, V Kallan, MJ Tate, JP Localio, AR Lim, JK Goetz, MB Klein, MB Rimland, D Rodriguez-Barradas, MC Butt, AA Gibert, CL Brown, ST Park, L Dubrow, R Reddy, KR Kostman, JR Strom, BL Justice, AC AF Lo Re, Vincent, III Kallan, Michael J. Tate, Janet P. Localio, A. Russell Lim, Joseph K. Goetz, Matthew Bidwell Klein, Marina B. Rimland, David Rodriguez-Barradas, Maria C. Butt, Adeel A. Gibert, Cynthia L. Brown, Sheldon T. Park, Lesley Dubrow, Robert Reddy, K. Rajender Kostman, Jay R. Strom, Brian L. Justice, Amy C. TI Hepatic Decompensation in Antiretroviral-Treated Patients Co-Infected With HIV and Hepatitis C Virus Compared With Hepatitis C Virus-Monoinfected Patients A Cohort Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHRONIC LIVER-DISEASE; POLYMERASE CHAIN-REACTION; SIMPLE NONINVASIVE INDEX; VETERANS AGING COHORT; PROTEIN-S DEFICIENCY; SOCIETY-USA PANEL; FIBROSIS PROGRESSION; HEPATOCELLULAR-CARCINOMA; HIV/HCV COINFECTION AB Background: The incidence and determinants of hepatic decompensation have been incompletely examined among patients co-infected with HIV and hepatitis C virus (HCV) in the antiretroviral therapy (ART) era, and few studies have compared outcome rates with those of patients with chronic HCV alone. Objective: To compare the incidence of hepatic decompensation between antiretroviral-treated patients co-infected with HIV and HCV and HCV-monoinfected patients and to evaluate factors associated with decompensation among co-infected patients receiving ART. Design: Retrospective cohort study. Setting: Veterans Health Administration. Patients: 4280 co-infected patients who initiated ART and 6079 HCV-monoinfected patients receiving care between 1997 and 2010. All patients had detectable HCV RNA and were HCV treatment-naive. Measurements: Incident hepatic decompensation, determined by diagnoses of ascites, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage. Results: The incidence of hepatic decompensation was greater among co-infected than monoinfected patients (7.4% vs. 4.8% at 10 years; P < 0.001). Compared with HCV-monoinfected patients, co-infected patients had a higher rate of hepatic decompensation (hazard ratio [HR] accounting for competing risks, 1.56 [95% CI, 1.31 to 1.86]). Co-infected patients who maintained HIV RNA levels less than 1000 copies/mL still had higher rates of decompensation than HCV-monoinfected patients (HR, 1.44 [CI, 1.05 to 1.99]). Baseline advanced hepatic fibrosis (FIB-4 score >3.25) (HR, 5.45 [CI, 3.79 to 7.84]), baseline hemoglobin level less than 100 g/L (HR, 2.24 [CI, 1.20 to 4.20]), diabetes mellitus (HR, 1.88 [CI, 1.38 to 2.56]), and nonblack race (HR, 2.12 [CI, 1.65 to 2.72]) were each associated with higher rates of decompensation among co-infected patients. Limitation: Observational study of predominantly male patients. Conclusion: Despite receiving ART, patients co-infected with HIV and HCV had higher rates of hepatic decompensation than HCV-monoinfected patients. Rates of decompensation were higher for co-infected patients with advanced liver fibrosis, severe anemia, diabetes, and nonblack race. C1 Univ Penn, Philadelphia, PA 19104 USA. Philadelphia VA Med Ctr, Philadelphia, PA USA. VA Connecticut Healthcare Syst, West Haven, CT 06516 USA. Yale Univ, Sch Med, West Haven, CT 06516 USA. Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. McGill Univ, Ctr Hlth, Montreal, PQ, Canada. Atlanta VA Med Ctr, Atlanta, GA 30033 USA. Emory Univ, Sch Med, Atlanta, GA USA. Michael E DeBakey VA Med Ctr, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. Sheikh Khalifa Med City, Abu Dhabi, U Arab Emirates. Washington DC VA Med Ctr, Washington, DC 20422 USA. George Washington Univ, Med Ctr, Washington, DC 20037 USA. James J Peters VA Med Ctr, New York, NY USA. Mt Sinai Sch Med, New York, NY USA. Rutgers State Univ, Newark, NJ 07103 USA. RP Lo Re, V (reprint author), Univ Penn, Penn Ctr AIDS Res, Ctr Clin Epidemiol & Biostat, Div Infect Dis,Dept Med,Perelman Sch Med, 836 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM vincentl@mail.med.upenn.edu RI Lo Re, Vincent/N-7817-2015; OI Butt, Adeel/0000-0002-1118-1826; Goetz, Matthew/0000-0003-4542-992X FU National Institute of Allergy and Infectious Diseases [K01 AI070001]; National Institute on Alcohol Abuse and Alcoholism [U01 AA13566]; National Institute of Mental Health [T32 MH020031]; National Institutes of Health FX National Institutes of Health. NR 67 TC 71 Z9 71 U1 1 U2 8 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 18 PY 2014 VL 160 IS 6 BP 369 EP + DI 10.7326/M13-1829 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA AD8MW UT WOS:000333521300013 PM 24723077 ER PT J AU Wang, Y Choueiri, TK Lee, JL Tan, MH Rha, SY North, SA Kollmannsberger, CK McDermott, DF Heng, DYC AF Wang, Y. Choueiri, T. K. Lee, J-L Tan, M-H Rha, S. Y. North, S. A. Kollmannsberger, C. K. McDermott, D. F. Heng, D. Y. C. TI Anti-VEGF therapy in mRCC: differences between Asian and non-Asian patients SO BRITISH JOURNAL OF CANCER LA English DT Article DE sunitinib; sorafenib; ethnicity; VEGF; progression-free survival; overall survival ID RENAL-CELL CARCINOMA; JAPANESE PATIENTS; PHASE-II; INTERFERON-ALPHA; SUNITINIB; EFFICACY; SAFETY; SORAFENIB; TOXICITY; CANCER AB Background: Several reports suggest that vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in Asian vs non-Asian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterised. Methods: A multicentre, retrospective, cohort study using Asian and non-Asian centres which collected data on ethnicity, dose reductions and outcomes using the International mRCC Database Consortium. Results: This study included 1024 (464 Asian, 560 non-Asian) patients with a 29.4 months median follow-up. The percentage of dose modifications/ reductions between non-Asians and Asians was similar (55% vs 61% P = 0.1197). When adjusted for risk groups, there was no difference in overall or progression-free survival between non-Asians and Asians. Patients with dose reductions due to toxicity had longer treatment durations and overall survival than those who did not in both non-Asian (10.6 vs 5.0 months, P<0.0001; 22.6 vs 16.1 months, P = 0.0016, respectively) and Asian populations (8.9 vs 5.4 months, P = 0.0028; 28.0 vs 18.7 months, P = 0.0069, respectively). Conclusions: Adjusting for risk groups, there appears to be no difference in outcome between Asian vs non-Asian patients with mRCC treated with VEGF-targeted therapy. Judicious dose reductions may allow for better outcomes in both populations due to longer treatment durations, but direct comparisons are needed. C1 [Wang, Y.] Univ Calgary, Calgary, AB, Canada. [Choueiri, T. K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Kidney Canc Ctr,Dana Farber Canc Inst, Boston, MA 02115 USA. [Lee, J-L] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul, South Korea. [Tan, M-H] Natl Canc Ctr, Singapore, Singapore. [Rha, S. Y.] Yonsei Univ, Coll Med, Yonsei Canc Ctr, Seoul, South Korea. [North, S. A.] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Kollmannsberger, C. K.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [McDermott, D. F.] Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA USA. [Heng, D. Y. C.] Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. RP Heng, DYC (reprint author), Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. EM daniel.heng@albertahealthservices.ca FU (Alberta Health Services Cancer Care, British Columbia Cancer Agency); Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center); (Asan Medical Center, Yonsei Cancer Center); (National Cancer Center) FX Authors would like to acknowledge the support they have received from host institutions including cancer centres in Canada (Alberta Health Services Cancer Care, British Columbia Cancer Agency), the United States of America (Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center), Korea (Asan Medical Center, Yonsei Cancer Center), and Singapore (National Cancer Center). NR 29 TC 8 Z9 8 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD MAR 18 PY 2014 VL 110 IS 6 BP 1433 EP 1437 DI 10.1038/bjc.2014.28 PG 5 WC Oncology SC Oncology GA AD4DB UT WOS:000333195800005 PM 24548864 ER PT J AU Hirata, H Hinoda, Y Shahryari, V Deng, G Tanaka, Y Tabatabai, ZL Dahiya, R AF Hirata, H. Hinoda, Y. Shahryari, V. Deng, G. Tanaka, Y. Tabatabai, Z. L. Dahiya, R. TI Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells SO BRITISH JOURNAL OF CANCER LA English DT Article DE genistein; miR-1260b; PC; sFRP1; Smad4; apoptosis ID WNT SIGNALING PATHWAY; UNITED-STATES; EPIGENETIC INACTIVATION; COLORECTAL-CANCER; INCIDENCE TRENDS; ALTERS GROWTH; GENES; METHYLATION; PROGRESSION; EXPRESSION AB Background: Recently several microRNAs (miRNAs) have been found to be regulated by genistein in cancer cells. In this study, we focused on the gene regulatory effect of genistein on microRNA and its target genes in prostate cancer (PC). Methods: Initially, we investigated the effect of genistein on prostate cancer cells and identified that the expression of miRNA1260b was decreased by genistein. We performed functional analyses and investigated the relationship between miRNA-1260b expression and prostate cancer patient outcomes. Two target genes (sFRP1 and Smad4) of miR-1260b were identified based on computer algorithm and 3 ' UTR luciferase assay was carried out to determine direct miRNA regulation of the genes. Results: Genistein promoted apoptosis while inhibiting prostate cancer cell proliferation, invasion and TCF reporter activity in PC cells. MiR-1260b was highly expressed in prostate cancer tissues and significantly downregulated by genistein in PC cells. After knocking down miR-1260b, cell proliferation, invasion, migration and TCF reporter activity were decreased in PC cells. Western analysis and 30UTR luciferase assay showed that the two target genes (sFRP1 and Smad4) were directly regulated by miR-1260b. The expression of sFRP1 and Smad4 was significantly decreased in prostate cancer tissues. Genistein also increased expression of these two genes via DNA demethylation and histone modifications. Conclusions: Our data suggest that genistein exerts its anti-tumour effect via downregulation of miR-1260b that targeted sRRP1 and Smad4 genes in prostate cancer cells. The expression of sFRP1 and Smad4 was also modulated by genistein via DNA methylation or histone modifications in PC cell lines. C1 [Hirata, H.; Shahryari, V.; Deng, G.; Tanaka, Y.; Dahiya, R.] San Francisco VA Med Ctr, Dept Urol, San Francisco, CA 94121 USA. [Hirata, H.; Shahryari, V.; Deng, G.; Tanaka, Y.; Tabatabai, Z. L.; Dahiya, R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hinoda, Y.] Yamaguchi Univ, Grad Sch Med, Dept Oncol & Lab Med, Yamaguchi, Japan. [Tabatabai, Z. L.] San Francisco VA Med Ctr, Dept Pathol, San Francisco, CA USA. 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 [RO1CA138642, RO1CA130860, RO1CA160079, I01BX001123]; VA Merit Review, VA Program Project; Yamada Science Foundation FX We thank Dr Roger Erickson for his support and assistance with the preparation of the manuscript. This study was supported by National Center for Research Resources of the National Institutes of Health through Grant Number RO1CA138642, RO1CA130860, RO1CA160079, I01BX001123, VA Merit Review, VA Program Project (PI: R Dahiya) and Yamada Science Foundation. NR 46 TC 19 Z9 22 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD MAR 18 PY 2014 VL 110 IS 6 BP 1645 EP 1654 DI 10.1038/bjc.2014.48 PG 10 WC Oncology SC Oncology GA AD4DB UT WOS:000333195800029 PM 24504368 ER PT J AU Li, XY Tao, H Xie, KW Ni, ZH Yan, YC Wei, K Chuang, PY He, JC Gu, LY AF Li, Xiaoying Tao, Hua Xie, Kewei Ni, Zhaohui Yan, Yucheng Wei, Kai Chuang, Peter Y. He, John Cijiang Gu, Leyi TI cAMP Signaling Prevents Podocyte Apoptosis via Activation of Protein Kinase A and Mitochondrial Fusion SO PLOS ONE LA English DT Article ID GLOMERULAR PODOCYTES; EPITHELIAL-CELLS; MOUSE MODEL; IN-VITRO; PATHWAY; EXPRESSION; RECEPTOR; NEPHROPATHY; DAMAGE; STRESS AB Our previous in vitro studies suggested that cyclic AMP (cAMP) signaling prevents adriamycin (ADR) and puromycin aminonucleoside (PAN)-induced apoptosis in podocytes. As cAMP is an important second messenger and plays a key role in cell proliferation, differentiation and cytoskeleton formation via protein kinase A (PKA) or exchange protein directly activated by cAMP (Epac) pathways, we sought to determine the role of PKA or Epac signaling in cAMP-mediated protection of podocytes. In the ADR nephrosis model, we found that forskolin, a selective activator of adenylate cyclase, attenuated albuminuria and improved the expression of podocyte marker WT-1. When podocytes were treated with pCPT-cAMP (a selective cAMP/PKA activator), PKA activation was increased in a time-dependent manner and prevented PAN-induced podocyte loss and caspase 3 activation, as well as a reduction in mitochondrial membrane potential. We found that PAN and ADR resulted in a decrease in Mfn1 expression and mitochondrial fission in podocytes. pCPT-cAMP restored Mfn1 expression in puromycin or ADR-treated podocytes and induced Drp1 phosphorylation, as well as mitochondrial fusion. Treating podocytes with arachidonic acid resulted in mitochondrial fission, podocyte loss and cleaved caspase 3 production. Arachidonic acid abolished the protective effects of pCPT-cAMP on PAN-treated podocytes. Mdivi, a mitochondrial division inhibitor, prevented PAN-induced cleaved caspase 3 production in podocytes. We conclude that activation of cAMP alleviated murine podocyte caused by ADR. PKA signaling resulted in mitochondrial fusion in podocytes, which at least partially mediated the effects of cAMP. C1 [Li, Xiaoying; Tao, Hua; Xie, Kewei; Ni, Zhaohui; Yan, Yucheng; Wei, Kai; Gu, Leyi] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Div Renal, Shanghai 200030, Peoples R China. [Li, Xiaoying; Tao, Hua; Xie, Kewei; Ni, Zhaohui; Yan, Yucheng; Wei, Kai; Gu, Leyi] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Mol Cell Lab Kidney Dis, Shanghai 200030, Peoples R China. [Chuang, Peter Y.; He, John Cijiang] Icahn Sch Med Mt Sinai, Div Nephrol, New York, NY USA. [He, John Cijiang] James J Peter Vet Affairs Med Ctr, Renal Sect, Bronx, NY USA. RP Gu, LY (reprint author), Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Div Renal, Shanghai 200030, Peoples R China. EM guleyi@aliyun.com FU National Nature Science Foundation Grant of China [30971363, 81270781]; Nature Science Foundation Grant of Shanghai [08ZR1413200]; National Basic Research Program of China 973 Program [2012CB517602]; Nature Science Foundation of Shanghai [10JC1410200] FX This work was supported by the National Nature Science Foundation Grant of China (30971363 and 81270781, http://www.nsfc.gov.cn) and Nature Science Foundation Grant of Shanghai (08ZR1413200, http://www.stcsm.gov.cn) to Dr Gu. National Basic Research Program of China 973 Program (2012CB517602,http://program.most.gov.cn) to Dr Ni as well as by a grant (10JC1410200,http://www.stcsm.gov.cn) from the Nature Science Foundation of Shanghai to Dr Yan. The funders had no role in study design, data collection and analysis, decision to publish, or preparaton of the manuscript. NR 43 TC 6 Z9 8 U1 1 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 18 PY 2014 VL 9 IS 3 AR e92003 DI 10.1371/journal.pone.0092003 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD4ZE UT WOS:000333259900058 PM 24642777 ER PT J AU Anderson, RF Shinde, SS Hille, R Rothery, RA Weiner, JH Rajagukguk, S Maldashina, E Cecchini, G AF Anderson, Robert F. Shinde, Sujata S. Hille, Russ Rothery, Richard A. Weiner, Joel H. Rajagukguk, Sany Maldashina, Elena Cecchini, Gary TI Electron-Transfer Pathways in the Heme and Quinone-Binding Domain of Complex II (Succinate Dehydrogenase) SO BIOCHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; UBIQUINONE OXIDOREDUCTASE; FUMARATE REDUCTASE; CATALYTIC-ACTIVITY; RESPIRATORY-CHAIN; SITE; PARAGANGLIOMAS; SUPEROXIDE; MUTATIONS; OXIDASE AB Single electron transfers have been examined in complex II (succinate:ubiquinone oxidoreductase) by the method of pulse radiolysis. Electrons are introduced into the enzyme initially at the [3Fe-4S] and ubiquinone sites followed. by intramolecular equilibration with the b heme of the enzyme. To define thermodynamic and other controlling parameters for the pathways of electron transfer in complex II, site-directed variants were constructed and analyzed. Variants at SdhB-His207 and SdhB-Ile209 exhibit significantly perturbed electron transfer between the [3Fe-4S] cluster and ubiquinone. Analysis of the data using Marcus theory shows that the electronic coupling constants for wild-type and variant enzyme are all small, indicating that electron transfer occurs by diabatic tunneling. The presence of the ubiquinone is necessary for efficient electron transfer to the heme, which only slowly equilibrates with the [3Fe-4S] cluster in the absence of the quinone. C1 [Anderson, Robert F.; Shinde, Sujata S.] Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc Res Ctr, Auckland 1142, New Zealand. [Hille, Russ] Univ Calif Riverside, Dept Biochem, Riverside, CA 92521 USA. [Rothery, Richard A.; Weiner, Joel H.] Univ Alberta, Dept Biochem, Membrane Protein Res Grp, Edmonton, AB T6G 2H7, Canada. [Rajagukguk, Sany; Maldashina, Elena; Cecchini, Gary] San Francisco VA Med Ctr, Div Mol Biol, San Francisco, CA 94121 USA. [Maldashina, Elena; Cecchini, Gary] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA. RP Cecchini, G (reprint author), Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc Res Ctr, Auckland 1142, New Zealand. EM r.anderson@auckland.ac.nz; gary.cecchini@ucsf.edu FU Department of Veterans Affairs Biomedical Laboratory Research and Development Merit Award [BX001077]; National Institutes of Health [GM61606]; U.S. Department of Energy [DE-SC0010666]; Canadian Institutes of Health Research [MOP89735] FX The work in the authors' laboratories was supported in whole or in part by the Department of Veterans Affairs Biomedical Laboratory Research and Development Merit Award (BX001077), the National Institutes of Health (GM61606), the U.S. Department of Energy (DE-SC0010666), and the Canadian Institutes of Health Research (MOP89735). NR 49 TC 1 Z9 1 U1 2 U2 30 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 18 PY 2014 VL 53 IS 10 BP 1637 EP 1646 DI 10.1021/bi401630m PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AD4QM UT WOS:000333235600012 PM 24559074 ER PT J AU Seely, EW Ecker, J AF Seely, Ellen W. Ecker, Jeffrey TI Chronic Hypertension in Pregnancy SO CIRCULATION LA English DT Article DE hypertension; pre-eclampsia; pregnancy; pregnancy complications ID CONVERTING ENZYME-INHIBITORS; DIETARY-SODIUM RESTRICTION; HIGH BLOOD-PRESSURE; DEVELOPMENTAL TOXICITY; RECEPTOR ANTAGONISTS; PREVENT PREECLAMPSIA; 1ST TRIMESTER; RISK-FACTORS; WOMEN; MANAGEMENT C1 [Seely, Ellen W.] Harvard Univ, Brigham & Womens Hosp, Endocrinol Diabet & Hypertens Div, Sch Med, Boston, MA 02115 USA. [Ecker, Jeffrey] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Maternal Fetal Med, Boston, MA USA. RP Seely, EW (reprint author), Brigham & Womens Hosp, Endocrinol Diabet & Hypertens Div, 221 Longwood Ave, Boston, MA 02115 USA. EM eseely@partners.org FU Bayer Health Care FX Dr Seely received support from Bayer Health Care for an investigator-initiated study of postmenopausal women ending in 2012. Dr Ecker reports no conflicts. NR 63 TC 15 Z9 16 U1 1 U2 13 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 18 PY 2014 VL 129 IS 11 BP 1254 EP 1261 DI 10.1161/CIRCULATIONAHA.113.003904 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AD3MN UT WOS:000333145200015 PM 24637432 ER PT J AU Pishesha, N Thiru, P Shi, JH Eng, JC Sankaran, VG Lodish, HF AF Pishesha, Novalia Thiru, Prathapan Shi, Jiahai Eng, Jennifer C. Sankaran, Vijay G. Lodish, Harvey F. TI Transcriptional divergence and conservation of human and mouse erythropoiesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hematopoiesis; comparative genomics; microarray ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ANEMIA TYPE-II; ERYTHROID-DIFFERENTIATION; HUMAN IMMUNOLOGY; GENE-EXPRESSION; DISTINCT STAGES; HEMATOPOIESIS; MUTATIONS; COPII; CELLS AB Mouse models have been used extensively for decades and have been instrumental in improving our understanding of mammalian erythropoiesis. Nonetheless, there are several examples of variation between human and mouse erythropoiesis. We performed a comparative global gene expression study using data from morphologically identical stage-matched sorted populations of human and mouse erythroid precursors from early to late erythroblasts. Induction and repression of major transcriptional regulators of erythropoiesis, as well as major erythroid-important proteins, are largely conserved between the species. In contrast, at a global level we identified a significant extent of divergence between the species, both at comparable stages and in the transitions between stages, especially for the 500 most highly expressed genes during development. This suggests that the response of multiple developmentally regulated genes to key erythroid transcriptional regulators represents an important modification that has occurred in the course of erythroid evolution. In developing a systematic framework to understand and study conservation and divergence between human and mouse erythropoiesis, we show how mouse models can fail to mimic specific human diseases and provide predictions for translating findings from mouse models to potential therapies for human disease. C1 [Pishesha, Novalia; Thiru, Prathapan; Shi, Jiahai; Eng, Jennifer C.; Sankaran, Vijay G.; Lodish, Harvey F.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Pishesha, Novalia; Lodish, Harvey F.] MIT, Dept Biol Engn, Cambridge, MA 02142 USA. [Lodish, Harvey F.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Sankaran, Vijay G.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Sankaran, Vijay G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Sankaran, Vijay G.; Lodish, Harvey F.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Sankaran, VG (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM sankaran@broadinstitute.org; lodish@wi.mit.edu RI shi, jiahai/D-7650-2013 OI shi, jiahai/0000-0002-6467-8289 FU National Institutes of Health (NIH) [P01 HL32262, T32 HL007574-30]; Schlumberger Foundation Faculty for the Future; American Association of University Women International Fellowship; Philanthropic Educational Organization International Peace Scholarship Fund FX We thank Tom DiCesare for assistance with illustrations and Marko Knoll and Leif Si-Hun Ludwig for discussion and critical proofreading of the manuscript. This work was supported by National Institutes of Health (NIH) Grants P01 HL32262 (to H. F. L.) and T32 HL007574-30 (to V. G. S.). N.P. was supported by grants from the Schlumberger Foundation Faculty for the Future, the American Association of University Women International Fellowship, and the Philanthropic Educational Organization International Peace Scholarship Fund. NR 46 TC 21 Z9 21 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 18 PY 2014 VL 111 IS 11 BP 4103 EP 4108 DI 10.1073/pnas.1401598111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD1XV UT WOS:000333027900054 PM 24591581 ER PT J AU Lakkireddy, D Reddy, YM Di Biase, L Vallakati, A Mansour, MC Santangeli, P Gangireddy, S Swarup, V Chalhoub, F Atkins, D Bommana, S Verma, A Sanchez, JE Burkhardt, JD Barrett, CD Baheiry, S Ruskin, J Reddy, V Natale, A AF Lakkireddy, Dhanunjaya Reddy, Yeruva Madhu Di Biase, Luigi Vallakati, Ajay Mansour, Moussa C. Santangeli, Pasquale Gangireddy, Sandeep Swarup, Vijay Chalhoub, Fadi Atkins, Donita Bommana, Sudharani Verma, Atul Sanchez, Javier E. Burkhardt, J. David Barrett, Conor D. Baheiry, Salwa Ruskin, Jeremy Reddy, Vivek Natale, Andrea TI Feasibility and Safety of Uninterrupted Rivaroxaban for Periprocedural Anticoagulation in Patients Undergoing Radiofrequency Ablation for Atrial Fibrillation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE periprocedural anticoagulation; radiofrequency ablation; rivaroxaban; warfarin ID INTERNATIONAL NORMALIZED RATIO; CATHETER ABLATION; ORAL ANTICOAGULANTS; DABIGATRAN; WARFARIN; COMPLICATIONS; PHARMACODYNAMICS; PHARMACOKINETICS; MANAGEMENT; THROMBOEMBOLISM AB Objectives The purpose of this study was to evaluate the feasibility and safety of uninterrupted rivaroxaban therapy during atrial fibrillation (AF) ablation. Background Optimal periprocedural anticoagulation strategy is essential for minimizing bleeding and thromboembolic complications during and after AF ablation. The safety and efficacy of uninterrupted rivaroxaban therapy as a periprocedural anticoagulant for AF ablation are unknown. Methods We performed a multicenter, observational, prospective study of a registry of patients undergoing AF ablation in 8 centers in North America. Patients taking uninterrupted periprocedural rivaroxaban were matched by age, sex, and type of AF with an equal number of patients taking uninterrupted warfarin therapy who were undergoing AF ablation during the same period. Results A total of 642 patients were included in the study, with 321 in each group. Mean age was 63 +/- 10 years, with 442 (69%) males and 328 (51%) patients with paroxysmal AF equally distributed between the 2 groups. Patients in the warfarin group had a slightly higher mean HAS- BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) score (1.70 +/- 1.0 vs. 1.47 +/- 0.9, respectively; p = 0.032). Bleeding and embolic complications occurred in 47 (7.3%) and 2 (0.3%) patients (both had transient ischemic attacks) respectively. There were no differences in the number of major bleeding complications (5 [1.6%] vs. 7 [1.9%], respectively; p = 0.772), minor bleeding complications (16 [5.0%] vs. 19 [5.9%], respectively; p = 0.602), or embolic complications (1 [0.3%] vs. 1 [0.3%], respectively; p = 1.0) between the rivaroxaban and warfarin groups in the first 30 days. Conclusions Uninterrupted rivaroxaban therapy appears to be as safe and efficacious in preventing bleeding and thromboembolic events in patients undergoing AF ablation as uninterrupted warfarin therapy. (C) 2014 by the American College of Cardiology Foundation C1 [Lakkireddy, Dhanunjaya; Reddy, Yeruva Madhu; Vallakati, Ajay; Atkins, Donita; Bommana, Sudharani] Univ Kansas Hosp & Med Ctr, Cardiovasc Res Inst, Div Cardiovasc Dis, Mid Amer Cardiol, Kansas City, KS USA. Texas Cardiac Arrhythmia Inst, Austin, TX USA. [Di Biase, Luigi] Univ Foggia, Dept Cardiol, Foggia, Italy. [Di Biase, Luigi; Natale, Andrea] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Mansour, Moussa C.; Chalhoub, Fadi; Ruskin, Jeremy] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gangireddy, Sandeep; Reddy, Vivek] Mt Sinai Med Ctr, New York, NY 10029 USA. [Swarup, Vijay] Arizona Heart Rhythm Ctr, Phoenix, AZ USA. [Verma, Atul] Southlake Reg Med Ctr, Toronto, ON, Canada. [Baheiry, Salwa] Calif Pacific Med Ctr, San Francisco, CA USA. [Barrett, Conor D.] St Lukes Roosevelt Hosp, New York, NY 10025 USA. RP Lakkireddy, D (reprint author), Univ Kansas, Cardiovasc Res Inst, 3901 Rainbow Blvd,MS 4023, Kansas City, KS 66160 USA. EM dlakkireddy@kumc.edu FU consultant with Biosense Webster; Bristol-Myers Squibb; Boston Scientific; Medtronic; Pfizer; Sanofi-Aventis; St. Jude Medical; Advanced Medical Education FX From the *Division of Cardiovascular Diseases, Cardiovascular Research Institute, Mid America Cardiology, University of Kansas Hospital & Medical Center, Kansas City, Kansas; |Texas Cardiac Arrhythmia Institute, Austin, Texas; double dagger Department of Cardiology, University of Foggia, Foggia, Italy; Department of Biomedical Engineering, University of Texas, Austin, Texas; parallel to Massachusetts General Hospital, Boston, Massachusetts; Mount Sinai Medical Center, New York, New York; #Arizona Heart Rhythm Center, Phoenix, Arizona; **Southlake Regional Medical Center, Toronto, Ontario, Canada; dagger dagger California Pacific Medical Center, San Francisco, California; and the double dagger double dagger St. Lukes Roosevelt Hospital, New York, New York. Dr. Lakkireddy has received speaker honoraria from St. JudeMedical, Boehringer Ingelheim, Jansen, and Bristol Meyers Squibb. Dr. Di Biase is a consultant for Hansen Medical, St. JudeMedical, and Biosense Webster. Dr. Mansour received research grants from Biosense Webster, St. Jude Medical, Boston Scientific, and MC 10. Dr. Swarup has a research relationship with Biosense Webster, St. Jude Medical, Boston Scientific, Medtronic, and Biotronik. Dr. Verma serves on the advisory boards of Bayer, Boehringer Ingelheim, and Pfizer. Dr. Sanchez has received speaker fees from Janssen. Dr. Burkhardt is a speaker for Boehringer Ingelheim and a consultant with Biosense Webster. Dr. Ruskin has received fellowship grants and/or is a consultant with Biosense Webster, Bristol-Myers Squibb, Boston Scientific, Medtronic, Pfizer, Sanofi-Aventis, St. Jude Medical, and Advanced Medical Education. Dr. Natale is a consultant with Medtronic, BiosenseWebster, Boston Scientific, St. Jude Medical, and Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Lakkireddy and Reddy contributed equally and are primary coauthors of the manuscript. NR 38 TC 79 Z9 83 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 18 PY 2014 VL 63 IS 10 BP 982 EP 988 DI 10.1016/j.jacc.2013.11.039 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AC4ZG UT WOS:000332529400007 PM 24412445 ER PT J AU Hawkins, BM McCoy, LA Neely, ML Adusumalli, S Messenger, JC Drachman, DE Bass, TA O'Gara, PT Rao, SV Yeh, RW AF Hawkins, Beau M. McCoy, Lisa A. Neely, Megan L. Adusumalli, Srinath Messenger, John C. Drachman, Douglas E. Bass, Theodore A. O'Gara, Patrick T. Rao, Sunil V. Yeh, Robert W. TI Impact of Academic Year Timing on Percutaneous Coronary Intervention Outcomes at Training Institutions SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter C1 [Yeh, Robert W.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Hawkins, Beau M.] Univ Oklahoma, Hlth Sci Ctr, Dept Internal Med, Cardiovasc Sect, Oklahoma City, OK USA. [McCoy, Lisa A.; Neely, Megan L.; Rao, Sunil V.] Duke Clin Res Inst, Durham, NC USA. [Adusumalli, Srinath; Drachman, Douglas E.; Yeh, Robert W.] Massachusetts Gen Hosp, Div Cardiol, Dept Internal Med, Boston, MA 02114 USA. [Messenger, John C.] Univ Colorado Hosp Denver, Dept Med, Aurora, CO USA. [Messenger, John C.] Hlth Sci Ctr, Aurora, CO USA. [Bass, Theodore A.] Univ Florida, Coll Med Jacksonville, Jacksonville, FL USA. [O'Gara, Patrick T.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. RP Yeh, RW (reprint author), Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St GRB 800, Boston, MA 02114 USA. EM ryeh@partners.org NR 6 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 18 PY 2014 VL 63 IS 10 BP 1025 EP 1026 DI 10.1016/j.jacc.2013.11.019 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AC4ZG UT WOS:000332529400016 PM 24333492 ER PT J AU Preti, MG Makris, N Papadimitriou, G Lagana, MM Griffanti, L Clerici, M Nemni, R Westin, CF Baselli, G Baglio, F AF Preti, Maria Giulia Makris, Nikos Papadimitriou, George Lagana, Maria Marcella Griffanti, Ludovica Clerici, Mario Nemni, Raffaello Westin, Carl-Fredrik Baselli, Giuseppe Baglio, Francesca TI A Novel Approach of Groupwise fMRI-Guided Tractography Allowing to Characterize the Clinical Evolution of Alzheimer's Disease SO PLOS ONE LA English DT Article ID MILD COGNITIVE IMPAIRMENT; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; BRAIN ACTIVATION; DIFFUSION; DTI; RECOMMENDATIONS; DISCONNECTION; DEMENTIA AB Guiding diffusion tract-based anatomy by functional magnetic resonance imaging (fMRI), we aim to investigate the relationship between structural connectivity and functional activity in the human brain. To this purpose, we introduced a novel groupwise fMRI-guided tractographic approach, that was applied on a population ranging between prodromic and moderate stages of Alzheimer's disease (AD). The study comprised of 15 subjects affected by amnestic mild cognitive impairment (aMCI), 14 diagnosed with AD and 14 elderly healthy adults who were used as controls. By creating representative (ensemble) functionally guided tracts within each group of participants, our methodology highlighted the white matter fiber connections involved in verbal fluency functions for a specific population, and hypothesized on brain compensation mechanisms that potentially counteract or reduce cognitive impairment symptoms in prodromic AD. Our hope is that this fMRI-guided tractographic approach could have potential impact in various clinical studies, while investigating white/gray matter connectivity, in both health and disease. C1 [Preti, Maria Giulia; Lagana, Maria Marcella; Griffanti, Ludovica; Clerici, Mario; Nemni, Raffaello; Baglio, Francesca] Fdn Don Carlo Gnocchi ONLUS, IRCCS, Milan, Italy. [Preti, Maria Giulia; Griffanti, Ludovica; Baselli, Giuseppe] Politecn Milan, Dept Elect Informat & Bioengn, I-20133 Milan, Italy. [Makris, Nikos; Papadimitriou, George] Harvard Univ, Sch Med, Dept Psychiat,Massachusetts Gen Hosp, Ctr Neural Syst Invest,Ctr Morphometr Anal,Athino, Boston, MA 02115 USA. [Makris, Nikos; Papadimitriou, George] Harvard Univ, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Neur, Ctr Neural Syst Invest,Ctr Morphometr Anal,Sch Me, Boston, MA USA. [Makris, Nikos] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat,Psychiat Neuroimaging Lab, Boston, MA 02115 USA. [Makris, Nikos] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Clerici, Mario; Nemni, Raffaello] Univ Milan, Dept Pathophysiol & Transplantat, Milan, Italy. [Westin, Carl-Fredrik] Brigham & Womens Hosp, Dept Radiol, Lab Math Imaging, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Preti, MG (reprint author), Fdn Don Carlo Gnocchi ONLUS, IRCCS, Milan, Italy. EM gpreti@dongnocchi.it RI Baglio, Francesca/K-2808-2016; OI Baglio, Francesca/0000-0002-6145-5274; Clerici, Mario/0000-0001-5920-6191; Griffanti, Ludovica/0000-0002-0540-9353 FU Ricerca Corrente; Italian Ministry of Health; National Institutes of Health (NIH) [R01MH074794, P41EB015902, R01AG042512, R01DA027804, R21NS079905, R21NS077059] FX The study was supported by 2011-2012 Ricerca Corrente, Italian Ministry of Health (http://www.salute.gov.it/portale/temi/p2_5. jsp?lingua = italiano&area = Ricerca%20sanita ria&menu = corrente), National Institutes of Health (NIH) R01MH074794, NIH P41EB015902, NIH R01AG042512, NIH R01DA027804, NIH R21NS079905 and NIH R21NS077059. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 4 Z9 4 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 17 PY 2014 VL 9 IS 3 AR e92026 DI 10.1371/journal.pone.0092026 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AD4XD UT WOS:000333254100102 PM 24637718 ER PT J AU Gutierrez, A Roderick, JE Kelliher, MA AF Gutierrez, Alejandro Roderick, Justine E. Kelliher, Michelle A. TI Leukemia Propagating Cells Akt Up SO CANCER CELL LA English DT Editorial Material ID ACUTE LYMPHOBLASTIC-LEUKEMIA; GLUCOCORTICOID RESISTANCE; INITIATING CELLS C1 [Gutierrez, Alejandro] Boston Childrens Hosp, Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. [Gutierrez, Alejandro] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Roderick, Justine E.; Kelliher, Michelle A.] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. RP Gutierrez, A (reprint author), Boston Childrens Hosp, Dana Farber Canc Inst, Div Hematol Oncol, Boston, MA 02115 USA. EM alejandro.gutierrez@childrens.harvard.edu; michelle.kelliher@umassmed.edu FU NCI NIH HHS [R01 CA096899] NR 11 TC 2 Z9 2 U1 0 U2 1 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 17 PY 2014 VL 25 IS 3 BP 263 EP 265 DI 10.1016/j.ccr.2014.02.022 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AD4PQ UT WOS:000333233400003 PM 24651006 ER PT J AU Arteaga, CL Engelman, JA AF Arteaga, Carlos L. Engelman, Jeffrey A. TI ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics SO CANCER CELL LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; CELL LUNG-CANCER; METASTATIC BREAST-CANCER; TYROSINE KINASE INHIBITOR; GENE COPY NUMBER; PERTUZUMAB PLUS TRASTUZUMAB; POLARIZED EPITHELIAL-CELLS; MUTANT COLORECTAL CANCERS; FACTOR-I RECEPTOR; ACQUIRED-RESISTANCE AB ERBB receptors were linked to human cancer pathogenesis approximately three decades ago. Biomedical investigators have since developed substantial understanding of the biology underlying the dependence of cancers on aberrant ERBB receptor signaling. An array of cancer-associated genetic alterations in ERBB receptors has also been identified. These findings have led to the discovery and development of mechanism-based therapies targeting ERBB receptors that have improved outcome for many cancer patients. In this Perspective, we discuss current paradigms of targeting ERBB receptors with cancer therapeutics and our understanding of mechanisms of action and resistance to these drugs. As current strategies still have limitations, we also discuss challenges and opportunities that lie ahead as basic scientists and clinical investigators work toward more breakthroughs. C1 [Arteaga, Carlos L.] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Engelman, Jeffrey A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Arteaga, CL (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. EM carlos.arteaga@vanderbilt.edu; jengelman@mgh.harvard.edu RI Mendez, Pedro /J-8955-2016 OI Mendez, Pedro /0000-0001-6713-7907 FU NCI [R01 CA80195, R01 CA137008, R01 CA164273, R01 CA140954]; ACS Clinical Research Professorship Grant [CRP-07-234]; Breast Cancer SPORE grant [P50 CA98131]; GI Cancer SPORE grant [P50 CA127003]; Department of Defense; Vanderbilt-Ingram Cancer Center Support grant [P30 CA68485] FX This work was supported by NCI grants R01 CA80195 (C.L.A.), R01 CA137008 (J.A.E.), R01 CA164273 (J.A.E.), and R01 CA140954 (J.A.E.), ACS Clinical Research Professorship Grant CRP-07-234 (CIA.), Breast Cancer SPORE grant P50 CA98131, GI Cancer SPORE grant P50 CA127003, the Department of Defense (J.A.E.), and Vanderbilt-Ingram Cancer Center Support grant P30 CA68485. NR 219 TC 172 Z9 177 U1 8 U2 40 PU CELL PRESS PI CAMBRIDGE PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD MAR 17 PY 2014 VL 25 IS 3 BP 282 EP 303 DI 10.1016/j.ccr.2014.02.025 PG 22 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AD4PQ UT WOS:000333233400008 PM 24651011 ER PT J AU Blackburn, JS Liu, SL Wilder, JL Dobrinski, KP Lobbardi, R Moore, FE Martinez, SA Chen, EY Lee, C Langenau, DM AF Blackburn, Jessica S. Liu, Sali Wilder, Jayme L. Dobrinski, Kimberly P. Lobbardi, Riadh Moore, Finola E. Martinez, Sarah A. Chen, Eleanor Y. Lee, Charles Langenau, David M. TI Clonal Evolution Enhances Leukemia-Propagating Cell Frequency in T Cell Acute Lymphoblastic Leukemia through Akt/mTORC1 Pathway Activation SO CANCER CELL LA English DT Article ID GLUCOCORTICOID RESISTANCE; INHIBITOR NVP-BEZ235; INITIATING CELLS; CANCER MEDICINE; PTEN; MYC; HETEROGENEITY; ZEBRAFISH; RELAPSE; TRIAL AB Clonal evolution and intratumoral heterogeneity drive cancer progression through unknown molecular mechanisms. To address this issue, functional differences between single T cell acute lymphoblastic leukemia (T-ALL) clones were assessed using a zebrafish transgenic model. Functional variation was observed within individual clones, with a minority of clones enhancing growth rate and leukemia-propagating potential with time. Akt pathway activation was acquired in a subset of these evolved clones, which increased the number of leukemia-propagating cells through activating mTORC1, elevated growth rate likely by stabilizing the Myc protein, and rendered cells resistant to dexamethasone, which was reversed by combined treatment with an Akt inhibitor. Thus, T-ALL clones spontaneously and continuously evolve to drive leukemia progression even in the absence of therapy-induced selection. C1 [Blackburn, Jessica S.; Lobbardi, Riadh; Moore, Finola E.; Martinez, Sarah A.; Chen, Eleanor Y.; Langenau, David M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Blackburn, Jessica S.; Lobbardi, Riadh; Moore, Finola E.; Martinez, Sarah A.; Chen, Eleanor Y.; Langenau, David M.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Blackburn, Jessica S.; Wilder, Jayme L.; Lobbardi, Riadh; Moore, Finola E.; Chen, Eleanor Y.; Langenau, David M.] Harvard Stem Cell Inst, Boston, MA 02138 USA. [Liu, Sali] Northwestern Univ, Chicago, IL 60208 USA. [Dobrinski, Kimberly P.] Univ S Florida, Ctr Integrat Med, Tampa, FL 33620 USA. [Chen, Eleanor Y.] Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA. [Lee, Charles] Jackson Lab Genom Med, Farmington, CT 06030 USA. [Lee, Charles] Seoul Natl Univ, Sch Med, Dept Grad Studies, Seoul 110744, South Korea. RP Langenau, DM (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM dlangenau@mgh.harvard.edu FU Alex Lemonade Stand Foundation; Leukemia and Lymphoma Society; Massachusetts General Hospital Toteson Fund for Medical Discovery Postdoctoral Fellowship; National Institutes of Health (NIH) [1K99CA181500-01]; NIH [F32DK098875, R01-GM081533, U01-HG005725]; American Cancer Society; Leukemia Research Foundation; Harvard Stem Cell Institute; MGH Goodman Fellowship FX We thank Dr. Ravi Mylvaganam for expert advice and assistance with FAGS and Eric Stone and Marcellino Pena for excellent zebrafish husbandry. We thank Dr. Alejandro Gutierrez and Dr. Hui Feng for reagents and technical advice and Dr. Donna Neuberg for assistance with statistical analyses. J.S.B. is supported by the Alex Lemonade Stand Foundation Young Investigator Award, the Leukemia and Lymphoma Society Special Fellow Award, the Massachusetts General Hospital Toteson Fund for Medical Discovery Postdoctoral Fellowship, and National Institutes of Health (NIH) grant 1K99CA181500-01. F.E.M. is supported by NIH grant F32DK098875. C.L. received support from NIH grants R01-GM081533 and U01-HG005725. D.M.L. received funding for this project from the American Cancer Society, the Leukemia Research Foundation, the Harvard Stem Cell Institute, the MGH Goodman Fellowship, and the Alex Lemonade Stand Foundation Innovation Grant. NR 41 TC 26 Z9 29 U1 2 U2 14 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 17 PY 2014 VL 25 IS 3 BP 366 EP 378 DI 10.1016/j.ccr.2014.01.032 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AD4PQ UT WOS:000333233400013 PM 24613413 ER PT J AU Kool, M Jones, DTW Jager, N Northcott, PA Pugh, TJ Hovestadt, V Piro, RM Esparza, LA Markant, SL Remke, M Milde, T Bourdeaut, F Ryzhova, M Sturm, D Pfaff, E Stark, S Hutter, S Seker-Cin, H Johann, P Bender, S Schmidt, C Rausch, T Shih, D Reimand, J Sieber, L Wittmann, A Linke, L Witt, H Weber, UD Zapatka, M Konig, R Beroukhim, R Bergthold, G van Sluis, P Volckmann, R Koster, J Versteeg, R Schmidt, S Wolf, S Lawerenz, C Bartholomae, CC von Kalle, C Unterberg, A Herold-Mende, C Hofer, S Kulozik, AE von Deimling, A Scheurlen, W Felsberg, J Reifenberger, G Hasselblatt, M Crawford, JR Grant, GA Jabado, N Perry, A Cowdrey, C Croul, S Zadeh, G Korbel, JO Doz, F Delattre, O Bader, GD McCabe, MG Collins, VP Kieran, MW Cho, YJ Pomeroy, SL Witt, O Brors, B Taylor, MD Schuller, U Korshunov, A Eils, R Wechsler-Reya, RJ Lichter, P Pfister, SM AF Kool, Marcel Jones, David T. W. Jaeger, Natalie Northcott, Paul A. Pugh, Trevor J. Hovestadt, Volker Piro, Rosario M. Esparza, L. Adriana Markant, Shirley L. Remke, Marc Milde, Till Bourdeaut, Franck Ryzhova, Marina Sturm, Dominik Pfaff, Elke Stark, Sebastian Hutter, Sonja Seker-Cin, Huriye Johann, Pascal Bender, Sebastian Schmidt, Christin Rausch, Tobias Shih, David Reimand, Jueri Sieber, Laura Wittmann, Andrea Linke, Linda Witt, Hendrik Weber, Ursula D. Zapatka, Marc Koenig, Rainer Beroukhim, Rameen Bergthold, Guillaume van Sluis, Peter Volckmann, Richard Koster, Jan Versteeg, Rogier Schmidt, Sabine Wolf, Stephan Lawerenz, Chris Bartholomae, Cynthia C. von Kalle, Christof Unterberg, Andreas Herold-Mende, Christel Hofer, Silvia Kulozik, Andreas E. von Deimling, Andreas Scheurlen, Wolfram Felsberg, Joerg Reifenberger, Guido Hasselblatt, Martin Crawford, John R. Grant, Gerald A. Jabado, Nada Perry, Arie Cowdrey, Cynthia Croul, Sydney Zadeh, Gelareh Korbel, Jan O. Doz, Francois Delattre, Olivier Bader, Gary D. McCabe, Martin G. Collins, V. Peter Kieran, Mark W. Cho, Yoon-Jae Pomeroy, Scott L. Witt, Olaf Brors, Benedikt Taylor, Michael D. Schueller, Ulrich Korshunov, Andrey Eils, Roland Wechsler-Reya, Robert J. Lichter, Peter Pfister, Stefan M. CA ICGC PedBrain Tumor Project TI Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition SO CANCER CELL LA English DT Article ID TERT PROMOTER MUTATIONS; HEDGEHOG PATHWAY INHIBITOR; PEDIATRIC MEDULLOBLASTOMA; NERVOUS-SYSTEM; MOUSE MODELS; CANCER; GROWTH; TUMORS; ADULT; ITRACONAZOLE AB Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the gernnline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant. C1 [Kool, Marcel; Jones, David T. W.; Northcott, Paul A.; Sturm, Dominik; Pfaff, Elke; Stark, Sebastian; Hutter, Sonja; Seker-Cin, Huriye; Johann, Pascal; Bender, Sebastian; Schmidt, Christin; Sieber, Laura; Wittmann, Andrea; Linke, Linda; Witt, Hendrik; Korshunov, Andrey; Pfister, Stefan M.] German Canc Res Ctr, Div Pediat Neurooncol, D-69121 Heidelberg, Germany. [Jaeger, Natalie; Piro, Rosario M.; Koenig, Rainer; Brors, Benedikt; Eils, Roland] German Canc Res Ctr, Div Theoret Bioinformat, D-69121 Heidelberg, Germany. [Pugh, Trevor J.; Beroukhim, Rameen; Bergthold, Guillaume] Broad Inst MIT & Harvard, Cambridge, MA 02141 USA. [Hovestadt, Volker; Weber, Ursula D.; Zapatka, Marc; Lichter, Peter] German Canc Res Ctr, Div Mol Genet, D-69121 Heidelberg, Germany. [Esparza, L. Adriana; Markant, Shirley L.; Wechsler-Reya, Robert J.] Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA. [Remke, Marc; Shih, David; Taylor, Michael D.] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1L7, Canada. [Milde, Till; Witt, Hendrik; Kulozik, Andreas E.; Pfister, Stefan M.] Univ Heidelberg Hosp, Dept Pediat Oncol Hematol & Immunol, D-69120 Heidelberg, Germany. [Bourdeaut, Franck; Doz, Francois; Delattre, Olivier] Inst Curie, F-75005 Paris, France. [Bourdeaut, Franck; Delattre, Olivier] Inst Curie, INSERM, U830, F-75248 Paris, France. [Ryzhova, Marina] NN Burdenko Inst Neurosurg, Dept Neuropathol, Moscow 125047, Russia. [Rausch, Tobias; Korbel, Jan O.] EMBL, D-69117 Heidelberg, Germany. [Reimand, Jueri; Bader, Gary D.] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. [Koenig, Rainer] Jena Univ Hosp, Ctr Sepsis Control & Care, Integrated Res & Treatment Ctr, D-07747 Jena, Germany. [Koenig, Rainer] HKI, Leibniz Inst Nat Prod Res & Infect Biol, D-07745 Jena, Germany. [Beroukhim, Rameen; Bergthold, Guillaume] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Beroukhim, Rameen] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Beroukhim, Rameen; Pomeroy, Scott L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Bergthold, Guillaume] Univ Paris 11, Gustave Roussy Canc Inst, CNRS Vectorol & Anticanc Therapeut, UMR 8203, F-94805 Villejuif, France. [van Sluis, Peter; Volckmann, Richard; Koster, Jan; Versteeg, Rogier] Univ Amsterdam, Acad Med Ctr, Dept Oncogen, NL-1105 AZ Amsterdam, Netherlands. [Schmidt, Sabine; Wolf, Stephan] German Canc Res Ctr, Genom & Prote Core Facil, D-69121 Heidelberg, Germany. [Lawerenz, Chris] German Canc Res Ctr, Data Management Facil, D-69121 Heidelberg, Germany. [Bartholomae, Cynthia C.; von Kalle, Christof; Unterberg, Andreas; Herold-Mende, Christel] German Canc Res Ctr, Div Translat Oncol, D-69121 Heidelberg, Germany. [Bartholomae, Cynthia C.; von Kalle, Christof; Unterberg, Andreas; Herold-Mende, Christel] Natl Ctr Tumor Dis NCT, D-69121 Heidelberg, Germany. [Hofer, Silvia] Univ Zurich Hosp, Dept Oncol, CH-8006 Zurich, Switzerland. [von Deimling, Andreas; Korshunov, Andrey] Heidelberg Univ, Dept Neuropathol, D-69120 Heidelberg, Germany. [von Deimling, Andreas; Korshunov, Andrey] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, D-69121 Heidelberg, Germany. [Scheurlen, Wolfram] Nurnberg Childrens Hosp, Cnopfsche Kinderklin, D-90419 Nurnberg, Germany. [Felsberg, Joerg; Reifenberger, Guido] Univ Dusseldorf, Dept Neuropathol, D-40225 Dusseldorf, Germany. [Hasselblatt, Martin] Univ Hosp Munster, Inst Neuropathol, D-48149 Munster, Germany. [Crawford, John R.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Crawford, John R.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Crawford, John R.] Rady Childrens Hosp, San Diego, CA 92123 USA. [Grant, Gerald A.] Duke Univ, Med Ctr, Dept Pediat, Div Pediat Hematol Oncol, Durham, NC 27710 USA. [Grant, Gerald A.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Jabado, Nada] McGill Univ, Dept Pediat & Human Genet, Montreal, PQ H3H 1P3, Canada. [Perry, Arie; Cowdrey, Cynthia] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Perry, Arie] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Cowdrey, Cynthia] Univ Calif San Francisco, Dept Neurol Surg, Brain Tumor Res Ctr, San Francisco, CA 94143 USA. [Croul, Sydney; Zadeh, Gelareh] Arthur & Sonia Labatt Brain Tumour Res Ctr, Dept Neuropathol, Toronto, ON M5G 1L7, Canada. [Doz, Francois] Univ Paris 05, F-75006 Paris, France. [McCabe, Martin G.] Manchester Acad Hlth Sci Ctr, Manchester M13 9NT, Lancs, England. [Collins, V. Peter] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Kieran, Mark W.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Kieran, Mark W.; Pomeroy, Scott L.] Boston Childrens Hosp, Boston, MA 02215 USA. [Cho, Yoon-Jae] Stanford Univ, Sch Med, Dept Neurol & Neurosurg, Stanford, CA 94305 USA. [Witt, Olaf] German Canc Res Ctr, CCU Pediat Oncol, D-69121 Heidelberg, Germany. [Schueller, Ulrich] Univ Munich, Ctr Neuropathol & Prion Res, D-81377 Munich, Germany. RP Kool, M (reprint author), German Canc Res Ctr, Div Pediat Neurooncol, D-69121 Heidelberg, Germany. EM m.kool@dkfz.de RI Korbel, Jan/G-6470-2012; Pfister, Stefan/F-6860-2013; Brors, Benedikt/E-5620-2013; Kool, Marcel/H-2541-2013; Shih, David/H-3186-2011; von Deimling, Andreas/F-7774-2013; Milde, Till/L-7755-2015; Witt, Hendrik/L-7810-2015; McCabe, Martin/P-5896-2015; Eils, Roland/B-6121-2009 OI Piro, Rosario/0000-0002-3066-7397; Kieran, Mark/0000-0003-2184-7692; Remke, Marc/0000-0002-9404-9993; Sturm, Dominik/0000-0003-0250-1696; Hovestadt, Volker/0000-0002-3480-6649; Hasselblatt, Martin/0000-0003-2707-8484; Rausch, Tobias/0000-0001-5773-5620; Korbel, Jan/0000-0002-2798-3794; Pfister, Stefan/0000-0002-5447-5322; Jaeger, Natalie/0000-0002-9589-7580; Brors, Benedikt/0000-0001-5940-3101; Shih, David/0000-0002-9802-4937; von Deimling, Andreas/0000-0002-5863-540X; McCabe, Martin/0000-0002-5138-0707; Eils, Roland/0000-0002-0034-4036 FU PedBrain Tumor Project; German Cancer Aid [109252]; German Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung) [01KU1201A, MedSys 0315416C, NGFNplus 01GS0883]; Dutch Cancer Foundations KWF [2010-4713]; KIKA; Brain Tumor Charity; Roche; Novartis FX For technical support and expertise, we thank the people from the DKFZ Genomics and Proteomics Core Facility, Malaika Knopf from the NCT Heidelberg, and GATC Biotech AG for sequencing services. This work was principally supported by the PedBrain Tumor Project (http://www.pedbraintumor.org) contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung, grant numbers 01KU1201A, MedSys 0315416C, and NGFNplus 01GS0883). Additional support came from the Dutch Cancer Foundations KWF (2010-4713) and KIKA (to M.K.), and the Brain Tumor Charity (to V.P.C.). G.R. received a research grant from Roche and honoraria for advisory boards from Merck Serono and Roche. R.B. and O.W. are consultants for and received grant funding from Novartis. NR 45 TC 134 Z9 138 U1 4 U2 43 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 17 PY 2014 VL 25 IS 3 BP 393 EP 405 DI 10.1016/j.ccr.2014.02.004 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AD4PQ UT WOS:000333233400015 PM 24651015 ER PT J AU Caravan, P AF Caravan, Peter TI Does anybody really know what (correlation) time it is? Designing Gd(III) complexes for high field, high relaxivity applications SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 247th National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 16-20, 2014 CL Dallas, TX SP Amer Chem Soc C1 [Caravan, Peter] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Caravan, Peter] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02129 USA. EM caravan@nmr.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 16 PY 2014 VL 247 MA 427-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA AZ8HZ UT WOS:000348457601511 ER PT J AU Chen, LJ Yap, JL Gallagher, C Walensky, LD Fletcher, S AF Chen, Lijia Yap, Jeremy L. Gallagher, Catherine Walensky, Loren D. Fletcher, Steven TI Towards novel anti-cancer agents: Tetrahydroquinoline-based small-molecules as selective Mcl-1 inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 247th National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 16-20, 2014 CL Dallas, TX SP Amer Chem Soc C1 [Chen, Lijia; Yap, Jeremy L.; Fletcher, Steven] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Gallagher, Catherine; Walensky, Loren D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Gallagher, Catherine; Walensky, Loren D.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA 02215 USA. EM lijiachen@umaryland.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 16 PY 2014 VL 247 MA 326-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA AZ8HZ UT WOS:000348457602480 ER PT J AU Iki, N Boros, E Nakamura, M Shinoda, K Caravan, P AF Iki, Nobuhiko Boros, Eszter Nakamura, Mami Shinoda, Kozo Caravan, Peter TI Can Gd(3)TCAS(2) be a new motif of contrast agent for MRI? Unexpected slow water exchange arising from the tri-Gd-III cluster sandwiched by two TCAS ligands (TCAS = thiacalix[4]arene-p-tetrasulfonate) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 247th National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 16-20, 2014 CL Dallas, TX SP Amer Chem Soc C1 [Iki, Nobuhiko; Nakamura, Mami] Tohoku Univ, Grad Sch Environm Studies, Sendai, Miyagi 9808579, Japan. [Boros, Eszter] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging,Med Sch, Boston, MA 02129 USA. [Shinoda, Kozo] Tohoku Univ, Inst Multidisciplinary Res Adv Mat, Sendai, Miyagi 9808577, Japan. EM iki@m.tohoku.ac.jp NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 16 PY 2014 VL 247 MA 559-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA AZ8HZ UT WOS:000348457601639 ER PT J AU Moore, A AF Moore, Anna TI Iron oxide nanoparticles as theranostic agents for siRNA nad microRNA therapies in cancer SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 247th National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 16-20, 2014 CL Dallas, TX SP Amer Chem Soc C1 [Moore, Anna] Massachusetts Gen Hosp, Dept Radiol, Charestown, MA 02129 USA. EM amoore@helix.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 16 PY 2014 VL 247 MA 812-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA AZ8HZ UT WOS:000348457601874 ER PT J AU Pagel, MD Yoo, B Hingorani, DV Daryaei, I Akhenblit, PJ AF Pagel, Marty D. Yoo, Byunghee Hingorani, Dina V. Daryaei, Iman Akhenblit, Paul J. TI CatalyCEST MRI contrast agents that detect enzyme activities SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 247th National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 16-20, 2014 CL Dallas, TX SP Amer Chem Soc C1 [Pagel, Marty D.; Hingorani, Dina V.; Daryaei, Iman] Univ Arizona, Tucson, AZ 85719 USA. [Pagel, Marty D.] Univ Arizona, Tucson, AZ 85724 USA. [Pagel, Marty D.; Akhenblit, Paul J.] Univ Arizona, Ctr Canc, Tucson, AZ 85724 USA. [Yoo, Byunghee] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Yoo, Byunghee] Harvard Univ, Sch Med, Boston, MA 02129 USA. EM mpagel@u.arizona.edu NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 16 PY 2014 VL 247 MA 740-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA AZ8HZ UT WOS:000348457601806 ER PT J AU Yap, JL Chauhan, J Chen, LJ Gallagher, C Walensky, LD Fletcher, S AF Yap, Jeremy L. Chauhan, Jay Chen, Lijia Gallagher, Catherine Walensky, Loren D. Fletcher, Steven TI Design, synthesis, and biological evaluation of 1-hydroxy-2-carboxy-substituted arenes as selective inhibitors of the Mcl-1 oncoprotein SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 247th National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 16-20, 2014 CL Dallas, TX SP Amer Chem Soc C1 [Yap, Jeremy L.; Chauhan, Jay; Chen, Lijia; Fletcher, Steven] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. [Gallagher, Catherine; Walensky, Loren D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. EM jyap001@umaryland.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 16 PY 2014 VL 247 MA 329-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA AZ8HZ UT WOS:000348457602483 ER PT J AU Zhu, J Caravan, P AF Zhu, Jiang Caravan, Peter TI Hexameric Mn(II)-EDTA complex as MRI contrast agent SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 247th National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 16-20, 2014 CL Dallas, TX SP Amer Chem Soc C1 [Zhu, Jiang; Caravan, Peter] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Zhu, Jiang] North Sichuan Med Coll, Sichuan Key Lab Med Imaging, Nanchong 637000, Sichuan, Peoples R China. EM jiangz@nmr.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 16 PY 2014 VL 247 MA 576-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA AZ8HZ UT WOS:000348457601656 ER PT J AU Bigman, CA AF Bigman, Cabral A. TI Social Comparison Framing in Health News and Its Effect on Perceptions of Group Risk SO HEALTH COMMUNICATION LA English DT Article ID AFRICAN-AMERICAN COMMUNITIES; MEDICAL DECISION-MAKING; COMPARISON INFORMATION; STD DISPARITIES; GROUP CUES; COMMUNICATION; COVERAGE; INEQUALITIES; NEWSPAPERS; JUDGMENTS AB News about health disparities often compares health risks faced by different demographic groups. Does this social comparison produce a contrast effect? It was hypothesized that when two racial groups are compared, people would perceive the relatively more at-risk group to be more, and the less at-risk group to be less, at-risk than if the same risk information was presented without the comparative reference group. Three experiments with Black and White respondents tested effects of intergroup social comparison framing (SCF) on perceptions of risk for sexually transmitted infections and skin cancer. SCF (including one White and two Black disparity frames) did not raise respondents' perceived risk regarding the more at-risk racial group, but consistently lowered respondents' risk ratings for the less at-risk racial group. The finding that the same statistic was perceived differently in comparative and noncomparative contexts underscores the importance of considering effects of communication about disparities. C1 [Bigman, Cabral A.] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Cambridge, MA 02138 USA. RP Bigman, CA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,LW 601, Boston, MA 02215 USA. EM Cabral_Bigman-Galimore@dfci.harvard.edu FU NCI NIH HHS [P20 CA095856, 5P20CA095856] NR 61 TC 1 Z9 1 U1 2 U2 8 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1041-0236 EI 1532-7027 J9 HEALTH COMMUN JI Health Commun. PD MAR 16 PY 2014 VL 29 IS 3 BP 267 EP 280 DI 10.1080/10410236.2012.745043 PG 14 WC Communication; Health Policy & Services SC Communication; Health Care Sciences & Services GA AH2DT UT WOS:000335931600005 PM 23829419 ER PT J AU Tseng, YD Paciorek, AT Martin, NE D'Amico, AV Cooperberg, MR Nguyen, PL AF Tseng, Yolanda D. Paciorek, Alan T. Martin, Neil E. D'Amico, Anthony V. Cooperberg, Matthew R. Nguyen, Paul L. TI Impact of National Guidelines on Brachytherapy Monotherapy Practice Patterns for Prostate Cancer SO CANCER LA English DT Article DE brachytherapy; prostate cancer; guidelines; public health policy; radiotherapy ID PERMANENT INTERSTITIAL BRACHYTHERAPY; CLINICAL-PRACTICE GUIDELINES; BEAM RADIATION-THERAPY; UNITED-STATES; AMERICAN BRACHYTHERAPY; RADICAL PROSTATECTOMY; RADIOTHERAPY; EXPERIENCE; MANAGEMENT; CARCINOMA AB BACKGROUNDIn 1999 and 2000, 2 national guidelines recommended brachytherapy monotherapy (BT) primarily for treatment of low-risk prostate cancer but not high-risk prostate cancer. This study examined rates of BT use before and after publication of these guidelines, as compared with 4 other treatment options. METHODSFrom 1990 to 2011, 8128 men with localized prostate cancer ( T3cN0M0) were treated definitively within the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry with 1 of 5 primary treatments: BT, external beam radiotherapy (EBRT), EBRT with androgen deprivation therapy, EBRT+BT, or radical prostatectomy. Men were categorized into low-, intermediate-, and high-risk groups based on the guidelines' risk-group definitions. Within each risk group, logistic regression was used to estimate odds ratios (OR) comparing BT with other treatment options between the 1990-1998 and 1999-2011 periods, adjusting for age, disease characteristics, and clinic type. RESULTSIn total, 1117 men received BT alone for low- (n=658), intermediate- (n=244), or high-risk disease (n=215). BT comprised 6.1% of all treatments in 1990-1998 versus 16.6% in 1999-2011 (P<.01). The odds of BT use remained increased after adjusting for potential confounders (OR=3.06; P<.001) and was seen among low- (OR=4.52; P<.001), intermediate- (OR=2.67; P<.001), and even high-risk groups (OR=2.11; P<.001). CONCLUSIONSNational guidelines did not appear to influence practice patterns, as BT monotherapy use increased relative to other treatments from the 1990-1998 to 1999-2011 periods in unfavorable risk groups including men with high-risk prostate cancer. Cancer 2014;120:824-832. (c) 2013 American Cancer Society. Brachytherapy monotherapy for treatment of localized prostate cancer increased from 1990 through 1998 to 1999 through 2011 among low-, intermediate-, and high-risk patients. This was seen relative to external beam radiotherapy and radical prostatectomy. C1 [Tseng, Yolanda D.] Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Paciorek, Alan T.; Cooperberg, Matthew R.] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA. [Martin, Neil E.; D'Amico, Anthony V.; Nguyen, Paul L.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Martin, Neil E.; D'Amico, Anthony V.; Nguyen, Paul L.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Tseng, YD (reprint author), Harvard Radiat Oncol Program, 75 Francis St,ASB L2, Boston, MA 02115 USA. EM ydtseng@partners.org RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 FU Prostate Cancer Foundation; Fitz's Cancer Warriors, David and Cynthia Chapin FX This work was funded by the Prostate Cancer Foundation, Fitz's Cancer Warriors, David and Cynthia Chapin, and a grant from an anonymous family foundation. NR 32 TC 0 Z9 0 U1 0 U2 1 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 2014 VL 120 IS 6 BP 824 EP 832 DI 10.1002/cncr.28492 PG 9 WC Oncology SC Oncology GA AB9UB UT WOS:000332140100010 PM 24301555 ER PT J AU Garrido, MM Prigerson, HG AF Garrido, Melissa M. Prigerson, Holly G. TI The End-of-Life Experience: Modifiable Predictors of Caregivers' Bereavement Adjustment SO CANCER LA English DT Article DE quality of life; end-of-life care; bereavement; depression; regrets ID MENTAL-HEALTH; FAMILY CAREGIVERS; PALLIATIVE CARE; ADVANCED CANCER; RISK-FACTORS; DEATH; DEPRESSION; QUESTIONNAIRE; ASSOCIATIONS; PREFERENCES AB BACKGROUNDThe objective of the current study was to determine the best set of predictors of psychological disorders, regrets, health-related quality of life, and mental health function among bereaved caregivers of patients with cancer, thereby identifying promising targets for interventions to improve bereavement adjustment. METHODSCoping with Cancer is a longitudinal study of patients with advanced cancer and their informal caregivers who were enrolled from 2002 to 2008. The main outcome measure was bereavement adjustment of 245 caregivers (eg, depression, anxiety, and regrets) 6 months after the loss of the patient. The Structured Clinical Interview of the Diagnostic and Statistical Manual of Mental Disorders determined whether caregivers met the criteria for major depressive disorder or an anxiety disorder. Changes in health-related quality of life and mental health function from baseline to after the patient's death were assessed with the Medical Outcomes Study Short Form (SF-36). RESULTSGreater than 50% of the caregivers reported regret about the cancer patient's end-of-life care; better patient quality of death (adjusted odds ratio, 0.77; 95% confidence interval, 0.67-0.88) reduced the risk of bereavement regret. The incidence of major depressive disorder or anxiety among the bereaved caregivers was 12.6% and was less likely for caregivers with better mental health before the loss of the patient (adjusted odds ratio, 0.03; 95% confidence interval, 0.004-0.25). Better patient quality of death also predicted improved caregiver health-related quality of life (adjusted standardized beta, .28; P<.001). The completion of a do-not-resuscitate order was found to be predictive of improved mental health from before the death of the patient to after the death (adjusted standardized beta, .29; P<.001). CONCLUSIONSReducing caregiver distress, encouraging advance care planning by patients, and improving patients' quality of death appear to be promising targets of interventions to improve caregiver bereavement adjustment. Cancer 2014;120:918-925. (c) 2013 American Cancer Society. Using prospective data from patients with advanced cancer and their primary informal caregivers, the results of the current study demonstrate that reducing caregiver distress, encouraging advance care planning by patients, and improving patients' quality of death appear to be promising targets of interventions to improve caregiver bereavement adjustment. C1 [Garrido, Melissa M.] James J Peters Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. [Garrido, Melissa M.] Icahn Sch Med Mt Sinai, Brookdale Dept Geriatr & Palliat Med, New York, NY USA. [Prigerson, Holly G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Psychosocial Epidemiol & Outcomes Res, Boston, MA 02115 USA. RP Prigerson, HG (reprint author), Dana Farber Canc Inst, Ctr Psychosocial Epidemiol & Outcomes Res, Dana 1134,450 Brookline Ave, Boston, MA 02215 USA. EM holly_prigerson@dfci.harvard.edu FU National Institute of Mental Health [MH63892]; National Cancer Institute [CA106370, CA156732]; Center for Psychosocial Epidemiology and Outcomes Research at the Dana-Farber Cancer Institute FX Supported in part by the following grants to Dr. Prigerson: MH63892 from the National Institute of Mental Health, CA106370 and CA156732 from the National Cancer Institute, and the Center for Psychosocial Epidemiology and Outcomes Research at the Dana-Farber Cancer Institute. NR 38 TC 19 Z9 19 U1 3 U2 17 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 2014 VL 120 IS 6 BP 918 EP 925 DI 10.1002/cncr.28495 PG 8 WC Oncology SC Oncology GA AB9UB UT WOS:000332140100021 PM 24301644 ER PT J AU Liu, LX Arany, Z AF Liu, Laura X. Arany, Zolt TI Maternal cardiac metabolism in pregnancy SO CARDIOVASCULAR RESEARCH LA English DT Review DE Pregnancy; Heart; Metabolism; Peripartum cardiomyopathy ID ACTIVATED PROTEIN-KINASE; ACUTE MYOCARDIAL-INFARCTION; TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; PROMOTES MITOCHONDRIAL BIOGENESIS; THORACIC ELECTRICAL BIOIMPEDANCE; LEFT-VENTRICULAR STRUCTURE; FATTY-ACID-METABOLISM; PERIPARTUM CARDIOMYOPATHY; DIASTOLIC FUNCTION; BLOOD-PRESSURE AB Pregnancy causes dramatic physiological changes in the expectant mother. The placenta, mostly foetal in origin, invades maternal uterine tissue early in pregnancy and unleashes a barrage of hormones and other factors. This foetal 'invasion' profoundly reprogrammes maternal physiology, affecting nearly every organ, including the heart and its metabolism. We briefly review here maternal systemic metabolic changes during pregnancy and cardiac metabolism in general. We then discuss changes in cardiac haemodynamic during pregnancy and review what is known about maternal cardiac metabolism during pregnancy. Lastly, we discuss cardiac diseases during pregnancy, including peripartum cardiomyopathy, and the potential contribution of aberrant cardiac metabolism to disease aetiology. C1 Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Arany, Z (reprint author), ECLS906 BIDMC,330 Brookline Ave, Boston, MA 02215 USA. EM zarany@bidmc.harvard.edu FU National Institute of Aging [F31AG041598]; NIH Heart, Lung, and Blood Institute; American Heart Association; Ellison Foundation FX L.L. is supported by the National Institute of Aging (F31AG041598) and Z.A. is supported by the NIH Heart, Lung, and Blood Institute, the American Heart Association, and the Ellison Foundation. NR 118 TC 19 Z9 20 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 EI 1755-3245 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR 15 PY 2014 VL 101 IS 4 BP 545 EP 553 DI 10.1093/cvr/cvu009 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AE6LL UT WOS:000334104300002 PM 24448314 ER PT J AU Selvarajah, S Pyne, S Chen, E Sompallae, R Ligon, AH Nielsen, GP Dranoff, G Stack, E Loda, M Flavin, R AF Selvarajah, Shamini Pyne, Saumyadipta Chen, Eleanor Sompallae, Ramakrishna Ligon, Azra H. Nielsen, Gunnlaugur P. Dranoff, Glenn Stack, Edward Loda, Massimo Flavin, Richard TI High-Resolution Array CGH and Gene Expression Profiling of Alveolar Soft Part Sarcoma SO CLINICAL CANCER RESEARCH LA English DT Article ID BREAST-CANCER; TRANSCRIPTION FACTOR; PROTEIN EXPRESSION; CELL; FUSION; ORIGIN; HYPERMETHYLATION; MYOD1; PAX6 AB Purpose: Alveolar soft part sarcoma (ASPS) is a soft tissue sarcoma with poor prognosis, and little molecular evidence exists for its origin, initiation, and progression. The aim of this study was to elucidate candidate molecular pathways involved in tumor pathogenesis. Experimental Design: We employed high-throughput array comparative genomic hybridization (aCGH) and cDNA-Mediated Annealing, Selection, Ligation, and Extension Assay to profile the genomic and expression signatures of primary and metastatic ASPS from 17 tumors derived from 11 patients. We used an integrative bioinformatics approach to elucidate the molecular pathways associated with ASPS progression. FISH was performed to validate the presence of the t(X;17)(p11.2;q25) ASPL-TFE3 fusion and, hence, confirm the aCGH observations. Results: FISH analysis identified the ASPL-TFE3 fusion in all cases. aCGH revealed a higher number of numerical aberrations in metastatic tumors relative to primaries, but failed to identify consistent alterations in either group. Gene expression analysis highlighted 1,063 genes that were differentially expressed between the two groups. Gene set enrichment analysis identified 16 enriched gene sets (P < 0.1) associated with differentially expressed genes. Notable among these were several stem cell gene expression signatures and pathways related to differentiation. In particular, the paired box transcription factor PAX6 was upregulated in the primary tumors, along with several genes whose mouse orthologs have previously been implicated in Pax6 DNA binding during neural stem cell differentiation. Conclusion: In addition to suggesting a tentative neural line of differentiation for ASPS, these results implicate transcriptional deregulation from fusion genes in the pathogenesis of ASPS. (C)2014 AACR. C1 [Selvarajah, Shamini; Chen, Eleanor; Ligon, Azra H.; Loda, Massimo; Flavin, Richard] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Selvarajah, Shamini; Pyne, Saumyadipta; Ligon, Azra H.; Dranoff, Glenn; Stack, Edward; Loda, Massimo; Flavin, Richard] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Nielsen, Gunnlaugur P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sompallae, Ramakrishna] Univ Iowa, Carver Coll Med, Iowa City, IA USA. [Flavin, Richard] St James Hosp, Dept Pathol, Dublin 8, Ireland. RP Flavin, R (reprint author), St James Hosp, Jamess St, Dublin 8, Ireland. EM flavinrichard@gmail.com FU iCureASPS; National Cancer Institute [RO1CA131945, PO1CA89021, P50 CA90381] FX Funding for this work was obtained from iCureASPS and a gift from Nuclea Biomarkers to the Jimmy Fund and the Loda laboratory. This work was also supported in part by the National Cancer Institute (RO1CA131945, PO1CA89021, and P50 CA90381) to M. Loda. NR 32 TC 8 Z9 9 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2014 VL 20 IS 6 BP 1521 EP 1530 DI 10.1158/1078-0432.CCR-13-2090 PG 10 WC Oncology SC Oncology GA AE2ON UT WOS:000333812700015 PM 24493828 ER PT J AU Garcia-Gomez, A Quwaider, D Canavese, M Ocio, EM Tian, Z Blanco, JF Berger, AJ Ortiz-de-Solorzano, C Hernandez-Iglesias, T Martens, ACM Groen, RWJ Mateo-Urdiales, J Fraile, S Galarraga, M Chauhan, D Miguel, JFS Raje, N Garayoa, M AF Garcia-Gomez, Antonio Quwaider, Dalia Canavese, Miriam Ocio, Enrique M. Tian, Ze Blanco, Juan F. Berger, Allison J. Ortiz-de-Solorzano, Carlos Hernandez-Iglesias, Teresa Martens, Anton C. M. Groen, Richard W. J. Mateo-Urdiales, Joaquin Fraile, Susana Galarraga, Miguel Chauhan, Dharminder San Miguel, Jesus F. Raje, Noopur Garayoa, Mercedes TI Preclinical Activity of the Oral Proteasome Inhibitor MLN9708 in Myeloma Bone Disease SO CLINICAL CANCER RESEARCH LA English DT Article ID MULTIPLE-MYELOMA; OSTEOBLAST DIFFERENTIATION; IN-VIVO; ANTITUMOR-ACTIVITY; BORTEZOMIB; CELLS; MODELS; WNT; OSTEOCLASTOGENESIS; BISPHOSPHONATES AB Purpose: MLN9708 (ixazomib citrate), which hydrolyzes to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity, but yet with an unknown effect on myeloma bone disease. Here, we investigated its bone anabolic and antiresorptive effects in the myeloma setting and in comparison with bortezomib in preclinical models. Experimental Design: The in vitro effect of MLN2238 was tested on osteoclasts and osteoclast precursors from healthy donors and patients with myeloma, and on osteoprogenitors derived from bone marrow mesenchymal stem cells also from both origins. We used an in vivo model of bone marrow-disseminated human myeloma to evaluate MLN2238 antimyeloma and bone activities. Results: Clinically achievable concentrations of MLN2238 markedly inhibited in vitro osteoclastogenesis and osteoclast resorption; these effects involved blockade of RANKL (receptor activator of NF-kB ligand)-induced NF-kB activation, F-actin ring disruption, and diminished expression of alpha V beta 3 integrin. A similar range of MLN2238 concentrations promoted in vitro osteoblastogenesis and osteoblast activity (even in osteoprogenitors from patients with myeloma), partly mediated by activation of TCF/beta-catenin signaling and upregulation of the IRE1 component of the unfolded protein response. In a mouse model of bone marrow-disseminated human multiple myeloma, orally administered MLN2238 was equally effective as bortezomib to control tumor burden and also provided a marked benefit in associated bone disease (sustained by both bone anabolic and anticatabolic activities). Conclusion: Given favorable data on pharmacologic properties and emerging clinical safety profile of MLN9708, it is conceivable that this proteasome inhibitor may achieve bone beneficial effects in addition to its antimyeloma activity in patients with myeloma. (C)2014 AACR. C1 [Garcia-Gomez, Antonio; Quwaider, Dalia; Ocio, Enrique M.; Hernandez-Iglesias, Teresa; Fraile, Susana; San Miguel, Jesus F.; Garayoa, Mercedes] Univ Salamanca, CSIC, IBMCC, Ctr Invest Canc, Salamanca 37007, Spain. [Garcia-Gomez, Antonio; San Miguel, Jesus F.; Garayoa, Mercedes] Ctr Red Med Regenerat & Terapia Celular Castilla, Salamanca, Spain. [Garcia-Gomez, Antonio; Ocio, Enrique M.; Blanco, Juan F.; San Miguel, Jesus F.; Garayoa, Mercedes] Hosp Univ Salamanca IBSAL, Salamanca, Spain. [Ortiz-de-Solorzano, Carlos; Mateo-Urdiales, Joaquin; Galarraga, Miguel] Univ Navarra, Lab Imagen Canc, Ctr Invest Med Aplicada, E-31080 Pamplona, Spain. [Canavese, Miriam; Raje, Noopur] Harvard Univ, Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA USA. [Tian, Ze; Chauhan, Dharminder] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Berger, Allison J.] Millennium Pharmaceut Inc, Cambridge, MA USA. [Martens, Anton C. M.; Groen, Richard W. J.] Univ Med Ctr Utrecht, Dept Cell Biol, Utrecht, Netherlands. [Martens, Anton C. M.] Univ Med Ctr Utrecht, Dept Immunol, Utrecht, Netherlands. RP Garcia-Gomez, A (reprint author), Univ Salamanca, CSIC, IBMCC, Ctr Invest Canc, Campus Miguel de Unamuno,Avda Univ Coimbra S-N, Salamanca 37007, Spain. EM agargo@usal.es RI Ortiz de Solorzano, Carlos/G-3278-2010; OI Ortiz de Solorzano, Carlos/0000-0001-8720-0205; SAN MIGUEL, JESUS/0000-0002-9183-4857; Groen, Richard/0000-0002-5010-4604 FU Spanish MICINN-ISCIII [PI081825, PI1202591]; Centro en Red of Regenerative Medicine and Cellular Therapy from Castilla and Leon; RTICC Hematology Program [RD12/0036/0058]; Spanish FIS [PS09/01897]; MINECO [DPI2012-38090-C03-02]; CIMA; Spanish Society of Hematology and Hemotherapy FX This work was supported by grants from the Spanish MICINN-ISCIII (PI081825; PI1202591), Centro en Red of Regenerative Medicine and Cellular Therapy from Castilla and Leon, RTICC Hematology Program (RD12/0036/0058), Spanish FIS (PS09/01897), MINECO DPI2012-38090-C03-02, and CIMA (The "UTE project CIMA"). A. Garcia-Gomez was supported by the "Spanish Society of Hematology and Hemotherapy." NR 49 TC 22 Z9 22 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2014 VL 20 IS 6 BP 1542 EP 1554 DI 10.1158/1078-0432.CCR-13-1657 PG 13 WC Oncology SC Oncology GA AE2ON UT WOS:000333812700017 PM 24486586 ER PT J AU Godbersen, JC Humphries, LA Danilova, OV Kebbekus, PE Brown, JR Eastman, A Danilov, AV AF Godbersen, J. Claire Humphries, Leigh Ann Danilova, Olga V. Kebbekus, Peter E. Brown, Jennifer R. Eastman, Alan Danilov, Alexey V. TI The Nedd8-Activating Enzyme Inhibitor MLN4924 Thwarts Microenvironment-Driven NF-kappa B Activation and Induces Apoptosis in Chronic Lymphocytic Leukemia B Cells SO CLINICAL CANCER RESEARCH LA English DT Article ID RECEPTOR SIGNALING PATHWAY; THERAPEUTIC TARGET; NOXA/MCL-1 BALANCE; IN-VIVO; EXPRESSION; SURVIVAL; RESISTANCE; PROLIFERATION; KINASE; BIM AB Background: Stromal-mediated signaling enhances NF-kappa B pathway activity in chronic lymphocytic leukemia (CLL) B cells, leading to cell survival and chemoresistance. Ubiquitination of I kappa B alpha may partially account for constitutive activation of NF-kappa B. MLN4924 is an investigational agent that inhibits the Nedd8-activating enzyme, thereby neutralizing Cullin-RING ubiquitin ligases and preventing degradation of their substrates. Experimental Design: We conducted a preclinical assessment of MLN4924 in CLL. Primary CLL cells were cocultured in vitro with CD40L-expressing stroma to mimic the prosurvival conditions present in lymphoid tissue. The effect of MLN4924 on CLL cell apoptosis, NF-kappa B pathway activity, Bcl-2 family members, and cell cycle was assessed by flow cytometry, Western blotting, PCR, and immunocytochemistry. Results: CD40L-expressing stroma protected CLL cells from spontaneous apoptosis and induced resistance to multiple drugs, accompanied by NF-kappa B activation and Bim repression. Treatment with MLN4924 induced CLL cell apoptosis and circumvented stroma-mediated resistance. This was accompanied by accumulation of phospho-I kappa B alpha, decreased nuclear translocation of p65 and p52 leading to inhibition of both the canonical and noncanonical NF-kappa B pathways, and reduced transcription of their target genes, notably chemokines. MLN4924 promoted induction of Bim and Noxa in the CLL cells leading to rebalancing of Bcl-2 family members toward the proapoptotic BH3-only proteins. siRNA-mediated knockdown of Bim or Noxa decreased sensitivity to MLN4924. MLN4924 enhanced the antitumor activity of the inhibitors of B-cell receptor (BCR)-associated kinases. Conclusions: MLN4924 disrupts NF-kappa B activation and induces Bim expression in CLL cells, thereby preventing stroma-mediated resistance. Our data provide rationale for further evaluation of MLN4924 in CLL. (C)2014 AACR. C1 [Godbersen, J. Claire; Humphries, Leigh Ann; Kebbekus, Peter E.; Danilov, Alexey V.] Dartmouth Hitchcock Med Ctr, Dept Med, Lebanon, NH 03766 USA. [Danilova, Olga V.] Dartmouth Hitchcock Med Ctr, Dept Pathol, Lebanon, NH 03766 USA. [Eastman, Alan] Geisel Sch Med Dartmouth, Dept Pharmacol & Toxicol, Hanover, NH USA. [Brown, Jennifer R.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Danilov, AV (reprint author), Norris Cotton Canc Ctr, 1 Med Ctr Dr, Lebanon, NH 03766 USA. EM Alexey.V.Danilov@hitchcock.org FU National Cancer Institute [3P30CA023108-31S4]; Leukemia & Lymphoma Society; American Cancer Society FX Support to A.V. Danilov is provided by a National Cancer Institute new faculty award (3P30CA023108-31S4) to the Norris Cotton Cancer Center. A. Eastman and A.V. Danilov are supported by a translational research award from the Leukemia & Lymphoma Society. J.R. Brown is supported by the Leukemia and Lymphoma Society and the American Cancer Society and is a Scholar in Clinical Research of the Leukemia and Lymphoma Society. NR 50 TC 29 Z9 29 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2014 VL 20 IS 6 BP 1576 EP 1589 DI 10.1158/1078-0432.CCR-13-0987 PG 14 WC Oncology SC Oncology GA AE2ON UT WOS:000333812700020 PM 24634471 ER PT J AU Oxnard, GR Paweletz, CP Kuang, YA Mach, SL O'Connell, A Messineo, MM Luke, JJ Butaney, M Kirschmeier, P Jackman, DM Janne, PA AF Oxnard, Geoffrey R. Paweletz, Cloud P. Kuang, Yanan Mach, Stacy L. O'Connell, Allison Messineo, Melissa M. Luke, Jason J. Butaney, Mohit Kirschmeier, Paul Jackman, David M. Janne, Pasi A. TI Noninvasive Detection of Response and Resistance in EGFR-Mutant Lung Cancer Using Quantitative Next-Generation Genotyping of Cell-Free Plasma DNA SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; METASTATIC BREAST-CANCER; ACQUIRED-RESISTANCE; KRAS MUTATIONS; DIGITAL PCR; COLORECTAL-CANCER; GEFITINIB; THERAPY; ADENOCARCINOMAS; INHIBITION AB Purpose: Tumor genotyping using cell-free plasma DNA (cfDNA) has the potential to allow noninvasive assessment of tumor biology, yet many existing assays are cumbersome and vulnerable to false-positive results. We sought to determine whether droplet digital PCR (ddPCR) of cfDNA would allow highly specific and quantitative assessment of tumor genotype. Experimental Design: ddPCR assays for EGFR, KRAS, and BRAF mutations were developed using plasma collected from patients with advanced lung cancer or melanoma of a known tumor genotype. Sensitivity and specificity were determined using cancers with nonoverlapping genotypes as positive and negative controls. Serial assessment of response and resistance was studied in patients with EGFR-mutant lung cancer on a prospective trial of erlotinib. Results: We identified a reference range for EGFR L858R and exon 19 deletions in specimens from KRAS-mutant lung cancer, allowing identification of candidate thresholds with high sensitivity and 100% specificity. Received operative characteristic curve analysis of four assays demonstrated an area under the curve in the range of 0.80 to 0.94. Sensitivity improved in specimens with optimal cfDNA concentrations. Serial plasma genotyping of EGFR-mutant lung cancer on erlotinib demonstrated pretreatment detection of EGFR mutations, complete plasma response in most cases, and increasing levels of EGFR T790M emerging before objective progression. Conclusions: Noninvasive genotyping of cfDNA using ddPCR demonstrates assay qualities that could allow effective translation into a clinical diagnostic. Serial quantification of plasma genotype allows noninvasive assessment of response and resistance, including detection of resistance mutations up to 16 weeks before radiographic progression. C1 [Oxnard, Geoffrey R.; Paweletz, Cloud P.; Kuang, Yanan; Mach, Stacy L.; O'Connell, Allison; Messineo, Melissa M.; Luke, Jason J.; Butaney, Mohit; Kirschmeier, Paul; Jackman, David M.; Janne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Paweletz, Cloud P.; Kuang, Yanan; O'Connell, Allison; Messineo, Melissa M.; Kirschmeier, Paul; Janne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA. [Oxnard, Geoffrey R.; Luke, Jason J.; Jackman, David M.; Janne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Luke, Jason J.; Jackman, David M.; Janne, Pasi A.] Harvard Univ, Sch Med, Boston, MA USA. RP Oxnard, GR (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 1234, Boston, MA 02215 USA. EM Geoffrey_Oxnard@DFCI.Harvard.edu FU National Cancer Institute at the NIH [R01-CA135257, P50-CA090578]; Conquer Cancer Foundation of ASCO (Career Development Award); Genentech FX This work was supported in part by the National Cancer Institute at the NIH (R01-CA135257, P50-CA090578), the Conquer Cancer Foundation of ASCO (Career Development Award), and research funding from Genentech. NR 31 TC 171 Z9 183 U1 4 U2 36 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2014 VL 20 IS 6 BP 1698 EP 1705 DI 10.1158/1078-0432.CCR-13-2482 PG 8 WC Oncology SC Oncology GA AE2ON UT WOS:000333812700031 PM 24429876 ER PT J AU Bell, ME Street, AE Stafford, J AF Bell, Margret E. Street, Amy E. Stafford, Jane TI Victims' Psychosocial Well-Being After Reporting Sexual Harassment in the Military SO JOURNAL OF TRAUMA & DISSOCIATION LA English DT Article DE reporting; military; sexual assault; sexual harassment ID RESPONSES; RAPE; EXPERIENCES; VETERANS; OUTCOMES; ASSAULT; SYSTEMS; WOMEN; LEGAL AB Given the importance of reporting to sexual harassment prevention and intervention efforts, it is not surprising that an extensive scientific literature has developed on predictors of victims' decisions about making a formal report to authorities about their experiences. In contrast, little empirical work has focused on how reporting affects victims, particularly their psychosocial well-being. This study used a national sample of 1,562 former military Reservists who had experienced sexual harassment during their service to examine the relationship between reporting; experiences reporting; and psychosocial well-being, as indicated by post-harassment functioning, worst symptoms of posttraumatic stress disorder (PTSD) following the harassment, and current symptoms of depression. Making a formal report was not associated with well-being, but among those who did report, perceiving that the report had resulted in the harassment being addressed by authorities was associated with better post-harassment functioning and fewer symptoms of PTSD. Satisfaction with the reporting process showed the strongest association with well-being, demonstrating small but meaningful associations with depression and medium-to-large and medium associations with post-harassment functioning and PTSD, respectively. Although findings did not vary by gender, predictors accounted for more variance in well-being for men than women. In the whole sample, satisfaction with the reporting process mediated the relationship between victims' perceptions of system responsiveness to the report and post-harassment functioning and PTSD. Findings suggest that a victim's perceptions of and satisfaction with the reporting process may impact well-being more strongly than whether the victim made a report to authorities. Men may be even more strongly impacted by their experiences with the reporting process than women C1 VA Boston Healthcare Syst, Natl Ctr Posttraumat Stress Disorder, Boston, MA 02130 USA. Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. RP Bell, ME (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div 116B 3, 150 South Huntington Ave, Boston, MA 02130 USA. EM margret.bell@va.gov NR 29 TC 5 Z9 5 U1 2 U2 15 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1529-9732 EI 1529-9740 J9 J TRAUMA DISSOCIATIO JI J. Trauma Dissociation PD MAR 15 PY 2014 VL 15 IS 2 BP 133 EP 152 DI 10.1080/15299732.2014.867563 PG 20 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AE4WT UT WOS:000333987700002 PM 24410254 ER PT J AU Shimony, A Afilalo, J Flynn, AW Langleben, D Agnihotri, AK Morin, JF Shahian, DM Picard, MH Rudski, LG AF Shimony, Avi Afilalo, Jonathan Flynn, Aidan W. Langleben, David Agnihotri, Arvin K. Morin, Jean-Francois Shahian, David M. Picard, Michael H. Rudski, Lawrence G. TI Usefulness of Right Ventricular Dysfunction to Predict New-Onset Atrial Fibrillation Following Coronary Artery Bypass Grafting SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CARDIAC-SURGERY; ECHOCARDIOGRAPHIC-ASSESSMENT; EUROPEAN-ASSOCIATION; CLINICAL IMPORTANCE; AMERICAN-SOCIETY; RISK; RECOMMENDATIONS; IMPACT; MECHANISMS; PATHOPHYSIOLOGY AB Postoperative atrial fibrillation (AF) is a serious yet common complication after coronary artery bypass grafting (CABG) surgery. Risk factors for postoperative AF have been identified, including echocardiographic parameters, and these are relied on to implement preventative strategies that reduce the incidence of AF. There has yet to be a study examining the impact of echocardiographic right-sided cardiac parameters on the prediction of postoperative AF. Thus, a panel of right-sided cardiac parameters was measured in a cohort of patients undergoing isolated CABG surgery, excluding those who did not have echocardiographic assessment within 30 days before surgery and those with any history of AF. The primary outcome was postoperative AF defined as any episode of AF requiring treatment during the index hospitalization. Postoperative AF occurred in 197 of 768 patients (25.6%); these were older and more likely to have hypertension and chronic kidney disease. After adjustment for clinical and echocardiographic variables, left atrial volume index >= 34 ml/m(2) (odds ratio [OR] 1.98, 95% confidence interval [CI] 1.36 to 2.87), abnormal right ventricular myocardial performance index (OR 1.50, 95% CI 1.01 to 2.24), and advancing age (OR 1.05, 95% CI 1.03 to 1.07) were found to be independent predictors of postoperative AF. In conclusion, right ventricular myocardial performance index is a novel predictor of postoperative AF in patients undergoing isolated CABG surgery and appears to be additive to established risk factors such as age and left atrial volume. (c) 2014 Elsevier Inc. All rights reserved. C1 [Shimony, Avi; Afilalo, Jonathan; Langleben, David; Rudski, Lawrence G.] McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Div Cardiol, Montreal, PQ H3T 1E2, Canada. [Morin, Jean-Francois] McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Div Cardiac Surg, Montreal, PQ H3T 1E2, Canada. [Afilalo, Jonathan; Flynn, Aidan W.; Picard, Michael H.] Harvard Univ, Massachusetts Gen Hosp, Div Cardiol, Cardiac Ultrasound Lab, Boston, MA 02115 USA. [Agnihotri, Arvin K.; Shahian, David M.] Harvard Univ, Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02115 USA. [Shahian, David M.] Harvard Univ, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA. [Shahian, David M.] Harvard Univ, Massachusetts Gen Hosp, Ctr Qual & Safety, Boston, MA 02115 USA. RP Rudski, LG (reprint author), McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Div Cardiol, Montreal, PQ H3T 1E2, Canada. EM lrudski@jgh.mcgill.ca OI Picard, Michael/0000-0002-9264-3243 FU Azrieli Foundation grant through the Jewish General Hospital Foundation, Montreal, Quebec, Canada FX Dr. Avi Shimony was supported by a Azrieli Foundation grant through the Jewish General Hospital Foundation, Montreal, Quebec, Canada. The other authors have no conflicts of interest to disclose. NR 30 TC 7 Z9 8 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAR 15 PY 2014 VL 113 IS 6 BP 913 EP 918 DI 10.1016/j.amjcard.2013.11.048 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AD7WD UT WOS:000333476700002 PM 24440329 ER PT J AU Feemster, LC Au, DH AF Feemster, Laura C. Au, David H. TI Penalizing Hospitals for Chronic Obstructive Pulmonary Disease Readmissions SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE quality indicators; chronic obstructive pulmonary disease; patient readmission; Medicate ID MEDICARE BENEFICIARIES; ACUTE EXACERBATIONS; HEALTH OUTCOMES; INPATIENT CARE; QUALITY; PROGRAM; RATES; REHOSPITALIZATION; HOSPITALIZATIONS; ASSOCIATION AB In October 2014, the U.S. Centers for Medicare and Medicaid Services (CMS) Will expand its Hospital Readmission Reduction Program (HRRP) to include chronic obstructive pulinonary disease (COPD). Under the new policy, hospitals with high risk-adjusted, 30-day all-cause unplanned readmission rates after an index hospitalization for a COPD exacerbation will be penalized with reduced reimbursement for the treatment of Medicare beneficiaries. In this perspective, we review the history of the HRRP, including the recent addition of COPD to the policy. We critically assess the use of 30-day all-cause COPD readmissions as an accountability measure, discussing potential benefits and then highlighting the substantial drawbacks and potential unintended consequences of the measure that could adversely affect providers, hospitals, and patients with COPD. We conclude by emphasizing the need to place the 30-day COPD readmission measure in the context of a reconceived model for postdischarge quality and review several frameworks that could help guide this process. C1 [Feemster, Laura C.; Au, David H.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Feemster, Laura C.; Au, David H.] Univ Washington, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. RP Feemster, LC (reprint author), 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM lcecere@uw.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health [K23HL111116]; VA Puget Sound Health Care System; Health Services Research and Developmen FX Supported by a National Heart, Lung, and Blood Institute, National Institutes of Health, K23 Award K23HL111116 (L.C.F.) and the VA Puget Sound Health Care System, Health Services Research and Development (LCF., D.H.A.). NR 36 TC 20 Z9 20 U1 1 U2 6 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAR 15 PY 2014 VL 189 IS 6 BP 634 EP 639 DI 10.1164/rccm.201308-1541PP PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AD6OQ UT WOS:000333381100007 PM 24460431 ER PT J AU de los Heros, P Alessi, DR Gourlay, R Campbell, DG Deak, M Macartney, TJ Kahle, KT Zhang, JW AF de los Heros, Paola Alessi, Dario R. Gourlay, Robert Campbell, David G. Deak, Maria Macartney, Thomas J. Kahle, Kristopher T. Zhang, Jinwei TI The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters SO BIOCHEMICAL JOURNAL LA English DT Article DE gamma-aminobutyric acid (GABA); blood pressure/hypertension; ion homoeostasis; K+-Cl- co-transporter 2 (KCC2); K+-Cl- co-transporter 3 (KCC3); Na+-Cl- co-transporter (NCC); Na+-K+-2Cl(-) co-transporter 1 (NKCC1); protein kinase; signal transduction ID CATION-CHLORIDE COTRANSPORTERS; ALANINE-RICH KINASE; BLOOD-PRESSURE; MOLECULAR PHYSIOLOGY; PROTEIN-KINASES; CELL-VOLUME; HYPOKALEMIC ALKALOSIS; BARTTERS-SYNDROME; SALT TRANSPORT; ION-TRANSPORT AB Precise homoeostasis of the intracellular concentration of Cl- is achieved via the co-ordinated activities of the Cl- influx and efflux. We demonstrate that the WNK (WNK lysine-deficient protein kinase)-activated SPAK (SPS1-related proline/alanine-rich kinase)/OSR1 (oxidative stress-responsive kinase 1) known to directly phosphorylate and stimulate the N[K]CCs (Na+-K+ ion co-transporters), also promote inhibition of the KCCs (K+-Cl- co-transporters) by directly phosphorylating a recently described C-terminal threonine residue conserved in all KCC isoforms [Site-2 (Thr(1048))]. First, we demonstrate that SPAK and OSR1, in the presence of the MO25 regulatory subunit, robustly phosphorylates all KCC isoforms at Site-2 in vitro. Secondly, STOCK1S-50699, a WNK pathway inhibitor, suppresses SPAK/OSR1 activation and KCC3A Site-2 phosphorylation with similar efficiency. Thirdly, in ES (embryonic stem) cells lacking SPAK/OSR1 activity, endogenous phosphorylation of KCC isoforms at Site-2 is abolished and these cells display elevated basal activity of Rb-86(+) uptake that was not markedly stimulated further by hypotonic high K+ conditions, consistent with KCC3A activation. Fourthly, a tight correlation exists between SPAK/OSR1 activity and the magnitude of KCC3A Site-2 phosphorylation. Lastly, a Site-2 alanine KCC3A mutant preventing SPAK/OSR1 phosphorylation exhibits increased activity. We also observe that KCCs are directly phosphorylated by SPAK/OSR1, at a novel Site-3 (Thr(5) in KCC1/KCC3 and Thr(6) in KCC2/KCC4), and a previously recognized KCC3-specific residue, Site-4 (Ser(96)). These data demonstrate that the WNK-regulated SPAK/OSR1 kinases directly phosphorylate the N[K]CCs and KCCs, promoting their stimulation and inhibition respectively. Given these reciprocal actions with anticipated net effects of increasing Cl- influx, we propose that the targeting of WNK-SPAK/OSR1 with kinase inhibitors might be a novel potent strategy to enhance cellular Cl- extrusion, with potential implications for the therapeutic modulation of epithelial and neuronal ion transport in human disease states. C1 [de los Heros, Paola; Alessi, Dario R.; Gourlay, Robert; Campbell, David G.; Deak, Maria; Macartney, Thomas J.; Zhang, Jinwei] Univ Dundee, Coll Life Sci, MRC, Prot Phosphorylat & Ubiguitylat Unit, Dundee DD1 5EH, Scotland. [Kahle, Kristopher T.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Kahle, Kristopher T.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kahle, Kristopher T.] Childrens Hosp Boston, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. RP Alessi, DR (reprint author), Univ Dundee, Coll Life Sci, MRC, Prot Phosphorylat & Ubiguitylat Unit, Dow St, Dundee DD1 5EH, Scotland. RI Campbell, David/K-1874-2015; OI Campbell, David/0000-0003-2278-2149; Alessi, Dario/0000-0002-2140-9185; Zhang, Jinwei/0000-0001-8683-509X FU Medical Research Council; Wellcome Trust [091415]; Manton Center for Orphan Diseases at Children's Hospital Boston at Harvard Medical School; Harvard /MIT Joint Research Grants Program in Basic Neuroscience; AstraZeneca; Boehringer-Ingelheim; GlaxoSmithKline; Merck KgaA; Janssen Pharmaceutica; Pfizer FX This work was supported by the Medical Research Council and the Wellcome Trust [grant number 091415] as well as the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA, Janssen Pharmaceutica and Pfizer). K.T.K. is supported by the Manton Center for Orphan Diseases at Children's Hospital Boston at Harvard Medical School, and the Harvard /MIT Joint Research Grants Program in Basic Neuroscience. NR 57 TC 34 Z9 34 U1 0 U2 8 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD MAR 15 PY 2014 VL 458 BP 559 EP 573 DI 10.1042/BJ20131478 PN 3 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AE1GT UT WOS:000333718500013 PM 24393035 ER PT J AU Ali, OA Verbeke, C Johnson, C Sands, RW Lewin, SA White, D Doherty, E Dranoff, G Mooney, DJ AF Ali, Omar A. Verbeke, Catia Johnson, Chris Sands, R. Warren Lewin, Sarah A. White, Des Doherty, Edward Dranoff, Glenn Mooney, David J. TI Identification of Immune Factors Regulating Antitumor Immunity Using Polymeric Vaccines with Multiple Adjuvants SO CANCER RESEARCH LA English DT Article ID DENDRITIC-CELL SUBSETS; TUMOR-NECROSIS-FACTOR; T-CELL; IN-VIVO; CANCER-IMMUNOTHERAPY; INNATE IMMUNITY; ANTIGEN; DIFFERENTIATION; INTERFERON; INTERLEUKIN-12 AB The innate cellular and molecular components required to mediate effective vaccination against weak tumor-associated antigens remain unclear. In this study, we used polymeric cancer vaccines incorporating different classes of adjuvants to induce tumor protection, to identify dendritic cell (DC) subsets and cytokines critical to this efficacy. Three-dimensional, porous polymer matrices loaded with tumor lysates and presenting distinct combinations of granulocyte macrophage colony-stimulating factor (GM-CSF) and various Toll-like receptor (TLR) agonists affected 70% to 90% prophylactic tumor protection in B16-F10 melanoma models. In aggressive, therapeutic B16 models, the vaccine systems incorporating GM-CSF in combination with P(I: C) or CpG-ODN induced the complete regression of solid tumors (<= 40 mm(2)), resulting in 33% long-term survival. Regression analysis revealed that the numbers of vaccine-resident CD8(+) DCs, plasmacytoid DCs (pDC), along with local interleukin (IL)-12, and granulocyte colony-stimulating factor (G-CSF) concentrations correlated strongly to vaccine efficacy regardless of adjuvant type. Furthermore, vaccine studies in Batf3(-/-) mice revealed that CD8(+) DCs are required to affect tumor protection, as vaccines in these mice were deficient in cytotoxic T lymphocytes priming and IL-12 induction in comparison with wild-type. These studies broadly demonstrate that three-dimensional polymeric vaccines provide a potent platform for prophylactic and therapeutic protection, and can be used as a tool to identify critical components of a desired immune response. Specifically, these results suggest that CD8(+) DCs, pDCs, IL-12, and G-CSF play important roles in priming effective antitumor responses with these vaccines. (C) 2014 AACR. C1 [Ali, Omar A.; Verbeke, Catia; Johnson, Chris; Sands, R. Warren; Lewin, Sarah A.; White, Des; Doherty, Edward; Mooney, David J.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Dranoff, Glenn] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med Oncol,Dana Farber Canc Inst, Boston, MA USA. [Dranoff, Glenn] Harvard Univ, Sch Med, Brigham & Womens Hosp, Canc Vaccine Ctr,Dana Farber Canc Inst, Boston, MA USA. [Dranoff, Glenn] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Ali, Omar A.; Verbeke, Catia; Sands, R. Warren; Mooney, David J.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. RP Mooney, DJ (reprint author), Harvard Univ, Sch Engn & Appl Sci, 29 Oxford St,319 Pierce Hall, Cambridge, MA 02138 USA. EM mooneyd@seas.harvard.edu FU NIBIB NIH HHS [R01 EB015498] NR 47 TC 22 Z9 22 U1 3 U2 24 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2014 VL 74 IS 6 BP 1670 EP 1681 DI 10.1158/0008-5472.CAN-13-0777 PG 12 WC Oncology SC Oncology GA AE2OD UT WOS:000333811700007 PM 24480625 ER PT J AU Steinert, G Scholch, S Niemietz, T Iwata, N Garcia, SA Behrens, B Voigt, A Kloor, M Benner, A Bork, U Rahbari, NN Buchler, MW Stoecklein, NH Weitz, J Koch, M AF Steinert, Gunnar Schoelch, Sebastian Niemietz, Thomas Iwata, Naoki Garcia, Sebastian A. Behrens, Bianca Voigt, Anita Kloor, Matthias Benner, Axel Bork, Ulrich Rahbari, Nuh N. Buechler, Markus W. Stoecklein, Nikolas H. Weitz, Juergen Koch, Moritz TI Immune Escape and Survival Mechanisms in Circulating Tumor Cells of Colorectal Cancer SO CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; INTEGRIN-ASSOCIATED PROTEIN; NON-HODGKIN-LYMPHOMA; BREAST-CANCER; BONE-MARROW; MICROSATELLITE INSTABILITY; MICROMETASTATIC CELLS; LIVER METASTASES; GENETIC-ANALYSIS; SINGLE CELLS AB The prognosis of colorectal cancer is closely linked to the occurrence of distant metastases. Systemic dissemination is most likely caused by circulating tumor cells (CTC). Despite the fundamental role of CTC within the metastatic cascade, technical obstacles have so far prevented detailed genomic and, in particular, phenotypic analyses of CTC, which may provide molecular targets to delay or prevent distant metastases. We show here a detailed genomic analysis of single colorectal cancer-derived CTC by array comparative genomic hybridization (aCGH), mutational profiling, and microsatellite instability (MSI) analysis. Furthermore, we report the first gene expression analysis of manually selected colorectal cancer-derived CTC by quantitative real-time PCR (qRT-PCR) to investigate transcriptional changes, enabling CTC to survive in circulation and form distant metastases. aCGH confirmed the tumor cell identity of CellSearch-isolated colorectal cancer-derived CTC. Mutational and MSI analyses revealed mutational profiles of CTC to be similar, but not identical to the corresponding tumor tissue. Several CTC exhibited mutations in key genes such as KRAS or TP53 that could not be detected in the tumor. Gene expression analyses revealed both a pronounced upregulation of CD47 as a potential immune-escape mechanism and a significant downregulation of several other pathways, suggesting a dormant state of viable CTC. Our results suggest mutational heterogeneity between tumor tissue and CTC that should be considered in future trials on targeted therapy and monitoring of response. The finding of upregulated immune-escape pathways, which may be responsible for survival of CTC in circulation, could provide a promising target to disrupt the metastatic cascade in colorectal cancer. (C) 2014 AACR. C1 [Steinert, Gunnar; Niemietz, Thomas; Iwata, Naoki; Buechler, Markus W.] Heidelberg Univ, Inst Pathol, Dept Gen Gastrointestinal & Transplant Surg, Heidelberg, Germany. [Voigt, Anita] Heidelberg Univ, Inst Pathol, Dept Appl Tumor Biol, Heidelberg, Germany. [Benner, Axel] German Canc Res Ctr, Div Biostat, Heidelberg, Germany. [Schoelch, Sebastian; Garcia, Sebastian A.; Bork, Ulrich; Weitz, Juergen; Koch, Moritz] Tech Univ Dresden, Med Fak Carl Gustav Carus, Dept Gastrointestinal Thorac & Vasc Surg, D-01307 Dresden, Germany. [Behrens, Bianca; Stoecklein, Nikolas H.] Univ Dusseldorf, Fac Med, Univ Hosp, Dept Gen Visceral & Paediat Surg, Dusseldorf, Germany. [Rahbari, Nuh N.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. [Rahbari, Nuh N.] Harvard Univ, Sch Med, Boston, MA USA. RP Koch, M (reprint author), Tech Univ Dresden, Med Fak Carl Gustav Carus, Dept Gastrointestinal Thorac & Vasc Surg, Fetscherstr 74, D-01307 Dresden, Germany. EM moritz.koch@uniklinikum-dresden.de OI Voigt, Anita Yvonne/0000-0002-6794-0385; Scholch, Sebastian/0000-0003-0012-3177 FU Deutsche Forschungsgemeinschaft (DFG) [WE 3548/4-1/2, KFO 227] FX This work was supported by the KFO 227 program (Clinical Research Group 227: Colorectal cancer: from primary tumor progression towards metastases (WE 3548/4-1/2) of Deutsche Forschungsgemeinschaft (DFG). NR 54 TC 49 Z9 51 U1 1 U2 26 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2014 VL 74 IS 6 BP 1694 EP 1704 DI 10.1158/0008-5472.CAN-13-1885 PG 11 WC Oncology SC Oncology GA AE2OD UT WOS:000333811700009 PM 24599131 ER PT J AU Zhao, JJ Lin, JH Zhu, D Wang, XJ Brooks, D Chen, M Chu, ZB Takada, K Ciccarelli, B Admin, S Tao, JG Tai, YT Treon, S Pinkus, G Kuo, WP Hideshima, T Bouxsein, M Munshi, N Anderson, K Carrasco, R AF Zhao, Jian-Jun Lin, Jianhong Zhu, Di Wang, Xujun Brooks, Daniel Chen, Ming Chu, Zhang-Bo Takada, Kohichi Ciccarelli, Bryan Admin, Samir Tao, Jianguo Tai, Yu-Tzu Treon, Steven Pinkus, Geraldine Kuo, Winston Patrick Hideshima, Teru Bouxsein, Mary Munshi, Nikhil Anderson, Kenneth Carrasco, Ruben TI miR-30-5p Functions as a Tumor Suppressor and Novel Therapeutic Tool by Targeting the Oncogenic Wnt/beta-Catenin/BCL9 Pathway SO CANCER RESEARCH LA English DT Article ID MULTIPLE-MYELOMA; IN-VITRO; MOLECULAR-ORIGINS; DOWN-REGULATION; BETA-CATENIN; STEM-CELLS; CANCER; EXPRESSION; MICRORNAS; DISEASE AB Wnt/beta-catenin signaling underlies the pathogenesis of a broad range of human cancers, including the deadly plasma cell cancer multiple myeloma. In this study, we report that downregulation of the tumor suppressor microRNA miR-30-5p is a frequent pathogenetic event in multiple myeloma. Evidence was developed that miR-30-5p downregulation occurs as a result of interaction between multiple myeloma cells and bone marrow stromal cells, which in turn enhances expression of BCL9, a transcriptional coactivator of the Wnt signaling pathway known to promote multiple myeloma cell proliferation, survival, migration, drug resistance, and formation of multiple myeloma cancer stem cells. The potential for clinical translation of strategies to re-express miR-30-5p as a therapeutic approach was further encouraged by the capacity of miR-30c and miR-30 mix to reduce tumor burden and metastatic potential in vivo in three murine xenograft models of human multiple myeloma without adversely affecting associated bone disease. Together, our findings offer a preclinical rationale to explore miR-30-5p delivery as an effective therapeutic strategy to eradicate multiple myeloma cells in vivo. (C) 2014 AACR. C1 [Zhao, Jian-Jun; Lin, Jianhong; Zhu, Di; Chen, Ming; Chu, Zhang-Bo; Takada, Kohichi; Ciccarelli, Bryan; Tai, Yu-Tzu; Treon, Steven; Hideshima, Teru; Munshi, Nikhil; Anderson, Kenneth; Carrasco, Ruben] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Lin, Jianhong; Tai, Yu-Tzu; Hideshima, Teru; Munshi, Nikhil; Anderson, Kenneth] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Admin, Samir] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Pinkus, Geraldine; Carrasco, Ruben] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kuo, Winston Patrick] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Brooks, Daniel; Bouxsein, Mary] Beth Israel Deaconess Med Ctr, Ctr Adv Orthopaed Studies, Boston, MA 02215 USA. [Tao, Jianguo] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Wang, Xujun] Tongji Univ, Sch Life Sci & Technol, Jerome Lipper Multiple Myeloma Ctr, Shanghai 200092, Peoples R China. RP Carrasco, R (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM ruben_carrasco@dfci.harvard.edu FU Multiple Myeloma Research Foundation (MMRF); SPORE in Multiple Myeloma Career Development Award; China Scholarship Council (CSC); Harvard Catalyst, The Harvard Clinical and Translational Science Center; MMRF [1R01CA151391] FX J.-J. Zhao was supported by a Multiple Myeloma Research Foundation (MMRF) research fellow award. J. Lin was supported by a SPORE in Multiple Myeloma Career Development Award. Z.-B. Chu was supported by a China Scholarship Council (CSC) award. W. P. Kuo was supported by Harvard Catalyst, The Harvard Clinical and Translational Science Center. K. Anderson is an American Cancer Society Clinical Research Professor. R. Carrasco is supported by an MMRF senior award and a 1R01CA151391. NR 45 TC 43 Z9 48 U1 1 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2014 VL 74 IS 6 BP 1801 EP 1813 DI 10.1158/0008-5472.CAN-13-3311-T PG 13 WC Oncology SC Oncology GA AE2OD UT WOS:000333811700018 PM 24599134 ER PT J AU Hong, J Yuan, YF Wang, JP Liao, YD Zou, RH Zhu, CL Li, BK Liang, Y Huang, PZ Wang, ZW Lin, WY Zeng, YX Dai, JL Chung, RT AF Hong, Jian Yuan, Yunfei Wang, Jianping Liao, Yadi Zou, Ruhai Zhu, Chuanlong Li, Binkui Liang, Yi Huang, Pinzhu Wang, Zongwei Lin, Wenyu Zeng, Yixin Dai, Jia Le Chung, Raymond T. TI Expression of Variant Isoforms of the Tyrosine Kinase SYK Determines the Prognosis of Hepatocellular Carcinoma SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; BREAST-CANCER CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; POOR-PROGNOSIS; LUNG-CANCER; GROWTH; PROGRESSION; INHIBITION; STRATEGY; MOTILITY AB The spleen tyrosine kinase (SYK) has been reported as a novel biomarker for human hepatocellular carcinoma, but the functional contributions of its two isoforms SYK(L) and SYK(S) are undefined. In this study, we investigated their biologic functions and possible prognostic values in hepatocellular carcinoma. SYK(L) was downregulated in 38% of human specimens of hepatocellular carcinoma examined, whereas SYK(S) was detectable in 40% of these specimens but not in normal liver tissue samples without cirrhosis. SYK(S) expression correlated with pathologic parameters characteristic of tumor metastasis, including multiple tumors (P = 0.003) and vascular invasion (P = 0.001). Further, SYK(S) was specifically associated with epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma specimens. Functional studies showed that SYK(S) promoted tumor growth, suppressed apoptosis, and induced EMT through the extracellular signal-regulated kinase pathway, countering the opposite effects of SYK(L). Patients with SYK(L+/S-) tumors exhibited longer overall survival and time to recurrence than those with SYK(L-/S-) or SYK(L+/S+) tumors (P < 0.001). Taken together, our findings showed that SYK(S) enhances invasion, whereas SYK(L) inhibits metastasis in hepatocellular carcinoma. We suggest that SYK(L) downregulation or SYK(S) elevation are strong predictors of poor survival in patients with hepatocellular carcinoma, indicative of a need for aggressive therapeutic intervention. (C) 2014 AACR. C1 [Hong, Jian; Yuan, Yunfei; Liao, Yadi; Zou, Ruhai; Li, Binkui; Liang, Yi; Huang, Pinzhu; Zeng, Yixin] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Guangzhou 510060, Guangdong, Peoples R China. [Hong, Jian; Yuan, Yunfei; Liao, Yadi; Li, Binkui] Sun Yat Sen Univ, Ctr Canc, Dept Hepatobiliary Oncol, Guangzhou 510060, Guangdong, Peoples R China. [Wang, Jianping] Sun Yat Sen Univ, Affiliated Hosp 6, Dept Surg, Guangzhou 510060, Guangdong, Peoples R China. [Hong, Jian; Zhu, Chuanlong; Wang, Zongwei; Lin, Wenyu; Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, Boston, MA USA. [Dai, Jia Le] Univ Texas MD Anderson Canc Ctr, Div Pharma, Houston, TX 77030 USA. RP Yuan, YF (reprint author), Sun Yat Sen Univ, Ctr Canc, Guangzhou 510060, Guangdong, Peoples R China. EM yuanyf@mail.sysu.edu.cn; rtchung@partners.org FU National Natural Science Foundation of China [81201634, 81172344, 81101863]; Natural Science Foundation of Guangdong Province of China [S2011040004570]; NIH [DK078772] FX This study was supported by the National Natural Science Foundation of China (81201634, 81172344, and 81101863), the Natural Science Foundation of Guangdong Province of China (S2011040004570), and NIH grant DK078772 (RTC). NR 39 TC 11 Z9 11 U1 3 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2014 VL 74 IS 6 BP 1845 EP 1856 DI 10.1158/0008-5472.CAN-13-2104 PG 12 WC Oncology SC Oncology GA AE2OD UT WOS:000333811700022 PM 24477596 ER PT J AU Ruff, CT Giugliano, RP Braunwald, E Hoffman, EB Deenadayalu, N Ezekowitz, MD Camm, AJ Weitz, JI Lewis, BS Parkhomenko, A Yamashita, T Antman, EM AF Ruff, Christian T. Giugliano, Robert P. Braunwald, Eugene Hoffman, Elaine B. Deenadayalu, Naveen Ezekowitz, Michael D. Camm, A. John Weitz, Jeffrey I. Lewis, Basil S. Parkhomenko, Alexander Yamashita, Takeshi Antman, Elliott M. TI Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials SO LANCET LA English DT Article ID RE-LY TRIAL; NORMALIZED RATIO CONTROL; STROKE PREVENTION; RISK-FACTORS; SUBGROUP ANALYSIS; DABIGATRAN; THERAPY; RIVAROXABAN; APIXABAN; THROMBOEMBOLISM AB Background Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes. Methods We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. We did a prespecified meta-analysis of all 71 683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. We used a random-effects model to compare pooled outcomes and tested for heterogeneity. Findings 42 411 participants received a new oral anticoagulant and 29 272 participants received warfarin. New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0.81, 95% CI 0.73-0.91; p<0.0001), mainly driven by a reduction in haemorrhagic stroke (0.49, 0.38-0.64; p<0.0001). New oral anticoagulants also significantly reduced all-cause mortality (0.90, 0.85-0.95; p=0.0003) and intracranial haemorrhage (0.48, 0.39-0.59; p<0.0001), but increased gastrointestinal bleeding (1.25, 1.01-1.55; p= 0.04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0.69, 0.59-0.81 vs 0.93, 0.76-1.13; p for interaction 0.022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1.03, 0.84-1.27; p= 0.74), and a more favourable bleeding profile (0.65, 0.43-1.00; p= 0.05), but significantly more ischaemic strokes (1.28, 1.02-1.60; p= 0.045). Interpretation This meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fibrillation. New oral anticoagulants had a favourable risk-benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our findings off er clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population. C1 [Ruff, Christian T.; Giugliano, Robert P.; Braunwald, Eugene; Hoffman, Elaine B.; Deenadayalu, Naveen; Antman, Elliott M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ruff, Christian T.; Giugliano, Robert P.; Braunwald, Eugene; Hoffman, Elaine B.; Deenadayalu, Naveen; Antman, Elliott M.] Harvard Univ, Sch Med, Boston, MA USA. [Ezekowitz, Michael D.] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. [Ezekowitz, Michael D.] Cardiovasc Res Fdn, New York, NY USA. [Camm, A. John] St Georges Univ, London, England. [Weitz, Jeffrey I.] McMaster Univ, Hamilton, ON, Canada. [Weitz, Jeffrey I.] Thrombosis & Atherosclerosis Res Inst, Hamilton, ON, Canada. [Lewis, Basil S.] Lady Davis Carmel Med Ctr, Haifa, Israel. [Parkhomenko, Alexander] ND Strazhesko Cardiol Res Inst, Kiev, Ukraine. [Yamashita, Takeshi] Cardiovasc Inst, Tokyo, Japan. RP Ruff, CT (reprint author), Thrombolysis Myocardial Infarct TIMI Study Grp, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. EM cruff@partners.org FU Daiichi Sankyo; Johnson Johnson; Merck; Duke University; AstraZeneca; Merck Co; Sanofi - Aventis; GlaxoSmith Kline; Bristol-Myers Squibb; Beckman Coulter; Roche Diagnostics; Pfizer; Genyzme; Amorcyte; Medicines Co; CardioRentis; CVRx; Eli Lilly; Menarini International; Medscape; Bayer; Boehringer Ingelheim FX CTR has served as a consultant and has received honoraria from Daiichi Sankyo, Boehringer Ingelheim, and Bristol-Myers Squibb. RPG has served as a consultant and has received honoraria from Bristol-Myers Squibb, Janssen, Daiichi Sankyo, Merck, Sanofi, and is a member of the TIMI Study Group, which has received research grant support from Daiichi Sankyo, Johnson & Johnson, and Merck. EB has recieved grants and personal fees for lectures from Daiichi Sankyo; grants from Duke University, AstraZeneca, Johnson & Johnson, Merck & Co, Sanofi - Aventis, GlaxoSmith Kline, Bristol-Myers Squibb, Beckman Coulter, Roche Diagnostics, and Pfizer; uncompensated personal fees for consultancy from Merck & Co; personal fees for consultancies from Genyzme, Amorcyte, Medicines Co, CardioRentis, and Sanofi - Aventis; uncompensated personal fees for lectures from Merck and CVRx; and personal fees for lectures from Eli Lilly, Menarini International, Medscape, and Bayer outside the submitted work. MDE has served as a consultant and has received honoraria from Boehringer Ingelheim, Bayer, Johnson & Johnson, Janssen, Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, Sanofi, Portola, Medtronics, Aegerion, Merck, Gilead, and Pozen. AJC has served as a consultant and has received honoraria from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo. JIW has served as a consultant and has received honoraria from Boehringer Ingelheim, Bayer, Janssen, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo. BSL has served as a consultant to Bayer, Bristol-Myers Squibb, and Pfizer and received research grants in these trials from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo. AP has received a research grant from Daiichi Sankyo, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb. TY has received honoraria from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Pfi zer, and Daiichi Sankyo. EMA has received a research grant from Daiichi Sankyo. All other authors declare that they have no conflicts of interest. NR 40 TC 666 Z9 694 U1 26 U2 139 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAR 15 PY 2014 VL 383 IS 9921 BP 955 EP 962 DI 10.1016/S0140-6736(13)62343-0 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AD8MR UT WOS:000333520700026 PM 24315724 ER PT J AU Mahmood, SS Levy, D Vasan, RS Wang, TJ AF Mahmood, Syed S. Levy, Daniel Vasan, Ramachandran S. Wang, Thomas J. TI The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective SO LANCET LA English DT Review ID ISOLATED SYSTOLIC HYPERTENSION; POPULATION-BASED COHORT; ATRIAL-FIBRILLATION; RISK-FACTORS; FOLLOW-UP; MYOCARDIAL-INFARCTION; DIABETES-MELLITUS; NATURAL-HISTORY; BLOOD PRESSURE; FAILURE AB On Sept 29, 2013, the Framingham Heart Study will celebrate 65 years since the examination of the first volunteer in 1948. During this period, the study has provided substantial insight into the epidemiology and risk factors of cardiovascular disease. The origins of the study are closely linked to the cardiovascular health of President Franklin D Roosevelt and his premature death from hypertensive heart disease and stroke in 1945. In this Review we describe the events leading to the foundation of the Framingham Heart Study, and provide a brief historical overview of selected contributions from the study. C1 [Mahmood, Syed S.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Levy, Daniel; Vasan, Ramachandran S.; Wang, Thomas J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Levy, Daniel] NHLBI, Populat Res Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Wang, Thomas J.] Vanderbilt Univ, Div Cardiovasc Med, Nashville, TN 37235 USA. RP Wang, TJ (reprint author), Vanderbilt Univ Sch Med, Div Cardiovasc Med, Nashville, TN 37232 USA. EM thomas.j.wang@vanderbilt.edu OI Mahmood, Syed Saad/0000-0001-6938-1321; Ramachandran, Vasan/0000-0001-7357-5970 FU NIH [N01-HC-25195] FX We thank Paul Sorlie (National Heart, Lung, and Blood Institute, Bethesda, MD, USA) for his assistance in granting access to the Framingham Archives. We thank Gerald Oppenheimer (Department of Sociomedical Sciences, Columbia University, New York, NY, USA) for comments on the history of the Framingham Heart Study. This work was supported by NIH contract N01-HC-25195. NR 81 TC 79 Z9 86 U1 8 U2 36 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD MAR 15 PY 2014 VL 383 IS 9921 BP 999 EP 1008 DI 10.1016/S0140-6736(13)61752-3 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AD8MR UT WOS:000333520700030 PM 24084292 ER PT J AU Klein, OJ Jung, YK Evans, CL AF Klein, O. J. Jung, Y. K. Evans, C. L. TI Longitudinal, quantitative monitoring of therapeutic response in 3D in vitro tumor models with OCT for high-content therapeutic screening SO METHODS LA English DT Article DE 3D in vitro models; Optical coherence tomography; Time-lapse; Overlay culture; Image analysis; Therapeutic response ID OPTICAL COHERENCE TOMOGRAPHY; CANCER BIOLOGY; GROWTH; CULTURE; CYTOTOXICITY; APOPTOSIS; EFFICACY; CELLS; PDT AB In vitro three-dimensional models of cancer have the ability to recapitulate many features of tumors found in vivo, including cell-cell and cell-matrix interactions, microenvironments that become hypoxic and acidic, and other barriers to effective therapy. These model tumors can be large, highly complex, heterogeneous, and undergo time-dependent growth and treatment response processes that are difficult to track and quantify using standard imaging tools. Optical coherence tomography is an optical ranging technique that is ideally suited for visualizing, monitoring, and quantifying the growth and treatment response dynamics occurring in these informative model systems. By optimizing both optical coherence tomography and 3D culture systems, it is possible to continuously and non-perturbatively monitor advanced in vitro models without the use of labels over the course of hours and days. In this chapter, we describe approaches and methods for creating and carrying out quantitative therapeutic screens with in vitro 3D cultures using optical coherence tomography to gain insights into therapeutic mechanisms and build more effective treatment regimens. (C) 2013 Elsevier Inc. All rights reserved. C1 [Klein, O. J.; Jung, Y. K.; Evans, C. L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Evans, CL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, CNY 3214,13th St, Charlestown, MA 02129 USA. EM oklein@partners.org; jung.yookyung@mgh.harvar-d.edu; evans.conor@mgh.harvard.edu FU National Institutes of Health (NIH) Innovative Molecular Analysis Technologies (IMAT) program [R21 CA155535]; NIH [DP2 OD007096] FX The authors would like to acknowledge the members of Evans group for their assistance in editing this manuscript. This research was support by the National Institutes of Health (NIH) Innovative Molecular Analysis Technologies (IMAT) program, grant number R21 CA155535, and the NIH Director's New Innovator Award, grant number DP2 OD007096. Information on the New Innovator Award Program is at http://nihroadmap.nih.gov/newinnovator/. NR 32 TC 4 Z9 4 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD MAR 15 PY 2014 VL 66 IS 2 BP 299 EP 311 DI 10.1016/j.ymeth.2013.08.028 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AE1ZM UT WOS:000333773100021 PM 24013042 ER PT J AU Kang, HK Cypel, Y Kilbourne, AM Magruder, KM Serpi, T Collins, JF Frayne, SM Furey, J Huang, GD Kimerling, R Reinhard, MJ Schumacher, K Spiro, A AF Kang, Han K. Cypel, Yasmin Kilbourne, Amy M. Magruder, Kathy M. Serpi, Tracey Collins, Joseph F. Frayne, Susan M. Furey, Joan Huang, Grant D. Kimerling, Rachel Reinhard, Matthew J. Schumacher, Karen Spiro, Avron, III TI HealthViEWS: Mortality Study of Female US Vietnam Era Veterans, 1965-2010 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE HealthViEWS; mortality; veterans; Vietnam; women ID UNITED-STATES-ARMY; CANCER MORTALITY; PROPORTIONATE MORTALITY; POSTSERVICE MORTALITY; REGISTERED NURSES; MILITARY SERVICE; LUNG-CANCER; FOLLOW-UP; DEATH; WOMEN AB We conducted a retrospective study among 4,734 women who served in the US military in Vietnam (Vietnam cohort), 2,062 women who served in countries near Vietnam (near-Vietnam cohort), and 5,313 nondeployed US military women (US cohort) to evaluate the associations of mortality outcomes with Vietnam War service. Veterans were identified from military records and followed for 40 years through December 31, 2010. Information on underlying causes of death was obtained from death certificates and the National Death Index. Based on 2,743 deaths, all 3 veteran cohorts had lower mortality risk from all causes combined and from several major causes, such as diabetes mellitus, heart disease, chronic obstructive pulmonary disease, and nervous system disease relative to comparable US women. However, excess deaths from motor vehicle accidents were observed in the Vietnam cohort (standardized mortality ratio = 3.67, 95% confidence interval (CI): 2.30, 5.56) and in the US cohort (standardized mortality ratio = 1.91, 95% CI: 1.02, 3.27). More than two-thirds of women in the study were military nurses. Nurses in the Vietnam cohort had a 2-fold higher risk of pancreatic cancer death (adjusted relative risk = 2.07, 95% CI: 1.00, 4.25) and an almost 5-fold higher risk of brain cancer death compared with nurses in the US cohort (adjusted relative risk = 4.61, 95% CI: 1.27, 16.83). Findings of all-cause and motor vehicle accident deaths among female Vietnam veterans were consistent with patterns of postwar mortality risk among other war veterans. C1 [Kang, Han K.; Cypel, Yasmin] US Dept Vet Affairs, Off Publ Hlth, Postdeployment Hlth Grp, Washington, DC 20420 USA. [Kilbourne, Amy M.; Schumacher, Karen] Vet Affairs Ann Arbor Ctr Clin Management Res, Ann Arbor, MI USA. [Kilbourne, Amy M.] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI USA. [Magruder, Kathy M.] Med Univ S Carolina, Dept Psychiat, Mental Hlth Serv, Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. [Serpi, Tracey; Collins, Joseph F.] Vet Affairs Maryland Hlth Care Syst, Cooperat Studies Program Coordinating Ctr, Perry Point, MD USA. [Frayne, Susan M.; Kimerling, Rachel] Vet Affairs Palo Alto Hlth Care Syst, Vet Affairs Hlth Serv Res & Dev Ctr Innovat Imple, Palo Alto, CA USA. [Frayne, Susan M.] Stanford Univ, Sch Med, Div Gen Med Disciplines, Palo Alto, CA 94304 USA. [Furey, Joan] US Dept Vet Affairs, Ctr Women Vet, Washington, DC 20420 USA. [Huang, Grant D.] US Dept Vet Affairs, Cooperat Studies Program, Cent Off, Off Res & Dev, Washington, DC 20420 USA. [Kimerling, Rachel] Natl Ctr Postttraumat Stress Disorder, Palo Alto, CA USA. [Reinhard, Matthew J.] DC Vet Affairs Med Ctr, War Related Illness & Injury Study Ctr, Washington, DC USA. [Reinhard, Matthew J.] Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC USA. [Spiro, Avron, III] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Spiro, Avron, III] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Spiro, Avron, III] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. RP Cypel, Y (reprint author), US Dept Vet Affairs, Program Epidemiol, Postdeployment Hlth Strateg Healthcare Grp 10P3A, Off Publ Hlth, Washington, DC 20420 USA. EM yasmin.cypel@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Cooperative Studies Program FX This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Cooperative Studies Program. NR 53 TC 9 Z9 9 U1 1 U2 3 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 2014 VL 179 IS 6 BP 721 EP 730 DI 10.1093/aje/kwt319 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AD4UP UT WOS:000333246800009 PM 24488510 ER PT J AU Yeh, YC Blouin, GC Reddy, P AF Yeh, Yu-Chen Blouin, Gayle C. Reddy, Prabashni TI Evidence to support use of palonosetron over generic serotonin type 3-receptor antagonists for chemotherapy-induced nausea and vomiting SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Editorial Material ID MODERATELY EMETOGENIC CHEMOTHERAPY; PHASE-III; GUIDELINE UPDATE; DOUBLE-BLIND; PREVENTION; ONDANSETRON; EFFICACY; TRIAL; METAANALYSIS C1 [Yeh, Yu-Chen; Reddy, Prabashni] Partners Healthcare, Ctr Drug Policy, Needham, MA USA. [Blouin, Gayle C.] Massachusetts Gen Hosp, Yawkey Ctr Outpatient Care, Boston, MA 02114 USA. RP Yeh, YC (reprint author), Partners Healthcare, Ctr Drug Policy, Needham, MA USA. EM yyeh@partners.org NR 40 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 EI 1535-2900 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD MAR 15 PY 2014 VL 71 IS 6 BP 500 EP 506 DI 10.2146/ajhp130394 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AD6OL UT WOS:000333380500010 PM 24589541 ER PT J AU Downey, LA Loftis, JM AF Downey, Luke A. Loftis, Jennifer M. TI Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Review DE Methamphetamine; 3,4-Methylenedioxy-N-methylamphetamine (MDMA); Neurodegenerative diseases; Inflammation; Oxidative stress; Bioenergetics ID OXIDATIVE STRESS; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; ECSTASY USERS; RAT-BRAIN; POSITRON EMISSION; USE DISORDERS; NEUROTOXICITY; IMPAIRMENT; GLUCOSE; DOPAMINE AB Central nervous system (CNS) damage associated with psychostimulant dependence may be an ongoing, degenerative process with adverse effects on neuropsychiatric function. However, the molecular mechanisms regarding how altered energy regulation affects immune response in the context of substance use disorders are not fully understood. This review summarizes the current evidence regarding the effects of psychostimulant [particularly 3,4-methylenedioxy-N-methylamphetamine (MDMA) and methamphetamine] exposure on brain energy regulation, immune response, and neuropsychiatric function. Importantly, the neuropsychiatric impairments (e.g., cognitive deficits, depression, and anxiety) that persist following abstinence are associated with poorer treatment outcomes - increased relapse rates, lower treatment retention rates, and reduced daily functioning. Qualifying the molecular changes within the CNS according to the exposure and use patterns of specifically abused substances should inform the development of new therapeutic approaches for addiction treatment. Published by Elsevier B.V. C1 [Downey, Luke A.] Swinburne Univ Technol, Ctr Human Psychopharmacol, Hawthorn, Vic 3122, Australia. [Downey, Luke A.] Swansea Univ, Dept Psychol, Swansea, W Glam, Wales. [Loftis, Jennifer M.] Portland VA Med Ctr, Res & Dev Serv, Portland, OR 97239 USA. [Loftis, Jennifer M.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97239 USA. [Loftis, Jennifer M.] Oregon Hlth & Sci Univ, Methamphetamine Abuse Res Ctr, Portland VA Med Ctr, Portland, OR 97239 USA. RP Loftis, JM (reprint author), Oregon Hlth & Sci Univ, Portland VA Med Ctr, Portland, OR 97239 USA. EM loftisj@ohsu.edu FU National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH) [DA028537, DA018165]; National Health and Medical Research Council (NHMRC) [APP1054279] FX The research discussed in this review was in part supported by National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH) Grants (DA028537 and DA018165). This material was also supported with resources and the use of facilities at the Portland Veterans Affairs (VA) Medical Center and Oregon Health & Sciences University. Dr. Jennifer Loftis is a Research Scientist at the Portland VA Medical Center, Dr. Luke Downey is supported by a National Health and Medical Research Council (NH&MRC) biomedical fellowship (APP1054279). NR 66 TC 5 Z9 5 U1 3 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 EI 1879-0712 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD MAR 15 PY 2014 VL 727 BP 125 EP 129 DI 10.1016/j.ejphar.2014.01.032 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AC8EY UT WOS:000332767500016 PM 24485894 ER PT J AU Winey, B Shih, HA Sahoo, N Lee, A Vapiwala, N Both, S AF Winey, Brian Shih, Helen A. Sahoo, Narayan Lee, Andrew Vapiwala, Neha Both, Stefan TI Core Physics Competencies for Proton Therapy Training of Radiation Oncology and Medical Physics Residents and Fellows SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material C1 [Winey, Brian; Shih, Helen A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Winey, Brian; Shih, Helen A.] Harvard Univ, Sch Med, Boston, MA USA. [Sahoo, Narayan; Lee, Andrew] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Vapiwala, Neha; Both, Stefan] Univ Penn, Philadelphia, PA 19104 USA. RP Winey, B (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 35 Fruit St, Boston, MA 02114 USA. EM winey.brian@mgh.harvard.edu NR 10 TC 1 Z9 1 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2014 VL 88 IS 4 BP 971 EP 972 DI 10.1016/j.ijrobp.2013.11.234 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AC4YN UT WOS:000332527400032 PM 24606858 ER PT J AU Pohar, S Fung, CY Olsen, C AF Pohar, Surjeet Fung, Claire Y. Olsen, Christine TI American Society for Radiation Oncology (ASTRO) 2012 Workforce Study: The Radiation Oncologists' and Residents' Perspectives Reply SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material C1 [Pohar, Surjeet] Indiana Univ Hlth Morgan Hosp, Dept Radiat Oncol, Martinsville, IN 46151 USA. [Fung, Claire Y.] Commonwealth Newburyport Canc Ctr, Newburyport, MA USA. [Olsen, Christine] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Pohar, S (reprint author), Indiana Univ Hlth Morgan Hosp, Dept Radiat Oncol, Martinsville, IN 46151 USA. OI Pohar, Surjeet/0000-0002-8206-6462 NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2014 VL 88 IS 4 BP 979 EP 979 DI 10.1016/j.ijrobp.2013.12.018 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AC4YN UT WOS:000332527400036 PM 24606862 ER PT J AU Morandi, F Di Carlo, E Ferrone, S Petretto, A Pistoia, V Airoldi, I AF Morandi, Fabio Di Carlo, Emma Ferrone, Soldano Petretto, Andrea Pistoia, Vito Airoldi, Irma TI IL-27 in Human Secondary Lymphoid Organs Attracts Myeloid Dendritic Cells and Impairs HLA Class I-Restricted Antigen Presentation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; PROINFLAMMATORY CYTOKINE PRODUCTION; MONOCLONAL-ANTIBODIES; ENDOPLASMIC-RETICULUM; IL-17 PRODUCTION; FLOW-CYTOMETRY; B-CELLS; INTERLEUKIN-27; RECEPTOR; WSX-1 AB Different cytokines play crucial roles in inflammation and in polarizing immune responses, including IL-27 that exerts pro-and anti-inflammatory functions. Although the activity of IL-27 is well characterized in murine immune cells, only limited information is available regarding the natural cellular sources of IL-27 in humans and its effects on human immune cells. Dendritic cells (DCs) are the most potent professional APCs that in the immature state are positioned throughout peripheral tissues by acting as sentinels, sensing the presence of Ags. Activated DCs migrate into the lymph nodes and direct Ag-specific T cell responses, thus acting as key players in both adaptive and innate immunity. In this study we asked whether IL-27 is produced by human secondary lymphoid organs and what is its functional role on human DCs. To our knowledge, we provide the first evidence that 1) in lymph nodes, macrophages are the major source for IL-27; 2) immature and mature human DCs express functional IL-27R; 3) IL-27 exerts immunosuppressive activity by crippling the Ag processing machinery in immature DCs under steady-state conditions and after pulsing with a viral Ag; and 4) IL-27 is chemotactic for human DCs. Our findings highlight novel mechanisms underlying the immunosuppressive activity of IL-27, suggesting that this cytokine may function as a homeostatic cytokine in secondary lymphoid organs by limiting duration and/or intensity of ongoing adaptive immune responses. The results presented in this study pave the way to future studies aimed at investigating whether dysregulation of IL-27 expression and function may be involved in pathogenesis of autoimmune disease and cancer. C1 [Morandi, Fabio; Pistoia, Vito; Airoldi, Irma] Ist Giannina Gaslini, Lab Oncol, I-16147 Genoa, Italy. [Di Carlo, Emma] Univ G DAnnunzio, Dept Med & Sci Aging, I-66013 Chieti, Italy. [Di Carlo, Emma] Univ G DAnnunzio Fdn, Ctr Aging Sci, I-66013 Chieti, Italy. [Ferrone, Soldano] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Petretto, Andrea] Ist Giannina Gaslini, Lab Immunol Clin & Sperimentale, I-16147 Genoa, Italy. RP Airoldi, I (reprint author), Ist Giannina Gaslini, Lab Oncol, Via Gerolamo Gaslini 1, I-16147 Genoa, Italy. EM irmaairoldi@ospedale-gaslini.ge.it OI Morandi, Fabio/0000-0002-2849-7595 FU Associazione Italiana Ricerca sul Cancro (Milan, Italy) [13018]; Ricerca Finalizzata Collaboratore Estero Ministero della Salute [RF-2010-2308270]; Cinque per Mille e Ricerca Corrente, Ministero della Salute FX This work was supported by Associazione Italiana Ricerca sul Cancro (Milan, Italy) Grant 13018 (to I. A.), Ricerca Finalizzata Collaboratore Estero Ministero della Salute Grant RF-2010-2308270 (to I. A.), and by Cinque per Mille e Ricerca Corrente, Ministero della Salute. NR 33 TC 4 Z9 5 U1 1 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2014 VL 192 IS 6 BP 2634 EP 2642 DI 10.4049/jimmunol.1302656 PG 9 WC Immunology SC Immunology GA AC7IX UT WOS:000332702700012 PM 24554774 ER PT J AU Kim-Howard, X Sun, C Molineros, JE Maiti, AK Chandru, H Adler, A Wiley, GB Kaufman, KM Kottyan, L Guthridge, JM Rasmussen, A Kelly, J Sanchez, E Raj, P Li, QZ Bang, SY Lee, HS Kim, TH Kang, YM Suh, CH Chung, WT Park, YB Choe, JY Shim, SC Lee, SS Han, BG Olsen, NJ Karp, DR Moser, K Pons-Estel, BA Wakeland, EK James, JA Harley, JB Bae, SC Gaffney, PM Alarcon-Riquelme, M Looger, LL Nath, SK AF Kim-Howard, Xana Sun, Celi Molineros, Julio E. Maiti, Amit K. Chandru, Hema Adler, Adam Wiley, Graham B. Kaufman, Kenneth M. Kottyan, Leah Guthridge, Joel M. Rasmussen, Astrid Kelly, Jennifer Sanchez, Elena Raj, Prithvi Li, Quan-Zhen Bang, So-Young Lee, Hye-Soon Kim, Tae-Hwan Kang, Young Mo Suh, Chang-Hee Chung, Won Tae Park, Yong-Beom Choe, Jung-Yoon Shim, Seung Cheol Lee, Shin-Seok Han, Bok-Ghee Olsen, Nancy J. Karp, David R. Moser, Kathy Pons-Estel, Bernardo A. Wakeland, Edward K. James, Judith A. Harley, John B. Bae, Sang-Cheol Gaffney, Patrick M. Alarcon-Riquelme, Marta Looger, Loren L. Nath, Swapan K. CA GENLES TI Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations SO HUMAN MOLECULAR GENETICS LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; PHAGOCYTE NADPH OXIDASE; GENOME-WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS; GENETIC SUSCEPTIBILITY; RNA SURVEILLANCE; REVISED CRITERIA; OXIDATIVE STRESS; CROHNS-DISEASE; RISK LOCI AB Recent reports have associated NCF2, encoding a core component of the multi-protein NADPH oxidase (NADPHO), with systemic lupus erythematosus (SLE) susceptibility in individuals of European ancestry. To identify ethnicity-specific and -robust variants within NCF2, we assessed 145 SNPs in and around the NCF2 gene in 5325 cases and 21 866 controls of European-American (EA), African-American (AA), Hispanic (HS) and Korean(KR) ancestry. Subsequent imputation, conditional, haplotype and bioinformatic analyses identified seven potentially functional SLE-predisposing variants. Association with non-synonymous rs17849502, previously reported in EA, was detected in EA, HS and AA (P-EA = 1.01 x 10(-54), P-HS = 3.68 x 10(-10), P-AA = 0.03); synonymous rs17849501 was similarly significant. These SNPs were monomorphic in KR. Novel associations were detected with coding variants at rs35937854 in AA (P-AA = 1.49 x 10(-9)), and rs13306575 in HS and KR (P-HS = 7.04 x 10(-7), P-KR = 3.30 x 10(-3)). In KR, a3-SNP haplotype was significantly associated (P 5 4.20 3 10 27), implying that SLE predisposing variants were tagged. Significant SNP-SNP interaction (P 5 0.02) was detected between rs13306575 and rs17849502 in HS, and adramatically increased risk(OR 5 6.55) with a risk allele at each locus. Molecular modeling predicts that these non-synonymous mutations could disrupt NADPHO complex assembly. The risk allele of rs17849501, located in a conserved transcriptional regulatory region, increased reporter gene activity, suggesting in vivo enhancer function. Our results not only establish allelic heterogeneity within NCF2 associated with SLE, but also emphasize the utility of multi-ethnic cohorts to identify predisposing variants explaining additional phenotypic variance ('missing heritability') of complex diseases like SLE. C1 [Kim-Howard, Xana; Sun, Celi; Molineros, Julio E.; Maiti, Amit K.; Chandru, Hema; Adler, Adam; Wiley, Graham B.; Guthridge, Joel M.; Rasmussen, Astrid; Kelly, Jennifer; Sanchez, Elena; Moser, Kathy; James, Judith A.; Gaffney, Patrick M.; Alarcon-Riquelme, Marta; Nath, Swapan K.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Kaufman, Kenneth M.; Kottyan, Leah; Harley, John B.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Kaufman, Kenneth M.; Kottyan, Leah; Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. [Raj, Prithvi; Li, Quan-Zhen; Wakeland, Edward K.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Bang, So-Young; Lee, Hye-Soon; Kim, Tae-Hwan; Bae, Sang-Cheol] Hanyang Univ, Dept Rheumatol, Hosp Rheumat Dis, Seoul 133791, South Korea. [Kang, Young Mo] Kyungpook Natl Univ Hosp, Taegu, South Korea. [Suh, Chang-Hee] Ajou Univ Hosp, Suwon, South Korea. [Chung, Won Tae] Dong A Univ Hosp, Pusan, South Korea. [Park, Yong-Beom] Yonsei Univ, Coll Med, Dept Internal Med, Seoul, South Korea. [Choe, Jung-Yoon] Daegu Catholic Univ Hosp, Taegu, South Korea. [Shim, Seung Cheol] Chungnam Natl Univ Hosp, Daejeon Rheumatoid & Degenerat Arthrit Ctr, Taejon, South Korea. [Lee, Shin-Seok] Chonnam Natl Univ Hosp, Kwangju, South Korea. [Han, Bok-Ghee] Korea Natl Inst Hlth, Osong, South Korea. [Olsen, Nancy J.] Penn State Med Sch, Dept Med, Div Rheumatol, Hershey, PA USA. [Karp, David R.] Univ Texas Southwest Med Ctr, Dept Med, Div Rheumat Dis, Dallas, TX USA. [Pons-Estel, Bernardo A.] Sanat Parque, Rosario, Santa Fe, Argentina. [Looger, Loren L.] Howard Hughes Med Inst, Ashburn, VA USA. RP Nath, SK (reprint author), Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 1025 NE 13th St, Oklahoma City, OK 73104 USA. EM swapan-nath@omrf.org RI Sanchez, Elena/B-4140-2017; OI Sanchez, Elena/0000-0002-7041-5485; Kottyan, Leah/0000-0003-3979-2220; Suh, Chang-Hee/0000-0001-6156-393X FU US National Institutes of Health [AI103399, AR060366, AI094377, AI083194, CA141700, AR058621, AI101934, AI082714, AR053483, GM103510, GM103456, A121983]; Ministry for Health & Welfare, Republic of Korea FX This work was supported by grants from the US National Institutes of Health (AI103399, AR060366, AI094377, AI083194, CA141700, AR058621, AI101934, AI082714, AR053483, GM103510, GM103456) and A121983, the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare, Republic of Korea. NR 98 TC 15 Z9 15 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAR 15 PY 2014 VL 23 IS 6 BP 1656 EP 1668 DI 10.1093/hmg/ddt532 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AB8MK UT WOS:000332044300022 PM 24163247 ER PT J AU Perez, VB Woods, SW Roach, BJ Ford, JM McGlashan, TH Srihari, VH Mathalon, DH AF Perez, Veronica B. Woods, Scott W. Roach, Brian J. Ford, Judith M. McGlashan, Thomas H. Srihari, Vinod H. Mathalon, Daniel H. TI Automatic Auditory Processing Deficits in Schizophrenia and Clinical High-Risk Patients: Forecasting Psychosis Risk with Mismatch Negativity SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Auditory cortex; clinical high-risk for psychosis; event-related potential; longitudinal; mismatch negativity; psychosis; schizophrenia ID EVENT-RELATED POTENTIALS; D-ASPARTATE RECEPTORS; ULTRA-HIGH-RISK; 1ST-EPISODE SCHIZOPHRENIA; INTERRATER RELIABILITY; SELECTIVE-ATTENTION; PREDICTIVE-VALIDITY; PRODROMAL SYNDROMES; SPECTRUM DISORDERS; STIMULUS DEVIANCE AB Background: Only about one third of patients at high risk for psychosis based on current clinical criteria convert to a psychotic disorder within a 2.5-year follow-up period. Targeting clinical high-risk (CHR) individuals for preventive interventions could expose many to unnecessary treatments, underscoring the need to enhance predictive accuracy with nonclinical measures. Candidate measures include event-related potential components with established sensitivity to schizophrenia. Here, we examined the mismatch negativity (MMN) component of the event-related potential elicited automatically by auditory deviance in CHR and early illness schizophrenia (ESZ) patients. We also examined whether MMN predicted subsequent conversion to psychosis in CHR patients. Methods: Mismatch negativity to auditory deviants (duration, frequency, and duration + frequency double deviant) was assessed in 44 healthy control subjects, 19 ESZ, and 38 CHR patients. Within CHR patients, 15 converters to psychosis were compared with 16 nonconverters with at least 12 months of clinical follow-up. Hierarchical Cox regression examined the ability of MMN to predict time to psychosis onset in CHR patients. Results: Irrespective of deviant type, MMN was significantly reduced in ESZ and CHR patients relative to healthy control subjects and in CHR converters relative to nonconverters. Mismatch negativity did not significantly differentiate ESZ and CHR patients. The duration + frequency double deviant MMN, but not the single deviant MMNs, significantly predicted the time to psychosis onset in CHR patients. Conclusions: Neurophysiological mechanisms underlying automatic processing of auditory deviance, as reflected by the duration + frequency double deviant MMN, are compromised before psychosis onset and can enhance the prediction of psychosis risk among CHR patients. C1 [Perez, Veronica B.; Roach, Brian J.; Ford, Judith M.; Mathalon, Daniel H.] Univ Calif San Francisco, San Francisco, CA 94121 USA. [Perez, Veronica B.; Roach, Brian J.; Ford, Judith M.; Mathalon, Daniel H.] San Francisco Vet Adm Med Ctr, San Francisco, CA USA. [Woods, Scott W.; McGlashan, Thomas H.; Srihari, Vinod H.] Yale Univ, Sch Med, New Haven, CT USA. RP Mathalon, DH (reprint author), Univ Calif San Francisco, San Francisco Vet Adm Med Ctr, Mental Hlth Serv 116D, 4150 Clement St, San Francisco, CA 94121 USA. EM daniel.mathalon@ucsf.edu OI Mathalon, Daniel/0000-0001-6090-4974; Roach, Brian/0000-0002-3264-1465; Srihari, Vinod/0000-0003-1556-2332 FU National Institutes of Health [R01 MH076989, U01 MH082022, K02 MH067967, T32 MH089920]; Brain and Behavior Research Foundation FX This study was supported by grants from the National Institutes of Health (R01 MH076989, U01 MH082022, K02 MH067967, and T32 MH089920) and from the Brain and Behavior Research Foundation. NR 89 TC 33 Z9 35 U1 4 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 15 PY 2014 VL 75 IS 6 BP 459 EP 469 DI 10.1016/j.biopsych.2013.07.038 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AB4AK UT WOS:000331731100006 PM 24050720 ER PT J AU Lee, TH Chang, J Kim, BM AF Lee, Tae Ho Chang, Jihoon Kim, Byeong Mo TI Saikosaponin C inhibits lipopolysaccharide-induced apoptosis by suppressing caspase-3 activation and subsequent degradation of focal adhesion kinase in human umbilical vein endothelial cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Lipopolysaccharide (LPS); Human umbilical vein endothelial cells (HUVECs); Endothelial cell apoptosis; Saikosaponin C (SSc); Caspase-3; Focal adhesion kinase (FAK) ID SOLUBLE CD14; CLEAVAGE; SURVIVAL; MECHANISM; PROTEINS; PATHWAY; GROWTH; INJURY; LINE AB Bacterial lipopolysaccharide (LPS) is an important mediator of inflammation and a potent inducer of endothelial cell damage and apoptosis. In this study, we investigated the protective effects of saikosaponin C (SSc), one of the active ingredients produced by the traditional Chinese herb, Radix Bupleuri, against LPS-induced apoptosis in human umbilical endothelial cells (HUVECs). LPS triggered caspase-3 activation, which was found to be important in LPS-induced HUVEC apoptosis. Inhibition of caspase-3 also inhibited LPS-induced degradation of focal adhesion kinase (FAK), indicating that caspase-3 is important in LPS-mediated FAK degradation as well as in apoptosis in HUVECs. SSc significantly inhibited LPS-induced apoptotic cell death in HUVECs through the selective suppression of caspase-3. SSc was also shown to rescue LPS-induced FAK degradation and other cell adhesion signals. Furthermore, the protective effects of SSc against LPS-induced apoptosis were abolished upon pretreatment with a FAK inhibitor, highlighting the importance of FAK in SSc activity. Taken together, these results show that SSc efficiently inhibited LPS-induced apoptotic cell death via inhibition of caspase-3 activation and caspase-3-mediated-FAK degradation. Therefore, SSc represents a promising therapeutic candidate for the treatment of vascular endothelial cell injury and cellular dysfunction. (C) 2014 Elsevier Inc. All rights reserved. C1 [Lee, Tae Ho; Kim, Byeong Mo] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gerontol,Dept Med, Boston, MA 02215 USA. [Chang, Jihoon] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. RP Kim, BM (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gerontol,Dept Med, Boston, MA 02215 USA. EM bkim2@bidmc.harvard.edu FU Korean Government [NRF-2011-356-C00085]; National Research Foundation of Korea Grant FX This work was supported by the National Research Foundation of Korea Grant funded by the Korean Government (NRF-2011-356-C00085). NR 26 TC 6 Z9 6 U1 1 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 14 PY 2014 VL 445 IS 3 BP 615 EP 621 DI 10.1016/j.bbrc.2014.02.046 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AE9JC UT WOS:000334323100014 PM 24565837 ER PT J AU Wang, J Bi, WN Cheng, A Freire, D Vempati, P Zhao, W Gong, B Janle, EM Chen, TY Ferruzzi, MG Schmeidler, J Ho, L Pasinetti, GM AF Wang, Jun Bi, Weina Cheng, Alice Freire, Daniel Vempati, Prashant Zhao, Wei Gong, Bing Janle, Elsa M. Chen, Tzu-Ying Ferruzzi, Mario G. Schmeidler, James Ho, Lap Pasinetti, Giulio M. TI Targeting multiple pathogenic mechanisms with polyphenols for the treatment of Alzheimer's disease-experimental approach and therapeutic implications SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Article DE Alzheimer's disease (AD); polyphenols; grape seed extract; grape juice; resveratrol; J20 mice ID LONG-TERM POTENTIATION; MOUSE MODEL; COGNITIVE DETERIORATION; TRANSGENIC MICE; RESVERATROL; NEUROPATHOLOGY; BRAIN; INFLAMMATION; SUPPLEMENTATION; CONSUMPTION AB Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging and currently has no cure. Its onset and progression are influenced by multiple factors. There is growing consensus that successful treatment will rely on simultaneously targeting multiple pathological features of AD. Polyphenol compounds have many proven health benefits. In this study, we tested the hypothesis that combining three polyphenolic preparations (grape seed extract, resveratrol, and Concord grape juice extract), with different polyphenolic compositions and partially redundant bioactivities, may simultaneously and synergistically mitigate amyloid-beta (A beta) mediated neuropathology and cognitive impairments in a mouse model of AD. We found that administration of the polyphenols in combination did not alter the profile of bioactive polyphenol metabolites in the brain. We also found that combination treatment resulted in better protection against cognitive impairments compared to individual treatments, in J20 AD mice. Electrophysiological examination showed that acute treatment with select brain penetrating polyphenol metabolites, derived from these polyphenols, improved oligomeric A beta (oA beta)-induced long term potentiation (LIP) deficits in hippocampal slices. Moreover, we found greatly reduced total amyloid content in the brain following combination treatment. Our studies provided experimental evidence that application of polyphenols targeting multiple disease-mechanisms may yield a greater likelihood of therapeutic efficacy. C1 [Wang, Jun; Bi, Weina; Cheng, Alice; Freire, Daniel; Vempati, Prashant; Zhao, Wei; Gong, Bing; Ho, Lap; Pasinetti, Giulio M.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY USA. [Wang, Jun; Pasinetti, Giulio M.] James J Peters Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. [Janle, Elsa M.; Chen, Tzu-Ying; Ferruzzi, Mario G.] Purdue Univ, Dept Food Sci, W Lafayette, IN 47907 USA. [Janle, Elsa M.; Chen, Tzu-Ying; Ferruzzi, Mario G.] Purdue Univ, Dept Foods & Nutr, W Lafayette, IN 47907 USA. [Schmeidler, James] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY USA. RP Pasinetti, GM (reprint author), Mt Sinai Sch Med, Dept Neurol, 1 Gustave L Levy Pl,Box 1137, New York, NY 10029 USA. EM giulio.pasinetti@mssm.edu NR 51 TC 22 Z9 24 U1 1 U2 29 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD MAR 14 PY 2014 VL 6 AR 42 DI 10.3389/fnagi.2014.00042 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA AC9HX UT WOS:000332846300001 PM 24672477 ER PT J AU Xiao, L Zhang, CK Li, XH Gong, SC Hu, RM Balasubramanian, R Crowley Jr, WF Hastings, MH Zhou, QY AF Xiao, Ling Zhang, Chengkang Li, Xiaohan Gong, Shiaoching Hu, Renming Balasubramanian, Ravikumar Crowley, William F. W., Jr. Hastings, Michael H. Zhou, Qun-Yong TI Signaling Role of Prokineticin 2 on the Estrous Cycle of Female Mice SO PLOS ONE LA English DT Article ID LUTEINIZING-HORMONE SURGE; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; SUPRACHIASMATIC NUCLEUS; CIRCADIAN-RHYTHMS; EFFERENT PROJECTIONS; OLFACTORY-BULB; PREOPTIC AREA; NEURONS; KISSPEPTIN; RATS AB The possible signaling role of prokineticin 2 (PK2) and its receptor, prokineticin receptor 2 (PKR2), on female reproduction was investigated. First, the expression of PKR2 and its co-localization with estrogen receptor (ER alpha) in the hypothalamus was examined. Sexually dimorphic expression of PKR2 in the preoptic area of the hypothalamus was observed. Compared to the male mice, there was more widespread PKR2 expression in the preoptic area of the hypothalamus in the female mice. The likely co-expression of PKR2 and ERa in the preoptic area of the hypothalamus was observed. The estrous cycles in female PK2-null, and PKR2-null heterozygous mice, as well as in PK2-null and PKR2-null compound heterozygous mice were examined. Loss of one copy of PK2 or PKR2 gene caused elongated and irregular estrous cycle in the female mice. The alterations in the estrous cycle were more pronounced in PK2-null and PKR2-null compound heterozygous mice. Consistent with these observations, administration of a small molecule PK2 receptor antagonist led to temporary blocking of estrous cycle at the proestrous phase in female mice. The administration of PKR2 antagonist was found to blunt the circulating LH levels. Taken together, these studies indicate PK2 signaling is required for the maintenance of normal female estrous cycles. C1 [Xiao, Ling; Zhang, Chengkang; Li, Xiaohan; Zhou, Qun-Yong] Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92717 USA. [Xiao, Ling] Fudan Univ, Jinshan Hosp, Dept Endocrinol, Shanghai 200433, Peoples R China. [Gong, Shiaoching] Rockefeller Univ, GENSAT Project, New York, NY 10021 USA. [Hu, Renming] Fudan Univ, Huashan Hosp, Inst Endocrinol & Diabetol, Shanghai 200433, Peoples R China. [Balasubramanian, Ravikumar; Crowley, William F. W., Jr.] Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr, Boston, MA 02114 USA. [Balasubramanian, Ravikumar; Crowley, William F. W., Jr.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. [Hastings, Michael H.] Med Res Council Lab Mol Biol, Div Neurobiol, Cambridge, England. RP Zhou, QY (reprint author), Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92717 USA. EM qzhou@uci.edu OI Hastings, Michael Harvey/0000-0001-8576-6651 FU NIH [HD15788] FX This work was supported by NIH grant HD15788. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 1 Z9 1 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 14 PY 2014 VL 9 IS 3 AR e90860 DI 10.1371/journal.pone.0090860 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC9MJ UT WOS:000332858400022 PM 24633064 ER PT J AU Mulak, A Tache, Y Larauche, M AF Mulak, Agata Tache, Yvette Larauche, Muriel TI Sex hormones in the modulation of irritable bowel syndrome SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Brain-gut axis; Irritable bowel syndrome; Microbiota; Pain modulation; Sex hormones ID INDUCED VISCERAL HYPERSENSITIVITY; CORTICOTROPIN-RELEASING HORMONE; MESSENGER-RNA EXPRESSION; ESTROGEN-RECEPTOR-ALPHA; FUNCTIONAL GASTROINTESTINAL DISORDERS; MAST-CELL SECRETION; MENSTRUAL-CYCLE; FEMALE RATS; GUT MICROBIOTA; POSTMENOPAUSAL WOMEN AB Compelling evidence indicates sex and gender differences in epidemiology, symptomatology, pathophysiology, and treatment outcome in irritable bowel syndrome (IBS). Based on the female predominance as well as the correlation between IBS symptoms and hormonal status, several models have been proposed to examine the role of sex hormones in gastrointestinal (GI) function including differences in GI symptoms expression in distinct phases of the menstrual cycle, in pre- and post-menopausal women, during pregnancy, hormonal treatment or after oophorectomy. Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity, motility, intestinal barrier function, and immune activation of intestinal mucosa. Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system, neuroimmune interactions triggered by stress, as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized. A concept of "microgenderome" related to the potential role of sex hormone modulation of the gut microbiota is also emerging. Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders, together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder. (C) 2014 Baishideng Publishing Group Co., Limited. All rights reserved. C1 [Mulak, Agata] Wroclaw Med Univ, Dept Gastroenterol & Hepatol, PL-50556 Wroclaw, Poland. [Tache, Yvette; Larauche, Muriel] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, CURE Digest Dis Res Ctr, Los Angeles, CA 90073 USA. [Tache, Yvette; Larauche, Muriel] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Oppenheimer Family Ctr Neurobiol Stress, Dept Med,Div Digest Dis, Los Angeles, CA 90073 USA. RP Mulak, A (reprint author), Wroclaw Med Univ, Dept Gastroenterol & Hepatol, Borowska 213, PL-50556 Wroclaw, Poland. EM agata.mulak@wp.pl OI Larauche, Muriel/0000-0003-3320-3675 FU The Veterans Administration Research Career Scientist Award; National Institute of Health [P50 DK-64539, K01-DK088937] FX Supported by The Veterans Administration Research Career Scientist Award (to Tache Y); National Institute of Health grants No. P50 DK-64539 (to Tache Y); and No. K01-DK088937 (to Larauche M) NR 164 TC 31 Z9 31 U1 4 U2 40 PU BAISHIDENG PUBLISHING GROUP INC PI PLEASANTON PA 8226 REGENCY DR, PLEASANTON, CA 94588 USA SN 1007-9327 EI 2219-2840 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD MAR 14 PY 2014 VL 20 IS 10 BP 2433 EP 2448 DI 10.3748/wjg.v20.i10.2433 PG 16 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AC7GY UT WOS:000332697400002 PM 24627581 ER PT J AU Hunter, ZR Xu, L Yang, G Zhou, YS Liu, X Cao, Y Manning, RJ Tripsas, C Patterson, CJ Sheehy, P Treon, SP AF Hunter, Zachary R. Xu, Lian Yang, Guang Zhou, Yangsheng Liu, Xia Cao, Yang Manning, Robert J. Tripsas, Christina Patterson, Christopher J. Sheehy, Patricia Treon, Steven P. TI The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; NF-KAPPA-B; CHRONIC LYMPHOCYTIC-LEUKEMIA; IGM MONOCLONAL GAMMOPATHY; BRUTONS TYROSINE KINASE; UNDETERMINED SIGNIFICANCE; TUMOR-SUPPRESSOR; RECEPTOR INTERNALIZATION; BINDING PROTEIN; TARGET GENES AB The genetic basis for Waldenstrom macroglobulinemia (WM) remains to be clarified. Although 6q losses are commonly present, recurring gene losses in this region remain to be defined. We therefore performed whole genome sequencing (WGS) in 30 WM patients, which included germline/tumor sequencing for 10 patients. Validated somatic mutations occurring in >10% of patients includedMYD88, CXCR4, and ARID1A that were present in 90%, 27%, and 17% of patients, respectively, and included the activating mutation L265P in MYD88 and warts, hypogammaglobulinemia, infection, and myelokathexis-syndrome-like mutations in CXCR4 that previously have only been described in the germline. WGS also delineated copy number alterations (CNAs) and structural variants in the 10 paired patients. The CXCR4 and CNA findings were validated in independent expansion cohorts of 147 and 30WM patients, respectively. Validated gene losses due to CNAs involved PRDM2 (93%), BTG1 (87%), HIVEP2 (77%), MKLN1 (77%), PLEKHG1 (70%), LYN (60%), ARID1B (50%), and FOXP1 (37%). Losses in PLEKHG1, HIVEP2, ARID1B, and BCLAF1 constituted the most common deletions within chromosome 6. Although no recurrent translocations were observed, in 2 patients deletions in 6q corresponded with translocation events. These studies evidence highly recurring somatic events, and provide a genomic basis for understanding the pathogenesis of WM. C1 [Hunter, Zachary R.; Xu, Lian; Yang, Guang; Zhou, Yangsheng; Liu, Xia; Cao, Yang; Manning, Robert J.; Tripsas, Christina; Patterson, Christopher J.; Sheehy, Patricia; Treon, Steven P.] Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02215 USA. [Hunter, Zachary R.] Boston Univ, Grad Sch Med Sci, Dept Pathol & Lab Med, Boston, MA 02215 USA. [Treon, Steven P.] Harvard Univ, Sch Med, Boston, MA USA. RP Treon, SP (reprint author), Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, M547,450 Brookline Ave, Boston, MA 02215 USA. EM steven_treon@dfci.harvard.edu RI Hunter, Zachary/H-3018-2013 OI Hunter, Zachary/0000-0002-1689-1691 FU International Waldenstrom's Macroglobulinemia Foundation; Coyote Fund for Waldenstrom's Macroglobulinemia; D'Amato Family Fund for Genomic Discovery; Edward and Linda Nelson Fund for Waldenstrom's Macroglobulinemia Research FX This work was supported by Peter S. Bing, the International Waldenstrom's Macroglobulinemia Foundation, the Coyote Fund for Waldenstrom's Macroglobulinemia, the D'Amato Family Fund for Genomic Discovery, the Edward and Linda Nelson Fund for Waldenstrom's Macroglobulinemia Research, and the WM patients who provided their samples. NR 70 TC 66 Z9 66 U1 1 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 13 PY 2014 VL 123 IS 11 BP 1637 EP 1646 DI 10.1182/blood-2013-09-525808 PG 10 WC Hematology SC Hematology GA AH0YW UT WOS:000335847700010 PM 24366360 ER PT J AU Chang, JE Li, HL Smith, MR Gascoyne, RD Paietta, EM Yang, DT Advani, RH Horning, SJ Kahl, BS AF Chang, Julie E. Li, Hailun Smith, Mitchell R. Gascoyne, Randy D. Paietta, Elisabeth M. Yang, David T. Advani, Ranjana H. Horning, Sandra J. Kahl, Brad S. TI Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405) SO BLOOD LA English DT Article ID PROGRESSION-FREE SURVIVAL; STUDY-GROUP GLSG; INDUCTION CHEMOIMMUNOTHERAPY; PLUS CHEMOTHERAPY; BORTEZOMIB; TRIAL; CYCLOPHOSPHAMIDE; MULTICENTER; COMBINATION; DOXORUBICIN AB Rituximab, bortezomib, modified hyper-cyclophosphamide, doxorubicin, vincristine, dexamethasone (VcR-CVAD) induction chemoimmunotherapy and maintenance rituximab (MR) were evaluated for efficacy and safety in Eastern Cooperative Oncology Group protocol E1405. Patients with previously untreated mantle cell lymphoma received VcR-CVAD chemotherapy every 21 days for 6 cycles, followed by MR for 2 years. Transplant-eligible patients had the option of autologous stem cell transplantation (ASCT) consolidation instead of MR. The primary end point was the complete response (CR) rate to VcR-CVAD. The secondary end points were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicities. Seventy-five eligible patients with a median age of 62 (range 40-76) were enrolled. The ORR was 95% and a CR was achieved in 68% of patients. After a median follow-up of 4.5 years, 3-year PFS and OS were 72% and 88%, respectively. No substantial difference in PFS or OS was observed between patients treated with MR (n = 44) vs ASCT (n = 22). There were no unexpected toxicities. VcR-CVAD produced high ORR and CR rates in mantle cell lymphoma. MR after VcR-CVAD induction performed similarly to ASCT and may improve response duration. Randomized clinical trials comparing MR against ASCT should be considered and randomized clinical trials evaluating bortezomib's contribution to conventional therapy are under way. This study was registered at www.clinicaltrials.gov as #NCT00433537. C1 [Chang, Julie E.; Yang, David T.; Kahl, Brad S.] Univ Wisconsin, Madison, WI 53705 USA. [Li, Hailun] Dana Farber Canc Inst, Boston, MA 02115 USA. [Smith, Mitchell R.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Paietta, Elisabeth M.] Montefiore Med Ctr, North Div, Bronx, NY 10467 USA. [Advani, Ranjana H.] Stanford Univ, Stanford, CA 94305 USA. [Horning, Sandra J.] Genentech Inc, San Francisco, CA 94080 USA. RP Kahl, BS (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Inst Med Res, 1111 Highland Ave,4059, Madison, WI 53705 USA. EM bsk@medicine.wisc.edu OI Smith, Mitchell/0000-0003-1428-8765 FU Public Health Service Grants [CA21115, CA23318, CA66636, CA27525, CA21076, CA14958]; National Cancer Institute, National Institutes of Health; Department of Health and Human Services FX This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, chair) and supported in part by Public Health Service Grants (CA21115, CA23318, CA66636, CA27525, CA21076, 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 41 TC 25 Z9 28 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 13 PY 2014 VL 123 IS 11 BP 1665 EP 1673 DI 10.1182/blood-2013-08-523845 PG 9 WC Hematology SC Hematology GA AH0YW UT WOS:000335847700013 PM 24458437 ER PT J AU Chambwe, N Kormaksson, M Geng, HM De, S Michor, F Johnson, NA Morin, RD Scott, DW Godley, LA Gascoyne, RD Melnick, A Campagne, F Shaknovich, R AF Chambwe, Nyasha Kormaksson, Matthias Geng, Huimin De, Subhajyoti Michor, Franziska Johnson, Nathalie A. Morin, Ryan D. Scott, David W. Godley, Lucy A. Gascoyne, Randy D. Melnick, Ari Campagne, Fabien Shaknovich, Rita TI Variability in DNA methylation defines novel epigenetic subgroups of DLBCL associated with different clinical outcomes SO BLOOD LA English DT Article ID B-CELL LYMPHOMA; ACUTE MYELOID-LEUKEMIA; CYTOSINE METHYLATION; SOMATIC MUTATIONS; PROGNOSTIC-FACTOR; HODGKIN-LYMPHOMA; EXPRESSION; METHYLTRANSFERASE; HYPERMETHYLATION; PROTEIN AB Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive form of non-Hodgkin lymphoma with variable biology and clinical behavior. The current classification does not fully explain the biological and clinical heterogeneity of DLBCLs. In this study, we carried out genomewide DNA methylation profiling of 140 DLBCL samples and 10 normal germinal center B cells using the HpaII tiny fragment enrichment by ligation-mediated polymerase chain reaction assay and hybridization to a custom Roche NimbleGen promoter array. We defined methylation disruption as a main epigenetic event in DLBCLs and designed a method for measuring the methylation variability of individual cases. We then used a novel approach for unsupervised hierarchical clustering based on the extent of DNA methylation variability. This approach identified 6 clusters (A-F). The extent of methylation variability was associated with survival outcomes, with significant differences in overall and progression-free survival. The novel clusters are characterized by disruption of specific biological pathways such as cytokine-mediated signaling, ephrin signaling, and pathways associated with apoptosis and cell-cycle regulation. In a subset of patients, we profiled gene expression and genomic variation to investigate their interplay with methylation changes. This study is the first to identify novel epigenetic clusters of DLBCLs and their aberrantly methylated genes, molecular associations, and survival. C1 [Chambwe, Nyasha; Campagne, Fabien] Weill Cornell Med Ctr, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY USA. [Chambwe, Nyasha; Campagne, Fabien] Weill Cornell Med Ctr, Dept Physiol & Biophys, New York, NY USA. [Chambwe, Nyasha] Weill Cornell Med Ctr, Tri Inst Training Program Computat Biol & Med, New York, NY USA. [Kormaksson, Matthias] Weill Cornell Med Ctr, Dept Publ Hlth, New York, NY USA. [Kormaksson, Matthias] IBM Res Brazil, Rio De Janeiro, Brazil. [Geng, Huimin] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [De, Subhajyoti] Univ Colorado, Sch Med, Dept Med, Aurora, CO USA. [De, Subhajyoti] Colorado Sch Publ Hlth, Dept Biostat & Informat, Aurora, CO USA. [De, Subhajyoti] Univ Colorado, Ctr Canc, Mol Oncol Program, Aurora, CO USA. [Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Johnson, Nathalie A.] McGill Univ, Jewish Gen Hosp, Dept Med, Montreal, PQ H3T 1E2, Canada. [Morin, Ryan D.] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada. [Morin, Ryan D.] British Columbia Canc Agcy, Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada. [Scott, David W.; Gascoyne, Randy D.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 4E6, Canada. [Godley, Lucy A.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Gascoyne, Randy D.] Univ British Columbia, Dept Pathol, Vancouver, BC, Canada. [Melnick, Ari] Weill Cornell Med Coll, Dept Pharmacol, New York, NY USA. [Melnick, Ari; Shaknovich, Rita] Weill Cornell Med Coll, Div Hematol & Oncol, New York, NY USA. [Shaknovich, Rita] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY USA. RP Shaknovich, R (reprint author), Weill Cornell Med Coll, 1300 York Ave,Bldg C,Room 620C, New York, NY 10065 USA. EM fac2003@campagnelab.org; ris9004@med.cornell.edu OI Campagne, Fabien/0000-0001-6237-3564; Chambwe, Nyasha/0000-0002-2812-0122 FU Tri-Institutional Training Program in Computational Biology and Medicine; National Institutes of Health [K08 CA127353]; Leukemia & Lymphoma Society [6304-11, U54CA143798] FX This work was supported by grants from the Tri-Institutional Training Program in Computational Biology and Medicine (N.C.), the National Institutes of Health Clinical Investigator Award (K08 CA127353), and The Leukemia & Lymphoma Society (6304-11) (R.S.) (U54CA143798) (S.D. and F.M.). NR 53 TC 24 Z9 24 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 13 PY 2014 VL 123 IS 11 BP 1699 EP 1708 DI 10.1182/blood-2013-07-509885 PG 10 WC Hematology SC Hematology GA AH0YW UT WOS:000335847700017 PM 24385541 ER PT J AU Menche, J Sharma, A Cho, MH Mayer, RJ Rennard, SI Celli, B Miller, BE Locantore, N Tal-Singer, R Ghosh, S Larminie, C Bradley, G Riley, JH Agusti, A Silverman, EK Barabasi, AL AF Menche, Joerg Sharma, Amitabh Cho, Michael H. Mayer, Ruth J. Rennard, Stephen I. Celli, Bartolome Miller, Bruce E. Locantore, Nick Tal-Singer, Ruth Ghosh, Soumitra Larminie, Chris Bradley, Glyn Riley, John H. Agusti, Alvar Silverman, Edwin K. Barabasi, Albert-Laszlo TI A diVIsive Shuffling Approach (VIStA) for gene expression analysis to identify subtypes in Chronic Obstructive Pulmonary Disease SO BMC SYSTEMS BIOLOGY LA English DT Article; Proceedings Paper CT High-Throughput Omics and Data Integration Workshop CY FEB 13-15, 2013 CL Barcelona, SPAIN ID SMOKERS; ECLIPSE; CANCER; TISSUE AB Background: An important step toward understanding the biological mechanisms underlying a complex disease is a refined understanding of its clinical heterogeneity. Relating clinical and molecular differences may allow us to define more specific subtypes of patients that respond differently to therapeutic interventions. Results: We developed a novel unbiased method called diVIsive Shuffling Approach (VIStA) that identifies subgroups of patients by maximizing the difference in their gene expression patterns. We tested our algorithm on 140 subjects with Chronic Obstructive Pulmonary Disease (COPD) and found four distinct, biologically and clinically meaningful combinations of clinical characteristics that are associated with large gene expression differences. The dominant characteristic in these combinations was the severity of airflow limitation. Other frequently identified measures included emphysema, fibrinogen levels, phlegm, BMI and age. A pathway analysis of the differentially expressed genes in the identified subtypes suggests that VIStA is capable of capturing specific molecular signatures within in each group. Conclusions: The introduced methodology allowed us to identify combinations of clinical characteristics that correspond to clear gene expression differences. The resulting subtypes for COPD contribute to a better understanding of its heterogeneity. C1 [Menche, Joerg; Sharma, Amitabh; Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA. [Menche, Joerg; Sharma, Amitabh; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Menche, Joerg; Sharma, Amitabh; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Menche, Joerg; Barabasi, Albert-Laszlo] Budapest Univ Technol & Econ, Dept Theoret Phys, H-1111 Budapest, Hungary. [Cho, Michael H.; Silverman, Edwin K.] Harvard Univ, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Cho, Michael H.; Silverman, Edwin K.] Harvard Univ, Sch Med, Div Pulm & Crit Care Med, Dept Med,Brigham & Womens Hosp, Boston, MA 02115 USA. [Mayer, Ruth J.; Miller, Bruce E.; Tal-Singer, Ruth; Ghosh, Soumitra] GlaxoSmithKline, King Of Prussia, PA 19406 USA. [Rennard, Stephen I.] Univ Nebraska Med Ctr, Omaha, NE 68198 USA. [Celli, Bartolome] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Pulm & Crit Care, Boston, MA 02115 USA. [Locantore, Nick] GlaxoSmithKline, Res Triangle Pk, NC 27709 USA. [Larminie, Chris; Bradley, Glyn; Riley, John H.] GlaxoSmithKline, Stevenage SG1 2NY, Herts, England. [Agusti, Alvar] Univ Barcelona, Thorax Inst, IDIBAPS, Hosp Clin, E-08036 Barcelona, Spain. [Barabasi, Albert-Laszlo] Cent European Univ, Ctr Network Sci, H-1051 Budapest, Hungary. [Barabasi, Albert-Laszlo] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Agusti, Alvar] CIBERES, FISIB, Mallorca 07110, Spain. RP Barabasi, AL (reprint author), Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA. EM barabasi@gmail.com RI Menche, Jorg/G-3994-2015 OI Menche, Jorg/0000-0002-1583-6404 NR 18 TC 9 Z9 9 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD MAR 13 PY 2014 VL 8 SU 2 AR S8 DI 10.1186/1752-0509-8-S2-S8 PG 13 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AE0UI UT WOS:000333681300009 PM 25032995 ER PT J AU Cho, TA Chi, AS Schaefer, PW Louis, DN AF Cho, Tracey A. Chi, Andrew S. Schaefer, Pamela W. Louis, David N. TI Case 8-2014: A 29-Year- Old Man with Headache, Vomiting, and Diplopia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DIFFUSE LEPTOMENINGEAL GLIOMATOSIS; GLIOBLASTOMA-MULTIFORME; TUBERCULOUS MENINGITIS; TEMOZOLOMIDE AB A 29-year-old man was admitted to the hospital because of headache, vomiting, photophobia, diplopia, and stiff neck. He was born in Southeast Asia. Brain imaging showed diffuse leptomeningeal enhancement. Cultures were sterile. A diagnostic procedure was performed. Presentation of CaseDr. Xuemei Cai (Neurology): A 29-year-old man was admitted to this hospital because of headache, vomiting, and diplopia. The patient had been well until 3 weeks before admission, when headaches, blurred vision, nausea, and vomiting developed, followed by anorexia and weight loss (7.3 kg). Evaluation at a student health center, including computed tomography (CT) of the brain, reportedly revealed no abnormalities. Three days before admission, photophobia, diplopia, neck stiffness, tremulousness of the left hand, and somnolence developed. On the day of admission, the patient became mute. Earlier that day, magnetic resonance imaging (MRI) of the brain and ... C1 [Cho, Tracey A.; Chi, Andrew S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Schaefer, Pamela W.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Louis, David N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Cho, Tracey A.; Chi, Andrew S.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Schaefer, Pamela W.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Louis, David N.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Cho, TA (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NR 17 TC 1 Z9 1 U1 1 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 13 PY 2014 VL 370 IS 11 BP 1049 EP 1059 DI 10.1056/NEJMcpc1214216 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AC7ED UT WOS:000332689100013 PM 24620869 ER PT J AU Parikh, RB Temel, JS AF Parikh, Ravi B. Temel, Jennifer S. TI Early Specialty Palliative Care REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Parikh, Ravi B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Temel, Jennifer S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Parikh, RB (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM jtemel@partners.org NR 4 TC 4 Z9 4 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 13 PY 2014 VL 370 IS 11 BP 1075 EP 1076 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AC7ED UT WOS:000332689100034 PM 24620886 ER PT J AU Ray, A Boyer, D Harris, NL AF Ray, Alaka Boyer, Daniel Harris, Nancy Lee TI Case 38-2013: A Man with Fever and Lymphadenopathy REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Ray, Alaka; Boyer, Daniel; Harris, Nancy Lee] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ray, A (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 13 PY 2014 VL 370 IS 11 BP 1077 EP 1077 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AC7ED UT WOS:000332689100038 PM 24620889 ER PT J AU Lu, A Magupalli, VG Ruan, J Yin, Q Atianand, MK Vos, MR Schroder, GF Fitzgerald, KA Wu, H Egelman, EH AF Lu, Alvin Magupalli, Venkat Giri Ruan, Jianbin Yin, Qian Atianand, Maninjay K. Vos, Matthijn R. Schroeder, Gunnar F. Fitzgerald, Katherine A. Wu, Hao Egelman, Edward H. TI Unified Polymerization Mechanism for the Assembly of ASC-Dependent Inflammasomes SO CELL LA English DT Article ID CRYSTAL-STRUCTURE; PYRIN DOMAIN; ELECTRON CRYOMICROSCOPY; AIM2 INFLAMMASOME; CRYO-EM; ACTIVATION; PROTEIN; DEATH; RESOLUTION; OLIGOMERIZATION AB Inflammasomes elicit host defense inside cells by activating caspase-1 for cytokine maturation and cell death. AIM2 and NLRP3 are representative sensor proteins in two major families of inflammasomes. The adaptor protein ASC bridges the sensor proteins and caspase-1 to form ternary inflammasome complexes, achieved through pyrin domain ( PYD) interactions between sensors and ASC and through caspase activation and recruitment domain ( CARD) interactions between ASC and caspase-1. We found that PYD and CARD both form filaments. Activated AIM2 and NLRP3 nucleate PYD filaments of ASC, which, in turn, cluster the CARD of ASC. ASC thus nucleates CARD filaments of caspase-1, leading to proximity-induced activation. Endogenous NLRP3 inflammasome is also filamentous. The cryoelectron microscopy structure of ASC(PYD) filament at near-atomic resolution provides a template for homo-and hetero-PYD/PYD associations, as confirmed by structure-guided mutagenesis. We propose that ASC-dependent inflammasomes in both families share a unified assembly mechanism that involves two successive steps of nucleation-induced polymerization. C1 [Lu, Alvin; Magupalli, Venkat Giri; Ruan, Jianbin; Yin, Qian; Wu, Hao] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Lu, Alvin; Magupalli, Venkat Giri; Ruan, Jianbin; Yin, Qian; Wu, Hao] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Atianand, Maninjay K.; Fitzgerald, Katherine A.] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA 01655 USA. [Vos, Matthijn R.] FEI Co, Nanoport Europe, NL-5651 GG Eindhoven, Netherlands. [Schroeder, Gunnar F.] Forschungszentrum Julich, Inst Complex Syst, D-52425 Julich, Germany. [Schroeder, Gunnar F.] Univ Dusseldorf, Dept Phys, D-40225 Dusseldorf, Germany. [Egelman, Edward H.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. RP Wu, H (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM hao.wu@childrens.harvard.edu RI Schroder, Gunnar/H-5261-2013; OI Schroder, Gunnar/0000-0003-1803-5431; Lu, Alvin/0000-0003-2353-848X; Egelman, Edward/0000-0003-4844-5212; Ruan, Jianbin/0000-0001-5843-8273 FU National Institutes of Health [AI050872, EB001567, AI083713] FX We thank Natacha Opalka, Seth Darst, Leona Cohen-Gould, Maria Ericsson, William Rice, and Mariena Silvestry Ramos for help with EM imaging, Harry Leung for help with confocal microscopy, Gabriel Nunez for providing cDNAs, and the National Institutes of Health for funding support (AI050872 to H.W., EB001567 to E.H.E., and AI083713 to K.A.F.). NR 42 TC 182 Z9 188 U1 11 U2 50 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 13 PY 2014 VL 156 IS 6 BP 1193 EP 1206 DI 10.1016/j.cell.2014.02.008 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AD0ST UT WOS:000332945100010 PM 24630722 ER PT J AU McFadden, DG Papagiannakopoulos, T Taylor-Weiner, A Stewart, C Carter, SL Cibulskis, K Bhutkar, A McKenna, A Dooley, A Vernon, A Sougnez, C Malstrom, S Heimann, M Park, J Chen, F Farago, AF Dayton, T Shefler, E Gabriel, S Getz, G Jacks, T AF McFadden, David G. Papagiannakopoulos, Thales Taylor-Weiner, Amaro Stewart, Chip Carter, Scott L. Cibulskis, Kristian Bhutkar, Arjun McKenna, Aaron Dooley, Alison Vernon, Amanda Sougnez, Carrie Malstrom, Scott Heimann, Megan Park, Jennifer Chen, Frances Farago, Anna F. Dayton, Talya Shefler, Erica Gabriel, Stacey Getz, Gad Jacks, Tyler TI Genetic and Clonal Dissection of Murine Small Cell Lung Carcinoma Progression by Genome Sequencing SO CELL LA English DT Article ID TUMOR-SUPPRESSOR GENE; COPY-NUMBER ALTERATION; PANCREATIC-CANCER; MOUSE MODEL; SOMATIC MUTATIONS; EVOLUTION; PTEN; HETEROGENEITY; INACTIVATION; INSTABILITY AB Small cell lung carcinoma (SCLC) is a highly lethal, smoking-associated cancer with few known targetable genetic alterations. Using genome sequencing, we characterized the somatic evolution of a genetically engineered mouse model (GEMM) of SCLC initiated by loss of Trp53 and Rb1. We identified alterations in DNA copy number and complex genomic rearrangements and demonstrated a low somatic point mutation frequency in the absence of tobacco mutagens. Alterations targeting the tumor suppressor Pten occurred in the majority of murine SCLC studied, and engineered Pten deletion accelerated murine SCLC and abrogated loss of Chr19 in Trp53; Rb1; Pten compound mutant tumors. Finally, we found evidence for polyclonal and sequential metastatic spread of murine SCLC by comparative sequencing of families of related primary tumors and metastases. We propose a temporal model of SCLC tumorigenesis with implications for human SCLC therapeutics and the nature of cancer-genome evolution in GEMMs. C1 [McFadden, David G.; Papagiannakopoulos, Thales; Bhutkar, Arjun; Dooley, Alison; Vernon, Amanda; Malstrom, Scott; Heimann, Megan; Park, Jennifer; Chen, Frances; Farago, Anna F.; Dayton, Talya; Jacks, Tyler] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [McFadden, David G.; Papagiannakopoulos, Thales; Bhutkar, Arjun; Dooley, Alison; Vernon, Amanda; Malstrom, Scott; Heimann, Megan; Park, Jennifer; Chen, Frances; Farago, Anna F.; Dayton, Talya; Jacks, Tyler] MIT, Dept Biol, Cambridge, MA 02142 USA. [Jacks, Tyler] MIT, Howard Hughes Med Inst, Cambridge, MA 02142 USA. [Taylor-Weiner, Amaro; Stewart, Chip; Carter, Scott L.; Cibulskis, Kristian; McKenna, Aaron; Sougnez, Carrie; Shefler, Erica; Gabriel, Stacey; Getz, Gad] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA. [Getz, Gad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Getz, G (reprint author), Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA. EM gadgetz@broadinstitute.org; tjacks@mit.edu FU Ludwig Center for Molecular Oncology at MIT; Howard Hughes Medical Institute; National Human Genome Research Institute; NIH-NCI Career Development award [K08CA160658]; Hope Funds for Cancer Research Fellowship FX We acknowledge Denise Crowley and the Swanson Biotechnology Core Facility for histology preparation and IHC; Harold Varmus, Nadya Dimitrova, and Eric L. Snyder for critical review of the manuscript; and Peter Campbell for a fruitful discussion. This work was supported by the Ludwig Center for Molecular Oncology at MIT (to T.J.), the Howard Hughes Medical Institute (to T.J.), the National Human Genome Research Institute (to S. G. and G. G.), NIH-NCI Career Development award K08CA160658 (to D. G. M.), and a Hope Funds for Cancer Research Fellowship (to T. P.). G. G. is the Paul C. Zamecnik, MD, Chair in Oncology at Massachusetts General Hospital. T.J. is the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar at MIT. The authors wish to dedicate this paper to the memory of Officer Sean Collier, for his caring service to the MIT community and for his sacrifice. NR 55 TC 72 Z9 75 U1 1 U2 21 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 13 PY 2014 VL 156 IS 6 BP 1298 EP 1311 DI 10.1016/j.cell.2014.02.031 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AD0ST UT WOS:000332945100018 PM 24630729 ER PT J AU Rajbhandari, P Schalper, KA Solodin, NM Ellison-Zelski, SJ Lu, KP Rimm, DL Alarid, ET AF Rajbhandari, P. Schalper, K. A. Solodin, N. M. Ellison-Zelski, S. J. Lu, K. Ping Rimm, D. L. Alarid, E. T. TI Pin1 modulates ER alpha levels in breast cancer through inhibition of phosphorylation-dependent ubiquitination and degradation SO ONCOGENE LA English DT Article DE breast cancer; E3 ligase; proteasome; survival ID ESTROGEN-RECEPTOR-ALPHA; PROLYL ISOMERASE PIN1; GENE-EXPRESSION; POSTTRANSLATIONAL MODIFICATIONS; TRANSCRIPTIONAL ACTIVATION; SUBCELLULAR-LOCALIZATION; DIFFERENTIAL REGULATION; E6-ASSOCIATED PROTEIN; TAMOXIFEN RESISTANCE; NUCLEAR RECEPTORS AB Estrogen receptor-alpha (ER alpha) is an important biomarker used to classify and direct therapy decisions in breast cancer (BC). Both ER alpha protein and its transcript, ESR1, are used to predict response to tamoxifen therapy, yet certain tumors have discordant levels of ER alpha protein and ESR1, which is currently unexplained. Cellular ER alpha protein levels can be controlled post-translationally by the ubiquitin-proteasome pathway through a mechanism that depends on phosphorylation at residue S118. Phospho-S118 (pS118-ER alpha) is a substrate for the peptidyl prolyl isomerase, Pin1, which mediates cis-trans isomerization of the pS118-P119 bond to enhance ER alpha transcriptional function. Here, we demonstrate that Pin1 can increase ER alpha protein without affecting ESR1 transcript levels by inhibiting proteasome-dependent receptor degradation. Pin1 disrupts ER alpha ubiquitination by interfering with receptor interactions with the E3 ligase, E6AP, which also is shown to bind pS118-ER alpha. Quantitative in situ assessments of ER alpha protein, ESR1, and Pin1 in human tumors from a retrospective cohort show that Pin1 levels correlate with ER alpha protein but not to ESR1 levels. These data show that ER alpha protein is post-translationally regulated by Pin1 in a proportion of breast carcinomas. As Pin1 impacts both ER alpha protein levels and transactivation function, these data implicate Pin1 as a potential surrogate marker for predicting outcome of ER alpha-positive BC. C1 [Rajbhandari, P.; Solodin, N. M.; Ellison-Zelski, S. J.; Alarid, E. T.] Univ Wisconsin, UW Carbone Comprehens Canc Ctr, Dept Oncol, Madison, WI 53705 USA. [Schalper, K. A.; Rimm, D. L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Lu, K. Ping] Harvard Univ, Sch Med, Dept Med, Canc Biol Program,Beth Isreal Deaconess Med Ctr, Boston, MA USA. RP Rajbhandari, P (reprint author), Univ Wisconsin, UW Carbone Comprehens Canc Ctr, Dept Oncol, Wisconsin Inst Med Res 6151, Madison, WI 53705 USA. EM alarid@oncology.wisc.edu FU NIH [CA159578, T32 CA009135]; Genoptix/Novartis FX We thank McArdle Laboratories for Cancer Research for support of this project. We also thank the UW Carbone Comprehensive Cancer Center (UWCCC) for use of its shared services to complete this research. We thank Drs Pierre Chambon, Vladimir Spiegelman, Robert Kalejta and Greg Finn for providing us appropriate expression plasmids and reagents. We also thank Dr Wei Xu for insightful comments. This work was supported by NIH grants CA159578 (to E.T.A.) and T32 CA009135 (to P.R.) and a sponsored research award from Genoptix/Novartis (to D.R.). NR 72 TC 16 Z9 18 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD MAR 13 PY 2014 VL 33 IS 11 BP 1438 EP 1447 DI 10.1038/onc.2013.78 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AD0SD UT WOS:000332943500011 PM 23542176 ER PT J AU Hoeppner, MP Lundquist, A Pirun, M Meadows, JRS Zamani, N Johnson, J Sundstrom, G Cook, A FitzGerald, MG Swofford, R Mauceli, E Moghadam, BT Greka, A Alfoldi, J Abouelleil, A Aftuck, L Bessette, D Berlin, A Brown, A Gearin, G Lui, A Macdonald, JP Priest, M Shea, T Turner-Maier, J Zimmer, A Lander, ES di Palma, F Lindblad-Toh, K Grabherr, MG AF Hoeppner, Marc P. Lundquist, Andrew Pirun, Mono Meadows, Jennifer R. S. Zamani, Neda Johnson, Jeremy Sundstrom, Gorel Cook, April FitzGerald, Michael G. Swofford, Ross Mauceli, Evan Moghadam, Behrooz Torabi Greka, Anna Alfoeldi, Jessica Abouelleil, Amr Aftuck, Lynne Bessette, Daniel Berlin, Aaron Brown, Adam Gearin, Gary Lui, Annie Macdonald, J. Pendexter Priest, Margaret Shea, Terrance Turner-Maier, Jason Zimmer, Andrew Lander, Eric S. di Palma, Federica Lindblad-Toh, Kerstin Grabherr, Manfred G. TI An Improved Canine Genome and a Comprehensive Catalogue of Coding Genes and Non-Coding Transcripts SO PLOS ONE LA English DT Article ID WIDE ASSOCIATION; RNA-SEQ; SEQUENCE; DOG; CIS; DIFFERENTIATION; IDENTIFICATION; DOMESTICATION; LANDSCAPE; COMPLEXES AB The domestic dog, Canis familiaris, is a well-established model system for mapping trait and disease loci. While the original draft sequence was of good quality, gaps were abundant particularly in promoter regions of the genome, negatively impacting the annotation and study of candidate genes. Here, we present an improved genome build, canFam3.1, which includes 85 MB of novel sequence and now covers 99.8% of the euchromatic portion of the genome. We also present multiple RNA-Sequencing data sets from 10 different canine tissues to catalog similar to 175,000 expressed loci. While about 90% of the coding genes previously annotated by EnsEMBL have measurable expression in at least one sample, the number of transcript isoforms detected by our data expands the EnsEMBL annotations by a factor of four. Syntenic comparison with the human genome revealed an additional similar to 3,000 loci that are characterized as protein coding in human and were also expressed in the dog, suggesting that those were previously not annotated in the EnsEMBL canine gene set. In addition to,20,700 high-confidence protein coding loci, we found,4,600 antisense transcripts overlapping exons of protein coding genes, similar to 7,200 intergenic multi-exon transcripts without coding potential, likely candidates for long intergenic non-coding RNAs (lincRNAs) and,11,000 transcripts were reported by two different library construction methods but did not fit any of the above categories. Of the lincRNAs, about 6,000 have no annotated orthologs in human or mouse. Functional analysis of two novel transcripts with shRNA in a mouse kidney cell line altered cell morphology and motility. All in all, we provide a much-improved annotation of the canine genome and suggest regulatory functions for several of the novel non-coding transcripts. C1 [Hoeppner, Marc P.; Meadows, Jennifer R. S.; Zamani, Neda; Sundstrom, Gorel; Lindblad-Toh, Kerstin; Grabherr, Manfred G.] Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Labs, Uppsala, Sweden. [Lundquist, Andrew; Johnson, Jeremy; Cook, April; FitzGerald, Michael G.; Swofford, Ross; Greka, Anna; Alfoeldi, Jessica; Abouelleil, Amr; Aftuck, Lynne; Bessette, Daniel; Berlin, Aaron; Brown, Adam; Gearin, Gary; Lui, Annie; Macdonald, J. Pendexter; Priest, Margaret; Shea, Terrance; Turner-Maier, Jason; Zimmer, Andrew; Lander, Eric S.; di Palma, Federica; Lindblad-Toh, Kerstin; Grabherr, Manfred G.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Lundquist, Andrew] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA USA. [Lundquist, Andrew] Harvard Univ, Sch Med, Charlestown, MA USA. [Pirun, Mono] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Mauceli, Evan] Boston Childrens Hosp, Boston, MA USA. [Moghadam, Behrooz Torabi] Uppsala Univ, Dept Cell & Mol Biol, Uppsala, Sweden. [di Palma, Federica] Genome Anal Ctr, Norwich, Norfolk, England. RP Lindblad-Toh, K (reprint author), Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Labs, Uppsala, Sweden. EM kersli@broadinstitute.org; manfred.grabherr@imbim.uu.se FU NHGRI [U54 HG003067]; Uppsala University; Swedish Medical Research Council; Research Council FORMAS; European Commission [FP7-LUPA, GA-201370]; Science for Life Laboratory FX This work was funded in part by NHGRI (U54 HG003067), Uppsala University, Swedish Medical Research Council, Research Council FORMAS, and the European Commission (FP7-LUPA, GA-201370), and a start-up grant from the Science for Life Laboratory to MGG. KLT is a recipient of a EURYI from the ESF and received a Consolidator Award from ERC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 40 Z9 40 U1 2 U2 24 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 2014 VL 9 IS 3 AR e91172 DI 10.1371/journal.pone.0091172 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC9JS UT WOS:000332851300061 PM 24625832 ER PT J AU Zhang, GL Riemer, AB Keskin, DB Chitkushev, L Reinherz, EL Brusic, V AF Zhang, Guang Lan Riemer, Angelika B. Keskin, Derin B. Chitkushev, Lou Reinherz, Ellis L. Brusic, Vladimir TI HPVdb: a data mining system for knowledge discovery in human papillomavirus with applications in T cell immunology and vaccinology SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID BINDING PREDICTION SERVERS; INVASIVE CERVICAL-CANCER; VACCINATION; CLASSIFICATION; ONCOPROTEINS; RECOMBINANT; WORLDWIDE; PEPTIDES; TYPE-16; TOOL AB High-risk human papillomaviruses (HPVs) are the causes of many cancers, including cervical, anal, vulvar, vaginal, penile and oropharyngeal. To facilitate diagnosis, prognosis and characterization of these cancers, it is necessary to make full use of the immunological data on HPV available through publications, technical reports and databases. These data vary in granularity, quality and complexity. The extraction of knowledge from the vast amount of immunological data using data mining techniques remains a challenging task. To support integration of data and knowledge in virology and vaccinology, we developed a framework called KB-builder to streamline the development and deployment of web-accessible immunological knowledge systems. The framework consists of seven major functional modules, each facilitating a specific aspect of the knowledge-base construction process. Using KB-builder, we constructed the Human Papillomavirus T cell Antigen Database (HPVdb). It contains 2781 curated antigen entries of antigenic proteins derived from 18 genotypes of high-risk HPV and 18 genotypes of low-risk HPV. The HPVdb also catalogs 191 verified T cell epitopes and 45 verified human leukocyte antigen (HLA) ligands. Primary amino acid sequences of HPV antigens were collected and annotated from the UniProtKB. T cell epitopes and HLA ligands were collected from data mining of scientific literature and databases. The data were subject to extensive quality control (redundancy elimination, error detection and vocabulary consolidation). A set of computational tools for an in-depth analysis, such as sequence comparison using BLAST search, multiple alignments of antigens, classification of HPV types based on cancer risk, T cell epitope/HLA ligand visualization, T cell epitope/HLA ligand conservation analysis and sequence variability analysis, has been integrated within the HPVdb. Predicted Class I and Class II HLA binding peptides for 15 common HLA alleles are included in this database as putative targets. HPVdb is a knowledge-based system that integrates curated data and information with tailored analysis tools to facilitate data mining for HPV vaccinology and immunology. To our best knowledge, HPVdb is a unique data source providing a comprehensive list of HPV antigens and peptides. C1 [Zhang, Guang Lan; Keskin, Derin B.; Reinherz, Ellis L.; Brusic, Vladimir] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Zhang, Guang Lan; Chitkushev, Lou; Brusic, Vladimir] Boston Univ, Dept Comp Sci, Metropolitan Coll, Boston, MA 02215 USA. [Zhang, Guang Lan; Keskin, Derin B.; Reinherz, Ellis L.; Brusic, Vladimir] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA. [Riemer, Angelika B.] German Canc Res Ctr, D-69120 Heidelberg, Germany. RP Zhang, GL (reprint author), Dana Farber Canc Inst, Canc Vaccine Ctr, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM guanglan@bu.edu; vladimir_brusic@dfci.harvard.edu FU NIH [UO1 AI090043] FX Funding for open access charge: NIH grant UO1 AI090043. NR 35 TC 6 Z9 6 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD MAR 12 PY 2014 AR bau031 DI 10.1093/database/bau031 PG 12 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA AO9UL UT WOS:000341703500001 ER PT J AU Sears, CL Garrett, WS AF Sears, Cynthia L. Garrett, Wendy S. TI Microbes, Microbiota, and Colon Cancer SO CELL HOST & MICROBE LA English DT Review ID HUMAN GUT MICROBIOME; ENTEROTOXIGENIC BACTEROIDES-FRAGILIS; STREPTOCOCCUS-GALLOLYTICUS INFECTION; BETA-GLUCURONIDASE INHIBITION; NF-KAPPA-B; COLORECTAL-CANCER; ESCHERICHIA-COLI; TUMOR MICROENVIRONMENT; URSODEOXYCHOLIC ACID; COMMENSAL BACTERIA AB Colorectal cancer (CRC) presents a considerable disease burden worldwide. The human colon is also an anatomical location with the largest number of microbes. It is natural, therefore, to anticipate a role for microbes, particularly bacteria, in colorectal carcinogenesis. The increasing accessibility of microbial meta'omics is fueling a surge in our understanding of the role that microbes and the microbiota play in CRC. In this review, we will discuss recent insights into contributions of the microbiota to CRC and explore conceptual frameworks for evaluating the role of microbes in cancer causation. We also highlight new findings on candidate CRC-potentiating species and current knowledge gaps. Finally, we explore the roles of microbial metabolism as it relates to bile acids, xenobiotics, and diet in the etiology and therapeutics of CRC. C1 [Sears, Cynthia L.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Sears, Cynthia L.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Sears, Cynthia L.] Johns Hopkins Univ, Sch Med, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Sears, Cynthia L.] Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Garrett, Wendy S.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Garrett, Wendy S.] Broad Inst Harvard, Cambridge, MA 02142 USA. [Garrett, Wendy S.] MIT, Cambridge, MA 02142 USA. RP Sears, CL (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. EM csears@jhmi.edu; wgarrett@hsph.harvard.edu FU NIH [R01CA151393, R21CA170492, R01CA151325, R01CA179440, R01CA154426, K08AI078942]; Merieux Institute; Wellcome Career in Medical Sciences Award; Searle Scholars Award; Cancer Research Institute Investigator Award FX We thank current and former members of the Sears and Garrett labs. C.L.S. also thanks Drew Pardoll, Ken Kinzler, Bert Vogelstein, and members of their groups for helpful discussions over time; W.S.G. also thanks Aleksandar D. Kostic, Andrew T. Chan, and Curtis Huttenhower for thoughtful discussions. C.L.S. acknowledges the following funding sources: NIH (R01CA151393, R21CA170492, R01CA151325, R01CA179440) and the Merieux Institute. W.S.G. acknowledges the following funding sources: NIH (R01CA154426 and K08AI078942), a Burroughs Wellcome Career in Medical Sciences Award, a Searle Scholars Award, and a Cancer Research Institute Investigator Award. NR 90 TC 115 Z9 124 U1 18 U2 108 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD MAR 12 PY 2014 VL 15 IS 3 BP 317 EP 328 DI 10.1016/j.chom.2014.02.007 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AD2WZ UT WOS:000333098600010 PM 24629338 ER PT J AU Gevers, D Kugathasan, S Denson, LA Vazquez-Baeza, Y Van Treuren, W Ren, BY Schwager, E Knights, D Song, SJ Yassour, M Morgan, XC Kostic, AD Luo, CW Gonzalez, A McDonald, D Haberman, Y Walters, T Baker, S Rosh, J Stephens, M Heyman, M Markowitz, J Baldassano, R Griffiths, A Sylvester, F Mack, D Kim, S Crandall, W Hyams, J Huttenhower, C Knight, R Xavier, RJ AF Gevers, Dirk Kugathasan, Subra Denson, Lee A. Vazquez-Baeza, Yoshiki Van Treuren, Will Ren, Boyu Schwager, Emma Knights, Dan Song, Se Jin Yassour, Moran Morgan, Xochitl C. Kostic, Aleksandar D. Luo, Chengwei Gonzalez, Antonio McDonald, Daniel Haberman, Yael Walters, Thomas Baker, Susan Rosh, Joel Stephens, Michael Heyman, Melvin Markowitz, James Baldassano, Robert Griffiths, Anne Sylvester, Francisco Mack, David Kim, Sandra Crandall, Wallace Hyams, Jeffrey Huttenhower, Curtis Knight, Rob Xavier, Ramnik J. TI The Treatment-Naive Microbiome in New-Onset Crohn's Disease SO CELL HOST & MICROBE LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; GUT MICROBIOME; TRANSPLANTATION; PATHOGENESIS; BACTERIA; CELLS AB Inflammatory bowel diseases (IBDs), including Crohn's disease (CD), are genetically linked to host pathways that implicate an underlying role for aberrant immune responses to intestinal microbiota. However, patterns of gut microbiome dysbiosis in IBD patients are inconsistent among published studies. Using samples from multiple gastrointestinal locations collected prior to treatment in new-onset cases, we studied the microbiome in the largest pediatric CD cohort to date. An axis defined by an increased abundance in bacteria which include Enterobacteriaceae, Pasteurellacaea, Veillonellaceae, and Fusobacteriaceae, and decreased abundance in Erysipelotrichales, Bacteroidales, and Clostridiales, correlates strongly with disease status. Microbiome comparison between CD patients with and without antibiotic exposure indicates that antibiotic use amplifies the microbial dysbiosis associated with CD. Comparing the microbial signatures between the ileum, the rectum, and fecal samples indicates that at this early stage of disease, assessing the rectal mucosal-associated microbiome offers unique potential for convenient and early diagnosis of CD. C1 [Gevers, Dirk; Yassour, Moran; Kostic, Aleksandar D.; Luo, Chengwei; Huttenhower, Curtis; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kugathasan, Subra] Emory Univ, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Atlanta, GA 30322 USA. [Denson, Lee A.; Haberman, Yael] Cincinnati Childrens Hosp, Med Ctr, Div Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA. [Vazquez-Baeza, Yoshiki] Univ Colorado, Dept Comp Sci, Boulder, CO 80309 USA. [Van Treuren, Will; Song, Se Jin; Gonzalez, Antonio; McDonald, Daniel; Knight, Rob] Univ Colorado, BioFrontiers Inst, Boulder, CO 80309 USA. [Ren, Boyu; Schwager, Emma; Morgan, Xochitl C.; Huttenhower, Curtis] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Knights, Dan] Univ Minnesota, Dept Comp Sci & Engn, Minneapolis, MN 55108 USA. [Knights, Dan] Univ Minnesota, Inst Biotechnol, St Paul, MN 55108 USA. [Walters, Thomas] Univ Toronto, Hosp Sick Children, Div Gastroenterol Hepatol & Nutr, Toronto, ON M5G IX8, Canada. [Baker, Susan] Childrens Hosp Buffalo, Buffalo, NY 14222 USA. [Rosh, Joel] Goryeb Childrens Hosp, Morristown, NJ 07960 USA. [Stephens, Michael] Mayo Clin, Rochester, MN 55902 USA. [Heyman, Melvin] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Markowitz, James] North Shore Long Isl Jewish Med Ctr, New Hyde Pk, NY 11040 USA. [Baldassano, Robert] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Griffiths, Anne] Hosp Sick Children, Toronto, ON M5G IX8, Canada. [Sylvester, Francisco; Hyams, Jeffrey] Connecticut Childrens Med Ctr, Hartford, CT 06106 USA. [Mack, David] Childrens Hosp Eastern Ontario, Ottawa, ON K1H 8L1, Canada. [Kim, Sandra; Crandall, Wallace] Nationwide Childrens Hosp, Columbus, OH 43228 USA. [Knight, Rob] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA. [Knight, Rob] Howard Hughes Med Inst, Boulder, CO 80309 USA. RP Xavier, RJ (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM xavier@molbio.mgh.harvard.edu RI Crandall, Wallace/E-2928-2011; Knight, Rob/D-1299-2010 OI Morgan, Xochitl/0000-0002-6264-6961; Kostic, Aleksandar/0000-0002-0837-4360; FU Crohn's and Colitis Foundation of America; Leona M. and Harry B. Helmsley Charitable Trust; ARO [W911NF-11-1-0473]; NIH [U54 DE023798, R01 HG005969, R01 DK092405] FX We thank the patients who donated samples for this study, the health professionals who collected them, and the Crohn's and Colitis Foundation of America for supporting the RISK cohort. We thank Douglas Wendel, Gail Ackermann, Tim Vigers, and Tim L. Tickle for their valuable input and helpful discussions. We thank participating clinicians Marla Dubinsky, Joshua Noe, Scott Snapper, Richard Kellermayer, Michael Kappleman, Anthony Otley, Mirian Pfefferkorn, Stanley Cohen, Stephen Guthery, Neal LeLeiko, Maria Oliva-Hemker, David Keljo, Dedrick Moulton, Barbara Kircshner, Ashish Patel, David Ziring, Jonathan Evans, Jonah Essers, Bruce Aronow, and MiOk Kim. Work was supported by grants from the Crohn's and Colitis Foundation of America, The Leona M. and Harry B. Helmsley Charitable Trust, ARO grant W911NF-11-1-0473 (C.H.), and by NIH grants U54 DE023798, R01 HG005969 (C.H.), and R01 DK092405 (R.J.X., C.H., and D.G.). NR 40 TC 382 Z9 389 U1 29 U2 129 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD MAR 12 PY 2014 VL 15 IS 3 BP 382 EP 392 DI 10.1016/j.chom.2014.02.005 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AD2WZ UT WOS:000333098600016 PM 24629344 ER PT J AU Hashmi, JA Kong, J Spaeth, R Khan, S Kaptchuk, TJ Gollub, RL AF Hashmi, Javeria Ali Kong, Jian Spaeth, Rosa Khan, Sheraz Kaptchuk, Ted J. Gollub, Randy L. TI Functional Network Architecture Predicts Psychologically Mediated Analgesia Related to Treatment in Chronic Knee Pain Patients SO JOURNAL OF NEUROSCIENCE LA English DT Article DE brain network; chronic pain; placebo; predictive analysis; resting state; synchronization ID PLACEBO ANALGESIA; BRAIN NETWORKS; NEUROBIOLOGICAL MECHANISMS; INDIVIDUAL-DIFFERENCES; ACUPUNCTURE TREATMENT; INDUCED EXPECTATIONS; PREFRONTAL CORTEX; BACK-PAIN; CONNECTIVITY; ANTICIPATION AB Placebo analgesia is an indicator of how efficiently the brain translates psychological signals conveyed by a treatment procedure into pain relief. It has been demonstrated that functional connectivity between distributed brain regions predicts placebo analgesia in chronic back pain patients. Greater network efficiency in baseline brain networks may allow better information transfer and facilitate adaptive physiological responses to psychological aspects of treatment. Here, we theorized that topological network alignments in resting state scans predict psychologically conditioned analgesic responses to acupuncture treatment in chronic knee osteoarthritis pain patients (n = 45). Analgesia was induced by building positive expectations toward acupuncture treatment with verbal suggestion and heat pain conditioning on a test site of the arm. This procedure induced significantly more analgesia after sham or real acupuncture on the test site than in a control site. The psychologically conditioned analgesia was invariant to sham versus real treatment. Efficiency of information transfer within local networks calculated with graph-theoretic measures (local efficiency and clustering coefficients) significantly predicted conditioned analgesia. Clustering coefficients in regions associated with memory, motivation, and pain modulation were closely involved in predicting analgesia. Moreover, women showed higher clustering coefficients and marginally greater pain reduction than men. Overall, analgesic response to placebo cues can be predicted from a priori resting state data by observing local network topology. Such low-cost synchronizations may represent preparatory resources that facilitate subsequent performance of brain circuits in responding to adaptive environmental cues. This suggests a potential utility of network measures in predicting placebo response for clinical use. C1 [Hashmi, Javeria Ali; Kong, Jian; Spaeth, Rosa; Gollub, Randy L.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Hashmi, Javeria Ali; Kong, Jian; Khan, Sheraz] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Khan, Sheraz] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Hashmi, Javeria Ali; Kong, Jian; Khan, Sheraz; Gollub, Randy L.] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Khan, Sheraz] MIT, Cambridge, MA 02139 USA. [Kaptchuk, Ted J.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Program Placebo Studies, Boston, MA 02215 USA. RP Hashmi, JA (reprint author), 120 Second Ave,Suite 103, Charlestown, MA 02129 USA. EM javeria.hashmi@utoronto.ca; rgollub@partners.org OI Gollub, Randy L./0000-0002-9434-4044; Khan, Sheraz/0000-0002-6792-3577 FU Nancy Lurie Marks Family Foundation; [R01AT005280]; [R01AT006364]; [P01-AT002048] FX Funding and support for this study came from R01AT005280 (R.L.G. and T.J.K.), R01AT006364 (J.K.), and P01-AT002048 to Bruce Rosen (Massachusetts General Hospital, Charlestown, MA). S.K. is funded by Nancy Lurie Marks Family Foundation Fellowship. We thank Irving Kirsch and Mark Vangel for their valuable suggestions and comments. NR 76 TC 14 Z9 15 U1 2 U2 22 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 12 PY 2014 VL 34 IS 11 BP 3924 EP 3936 DI 10.1523/JNEUROSCI.3155-13.2014 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AC9UG UT WOS:000332879500012 PM 24623770 ER PT J AU Cha, J Greenberg, T Carlson, JM DeDora, DJ Hajcak, G Mujica-Parodi, LR AF Cha, Jiook Greenberg, Tsafrir Carlson, Joshua M. DeDora, Daniel J. Hajcak, Greg Mujica-Parodi, Lilianne R. TI Circuit-Wide Structural and Functional Measures Predict Ventromedial Prefrontal Cortex Fear Generalization: Implications for Generalized Anxiety Disorder SO JOURNAL OF NEUROSCIENCE LA English DT Article DE anxiety; fear conditioning; connectivity; tractography; resting-state; fear generalizaton ID TRAIT ANXIETY; SEROTONIN TRANSPORTER; CONDITIONED FEAR; INDIVIDUAL-DIFFERENCES; POLYMORPHISM 5-HTTLPR; MEDIODORSAL THALAMUS; EXTINCTION MEMORY; AMYGDALA; CONNECTIVITY; HUMANS AB The ventromedial prefrontal cortex (vmPFC) plays a critical role in a number of evaluative processes, including risk assessment. Impaired discrimination between threat and safety is considered a hallmark of clinical anxiety. Here, we investigated the circuit-wide structural and functional mechanisms underlying vmPFC threat-safety assessment in humans. We tested patients with generalized anxiety disorder (GAD; n = 32, female) and healthy controls (n = 25, age-matched female) on a task that assessed the generalization of conditioned threat during fMRI scanning. The task consisted of seven rectangles of graded widths presented on a screen; only the midsize one was paired with mild electric shock [conditioned stimulus (CS)], while the others, safety cues, systematically varied in width by +/- 20, 40, and 60% [generalization stimuli (GS)] compared with the CS. We derived an index reflecting vmPFC functioning from the BOLD reactivity on a continuum of threat (CS) to safety (GS least similar to CS); patients with GAD showed less discrimination between threat and safety cues, compared with healthy controls (Greenberg et al., 2013b). Using structural, functional (i.e., resting-state), and diffusion MRI, we measured vmPFC thickness, vmPFC functional connectivity, and vmPFC structural connectivity within the corticolimbic systems. The results demonstrate that all three factors predict individual variability of vmPFC threat assessment in an independent fashion. Moreover, these neural features are also linked to GAD, most likely via an vmPFC fear generalization. Our results strongly suggest that vmPFC threat processing is closely associated with broader corticolimbic circuit anomalies, which may synergistically contribute to clinical anxiety. C1 [Cha, Jiook; Mujica-Parodi, Lilianne R.] SUNY Stony Brook, Program Neurosci, Stony Brook, NY 11794 USA. [Greenberg, Tsafrir; Hajcak, Greg] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Carlson, Joshua M.; DeDora, Daniel J.; Mujica-Parodi, Lilianne R.] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Carlson, Joshua M.] No Michigan Univ, Dept Psychol, Marquette, MI 49855 USA. [Mujica-Parodi, Lilianne R.] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Mujica-Parodi, LR (reprint author), SUNY Stony Brook, Lab Computat Neurodiag, Dept Biomed Engn, Bioengn Bldg Room 119,100 Nicolls Rd, Stony Brook, NY 11794 USA. EM Lilianne.strey@stonybrook.edu RI Cha, Jiook/A-5678-2013; Greenberg, Tsafrir /Q-7831-2016; OI Cha, Jiook/0000-0002-5314-7992; Mujica-Parodi, Lilianne/0000-0002-3752-5519 FU Office of Naval Research [N0014-04-1-005]; National Science Foundation [0954643] FX This work was supported by function from the Office of Naval Research (# N0014-04-1-005, to L.R. M.-P.) and the National Science Foundation (# 0954643, to L.R. M.-P.). NR 53 TC 25 Z9 26 U1 3 U2 24 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 12 PY 2014 VL 34 IS 11 BP 4043 EP 4053 DI 10.1523/JNEUROSCI.3372-13.2014 PG 11 WC Neurosciences SC Neurosciences & Neurology GA AC9UG UT WOS:000332879500023 PM 24623781 ER PT J AU Das, S McCaffrey, PG Talkington, MWT Andrews, NA Corlosquet, S Ivinson, AJ Clark, T AF Das, Sudeshna McCaffrey, Patricia G. Talkington, Megan W. T. Andrews, Neil A. Corlosquet, Stephane Ivinson, Adrian J. Clark, Tim TI Pain Research Forum: application of scientific social media frameworks in neuroscience SO FRONTIERS IN NEUROINFORMATICS LA English DT Article DE social media; neuropathic pain; content management systems; Drupal ID WEB COMMUNITIES; SCIENCE; COLLABORATORIES; ALZFORUM AB Background: Social media has the potential to accelerate the pace of biomedical research through online collaboration, discussions, and faster sharing of information. Focused web-based scientific social collaboratories such as the Alzheimer Research Forum have been successful in engaging scientists in open discussions of the latest research and identifying gaps in knowledge. However, until recently, tools to rapidly create such communities and provide high-bandwidth information exchange between collaboratories in related fields did not exist. Methods: We have addressed this need by constructing a reusable framework to build online biomedical communities, based on Drupal, an open-source content management system. The framework incorporates elements of Semantic Web technology combined with social media. Here we present, as an exemplar of a web community built on our framework, the Pain Research Forum (PRF) (hftp://painresearchforum.org). PRF is a community of chronic pain researchers, established with the goal of fostering collaboration and communication among pain researchers. Results: Launched in 2011, PRF has over 1300 registered members with permission to submit content. It currently hosts over 150 topical news articles on research; more than 30 active or archived forum discussions and journal club features; a webinar series; an editor-curated weekly updated listing of relevant papers; and several other resources for the pain research community. All content is licensed for reuse under a Creative Commons license; the software is freely available. The framework was reused to develop other sites, notably the Multiple Sclerosis Discovery Forum (hftp://msdiscovery.org) and StemBook (hftp://stembook.org). Discussion: Web-based collaboratories are a crucial integrative tool supporting rapid information transmission and translation in several important research areas. In this article, we discuss the success factors, lessons learned, and ongoing challenges in using PRF as a driving force to develop tools for online collaboration in neuroscience. We also indicate ways these tools can be applied to other areas and uses. C1 [Das, Sudeshna; Ivinson, Adrian J.; Clark, Tim] MIT, Massachusetts Gen Hosp, Inst Neurodegenerat Dis, Cambridge, MA 02139 USA. [Das, Sudeshna; Clark, Tim] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [McCaffrey, Patricia G.; Talkington, Megan W. T.; Andrews, Neil A.; Ivinson, Adrian J.] Harvard Univ, Sch Med, Harvard NeuroDiscovery Ctr, Boston, MA 02115 USA. [Clark, Tim] Univ Manchester, Sch Comp Sci, Manchester, Lancs, England. RP Das, S (reprint author), MIT, Massachusetts Gen Hosp, Inst Neurodegenerat Dis, 65 Landsdowne St, Cambridge, MA 02139 USA. EM sdas5@mgh.harvard.edu OI Clark, Timothy/0000-0003-4060-7360 FU Curvey Family Foundation; Mayday Fund; Guthart Family Foundation; Purdue Pharma L.P.; Genentech FX We gratefully acknowledge essential funding from the Curvey Family Foundation, the Mayday Fund, the Guthart Family Foundation, Purdue Pharma L.P. and Genentech. We thank Alzforum and PDOnline editors for their feedback and ideas, Nick Maloney, Paul Northup, Jake Strawn, and Chris Akeley for their contributions to software development, and Stoltze Design for graphic design. NR 25 TC 2 Z9 2 U1 0 U2 13 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5196 J9 FRONT NEUROINFORM JI Front. Neuroinformatics PD MAR 11 PY 2014 VL 8 AR 21 DI 10.3389/fninf.2014.00021 PG 13 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA AZ3DA UT WOS:000348106700001 PM 24653693 ER PT J AU Mackin, RS Insel, P Truran, D Vichinsky, EP Neumayr, LD Armstrong, FD Gold, JI Kesler, K Brewer, J Weiner, MW AF Mackin, R. Scott Insel, Philip Truran, Diana Vichinsky, Elliot P. Neumayr, Lynne D. Armstrong, F. D. Gold, Jeffrey I. Kesler, Karen Brewer, Joseph Weiner, Michael W. CA Neuropsychological Dysfunction Neu TI Neuroimaging abnormalities in adults with sickle cell anemia Associations with cognition SO NEUROLOGY LA English DT Article ID HUMAN CEREBRAL-CORTEX; CORTICAL THICKNESS; BIOLOGICAL MARKERS; BASAL GANGLIA; RISK-FACTORS; GRAY-MATTER; BACK-PAIN; DISEASE; CHILDREN; BRAIN AB Objective:This study was conducted to determine the relationship of frontal lobe cortical thickness and basal ganglia volumes to measures of cognition in adults with sickle cell anemia (SCA).Methods:Participants included 120 adults with SCA with no history of neurologic dysfunction and 33 healthy controls (HCs). Participants were enrolled at 12 medical center sites, and raters were blinded to diagnostic group. We hypothesized that individuals with SCA would exhibit reductions in frontal lobe cortex thickness and reduced basal ganglia and thalamus volumes compared with HCs and that these structural brain abnormalities would be associated with measures of cognitive functioning (Wechsler Adult Intelligence Scale, 3rd edition).Results:After adjusting for age, sex, education level, and intracranial volume, participants with SCA exhibited thinner frontal lobe cortex (t = -2.99, p = 0.003) and reduced basal ganglia and thalamus volumes compared with HCs (t = -3.95, p < 0.001). Reduced volume of the basal ganglia and thalamus was significantly associated with lower Performance IQ (model estimate = 3.75, p = 0.004) as well as lower Perceptual Organization (model estimate = 1.44, p = 0.007) and Working Memory scores (model estimate = 1.37, p = 0.015). Frontal lobe cortex thickness was not significantly associated with any cognitive measures.Conclusions:Our findings suggest that basal ganglia and thalamus abnormalities may represent a particularly salient contributor to cognitive dysfunction in adults with SCA. C1 [Mackin, R. Scott] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Mackin, R. Scott; Insel, Philip; Truran, Diana; Brewer, Joseph; Weiner, Michael W.] San Francisco Vet Adm Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA USA. [Vichinsky, Elliot P.; Neumayr, Lynne D.] Childrens Hosp & Res Ctr Oakland, Dept Hematol Oncol, Oakland, CA 94609 USA. [Gold, Jeffrey I.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90089 USA. [Gold, Jeffrey I.] Childrens Hosp Los Angeles, Dept Anesthesiol, Los Angeles, CA 90027 USA. [Gold, Jeffrey I.] Childrens Hosp Los Angeles, Dept Pediat, Los Angeles, CA 90027 USA. [Kesler, Karen] Rho Inc, Res Triangle Pk, NC USA. [Armstrong, F. D.] Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33136 USA. [Armstrong, F. D.] Holtz Childrens Hosp, Miami, FL USA. [Weiner, Michael W.] Univ Calif San Francisco, Vet Adm Med Ctr, San Francisco, CA USA. [Weiner, Michael W.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. [Weiner, Michael W.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Weiner, Michael W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Weiner, Michael W.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. RP Mackin, RS (reprint author), Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. EM scottm@lppi.ucsf.edu FU National Heart, Lung, and Blood Institute [U54HL070587]; National Institute of Mental Health [K08MH081065] FX Supported by the National Heart, Lung, and Blood Institute (U54HL070587) and the National Institute of Mental Health (K08MH081065). NR 40 TC 14 Z9 14 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 11 PY 2014 VL 82 IS 10 BP 835 EP 841 DI 10.1212/WNL.0000000000000188 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA AH9TJ UT WOS:000336485100008 PM 24523480 ER PT J AU Rosas, HD Doros, G Gevorkian, S Malarick, K Reuter, M Coutu, JP Triggs, TD Wilkens, PJ Matson, W Salat, DH Hersch, SM AF Rosas, Herminia D. Doros, Gheorghe Gevorkian, Sona Malarick, Keith Reuter, Martin Coutu, Jean-Philippe Triggs, Tyler D. Wilkens, Paul J. Matson, Wayne Salat, David H. Hersch, Steven M. TI PRECREST: A phase II prevention and biomarker trial of creatine in at-risk Huntington disease SO NEUROLOGY LA English DT Article ID EPISODIC MEMORY; PREMANIFEST; PROGRESSION; DIAGNOSIS; COGNITION; 8OHDG; HD AB Objective:To assess the safety and tolerability of high-dose creatine, the feasibility of enrolling premanifest and 50% at-risk subjects in a prevention trial, and the potential of cognitive, imaging, and blood markers.Methods:Sixty-four eligible consenting participants were randomly allocated (1:1) to 15 g twice daily of creatine monohydrate or placebo for a 6-month double-blind phase followed by a 12-month open-label extension. Subjects included premanifest (tested) and at-risk (not tested) individuals without clinical symptoms or signs of Huntington disease (HD). Primary outcomes were safety and tolerability. Exploratory endpoints included fine motor, visuospatial, and memory performance; structural and diffusion MRI; and selected blood markers.Results:Forty-seven HD carriers and 17 non-HD controls were enrolled. Fifteen discontinued treatment (2 assigned to placebo); all were followed for the entire study period. Primary analysis was by intent to treat. The most common adverse events were gastrointestinal. Neuroimaging demonstrated treatment-related slowing of cortical and striatal atrophy at 6 and 18 months.Conclusion:We describe a design that preserves the autonomy of subjects not wanting genetic testing while including controls for assessing the specificity of treatment effects. Our results demonstrate the feasibility of prevention trials for HD and the safety of high-dose creatine, provide possible evidence of disease modification, support future studies of creatine, and illustrate the value of prodromal biomarkers.Classification of evidence:This study provides Class I evidence that high-dose creatine is safe and tolerable. C1 [Rosas, Herminia D.; Gevorkian, Sona; Malarick, Keith; Reuter, Martin; Triggs, Tyler D.; Wilkens, Paul J.; Hersch, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Rosas, Herminia D.; Gevorkian, Sona; Malarick, Keith; Reuter, Martin; Coutu, Jean-Philippe; Triggs, Tyler D.; Wilkens, Paul J.; Salat, David H.] Massachusetts Gen Hosp, Ctr Neuroimaging Aging & Neurodegenerat Dis, Boston, MA 02114 USA. [Rosas, Herminia D.; Gevorkian, Sona; Malarick, Keith; Reuter, Martin; Triggs, Tyler D.; Wilkens, Paul J.; Salat, David H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Rosas, Herminia D.; Reuter, Martin] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Doros, Gheorghe] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Coutu, Jean-Philippe] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. [Matson, Wayne] New England Vet Adm, Geriatr Res Educ Clin Ctr, Bedford, MA USA. RP Rosas, HD (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM rosas@helix.mgh.harvard.edu RI Reuter, Martin/B-3456-2010; OI Reuter, Martin/0000-0002-2665-9693; /0000-0003-4895-5642 FU NIH [P01NS058793, NS042861, NS058793, AT000613, FD003359] FX Support by the NIH (grants P01NS058793, NS042861, NS058793, AT000613, and FD003359 to H. D. R. and S. M. H., and NS058793 to G.D.). NR 24 TC 29 Z9 29 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 11 PY 2014 VL 82 IS 10 BP 850 EP 857 DI 10.1212/WNL.0000000000000187 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AH9TJ UT WOS:000336485100010 PM 24510496 ER PT J AU Bramhall, NF Shi, F Arnold, K Hochedlinger, K Edge, ASB AF Bramhall, Naomi F. Shi, Fuxin Arnold, Katrin Hochedlinger, Konrad Edge, Albert S. B. TI Lgr5-Positive Supporting Cells Generate New Hair Cells in the Postnatal Cochlea SO STEM CELL REPORTS LA English DT Article ID EAR SENSORY EPITHELIA; MAMMALIAN INNER-EAR; PROGENITOR CELLS; REGENERATIVE PROLIFERATION; INTESTINAL CRYPTS; ACOUSTIC TRAUMA; STEM-CELLS; NOTCH; MOUSE; INHIBITION AB The prevalence of hearing loss after damage to the mammalian cochlea has been thought to be due to a lack of spontaneous regeneration of hair cells, the primary receptor cells for sound. Here, we show that supporting cells, which surround hair cells in the normal cochlear epithelium, differentiate into new hair cells in the neonatal mouse following ototoxic damage. Using lineage tracing, we show that new hair cells, predominantly outer hair cells, arise from Lgr5-expressing inner pillar and third Deiters cells and that new hair cell generation is increased by pharmacological inhibition of Notch. These data suggest that the neonatal mammalian cochlea has some capacity for hair cell regeneration following damage alone and that Lgr5-positive cells act as hair cell progenitors in the cochlea. C1 [Bramhall, Naomi F.; Shi, Fuxin; Edge, Albert S. B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Bramhall, Naomi F.; Shi, Fuxin; Edge, Albert S. B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Bramhall, Naomi F.; Edge, Albert S. B.] Harvard & MIT, Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. [Arnold, Katrin; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. RP Edge, ASB (reprint author), Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. EM albert_edge@meei.harvard.edu FU NIH Ruth L. Kirschstein National Research Service Award; Tillotson Corporation; Shulsky Foundation; [RO1 DC007174]; [R21 DC010440]; [P30 DC05209]; [R01 DK96034] FX We thank Drs. M. Charles Liberman, Cynthia Morton, and Matthew Kelley for helpful comments. This work was supported by grants RO1 DC007174, R21 DC010440, P30 DC05209, and R01 DK96034; an NIH Ruth L. Kirschstein National Research Service Award; and the Tillotson Corporation, the Shulsky Foundation, and Robert Boucai. NR 42 TC 44 Z9 45 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD MAR 11 PY 2014 VL 2 IS 3 BP 311 EP 322 DI 10.1016/j.stemcr.2014.01.008 PG 12 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AI1XE UT WOS:000336647700007 PM 24672754 ER PT J AU Burke, MA Givertz, MM AF Burke, Michael A. Givertz, Michael M. TI Assessment and Management of Heart Failure After Left Ventricular Assist Device Implantation SO CIRCULATION LA English DT Article ID MECHANICAL CIRCULATORY SUPPORT; CONTINUOUS-FLOW; PULMONARY-HYPERTENSION; INTERNATIONAL SOCIETY; TRANSPLANTATION; THROMBOSIS; NONPULSATILE; THERAPY C1 [Burke, Michael A.; Givertz, Michael M.] Harvard Univ, Brigham & Womens Hosp, Cardiovasc Div, Dept Med,Med Sch, Boston, MA 02115 USA. [Burke, Michael A.] VA Boston Healthcare Syst, Boston, MA USA. RP Givertz, MM (reprint author), Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA. EM mgivertz@partners.org NR 20 TC 5 Z9 6 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 11 PY 2014 VL 129 IS 10 BP 1161 EP U197 DI 10.1161/CIRCULATIONAHA.113.002836 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AI2ZH UT WOS:000336727200018 PM 24615964 ER PT J AU Eisendrath, SJ Gillung, EP Delucchi, KL Chartier, M Mathalon, DH Sullivan, JC Segal, ZV Feldman, MD AF Eisendrath, Stuart J. Gillung, Erin P. Delucchi, Kevin L. Chartier, Maggie Mathalon, Daniel H. Sullivan, Jude C. Segal, Zindel V. Feldman, Mitchell D. TI Mindfulness-based cognitive therapy (MBCT) versus the health-enhancement program (HEP) for adults with treatment-resistant depression: a randomized control trial study protocol SO BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE LA English DT Article DE Depression; Treatment-resistant; Mindfulness; Meditation; MBCT ID QUALITY-OF-LIFE; COMORBIDITY SURVEY REPLICATION; ILLNESS RATING-SCALE; MAJOR DEPRESSION; LONGITUDINAL DATA; PRIMARY-CARE; DISORDER; ANXIETY; OUTPATIENTS; CLINICIAN AB Background: Major depressive disorder (MDD) is the leading cause of disability in the developed world, yet broadly effective treatments remain elusive. Up to 40% of patients with depression are unresponsive to at least two trials of antidepressant medication and thus have "treatment-resistant depression" (TRD). There is an urgent need for cost-effective, non-pharmacologic, evidence-based treatments for TRD. Mindfulness-Based Cognitive Therapy (MBCT) is an effective treatment for relapse prevention and residual depression in major depression, but has not been previously studied in patients with TRD in a large randomized trial. Methods/Design: The purpose of this study was to evaluate whether MBCT is an effective augmentation of antidepressants for adults with MDD who failed to respond to standard pharmacotherapy. MBCT was compared to an active control condition, the Health-Enhancement Program (HEP), which incorporates physical activity, functional movement, music therapy and nutritional advice. HEP was designed as a comparator condition for mindfulness-based interventions to control for non-specific effects. Originally investigated in a non-clinical sample to promote stress reduction, HEP was adapted for a depressed population for this study. Individuals age 18 and older with moderate to severe TRD, who failed to respond to at least two trials of antidepressants in the current episode, were recruited to participate. All participants were taking antidepressants (Treatment as usual; TAU) at the time of enrollment. After signing an informed consent, participants were randomly assigned to either MBCT or HEP condition. Participants were followed for 1 year and assessed at weeks 1-7, 8, 24, 36, and 52. Change in depression severity, rate of treatment response and remission after 8 weeks were the primary outcomes measured by the clinician-rated Hamilton Depression Severity Rating (HAM-D) 17-item scale. The participant-rated Quick Inventory of Depression Symptomology (QIDS-SR) 16-item scale was the secondary outcome measure of depression severity, response, and remission. Discussion: Treatment-resistant depression entails significant morbidity and has few effective treatments. We studied the effect of augmenting antidepressant medication with MBCT, compared with a HEP control, for patients with TRD. Analyses will focus on clinician and patient assessment of depression, participants' clinical global impression change, employment and social functioning scores and quality of life and satisfaction ratings. C1 [Eisendrath, Stuart J.; Gillung, Erin P.; Delucchi, Kevin L.; Mathalon, Daniel H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Chartier, Maggie; Mathalon, Daniel H.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Sullivan, Jude C.] Univ Wisconsin, Madison Hosp, Madison, WI 53711 USA. [Sullivan, Jude C.] Univ Wisconsin, Clin Sports Med Ctr, Madison, WI 53711 USA. [Segal, Zindel V.] Univ Toronto, Dept Psychiat, Toronto, ON M5T 1R8, Canada. [Feldman, Mitchell D.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. RP Eisendrath, SJ (reprint author), Univ Calif San Francisco, Dept Psychiat, 401 Parnassus Ave,Box 0984 AIP, San Francisco, CA 94143 USA. EM StuartE@lppi.ucsf.edu RI Segal, Zindel/F-8008-2014 FU NIH/National Center for Complementary and Alternative Medicine (NCCAM) [R01AT004572] FX This study is funded by the NIH/National Center for Complementary and Alternative Medicine (NCCAM) grant number R01AT004572. The authors would like to gratefully thank Ms. Lauren Erickson, Christa Hogan, Natalie Holbrook and other members of the research staff who were responsible for subject recruitment, tracking/scheduling and data collection. NR 64 TC 12 Z9 12 U1 10 U2 67 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6882 J9 BMC COMPLEM ALTERN M JI BMC Complement. Altern. Med. PD MAR 11 PY 2014 VL 14 AR 95 DI 10.1186/1472-6882-14-95 PG 11 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA AD8LZ UT WOS:000333518800002 PM 24612825 ER PT J AU Kim, H Cho, J Kim, YR Song, Y Chun, SI Suh, JY Kim, JK Ryu, YH Choi, SM Cho, H Cho, G AF Kim, Hyungjun Cho, Junghun Kim, Young R. Song, Youngkyu Chun, Song-I Suh, Ji-Yeon Kim, Jeong Kon Ryu, Yeon-Hee Choi, Sun-Mi Cho, Hyungjoon Cho, Gyunggoo TI Response of the Primary Auditory and Non-Auditory Cortices to Acoustic Stimulation: A Manganese-Enhanced MRI Study SO PLOS ONE LA English DT Article ID RESONANCE-IMAGING MEMRI; MEDIAL GENICULATE-BODY; VISUAL-CORTEX; INFERIOR COLLICULUS; FUNCTIONAL-ACTIVITY; SOCIAL STRESS; RAT; PROJECTIONS; PATHWAY; ORGANIZATION AB Structural and functional features of various cerebral cortices have been extensively explored in neuroscience research. We used manganese-enhanced MRI, a non-invasive method for examining stimulus-dependent activity in the whole brain, to investigate the activity in the layers of primary cortices and sensory, such as auditory and olfactory, pathways under acoustic stimulation. Male Sprague-Dawley rats, either with or without exposure to auditory stimulation, were scanned before and 24-29 hour after systemic MnCl2 injection. Cortex linearization and layer-dependent signal extraction were subsequently performed for detecting layer-specific cortical activity. We found stimulus-dependent activity in the deep layers of the primary auditory cortex and the auditory pathways. The primary sensory and visual cortices also showed the enhanced activity, whereas the olfactory pathways did not. Further, we performed correlation analysis of the signal intensity ratios among different layers of each cortex, and compared the strength of correlations between with and without the auditory stimulation. In the primary auditory cortex, the correlation strength between left and right hemisphere showed a slight but not significant increase with the acoustic simulation, whereas, in the primary sensory and visual cortex, the correlation coefficients were significantly smaller. These results suggest the possibility that even though the primary auditory, sensory, and visual cortices showed enhanced activity to the auditory stimulation, these cortices had different associations for auditory processing in the brain network. C1 [Kim, Hyungjun; Song, Youngkyu; Chun, Song-I; Suh, Ji-Yeon; Kim, Jeong Kon; Cho, Gyunggoo] Korea Basic Sci Inst, Div MR, Ochang Eup, Chungbuk, South Korea. [Kim, Hyungjun; Ryu, Yeon-Hee; Choi, Sun-Mi] Korea Inst Oriental Med, Div Med Res, Taejon, South Korea. [Cho, Junghun; Cho, Hyungjoon] UNIST, Sch Nanobiosci & Chem Engn, Ulsan, South Korea. [Kim, Young R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA USA. [Kim, Jeong Kon] Univ Ulsan, Dept Radiol, Asan Med Ctr, Seoul, South Korea. RP Cho, H (reprint author), UNIST, Sch Nanobiosci & Chem Engn, Ulsan, South Korea. EM hjcho@unist.ac.kr; gyunggoo@kbsi.re.kr RI Cho, HyungJoon/F-1423-2010 FU Korea Basic Science Institute [E33601]; UNIST (Ulsan National Institute of Science and Technology) [1.130030.01]; Korea Institute of Oriental Medicine [K13290] FX This research was supported by grants from the Korea Basic Science Institute (E33601), from the 2013 Future Challenge Research Fund (Project No. 1.130030.01) of UNIST (Ulsan National Institute of Science and Technology), and from the Korea Institute of Oriental Medicine (K13290). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 3 Z9 3 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 11 PY 2014 VL 9 IS 3 AR e90427 DI 10.1371/journal.pone.0090427 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC9GM UT WOS:000332842400018 PM 24618696 ER PT J AU Morris, JC Tan, AR Olencki, TE Shapiro, GI Dezube, BJ Reiss, M Hsu, FJ Berzofsky, JA Lawrence, DP AF Morris, John C. Tan, Antoinette R. Olencki, Thomas E. Shapiro, Geoffrey I. Dezube, Bruce J. Reiss, Michael Hsu, Frank J. Berzofsky, Jay A. Lawrence, Donald P. TI Phase I Study of GC1008 (Fresolimumab): A Human Anti-Transforming Growth Factor-Beta (TGF beta) Monoclonal Antibody in Patients with Advanced Malignant Melanoma or Renal Cell Carcinoma SO PLOS ONE LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSDIFFERENTIATION; METASTATIC BREAST-CANCER; SOLID TUMORS; T-CELLS; PROGRESSION; INHIBITION; EFFICACY; SURVIVAL; VIVO; KERATOACANTHOMAS AB Background: In advanced cancers, transforming growth factor-beta (TGFb) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFb monoclonal antibody that neutralizes all isoforms of TGFb. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma. Methods: In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed. Results: Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4-44.4 weeks). Conclusions: GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments. C1 [Morris, John C.; Berzofsky, Jay A.] NCI, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Morris, John C.; Berzofsky, Jay A.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Tan, Antoinette R.; Reiss, Michael] Canc Inst New Jersey, Dept Med, New Brunswick, NJ USA. [Olencki, Thomas E.] Ohio State Univ, Dept Med, Columbus, OH 43210 USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Dezube, Bruce J.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Hsu, Frank J.] Genzyme Corp, Cambridge, MA USA. [Lawrence, Donald P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Morris, JC (reprint author), Univ Cincinnati, Dept Med, Div Hematol Oncol, Vontz Ctr Mol Studies, ML0562, Cincinnati, OH 45221 USA. EM morri2j7@ucmail.uc.edu; berzofsj@mail.nih.gov FU Genzyme Corporation; Center for Cancer Research, National Cancer Institute (NCI); Genzyme FX This work was supported by Genzyme Corporation, and in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI). Genzyme provided financial support, the investigational agent GC1008, and supported study design, data collection and analysis, the decision to publish, and preparation of the manuscript. NR 50 TC 41 Z9 46 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 11 PY 2014 VL 9 IS 3 AR e90353 DI 10.1371/journal.pone.0090353 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC9GM UT WOS:000332842400014 PM 24618589 ER PT J AU Yoon, JC Ling, AJY Isik, M Lee, DYD Steinbaugh, MJ Sack, LM Boduch, AN Blackwell, TK Sinclair, DA Elledge, SJ AF Yoon, John C. Ling, Alvin J. Y. Isik, Meltem Lee, Dong-Young Donna Steinbaugh, Michael J. Sack, Laura M. Boduch, Abigail N. Blackwell, T. Keith Sinclair, David A. Elledge, Stephen J. TI GLTSCR2/PICT1 links mitochondrial stress and Myc signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RIBOSOMAL-PROTEIN L11; C-MYC; MAMMALIAN-CELLS; EXPRESSION; GENES; INHIBITION; ACTIVATION; LONGEVITY; APOPTOSIS; PATHWAY AB Mitochondrial defects underlie a multitude of human diseases. Genetic manipulation of mitochondrial regulatory pathways represents a potential therapeutic approach. We have carried out a high-throughput overexpression screen for genes that affect mitochondrial abundance or activity using flow-cytometry-based enrichment of a cell population expressing a high-complexity, concentration-normalized pool of human ORFs. The screen identified 94 candidate mitochondrial regulators including the nuclear protein GLTSCR2, also known as PICT1. GLTSCR2 enhances mitochondrial function and is required for the maintenance of oxygen consumption, consistent with a pivotal role in the control of cellular respiration. RNAi inactivation of the Caenorhabditis elegans ortholog of GLTSCR2 reduces respiration in worms, indicating functional conservation across species. GLTSCR2 controls cellular proliferation and metabolism via the transcription factor Myc, and is induced by mitochondrial stress, suggesting it may constitute a significant component of the mitochondrial signaling pathway. C1 [Yoon, John C.; Ling, Alvin J. Y.; Isik, Meltem; Lee, Dong-Young Donna; Steinbaugh, Michael J.; Sack, Laura M.; Boduch, Abigail N.; Blackwell, T. Keith; Sinclair, David A.; Elledge, Stephen J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Yoon, John C.; Lee, Dong-Young Donna; Sack, Laura M.; Boduch, Abigail N.; Elledge, Stephen J.] Brigham & Womens Hosp, Howard Hughes Med Inst, Div Genet, Boston, MA 02114 USA. [Yoon, John C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Ling, Alvin J. Y.; Sinclair, David A.] Harvard Univ, Sch Med, Paul F Glenn Labs Biol Mech Aging, Boston, MA 02115 USA. [Isik, Meltem; Steinbaugh, Michael J.; Blackwell, T. Keith] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Elledge, SJ (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM jcyoon@partners.org; david_sinclair@hms.harvard.edu; selledge@genetics.med.harvard.edu OI Steinbaugh, Michael/0000-0002-2403-2221; Sinclair, David/0000-0002-9936-436X FU National Institutes of Health; Paul F. Glenn Foundation; United Mitochondrial Disease Foundation; Juvenile Diabetes Foundation; [K08DK081612]; [R01GM094398] FX We thank the Institute of Chemistry and Cell Biology for assistance with the mini-RNAi screening. This work was supported by K08DK081612 (to J.C.Y.), R01GM094398 (to T.K.B.), and National Institutes of Health research grants (to D.A.S. and S.J.E.). D.A.S. is also supported by the Paul F. Glenn Foundation, the United Mitochondrial Disease Foundation, the Juvenile Diabetes Foundation, and a gift from the Schulak family. S.J.E. is an investigator with the Howard Hughes Medical Institute. NR 31 TC 6 Z9 6 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 11 PY 2014 VL 111 IS 10 BP 3781 EP 3786 DI 10.1073/pnas.1400705111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC5MK UT WOS:000332564800040 PM 24556985 ER PT J AU Spring, BQ Abu-Yousif, AO Palanisami, A Rizvi, I Zheng, X Mai, ZM Anbil, S Sears, RB Mensah, LB Goldschmidt, R Erdem, SS Oliva, E Hasan, T AF Spring, Bryan Q. Abu-Yousif, Adnan O. Palanisami, Akilan Rizvi, Imran Zheng, Xiang Mai, Zhiming Anbil, Sriram Sears, R. Bryan Mensah, Lawrence B. Goldschmidt, Ruth Erdem, S. Sibel Oliva, Esther Hasan, Tayyaba TI Selective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugates SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE activatable therapeutic agent; activatable imaging agent; photodynamic therapy; ovarian cancer; molecular imaging ID GROWTH-FACTOR RECEPTOR; EPITHELIAL OVARIAN-CANCER; INTRAPERITONEAL PHOTODYNAMIC THERAPY; PERITONEAL CARCINOMATOSIS; PANCREATIC-CANCER; MURINE MODEL; EX-VIVO; PHOTOIMMUNOTHERAPY; CELLS; MICROENDOSCOPY AB Drug-resistant micrometastases that escape standard therapies often go undetected until the emergence of lethal recurrent disease. Here, we show that it is possible to treat microscopic tumors selectively using an activatable immunoconjugate. The immunoconjugate is composed of self-quenching, near-infrared chromophores loaded onto a cancer cell-targeting antibody. Chromophore phototoxicity and fluorescence are activated by lysosomal proteolysis, and light, after cancer cell internalization, enabling tumor-confined photo-cytotoxicity and resolution of individual micrometastases. This unique approach not only introduces a therapeutic strategy to help destroy residual drug-resistant cells but also provides a sensitive imaging method to monitor micrometastatic disease in common sites of recurrence. Using fluorescence microendoscopy to monitor immunoconjugate activation and micrometastatic disease, we demonstrate these concepts of "tumor-targeted, activatable photoimmunotherapy" in a mouse model of peritoneal carcinomatosis. By introducing targeted activation to enhance tumor selectively in complex anatomical sites, this study offers prospects for catching early recurrent micrometastases and for treating occult disease. C1 [Spring, Bryan Q.; Abu-Yousif, Adnan O.; Palanisami, Akilan; Rizvi, Imran; Zheng, Xiang; Mai, Zhiming; Anbil, Sriram; Sears, R. Bryan; Mensah, Lawrence B.; Goldschmidt, Ruth; Erdem, S. Sibel; Hasan, Tayyaba] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Spring, Bryan Q.; Abu-Yousif, Adnan O.; Palanisami, Akilan; Rizvi, Imran; Zheng, Xiang; Mai, Zhiming; Anbil, Sriram; Mensah, Lawrence B.; Goldschmidt, Ruth; Erdem, S. Sibel; Hasan, Tayyaba] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Oliva, Esther] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hasan, Tayyaba] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Hasan, Tayyaba] Harvard Univ, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Hasan, Tayyaba] MIT, Cambridge, MA 02139 USA. RP Hasan, T (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM thasan@mgh.harvard.edu FU National Institutes of Health [R01-AR40352, RC1-CA146337, R01-CA160998, P01-CA084203, F32-CA144210] FX We thank Drs. Jonathan P. Celli and Conor L. Evans for insightful discussions; Dr. Jie Zhao, Julie LaGraves, Elena Salomatina, and Peggy Sherwood for expert technical assistance; and Rina P. Spring for a critical reading. This work was supported by National Institutes of Health Grants R01-AR40352, RC1-CA146337, R01-CA160998, and P01-CA084203 (to T.H.) and F32-CA144210 (to B.Q.S.). NR 56 TC 24 Z9 24 U1 6 U2 46 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 11 PY 2014 VL 111 IS 10 BP E933 EP E942 DI 10.1073/pnas.1319493111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC5MK UT WOS:000332564800011 PM 24572574 ER PT J AU Connors, EC Chrastil, ER Sanchez, J Merabet, LB AF Connors, Erin C. Chrastil, Elizabeth R. Sanchez, Jaime Merabet, Lotfi B. TI Action video game play and transfer of navigation and spatial cognition skills in adolescents who are blind SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE early blind; adolescent; navigation; spatial cognition; gaming for learning; serious videogames; virtual environment ID VIRTUAL-REALITY; PEOPLE; MOBILITY; PERCEPTION; CHILDREN; INDIVIDUALS; ENVIRONMENT; VISION; SYSTEM; MEMORY AB For individuals who are blind, navigating independently in an unfamiliar environment represents a considerable challenge. Inspired by the rising popularity of video games, we have developed a novel approach to train navigation and spatial cognition skills in adolescents who are blind. Audio-based Environment Simulator (AbES) is a software application that allows for the virtual exploration of an existing building set in an action video game metaphor. Using this ludic-based approach to learning, we investigated the ability and efficacy of adolescents with early onset blindness to acquire spatial information gained from the exploration of a target virtual indoor environment. Following game play, participants were assessed on their ability to transfer and mentally manipulate acquired spatial information on a set of navigation tasks carried out in the real environment. Success in transfer of navigation skill performance was markedly high suggesting that interacting with AbES leads to the generation of an accurate spatial mental representation. Furthermore, there was a positive correlation between success in game play and navigation task performance. The role of virtual environments and gaming in the development of mental spatial representations is also discussed. We conclude that this game based learning approach can facilitate the transfer of spatial knowledge and further, can be used by individuals who are blind for the purposes of navigation in real-world environments. C1 [Connors, Erin C.; Merabet, Lotfi B.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Lab Visual Neuroplast, Boston, MA 02114 USA. [Chrastil, Elizabeth R.] Boston Univ, Ctr Memory & Brain, Dept Psychol & Brain Sci, Boston, MA 02215 USA. [Sanchez, Jaime] Univ Chile, Ctr Adv Res Educat, Dept Comp Sci, Santiago, Chile. RP Merabet, LB (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Lab Visual Neuroplast, 243 Charles St, Boston, MA 02114 USA. EM lotfi_merabet@meei.harvard.edu OI Chrastil, Elizabeth/0000-0003-2544-0152 FU NIH/NEI ROI [EY019924]; Chilean National Rind of Science and Technology, Fondecyt [1120330]; Program Center Education PBCT-Conicyt [CIE-05] FX This work was supported by an NIH/NEI ROI GRANT EY019924 (Lotfi B. Merabet) and also funded by the Chilean National Rind of Science and Technology, Fondecyt #1120330 and Project CIE-05 Program Center Education PBCT-Conicyt (Jaime Sanchez). The authors would like to thank the research participants, as well as Molly Connors, Rabih Dow, Padma Rajagopal and the staff of the Carroll Center for the Blind (Newton MA, USA) for their support in carrying out this research. NR 44 TC 4 Z9 4 U1 6 U2 47 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 11 PY 2014 VL 8 AR 133 DI 10.3389/fnhum.2014.00133 PG 8 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AC7DB UT WOS:000332686300001 PM 24653690 ER PT J AU Goodman, SG Wojdyla, DM Piccini, JP White, HD Paolini, JF Nessel, CC Berkowitz, SD Mahaffey, KW Patel, MR Sherwood, MW Becker, RC Halperin, JL Hacke, W Singer, DE Hankey, GJ Breithardt, G Fox, KAA Califf, RM AF Goodman, Shaun G. Wojdyla, Daniel M. Piccini, Jonathan P. White, Harvey D. Paolini, John F. Nessel, Christopher C. Berkowitz, Scott D. Mahaffey, Kenneth W. Patel, Manesh R. Sherwood, Matthew W. Becker, Richard C. Halperin, Jonathan L. Hacke, Werner Singer, Daniel E. Hankey, Graeme J. Breithardt, Gunter Fox, Keith A. A. Califf, Robert M. CA ROCKET AF Investigators TI Factors Associated With Major Bleeding Events SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE anticoagulants; atrial fibrillation; hemorrhage ID NONVALVULAR ATRIAL-FIBRILLATION; STROKE PREVENTION; RISK-FACTORS; WARFARIN; ANTICOAGULATION; TRIAL; RIVAROXABAN; COMPLICATIONS; HEMORRHAGE; PREDICTION AB Objectives This study sought to report additional safety results from the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). Background The ROCKET AF trial demonstrated similar risks of stroke/systemic embolism and major/nonmajor clinically relevant bleeding (principal safety endpoint) with rivaroxaban and warfarin. Methods The risk of the principal safety and component bleeding endpoints with rivaroxaban versus warfarin were compared, and factors associated with major bleeding were examined in a multivariable model. Results The principal safety endpoint was similar in the rivaroxaban and warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95% confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but there were no differences between treatments in each age category (<65, 65 to 74, >= 75 years; p(interaction) = 0.59). Compared with those without (n = 13,455), patients with a major bleed (n = 781) were more likely to be older, current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior stroke/transient ischemic attack. Increasing age, baseline diastolic blood pressure (DBP) >= 90 mm Hg, history of chronic obstructive pulmonary disease or GI bleeding, prior acetylsalicylic acid use, and anemia were independently associated with major bleeding risk; female sex and DBP <90 mm Hg were associated with a decreased risk. Conclusions Rivaroxaban and warfarin had similar risk for major/nonmajor clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior acetylsalicylic acid use, and anemia were associated with the risk of major bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation: NCT00403767) (C) 2014 by the American College of Cardiology Foundation C1 [Goodman, Shaun G.] Univ Toronto, St Michaels Hosp, Canadian Heart Res Ctr, Toronto, ON M5B 1W8, Canada. [Goodman, Shaun G.] Univ Toronto, St Michaels Hosp, Terrence Donnelly Heart Ctr, Div Cardiol, Toronto, ON M5B 1W8, Canada. [Wojdyla, Daniel M.; Piccini, Jonathan P.; Mahaffey, Kenneth W.; Patel, Manesh R.; Sherwood, Matthew W.; Becker, Richard C.; Califf, Robert M.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [White, Harvey D.] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand. [Paolini, John F.; Berkowitz, Scott D.] Bayer HealthCare Pharmaceut, Montville, NJ USA. [Nessel, Christopher C.] Janssen Res & Dev, Raritan, NJ USA. [Halperin, Jonathan L.] Mt Sinai Med Ctr, Cardiovasc Inst, New York, NY 10029 USA. [Hacke, Werner] Heidelberg Univ, Heidelberg, Germany. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [Hankey, Graeme J.] Royal Perth Hosp, Perth, WA 6001, Australia. [Breithardt, Gunter] Hosp Univ Munster, Munster, Germany. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. [Califf, Robert M.] Duke Univ, Med Ctr, Duke Translat Med Inst, Durham, NC USA. RP Goodman, SG (reprint author), Univ Toronto, St Michaels Hosp, 30 Bond St,Room 6-034 Queen, Toronto, ON M5B 1W8, Canada. EM goodmans@chrc.net RI Hankey, Graeme /H-4968-2014 OI Hankey, Graeme /0000-0002-6044-7328 FU Johnson & Johnson Pharmaceutical Research and Development; Bayer HealthCare; Bayer; Johnson Johnson; Boehringer Ingelheim; Bristol-Myers Squibb; Sanofi-Aventis; Resmed; ARCA Biopharma; BMS/Pfizer; Medtronic, Inc.; Spectranetics; Forest Laboratories; Eli Lilly; AstraZeneca; Eli Lilly and Company; GlaxoSmithKline; Merck Co., Inc.; Novartis Pharmaceuticals Corporation; Pozen; Regado Biosciences; Schering-Plough; Medicines Company; Daiichi Sankyo; Pfizer; AHRQ; NHBLI; Otsuka Pharmaceutical Co., Ltd.; Ortho McNeil Janssen; Regado; AG HealthCare; Biotronik, Inc.; Duke Clinical Research Institute; Boston Scientific; Ortho-McNeil-Janssen Pharmaceuticals; CSL Behring; CVS Caremark; theheart.org; Meda Pharma; St. Jude; MSD; 3M FX The ROCKET AF trial was supported by Johnson & Johnson Pharmaceutical Research and Development and Bayer HealthCare. The Duke Clinical Research Institute coordinated the trial, managed the database, and performed the analyses independently of the sponsors. The Executive Committee designed the trial, was responsible for overseeing the conduct of the study, retained the ability to independently analyze and present the data, made the decision to submit the manuscript for publication, and takes responsibility for the accuracy and completeness of the data and all analyses. Dr. Goodman has received consulting fees/honoraria and/or research grant support from Bayer, Johnson & Johnson, Boehringer Ingelheim, Bristol-Myers Squibb, Sanofi-Aventis. Dr. Piccini has received consulting fees/honoraria and/or research grant support from Johnson & Johnson, GE Healthcare, Resmed, ARCA Biopharma, BMS/Pfizer, Sanofi-Aventis, Medtronic, Inc., Spectranetics, and Forest Laboratories. Dr. White has received consulting fees/honoraria and/or research grant support from Sanofi-Aventis, Eli Lilly, The Medicines Company, National Institutes of Health, Pfizer, Roche, Johnson& Johnson, Schering-Plough, Merck & Co., Inc. Sharp and Dohme, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, Bristol-Myers Squibb, and Regado. Dr. Paolini was employed by and has held stock options for Bayer HealthCare. Dr. Nessel is employed by and owns stock in Johnson & Johnson. Dr. Berkowitz is employed by Bayer HealthCare. Dr. Mahaffey has received consulting fees/honoraria and/or research grant support from Johnson & Johnson, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pozen, Regado Biosciences, Sanofi-Aventis, Schering-Plough, The Medicines Company, Daiichi Sankyo, and Pfizer. Dr. Patel has received consulting fees/honoraria and/or research grant support from Johnson & Johnson, AstraZeneca, AHRQ, NHBLI, Bayer, Otsuka Pharmaceutical Co., Ltd., and Ortho McNeil Janssen. Dr. Becker has received consulting fees/honoraria and/or research grant support from Johnson & Johnson, Regado, Boehringer Ingelheim, AstraZeneca, Daiichi Sankyo, and Bayer. Dr. Halperin has received consulting fees/honoraria and/or research grant support from AstraZeneca, Bayer AG HealthCare, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Pfizer, Sanofi-Aventis, Biotronik, Inc., Duke Clinical Research Institute, Boston Scientific, and Ortho-McNeil-Janssen Pharmaceuticals. Dr. Hacke has received consulting fees/honoraria and/or research grant support from Bayer, Johnson & Johnson, and Boehringer Ingelheim. Dr. Singer has received consulting fees/honoraria and/or research grant support from Bayer, Bristol-Myers Squibb, CSL Behring, Johnson & Johnson, Merck & Co., Inc. Pfizer, Sanofi-Aventis, CVS Caremark, Boehringer Ingelheim, Daiichi Sankyo, Bristol-Myers Squibb, CSL Behring, and Pfizer. Dr. Hankey has received consulting fees/honoraria and/or research grant support from Johnson & Johnson, Bayer, and theheart.org. Dr. Breithardt has received consulting fees/honoraria and/or research grant support from Bayer HealthCare, Johnson & Johnson, Meda Pharma, Sanofi-Aventis, St. Jude, Boehringer Ingelheim, Boston Scientific, Otsuka Pharmaceutical Co., Ltd., MSD, and 3M. Dr. Fox has received consulting fees/honoraria and/or research grant support from Bayer, Johnson & Johnson, Eli Lilly and Company, Sanofi-Aventis, AstraZeneca, and Boehringer Ingelheim. Dr.; Califf has received consulting fees/honoraria and/or research grant support from Johnson & Johnson, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, and Daiichi Sankyo. Dr. Mahaffey is now affiliated with the Department of Medicine, Stanford University, Stanford, California. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 24 TC 63 Z9 63 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 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 11 PY 2014 VL 63 IS 9 BP 891 EP 900 DI 10.1016/j.jacc.2013.11.013 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AC3FE UT WOS:000332399700007 PM 24315894 ER PT J AU Colleoni, M Gelber, RD AF Colleoni, Marco Gelber, Richard D. TI Time to Initiation of Adjuvant Chemotherapy for Early Breast Cancer and Outcome: The Earlier, the Better? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID SURVIVAL; SURGERY; THERAPY; TUMORS C1 [Colleoni, Marco] European Inst Oncol, Int Breast Canc Study Grp, Milan, Italy. [Gelber, Richard D.] Dana Farber Canc Inst, Int Breast Canc Study Grp, Boston, MA 02115 USA. RP Colleoni, M (reprint author), European Inst Oncol, Int Breast Canc Study Grp, Milan, Italy. NR 20 TC 7 Z9 7 U1 2 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2014 VL 32 IS 8 BP 717 EP + DI 10.1200/JCO.2013.54.3942 PG 4 WC Oncology SC Oncology GA AC4IB UT WOS:000332483400003 PM 24516011 ER PT J AU Wood, ME Kadlubek, P Pham, TH Wollins, DS Lu, KH Weitzel, JN Neuss, MN Hughes, KS AF Wood, Marie E. Kadlubek, Pamela Pham, Trang H. Wollins, Dana S. Lu, Karen H. Weitzel, Jeffrey N. Neuss, Michael N. Hughes, Kevin S. TI Quality of Cancer Family History and Referral for Genetic Counseling and Testing Among Oncology Practices: A Pilot Test of Quality Measures As Part of the American Society of Clinical Oncology Quality Oncology Practice Initiative SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PRIMARY-CARE PHYSICIANS; RISK-ASSESSMENT; COLORECTAL-CANCER; OVARIAN-CANCER; BREAST; SUSCEPTIBILITY; GUIDELINES; MANAGEMENT; STATEMENT; KNOWLEDGE AB Purpose Family history of cancer (CFH) is important for identifying individuals to receive genetic counseling/testing (GC/GT). Prior studies have demonstrated low rates of family history documentation and referral for GC/GT. Methods CFH quality and GC/GT practices for patients with breast (BC) or colon cancer (CRC) were assessed in 271 practices participating in the American Society of Clinical Oncology Quality Oncology Practice Initiative in fall 2011. Results A total of 212 practices completed measures regarding CFH and GC/GT practices for 10,466 patients; 77.4% of all medical records reviewed documented presence or absence of CFH in first-degree relatives, and 61.5% of medical records documented presence or absence of CFH in second-degree relatives, with significantly higher documentation for patients with BC compared with CRC. Age at diagnosis was documented for all relatives with cancer in 30.7% of medical records (BC, 45.2%; CRC, 35.4%; P .001). Referall for GC/GT occurred in 22.1% of all patients with BC or CRC. Of patients with increased risk for hereditary cancer, 52.2% of patients with BC and 26.4% of those with CRC were referred for GC/GT. When genetic testing was performed, consent was documented 77.7% of the time, and discussion of results was documented 78.8% of the time. Conclusion We identified low rates of complete CFH documentation and low rates of referral for those with BC or CRC meeting guidelines for referral among US oncologists. Documentation and referral were greater for patients with BC compared with CRC. Education and support regarding the importance of accurate CFH and the benefits of proactive high-risk patient management are clearly needed. C1 [Wood, Marie E.] Univ Vermont, Burlington, VT 05405 USA. [Kadlubek, Pamela; Pham, Trang H.; Wollins, Dana S.] Amer Soc Clin Oncol, Alexandria, VA USA. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Neuss, Michael N.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Hughes, Kevin S.] Mass Gen Hosp, Avon Comprehens Breast Evaluat Ctr, Boston, MA USA. RP Wood, ME (reprint author), Univ Vermont, Hem Onc, Given E214,89 Beaumont, Burlington, VT 05405 USA. EM marie.wood@uvm.edu OI Hughes, Kevin/0000-0003-4084-6484 FU NCI NIH HHS [P30 CA016672, P50 CA083639] NR 34 TC 36 Z9 36 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2014 VL 32 IS 8 BP 824 EP 829 DI 10.1200/JCO.2013.51.4661 PG 6 WC Oncology SC Oncology GA AC4IB UT WOS:000332483400020 PM 24493722 ER PT J AU Nikiforow, S LaCasce, AS AF Nikiforow, Sarah LaCasce, Ann S. TI Targeting Epstein-Barr Virus-Associated Lymphomas SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CYTOTOXIC T-CELLS; B-CELL; IN-VIVO; EBV; RESPONSES; DISEASE; ANTIGEN; CD4(+); TRANSPLANTATION; IDENTIFICATION C1 [Nikiforow, Sarah; LaCasce, Ann S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Nikiforow, S (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 32 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2014 VL 32 IS 8 BP 830 EP 832 DI 10.1200/JCO.2013.53.2994 PG 3 WC Oncology SC Oncology GA AC4IB UT WOS:000332483400021 PM 24493729 ER PT J AU Lu, KH Wood, ME Daniels, M Burke, C Ford, J Kauff, ND Kohlmann, W Lindor, NM Mulvey, TM Robinson, L Rubinstein, WS Stoffel, EM Snyder, C Syngal, S Merrill, JK Wollins, DS Hughes, KS AF Lu, Karen H. Wood, Marie E. Daniels, Molly Burke, Cathy Ford, James Kauff, Noah D. Kohlmann, Wendy Lindor, Noralane M. Mulvey, Therese M. Robinson, Linda Rubinstein, Wendy S. Stoffel, Elena M. Snyder, Carrie Syngal, Sapna Merrill, Janette K. Wollins, Dana Swartzberg Hughes, Kevin S. TI American Society of Clinical Oncology Expert Statement: Collection and Use of a Cancer Family History for Oncology Providers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LI-FRAUMENI SYNDROME; COLORECTAL-CANCER; RISK-ASSESSMENT; LYNCH-SYNDROME; POLICY STATEMENT; BREAST-CANCER; GENETIC COUNSELORS; GERMLINE MUTATIONS; NATIONAL SOCIETY; OVARIAN-CANCER C1 [Lu, Karen H.; Daniels, Molly; Burke, Cathy] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Robinson, Linda] Simmons Comprehens Canc Ctr, Dallas, TX USA. [Wood, Marie E.] Univ Vermont, Burlington, VT 05405 USA. [Ford, James] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Kauff, Noah D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kohlmann, Wendy] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Lindor, Noralane M.] Mayo Clin, Scottsdale, AZ USA. [Mulvey, Therese M.] Southcoast Ctr Canc Care, Fall River, MA USA. [Syngal, Sapna] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Hughes, Kevin S.] Massachusetts Gen Hosp, Avon Comprehens Breast Evaluat Ctr, Boston, MA 02114 USA. [Rubinstein, Wendy S.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Stoffel, Elena M.] Univ Michigan, Ann Arbor, MI 48109 USA. [Snyder, Carrie] Creighton Univ, Omaha, NE 68178 USA. [Merrill, Janette K.; Wollins, Dana Swartzberg] Amer Soc Clin Oncol, Alexandria, VA USA. RP Wood, ME (reprint author), Univ Vermont, Hem Onc, Given E214,89 Beaumont, Burlington, VT 05405 USA. EM marie.wood@uvm.edu OI Daniels, Molly/0000-0002-5093-5539; Kauff, Noah/0000-0001-7242-6156; Hughes, Kevin/0000-0003-4084-6484 FU NCI NIH HHS [P50 CA083639, P30 CA016672] NR 51 TC 43 Z9 46 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2014 VL 32 IS 8 BP 833 EP + DI 10.1200/JCO.2013.50.9257 PG 9 WC Oncology SC Oncology GA AC4IB UT WOS:000332483400022 PM 24493721 ER PT J AU Freidlin, B Sun, ZX Gray, R Korn, EL AF Freidlin, Boris Sun, Zhuoxin Gray, Robert Korn, Edward L. TI Reply to S. Goteti et al SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID RANDOMIZED CLINICAL-TRIALS; ONCOLOGY C1 [Freidlin, Boris; Korn, Edward L.] NCI, Bethesda, MD 20892 USA. [Sun, Zhuoxin; Gray, Robert] Dana Farber Canc Inst, Eastern Cooperat Oncol Grp, Boston, MA 02115 USA. RP Freidlin, B (reprint author), NCI, Bethesda, MD 20892 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2014 VL 32 IS 8 BP 856 EP 856 DI 10.1200/JCO.2013.53.8934 PG 1 WC Oncology SC Oncology GA AC4IB UT WOS:000332483400029 PM 24493728 ER PT J AU Yang, JCH Sequist, LV AF Yang, James Chih-Hsin Sequist, Lecia V. TI Reply to E. R. Haspinger et al SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Yang, James Chih-Hsin] Natl Taiwan Univ Hosp, Taipei, Taiwan. [Sequist, Lecia V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sequist, Lecia V.] Harvard Univ, Sch Med, Boston, MA USA. RP Yang, JCH (reprint author), Natl Taiwan Univ Hosp, Taipei, Taiwan. OI Yang, James Chih-Hsin/0000-0002-5586-5138 NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2014 VL 32 IS 8 BP 863 EP 864 DI 10.1200/JCO.2013.54.1920 PG 2 WC Oncology SC Oncology GA AC4IB UT WOS:000332483400033 PM 24493734 ER PT J AU Yang, JCH Sequist, LV AF Yang, James Chih-Hsin Sequist, Lecia V. TI Reply to F. de Marinis et al SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Yang, James Chih-Hsin] Natl Taiwan Univ Hosp, Taipei, Taiwan. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Yang, JCH (reprint author), Natl Taiwan Univ Hosp, Taipei, Taiwan. OI Yang, James Chih-Hsin/0000-0002-5586-5138 NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2014 VL 32 IS 8 BP 865 EP 865 DI 10.1200/JCO.2013.54.1904 PG 1 WC Oncology SC Oncology GA AC4IB UT WOS:000332483400035 PM 24493733 ER PT J AU Ciocalteu, A Saftoiu, A Cartana, T Gruionu, LG Pirici, D Georgescu, CC Georgescu, CV Gheonea, DI Gruionu, G AF Ciocalteu, Adriana Saftoiu, Adrian Cartana, Tatiana Gruionu, Lucian Gheorghe Pirici, Daniel Georgescu, Corneliu Cristian Georgescu, Claudia-Valentina Gheonea, Dan Ionut Gruionu, Gabriel TI Evaluation of New Morphometric Parameters of Neoangiogenesis in Human Colorectal Cancer Using Confocal Laser Endomicroscopy (CLE) and Targeted Panendothelial Markers SO PLOS ONE LA English DT Article ID ANTI-ANGIOGENIC THERAPY; IN-VIVO; VASCULATURE; MICROVASCULATURE; VASCULARIZATION; NORMALIZATION; ARCHITECTURE; TORTUOSITY; TUMORS; MODEL AB The tumor microcirculation is characterized by an abnormal vascular network with dilated, tortuous and saccular vessels. Therefore, imaging the tumor vasculature and determining its morphometric characteristics represent a critical goal for optimizing the cancer treatment that targets the blood vessels (i.e. antiangiogenesis therapy). The aim of this study was to evaluate new vascular morphometric parameters in colorectal cancer, difficult to achieve through conventional immunohistochemistry, by using the confocal laser endomicroscopy method. Fresh biopsies from tumor and normal tissue were collected during colonoscopy from five patients with T3 colorectal carcinoma without metastasis and were marked with fluorescently labeled anti-CD31 antibodies. A series of optical slices spanning 250 mm inside the tissue were immediately collected for each sample using a confocal laser endomicroscope. All measurements were expressed as the mean +/- standard error. The mean diameter of tumor vessels was significantly larger than the normal vessels (9.46 +/- 0.4 mu m vs. 7.60 +/- 0.3 mu m, p = 0.0166). The vessel density was also significantly higher in the cancer vs. normal tissue samples (5541.05 +/- 262.81 vs. 3755.79 +/- 194.96 vessels/mm(3), p = 0.0006). These results were confirmed by immunohistochemistry. In addition, the tortuosity index and vessel lengths were not significantly different (1.05 +/- 0.016 and 28.30 +/- 3.27 mu m in normal tissue, vs. 1.07 +/- 0.008 and 26.49 +/- 3.18 mu m in tumor tissue respectively, p = 0.5357 and p = 0.7033). The daughter/mother ratio (ratio of the sum of the squares of daughter vessel radii over the square of the mother vessel radius) was 1.15 +/- 0.09 in normal tissue, and 1.21 +/- 0.08 in tumor tissue (p = 0.6531). The confocal laser endomicroscopy is feasible for measuring more vascular parameters from fresh tumor biopsies than conventional immunohistochemistry alone. Provided new contrast agents will be clinically available, future in vivo use of CLE could lead to identification of novel biomarkers based on the morphometric characteristics of tumor vasculature. C1 [Ciocalteu, Adriana; Saftoiu, Adrian; Cartana, Tatiana; Gruionu, Lucian Gheorghe; Gheonea, Dan Ionut; Gruionu, Gabriel] Univ Med & Pharm Craiova, Res Ctr Gastroenterol & Hepatol, Craiova, Romania. [Gruionu, Lucian Gheorghe] Univ Craiova, Dept Mech Engn, Craiova, Romania. [Pirici, Daniel] Univ Med & Pharm Craiova, Dept Histol, Craiova, Romania. [Georgescu, Corneliu Cristian] Univ Med & Pharm Craiova, Dept Pharmacol, Craiova, Romania. [Georgescu, Corneliu Cristian] Emergency Cty Hosp, Dept Anesthesiol & Intens Care, Craiova, Romania. [Georgescu, Claudia-Valentina] Emergency Cty Hosp, Dept Pathol, Craiova, Romania. [Gruionu, Gabriel] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol,Edwin L Steele Lab Tumor Biol, Boston, MA USA. RP Saftoiu, A (reprint author), Univ Med & Pharm Craiova, Res Ctr Gastroenterol & Hepatol, Craiova, Romania. EM adrian.saftoiu@umfcv.ro RI Gheonea, Dan Ionut/C-3578-2012; Saftoiu, Adrian/C-2792-2011; Gruionu, Lucian/F-6121-2011; OI Gruionu, Lucian/0000-0002-4526-0864; Pirici, Daniel/0000-0002-0196-0949; Pirici, Daniel/0000-0001-9192-7319 FU National Research Council (CNCS), Romania [PN-II-ID-PCE-2011-3-0664, PN-II-CT-ERC-2012-1] FX This work was supported from two research grants funded by the National Research Council (CNCS), Romania, entitled "Clinical and Biomathematical Modeling of Vascular Changes Following Anti-Angiogenic Therapy in Advanced Colorectal Carcinoma," contract number PN-II-ID-PCE-2011-3-0664, and "Real-time Evaluation of Treatment Effects in Advanced Colorectal Carcinoma," contract number PN-II-CT-ERC-2012-1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 5 Z9 5 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 10 PY 2014 VL 9 IS 3 AR e91084 DI 10.1371/journal.pone.0091084 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC9FH UT WOS:000332839300074 PM 24614504 ER PT J AU Chen, LQ Bourguignon, LYW AF Chen, Liqun Bourguignon, Lilly Y. W. TI Hyaluronan-CD44 interaction promotes c-Jun signaling and miRNA21 expression leading to Bcl-2 expression and chemoresistance in breast cancer cells SO MOLECULAR CANCER LA English DT Article ID CYTOSKELETON ACTIVATION; CARCINOMA PROGRESSION; CYCLE PROGRESSION; TUMOR PROGRESSION; HOMING RECEPTOR; BINDING PROTEIN; GENE-EXPRESSION; UP-REGULATION; MARKER NANOG; KINASE AB MicroRNA-21 (miR-21) is associated with the development of solid tumors progression including breast cancer. In this study we investigated matrix hyaluronan (HA)-CD44 (a primary HA receptor) interaction with c-Jun N-Terminal Kinase (JNK)/c-Jun signaling in MDA-MB-468 breast cancer cells [a triple-negative (estrogen receptor-negative/progesterone receptor-negative/HER2-negative) breast cancer cell line]. Our results indicated that HA binding to CD44 promotes c-Jun nuclear translocation and transcriptional activation. Further analyses revealed that miR-21 is regulated by an upstream promoter containing AP1 binding site(s), and chromatin immunoprecipitation (CHIP) assays demonstrated that stimulation of miR-21 expression by HA/CD44 interaction is c-Jun-dependent in these breast cancer cells. This process results in an increase of the anti-apoptosis protein Bcl-2 and upregulation of inhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in MDA-MB-468 cells. Treatment with c-Jun specific small interfering RNAs effectively blocks HA-mediated c-Jun signaling and abrogates miR-21 production as well as causes downregulation of survival proteins (Bcl-2 and IAPs) and enhancement of chemosensitivity. In addition, our results demonstrated that anti-miR-21 inhibitor not only downregulates Bcl-2/IAP expression but also increases chemosensitivity in HA-treated breast cancer cells. Together, these findings suggest that the HA/CD44-induced c-Jun signaling plays a pivotal role in miR-21 production leading to survival protein (Bcl-2/IAP) upregulation and chemoresistance in triple negative breast cancer cells such as MDA-MB-468 cell line. This novel HA/CD44-mediated c-Jun signaling pathway and miR-21 production provide a new drug target for the future intervention strategies to treat breast cancer. C1 [Bourguignon, Lilly Y. W.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. Endocrine Unit 111N2, San Francisco, CA 94121 USA. RP Bourguignon, LYW (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM lilly.bourguignon@ucsf.edu FU Veterans Affairs (VA) [RR & D-1101 RX000601, BIR & D-5101 BX000628]; United States Public Health [R01 CA66163, P01 CA0052925]; DOD grant FX We gratefully acknowledge the assistance of Dr. Gerard J. Bourguignon in the preparation and review of this manuscript. This work was supported by Veterans Affairs (VA) Merit Review Awards (RR & D-1101 RX000601 and BIR & D-5101 BX000628), United States Public Health grants (R01 CA66163; P01 CA0052925) and DOD grant. L.Y.W.B is a VA Senior Research Career NR 60 TC 27 Z9 29 U1 0 U2 10 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 8 PY 2014 VL 13 AR 52 DI 10.1186/1476-4598-13-52 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA AF2KY UT WOS:000334542200002 PM 24606718 ER PT J AU Chahil-Graf, R Madani, N AF Chahil-Graf, Renu Madani, Navid TI Women, culture and the HIV epidemic in MENA SO JOURNAL OF THE INTERNATIONAL AIDS SOCIETY LA English DT Editorial Material C1 [Chahil-Graf, Renu] UNAIDS Middle East & North Africa, Reg Support Team, Cairo, Egypt. [Madani, Navid] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Dept Global Hlth & Socia, Boston, MA 02115 USA. RP Madani, N (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,CLSB 1010, Boston, MA 02215 USA. EM navid_madani@dfci.harvard.edu NR 10 TC 1 Z9 1 U1 0 U2 6 PU INT AIDS SOCIETY PI GENEVA PA AVENUE DE FRANCE 23, GENEVA, 1202, SWITZERLAND SN 1758-2652 J9 J INT AIDS SOC JI J. Int. AIDS Soc. PD MAR 8 PY 2014 VL 17 AR 19074 DI 10.7448/IAS.17.1.19074 PG 2 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AC8JM UT WOS:000332779300001 PM 24629846 ER PT J AU Luo, J Baranov, P Patel, S Ouyang, H Quach, J Wu, F Qiu, A Luo, HR Hicks, C Zeng, J Zhu, J Lu, J Sfeir, N Wen, C Zhang, MX Reade, V Patel, S Sinden, J Sun, XD Shaw, P Young, M Zhang, K AF Luo, Jing Baranov, Petr Patel, Sherrina Ouyang, Hong Quach, John Wu, Frances Qiu, Austin Luo, Hongrong Hicks, Caroline Zeng, Jing Zhu, Jing Lu, Jessica Sfeir, Nicole Wen, Cindy Zhang, Meixia Reade, Victoria Patel, Sara Sinden, John Sun, Xiaodong Shaw, Peter Young, Michael Zhang, Kang TI Human Retinal Progenitor Cell Transplantation Preserves Vision SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Eye; Neuroprogenitor Cell; Retinal Degeneration; Stem Cells; Transplantation; Retinal Progenitor Cells ID VISUAL FUNCTION; STEM-CELLS; RCS RATS; PHOTORECEPTOR DEGENERATION; MACULAR DEGENERATION; GEOGRAPHIC ATROPHY; ROYAL-COLLEGE; RESTORATION; RESCUE; MODEL AB Background: Human retinal progenitor cells (hRPCs) are expandable in vitro and represent a possible therapy for retinal degenerative diseases. Results: In a rat model of retinal degeneration, transplantation of hRPCs preserved photoreceptors and visual function. Conclusion: Subretinal injection of hRPCs rescues photoreceptors without causing adverse effects. Significance: This study provides proof of concept for hRPC transplantation and paves the way for further studies and human trials. Cell transplantation is a potential therapeutic strategy for retinal degenerative diseases involving the loss of photoreceptors. However, it faces challenges to clinical translation due to safety concerns and a limited supply of cells. Human retinal progenitor cells (hRPCs) from fetal neural retina are expandable in vitro and maintain an undifferentiated state. This study aimed to investigate the therapeutic potential of hRPCs transplanted into a Royal College of Surgeons (RCS) rat model of retinal degeneration. At 12 weeks, optokinetic response showed that hRPC-grafted eyes had significantly superior visual acuity compared with vehicle-treated eyes. Histological evaluation of outer nuclear layer (ONL) characteristics such as ONL thickness, spread distance, and cell count demonstrated a significantly greater preservation of the ONL in hRPC-treated eyes compared with both vehicle-treated and control eyes. The transplanted hRPCs arrested visual decline over time in the RCS rat and rescued retinal morphology, demonstrating their potential as a therapy for retinal diseases. We suggest that the preservation of visual acuity was likely achieved through host photoreceptor rescue. We found that hRPC transplantation into the subretinal space of RCS rats was well tolerated, with no adverse effects such as tumor formation noted at 12 weeks after treatment. C1 [Luo, Jing; Zhang, Kang] Cent S Univ, Xiangya Hosp 2, Dept Ophthalmol, Changsha 410011, Hunan, Peoples R China. [Luo, Jing; Zhang, Kang] Cent S Univ, Int Acad Translat Med, Changsha 410011, Hunan, Peoples R China. [Luo, Jing; Patel, Sherrina; Ouyang, Hong; Quach, John; Wu, Frances; Qiu, Austin; Luo, Hongrong; Zeng, Jing; Zhu, Jing; Lu, Jessica; Sfeir, Nicole; Wen, Cindy; Shaw, Peter; Zhang, Kang] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA. [Luo, Jing; Patel, Sherrina; Ouyang, Hong; Quach, John; Wu, Frances; Qiu, Austin; Luo, Hongrong; Zeng, Jing; Zhu, Jing; Lu, Jessica; Sfeir, Nicole; Wen, Cindy; Shaw, Peter; Zhang, Kang] Univ Calif San Diego, Shiley Eye Ctr, La Jolla, CA 92093 USA. [Baranov, Petr; Young, Michael] Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. [Qiu, Austin; Luo, Hongrong; Zhu, Jing; Zhang, Meixia; Patel, Sara; Sinden, John; Zhang, Kang] West China Hosp, Mol Med Res Ctr, Chengdu 610041, Sichuan, Peoples R China. [Hicks, Caroline] ReNeuron Ltd, Guildford GU2 7AF, Surrey, England. [Zeng, Jing] Guangxi Med Univ, Affiliated Hosp 1, Dept Ophthalmol, Nanning 530021, Guangxi, Peoples R China. [Reade, Victoria] Da Vinci Consulting, Los Angeles, CA 90069 USA. [Sun, Xiaodong] Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 1, Dept Ophthalmol, Shanghai 200080, Peoples R China. [Sun, Xiaodong] Shanghai Jiao Tong Univ, Eye Res Inst, Shanghai 200080, Peoples R China. [Zhang, Kang] Vet Affairs Healthcare Syst, San Diego, CA 92161 USA. RP Sun, XD (reprint author), Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 1, Dept Ophthalmol, Shanghai 200080, Peoples R China. EM xdsun@sjtu.edu.cn; kang.zhang@gmail.com RI luo, hongrong/B-2714-2015 OI luo, hongrong/0000-0001-7994-1193 FU 973 Program [2013CB967504, 2014CB964900]; Natural Science Foundation of China [81130017, 81276019]; National Institutes of Health Director's Transformative R01 Program [R01 EY021374]; National Institutes of Health, NEI [R01 EY018660, P30 EY022589]; King Abdulaziz City for Science and Technology-University of California San Diego Center of Excellence in Nanomedicine; Macula Vision Research Foundation; Beckman Initiative for Macular Research; Macular Society; Burroughs Wellcome Fund Clinical Scientist Award in Translational Research; ReNeuron Ltd. FX This work was supported by grants from the 973 Program (2013CB967504 and 2014CB964900), Natural Science Foundation of China (81130017 and 81276019), National Institutes of Health Director's Transformative R01 Program (Grant R01 EY021374), and National Institutes of Health Grants R01 EY018660 and P30 EY022589 from the NEI. This work was also supported by a grant from the King Abdulaziz City for Science and Technology-University of California San Diego Center of Excellence in Nanomedicine, Macula Vision Research Foundation, Beckman Initiative for Macular Research, Macular Society, the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, and a contract from ReNeuron Ltd. NR 35 TC 20 Z9 22 U1 0 U2 10 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 7 PY 2014 VL 289 IS 10 BP 6362 EP 6371 DI 10.1074/jbc.M113.513713 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC3BG UT WOS:000332389400005 PM 24407289 ER PT J AU Lakshmi, SP Reddy, AT Zhang, YZ Sciurba, FC Mallampalli, RK Duncan, SR Reddy, RC AF Lakshmi, Sowmya P. Reddy, Aravind T. Zhang, Yingze Sciurba, Frank C. Mallampalli, Rama K. Duncan, Steven R. Reddy, Raju C. TI Down-regulated Peroxisome Proliferator-activated Receptor gamma (PPAR gamma) in Lung Epithelial Cells Promotes a PPAR gamma Agonist-reversible Proinflammatory Phenotype in Chronic Obstructive Pulmonary Disease (COPD) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Chromatin Histone Modification; Cigarette Smoke; Glucocorticoid Receptor; Histone Deacetylase; Inflammation; NF-kappa B (NF-KB); I-kappa-B Kinase; Human Bronchial Epithelial Cells; Oxidative Stress ID KAPPA-B; GLUCOCORTICOID-RECEPTOR; OXIDATIVE STRESS; PROTEIN-KINASE; PHOSPHORYLATION; EXPRESSION; RATS; DEGRADATION; INHIBITION; NITRATION AB Background: The mechanistic role of peroxisome proliferator-activated receptor (PPAR) in chronic obstructive pulmonary disease (COPD) is poorly understood. Results: COPD and cigarette smoke exposure down-regulated PPAR and produced inflammation that PPAR agonists reversed through multiple pathways. Conclusion: PPAR plays a pivotal role in COPD. Significance: PPAR agonists may be the first effective treatment for COPD. Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition and a leading cause of death, with no available cure. We assessed the actions in pulmonary epithelial cells of peroxisome proliferator-activated receptor (PPAR), a nuclear hormone receptor with anti-inflammatory effects, whose role in COPD is largely unknown. We found that PPAR was down-regulated in lung tissue and epithelial cells of COPD patients, via both reduced expression and phosphorylation-mediated inhibition, whereas pro-inflammatory nuclear factor-B (NF-B) activity was increased. Cigarette smoking is the main risk factor for COPD, and exposing airway epithelial cells to cigarette smoke extract (CSE) likewise down-regulated PPAR and activated NF-B. CSE also down-regulated and post-translationally inhibited the glucocorticoid receptor (GR-) and histone deacetylase 2 (HDAC2), a corepressor important for glucocorticoid action and whose down-regulation is thought to cause glucocorticoid insensitivity in COPD. Treating epithelial cells with synthetic (rosiglitazone) or endogenous (10-nitro-oleic acid) PPAR agonists strongly up-regulated PPAR expression and activity, suppressed CSE-induced production and secretion of inflammatory cytokines, and reversed its activation of NF-B by inhibiting the IB kinase pathway and by promoting direct inhibitory binding of PPAR to NF-B. In contrast, PPAR knockdown via siRNA augmented CSE-induced chemokine release and decreases in HDAC activity, suggesting a potential anti-inflammatory role of endogenous PPAR. The results imply that down-regulation of pulmonary epithelial PPAR by cigarette smoke promotes inflammatory pathways and diminishes glucocorticoid responsiveness, thereby contributing to COPD pathogenesis, and further suggest that PPAR agonists may be useful for COPD treatment. C1 [Lakshmi, Sowmya P.; Reddy, Aravind T.; Zhang, Yingze; Sciurba, Frank C.; Mallampalli, Rama K.; Duncan, Steven R.; Reddy, Raju C.] Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Sch Med, Pittsburgh, PA 15213 USA. [Lakshmi, Sowmya P.; Reddy, Aravind T.; Mallampalli, Rama K.; Reddy, Raju C.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. RP Reddy, RC (reprint author), Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Univ Dr C, Pittsburgh, PA 15240 USA. EM reddyrc@upmc.edu FU United States Department of Veterans Affairs; National Institutes of Health [HL093196] FX This work was supported by a Merit Review award from the United States Department of Veterans Affairs and National Institutes of Health Grant HL093196 (to R. C. R). NR 33 TC 19 Z9 20 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 7 PY 2014 VL 289 IS 10 BP 6383 EP 6393 DI 10.1074/jbc.M113.536805 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC3BG UT WOS:000332389400007 PM 24368768 ER PT J AU Polito, D Cukras, S Wang, XZ Spence, P Moreau, L D'Andrea, AD Kee, Y AF Polito, David Cukras, Scott Wang, Xiaozhe Spence, Paige Moreau, Lisa D'Andrea, Alan D. Kee, Younghoon TI The Carboxyl Terminus of FANCE Recruits FANCD2 to the Fanconi Anemia (FA) E3 Ligase Complex to Promote the FA DNA Repair Pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE DNA Damage; DNA Repair; E3 Ubiquitin Ligase; Protein Degradation; Protein Dynamics; Protein Folding; Protein Targeting; Protein-protein Interactions; Ubiquitin ID CROSS-LINK REPAIR; MONOUBIQUITINATED FANCD2; NUCLEAR ACCUMULATION; SENSITIZES CELLS; DAMAGE RESPONSE; CORE COMPLEX; S-PHASE; PROTEIN; INHIBITION; IDENTIFICATION AB Background: Monoubiquitination of FANCD2 and FANCI is critical in the FA pathway. Results: Specific mutations in FANCE that disrupt FANCD2 binding impair the FA pathway. Conclusion: Inhibition of the FANCE-FANCD2 interaction via FANCE point mutations in the C terminus disrupts the FA pathway. Significance: Recruitment of FANCD2 and FANCI to the FA E3 ligase is a critical step in the FA pathway. Fanconi anemia (FA) is a genome instability syndrome characterized by bone marrow failure and cellular hypersensitivity to DNA cross-linking agents. In response to DNA damage, the FA pathway is activated through the cooperation of 16 FA proteins. A central player in the pathway is a multisubunit E3 ubiquitin ligase complex or the FA core complex, which monoubiquitinates its substrates FANCD2 and FANCI. FANCE, a subunit of the FA core complex, plays an essential role by promoting the integrity of the complex and by directly recognizing FANCD2. To delineate its role in substrate ubiquitination from the core complex assembly, we analyzed a series of mutations within FANCE. We report that a phenylalanine located at the highly conserved extreme C terminus, referred to as Phe-522, is a critical residue for mediating the monoubiquitination of the FANCD2-FANCI complex. Using the FANCE mutant that specifically disrupts the FANCE-FANCD2 interaction as a tool, we found that the interaction-deficient mutant conferred cellular sensitivity in reconstituted FANCE-deficient cells to a similar degree as FANCE null cells, suggesting the significance of the FANCE-FANCD2 interaction in promoting cisplatin resistance. Intriguingly, ectopic expression of the FANCE C terminus fragment alone in FA normal cells disrupts DNA repair, consolidating the importance of the FANCE-FANCD2 interaction in the DNA cross-link repair. C1 [Polito, David; Cukras, Scott; Spence, Paige; Kee, Younghoon] Univ S Florida, Coll Arts & Sci, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL 33620 USA. [Wang, Xiaozhe; D'Andrea, Alan D.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Moreau, Lisa] Dana Farber Canc Inst, Cytogenet Core Lab, Boston, MA 02115 USA. RP Kee, Y (reprint author), Univ S Florida, Coll Arts & Sci, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL 33620 USA. EM Ykee@usf.edu FU National Institutes of Health [RO1HL52725]; University of South Florida departmental startup funds FX This work was supported, in whole or in part, by National Institutes of Health Grant RO1HL52725 (to A.D.D.) and University of South Florida departmental startup funds (to Y.K.). NR 31 TC 10 Z9 11 U1 0 U2 2 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 7 PY 2014 VL 289 IS 10 BP 7003 EP 7010 DI 10.1074/jbc.M113.533976 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC3BG UT WOS:000332389400060 PM 24451376 ER PT J AU Chen, Y Li, J Dunn, S Xiong, S Chen, W Zhao, YT Chen, BB Mallampalli, RK Zou, CB AF Chen, Yan Li, Jin Dunn, Sarah Xiong, Sheng Chen, Wei Zhao, Yutong Chen, Bill B. Mallampalli, Rama K. Zou, Chunbin TI Histone Deacetylase 2 (HDAC2) Protein-dependent Deacetylation of Mortality Factor 4-like 1 (MORF4L1) Protein Enhances Its Homodimerization SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Epigenetics; Histone Acetylase; Histone Deacetylase; Posttranslational Modification; Proliferation; Protein Complexes; Protein Structure; Site-directed Mutagenesis ID CELL-DIFFERENTIATION; CHROMODOMAIN PROTEIN; MESSENGER-RNA; DNA-REPAIR; MRG15; COMPLEX; GENE; PROLIFERATION; DOMAIN; DIMERIZATION AB Background: Histone acetyltransferase MORF4L1 forms a homodimer to perform its epigenetic function, but the molecular mechanisms for its homodimerization are unknown. Results: Histone deacetylase HDAC2 deacetylates MORF4L1 at Lys-148 to enhance MORF4L1 homodimerization. Conclusion: HDAC2-dependent deacetylation of MORF4L1 enhances MORF4L1 homodimerization, which facilitates complex formation to repress cellular proliferation. Significance: The molecular control of MORF4L1 homodimerization may impact fundamental cellular processes such as proliferation. Histone acetyltransferase mortality factor 4-like 1 (MORF4L1) is a relatively new histone acetyltransferase component that exists as a homodimer to exert its epigenetic function. The mechanism of MORF4L1 self-assembly is unknown. Here we report that Lys-148 deacetylation is indispensable for facilitating MORF4L1 self-assembly into a homodimeric unit. Among a stretch of approximate to 10 amino acids in the NH2 terminus between the chromodomain and MORF4-related gene (MRG) domain within MORF4L1, Lys-148 is normally acetylated. Substitution of Lys-148 with arginine augments MORF4L1 self-assembly. However, acetylation mimics of MORF4L1, including K148L and K148Q, abolished its self-assembly of the histone acetyltransferase component. HDAC2, a deacetylase, interacts with and keeps MORF4L1 in a deacetylation status at Lys(148) that triggers MORF4L1 self-assembly. Knockdown of HDAC2 reduces MORF4L1 self-assembly. HDAC2-dependent deacetylation of MORF4L1 enhances MORF4L1 homodimerization, thus facilitating the functionality of complex formation to repress cell proliferation. C1 [Chen, Yan; Li, Jin; Dunn, Sarah; Xiong, Sheng; Chen, Wei; Zhao, Yutong; Chen, Bill B.; Mallampalli, Rama K.; Zou, Chunbin] Univ Pittsburgh, Dept Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15213 USA. [Zhao, Yutong; Chen, Bill B.; Mallampalli, Rama K.] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. [Zhao, Yutong; Chen, Bill B.; Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA 15240 USA. [Chen, Yan] Cent S Univ, Xiangya Hosp 2, Dept Resp Med, Changsha 410011, Hunan, Peoples R China. RP Chen, Y (reprint author), Cent S Univ, Xiangya Hosp 2, Dept Resp Med, Changsha 410011, Hunan, Peoples R China. EM chenyan99727@163.com; zouc@upmc.edu FU National Institutes of Health [HL096376, HL097376, HL098174, P01 HL114453]; American Heart Association [12SDG12040330]; United States Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; United States Department of Veterans Affairs; Natural Science Foundation of China [81070039, 81270100] FX This work was supported, in whole or in part, National Institutes of Health Grants HL096376, HL097376, HL098174, and P01 HL114453 (to R. K. M.). This work was also supported by American Heart Association Award 12SDG12040330 (to C. Z.); by the United States Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; and by a merit review award from the United States Department of Veterans Affairs.; Supported by Natural Science Foundation of China Grants 81070039 and 81270100. To whom correspondence may be addressed: Dept. of Respiratory Medicine, The Second Xiangya Hospital, Central-South University, Changsha, Hunan 410011, China. E-mail: chenyan99727@163.com. NR 30 TC 2 Z9 2 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 7 PY 2014 VL 289 IS 10 BP 7092 EP 7098 DI 10.1074/jbc.M113.527507 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AC3BG UT WOS:000332389400068 PM 24451372 ER PT J AU Borand, L Madec, Y Laureillard, D Chou, M Marcy, O Pheng, P Prak, N Kim, C Lak, KK Hak, C Dim, B Nerrienet, E Fontanet, A Sok, T Goldfeld, AE Blanc, FX Taburet, AM AF Borand, Laurence Madec, Yoann Laureillard, Didier Chou, Monidarin Marcy, Olivier Pheng, Phearavin Prak, Narom Kim, Chindamony Lak, Khemarin Kim Hak, Chanroeun Dim, Bunnet Nerrienet, Eric Fontanet, Arnaud Sok, Thim Goldfeld, Anne E. Blanc, Francois-Xavier Taburet, Anne-Marie TI Plasma Concentrations, Efficacy and Safety of Efavirenz in HIV-Infected Adults Treated for Tuberculosis in Cambodia (ANRS 1295-CIPRA KH001 CAMELIA Trial) SO PLOS ONE LA English DT Article ID TRANSCRIPTASE INHIBITOR EFAVIRENZ; ANTIRETROVIRAL TREATMENT; PHARMACOKINETIC INTERACTIONS; RANDOMIZED-TRIAL; ADVERSE EVENTS; RIFAMPICIN; NEVIRAPINE; THERAPY; CYP2B6; POLYMORPHISMS AB Objective: To assess efavirenz plasma concentrations and their association with treatment efficacy and tolerance of efavirenz 600 mg daily in HIV-tuberculosis co-infected patients. Methods: HIV-infected adults with CD4+ T cell count <= 200/mm(3) received standard 6-month tuberculosis treatment and antiretroviral therapy including a daily-dose of 600 mg of efavirenz, irrespective of their body weight. Mid-dose blood samples were drawn both on tuberculosis treatment (week +2 and week +6 after antiretroviral therapy initiation, and week 22 of follow-up) and off tuberculosis treatment (week 50 of follow-up). Considered therapeutic range was 1,000 to 4,000 ng/mL. Multivariate analysis was performed to evaluate the association between efavirenz concentration below 1,000 ng/mL and virological failure. Linear regression was used to test the association between efavirenz exposure and CD4+ T cell gain. Severe side effects potentially related to efavirenz were described and their association with efavirenz exposure was tested by multivariate analysis. Results: Efavirenz plasma concentrations were available in 540 patients. Median [interquartile range] efavirenz concentrations were 2,674 ng/mL [1,690-4,533], 2,667 ng/mL [1,753-4,494] and 2,799 ng/mL [1,804-4,744] at week +2, week +6, week 22, respectively, and 2,766 ng/mL [1,941-3,976] at week 50. Efavirenz concentrations were lower at week 50 (off rifampicin) compared to week 22 (on rifampicin) (p < 0.001). Late attendance to study visit and low hemoglobinemia were the only factors associated with an increased risk of efavirenz concentration below 1,000 ng/mL. Efavirenz concentration below 1,000 ng/mL was not associated with treatment failure. Efavirenz concentration above 4,000 ng/mL was associated with higher risk of central nervous system side effects (p < 0.001) and of hepatotoxicity (p < 0.001). Conclusion: Body weight and tuberculosis treatment were not associated with low efavirenz concentrations or treatment failure, supporting the 600 mg daily-dose of efavirenz in HIV-tuberculosis co-infected patients. High efavirenz concentrations were related to a higher risk of central nervous system side effects and hepatotoxicity. C1 [Borand, Laurence; Marcy, Olivier; Pheng, Phearavin] Inst Pasteur Cambodge, Epidemiol & Publ Hlth Unit, Phnom Penh, Cambodia. [Madec, Yoann; Fontanet, Arnaud] Inst Pasteur, Unite Rech & Expertise Epidemiol Malad Emergentes, Paris, France. [Laureillard, Didier] ANRS, Ho Chi Minh City, Vietnam. [Chou, Monidarin] Univ Hlth Sci, Fac Pharm, Phnom Penh, Cambodia. [Prak, Narom] Khmer Soviet Friendship Hosp, Phnom Penh, Cambodia. [Kim, Chindamony] Donkeo Prov Hosp, Takeo, Cambodia. [Kim, Chindamony; Dim, Bunnet] Medecins Sans Frontieres, Phnom Penh, Cambodia. [Lak, Khemarin Kim] Svay Rieng Prov Hosp, Svay Rieng, Cambodia. [Lak, Khemarin Kim; Sok, Thim; Goldfeld, Anne E.] Cambodian Hlth Comm, Phnom Penh, Cambodia. [Hak, Chanroeun] Calmette Hosp, Phnom Penh, Cambodia. [Dim, Bunnet] Siem Reap Referral Hosp, Siem Reap, Cambodia. [Nerrienet, Eric] Inst Pasteur Cambodge, HIV Hepatitis Lab, Phnom Penh, Cambodia. [Fontanet, Arnaud] Conservatoire Natl Arts & Metiers, Paris, France. [Goldfeld, Anne E.] Harvard Univ, Childrens Hosp, Sch Med, Program Cellular & Mol Med, Boston, MA 02115 USA. [Blanc, Francois-Xavier] Hop Univ Paris Sud, Hop Bicetre, AP HP, Dept Pneumol, Le Kremlin Bicetre, France. [Blanc, Francois-Xavier] Univ Nantes, CHU Nantes, DHU2020,Serv Pneumol, UMR INSERM 1087,CNRS UMR 6291,Inst Thorax, F-44035 Nantes, France. [Taburet, Anne-Marie] Hop Univ Paris Sud, Hop Bicetre, AP HP, Dept Clin Pharm, Le Kremlin Bicetre, France. RP Taburet, AM (reprint author), Hop Univ Paris Sud, Hop Bicetre, AP HP, Dept Clin Pharm, Le Kremlin Bicetre, France. EM anne-marie.taburet@bct.aphp.fr RI Blanc, Francois-Xavier/D-7425-2015 FU French National Agency for Research on AIDS and Viral Hepatitis (ANRS); U.S. National Institutes of Health Division of AIDS; Merieux Foundation FX The French National Agency for Research on AIDS and Viral Hepatitis (ANRS), the U.S. National Institutes of Health Division of AIDS and the Merieux Foundation have supported this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 6 Z9 6 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 7 PY 2014 VL 9 IS 3 AR e90350 DI 10.1371/journal.pone.0090350 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC4IY UT WOS:000332485800020 PM 24608960 ER PT J AU Tuggle, KL Birket, SE Cui, XX Hong, J Warren, J Reid, L Chambers, A Ji, D Gamber, K Chu, KK Tearney, G Tang, LP Fortenberry, JA Du, M Cadillac, JM Bedwell, DM Rowe, SM Sorscher, EJ Fanucchi, MV AF Tuggle, Katherine L. Birket, Susan E. Cui, Xiaoxia Hong, Jeong Warren, Joe Reid, Lara Chambers, Andre Ji, Diana Gamber, Kevin Chu, Kengyeh K. Tearney, Guillermo Tang, Li Ping Fortenberry, James A. Du, Ming Cadillac, Joan M. Bedwell, David M. Rowe, Steven M. Sorscher, Eric J. Fanucchi, Michelle V. TI Characterization of Defects in Ion Transport and Tissue Development in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Knockout Rats SO PLOS ONE LA English DT Article ID ZINC-FINGER NUCLEASES; SURFACE LIQUID DEPTH; NASAL EPITHELIUM; AIRWAY EPITHELIA; MOUSE MODELS; CFTR; NA+; CL; GENE; HYPERABSORPTION AB Animal models for cystic fibrosis (CF) have contributed significantly to our understanding of disease pathogenesis. Here we describe development and characterization of the first cystic fibrosis rat, in which the cystic fibrosis transmembrane conductance regulator gene (CFTR) was knocked out using a pair of zinc finger endonucleases (ZFN). The disrupted Cftr gene carries a 16 base pair deletion in exon 3, resulting in loss of CFTR protein expression. Breeding of heterozygous (CFTR+/-) rats resulted in Mendelian distribution of wild-type, heterozygous, and homozygous (CFTR-/-) pups. Nasal potential difference and transepithelial short circuit current measurements established a robust CF bioelectric phenotype, similar in many respects to that seen in CF patients. Young CFTR-/- rats exhibited histological abnormalities in the ileum and increased intracellular mucus in the proximal nasal septa. By six weeks of age, CFTR-/- males lacked the vas deferens bilaterally. Airway surface liquid and periciliary liquid depth were reduced, and submucosal gland size was abnormal in CFTR-/- animals. Use of ZFN based gene disruption successfully generated a CF animal model that recapitulates many aspects of human disease, and may be useful for modeling other CF genotypes, including CFTR processing defects, premature truncation alleles, and channel gating abnormalities. C1 [Tuggle, Katherine L.; Birket, Susan E.; Hong, Jeong; Tang, Li Ping; Fortenberry, James A.; Du, Ming; Bedwell, David M.; Rowe, Steven M.; Sorscher, Eric J.; Fanucchi, Michelle V.] Univ Alabama Birmingham, Gregory Fleming James Cyst Fibrosis Res Ctr, Birmingham, AL 35294 USA. [Tuggle, Katherine L.; Fanucchi, Michelle V.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Environm Hlth Sci, Birmingham, AL 35294 USA. [Birket, Susan E.; Rowe, Steven M.; Sorscher, Eric J.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Cui, Xiaoxia; Warren, Joe; Reid, Lara; Chambers, Andre; Ji, Diana; Gamber, Kevin] SAGE Labs Inc, St Louis, MO USA. [Hong, Jeong] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL USA. [Chu, Kengyeh K.; Tearney, Guillermo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Chu, Kengyeh K.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Tearney, Guillermo] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Du, Ming; Cadillac, Joan M.] Univ Alabama Birmingham, Anim Resources Program, Off Vice President Res, Birmingham, AL USA. [Bedwell, David M.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. RP Fanucchi, MV (reprint author), Univ Alabama Birmingham, Gregory Fleming James Cyst Fibrosis Res Ctr, Birmingham, AL 35294 USA. EM fanucchi@uab.edu OI Gamber, Kevin/0000-0002-0694-7639 FU CF Foundation [R464-CR07]; NIH [P30 DK072482, R01 HL116213] FX This work was supported by CF Foundation Grant R464-CR07 (www.cff.org) and NIH P30 DK072482 (www.nih.gov) to EJS and R01 HL116213 to SMR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 27 Z9 27 U1 1 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 7 PY 2014 VL 9 IS 3 AR e91253 DI 10.1371/journal.pone.0091253 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC4IY UT WOS:000332485800118 PM 24608905 ER PT J AU Lee, MN Ye, C Villani, AC Raj, T Li, WB Eisenhaure, TM Imboywa, SH Chipendo, PI Ran, FA Slowikowski, K Ward, LD Raddassi, K McCabe, C Lee, MH Frohlich, IY Hafler, DA Kellis, M Raychaudhuri, S Zhang, F Stranger, BE Benoist, CO De Jager, PL Regev, A Hacohen, N AF Lee, Mark N. Ye, Chun Villani, Alexandra-Chloe Raj, Towfique Li, Weibo Eisenhaure, Thomas M. Imboywa, Selina H. Chipendo, Portia I. Ran, F. Ann Slowikowski, Kamil Ward, Lucas D. Raddassi, Khadir McCabe, Cristin Lee, Michelle H. Frohlich, Irene Y. Hafler, David A. Kellis, Manolis Raychaudhuri, Soumya Zhang, Feng Stranger, Barbara E. Benoist, Christophe O. De Jager, Philip L. Regev, Aviv Hacohen, Nir TI Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells SO SCIENCE LA English DT Article ID PATTERN-RECOGNITION RECEPTORS; MYCOBACTERIUM-TUBERCULOSIS INFECTION; GENOME-WIDE ASSOCIATION; TOLL-LIKE RECEPTORS; INNATE IMMUNITY; EXPRESSION; LOCI; ARCHITECTURE; RESISTANCE; INFLUENZA AB Little is known about how human genetic variation affects the responses to environmental stimuli in the context of complex diseases. Experimental and computational approaches were applied to determine the effects of genetic variation on the induction of pathogen-responsive genes in human dendritic cells. We identified 121 common genetic variants associated in cis with variation in expression responses to Escherichia coli lipopolysaccharide, influenza, or interferon-beta (IFN-beta). We localized and validated causal variants to binding sites of pathogen-activated STAT ( signal transducer and activator of transcription) and IRF (IFN-regulatory factor) transcription factors. We also identified a common variant in IRF7 that is associated in trans with type I IFN induction in response to influenza infection. Our results reveal common alleles that explain interindividual variation in pathogen sensing and provide functional annotation for genetic variants that alter susceptibility to inflammatory diseases. C1 [Lee, Mark N.; Ye, Chun; Villani, Alexandra-Chloe; Raj, Towfique; Li, Weibo; Eisenhaure, Thomas M.; Ran, F. Ann; Ward, Lucas D.; McCabe, Cristin; Kellis, Manolis; Raychaudhuri, Soumya; De Jager, Philip L.; Regev, Aviv; Hacohen, Nir] Broad Inst Massachusetts Inst Technol MIT & Harva, Cambridge, MA 02142 USA. [Lee, Mark N.; Villani, Alexandra-Chloe; Raj, Towfique; Imboywa, Selina H.; Chipendo, Portia I.; Lee, Michelle H.; Frohlich, Irene Y.; Raychaudhuri, Soumya; Benoist, Christophe O.; De Jager, Philip L.; Hacohen, Nir] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Lee, Mark N.; Li, Weibo; Eisenhaure, Thomas M.; Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Raj, Towfique; McCabe, Cristin; De Jager, Philip L.] Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA. [Ran, F. Ann] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Ran, F. Ann] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Ran, F. Ann; Zhang, Feng] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Ran, F. Ann; Hafler, David A.; Zhang, Feng] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Slowikowski, Kamil] Harvard Univ, Grad Sch Arts & Sci, Cambridge, MA 02138 USA. [Ward, Lucas D.; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Raddassi, Khadir] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06511 USA. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Dept Med, Div Rheumatol, Boston, MA 02115 USA. [Raychaudhuri, Soumya] Univ Manchester, Manchester Acad Hlth Sci Ctr, Musculoskeletal Res Grp, Arthrit Res UK Epidemiol Unit, Manchester M13 9NT, Lancs, England. [Stranger, Barbara E.] Univ Chicago, Med Genet Sect, Chicago, IL 60637 USA. [Stranger, Barbara E.] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA. [Regev, Aviv] MIT, Dept Biol, Cambridge, MA 02139 USA. [Regev, Aviv] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Regev, A (reprint author), Broad Inst Massachusetts Inst Technol MIT & Harva, Cambridge, MA 02142 USA. EM aregev@broad.mit.edu; nhacohen@partners.org OI Ward, Lucas/0000-0002-8017-809X; Stranger, Barbara/0000-0001-9021-7331 FU National Institute of General Medical Sciences, NIH [RC2 GM093080]; National Institute of Allergy and Infectious Diseases [U19 AI082630]; NIH [DP2 OD002230, DP1 CA174427, R01 HG004037, DP1 MH100706, R01 DK097768, T32 GM007753, F32 AG043267, T32 HG002295]; National Human Genome Research Institute [P50 HG006193]; Howard Hughes Medical Institute; Keck Foundation; McKnight Foundation; Merkin Foundation; Vallee Foundation; Damon Runyon Foundation; Searle Scholars Foundation; Klingenstein Foundation; Simons Foundation FX We thank all study participants in the PhenoGenetic project for their contributions. We are grateful to Q. Sievers and C. Wu for advice about preparing primary cells and V. Agarwala and D. A. Landau for valuable discussions. This work was supported by the National Institute of General Medical Sciences, NIH, grant RC2 GM093080 (C.O.B. and N.H.); the National Institute of Allergy and Infectious Diseases grant U19 AI082630 and NIH Director's New Innovator Award DP2 OD002230 (N.H.); the National Human Genome Research Institute grant P50 HG006193, NIH Director's Pioneer Award DP1 CA174427, and Howard Hughes Medical Institute (A.R.); and NIH grant R01 HG004037 (M.K.). F.Z. is supported by an NIH Director's Pioneer Award (DP1 MH100706), an NIH Transformative R01 grant (R01 DK097768), the Keck, McKnight, Merkin, Vallee, Damon Runyon, Searle Scholars, Klingenstein, and Simons Foundations, Bob Metcalfe, and Jane Pauley. M.N.L. is supported by the NIH Medical Scientist Training Program fellowship (T32 GM007753). T.R. is supported by NIH fellowship F32 AG043267. K.S. is supported by NIH grant T32 HG002295. Gene expression data are deposited in National Center for Biotechnology Information's Gene Expression Omnibus under accession no. GSE53166. NR 44 TC 111 Z9 111 U1 4 U2 37 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD MAR 7 PY 2014 VL 343 IS 6175 BP 1119 EP + AR 1246980 DI 10.1126/science.1246980 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC2LB UT WOS:000332331500042 PM 24604203 ER PT J AU Petibon, Y El Fakhri, G Nezafat, R Johnson, N Brady, T Ouyang, J AF Petibon, Y. El Fakhri, G. Nezafat, R. Johnson, N. Brady, T. Ouyang, J. TI Towards coronary plaque imaging using simultaneous PET-MR: a simulation study SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE motion correction; PET-MR; coronary plaque imaging; fat-MR ID POSITRON-EMISSION-TOMOGRAPHY; ATHEROSCLEROTIC PLAQUE; MOTION COMPENSATION; LESION DETECTION; RISK-FACTORS; INFLAMMATION; FAT; RECONSTRUCTION; FEASIBILITY; SEPARATION AB Coronary atherosclerotic plaque rupture is the main cause of myocardial infarction and the leading killer in the US. Inflammation is a known bio-marker of plaque vulnerability and can be assessed non-invasively using fluorodeoxyglucose-positron emission tomography imaging (FDG-PET). However, cardiac and respiratory motion of the heart makes PET detection of coronary plaque very challenging. Fat surrounding coronary arteries allows the use of MRI to track plaque motion during simultaneous PET-MR examination. In this study, we proposed and assessed the performance of a fat-MR based coronary motion correction technique for improved FDG-PET coronary plaque imaging in simultaneous PET-MR. The proposed methods were evaluated in a realistic four-dimensional PET-MR simulation study obtained by combining patient water-fat separated MRI and XCAT anthropomorphic phantom. Five small lesions were digitally inserted inside the patients coronary vessels to mimic coronary atherosclerotic plaques. The heart of the XCAT phantom was digitally replaced with the patient's heart. Motion-dependent activity distributions, attenuation maps, and fat-MR volumes of the heart, were generated using the XCAT cardiac and respiratory motion fields. A full Monte Carlo simulation using Siemens mMR's geometry was performed for each motion phase. Cardiac/respiratory motion fields were estimated using nonrigid registration of the transformed fat-MR volumes and incorporated directly into the system matrix of PET reconstruction along with motion-dependent attenuation maps. The proposed motion correction method was compared to conventional PET reconstruction techniques such as no motion correction, cardiac gating, and dual cardiac-respiratory gating. Compared to uncorrected reconstructions, fat-MR based motion compensation yielded an average improvement of plaque-to-background contrast of 29.6%, 43.7%, 57.2%, and 70.6% for true plaque-to-blood ratios of 10, 15, 20 and 25: 1, respectively. Channelized Hotelling observer (CHO) signal-to-noise ratio (SNR) was used to quantify plaque detectability. CHO-SNR improvement ranged from 105% to 128% for fat-MR-based motion correction as compared to no motion correction. Likewise, CHO-SNR improvement ranged from 348% to 396% as compared to both cardiac and dual cardiac-respiratory gating approaches. Based on this study, our approach, a fat-MR based motion correction for coronary plaque PET imaging using simultaneous PET-MR, offers great potential for clinical practice. The ultimate performance and limitation of our approach, however, must be fully evaluated in patient studies. C1 [Petibon, Y.; El Fakhri, G.; Johnson, N.; Brady, T.; Ouyang, J.] Massachusetts Gen Hosp, Dept Imaging, Div Nucl Med & Mol Imaging, Ctr Adv Med Imaging Sci, Boston, MA 02114 USA. [Petibon, Y.] UPMC Univ Paris 06, Univ Sorbonne, INSERM, Lab Imagerie Biomed,CNRS,UMR S 1146,UMR 7371, F-75013 Paris, France. [El Fakhri, G.; Nezafat, R.; Brady, T.; Ouyang, J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Nezafat, R.] Beth Israel Med Deaconess Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. RP Ouyang, J (reprint author), Massachusetts Gen Hosp, Dept Imaging, Div Nucl Med & Mol Imaging, Ctr Adv Med Imaging Sci, Boston, MA 02114 USA. EM ouyang.jinsong@mgh.harvard.edu FU NIH [R21-EB012326, R01-CA165221, R01-EB008743] FX This work was supported in part by NIH grants R21-EB012326, R01-CA165221 and R01-EB008743. The authors would like to thank Dr Carmella Nappi for her help on the locations of the inserted plaques. NR 42 TC 14 Z9 14 U1 1 U2 9 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 2014 VL 59 IS 5 DI 10.1088/0031-9155/59/5/1203 PG 20 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AB7DR UT WOS:000331950000008 PM 24556608 ER PT J AU Babitt, JL Lin, HY AF Babitt, Jodie L. Lin, Herbert Y. TI BuMPing iron with modified heparins SO BLOOD LA English DT Editorial Material ID HEPCIDIN EXPRESSION; INFLAMMATION; METABOLISM; ANEMIA C1 [Babitt, Jodie L.; Lin, Herbert Y.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Babitt, JL (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. FU NIDDK NIH HHS [R01 DK071837, R01 DK087727] NR 10 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 6 PY 2014 VL 123 IS 10 BP 1440 EP 1441 DI 10.1182/blood-2014-01-549519 PG 4 WC Hematology SC Hematology GA AH0XR UT WOS:000335844600006 PM 24627550 ER PT J AU Richardson, PG Xie, WL Jagannath, S Jakubowiak, A Lonial, S Raje, NS Alsina, M Ghobrial, IM Schlossman, RL Munshi, NC Mazumder, A Vesole, DH Kaufman, JL Colson, K McKenney, M Lunde, LE Feather, J Maglio, ME Warren, D Francis, D Hideshima, T Knight, R Esseltine, DL Mitsiades, CS Weller, E Anderson, KC AF Richardson, Paul G. Xie, Wanling Jagannath, Sundar Jakubowiak, Andrzej Lonial, Sagar Raje, Noopur S. Alsina, Melissa Ghobrial, Irene M. Schlossman, Robert L. Munshi, Nikhil C. Mazumder, Amitabha Vesole, David H. Kaufman, Jonathan L. Colson, Kathleen McKenney, Mary Lunde, Laura E. Feather, John Maglio, Michelle E. Warren, Diane Francis, Dixil Hideshima, Teru Knight, Robert Esseltine, Dixie-Lee Mitsiades, Constantine S. Weller, Edie Anderson, Kenneth C. TI A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma SO BLOOD LA English DT Article ID DIAGNOSED MULTIPLE-MYELOMA; STEM-CELL TRANSPLANTATION; LOW-DOSE DEXAMETHASONE; PEGYLATED LIPOSOMAL DOXORUBICIN; THALIDOMIDE PLUS DEXAMETHASONE; TERM-FOLLOW-UP; PERIPHERAL NEUROPATHY; INDUCTION TREATMENT; RANDOMIZED PHASE-3; III TRIAL AB In this prospective, multicenter, phase 2 study, 64 patients with relapsed or relapsed and refractory multiple myeloma (MM) received up to 8 21-day cycles of bortezomib 1.0 mg/m(2) (days 1, 4, 8, and 11), lenalidomide 15 mg/day (days 1-14), and dexamethasone 40/20 mg/day (cycles 1-4) and 20/10 mg/day (cycles 5-8) (days of/after bortezomib dosing). Responding patients could receive maintenance therapy. Median age was 65 years; 66% were male, 58% had relapsed and 42% had relapsed and refractory MM, and 53%, 75%, and 6% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Forty-eight of 64 patients (75%; 90% confidence interval, 65-84) were alive without progressive disease at 6 months (primary end point). The rate of partial response or better was 64%; median duration of response was 8.7 months. Median progression-free and overall survivals were 9.5 and 30 months, respectively (median follow-up: 44 months). Common treatment-related toxicities included sensory neuropathy (53%), fatigue (50%), and neutropenia (42%); common grade 3/4 treatment-related toxicities included neutropenia (30%), thrombocytopenia (22%), and lymphopenia (11%). Grade 3 motor neuropathy was reported in 2 patients. Lenalidomide-bortezomib-dexamethasone appears effective and tolerable in patients with relapsed or relapsed and refractory MM, demonstrating substantial activity among patients with diverse prior therapies and adverse prognostic characteristics. This trial is registered with www.clinicaltrials.gov as #NCT00378209. C1 [Richardson, Paul G.; Xie, Wanling; Ghobrial, Irene M.; Schlossman, Robert L.; Munshi, Nikhil C.; Colson, Kathleen; McKenney, Mary; Lunde, Laura E.; Feather, John; Maglio, Michelle E.; Warren, Diane; Hideshima, Teru; Mitsiades, Constantine S.; Weller, Edie; Anderson, Kenneth C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jagannath, Sundar] Mt Sinai Med Ctr, Tisch Canc Inst, New York, NY 10029 USA. [Jakubowiak, Andrzej] Univ Michigan, Ctr Comprehens Canc, Div Hematol Oncol, Ann Arbor, MI 48109 USA. [Lonial, Sagar; Kaufman, Jonathan L.; Francis, Dixil] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Raje, Noopur S.] Massachusetts Gen Hosp, Ctr Multiple Myeloma, Boston, MA 02114 USA. [Alsina, Melissa] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Blood & Marrow Transplantat, Tampa, FL 33682 USA. [Mazumder, Amitabha] NYU, Dept Med, Ctr Comprehens Canc, New York, NY 10016 USA. [Vesole, David H.] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Multiple Myeloma Div, Hackensack, NJ USA. [Knight, Robert] Celgene Inc, Oncol Res & Dev, Summit, NJ USA. [Esseltine, Dixie-Lee] Millennium, Oncol Clin Res, Cambridge, MA USA. RP Richardson, PG (reprint author), Dana Farber Canc Inst, 44 Binney St,Dana 1B02, Boston, MA 02115 USA. EM paul_richardson@dfci.harvard.edu FU The Rick Corman Multiple Myeloma Research Fund; Millennium: The Takeda Oncology Company; Celgene Corporation FX This work was supported by The Rick Corman Multiple Myeloma Research Fund, Millennium: The Takeda Oncology Company, and the Celgene Corporation. NR 51 TC 63 Z9 65 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 6 PY 2014 VL 123 IS 10 BP 1461 EP 1469 DI 10.1182/blood-2013-07-517276 PG 9 WC Hematology SC Hematology GA AH0XR UT WOS:000335844600012 PM 24429336 ER PT J AU Bitan, M He, WS Zhang, MJ Abdel-Azim, H Ayas, MF Bielorai, B Carpenter, PA Cairo, MS Diaz, MA Horan, JT Jodele, S Kitko, CL Schultz, KR Kletzel, M Kasow, KA Lehmann, LE Mehta, PA Shah, N Pulsipher, MA Prestidge, T Seber, A Shenoy, S Woolfrey, AE Yu, LC Davies, SM AF Bitan, Menachem He, Wensheng Zhang, Mei-Jie Abdel-Azim, Hisham Ayas, Mouhab Fakhreddine Bielorai, Bella Carpenter, Paul A. Cairo, Mitchell S. Angel Diaz, Miguel Horan, John T. Jodele, Sonata Kitko, Carrie L. Schultz, Kirk R. Kletzel, Morris Kasow, Kimberly A. Lehmann, Leslie E. Mehta, Parinda A. Shah, Nirali Pulsipher, Michael A. Prestidge, Tim Seber, Adriana Shenoy, Shalini Woolfrey, Ann E. Yu, Lolie C. Davies, Stella M. TI Transplantation for children with acute myeloid leukemia: a comparison of outcomes with reduced intensity and myeloablative regimens SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; ALLOGENEIC TRANSPLANTATION; CURRENT CONTROVERSIES; SURVIVAL; DISEASE; THERAPY; FAILURE; RECEIVE; VIEW AB The safety and efficacy of reduced-intensity conditioning (RIC) regimens for the treatment of pediatric acute myeloid leukemia is unknown. We compared the outcome of allogeneic hematopoietic cell transplantation in children with acute myeloid leukemia using RIC regimens with those receiving myeloablative-conditioning (MAC) regimens. A total of 180 patients were evaluated (39 with RIC and 141 with MAC regimens). Results of univariate and multivariate analysis showed no significant differences in the rates of acute and chronic graft-versus-host disease, leukemia-free, and overall survival between treatment groups. The 5-year probabilities of overall survival with RIC and MAC regimens were 45% and 48%, respectively (P = .99). Moreover, relapse rates were not higher with RIC compared with MAC regimens (39% vs 39%; P = .95), and recipients of MAC regimens were not at higher risk for transplant-related mortality compared with recipients of RIC regimens (16% vs 16%; P = .73). After carefully controlled analyses, we found that in this relatively modest study population, the data supported a role for RIC regimens for acute myeloid leukemia in children undergoing allogeneic hematopoietic cell transplantation. The data also provided justification for designing a carefully controlled randomized clinical trial that examines the efficacy of regimen intensity in this population. C1 [Bitan, Menachem] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Pediat Hematol Oncol, IL-69978 Tel Aviv, Israel. [He, Wensheng] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Zhang, Mei-Jie] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Zhang, Mei-Jie] Childrens Hosp Los Angeles, Div Hematol Oncol & Blood Marrow Transplant Res I, Los Angeles, CA USA. [Abdel-Azim, Hisham] Univ So Calif, Dept Pediat, Keck Sch Med, Los Angeles, CA 90089 USA. [Ayas, Mouhab Fakhreddine] King Faisal Specialist Hosp & Res Ctr, Dept Pediat Hematol Oncol, Riyadh 11211, Saudi Arabia. [Bielorai, Bella] Chaim Sheba Med Ctr, Dept Pediat Hematol Oncol & BMT, IL-52621 Tel Hashomer, Israel. [Carpenter, Paul A.; Woolfrey, Ann E.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Pediat, Valhalla, NY 10595 USA. [Angel Diaz, Miguel] Hosp Nino Jesus, Unidad Trasplante Hematopoyet, Madrid, Spain. [Horan, John T.] Childrens Healthcare Atlanta Egleston, Atlanta, GA USA. [Jodele, Sonata; Mehta, Parinda A.; Davies, Stella M.] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA. [Kitko, Carrie L.] Univ Michigan, Pediat & Communicable Dis Blood & Marrow Transpla, Ann Arbor, MI 48109 USA. [Schultz, Kirk R.] British Columbia Childrens Hosp, Vancouver, BC, Canada. [Kletzel, Morris] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA. [Kasow, Kimberly A.] Univ North Carolina Hosp, Div Pediat Hematol Oncol, Chapel Hill, NC USA. [Lehmann, Leslie E.] Dana Farber Canc Inst, Pediat Stem Cell Transplant Unit, Boston, MA 02115 USA. [Shah, Nirali] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Pulsipher, Michael A.] Univ Utah, Primary Childrens Med Ctr, Div Hematol Hematol Malignancies, Huntsman Canc Inst, Salt Lake City, UT USA. [Prestidge, Tim] Starship Childrens Hosp, Auckland, New Zealand. [Seber, Adriana] Inst Oncol Pediat, Sao Paulo, Brazil. [Shenoy, Shalini] Washington Univ, St Louis Childrens Hosp, Pediat Stem Cell Transplant Program, St Louis, MO 63110 USA. [Yu, Lolie C.] Louisiana State Univ, Div Hematol Oncol, Childrens Hosp, New Orleans, LA USA. RP Davies, SM (reprint author), Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave,MLC 11027, Cincinnati, OH 45229 USA. EM stella.davies@cchmc.org FU Public Health Service grant from the National Cancer Institute [U24-CA76518]; National Heart Lung and Blood Institute; National Institute of Allergy and Infectious Diseases; Health Resources and Services Administration [HHSH234200637051C] FX This study was funded by Public Health Service grant (U24-CA76518) from the National Cancer Institute, the National Heart Lung and Blood Institute, the National Institute of Allergy and Infectious Diseases, and the Health Resources and Services Administration (HHSH234200637051C). NR 24 TC 16 Z9 17 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 6 PY 2014 VL 123 IS 10 BP 1615 EP 1620 DI 10.1182/blood-2013-10-535716 PG 6 WC Hematology SC Hematology GA AH0XR UT WOS:000335844600030 PM 24435046 ER PT J AU Ecker, JL AF Ecker, Jeffrey L. TI NEW ENGLAND JOURNAL of MEDICINE SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material AB The case of Marlise Munoz, in which a Texas hospital was made to withdraw support from a pregnant woman who had been brain dead for 2 months, should underscore women's right to determine the course of their end-of-life care, whether or not they are pregnant. Marlise Munoz was 33 years old and the mother of a 15-month-old when she collapsed on November 26, 2013, from what was later determined to be a massive pulmonary embolism. Initially described as apneic but alive, she was brought to the county hospital where her family was soon told that she was brain dead. Ms. Munoz and her husband, both emergency medical technicians (EMTs), had discussed their feelings about such situations. So Erik Munoz felt confident in asserting that his wife would not want continued support. Her other family members agreed, and they requested withdrawal of ventilation and other measures ... C1 [Ecker, Jeffrey L.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Ecker, Jeffrey L.] Harvard Univ, Sch Med, Boston, MA USA. RP Ecker, JL (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. NR 2 TC 4 Z9 4 U1 1 U2 10 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 6 PY 2014 VL 370 IS 10 BP 889 EP 891 DI 10.1056/NEJMp1400969 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AC2EB UT WOS:000332309800003 PM 24499176 ER PT J AU Lieber, DS Hershman, SG Slate, NG Calvo, SE Sims, KB Schmahmann, JD Mootha, VK AF Lieber, Daniel S. Hershman, Steven G. Slate, Nancy G. Calvo, Sarah E. Sims, Katherine B. Schmahmann, Jeremy D. Mootha, Vamsi K. TI Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency SO BMC MEDICAL GENETICS LA English DT Article DE HSD17B4; DBP; D-bifunctional protein deficiency; Perrault syndrome; Next-generation sequencing; Exome sequencing; Copy number variants; CNV; Mitochondria; Mitochondrial disorders; Mitochondrial disease; Mendelian disorders; Human genetics; Ataxia; Multi-system disorders; Peroxisomal defects ID BIFUNCTIONAL PROTEIN-DEFICIENCY; CAUSE OVARIAN DYSGENESIS; PERRAULT SYNDROME; BETA-OXIDATION; HEARING-LOSS; MUTATIONS; TYPE-4; MICE AB Background: D-bifunctional protein deficiency, caused by recessive mutations in HSD17B4, is a severe, infantile-onset disorder of peroxisomal fatty acid oxidation. Few affected patients survive past two years of age. Compound heterozygous mutations in HSD17B4 have also been reported in two sisters diagnosed with Perrault syndrome (MIM # 233400), who presented in adolescence with ovarian dysgenesis, hearing loss, and ataxia. Case presentation: An adult male presented with cerebellar ataxia, peripheral neuropathy, hearing loss, and azoospermia. The clinical presentation, in combination with biochemical findings in serum, urine, and muscle biopsy, suggested a mitochondrial disorder. Commercial genetic testing of 18 ataxia and mitochondrial disease genes was negative. Targeted exome sequencing followed by analysis of single nucleotide variants and small insertions/deletions failed to reveal a genetic basis of disease. Application of a computational algorithm to infer copy number variants (CNVs) from exome data revealed a heterozygous 12 kb deletion of exons 10-13 of HSD17B4 that was compounded with a rare missense variant (p.A196V) at a highly conserved residue. Retrospective review of patient records revealed mildly elevated ratios of pristanic: phytanic acid and arachidonic: docosahexaenoic acid, consistent with dysfunctional peroxisomal fatty acid oxidation. Conclusion: Our case expands the phenotypic spectrum of HSD17B4-deficiency, representing the first male case reported with infertility. Furthermore, it points to crosstalk between mitochondria and peroxisomes in HSD17B4-deficiency and Perrault syndrome. C1 [Lieber, Daniel S.; Hershman, Steven G.; Slate, Nancy G.; Calvo, Sarah E.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Lieber, Daniel S.; Hershman, Steven G.; Slate, Nancy G.; Calvo, Sarah E.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Lieber, Daniel S.; Hershman, Steven G.; Slate, Nancy G.; Calvo, Sarah E.; Sims, Katherine B.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Lieber, Daniel S.; Hershman, Steven G.; Calvo, Sarah E.; Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Lieber, Daniel S.; Hershman, Steven G.; Calvo, Sarah E.; Mootha, Vamsi K.] Broad Inst Harvard & MIT, Cambridge, MA 02141 USA. [Sims, Katherine B.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sims, Katherine B.; Schmahmann, Jeremy D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Schmahmann, Jeremy D.] Massachusetts Gen Hosp, Dept Neurol, Lab Neuroanat & Cerebellar Neurobiol, Cognit Behav Neurol Unit,Ataxia Unit, Boston, MA 02114 USA. [Mootha, Vamsi K.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Schmahmann, JD (reprint author), Massachusetts Gen Hosp, Dept Neurol, Lab Neuroanat & Cerebellar Neurobiol, Cognit Behav Neurol Unit,Ataxia Unit, Boston, MA 02114 USA. EM jschmahmann@partners.org; vamsi@hms.harvard.edu OI Hershman, Steven/0000-0001-9167-7380 FU NSF Graduate Research Fellowship; DOD National Defense Science and Engineering Graduate Fellowship; NGHRI/NIH [RC2HG005556, R01GM97136]; Marriott Mitochondrial Disorders Clinical Research Fund; Birmingham and MINDlink Foundations FX We thank S. Vafai, D. McGuone, M. Frosch for discussion and J. Macmore for research assistance. This work was supported by NSF Graduate Research Fellowship (DSL), DOD National Defense Science and Engineering Graduate Fellowship (SGH), grant RC2HG005556 and R01GM97136 from the NGHRI/NIH (VKM), the Marriott Mitochondrial Disorders Clinical Research Fund (VKM), and the Birmingham and MINDlink Foundations (JDS). NR 25 TC 14 Z9 14 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD MAR 6 PY 2014 VL 15 AR 30 DI 10.1186/1471-2350-15-30 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA AF2IT UT WOS:000334536500001 PM 24602372 ER PT J AU Sun, ZYJ Cheng, YX Kim, M Song, LK Choi, J Kudahl, UJ Brusic, V Chowdhury, B Yu, L Seaman, MS Bellot, G Shih, WM Wagner, G Reinherz, EL AF Sun, Zhen-Yu J. Cheng, Yuxing Kim, Mikyung Song, Likai Choi, Jaewon Kudahl, Ulrich J. Brusic, Vladimir Chowdhury, Barnali Yu, Lu Seaman, Michael S. Bellot, Gaetan Shih, William M. Wagner, Gerhard Reinherz, Ellis L. TI Disruption of Helix-Capping Residues 671 and 674 Reveals a Role in HIV-1 Entry for a Specialized Hinge Segment of the Membrane Proximal External Region of gp41 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE viral membrane fusion; NMR solution structure; helix-hinge-helix motif; helix capping; broadly neutralizing antibody ID VIRUS TYPE-1 GP41; T-CELL-RECEPTOR; NEUTRALIZING ANTIBODY; ENVELOPE GLYCOPROTEIN; DIPOLAR COUPLINGS; ATOMIC-STRUCTURE; VIRAL MEMBRANE; FUSION; PROTEINS; EPITOPE AB HIV-1 (human immunodeficiency virus type /) uses its trimeric gp160 envelope (Env) protein consisting of non-covalently associated gp120 and gp41 subunits to mediate entry into human T lymphocytes. A facile virus fusion mechanism compensates for the sparse Env copy number observed on viral particles and includes a 22-amino-acid, lentivirus-specific adaptation at the gp41 base (amino acid residues 662-683), termed the membrane proximal external region (MPER). We show by NMR and EPR that the MPER consists of a structurally conserved pair of viral lipid-immersed helices separated by a hinge with tandem joints that can be locked by capping residues between helices. This design fosters efficient HIV-1 fusion via interconverting structures while, at the same time, affording immune escape. Disruption of both joints by double alanine mutations at Env positions 671 and 674 (AA) results in attenuation of Env-mediated cell cell fusion and hemifusion, as well as viral infectivity mediated by both CD4-dependent and CD4-independent viruses. The potential mechanism of disruption was revealed by structural analysis of MPER conformational changes induced by AA mutation. A deeper acyl chain-buried MPER middle section and the elimination of cross-hinge rigid-body motion almost certainly impede requisite structural rearrangements during the fusion process, explaining the absence of MPER AA variants among all known naturally occurring HIV-1 viral sequences. Furthermore, those broadly neutralization antibodies directed against the HIV-1 MPER exploit the tandem joint architecture involving helix capping, thereby disrupting hinge function. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Sun, Zhen-Yu J.; Bellot, Gaetan; Shih, William M.; Wagner, Gerhard] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Cheng, Yuxing; Kim, Mikyung; Choi, Jaewon; Reinherz, Ellis L.] Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. [Cheng, Yuxing; Kim, Mikyung; Choi, Jaewon; Kudahl, Ulrich J.; Brusic, Vladimir; Reinherz, Ellis L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kim, Mikyung; Brusic, Vladimir; Reinherz, Ellis L.] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA. [Song, Likai; Chowdhury, Barnali; Yu, Lu] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32310 USA. [Kudahl, Ulrich J.; Brusic, Vladimir] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA. [Bellot, Gaetan; Shih, William M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Bellot, Gaetan; Shih, William M.] Wyss Inst Biol Inspired Engn Harvard, Boston, MA 02115 USA. RP Reinherz, EL (reprint author), Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. EM Ellis_Reinherz@dfci.harvard.edu FU National Institutes of Health [A1084785, A1091693, GM047467, 1DP20D004641, 1U54GM094608]; Biological Sciences in Public Health at Harvard School of Public Health, Boston, MA, USA; National High Magnetic Field Laboratory User Collaboration Grants Program [5080]; National Science Foundation [DMR1157490]; Department of Energy and the State of Florida FX This work is funded by National Institutes of Health Grants A1084785 and A1091693 to E.L.R., GM047467 to G.W. and 1DP20D004641 and 1U54GM094608 to W.S., as well as Gates Foundation Grants to E.L.R. and M.S.S. Y.C. is affiliated with the PhD Program in Biological Sciences in Public Health at Harvard School of Public Health, Boston, MA, USA. L.S. acknowledges the support of National High Magnetic Field Laboratory User Collaboration Grants Program Grant No. 5080. The National High Magnetic Field Laboratory is funded by National Science Foundation Cooperative Agreement No. DMR1157490, Department of Energy and the State of Florida. We thank Drs. J. G. Sodroski, B. Haynes, R. Swanstrom and R. T. Wyatt for reagents; Drs. J. Chou and M. Allan for advice with RDC data; J. -H. Wang for comments; and G. Heffron for assistance with NMR instruments. NR 42 TC 12 Z9 14 U1 0 U2 11 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD MAR 6 PY 2014 VL 426 IS 5 SI SI BP 1095 EP 1108 DI 10.1016/j.jmb.2013.09.030 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AD0FG UT WOS:000332909300009 PM 24075869 ER PT J AU Cardo, LF Coto, E de Mena, L Ribacoba, R Mata, IF Menendez, M Moris, G Alvarez, V AF Cardo, Lucia F. Coto, Eliecer de Mena, Lorena Ribacoba, Rene Mata, Ignacio F. Menendez, Manuel Moris, German Alvarez, Victoria TI Alpha-synuclein transcript isoforms in three different brain regions from Parkinson's disease and healthy subjects in relation to the SNCA rs356165/rs11931074 polymorphisms SO NEUROSCIENCE LETTERS LA English DT Article DE Parkinson's disease; Alpha-synuclein isoforms; DNA polymorphisms; Genetic risk ID MESSENGER-RNA EXPRESSION; GENE; SUSCEPTIBILITY; VARIANTS AB Mutations in the alpha-synuclein (SNCA) gene cause autosomal dominant Parkinson's disease (PD). Common SNCA polymorphisms have been associated with the risk of developing PD. Abnormal expression and post-translational modification of SNCA has been found in PD-brains. In addition to a full length transcript (SNCA-140) there are three short isoforms (SNCA-98, -112, and -126) that could be prone to aggregation. The association between SNCA polymorphisms and PD could be explained through an increased expression of these alternative transcripts. Our aim was to measure the different SNCA transcripts in the substantia nigra (SN), cerebellum (CB), and occipital cortex (OC) from PD-patients (n = 9) and healthy subjects (n = 6). In addition, we determined whether two SNCA polymorphisms (SNPs rs356165 and rs11931074) were related to differences in transcript isoform expression. PD brain tissues showed higher levels of the three short transcripts in the SN, but only SNCA-112 and SNCA-98 were significantly increased in the CB of patients vs. controls (p = 0.02, p = 0.03). The genotyping of a large cohort of PD-patients and controls showed that haplotype rs356165-A+rs11931074-G had a protective effect (OR = 0.71; CI = 0.59-0.83), while the G-T haplotype increased the risk for PD (OR = 1.44; CI = 1.06-1.96). We did not find significant differences for the SNCA levels between the haplotypes. In conclusion, we found statistically significant higher levels of the SNCA-112 and SNCA-98 transcripts in the CB of PD brains, and a trend toward higher levels of the short transcript isoforms in the SN of PD brains. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Cardo, Lucia F.; Coto, Eliecer; de Mena, Lorena; Alvarez, Victoria] Hosp Univ Cent Asturias, Genet Mol Lab Med, Oviedo, Spain. [Ribacoba, Rene; Menendez, Manuel; Moris, German] Hosp Univ Cent Asturias, Asturias, Spain. [Ribacoba, Rene; Menendez, Manuel; Moris, German] Alvarez Buylla Mieres, Asturias, Spain. [Mata, Ignacio F.] Vet Affairs Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA USA. [Mata, Ignacio F.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. RP Alvarez, V (reprint author), Hosp Cent Asturias Maternidad, Oviedo 33006, Spain. EM victoria.alvarez@sespa.princast.es FU Spanish "Fondo de Investigaciones Sanitarias-Fondos FEDER" European Union [FIS 11/0093]; FICYT-Principado de Asturias; Fundacion Parkinson Asturias; Obra Social Cajastur FX We thank Dr. Claire Troakes and the London Neurodegenerative Diseases Brain Bank for supplying all postmortem brain samples. Authors thank the "Fundacion Parkinson Asturias" and "Obra Social Cajastur" for their support. This work was supported by grants from the Spanish "Fondo de Investigaciones Sanitarias-Fondos FEDER" European Union (FIS 11/0093). LFC and LDM are predoctoral fellowships of FICYT-Principado de Asturias. NR 20 TC 10 Z9 10 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 6 PY 2014 VL 562 BP 45 EP 49 DI 10.1016/j.neulet.2014.01.009 PG 5 WC Neurosciences SC Neurosciences & Neurology GA AD0FM UT WOS:000332909900009 PM 24418406 ER PT J AU Spires-Jones, TL Friedman, T Pitstick, R Polydoro, M Roe, A Carlson, GA Hyman, BT AF Spires-Jones, Tara L. Friedman, Taylor Pitstick, Rose Polydoro, Manuela Roe, Allyson Carlson, George A. Hyman, Bradley T. TI Methylene blue does not reverse existing neurofibrillary tangle pathology in the rTg4510 mouse model of tauopathy SO NEUROSCIENCE LETTERS LA English DT Article DE Alzheimer; Tau; Methylene blue ID EARLY ALZHEIMERS-DISEASE; TAU; NEUROPROTECTION; PHENOTHIAZINES; INHIBITION AB Alzheimer's disease is characterized pathologically by aggregation of amyloid beta into senile plaques and aggregation of pathologically modified tau into neurofibrillary tangles. While changes in amyloid processing are strongly implicated in disease initiation, the recent failure of amyloid-based therapies has highlighted the importance of tau as a therapeutic target. "Tangle busting" compounds including methylene blue and analogous molecules are currently being evaluated as therapeutics in Alzheimer's disease. Previous studies indicated that methylene blue can reverse tau aggregation in vitro after 10 min, and subsequent studies suggested that high levels of drug reduce tau protein levels (assessed biochemically) in vivo. Here, we tested whether methylene blue could remove established neurofibrillary tangles in the rTg4510 model of tauopathy, which develops robust tangle pathology. We find that 6 weeks of methylene blue dosing in the water from 16 months to 17.5 months of age decreases soluble tau but does not remove sarkosyl insoluble tau, or histologically defined PHF1 or Gallyas positive tangle pathology. These data indicate that methylene blue treatment will likely not rapidly reverse existing tangle pathology. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Spires-Jones, Tara L.; Friedman, Taylor; Polydoro, Manuela; Roe, Allyson; Hyman, Bradley T.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Pitstick, Rose; Carlson, George A.] McLaughlin Res Inst, Great Falls, MT USA. RP Spires-Jones, TL (reprint author), Univ Edinburgh, Ctr Cognit & Neural Syst, 1 George Sq, Edinburgh EH9 3EL, Midlothian, Scotland. EM tara.spires-jones@ed.ac.uk OI Spires-Jones, Tara/0000-0003-2530-0598 FU NIA NIH HHS [R00 AG033670, R01 AG026249, P50 AG005134] NR 18 TC 19 Z9 19 U1 0 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 6 PY 2014 VL 562 BP 63 EP 68 DI 10.1016/j.neulet.2014.01.013 PG 6 WC Neurosciences SC Neurosciences & Neurology GA AD0FM UT WOS:000332909900013 PM 24462887 ER PT J AU Tragante, V Barnes, MR Ganesh, SK Lanktree, MB Guo, W Franceschini, N Smith, EN Johnson, T Holmes, MV Padmanabhan, S Karczewski, KJ Almoguera, B Barnard, J Baumert, J Chang, YPC Elbers, CC Farrall, M Fischer, ME Gaunt, TR Gho, JMIH Gieger, C Goel, A Gong, Y Isaacs, A Kleber, ME Leach, IM McDonough, CW Meijs, MFL Melander, O Nelson, CP Nolte, IM Pankratz, N Price, TS Shaffer, J Shah, S Tomaszewski, M van der Most, PJ Van Iperen, EPA Vonk, JM Witkowska, K Wong, COL Zhang, L Beitelshees, AL Berenson, GS Bhatt, DL Brown, M Burt, A Cooper-DeHoff, RM Connell, JM Cruickshanks, KJ Curtis, SP Davey-Smith, G Delles, C Gansevoort, RT Guo, XQ Haiqing, S Hastie, CE Hofker, MH Hovingh, GK Kim, DS Kirkland, SA Klein, BE Klein, R Li, YR Maiwald, S Newton-Cheh, C O'Brien, ET Onland-Moret, NC Palmas, W Parsa, A Penninx, BW Pettinger, M Vasan, RS Ranchalis, JE Ridker, PM Rose, LM Sever, P Shimbo, D Steele, L Stolk, RP Thorand, B Trip, MD van Duijn, CM Verschuren, WM Wijmenga, C Wyatt, S Young, JH Zwinderman, AH Bezzina, CR Boerwinkle, E Casas, JP Caulfield, MJ Chakravarti, A Chasman, DI Davidson, KW Doevendans, PA Dominiczak, AF FitzGerald, GA Gums, JG Fornage, M Hakonarson, H Halder, I Hillege, HL Illig, T Jarvik, GP Johnson, JA Kastelein, JJP Koenig, W Kumari, M Marz, W Murray, SS O'Connell, JR Oldehinkel, AJ Pankow, JS Rader, DJ Redline, S Reilly, MP Schadt, EE Kottke-Marchant, K Snieder, H Snyder, M Stanton, AV Tobin, MD Uitterlinden, AG van der Harst, P van der Schouw, YT Samani, NJ Watkins, H Johnson, AD Reiner, AP Zhu, XF de Bakker, PIW Levy, D Asselbergs, FW Munroe, PB Keating, BJ AF Tragante, Vinicius Barnes, Michael R. Ganesh, Santhi K. Lanktree, Matthew B. Guo, Wei Franceschini, Nora Smith, Erin N. Johnson, Toby Holmes, Michael V. Padmanabhan, Sandosh Karczewski, Konrad J. Almoguera, Berta Barnard, John Baumert, Jens Chang, Yen-Pei Christy Elbers, Clara C. Farrall, Martin Fischer, Mary E. Gaunt, Tom R. Gho, Johannes M. I. H. Gieger, Christian Goel, Anuj Gong, Yan Isaacs, Aaron Kleber, Marcus E. Leach, Irene Mateo McDonough, Caitrin W. Meijs, Matthijs F. L. Melander, Olle Nelson, Christopher P. Nolte, Ilja M. Pankratz, Nathan Price, Tom S. Shaffer, Jonathan Shah, Sonia Tomaszewski, Maciej van der Most, Peter J. Van Iperen, Erik P. A. Vonk, Judith M. Witkowska, Kate Wong, Caroline O. L. Zhang, Li Beitelshees, Amber L. Berenson, Gerald S. Bhatt, Deepak L. Brown, Morris Burt, Amber Cooper-DeHoff, Rhonda M. Connell, John M. Cruickshanks, Karen J. Curtis, Sean P. Davey-Smith, George Delles, Christian Gansevoort, Ron T. Guo, Xiuqing Haiqing, Shen Hastie, Claire E. Hofker, Marten H. Hovingh, G. Kees Kim, Daniel S. Kirkland, Susan A. Klein, Barbara E. Klein, Ronald Li, Yun R. Maiwald, Steffi Newton-Cheh, Christopher O'Brien, Eoin T. Onland-Moret, N. Charlotte Palmas, Walter Parsa, Afshin Penninx, Brenda W. Pettinger, Mary Vasan, Ramachandran S. Ranchalis, Jane E. Ridker, Paul M. Rose, Lynda M. Sever, Peter Shimbo, Daichi Steele, Laura Stolk, Ronald P. Thorand, Barbara Trip, Mieke D. van Duijn, Cornelia M. Verschuren, W. Monique Wijmenga, Cisca Wyatt, Sharon Young, J. Hunter Zwinderman, Aeilko H. Bezzina, Connie R. Boerwinkle, Eric Casas, Juan P. Caulfield, Mark J. Chakravarti, Aravinda Chasman, Daniel I. Davidson, Karina W. Doevendans, Pieter A. Dominiczak, Anna F. FitzGerald, Garret A. Gums, John G. Fornage, Myriam Hakonarson, Hakon Halder, Indrani Hillege, Hans L. Illig, Thomas Jarvik, Gail P. Johnson, Julie A. Kastelein, John J. P. Koenig, Wolfgang Kumari, Meena Maerz, Winfried Murray, Sarah S. O'Connell, Jeffery R. Oldehinkel, Albertine J. Pankow, James S. Rader, Daniel J. Redline, Susan Reilly, Muredach P. Schadt, Eric E. Kottke-Marchant, Kandice Snieder, Harold Snyder, Michael Stanton, Alice V. Tobin, Martin D. Uitterlinden, Andre G. van der Harst, Pim van der Schouw, Yvonne T. Samani, Nilesh J. Watkins, Hugh Johnson, Andrew D. Reiner, Alex P. Zhu, Xiaofeng de Bakker, Paul I. W. Levy, Daniel Asselbergs, Folkert W. Munroe, Patricia B. Keating, Brendan J. TI Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; HUMAN PREFRONTAL CORTEX; FACTOR-KAPPA-B; ESSENTIAL-HYPERTENSION; SUSCEPTIBILITY LOCUS; CANDIDATE GENES; COMMON VARIANTS; DRUG DISCOVERY; PULSE PRESSURE AB Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped similar to 50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 x 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification. C1 [Tragante, Vinicius; Gho, Johannes M. I. H.; Meijs, Matthijs F. L.; Doevendans, Pieter A.; Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, NL-3584 CX Utrecht, Netherlands. [Tragante, Vinicius; Elbers, Clara C.; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CX Utrecht, Netherlands. [Barnes, Michael R.] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Inst Hlth Biomed Res Unit, London EC1M 6BQ, England. [Ganesh, Santhi K.] Univ Michigan Hlth Syst, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Ganesh, Santhi K.] Univ Michigan Hlth Syst, Dept Human Genet, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Lanktree, Matthew B.] McMaster Univ, Dept Med, Hamilton, ON L8S 4L8, Canada. [Guo, Wei; Zhu, Xiaofeng] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Franceschini, Nora] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Smith, Erin N.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Smith, Erin N.] Univ Calif San Diego, Radys Childrens Hosp, La Jolla, CA 92093 USA. [Johnson, Toby; Witkowska, Kate; Wong, Caroline O. L.; Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, London EC1M 6BQ, England. [Johnson, Toby; Witkowska, Kate; Wong, Caroline O. L.; Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Barts & London Genome Ctr, London EC1M 6BQ, England. [Holmes, Michael V.; Steele, Laura; Keating, Brendan J.] Univ Penn, Dept Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. [Padmanabhan, Sandosh; Dominiczak, Anna F.] Univ Glasgow, BHF, Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. [Karczewski, Konrad J.; Snyder, Michael] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. [Almoguera, Berta; Li, Yun R.; Keating, Brendan J.] Childrens Hosp Philadelphia, Abramson Res Ctr, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Barnard, John; Zhang, Li] Cleveland Clin, Lerner Res Inst, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. [Baumert, Jens; Thorand, Barbara] Helmholtz Zentrum Mu nchen, German Res Ctr Environm Hlth, Inst Epidemiol2, D-85764 Neuherberg, Germany. [Chang, Yen-Pei Christy] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Chang, Yen-Pei Christy] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Elbers, Clara C.; Hofker, Marten H.; Onland-Moret, N. Charlotte; van der Schouw, Yvonne T.; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3584 CX Utrecht, Netherlands. [Farrall, Martin; Goel, Anuj; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Farrall, Martin; Goel, Anuj; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford OX3 9DU, England. [Fischer, Mary E.; Cruickshanks, Karen J.; Klein, Barbara E.; Klein, Ronald] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI 53726 USA. [Gaunt, Tom R.; Davey-Smith, George] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England. [Gieger, Christian] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany. [Gong, Yan; McDonough, Caitrin W.; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.] Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL 32610 USA. [Gong, Yan; McDonough, Caitrin W.; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.] Univ Florida, Ctr Pharmacogenom, Gainesville, FL 32610 USA. [Isaacs, Aaron; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands. [Kleber, Marcus E.; Jarvik, Gail P.; Maerz, Winfried] Heidelberg Univ, Med Fac Mannheim, Med Clin 5, D-68167 Mannheim, Germany. [Leach, Irene Mateo; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. [Melander, Olle] Lund Univ, Dept Clin Sci, S-20502 Malmo, Sweden. [Melander, Olle] Skane Univ Hosp, Ctr Emergency Med, S-20502 Malmo, Sweden. [Nelson, Christopher P.; Tomaszewski, Maciej; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England. [Nelson, Christopher P.; Samani, Nilesh J.] Glenfield Hosp, NIHR, Lecister Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England. [Nolte, Ilja M.; van der Most, Peter J.; Vonk, Judith M.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-9700 RB Groningen, Netherlands. [Pankratz, Nathan] Univ Minnesota, Dept Lab Med & Pathol, Inst Human Genet, Minneapolis, MN 55455 USA. [Price, Tom S.] Inst Psychiat, MRC, SGDP Ctr, London SE5 8AF, England. [Shaffer, Jonathan; Shimbo, Daichi] Columbia Univ, Dept Med, New York, NY 10032 USA. [Shah, Sonia] UCL, Genet Inst, Dept Genet Evolut & Environm, London WC1E 6BT, England. [Van Iperen, Erik P. A.; van der Harst, Pim; Asselbergs, Folkert W.] ICIN, Durrer Ctr Cardiogenet Res, Netherlands Heart Inst, NL-3511 GC Utrecht, Netherlands. [Van Iperen, Erik P. A.; Zwinderman, Aeilko H.] Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, NL-1105 AZ Amsterdam, Netherlands. [Beitelshees, Amber L.; Haiqing, Shen; Parsa, Afshin] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Berenson, Gerald S.] Tulane Univ, Dept Epidemiol, New Orleans, LA 70118 USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Brown, Morris] Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol Unit, Cambridge CB2 2QQ, England. [Burt, Amber; Ranchalis, Jane E.] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA. [Connell, John M.] Univ Dundee, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Scotland. [Cruickshanks, Karen J.] Univ Wisconsin, Dept Populat Hlth Sci, Madison, WI 53726 USA. [Curtis, Sean P.] Merck Res Labs, Rahway, NJ 07065 USA. [Delles, Christian; Hastie, Claire E.] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland. [Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Med, Div Nephrol, NL-9700 RB Groningen, Netherlands. [Guo, Xiuqing] Cedars Sinai Med Ctr, PEDS, Los Angeles, CA 90048 USA. [Hofker, Marten H.] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Med Biol Div, NL-9700 RB Groningen, Netherlands. [Hovingh, G. Kees; Maiwald, Steffi; Kastelein, John J. P.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Kim, Daniel S.] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA. [Kim, Daniel S.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Kirkland, Susan A.] Dalhousie Univ, Dept Community Hlth & Epidemiol, Halifax, NS B3H 1V7, Canada. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [O'Brien, Eoin T.] Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 4, Ireland. [Penninx, Brenda W.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst, Dept Psychiat, NL-1081 BT Amsterdam, Netherlands. [Pettinger, Mary] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Ridker, Paul M.; Rose, Lynda M.; Chasman, Daniel I.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Ridker, Paul M.; Chasman, Daniel I.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Sever, Peter] Univ London Imperial Coll Sci Technol & Med, Int Ctr Circulatory Hlth, London W2 1LA, England. [Trip, Mieke D.] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands. [Verschuren, W. Monique] Natl Inst Publ Hlth & Environm, RIVM, NL-3720 BA Bilthoven, Netherlands. [Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Wyatt, Sharon] Univ Mississippi, Med Ctr, Sch Nursing, Jackson, MS 39216 USA. [Wyatt, Sharon] Univ Mississippi, Med Ctr, Sch Med, Jackson, MS 39216 USA. [Young, J. Hunter] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Bezzina, Connie R.] Univ Amsterdam, Acad Med Ctr, Heart Failure Res Ctr, Dept Clin & Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands. [Bezzina, Connie R.] Univ Amsterdam, Acad Med Ctr, Mol & Expt Cardiol Grp, NL-1105 AZ Amsterdam, Netherlands. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Houston, TX 77030 USA. [Casas, Juan P.] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1E 7HT, England. [Casas, Juan P.] UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London WC1E 6BT, England. [Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Davidson, Karina W.] Columbia Univ, Dept Med, New York, NY 10032 USA. [Davidson, Karina W.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [FitzGerald, Garret A.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Gums, John G.] Univ Florida, Dept Pharmacotherapy & Translat Res, Gainesville, FL 32610 USA. [Gums, John G.] Univ Florida, Dept Community Hlth, Gainesville, FL 32610 USA. [Gums, John G.] Univ Florida, Dept Family Med, Gainesville, FL 32610 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Halder, Indrani] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15261 USA. [Illig, Thomas] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany. [Illig, Thomas] Hannover Med Sch, Hannover Unified Biobank, D-30625 Hannover, Germany. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89081 Ulm, Germany. [Kumari, Meena] UCL, Dept Epidemiol & Publ Hlth, Div Populat Hlth, London WC1E 7HB, England. [Jarvik, Gail P.] Synlab Serv GmbH, Synlab Acad, D-69214 Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Inst Clin Med, A-8036 Graz, Austria. [Maerz, Winfried] Med Univ Graz, Chem Lab Diagnost, A-8036 Graz, Austria. [Murray, Sarah S.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92037 USA. [Oldehinkel, Albertine J.] Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, NL-9700 RB Groningen, Netherlands. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Redline, Susan] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Schadt, Eric E.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. [Kottke-Marchant, Kandice] Cleveland Clin, Pathol & Lab Med Inst, Cleveland, OH 44195 USA. [Stanton, Alice V.] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [Tobin, Martin D.] Univ Leicester, Dept Hlth Sci, Leicester LE1 7RH, Leics, England. [Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands. [Johnson, Andrew D.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [de Bakker, Paul I. W.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Framingham, MA 01702 USA. [Asselbergs, Folkert W.] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, London WC1E 6BT, England. [Keating, Brendan J.] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Munroe, PB (reprint author), Queen Mary Univ London, London EC1M 6BQ, England. EM p.b.munroe@qmul.ac.uk; bkeating@mail.med.upenn.edu RI Davey Smith, George/A-7407-2013; Johnson, Andrew/G-6520-2013; Padmanabhan, Sandosh/S-3963-2016; Wijmenga, Cisca/D-2173-2009; van der Schouw, Yvonne/F-8327-2014; Shah, Sonia/N-7547-2013; Price, Thomas/B-7372-2008; Stanton, Alice/F-4697-2012; Jarvik, Gail/N-6476-2014; Gaunt, Tom/O-3918-2014; de Bakker, Paul/B-8730-2009; Onland-Moret, N. Charlotte/G-9185-2011; Thorand, Barbara/B-5349-2014 OI Kleber, Marcus/0000-0003-0663-7275; Davey Smith, George/0000-0002-1407-8314; Stanton, Alice/0000-0002-4961-165X; Wijmenga, Cisca/0000-0002-5635-1614; Johnson, Toby/0000-0002-5998-3270; Karczewski, Konrad/0000-0003-2878-4671; Padmanabhan, Sandosh/0000-0003-3869-5808; Ramachandran, Vasan/0000-0001-7357-5970; Gieger, Christian/0000-0001-6986-9554; Watkins, Hugh/0000-0002-5287-9016; Pankow, James/0000-0001-7076-483X; van der Schouw, Yvonne/0000-0002-4605-435X; Shah, Sonia/0000-0001-5860-4526; Price, Thomas/0000-0001-7356-2109; Jarvik, Gail/0000-0002-6710-8708; Gaunt, Tom/0000-0003-0924-3247; de Bakker, Paul/0000-0001-7735-7858; Thorand, Barbara/0000-0002-8416-6440 FU British Heart Foundation [FS/11/35/28871, FS/12/33/29561, FS/12/8/29377, FS/14/12/30540, PG/07/085/23349, PG/09/022/26739, SP/08/002/24118]; Medical Research Council [G0802432, G0902313, G9521010, MC_UU_12013/1, MC_UU_12013/8, MR/K006584/1, MR/K013351/1]; NCATS NIH HHS [UL1 TR000064, UL1 TR000124]; NHLBI NIH HHS [R01 HL074730]; NIA NIH HHS [R01 AG016592, R01 AG021917, R37 AG011099]; NIDDK NIH HHS [P30 DK063491, P30 DK072488]; NIGMS NIH HHS [U01 GM074492]; Wellcome Trust [090532] NR 114 TC 50 Z9 51 U1 3 U2 29 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD MAR 6 PY 2014 VL 94 IS 3 BP 349 EP 360 DI 10.1016/j.ajhg.2013.12.016 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA AC6DK UT WOS:000332611400009 PM 24560520 ER PT J AU Mihaylova, MM Sabatini, DM Yilmaz, OH AF Mihaylova, Maria M. Sabatini, David M. Yilmaz, Oemer H. TI Dietary and Metabolic Control of Stem Cell Function in Physiology and Cancer SO CELL STEM CELL LA English DT Review ID HIGH-FAT DIET; ACUTE MYELOGENOUS LEUKEMIA; RESTRICTED KETOGENIC DIET; IN-VITRO EXPANSION; HEMATOPOIETIC STEM; SELF-RENEWAL; CALORIE RESTRICTION; SKELETAL-MUSCLE; ENERGY-METABOLISM; OXIDATIVE STRESS AB Organismal diet has a profound impact on tissue homeostasis and health in mammals. Adult stem cells are a keystone of tissue homeostasis that alters tissue composition by balancing self-renewal and differentiation divisions. Because somatic stem cells may respond to shifts in organismal physiology to orchestrate tissue remodeling and some cancers are understood to arise from transformed stem cells, there is a likely possibility that organismal diet, stem cell function, and cancer initiation are interconnected. Here we will explore the emerging effects of diet on nutrient-sensing pathways active in mammalian tissue stem cells and their relevance to normal and cancerous growth. C1 [Mihaylova, Maria M.; Sabatini, David M.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Mihaylova, Maria M.; Sabatini, David M.] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Mihaylova, Maria M.; Sabatini, David M.] Broad Inst Harvard & MIT, Seven Cambridge Ctr, Cambridge, MA 02142 USA. [Mihaylova, Maria M.; Sabatini, David M.; Yilmaz, Oemer H.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Mihaylova, Maria M.; Sabatini, David M.; Yilmaz, Oemer H.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Yilmaz, Oemer H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Yilmaz, Oemer H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Sabatini, DM (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM sabatini@wi.mit.edu; ohyilmaz@mit.edu FU NIH [CA129105, CA103866, AI047389]; Koch Institute Frontier Research Program; Ellison Medical Foundation; K99/R00 Pathway to Independence Award from the NIH/NIA [AG045144]; CSIBD from NIDDK/NIH [DK043351] FX We apologize for being unable to discuss multiple primary studies due to references and space limitations. M. M. is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation, DRG-2146-13. D. M. S. is an investigator of the Howard Hughes Medical Institute and is supported by awards from the NIH (CA129105, CA103866, and AI047389), Koch Institute Frontier Research Program, and the Ellison Medical Foundation. O.H.Y. is supported by a K99/R00 Pathway to Independence Award from the NIH/NIA AG045144 and a CSIBD grant from the NIDDK/NIH (DK043351). NR 143 TC 30 Z9 31 U1 2 U2 25 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 6 PY 2014 VL 14 IS 3 BP 292 EP 305 DI 10.1016/j.stem.2014.02.008 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AC5AR UT WOS:000332533400007 PM 24607404 ER PT J AU Choudhuri, K Llodra, J Roth, EW Tsai, J Gordo, S Wucherpfennig, KW Kam, LC Stokes, DL Dustin, ML AF Choudhuri, Kaushik Llodra, Jaime Roth, Eric W. Tsai, Jones Gordo, Susana Wucherpfennig, Kai W. Kam, Lance C. Stokes, David L. Dustin, Michael L. TI Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse SO NATURE LA English DT Article ID SUPRAMOLECULAR ACTIVATION CLUSTER; ELECTRON TOMOGRAPHY; CLASS-II; PROTEIN; COMPLEX; PROLIFERATION; MICROSCOPY; MOLECULES; DYNAMICS; ADHESION AB The recognition events that mediate adaptive cellular immunity and regulate antibody responses depend on intercellular contacts between T cells and antigen-presenting cells (APCs)(1). T-cell signalling is initiated at these contacts when surface-expressed T-cell receptors (TCRs) recognize peptide fragments (antigens) of pathogens bound to major histocompatibility complex molecules (pMHC) on APCs. This, along with engagement of adhesion receptors, leads to the formation of a specialized junction between T cells and APCs, known as the immunological synapse(2), which mediates efficient delivery of effector molecules and intercellular signals across the synaptic cleft(3). T-cell recognition of pMHC and the adhesion ligand intercellular adhesion molecule-1 (ICAM-1) on supported planar bilayers recapitulates the domain organization of the immunological synapse(4,5), which is characterized by central accumulation of TCRs(5), adjacent to a secretory domain(2), both surrounded by an adhesive ring(4,5). Although accumulation of TCRs at the immunological synapse centre correlates with T-cell function(4), this domain is itself largely devoid of TCR signalling activity(5,6), and is characterized by an unexplained immobilization of TCR-pMHC complexes relative to the highly dynamic immunological synapse periphery(4,5). Here we show that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the immunological synapse centre. Tumour susceptibility gene 101 (TSG101)(6) sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting 4 (VPS4)(7,8) mediates scission of microvesicles from the T-cell plasma membrane. The human immunodeficiency virus polyprotein Gag co-opts this process for budding of virus-like particles. B cells bearing cognate pMHC receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. We conclude that the immunological synapse orchestrates TCR sorting and release in extracellular microvesicles. These microvesicles deliver transcellular signals across antigen-dependent synapses by engaging cognate pMHC on APCs. C1 [Choudhuri, Kaushik] Skirball Inst Biomol Med, Program Mol Pathogenesis, Helen L & Martin S Kimmel Ctr Biol & Med, New York, NY 10016 USA. [Llodra, Jaime; Stokes, David L.] Skirball Inst Biomol Med, Program Struct Biol, Helen L & Martin S Kimmel Ctr Biol & Med, New York, NY 10016 USA. [Roth, Eric W.] Northwestern Univ, Atom & Nanoscale Characterizat Expt Ctr, Evanston, IL 60208 USA. [Tsai, Jones; Kam, Lance C.] Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA. [Gordo, Susana; Wucherpfennig, Kai W.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Gordo, Susana; Wucherpfennig, Kai W.] Harvard Univ, Sch Med, Program Immunol, Boston, MA 02215 USA. [Stokes, David L.] New York Struct Biol Ctr, New York, NY 10027 USA. [Dustin, Michael L.] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Dustin, Michael L.] Univ Oxford, Kennedy Inst Rheumatol, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford OX3 7FY, England. RP Dustin, ML (reprint author), NYU, Sch Med, Dept Pathol, 540 First Ave, New York, NY 10016 USA. EM stokes@nyu.edu; michael.dustin@kennedy.ox.ac.uk OI Dustin, Michael/0000-0003-4983-6389 FU New York Structural Biology Center; Cancer Research Institute; NIH [K99AI093884, AI043542, AI045757, AI055037, AI088377, AI093884, EY016586]; Wellcome Trust; Kennedy Trust FX We thank G. Schutz for suggesting the photoactivation experiment, H. Chen for microfabrication, W. Sundquist for providing Gag-GFP, VPS4-GFP and VPS4dn-GFP constructs, P. Bieniasz for Gag-mCherry, Gag Delta L-mCherry, ALIX-GFP and CHMP4B-GFP constructs, the New York Structural Biology Center for electron microscopy tomography, support and instrumentation and members of the Dustin laboratory for helpful discussions and contributions of reagents. We thank J. Nance for the gift of biotinylated duramycin-linked biotin. This work was supported in part by a Cancer Research Institute fellowship and NIH grant K99AI093884 (K.C.), a Wellcome Trust Principal Research Fellowship (M.L.D.), a Kennedy Trust Senior Research Fellowship (M.L.D.) and NIH grants AI043542, AI045757, AI055037, AI088377, AI093884 and EY016586 (Nanomedicine Development Center). NR 39 TC 93 Z9 94 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 6 PY 2014 VL 507 IS 7490 BP 118 EP + DI 10.1038/nature12951 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC0ZQ UT WOS:000332224400054 PM 24487619 ER PT J AU Jan, RK Lin, JC McLaren, DG Kirk, IJ Kydd, RR Russell, BR AF Jan, Reem K. Lin, Joanne C. McLaren, Donald G. Kirk, Ian J. Kydd, Rob R. Russell, Bruce R. TI The effects of methyphenidate on cognitive contron in active methamphetamine dependence using functional magnetic resonance imaging SO FRONTIERS IN PSYCHIATRY LA English DT Article DE cognitive control; BOLD; drug dependence; fMRI; methamphetamine; methylphenidate; Stroop AB Methamphetamine (MA) dependence is associated with cognitive deficits. Methylphenidate (MPH) has been shown to improve inhibitory control in healthy and cocaine-dependent subjects. This study aimed to understand the neurophysiological effects before and after acute MPH administration in active MA-dependent and control subjects. Fifteen MA-dependent and 18 control subjects aged 18-46 years were scanned using functional magnetic resonance imaging before and after either a single oral dose of MPH (18 mg) or placebo while performing a color-word Stroop task. Baseline accuracy was lower (p < 0.026) and response time (RT) was longer (p < 0.0001) for the incongruent compared to congruent condition, demonstrating the task probed cognitive control. Increased activation of the dorsolateral prefrontal cortex (DLPFC) and parietal cortex during the incongruent and Stroop effect conditions, respectively was observed in MA-dependent compared to control subjects (p < 0.05), suggesting the need to recruit neural resources within these regions for conflict resolution. Post- compared to pre-MPH treatment, increased RT and DLPFC activation for the Stroop effect were observed in MA-dependent subjects (p < 0.05). In comparison to MPH-treated controls and placebo-treated MA-dependent subjects, MPH-treated MA-dependent subjects showed decreased activation of parietal and occipital regions during the incongruent and Stroop effect conditions (p < 0.05). These findings suggest that in MA-dependent subjects, MPH facilitated increased recruitment of the DLPFC for Stroop conflict resolution, and a decreased need for recruitment of neural resources in parietal and occipital regions compared to the other groups, while maintaining a comparable level of task performance to that achieved pre-drug administration. Due to the small sample size, the results from this study are preliminary; however, they inform us about the effects of MPH on the neural correlates of cognitive control in active MA-dependent subjects. C1 [Jan, Reem K.; Lin, Joanne C.; Russell, Bruce R.] Univ Auckland, Sch Pharm, Auckland, New Zealand. [Jan, Reem K.; Lin, Joanne C.; Kirk, Ian J.; Kydd, Rob R.; Russell, Bruce R.] Univ Auckland, Ctr Brain Res, Auckland, New Zealand. [McLaren, Donald G.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [McLaren, Donald G.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McLaren, Donald G.] Harvard Med Sch, Boston, MA USA. [Kirk, Ian J.] Univ Auckland, Dept Psychol, Auckland, New Zealand. [Kydd, Rob R.] Univ Auckland, Dept Psychol Med, Auckland, New Zealand. RP Russell, BR (reprint author), Univ Auckland, Fac Med & Hlth Sci, Sch Pharm, Private Bag 92019, Auckland 1142, New Zealand. EM b.russell@auckland.ac.nz FU New Zealand Pharmacy Education Research Foundation [208]; University of Auckland Faculty Development Research Fund; Oakley Mental Health Research Foundation; University of Auckland Doctoral Scholarship; New Zealand Federation of Graduate Women FX This paper was supported by the New Zealand Pharmacy Education Research Foundation Grant Number 208, the University of Auckland Faculty Development Research Fund, and the Oakley Mental Health Research Foundation. Reem K. Jan was supported by the University of Auckland Doctoral Scholarship and the New Zealand Federation of Graduate Women. The authors thank Nicolas McNair, Mark Jenkinson, Avinesh Pillai, Chris Triggs, Maree Jensen, Peta Hardley, Jari Tiihonen, Janie Sheridan, Louise Curley, and Michelle Gordon, for their involvement invarious aspects of the trial, including planning, administration, subject recruitment or advice on statistical data analysis. NR 131 TC 3 Z9 3 U1 0 U2 2 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1664-0640 J9 FRONT PSYCHIATRY JI Front. Psychiatry PD MAR 6 PY 2014 VL 5 AR 20 DI 10.3389/fpsyt.2014.00020 PG 18 WC Psychiatry SC Psychiatry GA V46RF UT WOS:000209900600001 PM 24639656 ER PT J AU Fagan, AM Xiong, CJ Jasielec, MS Bateman, RJ Goate, AM Benzinger, TLS Ghetti, B Martins, RN Masters, CL Mayeux, R Ringman, JM Rossor, MN Salloway, S Schofield, PR Sperling, RA Marcus, D Cairns, NJ Buckles, VD Ladenson, JH Morris, JC Holtzman, DM AF Fagan, Anne M. Xiong, Chengjie Jasielec, Mateusz S. Bateman, Randall J. Goate, Alison M. Benzinger, Tammie L. S. Ghetti, Bernardino Martins, Ralph N. Masters, Colin L. Mayeux, Richard Ringman, John M. Rossor, Martin N. Salloway, Stephen Schofield, Peter R. Sperling, Reisa A. Marcus, Daniel Cairns, Nigel J. Buckles, Virginia D. Ladenson, Jack H. Morris, John C. Holtzman, David M. CA Dominantly Inherited Alzheimer Net TI Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer's Disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID MILD COGNITIVE IMPAIRMENT; CEREBROSPINAL-FLUID TAU; AMYLOID-BETA-PROTEIN; AUTOPSY-CONFIRMED DEMENTIA; QUALITY-CONTROL PROGRAM; A-BETA; PRESENILIN-1 MUTATION; LEWY BODIES; IN-VIVO; CLINICAL-DIAGNOSIS AB Clinicopathological evidence suggests that the pathology of Alzheimer's disease ( AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic ("preclinical") stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-beta(1-42) (A beta(1-42)) associated with the presence of Ab plaques, and elevated concentrations of CSF tau, ptau(181) (phosphorylated tau(181)), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials. C1 [Fagan, Anne M.; Bateman, Randall J.; Goate, Alison M.; Cairns, Nigel J.; Buckles, Virginia D.; Morris, John C.; Holtzman, David M.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Fagan, Anne M.; Xiong, Chengjie; Jasielec, Mateusz S.; Bateman, Randall J.; Goate, Alison M.; Benzinger, Tammie L. S.; Marcus, Daniel; Cairns, Nigel J.; Buckles, Virginia D.; Morris, John C.; Holtzman, David M.] Washington Univ, Sch Med, Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA. [Xiong, Chengjie; Jasielec, Mateusz S.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Goate, Alison M.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Benzinger, Tammie L. S.; Marcus, Daniel] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Ghetti, Bernardino] Indiana Univ, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. [Martins, Ralph N.] Edith Cowan Univ, WA Ctr Alzheimers Res & Care, Perth, WA 6009, Australia. [Masters, Colin L.] Univ Melbourne, Mental Hlth Res Inst, Melbourne, Vic 3052, Australia. [Mayeux, Richard] Columbia Univ, Taub Inst, Dept Neurol, New York, NY 10032 USA. [Mayeux, Richard] Columbia Univ, Sergievsky Ctr, New York, NY 10032 USA. [Ringman, John M.] Univ Calif Los Angeles, Mary S Easton Ctr Alzheimers Dis Res, Dept Neurol, Los Angeles, CA 90095 USA. [Rossor, Martin N.] UCL, Dementia Res Ctr, London WC1N 3BG, England. [Salloway, Stephen] Brown Univ, Butler Hosp, Warren Alpert Med Sch, Dept Neurol, Providence, RI 02906 USA. [Salloway, Stephen] Brown Univ, Butler Hosp, Warren Alpert Med Sch, Dept Psychiat, Providence, RI 02906 USA. [Schofield, Peter R.] Neurosci Res Australia, Sydney, NSW 2031, Australia. [Schofield, Peter R.] Univ New S Wales, Sch Med Sci, Sydney, NSW 2031, Australia. [Sperling, Reisa A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Brigham & Womens Hosp, Boston, MA 02129 USA. [Cairns, Nigel J.; Ladenson, Jack H.; Morris, John C.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. RP Fagan, AM (reprint author), Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. EM fagana@neuro.wustl.edu FU DIAN [U19 AG032438]; cooperative agreement grant [NCRAD U24 AG21886]; National Institute on Aging (NIA); DIAN Pharma Consortium FX Data collection and sharing for this project was supported by DIAN (U19 AG032438; to R.J.B., T.L.S. B., V.D.B., N.J.C., A.M.F., B.G., A.M.G., D.M.H., M.S.J., D.M., RN.M., C.L.M., R.M., J.C.M., J.M.R., M.N.R., S.S., P.R.S., R.A.S., and C.X.) and a cooperative agreement grant (NCRAD U24 AG21886) funded by the National Institute on Aging (NIA), the DIAN Pharma Consortium [Alzheimer's Immunotherapy Program (Janssen Alzheimer Immunotherapy and Pfizer Inc. Alliance), Biogen Idec Inc., Eisai Inc., Elan Pharmaceuticals Inc., Eli Lilly and Company, En Vivo Pharmaceuticals, Genentech Inc., F. Hoffman-La Roche Ltd., Mithridion Inc., Novartis International AG, Pfizer Inc., and Sanofi-Aventis Groupe] (to R.J.B., T.L.S.B., V.D.B., A.M.F., A.M.G., and C.X.), and in part by R01 EB009352 (to D.M.), P30 NS048056 (to D.M.), P50AG016750 (to J.M.R.), the National Institute for Health Research Queen Square Dementia Biomedical Research Unit (to M.N.R.), and the JO & JR Wicking Trust grants 13026 and 20821 (to P.R.S.). This article has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study presentations/publications. NR 103 TC 35 Z9 35 U1 2 U2 16 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 5 PY 2014 VL 6 IS 226 AR 226ra30 DI 10.1126/scitranslmed.3007901 PG 16 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AC6JV UT WOS:000332629500003 PM 24598588 ER PT J AU Veeraraghavalu, K Zhang, C Zhang, XQ Tanzi, RE Sisodia, SS AF Veeraraghavalu, Karthikeyan Zhang, Can Zhang, Xiaoqiong Tanzi, Rudolph E. Sisodia, Sangram S. TI Age-Dependent, Non-Cell-Autonomous Deposition of Amyloid from Synthesis of beta-Amyloid by Cells Other Than Excitatory Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE amyloid deposition; APP; dementia; mouse model; neurodegeneration; presenilin ID FAMILIAL ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; MUTANT PRESENILIN-1; MESSENGER-RNAS; EXPRESSION; LOCALIZATION; MODELS; BRAIN AB Rare, familial, early-onset autosomal dominant forms of familial Alzheimer's disease (FAD) are caused by mutations in genes encoding beta-amyloid (A beta) precursor protein (APP), presenilin-1 (PS1), and presenilin-2. Each of these genes is expressed ubiquitously throughout the CNS, but a widely held view is that excitatory neurons are the primary (or sole) source of the A beta peptides that promote synaptic dysfunction and neurodegeneration. These efforts notwithstanding, APP and the enzymes required for A beta production are synthesized by manyadditional cell types, and the degree to which those cells contribute to the production of A beta that drives deposition in the CNS has not been tested. We generated transgenic mice in which expression of an ubiquitously expressed, FAD-linked mutant PSEN1 gene was selectively inactivated within postnatal forebrain excitatory neurons, with continued synthesis in all other cells in the CNS. When combined with an additional transgene encoding an FAD-linked APP "Swedish" variant that is synthesized broadly within the CNS, cerebral A beta deposition during aging was found to be unaffected relative to mice with continued mutant PS1 synthesis in excitatory neurons. Thus, A beta accumulation is non-cell autonomous, with the primary age-dependent contribution to cerebral A beta deposition arising from mutant PS1-dependent cleavage of APP within cells other than excitatory neurons. C1 [Veeraraghavalu, Karthikeyan; Zhang, Xiaoqiong; Sisodia, Sangram S.] Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA. [Zhang, Can; Tanzi, Rudolph E.] Massachusetts Gen Hosp, Massachusetts Gen Inst Neurodegenerat Dis, Dept Neurol, Genet & Aging Res Unit, Charlestown, MA 02129 USA. [Zhang, Can; Tanzi, Rudolph E.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Sisodia, SS (reprint author), Univ Chicago, Dept Neurobiol, 947 East 58th St,AB 308, Chicago, IL 60637 USA. EM ssisodia@bsd.uchicago.edu FU National Institutes of Health [AG021494, AG027854]; Cure Alzheimer's Fund; Edward H. Levi Fund; Adler Foundation FX This work was supported by National Institutes of Health Grants AG021494 and AG027854 (S.S.S.), the Cure Alzheimer's Fund (S.S.S.), the Edward H. Levi Fund (K.V.), and the Adler Foundation (K.V., S.S.S.). We thank Dr. Vytas Bindokas, Microscopy Core Facility, for expert support with image analysis. NR 16 TC 8 Z9 10 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 5 PY 2014 VL 34 IS 10 BP 3668 EP 3673 DI 10.1523/JNEUROSCI.5079-13.2014 PG 6 WC Neurosciences SC Neurosciences & Neurology GA AC7HN UT WOS:000332698900020 PM 24599465 ER PT J AU Begum, G Yan, HQ Li, L Singh, A Dixon, CE Sun, D AF Begum, Gulnaz Yan, Hong Q. Li, Liaoliao Singh, Amneet Dixon, C. Edward Sun, Dandan TI Docosahexaenoic Acid Reduces ER Stress and Abnormal Protein Accumulation and Improves Neuronal Function Following Traumatic Brain Injury SO JOURNAL OF NEUROSCIENCE LA English DT Article DE amyloid precursor protein; controlled cortical impact injury; docosahexaenoic acid; phosphorylated tau; unfolded protein response ID ENDOPLASMIC-RETICULUM STRESS; DIFFUSE AXONAL INJURY; AMYLOID PRECURSOR PROTEIN; CORTICAL IMPACT MODEL; K+-CL-COTRANSPORTER; CELL-DEATH; CHEMICAL CHAPERONES; ASTROCYTES; ISCHEMIA; BETA AB In this study, we investigated the development of endoplasmic reticulum (ER) stress after traumatic brain injury (TBI) and the efficacy of post-TBI administration of docosahexaenoic acid (DHA) in reducing ER stress. TBI was induced by cortical contusion injury in Sprague-Dawley rats. Either DHA (16 mg/kg in DMSO) or vehicle DMSO (1 ml/kg) was administered intraperitoneally at 5 min after TBI, followed by a daily dose for 3-21 d. TBI triggered sustained expression of the ER stress marker proteins including phosphorylated eukaryotic initiation factor-2 alpha, activating transcription factor 4, inositol requiring kinase 1, and C/EBP homologous protein in the ipsilateral cortex at 3-21 d after TBI. The prolonged ER stress was accompanied with an accumulation of abnormal ubiquitin aggregates and increased expression of amyloid precursor protein (APP) and phosphorylated tau (p-Tau) in the frontal cortex after TBI. The ER stress marker proteins were colocalized with APP accumulation in the soma. Interestingly, administration of DHA attenuated all ER stress marker proteins and reduced the accumulation of both ubiquitinated proteins and APP/p-Tau proteins. In addition, the DHA-treated animals exhibited early recovery of their sensorimotor function after TBI. In summary, our study demonstrated that TBI induces a prolonged ER stress, which is positively correlated with abnormal APP accumulation. The sustained ER stress may play a role in chronic neuronal damage after TBI. Our findings illustrate that post-TBI administration of DHA has therapeutic potentials in reducing ER stress, abnormal protein accumulation, and neurological deficits. C1 [Begum, Gulnaz; Li, Liaoliao; Singh, Amneet; Sun, Dandan] Univ Pittsburgh, Brain Trauma Res Ctr, Dept Neurol, Pittsburgh, PA 15213 USA. [Yan, Hong Q.; Dixon, C. Edward] Univ Pittsburgh, Brain Trauma Res Ctr, Dept Neurosurg, Pittsburgh, PA 15213 USA. [Dixon, C. Edward; Sun, Dandan] Geriatr Res Educ & Clin Ctr, Vet Affairs Pittsburgh Hlth Care Syst, Pittsburgh, PA 15213 USA. RP Sun, D (reprint author), Univ Pittsburgh, Sch Med, Dept Neurol, S 598 S Biomedical Sci Tower,3500 Terrace St, Pittsburgh, PA 15213 USA. EM sund@upmc.edu FU University of Pittsburgh Neurology Departmental startup funds; University of Pittsburgh Medical Center endowed Chair Professorship on Brain Disorder Diseases; United States Department of Veterans Affairs VA RRD [B6761R] FX This work was supported in part by University of Pittsburgh Neurology Departmental startup funds and University of Pittsburgh Medical Center endowed Chair Professorship on Brain Disorder Diseases (D.S.) and the United States Department of Veterans Affairs VA RR&D#B6761R Grant (C.E.D.). NR 70 TC 24 Z9 27 U1 1 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 5 PY 2014 VL 34 IS 10 BP 3743 EP 3755 DI 10.1523/JNEUROSCI.2872-13.2014 PG 13 WC Neurosciences SC Neurosciences & Neurology GA AC7HN UT WOS:000332698900027 PM 24599472 ER PT J AU Heck, A Fastenrath, M Ackermann, S Auschra, B Bickel, H Coynel, D Gschwind, L Jessen, F Kaduszkiewicz, H Maier, W Milnik, A Pentzek, M Riedel-Heller, SG Ripke, S Spalek, K Sullivan, P Vogler, C Wagner, M Weyerer, S Wolfsgruber, S de Quervain, DJF Papassotiropoulos, A AF Heck, Angela Fastenrath, Matthias Ackermann, Sandra Auschra, Bianca Bickel, Horst Coynel, David Gschwind, Leo Jessen, Frank Kaduszkiewicz, Hanna Maier, Wolfgang Milnik, Annette Pentzek, Michael Riedel-Heller, Steffi G. Ripke, Stephan Spalek, Klara Sullivan, Patrick Vogler, Christian Wagner, Michael Weyerer, Siegfried Wolfsgruber, Steffen de Quervain, Dominique J. -F. Papassotiropoulos, Andreas TI Converging Genetic and Functional Brain Imaging Evidence Links Neuronal Excitability to Working Memory, Psychiatric Disease, and Brain Activity SO NEURON LA English DT Article ID GENOME-WIDE ASSOCIATION; BIPOLAR DISORDER; SET ANALYSIS; RISK LOCI; SCHIZOPHRENIA; SYSTEM; CEREBELLUM; REGISTRATION; CIRCUITRY; COGNITION AB Working memory, the capacity of actively maintaining task-relevant information during a cognitive task, is a heritable trait. Working memory deficits are characteristic for many psychiatric disorders. We performed genome-wide gene set enrichment analyses in multiple independent data sets of young and aged cognitively healthy subjects (n = 2,824) and in a large schizophrenia case-control sample (n = 32,143). The voltage-gated cation channel activity gene set, consisting of genes related to neuronal excitability, was robustly linked to performance in working memory-related tasks across ages and to schizophrenia. Functional brain imaging in 707 healthy participants linked this gene set also to working memory-related activity in the parietal cortex and the cerebellum. Gene set analyses may help to dissect the molecular underpinnings of cognitive dimensions, brain activity, and psychopathology. C1 [Heck, Angela; Fastenrath, Matthias; Ackermann, Sandra; Auschra, Bianca; Coynel, David; Gschwind, Leo; Milnik, Annette; Vogler, Christian; Weyerer, Siegfried; Papassotiropoulos, Andreas] Univ Basel, Dept Psychol, Div Mol Neurosci, CH-4055 Basel, Switzerland. [Heck, Angela; Milnik, Annette; Vogler, Christian; de Quervain, Dominique J. -F.; Papassotiropoulos, Andreas] Univ Basel, Dept Psychol, Psychiat Univ Clin, CH-4055 Basel, Switzerland. [Fastenrath, Matthias; Coynel, David; Gschwind, Leo; Spalek, Klara; de Quervain, Dominique J. -F.] Univ Basel, Dept Psychol, Div Cognit Neurosci, CH-4055 Basel, Switzerland. [Bickel, Horst] Tech Univ Munich, Dept Psychiat, D-85748 Munich, Germany. [Jessen, Frank; Maier, Wolfgang; Wagner, Michael; Wolfsgruber, Steffen] Univ Bonn, Dept Psychiat, D-53105 Bonn, Germany. [Jessen, Frank; Maier, Wolfgang; Wagner, Michael; Wolfsgruber, Steffen] German Ctr Neurogenerat Dis, DZNE, D-53105 Bonn, Germany. [Kaduszkiewicz, Hanna] Univ Med Ctr Hamburg Eppendorf, Ctr Psychosocial Med, Dept Primary Med Care, D-20246 Hamburg, Germany. [Pentzek, Michael] Univ Dusseldorf, Fac Med, Inst Gen Practice, D-40225 Dusseldorf, Germany. [Riedel-Heller, Steffi G.] Univ Leipzig, Fac Med, Inst Social Med Occupat Hlth & Publ Hlth, D-04103 Leipzig, Germany. [Ripke, Stephan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Sullivan, Patrick] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Weyerer, Siegfried] Cent Inst Mental Hlth, D-68159 Mannheim, Germany. [Papassotiropoulos, Andreas] Univ Basel, Dept Biozentrum, Life Sci Training Facil, CH-4056 Basel, Switzerland. [Papassotiropoulos, Andreas] Univ Basel, Transfac Res Platform, CH-4012 Basel, Switzerland. RP Heck, A (reprint author), Univ Basel, Dept Psychol, Div Mol Neurosci, CH-4055 Basel, Switzerland. EM angela.heck@unibas.ch; andreas.papas@unibas.ch RI Wagner, Michael/E-2325-2011; OI Wagner, Michael/0000-0003-2589-6440; Coynel, David/0000-0001-5028-5807; Milnik, Annette/0000-0002-3933-3289 FU Swiss National Science Foundation [CRSI33_130080]; European Union [HEALTH-F4-2009-242257]; National Center for Competence in Research SYNAPSY; German Research Network on Dementia (KND); German Research Network on Degenerative Dementia (KNDD), German Federal Ministry of Education and Research [01GI0420, 01GI0711] FX We thank Elmar Merkle, Christoph Stippich, and Oliver Bieri for granting access to the fMRI facilities of the University Hospital Basel. This work was funded by the Swiss National Science Foundation (Sinergia grant CRSI33_130080 to D.J.-F.d.Q. and A.P.), by the 7th framework programme of the European Union (ADAMS project, HEALTH-F4-2009-242257), by the National Center for Competence in Research SYNAPSY, and by the German Research Network on Dementia (KND) and the German Research Network on Degenerative Dementia (KNDD), German Federal Ministry of Education and Research grants 01GI0420 and 01GI0711. NR 51 TC 28 Z9 28 U1 2 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD MAR 5 PY 2014 VL 81 IS 5 BP 1203 EP 1213 DI 10.1016/j.neuron.2014.01.010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA AC4YH UT WOS:000332526700021 PM 24529980 ER PT J AU Neuille, M El Shamieh, S Orhan, E Michiels, C Antonio, A Lancelot, ME Condroyer, C Bujakowska, K Poch, O Sahel, JA Audo, I Zeitz, C AF Neuille, Marion El Shamieh, Said Orhan, Elise Michiels, Christelle Antonio, Aline Lancelot, Marie-Elise Condroyer, Christel Bujakowska, Kinga Poch, Olivier Sahel, Jose-Alain Audo, Isabelle Zeitz, Christina TI Lrit3 Deficient Mouse (nob6): A Novel Model of Complete Congenital Stationary Night Blindness (cCSNB) SO PLOS ONE LA English DT Article ID RICH REPEAT PROTEIN; METABOTROPIC GLUTAMATE-RECEPTOR; OPTICAL COHERENCE TOMOGRAPHY; ROD BIPOLAR CELLS; CGMP PHOSPHODIESTERASE; SYNAPTIC-TRANSMISSION; RETINAL DEGENERATION; MAMMALIAN RETINA; LIGHT RESPONSE; BETA-SUBUNIT AB Mutations in LRIT3, coding for a Leucine-Rich Repeat, immunoglobulin-like and transmembrane domains 3 protein lead to autosomal recessive complete congenital stationary night blindness (cCSNB). The role of the corresponding protein in the ON-bipolar cell signaling cascade remains to be elucidated. Here we genetically and functionally characterize a commercially available Lrit3 knock-out mouse, a model to study the function and the pathogenic mechanism of LRIT3. We confirm that the insertion of a Bgeo/Puro cassette in the knock-out allele introduces a premature stop codon, which presumably codes for a non-functional protein. The mouse line does not harbor other mutations present in common laboratory mouse strains or in other known cCSNB genes. Lrit3 mutant mice exhibit a so-called no b-wave (nob) phenotype with lacking or severely reduced b-wave amplitudes in the scotopic and photopic electroretinogram (ERG), respectively. Optomotor tests reveal strongly decreased optomotor responses in scotopic conditions. No obvious fundus auto-fluorescence or histological retinal structure abnormalities are observed. However, spectral domain optical coherence tomography (SD-OCT) reveals thinned inner nuclear layer and part of the retina containing inner plexiform layer, ganglion cell layer and nerve fiber layer in these mice. To our knowledge, this is the first time that SD-OCT technology is used to characterize an animal model for CSNB. This phenotype is noted at 6 weeks and at 6 months. The stationary nob phenotype of mice lacking Lrit3, which we named nob6, confirms the findings previously reported in patients carrying LRIT3 mutations and is similar to other cCSNB mouse models. This novel mouse model will be useful for investigating the pathogenic mechanism(s) associated with LRIT3 mutations and clarifying the role of LRIT3 in the ON-bipolar cell signaling cascade. C1 [Neuille, Marion; El Shamieh, Said; Orhan, Elise; Michiels, Christelle; Antonio, Aline; Lancelot, Marie-Elise; Condroyer, Christel; Bujakowska, Kinga; Sahel, Jose-Alain; Audo, Isabelle; Zeitz, Christina] INSERM, U968, Paris, France. [Neuille, Marion; El Shamieh, Said; Orhan, Elise; Michiels, Christelle; Antonio, Aline; Lancelot, Marie-Elise; Condroyer, Christel; Bujakowska, Kinga; Sahel, Jose-Alain; Audo, Isabelle; Zeitz, Christina] CNRS, UMR 7210, Paris, France. [Neuille, Marion; El Shamieh, Said; Orhan, Elise; Michiels, Christelle; Antonio, Aline; Lancelot, Marie-Elise; Condroyer, Christel; Bujakowska, Kinga; Sahel, Jose-Alain; Audo, Isabelle; Zeitz, Christina] Univ Paris 06, Univ Sorbonne, UMR S 968, Inst Vis, Paris, France. [Antonio, Aline; Sahel, Jose-Alain; Audo, Isabelle] Ctr Hosp Natl Ophtalmol Quinze Vingts, INSERM DHOS CIC 503, Paris, France. [Bujakowska, Kinga] Massachusetts Eye & Ear Infirm, Ocular Genom Inst, Boston, MA 02114 USA. [Poch, Olivier] CNRS, UMR 7357, ICube, Lab Bioinformat Integrat & Genom, Strasbourg, France. [Sahel, Jose-Alain; Audo, Isabelle] UCL, Inst Ophthalmol, London, England. [Sahel, Jose-Alain] Fdn Ophtalmol Adolphe Rothschild, Paris, France. [Sahel, Jose-Alain] Acad Sci Inst France, Paris, France. RP Zeitz, C (reprint author), INSERM, U968, Paris, France. EM christina.zeitz@inserm.fr RI Zeitz, Christina/F-2757-2017; Sahel, Jose-Alain/F-3172-2017; OI El Shamieh, Said/0000-0002-8522-0445 FU Agence Nationale de la Recherche [ANR-12-BSVS1-0012-01_GPR179]; Foundation Voir et Entendre; Prix Dalloz for "la recherche en ophtalmologie''; Fondation pour la Recherche Medicale (FRM); Fondation Roland Bailly; Ville de Paris; Region Ile de France; Agence Nationale de la Recherche within the Investissements d'Avenir programme [ANR-11-IDEX-0004-0]; Foundation Fighting Blindness center grant [C-CMM-0907-0428-INSERM04] FX The project was supported by Agence Nationale de la Recherche [ANR-12-BSVS1-0012-01_GPR179] (CZ), Foundation Voir et Entendre (CZ), Prix Dalloz for "la recherche en ophtalmologie'' (CZ), The Fondation pour la Recherche Medicale (FRM) in partnership with the Fondation Roland Bailly (CZ), Ville de Paris and Region Ile de France, LABEX LIFESENSES [reference ANR-10-LABX-65] supported by French state funds managed by the Agence Nationale de la Recherche within the Investissements d'Avenir programme [ANR-11-IDEX-0004-0], Foundation Fighting Blindness center grant [C-CMM-0907-0428-INSERM04]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 17 Z9 17 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 5 PY 2014 VL 9 IS 3 AR e90342 DI 10.1371/journal.pone.0090342 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC4GP UT WOS:000332479400065 PM 24598786 ER PT J AU Volpp, KG Galvin, R AF Volpp, Kevin G. Galvin, Robert TI Reward-Based Incentives for Smoking Cessation How a Carrot Became a Stick SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID FINANCIAL INCENTIVES C1 [Volpp, Kevin G.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Volpp, Kevin G.] Univ Penn, Leonard Davis Inst Hlth Econ, Ctr Hlth Incent & Behav Econ, Philadelphia, PA 19104 USA. [Galvin, Robert] Equ Healthcare, Blackstone Grp, Philadelphia, PA USA. [Galvin, Robert] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. RP Volpp, KG (reprint author), Univ Penn, Perelman Sch Med, Ctr Hlth Incent & Behav Econ, 423 Guardian Dr,1120 Blockley Hall, Philadelphia, PA 19104 USA. EM volpp70@wharton.upenn.edu FU NIA NIH HHS [P30 AG034546] NR 7 TC 13 Z9 13 U1 4 U2 10 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 5 PY 2014 VL 311 IS 9 BP 909 EP 910 DI 10.1001/jama.2014.418 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AC0FS UT WOS:000332170800015 PM 24493405 ER PT J AU Neuhaus, V Menendez, M Kurylo, JC Dyer, GS Jawa, A Ring, D AF Neuhaus, Valentin Menendez, Mariano Kurylo, John C. Dyer, George S. Jawa, Andrew Ring, David TI Risk Factors for Fracture Mobility Six Weeks After Initiation of Brace Treatment of Mid-Diaphyseal Humeral Fractures SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID SHAFT FRACTURES; FUNCTIONAL TREATMENT; NONUNION AB Background: Recent studies have identified specific subsets of diaphyseal humeral fractures for which functional bracing is less effective. The present study tested the hypothesis that a gap between fracture fragments may be a risk factor (after accounting for other potential risk factors) for fracture instability six weeks after functional bracing of humeral shaft fractures. Methods: We retrospectively identified seventy-nine adult patients (forty-six men, thirty-three women; forty-two fractures on the right side, thirty-seven fractures on the left), each with an acute, closed, AO type-A2 (oblique, >= 30 degrees) or type-A3 (transverse, <30 degrees) mid-diaphyseal humeral shaft fracture treated nonoperatively at three different level-I trauma centers from June 2004 to August 2011. The gap between the fracture fragments was measured on the first radiographs made after the affected upper extremity was placed in a brace. Results: Sixty-three patients (80%) had documented healing of the fracture. Sixteen patients (20%) had motion at the fracture site and a persistent fracture line shown on radiographs six weeks or more after injury. In multivariable analysis, each millimeter of gap between the main fragments with the patient wearing the brace (odds ratio [OR] = 1.4, 95% confidence interval [CI] = 1.1 to 1.7), smoking (OR = 5.8,95% CI = 1.4 to 25), and female sex (OR = 5.3,95% CI = 1.2 to 23) increased the risk of fracture instability six weeks after injury (R-2 = 0.38, area under the receiver operating characteristic [ROC] curve = 0.81). Conclusions: The magnitude of the gap between the fracture fragments is an independent risk factor for fracture instability and the lack of a bridging callus six weeks after a diaphyseal humeral fracture. C1 [Neuhaus, Valentin; Menendez, Mariano; Ring, David] Massachusetts Gen Hosp, Dept Orthopaed Surg, Hand & Upper Extrem Serv, Yawkey Ctr, Boston, MA 02114 USA. [Kurylo, John C.; Jawa, Andrew] Shapiro Ambulatory Care Ctr, Boston Med Ctr, Dept Orthopaed Surg, Boston, MA 02118 USA. [Dyer, George S.] Brigham & Womens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. RP Neuhaus, V (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Hand & Upper Extrem Serv, Yawkey Ctr, 55 Fruit St,Suite 2100, Boston, MA 02114 USA. EM dring@partners.org OI Neuhaus, Valentin/0000-0003-4012-5628 NR 22 TC 1 Z9 1 U1 0 U2 0 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 5 PY 2014 VL 96A IS 5 BP 403 EP 407 DI 10.2106/JBJS.M.00089 PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AC3RY UT WOS:000332440100008 PM 24599202 ER PT J AU Sacks, FM Hermans, MP Fioretto, P Valensi, P Davis, T Horton, E Wanner, C Al-Rubeaan, K Aronson, R Barzon, I Bishop, L Bonora, E Bunnag, P Chuang, LM Deerochanawong, C Goldenberg, R Harshfield, B Hernandez, C Herzlinger-Botein, S Itoh, H Jia, WP Jiang, YD Kadowaki, T Laranjo, N Leiter, L Miwa, T Odawara, M Ohashi, K Ohno, A Pan, CY Pan, J Pedro-Botet, J Reiner, Z Rotella, CM Simo, R Tanaka, M Tedeschi-Reiner, E Twum-Barima, D Zoppini, G Carey, VJ AF Sacks, Frank M. Hermans, Michel P. Fioretto, Paola Valensi, Paul Davis, Timothy Horton, Edward Wanner, Christoph Al-Rubeaan, Khalid Aronson, Ronnie Barzon, Isabella Bishop, Louise Bonora, Enzo Bunnag, Pongamorn Chuang, Lee-Ming Deerochanawong, Chaicharn Goldenberg, Ronald Harshfield, Benjamin Hernandez, Cristina Herzlinger-Botein, Susan Itoh, Hiroshi Jia, Weiping Jiang, Yi-Der Kadowaki, Takashi Laranjo, Nancy Leiter, Lawrence Miwa, Takashi Odawara, Masato Ohashi, Ken Ohno, Atsushi Pan, Changyu Pan, Jiemin Pedro-Botet, Juan Reiner, Zeljko Rotella, Carlo Maria Simo, Rafael Tanaka, Masami Tedeschi-Reiner, Eugenia Twum-Barima, David Zoppini, Giacomo Carey, Vincent J. TI Association Between Plasma Triglycerides and High-Density Lipoprotein Cholesterol and Microvascular Kidney Disease and Retinopathy in Type 2 Diabetes Mellitus A Global Case-Control Study in 13 Countries SO CIRCULATION LA English DT Article DE diabetes mellitus; diabetic retinopathy; epidemiology; kidney; lipids; risk factors ID INDEPENDENT RISK-FACTOR; CARDIOVASCULAR-DISEASE; MACULAR EDEMA; SERUM-LIPIDS; ATHEROSCLEROSIS RISK; APOLIPOPROTEIN-CIII; RENAL DYSFUNCTION; HARD EXUDATE; PROGRESSION; HYPERTRIGLYCERIDEMIA AB Background Microvascular renal and retinal diseases are common major complications of type 2 diabetes mellitus. The relation between plasma lipids and microvascular disease is not well established. Methods and Results The case subjects were 2535 patients with type 2 diabetes mellitus with an average duration of 14 years, 1891 of whom had kidney disease and 1218 with retinopathy. The case subjects were matched for diabetes mellitus duration, age, sex, and low-density lipoprotein cholesterol to 3683 control subjects with type 2 diabetes mellitus who did not have kidney disease or retinopathy. The study was conducted in 24 sites in 13 countries. The primary analysis included kidney disease and retinopathy cases. Matched analysis was performed by use of site-specific conditional logistic regression in multivariable models that adjusted for hemoglobin A(1c), hypertension, and statin treatment. Mean low-density lipoprotein cholesterol concentration was 2.3 mmol/L. The microvascular disease odds ratio increased by a factor of 1.16 (95% confidence interval, 1.11-1.22) for every 0.5 mmol/L (approximate to 1 quintile) increase in triglycerides or decreased by a factor of 0.92 (0.88-0.96) for every 0.2 mmol/L (approximate to 1 quintile) increase in high-density lipoprotein cholesterol. For kidney disease, the odds ratio increased by 1.23 (1.16-1.31) with triglycerides and decreased by 0.86 (0.82-0.91) with high-density lipoprotein cholesterol. Retinopathy was associated with triglycerides and high-density lipoprotein cholesterol in matched analysis but not significantly after additional adjustment. Conclusions Diabetic kidney disease is associated worldwide with higher levels of plasma triglycerides and lower levels of high-density lipoprotein cholesterol among patients with good control of low-density lipoprotein cholesterol. Retinopathy was less robustly associated with these lipids. These results strengthen the rationale for studying dyslipidemia treatment to prevent diabetic microvascular disease. C1 [Sacks, Frank M.; Bishop, Louise] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hermans, Michel P.] Catholic Univ Louvain, Clin Univ St Luc, B-1200 Brussels, Belgium. [Fioretto, Paola; Barzon, Isabella] Univ Padua, Dept Med, Padua, Italy. [Valensi, Paul] Univ Paris Nord, Ctr Rech Nutr Humaine Ille France, Jean Verdier Hosp, Dept Endocrinol Diabetol Nutr,AP HP, Bondy, France. [Davis, Timothy] Univ Western Australia, Crawley, Australia. [Horton, Edward; Herzlinger-Botein, Susan] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Wanner, Christoph] Univ Wurzburg, D-97070 Wurzburg, Germany. [Al-Rubeaan, Khalid] King Saud Univ, Coll Med, Riyadh 11461, Saudi Arabia. [Aronson, Ronnie] LMC Diabet & Endocrinol, Toronto, ON, Canada. [Bonora, Enzo; Zoppini, Giacomo] Univ Verona, Dept Med, Endocrinol Sect, I-37100 Verona, Italy. [Bunnag, Pongamorn] Ramathibodi Hosp, Bangkok, Thailand. [Chuang, Lee-Ming; Jiang, Yi-Der] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan. [Deerochanawong, Chaicharn] Rajavithi Hosp, Rangsit Sch Med, Bangkok, Thailand. [Goldenberg, Ronald] North York Gen Hosp, Toronto, ON, Canada. [Goldenberg, Ronald] LMC Diabet Ctr, Toronto, ON, Canada. [Goldenberg, Ronald] Endocrinol Ctr, Toronto, ON, Canada. [Harshfield, Benjamin; Laranjo, Nancy; Carey, Vincent J.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Hernandez, Cristina; Simo, Rafael] CIBERDEM, Barcelona, Spain. [Hernandez, Cristina; Simo, Rafael] Vall dHebron Res Inst, Barcelona, Spain. [Itoh, Hiroshi; Tanaka, Masami] Keio Univ, Sch Med, Tokyo, Japan. [Jia, Weiping] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai Diabet Inst, Shanghai Clin Ctr Diabet, Shanghai 200030, Peoples R China. [Kadowaki, Takashi] Univ Tokyo, Dept Diabet & Metab Dis, Tokyo, Japan. [Leiter, Lawrence] Univ Toronto, Toronto, ON, Canada. [Miwa, Takashi; Odawara, Masato] Tokyo Med Univ, Tokyo 1608402, Japan. [Ohashi, Ken] Natl Canc Ctr, Dept Gen Internal Med, Tokyo, Japan. [Ohno, Atsushi] Tokyo Med Univ, Hachioji Med Ctr, Tokyo 1608402, Japan. [Pan, Changyu] Beijing 301 Mil Hosp, Beijing, Peoples R China. [Pan, Jiemin] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Endocrinol & Metab, Shanghai 200030, Peoples R China. [Pedro-Botet, Juan] Univ Autonoma Barcelona, Hosp del Mar, E-08193 Barcelona, Spain. [Reiner, Zeljko] Univ Zagreb, Univ Hosp Ctr Zagreb Sch Med, Dept Internal Med, Zagreb 41000, Croatia. [Rotella, Carlo Maria] Univ Florence, Dept Clin Pathophysiol, Endocrinol Sect, Florence, Italy. [Tedeschi-Reiner, Eugenia] Univ Hosp Sestre Milosrdnice, Dept Ophthalmol, Zagreb, Croatia. [Twum-Barima, David] LMC Diabet & Endocrinol, Oakville, ON, Canada. RP Sacks, FM (reprint author), Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM fsacks@hsph.harvard.edu RI Davis, Timothy/M-5144-2014; Fernandez , Irene/E-5705-2016; OI Rotella, Carlo Maria/0000-0001-9462-2334; BONORA, Enzo/0000-0003-1074-5164; CHUANG, LEE-MING/0000-0003-0978-2662; Simo Canonge, Rafael/0000-0003-0475-3096 FU R3i (Residual Risk Reduction Institute) Foundation grant FX This study was funded by an R3i (Residual Risk Reduction Institute) Foundation grant to Brigham and Women's Hospital and Harvard School of Public Health and to the individual study sites. The sponsor provided logistical support to the sites and the coordinating center. NR 50 TC 44 Z9 48 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 4 PY 2014 VL 129 IS 9 BP 999 EP 1008 DI 10.1161/CIRCULATIONAHA.113.002529 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AB9UF UT WOS:000332140500012 PM 24352521 ER PT J AU Corato, M De Nittis, P Trenti, N Paganoni, S AF Corato, Manuel De Nittis, Pasquale Trenti, Nicoletta Paganoni, Sabrina TI Teaching NeuroImages: Median nerve MRI changes over time in neuralgic amyotrophy SO NEUROLOGY LA English DT Editorial Material AB A 40-year-old woman presented with 2 weeks of left arm pain followed by hand weakness and numbness. Electrodiagnostic testing revealed an isolated median sensorimotor axonopathy localizing proximal to the pronator teres. The working diagnosis of a forme fruste of neuralgic amyotrophy was made. MRI of the left arm was performed to exclude rare structural causes of proximal median neuropathy. The median nerve showed inflammatory features with a diffusely increased signal on short tau inversion recovery sequences that enhanced with gadolinium (figure, A). Two years after onset, symptoms had resolved. Repeat MRI showed resolution of the abnormal findings (figure, B). C1 [Corato, Manuel] Ist Clin Humanitas IRCCS, Emergency Neurol & Stroke Unit, Rozzano, Italy. [De Nittis, Pasquale] Ist Clin Humanitas IRCCS, Ultrasound Unit, Dept Diagnost Imaging, Rozzano, Italy. [Trenti, Nicoletta] Ist Clin Humanitas IRCCS, Dept Radiol, Rozzano, Italy. [Paganoni, Sabrina] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Paganoni, Sabrina] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [Paganoni, Sabrina] VA Boston Healthcare Syst, Boston, MA USA. RP Paganoni, S (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM spaganoni@partners.org NR 0 TC 2 Z9 2 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAR 4 PY 2014 VL 82 IS 9 BP E79 EP E79 DI 10.1212/WNL.0000000000000171 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AG9OD UT WOS:000335748100003 PM 24590253 ER PT J AU de Luca, A Smeekens, SP Casagrande, A Iannitti, R Conway, KL Gresnigt, MS Begun, J Plantinga, TS Joosten, LAB van der Meer, JWM Chamilos, G Netea, MG Xavier, RJ Dinarello, CA Romani, L van de Veerdonk, FL AF de Luca, Antonella Smeekens, Sanne P. Casagrande, Andrea Iannitti, Rossana Conway, Kara L. Gresnigt, Mark. S. Begun, Jakob Plantinga, Theo S. Joosten, Leo A. B. van der Meer, Jos W. M. Chamilos, Georgios Netea, Mihai G. Xavier, Ramnik J. Dinarello, Charles A. Romani, Luigina van de Veerdonk, Frank L. TI IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE interleukin-1; S. aureus; LPS; Crohn disease; autoinflammatory disease ID CROHNS-DISEASE; IL-1-BETA PRODUCTION; NADPH OXIDASES; ACTIVATION; COLITIS; CELLS; INTERLEUKIN-1-BETA; SUSCEPTIBILITY; COMPLICATIONS; DYSFUNCTION AB Patients with chronic granulomatous disease (CGD) have a mutated NADPH complex resulting in defective production of reactive oxygen species; these patients can develop severe colitis and are highly susceptible to invasive fungal infection. In NADPH oxidase-deficient mice, autophagy is defective but inflammasome activation is present despite lack of reactive oxygen species production. However, whether these processes are mutually regulated in CGD and whether defective autophagy is clinically relevant in patients with CGD is unknown. Here, we demonstrate that macrophages from CGD mice and blood monocytes from CGD patients display minimal recruitment of microtubule-associated protein 1 light chain 3 (LC3) to phagosomes. This defect in autophagy results in increased IL-1 beta release. Blocking IL-1 with the receptor antagonist (anakinra) decreases neutrophil recruitment and T helper 17 responses and protects CGD mice from colitis and also from invasive aspergillosis. In addition to decreased inflammasome activation, anakinra restored autophagy in CGD mice in vivo, with increased Aspergillus-induced LC3 recruitment and increased expression of autophagy genes. Anakinra also increased Aspergillus-induced LC3 recruitment from 23% to 51% (P < 0.01) in vitro in monocytes from CGD patients. The clinical relevance of these findings was assessed by treating CGD patients who had severe colitis with IL-1 receptor blockade using anakinra. Anakinra treatment resulted in a rapid and sustained improvement in colitis. Thus, inflammation in CGD is due to IL-1-dependent mechanisms, such as decreased autophagy and increased inflammasome activation, which are linked pathological conditions in CGD that can be restored by IL-1 receptor blockade. C1 [de Luca, Antonella; Casagrande, Andrea; Iannitti, Rossana; Romani, Luigina] Univ Perugia, Dept Expt Med & Biochem Sci, I-06122 Perugia, Italy. [Smeekens, Sanne P.; Gresnigt, Mark. S.; Plantinga, Theo S.; Joosten, Leo A. B.; van der Meer, Jos W. M.; Netea, Mihai G.; Dinarello, Charles A.; van de Veerdonk, Frank L.] Radboud Univ Nijmegen, Med Ctr, Dept Med, NL-6500 HB Nijmegen, Netherlands. [Smeekens, Sanne P.; Gresnigt, Mark. S.; Plantinga, Theo S.; Joosten, Leo A. B.; van der Meer, Jos W. M.; Netea, Mihai G.; Dinarello, Charles A.; van de Veerdonk, Frank L.] Nijmegen Inst Infect Inflammat & Immun, NL-6500 HB Nijmegen, Netherlands. [Conway, Kara L.; Begun, Jakob; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Conway, Kara L.; Begun, Jakob; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Chamilos, Georgios] Univ Crete, Dept Internal Med, Iraklion 71003, Crete, Greece. [Chamilos, Georgios] Fdn Res & Technol, Inst Mol Biol & Biotechnol, Iraklion 71003, Crete, Greece. [Xavier, Ramnik J.; Dinarello, Charles A.] Univ Colorado Denver, Div Infect Dis, Aurora, CO 80045 USA. [van de Veerdonk, Frank L.] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA. RP Dinarello, CA (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Med, NL-6500 HB Nijmegen, Netherlands. EM cdinarello@mac.com; f.veerdonk@aig.umcn.nl RI Smeekens, Sanne/G-8307-2011; Begun, Jakob/J-6793-2014; Plantinga, Theo/A-6895-2015; Joosten, Leo/H-3138-2015; Gresnigt, Mark/H-3530-2015; van de Veerdonk, Frank/C-7256-2008; Netea, Mihai/N-5155-2014; van der Meer, Jos/C-8521-2013; OI Romani, Luigina/0000-0002-1356-525X; Smeekens, Sanne/0000-0002-7835-914X; Begun, Jakob/0000-0001-5256-7672; Gresnigt, Mark/0000-0002-9514-4634; van de Veerdonk, Frank/0000-0002-1121-4894; van der Meer, Jos/0000-0001-5120-3690; DE LUCA, ANTONELLA/0000-0002-6866-5530 FU Veni grant of the Netherlands Organization for Scientific Research; Vici grant; European Union's Seventh Framework Programme [ERC-2011-AdG-293714]; National Institutes of Health (NIH) [DK-83756, AI-62773, DK-60049, DK-43351, AI-15614] FX This study was supported by a Veni grant of the Netherlands Organization for Scientific Research (to F.L.v.d.V.) and a Vici grant (to M.G.N.). It was also supported by the European Union's Seventh Framework Programme Agreement ERC-2011-AdG-293714 [metabolomics of fungal diseases: a systems biology approach for biomarkers discovery and therapy (FUNMETA)] (to L. R.) and by National Institutes of Health (NIH) Grants DK-83756, AI-62773, DK-60049, and DK-43351 (to R.J.X.) and NIH Grant AI-15614 (to C.A.D.). NR 45 TC 62 Z9 62 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 4 PY 2014 VL 111 IS 9 BP 3526 EP 3531 DI 10.1073/pnas.1322831111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AC5KR UT WOS:000332560300074 PM 24550444 ER PT J AU Rittling, SR Wejse, PL Yagiz, K Warot, GA Hui, T AF Rittling, S. R. Wejse, P. L. Yagiz, K. Warot, G. A. Hui, T. TI Suppression of tumour growth by orally administered osteopontin is accompanied by alterations in tumour blood vessels SO BRITISH JOURNAL OF CANCER LA English DT Article ID ENZYME-INHIBITORY PEPTIDES; IN-VITRO; INTEGRIN ALPHA-9-BETA-1; MICE LACKING; HUMAN-MILK; ANGIOGENESIS; CILENGITIDE; CANCER; CELLS; GLIOBLASTOMA AB Background: The integrin-binding protein osteopontin is strongly associated with tumour development, yet is an abundant dietary component as a constituent of human and bovine milk. Therefore, we tested the effect of orally administered osteopontin (o-OPN) on the development of subcutaneous tumours in mice. Methods: Bovine milk osteopontin was administered in drinking water to tumour-bearing immune-competent mice. Tumour growth, proliferation, necrosis, apoptosis and blood vessel size and number were measured. Expression of the alpha(9) integrin was determined. Results: o-OPN suppressed tumour growth, increased the extent of necrosis, and induced formation of abnormally large blood vessels. Anti-OPN reactivity detected in the plasma of OPN-null mice fed OPN suggested that tumour-blocking peptides were absorbed during digestion, but the o-OPN effect was likely distinct from that of an RGD peptide. Expression of the alpha(9) integrin was detected on both tumour cells and blood vessels. Potential active peptides from the alpha(9) binding site of OPN were identified by mass spectrometry following in vitro digestion, and injection of these peptides suppressed tumour growth. Conclusions: These results suggest that peptides derived from o-OPN are absorbed and interfere with tumour growth and normal vessel development. o-OPN-derived peptides that target the alpha(9) integrin are likely involved. C1 [Rittling, S. R.; Yagiz, K.; Warot, G. A.; Hui, T.] Forsyth Inst, Cambridge, MA 02412 USA. [Wejse, P. L.] Arla Foods Ingredients Grp PS, DK-8260 Viby J, Denmark. RP Rittling, SR (reprint author), Forsyth Inst, 245 First St, Cambridge, MA 02412 USA. EM srittling@forsyth.org FU Arla Foods Ingredients FX We thank Esben Sorensen for the gift of anti-OPN antibodies, Toshimitsu Uede for the gift of the alpha9 antibody and Simon Goodman for critical reading of the manuscript. The Cilengitide was generously provided by Merck KgaA and the CTEP, National Cancer Institute, NIH. We appreciate technical assistance by Hannah McLeod, Eva Xia and Carolina Brettler. This work was supported by grants from Arla Foods Ingredients. NR 51 TC 3 Z9 3 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD MAR 4 PY 2014 VL 110 IS 5 BP 1269 EP 1277 DI 10.1038/bjc.2014.10 PG 9 WC Oncology SC Oncology GA AC9EB UT WOS:000332836000021 PM 24473400 ER PT J AU de Koning, HJ Meza, R Plevritis, SK ten Haaf, K Munshi, VN Jeon, J Erdogan, SA Kong, CY Han, SS van Rosmalen, J Choi, SE Pinsky, PF de Gonzalez, AB Berg, CD Black, WC Tammemagi, MC Hazelton, WD Feuer, EJ McMahon, PM AF de Koning, Harry J. Meza, Rafael Plevritis, Sylvia K. ten Haaf, Kevin Munshi, Vidit N. Jeon, Jihyoun Erdogan, Saadet Ayca Kong, Chung Yin Han, Summer S. van Rosmalen, Joost Choi, Sung Eun Pinsky, Paul F. de Gonzalez, Amy Berrington Berg, Christine D. Black, William C. Tammemaegi, Martin C. Hazelton, William D. Feuer, Eric J. McMahon, Pamela M. TI Benefits and Harms of Computed Tomography Lung Cancer Screening Strategies: A Comparative Modeling Study for the US Preventive Services Task Force SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID LOW-DOSE CT; UNITED-STATES; SMOKING ABSTINENCE; SELECTION CRITERIA; NELSON TRIAL; POPULATION; MORTALITY; PROSTATE; STAGE; RISK AB Background: The optimum screening policy for lung cancer is unknown. Objective: To identify efficient computed tomography (CT) screening scenarios in which relatively more lung cancer deaths are averted for fewer CT screening examinations. Design: Comparative modeling study using 5 independent models. Data Sources: The National Lung Screening Trial; the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial; the Surveillance, Epidemiology, and End Results program; and the U.S. Smoking History Generator. Target Population: U.S. cohort born in 1950. Time Horizon: Cohort followed from ages 45 to 90 years. Perspective: Societal. Intervention: 576 scenarios with varying eligibility criteria (age, pack-years of smoking, years since quitting) and screening intervals. Outcome Measures: Benefits included lung cancer deaths averted or life-years gained. Harms included CT examinations, false-positive results (including those obtained from biopsy/surgery), overdiagnosed cases, and radiation-related deaths. Results of Best-Case Scenario: The most advantageous strategy was annual screening from ages 55 through 80 years for ever-smokers with a smoking history of at least 30 pack-years and ex-smokers with less than 15 years since quitting. It would lead to 50% (model ranges, 45% to 54%) of cases of cancer being detected at an early stage (stage I/II), 575 screening examinations per lung cancer death averted, a 14% (range, 8.2% to 23.5%) reduction in lung cancer mortality, 497 lung cancer deaths averted, and 5250 life-years gained per the 100 000-member cohort. Harms would include 67 550 false-positive test results, 910 biopsies or surgeries for benign lesions, and 190 overdiagnosed cases of cancer (3.7% of all cases of lung cancer [model ranges, 1.4% to 8.3%]). Results of Sensitivity Analysis: The number of cancer deaths averted for the scenario varied across models between 177 and 862; the number of overdiagnosed cases of cancer varied between 72 and 426. Limitations: Scenarios assumed 100% screening adherence. Data derived from trials with short duration were extrapolated to lifetime follow-up. Conclusion: Annual CT screening for lung cancer has a favorable benefit-harm ratio for individuals aged 55 through 80 years with 30 or more pack-years' exposure to smoking. C1 Erasmus MC, NL-3000 CA Rotterdam, Netherlands. Univ Michigan, Ann Arbor, MI 48109 USA. Stanford Univ, Stanford, CA 94305 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NCI, Bethesda, MD 20892 USA. Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. Brock Univ, St Catharines, ON L2S 3A1, Canada. RP de Koning, HJ (reprint author), Erasmus MC, Dept Publ Hlth, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM h.dekoning@erasmusmc.nl RI Berg , Christine/K-1047-2014 FU National Cancer Institute FX Primary Funding Source: National Cancer Institute. NR 42 TC 120 Z9 121 U1 6 U2 23 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 4 PY 2014 VL 160 IS 5 BP 311 EP + DI 10.7326/M13-2316 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA AC8OT UT WOS:000332793900003 PM 24379002 ER PT J AU Downs, J Good, C AF Downs, John Good, Chester TI New Cholesterol Guidelines: Has Godot Finally Arrived? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material C1 South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. RP Downs, J (reprint author), South Texas Vet Hlth Care Syst, Med Serv 111, 7400 Merton Minter, San Antonio, TX 78229 USA. EM john.downs@va.gov NR 9 TC 8 Z9 8 U1 0 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAR 4 PY 2014 VL 160 IS 5 BP 354 EP + DI 10.7326/M13-2850 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AC8OT UT WOS:000332793900008 PM 24473934 ER PT J AU Capasso, R Kezirian, E Jacobowitz, O Weaver, EM AF Capasso, Robson Kezirian, Eric Jacobowitz, Ofer Weaver, Edward M. TI Management of Obstructive Sleep Apnea in Adults SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID POSITIVE AIRWAY PRESSURE C1 [Capasso, Robson] Stanford Univ, Palo Alto, CA 94304 USA. [Kezirian, Eric] Univ So Calif, Los Angeles, CA USA. [Jacobowitz, Ofer] Mt Sinai Sch Med, New York, NY USA. [Weaver, Edward M.] Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. RP Capasso, R (reprint author), Stanford Univ, Palo Alto, CA 94304 USA. NR 5 TC 1 Z9 2 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 4 PY 2014 VL 160 IS 5 BP 367 EP 367 DI 10.7326/L14-5005 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AC8OT UT WOS:000332793900014 PM 24589933 ER PT J AU Shekelle, P Holty, JEC Owens, DK Qaseem, A AF Shekelle, Paul Holty, Jon-Erik C. Owens, Douglas K. Qaseem, Amir TI Management of Obstructive Sleep Apnea in Adults IN RESPONSE SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID TRIAL C1 [Shekelle, Paul] Greater Los Angeles Vet Affairs Hlth Ctr, Los Angeles, CA 90073 USA. [Shekelle, Paul] RAND Corp, Los Angeles, CA USA. [Holty, Jon-Erik C.; Owens, Douglas K.] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Qaseem, Amir] Amer Coll Physicians, Philadelphia, PA USA. RP Shekelle, P (reprint author), Greater Los Angeles Vet Affairs Hlth Ctr, Los Angeles, CA 90073 USA. NR 4 TC 2 Z9 4 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 4 PY 2014 VL 160 IS 5 BP 367 EP 368 DI 10.7326/L14-5005-2 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AC8OT UT WOS:000332793900015 PM 24737275 ER PT J AU Wright, AA Zhang, BH Keating, NL Weeks, JC Prigerson, HG AF Wright, Alexi A. Zhang, Baohui Keating, Nancy L. Weeks, Jane C. Prigerson, Holly G. TI Associations between palliative chemotherapy and adult cancer patients' end of life care and place of death: prospective cohort study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID CELL LUNG-CANCER; OF-LIFE; MEDICARE BENEFICIARIES; TREATMENT PREFERENCES; PROPENSITY SCORE; MENTAL-HEALTH; HOSPICE CARE; NEAR-DEATH; DISCUSSIONS; QUALITY AB Objectives To determine whether the receipt of chemotherapy among terminally ill cancer patients months before death was associated with patients' subsequent intensive medical care and place of death. Design Secondary analysis of a prospective, multi-institution, longitudinal study of patients with advanced cancer. Setting Eight outpatient oncology clinics in the United States. Participants 386 adult patients with metastatic cancers refractory to at least one chemotherapy regimen, whom physicians identified as terminally ill at study enrollment and who subsequently died. Main outcome measures Primary outcomes: intensive medical care (cardiopulmonary resuscitation, mechanical ventilation, or both) in the last week of life and patients' place of death (for example, intensive care unit). Secondary outcomes: survival, late hospice referrals (<= 1 week before death), and dying in preferred place of death. Results 216 (56%) of 386 terminally ill cancer patients were receiving palliative chemotherapy at study enrollment, a median of 4.0 months before death. After propensity score weighted adjustment, use of chemotherapy at enrollment was associated with higher rates of cardiopulmonary resuscitation, mechanical ventilation, or both in the last week of life (14% v 2%; adjusted risk difference 10.5%, 95% confidence interval 5.0% to 15.5%) and late hospice referrals (54% v 37%; 13.6%, 3.6% to 23.6%) but no difference in survival (hazard ratio 1.11, 95% confidence interval 0.90 to 1.38). Patients receiving palliative chemotherapy were more likely to die in an intensive care unit (11% v 2%; adjusted risk difference 6.1%, 1.1% to 11.1%) and less likely to die at home (47% v 66%; -10.8%, -1.0% to -20.6%), compared with those who were not. Patients receiving palliative chemotherapy were also less likely to die in their preferred place, compared with those who were not (65% v 80%; adjusted risk difference -9.4%, -0.8% to -18.1%). Conclusions The use of chemotherapy in terminally ill cancer patients in the last months of life was associated with an increased risk of undergoing cardiopulmonary resuscitation, mechanical ventilation or both and of dying in an intensive care unit. Future research should determine the mechanisms by which palliative chemotherapy affects end of life outcomes and patients' attainment of their goals. C1 [Wright, Alexi A.; Weeks, Jane C.] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. [Zhang, Baohui; Prigerson, Holly G.] Weill Cornell Med Coll, Ctr End Of Life Res, New York, NY 10065 USA. [Keating, Nancy L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Prigerson, HG (reprint author), Weill Cornell Med Coll, Ctr End Of Life Res, New York, NY 10065 USA. EM hgp2001@med.cornell.edu FU National Institute of Mental Health [MH63892]; National Cancer Institute [CA 106370, CA 156732, 1K07 CA166210, 1R01 CA164021]; American Cancer Society [MRSG-13-013]; Conquer Cancer Foundation of American Society for Clinical Oncology Career Development Award FX HGP has received research grants MH63892 from the National Institute of Mental Health and CA 106370 and CA 156732 from the National Cancer Institute; AAW has received research grants 1K07 CA166210 from the National Cancer Institute and MRSG-13-013 from the American Cancer Society and a Conquer Cancer Foundation of American Society for Clinical Oncology Career Development Award; NLK received research grant 1R01 CA164021 from the National Cancer Institute. The funding organizations had no role in the design and conduct of the study; collection, analysis, or preparation of the data; or preparation, review, or approval of the manuscript. Any opinions, findings, and conclusions expressed in this material are those of the authors and do not necessarily reflect those of the American Cancer Society, the American Society of Clinical Oncology, or the Conquer Cancer Foundation. NR 48 TC 49 Z9 49 U1 7 U2 28 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 4 PY 2014 VL 348 AR g1219 DI 10.1136/bmj.g1219 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AC6HV UT WOS:000332623400001 PM 24594868 ER PT J AU Ferreiro, JL Bhatt, DL Ueno, M Bauer, D Angiolillo, DJ AF Ferreiro, Jose L. Bhatt, Deepak L. Ueno, Masafumi Bauer, Deborah Angiolillo, Dominick J. TI Impact of Smoking on Long-Term Outcomes in Patients With Atherosclerotic Vascular Disease Treated With Aspirin or Clopidogrel SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE antiplatelet agents; clopidogrel; smoking; smoking paradox ID ACUTE CORONARY SYNDROMES; CIGARETTE-SMOKING; PLATELET INHIBITION; ARTERY-DISEASE; DIABETES-MELLITUS; DRUG-INTERACTIONS; ISCHEMIC EVENTS; EFFICACY; PRASUGREL; PARADOX AB Objectives The goal of this study was to investigate the differential efficacy of clopidogrel or aspirin monotherapy according to smoking status in patients with atherosclerotic vascular disease. Background Smoking enhances clopidogrel- induced platelet inhibition, which may explain the higher relative benefit among smokers observed in trials evaluating dual antiplatelet therapy. Whether smoking has an impact on clinical outcomes in patients requiring a single antiplatelet agent remains unknown. Methods This was a post- hoc analysis of the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial that compared clopidogrel and aspirin monotherapy in patients (N = 19,184) with atherosclerotic vascular disease. Results Current smokers (n = 5,688) had an increased risk of ischemic events compared with never smokers (n = 4,135; hazard ratio [HR]: 1.24 [95% confidence interval (CI): 1.08 to 1.42]) and ex- smokers (n = 9,381; HR: 1.32 [95% CI: 1.18 to 1.47]) (p< 0.001). Clopidogrel was associated with a reduction in ischemic events among current smokers (8.3% vs. 10.8%; HR: 0.76 [95% CI: 0.64 to 0.90]), whereas no benefit over aspirin was seen in the combined group of ex- smokers/never- smoked patients (10.4% vs. 10.6%; HR: 0.99 [95% CI: 0.89 to 1.10]; p = 0.01 for interaction). Among current smokers, clopidogrel also reduced myocardial infarction, vascular death, and death from any cause compared with aspirin. No interaction between smoking status and study treatment was observed for bleeding events. Conclusions In a post-hoc analysis of the CAPRIE population, current smokers appeared to have enhanced benefit with clopidogrel therapy for secondary prevention compared with aspirin. These results should be considered hypothesis generating for future prospective studies assessing the impact of specific platelet- inhibiting strategies according to smoking status. (c) 2014 by the American College of Cardiology Foundation C1 [Ferreiro, Jose L.; Ueno, Masafumi; Angiolillo, Dominick J.] Univ Florida Coll Med Jacksonville, Jacksonville, FL 32209 USA. [Ferreiro, Jose L.] Univ Barcelona, Hosp Univ Bellvitge IDIBELL, Heart Dis Inst, Barcelona, Spain. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Bauer, Deborah] Sanofi, Dept Biostat, Bridgewater, NJ USA. RP Angiolillo, DJ (reprint author), Univ Florida Coll Med Jacksonville, 655 West 8th St, Jacksonville, FL 32209 USA. EM dominick.angiolillo@jax.ufl.edu FU Sanofi; Bristol-Myers Squibb; Amarin; AstraZeneca; Eisai; Ethicon; Medtronic; sanofi-aventis; Medicines Company; Eli Lilly and Company; Daiichi Sankyo; Merck Co.; Evolva; Abbott Vascular; PLx Pharma; GlaxoSmithKline; Otsuka; Esther and King Biomedical Research Grant FX The CAPRIE trial was funded by Sanofi and Bristol-Myers Squibb. The study sponsor had no role in the design of the present analysis. Dr. Ferreiro has received honoraria for lectures from Eli Lilly and Company, Daiichi Sankyo, and AstraZeneca. Dr. Bhatt has been on the advisory boards of Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; has been on the board of directors of Boston VA Research Institute and the Society of Chest Pain Centers; has chaired the American Heart Association Get With the Guidelines Science Subcommittee; has received honoraria from the American College of Cardiology, Duke Clinical Research Institute, Slack Publications, and WebMD; has been a senior associate editor of the Journal of Invasive Cardiology; has been on data monitoring committees of Duke Clinical Research Institute, Mayo Clinic, and Population Health Research Institute; has received research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, sanofi-aventis, and The Medicines Company; has performed unfunded research for FlowCo, PLx Pharma, and Takeda; has been a principal investigator on the CHARISMA trial; has been on the steering committee of the TRILOGY-ACS trial; and has been on the executive committee of the PEGASUS trial(s). Ms. Bauer is an employee of sanofi-aventis. Dr. Angiolillo has received consulting fees or honoraria from Bristol-Myers Squibb, sanofi-aventis, Eli Lilly and Company, Daiichi Sankyo, The Medicines Company, AstraZeneca, Merck & Co., Evolva, Abbott Vascular, and PLx Pharma; has been a consultant for Johnson & Johnson, St. Jude Medical, and Sunovion; has received research grants (paid to his institution) from Bristol-Myers Squibb, sanofi-aventis, GlaxoSmithKline, Otsuka, Eli Lilly and Company, Daiichi Sankyo, The Medicines Company, AstraZeneca, and Evolva; and has received an Esther and King Biomedical Research Grant. Dr. Ueno has reported that he has no relationships relevant to the contents of this paper to disclose. NR 39 TC 13 Z9 15 U1 1 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 4 PY 2014 VL 63 IS 8 BP 769 EP 777 DI 10.1016/j.jacc.2013.10.043 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB3WM UT WOS:000331720900004 PM 24239662 ER PT J AU Shah, R Gayat, E Januzzi, JL Sato, N Cohen-Solal, A diSomma, S Fairman, E Harjola, VP Ishihara, S Lassus, J Maggioni, A Metra, M Mueller, C Mueller, T Parenica, J Pascual-Figal, D Peacock, WF Spinar, J van Kimmenade, R Mebazaa, A AF Shah, Ravi Gayat, Etienne Januzzi, James L., Jr. Sato, Naoki Cohen-Solal, Alain diSomma, Salvatore Fairman, Enrique Harjola, Veli-Pekka Ishihara, Shiro Lassus, Johan Maggioni, Aldo Metra, Marco Mueller, Christian Mueller, Thomas Parenica, Jiri Pascual-Figal, Domingo Peacock, William Frank Spinar, Jindrich van Kimmenade, Roland Mebazaa, Alexandre CA GREAT Global Res Acute Conditions TI Body Mass Index and Mortality in Acutely Decompensated Heart Failure Across the World SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE heart failure; obesity; obesity paradox ID OBESITY PARADOX; NATRIURETIC PEPTIDE; CARDIAC CACHEXIA; PREDICTORS; DIAGNOSIS; REGISTRY; CATABOLISM; ADIPOSITY; REDUCTION; PROGNOSIS AB Objectives This study sought to define the relationship between body mass index (BMI) and mortality in heart failure (HF) across the world and to identify specific groups in whom BMI may differentially mediate risk. Background Obesity is associated with incident HF, but it is paradoxically associated with better prognosis during chronic HF. Methods We studied 6,142 patients with acute decompensated HF from 12 prospective observational cohorts followed-up across 4 continents. Primary outcome was all-cause mortality. Cox proportional hazards models and net reclassification index described associations of BMI with all-cause mortality. Results Normal-weight patients (BMI 18.5 to 25 kg/ m2) were older with more advanced HF and lower cardiometabolic risk. Despite worldwide heterogeneity in clinical features across obesity categories, a higher BMI remained associated with decreased 30-day and 1-year mortality (11% decrease at 30 days; 9% decrease at 1 year per 5 kg/ m2; p < 0.05), after adjustment for clinical risk. The BMI obtained at index admission provided effective 1-year risk reclassification beyond current markers of clinical risk (net reclassification index 0.119, p < 0.001). Notably, the "protective" association of BMI with mortality was confined to persons with older age (> 75 years; hazard ratio [HR]: 0.82; p 0.006), decreased cardiac function (ejection fraction < 50%; HR: 0.85; p < 0.001), no diabetes (HR: 0.86; p < 0.001), and de novo HF (HR: 0.89; p 0.004). Conclusions A lower BMI is associated with age, disease severity, and a higher risk of death in acute decompensated HF. The "obesity paradox" is confined to older persons, with decreased cardiac function, less cardiometabolic illness, and recent-onset HF, suggesting that aging, HF severity/chronicity, and metabolism may explain the obesity paradox. (c) 2014 by the American College of Cardiology Foundation C1 [Shah, Ravi; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Gayat, Etienne] Univ Paris Diderot, Lariboisiere Univ Hosp, AP HP, Dept Anesthesiol & Intens Care, Paris, France. [Sato, Naoki] Musashi Kosugi Hosp, Nippon Med Sch, Tokyo, Japan. [Cohen-Solal, Alain] INSERM, UMR 942, Paris, France. [diSomma, Salvatore] Univ Roma La Sapienza, Emergency Dept, St Andrea Hosp, I-00185 Rome, Italy. [Fairman, Enrique] Area Invest SAC Azcuenaga, Soc Argentina Cardiol, Buenos Aires, DF, Argentina. [Harjola, Veli-Pekka] Univ Helsinki, Cent Hosp, Div Emergency Care, Helsinki, Finland. [Ishihara, Shiro] Steel Mem Yawata Hosp, Dept Cardiol, Kitakyushu, Fukuoka, Japan. [Lassus, Johan; Mebazaa, Alexandre] Univ Helsinki, Cent Hosp, Dept Med, Helsinki, Finland. [Maggioni, Aldo] ANMCO Res Ctr, Florence, Italy. [Metra, Marco] Univ Brescia, Dept Expt & Appl Med, Brescia, Italy. [Mueller, Christian] Univ Basel Hosp, Dept Internal Med, CH-4031 Basel, Switzerland. [Mueller, Thomas] Konventhosp Barmherzige Brueder, Dept Lab Med, Linz, Austria. [Parenica, Jiri; Spinar, Jindrich] Masaryk Univ, Fac Med, Univ Hosp Brno, Dept Internal Med & Cardiol, Brno, Czech Republic. [Pascual-Figal, Domingo] Univ Murcia, Fac Med, Dept Med, Cardiol Serv,Virgen de la Arrixaca Hosp, Murcia, Spain. [Peacock, William Frank] Baylor Coll Med, Houston, TX 77030 USA. [van Kimmenade, Roland] Univ Med Ctr, Utrecht, Netherlands. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Dept Cardiol, 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@partners.org RI Harjola, Veli-Pekka/G-9229-2015; Kimmenade, R.R.J./L-4432-2015; OI Metra, Marco/0000-0001-6691-8568; Pascual Figal, Domingo A./0000-0002-4993-9540 FU Servier; Roche Diagnostics; Siemens Diagnostics; Critical Diagnostics; Thermo-Fisher Diagnostics; Alere; Abbott; Baxter; Brahms AG; Novartis; Medicines Company; Eli Lily and Company FX Dr. Gayat has received speaker's honoraria from Bristol-Myers Squibb; and has received travel fees from Servier. Dr. Januzzi has received grants from Roche Diagnostics, Siemens Diagnostics, Critical Diagnostics, and Thermo-Fisher Diagnostics; and has received consultant fees from Roche Diagnostics and Critical Diagnostics. Dr. diSomma has received consultant fees from Alere and Thermo-Fisher Diagnostics. Dr. Harjola has received consultant fees from Roche Diagnostics. Dr. Lassus has received speaker's honoraria from Abbott; and has received consultant fees from Roche Diagnostics. Dr. C. Mueller has received research support and speaker's honoraria from Brahms AG, Alere, Abbott, and Critical Diagnostics. Dr. T. Mueller has received speaker's honoraria from Abbott Diagnostics, Brahms AG, and Roche Diagnostics. Dr. Pascual-Figal has received grants from Roche Diagnostics. Dr. Peacock has received research grants from Abbott, Alere, Baxter, Brahms AG, Novartis, and The Medicines Company; has received consultant fees from Abbott, Alere, Eli Lily and Company, and The Medicines Company; has received speaker's honoraria from Abbott, and Alere; and has ownership interest in Comprehensive Research Associates LLC, Vital Sensors, and Emergencies in Medicine LLC. Dr. Mebazaa has received speaker's honoraria from Alere, Brahms AG, Edwards, Orion, and Bayer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 36 TC 70 Z9 72 U1 1 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 4 PY 2014 VL 63 IS 8 BP 778 EP 785 DI 10.1016/j.jacc.2013.09.072 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB3WM UT WOS:000331720900005 PM 24315906 ER PT J AU Ky, B Putt, M Sawaya, H French, B Januzzi, JL Sebag, IA Plana, JC Cohen, V Banchs, J Carver, JR Wiegers, SE Martin, RP Picard, MH Gerszten, RE Halpern, EF Passeri, J Kuter, I Scherrer-Crosbie, M AF Ky, Bonnie Putt, Mary Sawaya, Heloisa French, Benjamin Januzzi, James L., Jr. Sebag, Igal A. Plana, Juan Carlos Cohen, Victor Banchs, Jose Carver, Joseph R. Wiegers, Susan E. Martin, Randolph P. Picard, Michael H. Gerszten, Robert E. Halpern, Elkan F. Passeri, Jonathan Kuter, Irene Scherrer-Crosbie, Marielle TI Early Increases in Multiple Biomarkers Predict Subsequent Cardiotoxicity in Patients With Breast Cancer Treated With Doxorubicin, Taxanes, and Trastuzumab SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardio-oncology; chemotherapy cardiotoxicity; trastuzumab cardiotoxicity ID CHRONIC HEART-FAILURE; RISK STRATIFICATION; TROPONIN-I; PROGNOSTIC VALUE; MYELOPEROXIDASE; ECHOCARDIOGRAPHY; ANTHRACYCLINE; TRIALS AB Objectives The aim of this study was to determine if individual or multiple biomarkers are associated with cardiotoxicity in patients with breast cancer undergoing cancer therapy. Background Current methods to identify patients at risk for cardiotoxicity from cancer therapy are inadequate. Methods We measured 8 biomarkers in a multicenter cohort of 78 patients with breast cancer undergoing doxorubicin and trastuzumab therapy: ultrasensitive troponin I (TnI), high-sensitivity C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt)-1, and galectin (gal)-3. Cardiotoxicity, defined by the Cardiac Review and Evaluation Committee criteria, was assessed every 3 months for up to 15 months. Hazard ratios (HRs) of cardiotoxicity risk were assessed for each biomarker at baseline, at visit 2 (3 months), and as a function of the difference between visit 2 and baseline. Joint models were assessed for the most promising biomarkers. Results TnI, CRP, GDF-15, MPO, PlGF, and sFlt-1 levels increased from baseline to visit 2 (p < 0.05). A greater risk of cardiotoxicity was associated with interval changes in TnI (HR: 1.38 per SD; 95% confidence interval: 1.05 to 1.81; p = 0.02) and MPO (HR: 1.34 per SD; 95% confidence interval: 1.00 to 1.80; p = 0.048) and in models combining both markers (p = 0.007 and p = 0.03, respectively). The risk of cardiotoxicity was 46.5% in patients with the largest changes in both markers (DTnI > 121.8 mg/l; DMPO > 422.6 pmol/l). Conclusions Early increases in TnI and MPO levels offer additive information about the risk of cardiotoxicity in patients undergoing doxorubicin and trastuzumab therapy. Independent validation of these findings is necessary before application to clinical practice. (C) 2014 by the American College of Cardiology Foundation C1 [Ky, Bonnie; Putt, Mary; French, Benjamin; Carver, Joseph R.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Ky, Bonnie; Putt, Mary; French, Benjamin] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Sawaya, Heloisa; Januzzi, James L., Jr.; Picard, Michael H.; Gerszten, Robert E.; Passeri, Jonathan; Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. [Sawaya, Heloisa; Januzzi, James L., Jr.; Picard, Michael H.; Gerszten, Robert E.; Passeri, Jonathan; Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Sawaya, Heloisa; Januzzi, James L., Jr.; Picard, Michael H.; Gerszten, Robert E.; Halpern, Elkan F.; Passeri, Jonathan; Kuter, Irene; Scherrer-Crosbie, Marielle] Harvard Univ, Sch Med, Boston, MA USA. [Sebag, Igal A.] Sir Mortimer B Davis Jewish Hosp, Echocardiog Lab, Montreal, PQ, Canada. [Sebag, Igal A.] Sir Mortimer B Davis Jewish Hosp, Div Cardiol, Montreal, PQ, Canada. [Sebag, Igal A.; Cohen, Victor] McGill Univ, Montreal, PQ, Canada. [Plana, Juan Carlos] Cleveland Clin Fdn, Div Cardiovasc Med, Cleveland, OH 44195 USA. [Cohen, Victor] Sir Mortimer B Davis Jewish Hosp, Segal Canc Ctr, Dept Med, Montreal, PQ, Canada. [Banchs, Jose] Univ Texas MD Anderson Canc Ctr, Dept Cardiovasc Med, Houston, TX 77030 USA. [Wiegers, Susan E.] Temple Univ, Div Cardiovasc Med, Philadelphia, PA 19122 USA. [Martin, Randolph P.] Piedmont Heart Inst, Atlanta, GA USA. [Halpern, Elkan F.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Kuter, Irene] Massachusetts Gen Hosp, Gillette Ctr Breast Canc, Boston, MA 02114 USA. RP Ky, B (reprint author), Univ Penn, Sch Med, Smilow Translat Res Ctr, 11-105,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM bonnie.ky@uphs.upenn.edu; marielle@crosbie.com OI Picard, Michael/0000-0002-9264-3243 FU Abbott Diagnostics; Critical Diagnostics; Roche Diagnostics; Siemens; BG Medicine; Thermo Fisher; Singulex; BRAHMS; Siemens Ultrasound FX The funding organizations, Abbott Diagnostics, and Siemens did not have a role in the design or the conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. Dr. Januzzi has received research funding from Critical Diagnostics, Roche Diagnostics, Siemens, BG Medicine, Thermo Fisher, Singulex, and BRAHMS. Dr. Wiegers holds stock in Merck & Co, Inc. Dr. Martin has received research support from Siemens Ultrasound and has received honoraria from Medtronic Heart Valve, Edwards Lifesciences, and Sorin. Dr. Halpern has served as a consultant for Hologic. All other authors have reported that they have no relationships relevant to the content of this paper to disclose. NR 25 TC 78 Z9 84 U1 1 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 4 PY 2014 VL 63 IS 8 BP 809 EP 816 DI 10.1016/j.jacc.2013.10.061 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB3WM UT WOS:000331720900010 PM 24291281 ER PT J AU Lau, AN Curtis, SJ Fillmore, CM Rowbotham, SP Mohseni, M Wagner, DE Beede, AM Montoro, DT Sinkevicius, KW Walton, ZE Barrios, J Weiss, DJ Camargo, FD Wong, KK Kim, CF AF Lau, Allison N. Curtis, Stephen J. Fillmore, Christine M. Rowbotham, Samuel P. Mohseni, Morvarid Wagner, Darcy E. Beede, Alexander M. Montoro, Daniel T. Sinkevicius, Kerstin W. Walton, Zandra E. Barrios, Juliana Weiss, Daniel J. Camargo, Fernando D. Wong, Kwok-Kin Kim, Carla F. TI Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis SO EMBO JOURNAL LA English DT Article DE CD24; lung cancer; metastasis; Taz; tumor propagating cells ID CANCER STEM-CELLS; INITIATING CELLS; BREAST-CANCER; ALDEHYDE DEHYDROGENASE; EXPRESSION PROFILES; SELF-RENEWAL; ADENOCARCINOMA; IDENTIFICATION; POPULATION; INVASION AB Metastasis is the leading cause of morbidity for lung cancer patients. Here we demonstrate that murine tumor propagating cells (TPCs) with the markers Sca1 and CD24 are enriched for metastatic potential in orthotopic transplantation assays. CD24 knockdown decreased the metastatic potential of lung cancer cell lines resembling TPCs. In lung cancer patient data sets, metastatic spread and patient survival could be stratified with a murine lung TPC gene signature. The TPC signature was enriched for genes in the Hippo signaling pathway. Knockdown of the Hippo mediators Yap1 or Taz decreased in vitro cellular migration and transplantation of metastatic disease. Furthermore, constitutively active Yap was sufficient to drive lung tumor progression in vivo. These results demonstrate functional roles for two different pathways, CD24-dependent and Yap/Taz-dependent pathways, in lung tumor propagation and metastasis. This study demonstrates the utility of TPCs for identifying molecules contributing to metastatic lung cancer, potentially enabling the therapeutic targeting of this devastating disease. C1 [Lau, Allison N.; Curtis, Stephen J.; Fillmore, Christine M.; Rowbotham, Samuel P.; Mohseni, Morvarid; Beede, Alexander M.; Montoro, Daniel T.; Sinkevicius, Kerstin W.; Barrios, Juliana; Camargo, Fernando D.; Kim, Carla F.] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Lau, Allison N.; Curtis, Stephen J.; Fillmore, Christine M.; Rowbotham, Samuel P.; Mohseni, Morvarid; Beede, Alexander M.; Montoro, Daniel T.; Sinkevicius, Kerstin W.; Barrios, Juliana; Camargo, Fernando D.; Kim, Carla F.] Harvard Stem Cell Inst, Cambridge, MA USA. [Lau, Allison N.; Curtis, Stephen J.; Fillmore, Christine M.; Rowbotham, Samuel P.; Beede, Alexander M.; Montoro, Daniel T.; Sinkevicius, Kerstin W.; Barrios, Juliana; Kim, Carla F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Mohseni, Morvarid; Camargo, Fernando D.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Wagner, Darcy E.; Weiss, Daniel J.] Univ Vermont, Dept Med, Burlington, VT USA. [Walton, Zandra E.; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Walton, Zandra E.; Wong, Kwok-Kin] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Walton, Zandra E.; Wong, Kwok-Kin] Harvard Canc Ctr, Ludwig Ctr Dana Farber, Boston, MA USA. RP Kim, CF (reprint author), Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. EM carla.kim@childrens.harvard.edu OI wong, kwok kin/0000-0001-6323-235X FU DoD; Air Force Office of Scientific Research; National Defense Science and Engineering Graduate Fellowships [32 CFR 168a]; American Cancer Society [PF-09-121-01-DDC, PF-12-151-01-DMC]; Ladies Auxilliary to the Veterans of Foreign Wars; Dana Farber Harvard Cancer Center Lung Cancer SPORE grant [P50 CA090578, R01 AG2400401, R01 CA122794, R01 CA140594]; V Foundation for Cancer Research; American Cancer Society Research Scholar Grant [RSG-08-082-01-MGO]; Freeman Trust; Harvard Stem Cell Institute; NIH/NHLBI [U01 HL100402, R01 HL090136]; Lung Cancer Alliance FX We thank the DFCI, BIDMC, and CHB HemOnc FACS facilities, M. Correll and S. Duan of the DFCI Center for Computational Cancer Biology, and members of the Kim Lab for technical assistance and discussions, R. Bronson for histopathology, L. Zon, C. Cepko, S. Armstrong, and W. Hahn for helpful discussions. This work was supported by DoD, Air Force Office of Scientific Research, National Defense Science and Engineering Graduate Fellowships, 32 CFR 168a (to S.J.C. and A.N.L.), PF-09-121-01-DDC and PF-12-151-01-DMC from the American Cancer Society (to K.W.S. and C.M.F., respectively), the Ladies Auxilliary to the Veterans of Foreign Wars (to C.M.F.), Dana Farber Harvard Cancer Center Lung Cancer SPORE grant P50 CA090578, R01 AG2400401, R01 CA122794, R01 CA140594 (to K-K.W.), the V Foundation for Cancer Research, American Cancer Society Research Scholar Grant #RSG-08-082-01-MGO, the Freeman Trust, the Harvard Stem Cell Institute, NIH/NHLBI U01 HL100402 and R01 HL090136 and The Lung Cancer Alliance (to C.F.K.). NR 50 TC 57 Z9 62 U1 2 U2 27 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD MAR 3 PY 2014 VL 33 IS 5 BP 468 EP 481 DI 10.1002/embj.201386082 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AC3CC UT WOS:000332391600009 PM 24497554 ER PT J AU Laitman, BM Gajewski, ND Mann, GL Kubin, L Morrison, AR Ross, RJ AF Laitman, Benjamin M. Gajewski, Nicholas D. Mann, Graziella L. Kubin, Leszek Morrison, Adrian R. Ross, Richard J. TI The alpha(1) adrenoceptor antagonist prazosin enhances sleep continuity in fear-conditioned Wistar-Kyoto rats SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Article DE Fear conditioning; Norepinephrine; Posttraumatic stress disorder; REM sleep; Wistar-Kyoto rats ID POSTTRAUMATIC-STRESS-DISORDER; RECEPTOR MESSENGER-RNA; EYE-MOVEMENT SLEEP; NEURONS IN-VITRO; NON-REM SLEEP; BRAIN NOREPINEPHRINE; DEPENDENT PLASTICITY; CLONIDINE INJECTIONS; COMBAT VETERANS; WKY RATS AB Fragmentation of rapid eye movement sleep (REMS) is well described in individuals with posttraumatic stress disorder (PTSD) and likely has significant functional consequences. Fear-conditioned rodents may offer an attractive-model of the changes in sleep that characterize PTSD. Following fear conditioning (FC), Wistar-Kyoto (WKY) rats, a strain known to be particularly stress-sensitive, have increased REMS fragmentation that can be quantified as a shift in the distribution of REMS episodes towards themore frequent occurrence of sequential REMS (inter-REMS episode interval <= 3min) vs. single REMS(interval > 3min). The alpha(1) adrenoceptor antagonist prazosin has demonstrated efficacy in normalizing sleep in PTSD. To determine the utility of fear-conditioned WKY rats as a model of sleep disturbances typical of PTSD and as a platformfor the development of new treatments, we tested the hypothesis that prazosin would reduce REMS fragmentation in fear-conditionedWKY rats. Sleep parameters and freezing (a standardmeasure of anxiety in rodents) were quantified at baseline and on Days 1, 7, and 14 following FC, with either prazosin (0.01 mg/kg, i. p.) or vehicle injections administered prior to testing in a betweengroup design. Fear conditioning was achieved by pairing tones with a mild electric foot shock (1.0 mA, 0.5 s). One, 7, and 14 days following FC, prazosin or vehicle was injected, the tone was presented, freezing was measured, and then sleep was recorded from 11 AM to 3 PM. WKY rats given prazosin, compared to those given vehicle, had a lower amount of seq-REMS relative to total REMS time 14 days after FC. They also had a shorter nonREMS latency and fewer non-REMS arousals at baseline and on Days 1 and 7 after FC. Thus, in FC rats, prazosin reduced both REMS fragmentation and non-REMS discontinuity. Published by Elsevier Inc. C1 [Laitman, Benjamin M.; Gajewski, Nicholas D.; Mann, Graziella L.; Kubin, Leszek; Morrison, Adrian R.; Ross, Richard J.] Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA. [Ross, Richard J.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ross, Richard J.] Vet Affairs Med Ctr, Philadelphia, PA USA. RP Laitman, BM (reprint author), Mt Sinai Sch Med, Grad Sch Biol Sci, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM benjamin.laitman@mssm.edu FU NIH [RO1-MH072897] FX The study was supported by NIH grant RO1-MH072897. The authors thank Dr. Philip R. Gehrman for his assistance with statistical analysis. The views presented in this article do not represent those of the Department of Veterans Affairs or of the US Government. NR 61 TC 2 Z9 2 U1 1 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD MAR 3 PY 2014 VL 49 BP 7 EP 15 DI 10.1016/j.pnpbp.2013.11.004 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 280WA UT WOS:000329060300002 PM 24246572 ER PT J AU Boyd, JE Otilingam, PG DeForge, BR AF Boyd, Jennifer E. Otilingam, Poorni G. DeForge, Bruce R. TI Brief Version of the Internalized Stigma of Mental Illness (ISMI) Scale: Psychometric Properties and Relationship to Depression, Self Esteem, Recovery Orientation, Empowerment, and Perceived Devaluation and Discrimination SO PSYCHIATRIC REHABILITATION JOURNAL LA English DT Article DE stigma of mental illness; questionnaire; depression; self-esteem; empowerment ID PEOPLE; CONSEQUENCES; SCHIZOPHRENIA; EXPERIENCES; OUTPATIENTS; DISORDERS; VALIDITY; PARADOX; MODEL AB Objective: The internalized stigma of mental illness impedes recovery and is associated with increased depression, reduced self-esteem, reduced recovery orientation, reduced empowerment, and increased perceived devaluation and discrimination. The Internalized Stigma of Mental Illness (ISMI) scale is a 29-item self-report questionnaire developed with consumer input that includes the following subscales: Alienation, Discrimination Experience, Social Withdrawal, Stereotype Endorsement, and Stigma Resistance. Here we present a 10-item version of the ISMI containing the two strongest items from each subscale. Method: Participants were all outpatient veterans with serious mental illness. Following the rigorous scale-reduction methods set forth by Stanton and colleagues (2002), we selected the 10 items, tested the psychometrics of the shortened scale in the original validation sample (N = 127), and cross-checked the results in a second dataset (N = 760). Results: As expected, the ISMI-10 retained the essential properties of the ISMI-29, including adequate internal consistency reliability and external validity in relation to depression, self-esteem, recovery orientation, perceived devaluation and discrimination, and empowerment. The ISMI-10 scores are normally distributed and have similar descriptive statistics to the ISMI-29. The reliability and depression findings were replicated in a cross-validation sample. Conclusions and Implications for Practice: We conclude that the ISMI-10 has strong psychometric properties and is a practical, reliable, and valid alternative to the original ISMI-29. Future work should test the ISMI-10 in more diverse samples. This shorter version should reduce respondent burden in program evaluation projects that seek to determine whether participation in psychosocial rehabilitation programming reduces internalized stigma. C1 [Boyd, Jennifer E.] San Francisco VA Med Ctr, Dept Psychiat, San Francisco, CA 94121 USA. [Boyd, Jennifer E.] Univ Calif San Francisco, San Francisco, CA 94121 USA. [Otilingam, Poorni G.] San Francisco VA Med Ctr, Mental Hlth Serv, San Francisco, CA 94121 USA. [DeForge, Bruce R.] Univ Maryland, Sch Social Work, Baltimore, MD 21201 USA. RP Boyd, JE (reprint author), San Francisco VA Med Ctr, Dept Psychiat, 4150 Clement St 116A, San Francisco, CA 94121 USA. EM jennifer.boyd@va.gov NR 38 TC 10 Z9 10 U1 4 U2 16 PU CENTER PSYCHIATRIC REHABILITATION PI BOSTON PA BOSTON UNIV, 930 COMMONWEALTH AVE, BOSTON, MA 02215 USA SN 1095-158X EI 1559-3126 J9 PSYCHIATR REHABIL J JI Psychiatr. Rehabil. J. PD MAR PY 2014 VL 37 IS 1 BP 17 EP 23 DI 10.1037/prj0000035 PG 7 WC Psychiatry; Rehabilitation SC Psychiatry; Rehabilitation GA CA0RP UT WOS:000348624600004 PM 24660946 ER PT J AU Beehler, S Clark, JA Eisen, SV AF Beehler, Sarah Clark, Jack A. Eisen, Susan V. TI Participant Experiences in Peer- and Clinician-Facilitated Mental Health Recovery Groups for Veterans SO PSYCHIATRIC REHABILITATION JOURNAL LA English DT Article DE mental health recovery; veteran; peer support; qualitative ID PARTNER INTERDEPENDENCE ANALYSIS; GROUP-PSYCHOTHERAPY; PROVIDED SERVICES; SUPPORT; CONSUMER; ILLNESS; SESSION; BEHAVIORS; ALLIANCE; CLIENTS AB Objective: The purpose of the study was to characterize and compare participants' experiences of peer-facilitated versus clinician-facilitated recovery groups for veterans with mental illness. Method: We analyzed qualitative data from 24 interviews with veterans who participated in mental health recovery groups led by peer or clinician facilitators. Results: Subtle differences in group structure, participation/communication and utility/relevance between peer- and clinician-facilitated groups were identified. Participants experienced both peer and clinician facilitators as helpful in promoting recovery, though they appeared to do this in different ways. Conclusions and Implications for Practice: Peer and clinician facilitators offer different strengths in the promotion of mental health recovery. C1 [Beehler, Sarah] VA Boston Healthcare Syst, CHOIR, Jamaica Plain, MA USA. [Beehler, Sarah] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Clark, Jack A.; Eisen, Susan V.] Edith Nourse Rogers Mem Vet Hosp, CHOIR, Bedford, MA USA. [Clark, Jack A.; Eisen, Susan V.] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. RP Beehler, S (reprint author), Univ Minnesota, Sch Med, Dept Biobehav Hlth & Populat Sci, Duluth Campus,1035 Univ Dr,SMed 241, Duluth, MN 55812 USA. EM sjbeehle@d.umn.edu NR 28 TC 1 Z9 1 U1 3 U2 3 PU CENTER PSYCHIATRIC REHABILITATION PI BOSTON PA BOSTON UNIV, 930 COMMONWEALTH AVE, BOSTON, MA 02215 USA SN 1095-158X EI 1559-3126 J9 PSYCHIATR REHABIL J JI Psychiatr. Rehabil. J. PD MAR PY 2014 VL 37 IS 1 BP 43 EP 50 DI 10.1037/prj0000048 PG 8 WC Psychiatry; Rehabilitation SC Psychiatry; Rehabilitation GA CA0RP UT WOS:000348624600008 PM 24660950 ER PT J AU Fazeli, PK Klibanski, A AF Fazeli, Pouneh K. Klibanski, Anne TI Bone Metabolism in Anorexia Nervosa SO CURRENT OSTEOPOROSIS REPORTS LA English DT Article DE Anorexia nervosa; Bone mineral density ID GROWTH-FACTOR-I; HYPOTHALAMIC-PITUITARY FUNCTION; LOW SERUM TRIIODOTHYRONINE; THYROID-HORMONE RECEPTORS; IGF-BINDING PROTEINS; ADOLESCENT GIRLS; HEALTHY ADOLESCENTS; SECRETORY DYNAMICS; YOUNG-WOMEN; MINERAL DENSITY AB Anorexia nervosa (AN), a psychiatric disorder predominantly affecting young women, is characterized by self-imposed, chronic nutritional deprivation and distorted body image. AN is associated with a number of medical comorbidities including low bone mass. The low bone mass in AN is due to an uncoupling of bone formation and bone resorption, which is the result of hormonal adaptations aimed at decreasing energy expenditure during periods of low energy intake. Importantly, the low bone mass in AN is associated with a significant risk of fractures and therefore treatments to prevent bone loss are critical. In this review, we discuss the hormonal determinants of low bone mass in AN and treatments that have been investigated in this population. C1 [Fazeli, Pouneh K.; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. RP Fazeli, PK (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, 55 Fruit St,Bulfinch 457, Boston, MA 02114 USA. EM pkfazeli@partners.org FU NIH [K23 DK094820, R24 DK092759] FX PK Fazeli has received research support from the NIH (K23 DK094820). A Klibanski has received research supplies from Ipsen (drug and placebo only for study) and Eli Lilly (drug and placebo only for study); and research support from the NIH (R24 DK092759). NR 96 TC 8 Z9 8 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA EI 1544-2241 J9 CURR OSTEOPOROS REP JI Curr. Osteoporos. Rep. PD MAR PY 2014 VL 12 IS 1 BP 82 EP 89 DI 10.1007/s11914-013-0186-8 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AY0IZ UT WOS:000347281700011 PM 24419863 ER PT J AU Huckans, M Fuller, BE Olavarria, H Sasaki, AW Chang, M Flora, KD Kolessar, M Kriz, D Anderson, JR Vandenbark, AA Loftis, JM AF Huckans, Marilyn Fuller, Bret E. Olavarria, Hannah Sasaki, Anna W. Chang, Michael Flora, Kenneth D. Kolessar, Michael Kriz, Daniel Anderson, Jeanne R. Vandenbark, Arthur A. Loftis, Jennifer M. TI Multi-analyte profile analysis of plasma immune proteins: altered expression of peripheral immune factors is associated with neuropsychiatric symptom severity in adults with and without chronic hepatitis C virus infection SO BRAIN AND BEHAVIOR LA English DT Article DE Anxiety; biological markers; chronic infection; cytokines; depression; fatigue; pain ID MAJOR DEPRESSIVE DISORDER; NECROSIS-FACTOR-ALPHA; INTERFERON-INDUCED DEPRESSION; QUALITY-OF-LIFE; NEUROTROPHIC FACTOR; CYTOKINE LEVELS; TNF-ALPHA; HEPATOCELLULAR-CARCINOMA; BEHAVIORAL CONSEQUENCES; PSYCHIATRIC-DISORDERS AB Background: The purpose of this study was to characterize hepatitis C virus (HCV)-associated differences in the expression of 47 inflammatory factors and to evaluate the potential role of peripheral immune activation in HCV-associated neuropsychiatric symptoms-depression, anxiety, fatigue, and pain. An additional objective was to evaluate the role of immune factor dysregulation in the expression of specific neuropsychiatric symptoms to identify biomarkers that may be relevant to the treatment of these neuropsychiatric symptoms in adults with or without HCV. Methods: Blood samples and neuropsychiatric symptom severity scales were collected from HCV-infected adults (HCV+, n = 39) and demographically similar noninfected controls (HCV-, n = 40). Multi-analyte profile analysis was used to evaluate plasma biomarkers. Results: Compared with HCV- controls, HCV+ adults reported significantly (P < 0.050) greater depression, anxiety, fatigue, and pain, and they were more likely to present with an increased inflammatory profile as indicated by significantly higher plasma levels of 40% (19/47) of the factors assessed (21%, after correcting for multiple comparisons). Within the HCV+ group, but not within the HCV- group, an increased inflammatory profile (indicated by the number of immune factors > the LDC) significantly correlated with depression, anxiety, and pain. Within the total sample, neuropsychiatric symptom severity was significantly predicted by protein signatures consisting of 4-10 plasma immune factors; protein signatures significantly accounted for 19-40% of the variance in depression, anxiety, fatigue, and pain. Conclusions: Overall, the results demonstrate that altered expression of a network of plasma immune factors contributes to neuropsychiatric symptom severity. These findings offer new biomarkers to potentially facilitate pharmacotherapeutic development and to increase our understanding of the molecular pathways associated with neuropsychiatric symptoms in adults with or without HCV. C1 [Huckans, Marilyn; Fuller, Bret E.; Olavarria, Hannah; Vandenbark, Arthur A.; Loftis, Jennifer M.] Portland VA Med Ctr, Res & Dev Serv, Portland, OR 97239 USA. [Huckans, Marilyn; Fuller, Bret E.] Portland VA Med Ctr, Mental Hlth & Clin Neurosci Div, Portland, OR 97239 USA. [Huckans, Marilyn; Loftis, Jennifer M.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97239 USA. [Sasaki, Anna W.; Chang, Michael] Portland VA Med Ctr, Gastroenterol Serv, Portland, OR 97239 USA. [Sasaki, Anna W.; Chang, Michael] Oregon Hlth & Sci Univ, Dept Internal Med, Portland, OR 97239 USA. [Flora, Kenneth D.] Oregon Clin, Portland Gastroenterol Div, Clackamas, OR 97015 USA. [Kolessar, Michael; Kriz, Daniel; Anderson, Jeanne R.] Pacific Univ, Sch Profess Psychol, Hillsboro, OR 97123 USA. [Vandenbark, Arthur A.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Vandenbark, Arthur A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. RP Loftis, JM (reprint author), Portland VA Med Ctr, R&D 16, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM loftisj@ohsu.edu FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences Research and Development FX This study was supported by career development awards to M. Huckans (Staff Psychologist and Neuropsychologist) and J. M. Loftis (Research Scientist) from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences Research and Development. NR 131 TC 11 Z9 12 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2162-3279 J9 BRAIN BEHAV JI Brain Behav. PD MAR PY 2014 VL 4 IS 2 BP 123 EP 142 DI 10.1002/brb3.200 PG 20 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AX5NJ UT WOS:000346973200003 PM 24683507 ER PT J AU Litt, JS Perrin, JM AF Litt, Jonathan S. Perrin, James M. TI Influence of Clinical and Sociodemographic Characteristics on Early Intervention Enrollment After NICU Discharge SO JOURNAL OF EARLY INTERVENTION LA English DT Article DE high-risk infant; low-birth-weight infant; early intervention; special services ID LOW-BIRTH-WEIGHT; CHILDREN BORN; OUTCOMES; PRETERM; INFANTS; AGE; EXPERIENCE AB This study aims to characterize participation of neonatal intensive care unit (NICU) graduates in early intervention (EI). We used data from the National Early Intervention Longitudinal Study. We fit models of days from referral to Individualized Family Service Plan creation (plan time), days from referral to initiation of services (service time), and parent-reported effort to enroll their child with clinical and sociodemographic predictors. The sample of 1,188 NICU graduates had median birth weight 1,942 g, gestational age 33.4 weeks, and maternal age 27.4 years. Plan time was shorter for those with health insurance (2.5 weeks, p =.04) and living in high-providing states (3.3 weeks, p =.005). Service time was shorter for those with global delay (8 days, p =.02) and health insurance (11 days, p =.03) and longer for those with single parents (24 days, p =.009). Single parents and parents of children with higher birth weight, congenital problems, and non-White race reported greater effort finding services. Single parents and parents of female and higher birth weight infants reported greater effort initiating services. These findings document disparities in enrollment timing and service provision by disability types, single parenthood, and being of non-White race. Further elucidation of such disparities could lead to improved enrollment and access to prescribed services. C1 [Litt, Jonathan S.] Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Litt, Jonathan S.; Perrin, James M.] Harvard Univ, Sch Med, Boston, MA USA. [Perrin, James M.] MassGen Hosp Children, Boston, MA USA. RP Litt, JS (reprint author), Beth Israel Deaconess Med Ctr, Dept Neonatol, 330 Brookline Ave,Rose 318, Boston, MA 02115 USA. EM jlitt@bidmc.harvard.edu NR 29 TC 2 Z9 2 U1 0 U2 2 PU COUNCIL EXCEPTIONAL CHILDREN PI ARLINGTON PA 1110 N GLEBE RD, ARLINGTON, VA 22201-5704 USA SN 1053-8151 EI 2154-3992 J9 J EARLY INTERVENTION JI J. Early Interv. PD MAR PY 2014 VL 36 IS 1 BP 37 EP 48 DI 10.1177/1053815114555575 PG 12 WC Education, Special; Psychology, Educational; Rehabilitation SC Education & Educational Research; Psychology; Rehabilitation GA AU5YL UT WOS:000345679300003 ER PT J AU Truong, QA Gewirtz, H AF Truong, Quynh A. Gewirtz, Henry TI Cardiac PET-CT for Monitoring Medical and Interventional Therapy in Patients with CAD: PET Alone Versus Hybrid PET-CT? SO CURRENT CARDIOLOGY REPORTS LA English DT Article DE Cardiac PET; Hybrid PET-CT; Myocardial blood flow; Coronary artery disease; Treatment of CAD; Coronary flow reserve; Medical and interventional therapy ID POSITRON-EMISSION-TOMOGRAPHY; CORONARY-ARTERY-DISEASE; ISCHEMIC-HEART-DISEASE; CARDIOVASCULAR MAGNETIC-RESONANCE; MYOCARDIAL-PERFUSION RESERVE; APPROPRIATE USE CRITERIA; CHRONIC TOTAL OCCLUSION; COMPUTED-TOMOGRAPHY; NUCLEAR CARDIOLOGY; DIAGNOSTIC-ACCURACY AB This review focuses on optimal use of PET and PET-CT in monitoring medical and interventional therapy in patients with CAD. PET provides quantitative measurement of absolute myocardial blood flow and thus permits comprehensive physiological assessment of the coronary circulation. Hybrid PET-CT, in particular CCTA, adds anatomical information to maximal MBF measurement and so facilitates distinction of triple vessel focal epicardial disease from coronary microvascular disease or diffuse coronary atherosclerosis without focal stenoses. Hybrid PET-CT also may be of value in determining appropriateness and feasibility of percutaneous interventional therapy for chronic total coronary occlusion. PET alone, however, is the preferred modality to address functional status of the coronary circulation and response over time, if required, to medical or interventional therapy. CT at a minimum provides attenuation correction. More detailed CCTA should be added only when a well-defined need for anatomical information is required to answer the clinical question posed. C1 [Truong, Quynh A.; Gewirtz, Henry] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div,Cardiac Unit, Boston, MA 02114 USA. [Truong, Quynh A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Cardiac MR PET CT Program, Boston, MA 02114 USA. RP Gewirtz, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div,Cardiac Unit, Yawkey 5E,55 Fruit St, Boston, MA 02114 USA. EM hgewirtz@partners.org FU NIH [K23HL098370, L30HL093896]; St. Jude's Medical; American College of Radiology Imaging Network; Duke Clinical Research Institute; Wild Family Foundation FX Quynh A. Truong was supported by the NIH (K23HL098370 and L30HL093896) and receives research grants from St. Jude's Medical, American College of Radiology Imaging Network, and Duke Clinical Research Institute.; Henry Gewirtz received partial support from an unrestricted grant from the Wild Family Foundation. NR 57 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3782 EI 1534-3170 J9 CURR CARDIOL REP JI Curr. Cardiol. Rep. PD MAR PY 2014 VL 16 IS 3 AR 460 DI 10.1007/s11886-013-0460-5 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT6ZD UT WOS:000345084700007 PM 24464305 ER PT J AU Thompson, JM Zamorski, MA Sweet, J VanTil, L Sareen, J Pietrzak, RH Hopman, WH MacLean, MB Pedlar, D AF Thompson, James M. Zamorski, Mark A. Sweet, Jill VanTil, Linda Sareen, Jitender Pietrzak, Robert H. Hopman, Wilma H. MacLean, Mary Beth Pedlar, David TI Roles of physical and mental health in suicidal ideation in Canadian Armed Forces Regular Force veterans SO CANADIAN JOURNAL OF PUBLIC HEALTH-REVUE CANADIENNE DE SANTE PUBLIQUE LA English DT Article DE Veterans; suicidal ideation; physical health; mental health; suicide ID OLDER MALE VETERANS; RISK-FACTORS; MILITARY PERSONNEL; NATIONAL-HEALTH; PREVALENCE; SOLDIERS; COMBAT; ASSOCIATION; AFGHANISTAN; PERSPECTIVE AB OBJECTIVES: Suicide in recent veterans is an international concern. An association between mental disorders and suicide has been established, but less information is available about an association between physical health problems and suicide among veterans. This study extends this area of inquiry by examining the relationship of both physical and mental health problems with suicidal ideation in a representative national sample of Canadian veterans. METHODS: Subjects were a stratified random sample of 2,658 veterans who had been released from the Canadian Armed Forces Regular Force during 1998-2007 and had participated in the 2010 Survey on Transition to Civilian Life. Associations between physical and mental health and past-year suicidal ideation were explored in multivariable regression models using three measures of physical and mental health. RESULTS: The prevalence of suicidal ideation was 5.8% (95% confidence interval [CI]: 5.0%-6.8%). After adjustment for covariates, ideation was associated with gastrointestinal disorders (adjusted odds ratio [AOR] 1.66, CI: 1.03-2.65), depression or anxiety (AOR 5.06, CI: 2.97-8.62) and mood disorders (AOR 2.91, CI: 1.67-5.07); number of physical (AOR 1.22, CI: 1.05-1.42) and mental conditions (AOR 2.32, CI: 2.01-2.68); and SF-12 Health Survey physical health (AOR 0.98, CI: 0.96-0.99 for each 1 point increase) and mental health (AOR 0.88, CI: 0.87-0.89). CONCLUSIONS: Physical health was independently associated with suicidal ideation after adjustment for mental health status and socio-demographic characteristics. The findings underscore the importance of considering physical health in population-based suicide prevention efforts and in mitigating suicide risk in individual veterans. C1 [Thompson, James M.; Sweet, Jill; VanTil, Linda; MacLean, Mary Beth; Pedlar, David] Vet Affairs Canada, Res Directorate, Charlottetown, PE C1A 8M9, Canada. [Thompson, James M.; Hopman, Wilma H.] Queens Univ, Dept Publ Hlth Sci, Kingston, ON, Canada. [Zamorski, Mark A.] Canadian Forces Hlth Serv Grp, Directorate Mental Hlth, Ottawa, ON, Canada. [Sareen, Jitender] Univ Manitoba, Dept Psychiat, Winnipeg, MB R3T 2N2, Canada. [Sareen, Jitender] Univ Manitoba, Dept Psychol, Winnipeg, MB R3T 2N2, Canada. [Sareen, Jitender] Univ Manitoba, Dept Community Hlth Sci, Winnipeg, MB R3T 2N2, Canada. [Pietrzak, Robert H.] VA Connecticut Healthcare Syst, Natl Ctr Posttraumat Stress Disorder, US Dept Vet Affairs, West Haven, CT USA. [Pietrzak, Robert H.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Hopman, Wilma H.] Kingston Gen Hosp, Clin Res Ctr, Kingston, ON K7L 2V7, Canada. RP Thompson, JM (reprint author), Vet Affairs Canada, POB 7700,Rm 406 DJM Bldg,161 Grafton St, Charlottetown, PE C1A 8M9, Canada. EM research-recherche@vac-acc.gc.ca NR 31 TC 1 Z9 1 U1 4 U2 6 PU CANADIAN PUBLIC HEALTH ASSOC PI OTTAWA PA 1565 CARLING AVE, SUITE 300, OTTAWA, ONTARIO K1Z 8R1, CANADA SN 0008-4263 EI 1920-7476 J9 CAN J PUBLIC HEALTH JI Can. J. Public Health-Rev. Can. Sante Publ. PD MAR-APR PY 2014 VL 105 IS 2 BP E109 EP E115 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AS9UG UT WOS:000344586200004 PM 24886845 ER PT J AU Manchikanti, L Falco, FJE Kaye, AD Hirsch, JA AF Manchikanti, Laxmaiah Falco, Frank J. E. Kaye, Alan D. Hirsch, Joshua A. TI The Disastrous but Preventable Consequences of ICD-10 SO PAIN PHYSICIAN LA English DT Article ID READY C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Manchikanti, Laxmaiah] Univ Louisville, Louisville, KY 40292 USA. [Falco, Frank J. E.] Mid Atlantic Spine & Pain Phys, Newark, DE USA. [Falco, Frank J. E.] Temple Univ Hosp & Med Sch, Philadelphia, PA 19140 USA. [Kaye, Alan D.] LSU Hlth Sci Ctr, New Orleans, LA USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 27 TC 6 Z9 6 U1 0 U2 0 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD MAR-APR PY 2014 VL 17 IS 2 BP E111 EP E118 PG 8 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA AS7EX UT WOS:000344421100013 PM 24658482 ER PT J AU Greaney, ML De Jesus, M Sprunck-Harrild, KM Tellez, T Bastani, R Battaglia, TA Michaelson, JS Emmons, KM AF Greaney, Mary L. De Jesus, Maria Sprunck-Harrild, Kim M. Tellez, Trinidad Bastani, Roshan Battaglia, Tracy A. Michaelson, James S. Emmons, Karen M. TI Designing Audience-Centered Interactive Voice Response Messages to Promote Cancer Screenings Among Low-Income Latinas SO PREVENTING CHRONIC DISEASE LA English DT Article ID FORCE RECOMMENDATION STATEMENT; COMMUNITY-HEALTH-CENTER; SOCIETY GUIDELINES; UNITED-STATES; CERVICAL-CANCER; INTERVENTION; IMPLEMENTATION; PREVENTION; BARRIERS; BREAST AB Introduction Cancer screening rates among Latinas are suboptimal. The objective of this study was to explore how Latinas perceive cancer screening and the use and design of interactive voice response (IVR) messages to prompt scheduling of 1 or more needed screenings. Methods Seven focus groups were conducted with Latina community health center patients (n = 40) in need of 1 or more cancer screenings: 5 groups were of women in need of 1 cancer screening (breast, cervical, or colorectal), and 2 groups were of women in need of multiple screenings. A bilingual researcher conducted all focus groups in Spanish using a semistructured guide. Focus groups were recorded, transcribed, and translated into English for analysis. Emergent themes were identified by using thematic content analysis. Results Participants were familiar with cancer screening and viewed it positively, although barriers to screening were identified (unaware overdue for screening, lack of physician referral, lack of insurance or insufficient insurance coverage, embarrassment or fear of screening procedures, fear of screening outcomes). Women needing multiple screenings voiced more concern about screening procedures, whereas women in need of a single screening expressed greater worry about the screening outcome. Participants were receptive to receiving IVR messages and believed that culturally appropriate messages that specified needed screenings while emphasizing the benefit of preventive screening would motivate them to schedule needed screenings. Conclusion Participants' receptiveness to IVR messages suggests that these messages may be an acceptable strategy to promote cancer screening among underserved Latina patients. Additional research is needed to determine the effectiveness of IVR messages in promoting completion of cancer screening. C1 [De Jesus, Maria] Amer Univ, Ctr Hlth Risk Soc, Washington, DC 20016 USA. [De Jesus, Maria] Amer Univ, Sch Int Serv, Washington, DC 20016 USA. [Sprunck-Harrild, Kim M.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Tellez, Trinidad] New Hampshire Dept Hlth & Human Serv, Concord, NH 03301 USA. [Bastani, Roshan] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Battaglia, Tracy A.] Boston Med Ctr, Boston, MA USA. [Battaglia, Tracy A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Michaelson, James S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Michaelson, James S.] Harvard Univ, Sch Med, Boston, MA USA. [Emmons, Karen M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Greaney, ML (reprint author), Univ Rhode Isl, Dept Kinesiol, 25 West Independence Way, Kingston, RI 02881 USA. EM mgreaney@mail.uri.edu FU National Cancer Institute [5R01CA126596, 1K05 CA124415] FX We thank the women who participated in this study and acknowledge Ms Martha Cruz and Ms Jewnifer Grullon for their effort on behalf of this research. This study was supported by grants from the National Cancer Institute, 5R01CA126596 and 1K05 CA124415. NR 31 TC 0 Z9 0 U1 0 U2 4 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD MAR PY 2014 VL 11 DI 10.5888/pcd11.130213N PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AR3XF UT WOS:000343521800007 ER PT J AU Homer, ML Perge, JA Black, MJ Harrison, MT Cash, SS Hochberg, LR AF Homer, Mark L. Perge, Janos A. Black, Michael J. Harrison, Matthew T. Cash, Sydney S. Hochberg, Leigh R. TI Adaptive Offset Correction for Intracortical Brain-Computer Interfaces SO IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING LA English DT Article DE Adaptive filtering; brain-computer interfaces (BCI); brain-machine interfaces (BMI); Kalman filter; motor cortex; neural decoding ID NEURAL-CONTROL; MACHINE INTERFACES; PROSTHETIC DEVICES; CORTICAL CONTROL; KALMAN FILTER; TETRAPLEGIA; ARM; ALGORITHM; MOVEMENT; DESIGN AB Intracortical brain-computer interfaces (iBCIs) decode intended movement from neural activity for the control of external devices such as a robotic arm. Standard approaches include a calibration phase to estimate decoding parameters. During iBCI operation, the statistical properties of the neural activity can depart from those observed during calibration, sometimes hindering a user's ability to control the iBCI. To address this problem, we adaptively correct the offset terms within a Kalman filter decoder via penalized maximum likelihood estimation. The approach can handle rapid shifts in neural signal behavior (on the order of seconds) and requires no knowledge of the intended movement. The algorithm, called multiple offset correction algorithm (MOCA), was tested using simulated neural activity and evaluated retrospectively using data collected from two people with tetraplegia operating an iBCI. In 19 clinical research test cases, where a nonadaptive Kalman filter yielded relatively high decoding errors, MOCA significantly reduced these errors (10.6 +/- 10.1%; p < 0.05, pairwise t-test). MOCA did not significantly change the error in the remaining 23 cases where a nonadaptive Kalman filter already performed well. These results suggest that MOCA provides more robust decoding than the standard Kalman filter for iBCIs. C1 [Homer, Mark L.] Brown Univ, Providence, RI 02912 USA. [Perge, Janos A.; Hochberg, Leigh R.] Brown Univ, Sch Engn, Providence, RI 02912 USA. [Black, Michael J.] Max Planck Inst Intelligent Syst, D-72076 Tubingen, Germany. [Black, Michael J.] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA. [Harrison, Matthew T.] Brown Univ, Div Appl Math, Providence, RI 02912 USA. [Cash, Sydney S.; Hochberg, Leigh R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Cash, Sydney S.; Hochberg, Leigh R.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Hochberg, Leigh R.] Dept Vet Affairs Med Ctr, Rehabil Res & Dev Serv, Ctr Neurorestorat & Neurotechnol, Providence, RI 02908 USA. RP Homer, ML (reprint author), Brown Univ, Providence, RI 02912 USA. EM mark_homer@brown.edu; janos_perge@brown.edu; black@tuebingen.mpg.de; matthew_harrison@brown.edu; scash@partners.org; leigh_hochberg@brown.edu OI Hochberg, Leigh/0000-0003-0261-2273 FU Rehabilitation Research and Development Service, Office of Research and Development, Department of Veterans Affairs [B6453R, B6310N]; National Institutes of Health: NIDCD [R01DC009899]; NICHD-NCMRR [N01HD53403, N01HD10018]; DARPA REPAIR [N66001-10-C-2010]; Doris Duke Charitable Foundation; MGH-Deane Institute for Integrated Research on Atrial Fibrillation and Stroke FX Manuscript received March 01, 2013; revised September 12, 2013; accepted October 14, 2013. Date of publication November 01, 2013; date of current version March 05, 2014. The research was supported by the Rehabilitation Research and Development Service, Office of Research and Development, Department of Veterans Affairs (Merit Review Award B6453R; Career Development Transition Award B6310N). Support was also provided by the National Institutes of Health: NIDCD (R01DC009899), NICHD-NCMRR (N01HD53403 and N01HD10018); DARPA REPAIR (N66001-10-C-2010); the Doris Duke Charitable Foundation; the MGH-Deane Institute for Integrated Research on Atrial Fibrillation and Stroke. The pilot clinical trial into which participant S3 was recruited was sponsored in part by Cyberkinetics Neurotechnology Systems (CKI). The contents do not represent the views of the Department of Veterans Affairs or the United States Government. NR 51 TC 1 Z9 3 U1 0 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1534-4320 EI 1558-0210 J9 IEEE T NEUR SYS REH JI IEEE Trans. Neural Syst. Rehabil. Eng. PD MAR PY 2014 VL 22 IS 2 BP 239 EP 248 DI 10.1109/TNSRE.2013.2287768 PG 10 WC Engineering, Biomedical; Rehabilitation SC Engineering; Rehabilitation GA AP4VV UT WOS:000342078300005 PM 24196868 ER PT J AU Cvetanovich, GL Bhatia, S Provencher, MT Cole, BJ AF Cvetanovich, Gregory L. Bhatia, Sanjeev Provencher, Matthew T. Cole, Brian J. TI Treatment of Bone Defects in Posterior Instability SO OPERATIVE TECHNIQUES IN SPORTS MEDICINE LA English DT Article DE posterior instability; allograft; posterior glenoid bone defect ID SHOULDER INSTABILITY; HUMERAL HEAD; ALLOGRAFT RECONSTRUCTION; MCLAUGHLIN PROCEDURE; SEGMENTAL DEFECTS; BLOCK PROCEDURE; DISLOCATION; OSTEOTOMY; GLENOPLASTY; SUBLUXATION AB When compared with anterior glenohumeral instability, posterior glenohumeral instability is a relatively rare condition, and it can pose a diagnostic and therapeutic challenge for the orthopaedic surgeon. Although many patients only have damage to the posterior capsulolabral structures, some have bone defects associated with posterior instability, including defects of the posterior glenoid rim, glenoid retroversion, and an anterosuperior impaction fracture of the humeral head known as the reverse Hill-Sachs lesion. When nonoperative treatments fail, surgical management aims to identify and address both soft tissue and bony factors involved in posterior instability so as to minimize the chances of recurrent instability after surgery. Operative treatment options vary for these different bone defects associated with posterior instability, and there are relatively little data to guide surgical indications and treatment decisions. In this article, we discuss our approach to the treatment of bone defects in posterior instability with emphasis on which techniques are used in different circumstances as well as technical pearls and pitfalls. (C) 2014 Elsevier Inc. All rights reserved. C1 [Cvetanovich, Gregory L.; Bhatia, Sanjeev; Cole, Brian J.] Rush Univ, Med Ctr, Div Sports Med, Dept Orthopaed Surg, Chicago, IL 60612 USA. [Provencher, Matthew T.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Sports Med Serv, Boston, MA 02114 USA. [Cole, Brian J.] Rush Univ, Med Ctr, Cartilage Restorat Ctr, Chicago, IL 60612 USA. RP Cole, BJ (reprint author), Rush Univ, Med Ctr, Div Sports Med, Dept Orthopaed Surg, 1611 W Harrison,Suite 300, Chicago, IL 60612 USA. EM bcole@rushortho.com NR 45 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1060-1872 EI 1557-9794 J9 OPER TECHN SPORT MED JI Oper. Tech. Sports Med. PD MAR PY 2014 VL 22 IS 1 BP 10 EP 17 DI 10.1053/j.otsm.2014.02.007 PG 8 WC Sport Sciences; Surgery SC Sport Sciences; Surgery GA AP5KZ UT WOS:000342119400003 ER PT J AU Frank, RM Golijanan, P Gross, DJ Provencher, MT AF Frank, Rachel M. Golijanan, Petar Gross, Daniel J. Provencher, Matthew T. TI The Arthroscopic Rotator Interval Closure: Why, When, and How? SO OPERATIVE TECHNIQUES IN SPORTS MEDICINE LA English DT Article DE rotator interval; shoulder instability; arthroscopic closure; biceps tendinopathy ID MULTIDIRECTIONAL SHOULDER INSTABILITY; CORACOHUMERAL LIGAMENT; CUFF INTERVAL; GLENOHUMERAL JOINT; POSTERIOR INSTABILITY; ALTERNATIVE TECHNIQUE; ADHESIVE CAPSULITIS; MR ARTHROGRAPHY; LONG HEAD; ANTERIOR AB The contribution of the rotator interval (RI) to the overall stability of the glenohumeral joint remains under debate. With improvements in the interpretation of both physical examination and diagnostic imaging findings, the diagnosis of RI pathology is becoming easier to identify. The clinical implications of RI pathology, however, still remain controversial. Injury to RI may contribute to glenohumeral instability, and both biomechanical and clinical studies have shown improvements in anterior shoulder stabilization following RI closure. The benefits of RI repair in the setting of posterior shoulder and multidirectional instability, however, are unclear. The optimal surgical technique is also unclear, and a variety of open and arthroscopic methods have been described. The purposes of this article are to review the surgical anatomy relevant to RI closure, discuss the biomechanical rationale for repairing the RI, and provide our preferred technique for performing arthroscopic RI closure. (C) 2014 Elsevier Inc. All rights reserved. C1 [Frank, Rachel M.] Rush Univ, Med Ctr, Dept Orthopaed Surg, Chicago, IL 60612 USA. [Golijanan, Petar; Gross, Daniel J.; Provencher, Matthew T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Provencher, MT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 175 Cambridge St,Suite 400, Boston, MA 02114 USA. EM mtprovencher@partners.org NR 72 TC 1 Z9 1 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1060-1872 EI 1557-9794 J9 OPER TECHN SPORT MED JI Oper. Tech. Sports Med. PD MAR PY 2014 VL 22 IS 1 BP 48 EP 57 DI 10.1053/j.otsm.2014.02.005 PG 10 WC Sport Sciences; Surgery SC Sport Sciences; Surgery GA AP5KZ UT WOS:000342119400008 ER PT J AU Hayakawa, K Pham, LDD Arai, K Lo, EH AF Hayakawa, Kazuhide Pham, Loc-Duyen D. Arai, Ken Lo, Eng H. TI Reactive astrocytes promote adhesive interactions between brain endothelium and endothelial progenitor cells via HMGB1 and beta-2 integrin signaling SO STEM CELL RESEARCH LA English DT Article ID GLYCATION END-PRODUCTS; GROUP BOX 1; CORTICAL ASTROCYTES; ISCHEMIC-STROKE; RECEPTOR; RAGE; MICE; DIFFERENTIATION; ANGIOGENESIS; AMPHOTERIN AB Endothelial progenitor cells (EPCs) may contribute to neurovascular repair after stroke and neurodegeneration. A key step in this process should involve adhesive interactions between EPCs and the targeted cerebral endothelium. Here, we tested the hypothesis that reactive astrocytes may play a critical role in enhancing adhesive interactions and transmigration of EPCs across cerebral endothelial cells. Transiently seeding EPCs onto a monolayer of RBE. 4 rat brain endothelial cells resulted in a time-dependent adherence between the two cell types. Blocking beta 2 integrins on EPCs or blocking the receptor for advanced glycation endproducts (RAGE) on endothelial cells significantly decreased EPC-endothelial adherence. Next, we tested whether reactive astrocytes can enhance this process by growing EPCs, brain endothelial cells and astrocytes together in a transwell co-culture system. The presence of reactive astrocytes in the lower chamber significantly promoted adherence between EPCs and endothelial cells in the upper chamber. This process involved the release of soluble HMGB1 from reactive astrocytes that then upregulated endothelial expression of RAGE via Egr1 signaling. Directly adding HMGB1 to the transwell system also promoted EPC-endothelial adhesion and accelerated EPC transmigration into the lower chamber. These initial findings provide proof-of-concept that reactive astrocytes promote crosstalk between cerebral endothelium and EPCs. Further investigation of this phenomenon may lead to a better understanding of cell-cell interactions required for neurovascular recovery after stroke. (C) 2013 The Authors. Published by Elsevier B. V. All rights reserved. C1 Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Radiol, Charlestown, MA USA. Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Neurol, Charlestown, MA USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Hayakawa, K (reprint author), Neuroprotect Res Lab, MGH 149-2401,13th St, Charlestown, MA 02129 USA. EM khayakawa1@partners.org; Lo@helix.mgh.harvard.edu FU Rappaport Foundation; NIH [R01-NS76694, R01-NS65089, K99-NS80991] FX Supported in part by Rappaport Foundation and NIH (R01-NS76694, R01-NS65089, K99-NS80991). NR 29 TC 9 Z9 12 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-5061 EI 1876-7753 J9 STEM CELL RES JI Stem Cell Res. PD MAR PY 2014 VL 12 IS 2 BP 531 EP 538 DI 10.1016/j.scr.2013.12.008 PG 8 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA AP7VU UT WOS:000342286600017 PM 24480450 ER PT J AU Himle, MB Capriotti, MR Hayes, LP Ramanujam, K Scahill, L Sukhodolsky, DG Wilhelm, S Deckersbach, T Peterson, AL Specht, MW Walkup, JT Chang, S Piacentini, J AF Himle, Michael B. Capriotti, Matthew R. Hayes, Loran P. Ramanujam, Krishnapriya Scahill, Lawrence Sukhodolsky, Denis G. Wilhelm, Sabine Deckersbach, Thilo Peterson, Alan L. Specht, Matt W. Walkup, John T. Chang, Susanna Piacentini, John TI Variables Associated With Tic Exacerbation in Children With Chronic Tic Disorders SO BEHAVIOR MODIFICATION LA English DT Article DE Tourette disorder; chronic tic disorder; Comprehensive Behavioral Intervention for Tics; function-based assessment ID TOURETTE-SYNDROME; DIFFERENTIAL REINFORCEMENT; FUNCTIONAL-ANALYSIS; BEHAVIOR-THERAPY; SEVERITY-SCALE; SUPPRESSION; SYMPTOMS; RELIABILITY; ADOLESCENTS; SCREEN AB Research has shown that motor and vocal tics fluctuate in frequency, intensity, and form in response to environmental and contextual cues. Behavioral models have proposed that some of the variation in tics may reflect context-dependent interactive learning processes such that once tics are performed, they are influenced by environmental contingencies. The current study describes the results of a function-based assessment of tics (FBAT) from a recently completed study comparing Comprehensive Behavioral Intervention for Tics (CBIT) with supportive psychotherapy. The current study describes the frequency with which antecedent and consequence variables were reported to exacerbate tics and the relationships between these functional variables and sample baseline characteristics, comorbidities, and measures of tic severity. Results showed that tic-exacerbating antecedents and consequences were nearly ubiquitous in a sample of children with chronic tic disorder. In addition, functional variables were related to baseline measures of comorbid internalizing symptoms and specific measures of tic severity. C1 [Himle, Michael B.] Univ Utah, Salt Lake City, UT 84112 USA. [Hayes, Loran P.; Ramanujam, Krishnapriya] Univ Utah, Clin Psychol Program, Salt Lake City, UT 84112 USA. [Capriotti, Matthew R.] Univ Wisconsin, Milwaukee, WI 53201 USA. [Scahill, Lawrence] Emory Univ, Sch Med, Atlanta, GA USA. [Scahill, Lawrence] Yale Univ, Sch Med, New Haven, CT USA. [Sukhodolsky, Denis G.] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA. [Wilhelm, Sabine] Massachusetts Gen Hosp, Related Disorders Program, Boston, MA 02114 USA. [Deckersbach, Thilo] Massachusetts Gen Hosp, Bipolar Clin, Boston, MA 02114 USA. [Deckersbach, Thilo] Massachusetts Gen Hosp, Res Program, Boston, MA 02114 USA. [Wilhelm, Sabine; Deckersbach, Thilo] Harvard Univ, Sch Med, Boston, MA USA. [Peterson, Alan L.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Specht, Matt W.; Walkup, John T.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Walkup, John T.] Weill Cornell Med Coll, Div Child & Adolescent Psychiat, New York, NY USA. [Chang, Susanna; Piacentini, John] Univ Calif Los Angeles, Child OCD Anxiety & Tic Disorders Program, Los Angeles, CA USA. RP Himle, MB (reprint author), Univ Utah, Dept Psychol, 380 S 1530 E,Rm 502, Salt Lake City, UT 84112 USA. EM michael.himle@utah.edu OI Scahill, Lawrence/0000-0001-5073-1707; Sukhodolsky, Denis/0000-0002-5401-792X FU NCRR NIH HHS [UL1 RR024139]; NIMH NIH HHS [R01 MH070802, R01MH070802] NR 33 TC 6 Z9 6 U1 1 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-4455 EI 1552-4167 J9 BEHAV MODIF JI Behav. Modificat. PD MAR PY 2014 VL 38 IS 2 SI SI BP 163 EP 183 DI 10.1177/0145445514531016 PG 21 WC Psychology, Clinical SC Psychology GA AN9SU UT WOS:000340949700001 PM 24778433 ER PT J AU Garcia, HA Finley, EP Ketchum, N Jakupcak, M Dassori, A Reyes, SC AF Garcia, Hector A. Finley, Erin P. Ketchum, Norma Jakupcak, Matthew Dassori, Albana Reyes, Stephanie C. TI A Survey of Perceived Barriers and Attitudes Toward Mental Health Care Among OEF/OIF Veterans at VA Outpatient Mental Health Clinics SO MILITARY MEDICINE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; COMBAT DEPLOYMENT; HELP-SEEKING; WAR VETERANS; OIF VETERANS; IRAQ; AFGHANISTAN; MASCULINITY; THERAPY; PTSD AB Objective: In an effort to improve our understanding of perceived treatment barriers among veterans of Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) relative to other era veterans, the current study examined veteran attitudes and beliefs about mental health treatment and treatment-seeking, and perceived patient and institution-level logistical barriers to care. Method: A survey was conducted. among 434 Combat veterans seeking care in nine Veterans Affairs mental health care outpatient clinics. Results: When compared to Vietnam and Gulf War veterans, OEF/OIF veterans were significantly more likely to endorse negative treatment attitudes as possible barriers to care. OEF/OIF veterans were also more likely than Vietnam veterans to endorse conflicting work demands as a potential barrier, although this was the only logistical barrier for which OEF/OIF veterans' responses differed significantly from those of veterans of other eras. Among OEF/OIF veterans, older veterans were more likely than younger veterans to endorse barriers related to cost and time commitments. Conclusions: These findings suggest an important role for outreach and engagement strategies that address attitudinal barriers to treatment utilization among veteran populations. C1 [Garcia, Hector A.; Finley, Erin P.; Dassori, Albana] South Texas Vet Hlth Care Syst, Mental Hlth Outpatient Serv, San Antonio, TX 78240 USA. [Garcia, Hector A.; Finley, Erin P.; Dassori, Albana] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Finley, Erin P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Ketchum, Norma] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Jakupcak, Matthew] Puget Sound Hlth Care Syst, Deployment Hlth Clin S 116, Seattle, WA 98108 USA. [Reyes, Stephanie C.] Univ Texas Hlth Sci Ctr San Antonio, PBRN Resource Ctr, Inst Integrat Med & Sci, San Antonio, TX 78229 USA. RP Garcia, HA (reprint author), South Texas Vet Hlth Care Syst, Mental Hlth Outpatient Serv, 5788 Eckhert Rd 116A1, San Antonio, TX 78240 USA. OI Finley, Erin/0000-0003-4497-7721 FU Institute for the Integration of Medicine and Science at the University of Texas Health Science Center, San Antonio; National Institutes of Health Clinical Translational Science Award (CTSA) FX This project was supported by the Institute for the Integration of Medicine and Science at the University of Texas Health Science Center, San Antonio, and an National Institutes of Health Clinical Translational Science Award (CTSA). NR 28 TC 7 Z9 7 U1 1 U2 6 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 MAR PY 2014 VL 179 IS 3 BP 273 EP 278 DI 10.7205/MILMED-D-13-00076 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA AN7UJ UT WOS:000340806200011 PM 24594461 ER PT J AU Murdoch, M Polusny, MA Street, A Noorbaloochi, S Simon, AB Bangerter, A Grill, J Voller, E AF Murdoch, Maureen Polusny, Melissa A. Street, Amy Noorbaloochi, Siamak Simon, Alisha B. Bangerter, Ann Grill, Joseph Voller, Emily TI Sexual Assault During the Time of Gulf War I: A Cross-Sectional Survey of US Service Men Who Later Applied for Department of Veterans Affairs PTSD Disability Benefits SO MILITARY MEDICINE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; POPULATION-BASED SURVEY; DEPLOYMENT STRESSORS; PSYCHIATRIC-SYMPTOMS; NONRESPONSE BIAS; HARASSMENT; MILITARY; WOMEN; ASSOCIATION; PREVALENCE AB Objectives: To estimate the cumulative incidence of sexual assault during the time of Gulf War I among male Gulf War I Veterans who later applied for Department of Veterans Affairs (VA) post-traumatic stress disorder disability benefits and to identify potential risk and protective factors for sexual assault within the population. Method: Mailed, national, cross-sectional survey supplemented with VA administrative and clinical data. Results: Of 2,415 Veterans sampled, 1,700 (70%) responded. After adjusting for nonignorable missing data, the cumulative incidence of sexual assault during Gulf War I in this population ranged from 18% [95% confidence intervals (CI): 5.0%-51.9%] to 21% (95% CI: 20.0-22.0). Deployment was not associated with sexual assault [Odds Ratio (OR), 0.96; 95% CI: 0.75-1.23], but combat exposure was (OR, 1.80; 95% CI: 1.52-2.10). Other correlates of sexual assault within the population included working in a unit with greater tolerance of sexual harassment (OR, 1.80; 95% CI: 1.52-2.10) and being exposed to more sexual identity challenges (OR, 1.76; 95% CI: 1.55-2.00). Conclusions: The 9-month cumulative incidence of sexual assault in this particular population exceeded the lifetime cumulative incidence of sexual assault in U.S. civilian women. Although Persian Gulf deployment was not associated with sexual assault in this population, combat exposure was. C1 [Murdoch, Maureen; Polusny, Melissa A.; Noorbaloochi, Siamak; Simon, Alisha B.; Bangerter, Ann; Grill, Joseph] Minneapolis VA Hlth Care Syst, VA Hlth Serv Res & Dev HSR&D Serv Ctr Excellence, Ctr Chron Dis Outcomes Res, Minneapolis, MN 55417 USA. [Murdoch, Maureen] Minneapolis VA Hlth Care Syst, Gen Internal Med Sect, Minneapolis, MN 55417 USA. [Murdoch, Maureen; Noorbaloochi, Siamak; Grill, Joseph] Univ Minnesota, Sch Med, Dept Internal Med, Minneapolis, MN 55455 USA. [Polusny, Melissa A.; Voller, Emily] Minneapolis VA Hlth Care Syst, Dept Psychiat, Minneapolis, MN 55417 USA. [Polusny, Melissa A.; Voller, Emily] Minneapolis VA Hlth Care Syst, Dept Psychol, Minneapolis, MN 55417 USA. [Polusny, Melissa A.] Univ Minnesota, Sch Med, Dept Psychiat, Minneapolis, MN 55455 USA. [Street, Amy] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. [Street, Amy] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. RP Murdoch, M (reprint author), Minneapolis VA Hlth Care Syst, VA Hlth Serv Res & Dev HSR&D Serv Ctr Excellence, Ctr Chron Dis Outcomes Res, One Vet Dr, Minneapolis, MN 55417 USA. FU VA HSRD service [GWI 04-352]; VA Health Services Research and Development Service Center of Excellence [HFP 98-001] FX We thank Dr. Karen Kattar for her assistance working with study participants. Tracking services were provided by the University of Minnesota's Health Survey Research Center, under Dr. Eileen Harwood's direction. This study was supported by grant no. GWI 04-352 from VA HSR&D service and conducted at the Center for Chronic Disease Outcomes Research, a VA Health Services Research and Development Service Center of Excellence (Center grant no. HFP 98-001). Drs. Murdoch and Polusny are core investigators, Ms. Bangerter is Senior Health Scientist, and Dr. Noorbaloochi is statistician for the Center for Chronic Disease Outcomes Research at the Minneapolis VA Medical Center. NR 47 TC 7 Z9 7 U1 1 U2 8 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 MAR PY 2014 VL 179 IS 3 BP 285 EP 293 DI 10.7205/MILMED-D-12-00513 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AN7UJ UT WOS:000340806200013 PM 24594463 ER PT J AU Amara, J Iverson, KM Krengel, M Pogoda, TK Hendricks, A AF Amara, Jomana Iverson, Katherine M. Krengel, Maxine Pogoda, Terri K. Hendricks, Ann TI Anticipating the Traumatic Brain Injury-Related Health Care Needs of Women Veterans After the Department of Defense Change in Combat Assignment Policy SO WOMENS HEALTH ISSUES LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; IRAQI FREEDOM; MILITARY; GENDER AB Background: Female service members' presence in combat zones during Operation Enduring Freedom and Operation Iraqi Freedom is unprecedented both in terms of the number of women deployed and the nature of their involvement. In light of changing Department of Defense policy governing the deployment of women in combat zones, this article intends to set the groundwork for estimating future combat-related injuries and subsequent Veterans Health Administration (VHA) utilization while focusing on traumatic brain injury (TBI). Methods: The article summarizes and presents the results of a study that examines veterans who present to VHA for TBI evaluation. For a national sample of veterans, a dataset including information on post-screening utilization, diagnoses, and location of care was constructed. The dataset included self-reported health symptoms and other information obtained from a standardized national VHA post-screening clinical evaluation, the comprehensive TBI evaluation (CTBIE). Findings: Both women and men utilize high levels of VHA health care after a CTBIE. However, there are gender differences in the volume and types of services used, with women utilizing different services than their male counterparts and incurring higher costs, including higher overall and outpatient costs. Conclusion: As women veterans seek more of their health care from the VHA, there will be a need for more coordinated care to identify and manage deployment-related TBI and common comorbidities such as posttraumatic stress disorder, depression, and chronic pain. Deployment-connected injuries are likely to rise because of the rescinding of the ban on women in combat. This in turn has critical implications for VHA strategic planning and budgeting. Published by Elsevier Inc. C1 [Amara, Jomana] Naval Postgrad Sch, DRMI, Monterey, CA 93943 USA. [Iverson, Katherine M.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Iverson, Katherine M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Krengel, Maxine] VA Boston Healthcare Syst, Boston, MA USA. [Krengel, Maxine] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Pogoda, Terri K.] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Pogoda, Terri K.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Hendricks, Ann] VA Boston Healthcare Syst, Hlth Care Financing & Econ Ctr, Boston, MA USA. RP Amara, J (reprint author), Naval Postgrad Sch, DRMI Code 64, 699 Dyer Rd,Bldg 234, Monterey, CA 93943 USA. EM jhamara@nps.edu NR 37 TC 4 Z9 4 U1 3 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 EI 1878-4321 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD MAR-APR PY 2014 VL 24 IS 2 BP E171 EP E176 DI 10.1016/j.whi.2013.12.004 PG 6 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA AO1ZG UT WOS:000341113500003 PM 24630421 ER PT J AU Gunn, CM Freund, KM Kaplan, SA Raj, A Carr, PL AF Gunn, Christine M. Freund, Karen M. Kaplan, Samantha A. Raj, Anita Carr, Phyllis L. TI Knowledge and Perceptions of Family Leave Policies Among Female Faculty in Academic Medicine SO WOMENS HEALTH ISSUES LA English DT Article ID CAREER SATISFACTION; WOMEN PHYSICIANS; GENDER; SCHOOL; FLEXIBILITY AB Objective: The purpose of this research was to examine the knowledge and perceptions of family leave policies and practices among senior leaders including American Association of Medical College members of the Group on Women in Medicine and Science (GWIMS) to identify perceived barriers to career success and satisfaction among female faculty. Methods: In 2011 and 2012, GWIMS representatives and senior leaders at 24 medical schools were invited to participate in an interview about faculty perceptions of gender equity and overall institutional climate. An inductive, thematic analysis of the qualitative data was conducted to identify themes represented in participant responses. The research team read and reviewed institutional family leave policies for concordance with key informant descriptions. Findings: There were 22 GWIMS representatives and senior leaders in the final sample. Participants were all female; 18 (82%) were full professors with the remainder being associate professors. Compared with publicly available policies at each institution, the knowledge of nine participants was consistent with policies, was discrepant for six, with the remaining seven acknowledging a lack of knowledge of policies. Four major themes were identified from the interview data: 1) Framing family leave as a personal issue undermines its effect on female faculty success; 2) poor communication of policies impairs access and affects organizational climate; 3) discrepancies in leave implementation disadvantage certain faculty in terms of time and pay; and 4) leave policies are valued and directly related to academic productivity. Conclusions: Family leave policies are an important aspect of faculty satisfaction and academic success, yet policy awareness among senior leaders is lacking. Further organizational support is needed to promote equitable policy creation and implementation to support women in medical academia. Copyright (C) 2014 by the Jacobs Institute of Women's Health. Published by Elsevier Inc. C1 [Gunn, Christine M.] Boston Univ, Sch Med, Dept Med, Womens Hlth Unit, Boston, MA 02118 USA. [Freund, Karen M.] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. [Kaplan, Samantha A.] Boston Univ, Sch Med, Dept Obstet & Gynecol, Boston, MA 02118 USA. [Raj, Anita] Univ Calif San Diego, Dept Med, Div Global Publ Hlth, La Jolla, CA 92093 USA. [Carr, Phyllis L.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Gunn, CM (reprint author), Boston Univ, Sch Med, Dept Med, Womens Hlth Unit, 801 Massachusetts Ave,1st Floor, Boston, MA 02118 USA. EM cgunn@bu.edu OI Freund, Karen/0000-0002-9049-5574; Gunn, Christine/0000-0003-3340-2834 FU NIGMS NIH HHS [5R01 GM088470-02, R01 GM088470] NR 26 TC 5 Z9 5 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 EI 1878-4321 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD MAR-APR PY 2014 VL 24 IS 2 BP E205 EP E210 DI 10.1016/j.whi.2013.12.008 PG 6 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA AO1ZG UT WOS:000341113500007 PM 24533979 ER PT J AU Kazerooni, R Vu, K Takizawa, A Broadhead, C Morreale, AP AF Kazerooni, Rashid Khanh Vu Takizawa, Atsuhiko Broadhead, Christine Morreale, Anthony P. TI Association of Copayment and Socioeconomic Status with Hormonal Contraceptive Adherence in a Female Veteran Population SO WOMENS HEALTH ISSUES LA English DT Article ID AFFORDABLE CARE ACT; UNINTENDED PREGNANCY; UNITED-STATES; LOW-INCOME; DISPARITIES; EXPERIENCES; PREDICTORS; OUTCOMES; POVERTY; WOMEN AB Background: There are limited studies available analyzing association between copayment and hormonal contraception adherence. The study was conducted to investigate the association between copayment status and hormonal contraceptive adherence in a female veteran population when stratified by socioeconomic status. Methods: This 4-year, retrospective, cohort study of women Veterans from the Veterans Integrated Service Network 22, a network of Veterans Affairs facilities that includes Southern California and Nevada, included patients who received a new hormonal contraceptive prescription between October 1, 2008, and September 30, 2012. Patients were split into five quintiles (one having the lowest income and five the highest) dependent on zip code-based median annual household income from the 2007-2011 American Community Survey data. Medication possession ratio difference of copayment versus no copayment group for each respective quintile was the primary outcome. Analysis was done using multiple linear regression models. Results: A total of 3,622 patients met the inclusion criteria and were included in the analysis. Over the entire population, copayment was significantly associated with reduced adherence (-0.034; 95% confidence interval [CI], -0.06 to -0.008). Patients in the highest socioeconomic group, quintile five, had the largest reduction in adherence associated with having a copayment (-0.073; 95% CI, -0.129 to -0.017). Patients in the other four quintiles saw varying levels of decreased adherence respectively, although the differences did not achieve statistical significance. Conclusion: The association between adherence and copayment status varied by socioeconomic status. Our findings suggest that even affluent patients may be discouraged from adherence when subject to a copayment. If larger studies substantiate these findings, consideration should be given to a policy that exempts women veterans from copayments for hormonal contraceptives. Published by Elsevier Inc. C1 [Kazerooni, Rashid; Khanh Vu; Takizawa, Atsuhiko] Vet Affairs San Diego Healthcare Syst, San Diego, CA 92161 USA. [Kazerooni, Rashid; Khanh Vu; Takizawa, Atsuhiko] UCSD Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA USA. [Broadhead, Christine] Sharp HealthCare, San Diego, CA USA. [Morreale, Anthony P.] US Dept Vet Affairs, Natl Pharm Benefits Management Serv, San Diego, CA USA. RP Kazerooni, R (reprint author), Vet Affairs San Diego Healthcare Syst, 3350 La Jolla Village Dr 119, San Diego, CA 92161 USA. EM rashid.kazerooni@va.gov OI Kazerooni, Rashid/0000-0003-3223-2597 NR 28 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 EI 1878-4321 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD MAR-APR PY 2014 VL 24 IS 2 BP E237 EP E241 DI 10.1016/j.whi.2013.12.002 PG 5 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA AO1ZG UT WOS:000341113500011 PM 24533983 ER PT J AU Robison, K Clark, L Eng, W Wu, L Raker, C Clark, M Tejada-Berges, T Dizon, DS AF Robison, Katina Clark, Lindsay Eng, Whitney Wu, Lily Raker, Christina Clark, Melissa Tejada-Berges, Trevor Dizon, Don S. TI Cervical Cancer Prevention: Asian-American Women's Knowledge and Participation in Screening Practices SO WOMENS HEALTH ISSUES LA English DT Article ID HUMAN-PAPILLOMAVIRUS VACCINE; UNITED-STATES AB Objective: The purpose of this study was to compare cervical cancer knowledge and prevention strategy participation among Chinese-American women compared with Southeast-Asian-American women. Methods: We performed a cross-sectional survey of Chinese and Southeast Asian women in Rhode Island. Anonymous surveys were administered following informed consent. The survey included demographics and questions related to health care practices, cervical cancer, and the human papilloma virus (HPV). Categorical variables were compared by Fisher's exact test. Mean scores of correct answers on the knowledge questions were compared by Student's t-test and analysis of variance. Results: Ninety-six Chinese women and 132 Southeast Asian women were included in the analysis. Sixty-seven percent of Chinese women had at least a college education compared with 37% of Southeast Asian women (p < .0001). Nineteen percent of Chinese women reported annual household incomes of greater than $100,000 compared with 3% of Southeast Asian women (p = .0003). Twenty percent of Southeast Asian women did not have health insurance compared with 10% of Chinese women (p = .06). Among both groups, 25% of participants either never had a pap test or did not know if they ever had a pap test. There was a greater lack of knowledge about the relationship between HPV and cervical cancer among Chinese (mean 2.9 out of 8 questions) compared with Southeast Asian (mean 3.6 out of 8 questions; p = .02). Conclusions: Regardless of ethnic subgroup, education, or income, all participants had a poor knowledge of cervical cancer and HPV. This study supports the need for improvement in cervical cancer prevention education among all Asian women. Copyright (C) 2014 by the Jacobs Institute of Women's Health. Published by Elsevier Inc. C1 [Robison, Katina; Clark, Lindsay; Eng, Whitney; Wu, Lily; Raker, Christina; Clark, Melissa; Tejada-Berges, Trevor] Brown Univ, Women & Infants Hosp Rhode Isl, Warren Alpert Med Sch, Providence, RI 02905 USA. [Dizon, Don S.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Robison, K (reprint author), Brown Univ, Women & Infants Hosp, Program Womens Oncol, 101 Dudley St, Providence, RI 02905 USA. EM krobison@wihri.org FU NICHD NIH HHS [K12HD050108] NR 15 TC 6 Z9 6 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 EI 1878-4321 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD MAR-APR PY 2014 VL 24 IS 2 BP E231 EP E236 DI 10.1016/j.whi.2013.12.005 PG 6 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA AO1ZG UT WOS:000341113500010 PM 24533982 ER PT J AU Arias, DAA Kim, HJ Zhou, P Holderried, TAW Wang, X Dranoff, G Cantor, H AF Arias, Diana A. Alvarez Kim, Hye-Jung Zhou, Penghui Holderried, Tobias A. W. Wang, Xuan Dranoff, Glenn Cantor, Harvey TI Disruption of CD8(+) Treg Activity Results in Expansion of T Follicular Helper Cells and Enhanced Antitumor Immunity SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID MONOCLONAL-ANTIBODY; AUTOIMMUNE-DISEASE; DENDRITIC CELLS; SELF-TOLERANCE; SYSTEMIC-LUPUS; TUMOR-CELLS; PHASE-II; CANCER; IMMUNOTHERAPY; RESPONSES AB Tumor growth is associated with the inhibition of host antitumor immune responses that can impose serious obstacles to cancer immunotherapy. To define the potential contribution of Qa-1-restricted CD8 regulatory T cells (Treg) to the development of tumor immunity, we studied B6.Qa-1 D227K mice that harbor a point mutation in the MHC class Ib molecule Qa-1 that impairs CD8 Treg suppressive activity. Here, we report that the growth of B16 melanoma is substantially delayed in these Qa-1-mutant mice after therapeutic immunization with B16 melanoma cells engineered to express granulocyte macrophage colony-stimulating factor compared with Qa-1 B6-WT controls. Reduced tumor growth is associated with enhanced expansion of follicular T helper cells, germinal center B cells, and high titers of antitumor autoantibodies, which provoke robust antitumor immune responses in concert with tumor-specific cytolytic T cells. Analysis of tumor-infiltrating T cells revealed that the Qa-1 DK mutation was associated with an increase in the ratio of CD8(+) T effectors compared with CD8 Tregs. These data suggest that the CD8(+) T effector-Treg ratio may provide a useful prognostic index for cancer development and raise the possibility that depletion or inactivation of CD8 Tregs represents a potentially effective strategy to enhance antitumor immunity. (C) 2013 AACR. C1 [Arias, Diana A. Alvarez; Kim, Hye-Jung; Zhou, Penghui; Holderried, Tobias A. W.; Wang, Xuan; Dranoff, Glenn; Cantor, Harvey] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Dranoff, Glenn] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Arias, Diana A. Alvarez; Kim, Hye-Jung; Zhou, Penghui; Holderried, Tobias A. W.; Cantor, Harvey] Harvard Univ, Dept Microbiol & Immunol, Div Immunol, Sch Med, Boston, MA 02115 USA. [Dranoff, Glenn] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Holderried, Tobias A. W.] Univ Dusseldorf, Dept Gastroenterol Hepatol & Infect Dis, Dusseldorf, Germany. RP Cantor, H (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM harvey_cantor@dfci.harvard.edu FU NIH [AI 037562]; NRSA [T32AI07386, T32CA070083]; University of Dusseldorf (Dusseldorf, Germany) FX This work was supported in part by NIH research grant AI 037562 and a gift from the LeRoy Schecter Research Foundation (to H. Cantor) and NRSA Fellowships (T32AI07386; to D. Alvarez Arias) and (T32CA070083; to H-J. Kim). T.A.W. Holderried is supported by the University of Dusseldorf (Dusseldorf, Germany). NR 38 TC 6 Z9 6 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD MAR PY 2014 VL 2 IS 3 BP 207 EP 216 DI 10.1158/2326-6066.CIR-13-0121 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA AM7GH UT WOS:000340032800004 ER PT J AU Bachireddy, P Wu, CJ AF Bachireddy, Pavan Wu, Catherine J. TI Understanding anti-leukemia responses to donor lymphocyte infusion SO ONCOIMMUNOLOGY LA English DT Editorial Material DE T cell exhaustion; donor lymphocyte infusion; CML; stem cell transplantation; tumor-infiltrating lymphocytes ID STEM-CELL TRANSPLANTATION; LEUKEMIA; EXHAUSTION; IMMUNITY AB Donor lymphocyte infusion (DLI) is an established and potentially curative immune therapy for relapsed leukemia after hematopoietic stem cell transplant (HSCT). Herein, we describe the utility of DLI as a tractable model system to glean fresh insights into understanding and predicting effective anti-leukemia immunity. C1 [Wu, Catherine J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. RP Wu, CJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM cwu@partners.org FU NCI NIH HHS [T32 CA009172] NR 10 TC 2 Z9 3 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 EI 2162-402X J9 ONCOIMMUNOLOGY JI OncoImmunology PD MAR PY 2014 VL 3 IS 3 AR e28187 DI 10.4161/onci.28187 PG 3 WC Oncology; Immunology SC Oncology; Immunology GA AM6EC UT WOS:000339954400006 PM 25340010 ER PT J AU Naritoku, WY Alexander, CB Bennett, BD Black-Schaffer, WS Brissette, MD Grimes, MM Hoffman, RD Hunt, JL Iezzoni, JC Johnson, R Kozel, J Mendoza, RM Post, MD Powell, SZ Procop, GW Steinberg, JJ Thorsen, LM Nestler, SP AF Naritoku, Wesley Y. Alexander, C. Bruce Bennett, Betsy D. Black-Schaffer, W. Stephen Brissette, Mark D. Grimes, Margaret M. Hoffman, Robert D. Hunt, Jennifer L. Iezzoni, Julia C. Johnson, Rebecca Kozel, Jessica Mendoza, Ricardo M. Post, Miriam D. Powell, Suzanne Z. Procop, Gary W. Steinberg, Jacob J. Thorsen, Linda M. Nestler, Steven P. TI The Pathology Milestones and the Next Accreditation System SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article AB Context.-In the late 1990s, the Accreditation Council for Graduate Medical Education developed the Outcomes Project and the 6 general competencies with the intent to improve the outcome of graduate medical education in the United States. The competencies were used as the basis for developing learning goals and objectives and tools to evaluate residents' performance. By the mid-2000s the stakeholders in resident education and the general public felt that the Outcomes Project had fallen short of expectations. Objective.-To develop a new evaluation method to track trainee progress throughout residency using bench-marks called milestones. A change in leadership at the Accreditation Council for Graduate Medical Education brought a new vision for the accreditation of training programs and a radically different approach to the evaluation of residents. Data Sources.-The Pathology Milestones Working Group reviewed examples of developing milestones in other specialties, the literature, and the Accreditation Council for Graduate Medical Education program requirements for pathology to develop pathology milestones. The pathology milestones are a set of objective descriptors for measuring progress in the development of competency in patient care, procedural skill sets, medical knowledge, practice-based learning and improvement, interpersonal and communication skills, professionalism, and systems-based practice. Conclusions.-The milestones provide a national standard for evaluation that will be used for the assessment of all residents in Accreditation Council for Graduate Medical Education-accredited pathology training programs. C1 [Naritoku, Wesley Y.] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Alexander, C. Bruce] Univ Alabama, Dept Pathol, Tuscaloosa, AL 35487 USA. [Bennett, Betsy D.; Johnson, Rebecca] Amer Board Pathol, Tampa, FL USA. [Black-Schaffer, W. Stephen] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Black-Schaffer, W. Stephen] Harvard Univ, Sch Med, Boston, MA USA. [Brissette, Mark D.] Joint Pathol Ctr, Hematopathol Div, Silver Spring, MD USA. [Brissette, Mark D.] Joint Pathol Ctr, Hematopathol Div, Washington, DC USA. [Grimes, Margaret M.] Virginia Commonwealth Univ, Dept Pathol, Med Ctr, Richmond, VA 23284 USA. [Hoffman, Robert D.] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA. [Hunt, Jennifer L.] Univ Arkansas Med Sci, Dept Pathol, Little Rock, AR 72205 USA. [Iezzoni, Julia C.] Univ Virginia Hlth Syst, Dept Pathol, Charlottesville, VA USA. [Kozel, Jessica] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Mendoza, Ricardo M.] E Carolina Univ, Dept Pathol, Greenville, NC USA. [Post, Miriam D.] Univ Colorado, Sch Med, Dept Pathol, Aurora, CO USA. [Powell, Suzanne Z.] Methodist Hosp, Dept Pathol & Genom Med, Houston, TX 77030 USA. [Procop, Gary W.] Cleveland Clin Fdn, Dept Mol Pathol, Pathol & Lab Med Inst, Cleveland, OH 44195 USA. [Steinberg, Jacob J.] Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10467 USA. [Thorsen, Linda M.; Nestler, Steven P.] Accreditat Council Grad Med Educ, Chicago, IL USA. RP Naritoku, WY (reprint author), Univ So Calif, Keck Sch Med, Dept Pathol, 1200 N State St,Clin Tower Room A7A119, Los Angeles, CA 90033 USA. EM naritoku@usc.edu NR 10 TC 9 Z9 9 U1 0 U2 6 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD MAR PY 2014 VL 138 IS 3 BP 307 EP 315 DI 10.5858/arpa.2013-0260-SA PG 9 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA AM0QI UT WOS:000339550300006 PM 24576024 ER PT J AU McQuitty, E Zhang, W Hendrickson, H Tio, FO Jagirdar, J Olsen, R Cagle, PT AF McQuitty, Elizabeth Zhang, Wei Hendrickson, Heather Tio, Fermin O. Jagirdar, Jaishree Olsen, Randall Cagle, Philip T. TI Lung Adenocarcinoma Biomarker Incidence in Hispanic Versus Non-Hispanic White Patients SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID CANCER PATIENTS; KRAS MUTATIONS; PIK3CA MUTATION; GENE; EGFR; FREQUENCY; SURVIVAL; FEATURES; THERAPY AB Context.-Lung cancer is the leading cause of cancer deaths in the United States and worldwide. Biomarker testing is critical to personalized therapy in lung adenocarcinoma and has been extensively investigated in non-Hispanic whites, Asians, and African Americans. However, little information addresses the underlying genetic changes in lung adenocarcinoma among Hispanic patients in the United States. Objective.-To identify targetable biomarkers other than EGFR and EML4-ALK in Hispanic patients with lung adenocarcinoma. Design.-We tested DNA extracted from 85 lung adenocarcinoma specimens collected from 40 Hispanic and 43 non-Hispanic white patients for previously reported mutations in KRAS, MET, BRAF, mTOR, STAT3, JAK2, PIK3CA, AKT1 through AKT3, and PTEN with a custom Sequenom massARRAY assay (Sequenom, San Diego, California). Results.-Mutations in KRAS were identified in 11 cases (13%; 6 Hispanic [7%], 5 non-Hispanic white [6%]) and had no correlation with sex, age, or smoking history. Mutations in PIK3CA were identified in 2 of the 40 Hispanic patients (5%), including one patient (2.5%) with a concurrent KRAS mutation. The tumors were wild type for all other genes tested. Conclusions.-Targetable biomarkers other than EGFR and EML4-ALK were identified in 7 of the 40 Hispanic patients (18%) and 5 of the 43 non-Hispanic white patients (12%), suggesting a similar mutational frequency. Our highly multiplexed genotyping assay detected actionable mutations in 14% (12 of 83) more patients than would have been identified by EGFR and EML4-ALK testing alone. C1 [Zhang, Wei; Jagirdar, Jaishree] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Tio, Fermin O.] South Texas Vet Hlth Care Syst, Dept Anat & Clin Pathol, San Antonio, TX USA. [McQuitty, Elizabeth; Hendrickson, Heather; Olsen, Randall; Cagle, Philip T.] Houston Methodist Hosp, Dept Pathol & Genom Med, Houston, TX 77030 USA. RP Cagle, PT (reprint author), Houston Methodist Hosp, Dept Pathol & Genom Med, 6565 Fannin St,M227, Houston, TX 77030 USA. EM pcagle@HoustonMethodist.org NR 30 TC 3 Z9 3 U1 2 U2 5 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD MAR PY 2014 VL 138 IS 3 BP 390 EP 394 DI 10.5858/arpa.2013-0225-OA PG 5 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA AM0QI UT WOS:000339550300017 PM 23802852 ER PT J AU O'Neil, ME Carlson, KF Storzbach, D Brenner, LA Freeman, M Quinones, AR Motu'apuaka, M Kansagara, D AF O'Neil, Maya E. Carlson, Kathleen F. Storzbach, Daniel Brenner, Lisa A. Freeman, Michele Quinones, Ana R. Motu'apuaka, Makalapua Kansagara, Devan TI Factors Associated with Mild Traumatic Brain Injury in Veterans and Military Personnel: A Systematic Review SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Review DE Mild traumatic brain injury; Veteran; Military; Systematic review; Combat deployment; Cognitive functioning; Deployment related conditions ID POSTTRAUMATIC-STRESS-DISORDER; SERVICE MEMBERS; NEUROPSYCHOLOGICAL PERFORMANCE; POSTCONCUSSIVE SYMPTOMS; OEF/OIF VETERANS; OIF/OEF VETERANS; WAR VETERANS; US SOLDIERS; COMBAT; BLAST AB A history of mild traumatic brain injury (mTBI) is common among military members who served in Operations Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/OIF/OND). We completed a systematic review to describe the cognitive, mental health, physical health, functional, social, and cost consequences of mTBI in Veteran and military personnel. Of 2668 reviewed abstracts, the 31 included studies provided very low strength evidence for the questions of interest. Cognitive, physical, and mental health symptoms were commonly reported by Veterans/military members with a history of mTBI. On average, these symptoms were not significantly more common in those with a history of mTBI than in those without, although a lack of significant mean differences does not preclude the possibility that some individuals could experience substantial effects related to mTBI history. Evidence of potential risk or protective factors moderating mTBI outcomes was unclear. Although the overall strength of evidence is very low due to methodological limitations of included studies, our findings are consistent with civilian studies. Appropriate re-integration services are needed to address common comorbid conditions, such as treatment for post-traumatic stress disorder, substance use disorders, headaches, and other difficulties that Veterans and members of the military may experience after deployment regardless of mTBI history. C1 [O'Neil, Maya E.; Carlson, Kathleen F.; Storzbach, Daniel; Freeman, Michele; Quinones, Ana R.; Motu'apuaka, Makalapua; Kansagara, Devan] Portland VA Med Ctr, Portland, OR USA. [O'Neil, Maya E.; Carlson, Kathleen F.; Storzbach, Daniel; Freeman, Michele; Kansagara, Devan] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Brenner, Lisa A.] VISN 19 MIRECC, Denver VA Med Ctr, Denver, CO USA. [Brenner, Lisa A.] Univ Colorado, Denver, CO 80202 USA. RP O'Neil, ME (reprint author), 3710 SW US Vet Hosp Rd,Mail Code R&D 71, Portland, OR 97239 USA. EM maya.oneil@va.gov FU Veterans Affairs Quality Enhancement Research Initiative (QUERI) Evidence-based Synthesis Program (ESP) FX This study was funded by the Veterans Affairs Quality Enhancement Research Initiative (QUERI) Evidence-based Synthesis Program (ESP). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. All authors declare no conflicts of interests involved in the research presented in the manuscript. The corresponding author (MEO) declares she had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. We thank Edwin Reid and Tomiye Akagi for their editorial assistance, and Rose Relevo for library assistance. NR 40 TC 10 Z9 10 U1 1 U2 15 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 EI 1469-7661 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD MAR PY 2014 VL 20 IS 3 BP 249 EP 261 DI 10.1017/S135561771300146X PG 13 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA AM0UG UT WOS:000339561800001 PM 24622505 ER PT J AU Gellad, WF Choi, P Mizah, M Good, CB Kesselheim, AS AF Gellad, Walid F. Choi, Phillip Mizah, Margaret Good, Chester B. Kesselheim, Aaron S. TI Assessing the Chiral Switch: Approval and Use of Single-Enantiomer Drugs, 2001 to 2011 SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; 8-WEEK COMPARATIVE TRIAL; EROSIVE ESOPHAGITIS; DOUBLE-BLIND; OMEPRAZOLE; COST; MULTICENTER; MEDICATION; HEALTH; NAMES AB Objectives: A "chiral switch" occurs in the pharmaceutical market when a drug made up of 2 enantiomer forms is replaced with a purified single-enantiomer version, often in the context of a patent expiration.We studied the prevalence of chiral switching in the United States over the past decade, including trends in use of, and expenditures on, these products in Medicaid. Study Design: Retrospective analysis. Methods: We used US Adopted Names prefixes (lev/levo/ar/es/dex/dextro) to identify all single-enantiomer drugs approved from 2001 to 2011. From publicly available US Food and Drug Administration (FDA) approval documents, we extracted the characteristics of the pivotal premarket trials for the single enantiomers. Specifically, we evaluated whether the single enantiomer was directly compared with the precursor racemic drug and whether there was evidence of superior efficacy. We used quarterly drug expenditure data from each state Medicaid program to chart trends in use of, and spending on, the single-enantiomer products and their racemic precursors during the study period. Results: From 2001 to 2011, the FDA approved 9 single-enantiomer products: dexlansoprazole, levoleucovorin, levocetirizine, armodafinil, arformoterol, eszopiclone, escitalopram, dexmethyl-phenidate, and esomeprazole. Of those 9 drugs, 3 had at least 1 pre-approval randomized trial that included the racemic precursor as a direct comparator, but there was no evidence of superiority of the single enantiomer over the racemic at comparable doses. Between 2001 and 2011, US Medicaid programs spent approximately $6.3 billion on these 9 single-enantiomer drugs. Conclusions: Recently approved single-enantiomer drugs showed no evidence of superior efficacy over the older racemic precursors in the pivotal trials leading to their approval, and in a majority of cases, they were not directly compared. C1 [Gellad, Walid F.; Mizah, Margaret; Good, Chester B.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA 15206 USA. [Gellad, Walid F.; Choi, Phillip; Good, Chester B.] Univ Pittsburgh, Dept Med, Santa Monica, CA USA. [Kesselheim, Aaron S.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Program Regulat Therapeut & Law PORTAL, Boston, MA 02115 USA. [Kesselheim, Aaron S.] Harvard Univ, Sch Med, Boston, MA USA. RP Gellad, WF (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, 7180 Highland Dr, Pittsburgh, PA 15206 USA. EM walid.gellad@va.gov FU VA Health Services Research & Development (HSR&D) career development award [CDA 09-207]; Harvard Program in Therapeutic Science, Greenwall Faculty Scholarship in Bioethics; Agency for Healthcare Research Quality [K08HS18465-01]; Robert Wood Johnson Foundation Investigator Award in Health Policy Research FX Dr Gellad is supported by a VA Health Services Research & Development (HSR&D) career development award (CDA 09-207). Dr Kesselheim is supported by the Harvard Program in Therapeutic Science, Greenwall Faculty Scholarship in Bioethics, a career development award from the Agency for Healthcare Research & Quality (K08HS18465-01) and a Robert Wood Johnson Foundation Investigator Award in Health Policy Research. None of the funders played any role in the preparation of this article. NR 44 TC 4 Z9 4 U1 3 U2 20 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD MAR PY 2014 VL 20 IS 3 BP E90 EP E97 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AL5AO UT WOS:000339146100006 PM 24773330 ER PT J AU Nutt, JG Siderowf, AD Guttman, M Schmidt, PN Zamudio, JI Wu, SS Okun, MS Simuni, T Parashos, FSA Dahodwala, NA Davis, TL Giladi, N Gurevich, T Hauser, RA Jankovic, J Lyons, KE Marsh, L Miyasaki, JM Morgan, JC Santiago, AJ Tarsy, D Mari, Z Malaty, IA Nelson, EC AF Nutt, J. G. Siderowf, A. D. Guttman, M. Schmidt, P. N. Zamudio, J. I. Wu, S. S. Okun, M. S. Simuni, T. Parashos, F. S. A. Dahodwala, N. A. Davis, T. L. Giladi, N. Gurevich, T. Hauser, R. A. Jankovic, J. Lyons, K. E. Marsh, L. Miyasaki, J. M. Morgan, J. C. Santiago, A. J. Tarsy, D. Mari, Z. Malaty, I. A. Nelson, E. C. CA Natl Parkinson Fdn Quality TI Mobility, mood and site of care impact health related quality of life in Parkinson's disease SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Parkinson's disease; Health related quality of life; Best practices; Quality improvement ID CONTROLLED-TRIAL; MORTALITY; QUESTIONNAIRE; DEPRESSION; DISABILITY; SYMPTOMS; NONMOTOR; CRITERIA AB Objective: Examine the correlates of Health Related Quality of Life (HRQL) in a large cohort of Parkinson's disease (PD) patients from National Parkinson Foundation (NPF) Centers of Excellence (COEs). Background: Improving outcomes for PD will depend upon uncovering disease features impacting HRQL to identify targets for intervention and variables for risk-adjustment models. Differences in HRQL outcomes between COEs could uncover modifiable aspects of care delivery. Methods: This cross-sectional study examined the relative contribution of demographic, social, clinical and treatment features potentially related to HRQL, as measured by the PDQ-39, in 4601 consecutive subjects from 18 COEs. Stepwise linear regression was utilized to identify correlates of HRQL. Results: The variability in the PDQ-39 summary index score correlated with MY stage (R-2 = 22%), Timed up and Go (TUG) (17%), disease duration (11%), comorbidities (8%), cognitive status (8%), antidepressant use (6%) and center at which a patient received care (5%). Stepwise regression reordered the importance of the variables, with the H&Y first and TUG and the center becoming equal and the second most important variables determining the PDQ-39 total score. All independent variables together accounted for 44% of the variability in HRQL. Conclusions: We confirmed many but not all HRQL associations found in smaller studies. A novel observation was that the site of care was an important contributor to HRQL, suggesting that comparison of outcomes and processes among centers may identify best practices. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Nutt, J. G.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Siderowf, A. D.; Dahodwala, N. A.] Univ Penn, Philadelphia, PA 19104 USA. [Guttman, M.] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Schmidt, P. N.; Zamudio, J. I.; Okun, M. S.] Natl Parkinson Fdn, Miami, FL USA. [Wu, S. S.; Malaty, I. A.] Univ Florida, Gainesville, FL 32611 USA. [Simuni, T.] Northwestern Univ, Evanston, IL 60208 USA. [Parashos, F. S. A.] Struthers Parkinson Ctr, Golden Valley, MN USA. [Davis, T. L.] Vanderbilt Univ, Nashville, TN USA. [Giladi, N.; Gurevich, T.] Tel Aviv Sourasky Med Ctr, Tel Aviv, Israel. [Hauser, R. A.] Univ S Florida, Tampa, FL 33620 USA. [Jankovic, J.] Baylor Coll Med, Houston, TX 77030 USA. [Lyons, K. E.] Univ Kansas, Lawrence, KS 66045 USA. [Marsh, L.] DeBakey Vet Affairs Med Ctr, Houston, TX USA. [Morgan, J. C.] Georgia Regents Univ, Augusta, GA USA. [Santiago, A. J.] Muhammad Ali Parkinson Ctr, Phoenix, AZ USA. [Santiago, A. J.] Barrow Neurol Inst, Phoenix, AZ USA. [Tarsy, D.] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Mari, Z.] Johns Hopkins Med Ctr, Baltimore, MD USA. [Nelson, E. C.] Dartmouth Hitchcock Med Ctr, Lebanon, NH USA. RP Nutt, JG (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. EM nuttj@ohsu.edu OI Okun, Michael/0000-0002-6247-9358; Miyasaki, Janis/0000-0002-6372-6007 FU National Parkinson Foundation FX National Parkinson Foundation. NR 29 TC 5 Z9 5 U1 3 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD MAR PY 2014 VL 20 IS 3 BP 274 EP 279 DI 10.1016/j.parkreldis.2013.10.004 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA AK4RX UT WOS:000338412900002 PM 24182524 ER PT J AU Bellows, CF Robinson, C Fitzgibbons, RJ Webber, LS Berger, DH AF Bellows, Charles F. Robinson, Celia Fitzgibbons, Robert J., Jr. Webber, Larry S. Berger, David H. TI Watchful Waiting for Ventral Hernias: A Longitudinal Study SO AMERICAN SURGEON LA English DT Article ID QUALITY-OF-LIFE; INCISIONAL HERNIA; INGUINAL-HERNIA; CLINICAL-TRIAL; REPAIR AB Ventral hernias are a common clinical problem. Immediate repair is recommended for most ventral hernias despite significant recurrence rates. This practice may be related to a lack of understanding of the natural history of ventral hernias. The purpose of this study was to determine the natural history of ventral hernias and to determine if watchful waiting is an acceptable and safe option. Forty-one patients with ventral hernias were enrolled in a longitudinal cohort study of watchful waiting. Primary outcomes were functional impairment resulting from hernia disease as measured by the Activities Assessment Scale (AAS) and changes from baseline to two years in the physical and mental component score of the SF-36 Health Survey. Secondary outcomes included complications such as incarceration. Mixed-effects model for repeated measures and Student's t tests were used to evaluate scale performance. The mean age of enrollees was 64 years, and the mean hernia size was 239 cm(2). Eleven patients were lost to follow-up, and seven patients died of other causes. All remaining patients were followed for two years. There was one incarceration during the follow-up period. There was no deterioration in the AAS score (baseline vs 24 months = 28 vs 25, P = 0.60). There was deterioration of the physical functioning dimension of the SF-36 (baseline vs 24 months = 40 vs 32, P < 0.01), but the mental functioning dimension was improved (45 vs 51; P = 0.01). Watchful waiting was a safe option for patients in this study with ventral hernias. C1 [Bellows, Charles F.; Fitzgibbons, Robert J., Jr.] Tulane Univ, Dept Surg, New Orleans, LA 70115 USA. [Robinson, Celia; Berger, David H.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [Webber, Larry S.] Creighton Univ, Sch Med, Omaha, NE USA. RP Bellows, CF (reprint author), Tulane Univ, Dept Surg, 1430 Tulane Ave, New Orleans, LA 70115 USA. EM cbellows@tulane.edu NR 18 TC 11 Z9 11 U1 0 U2 1 PU SOUTHEASTERN SURGICAL CONGRESS PI CUMMING PA 115 SAMARITAN DR, #200, CUMMING, GA 30040-2354 USA SN 0003-1348 EI 1555-9823 J9 AM SURGEON JI Am. Surg. PD MAR PY 2014 VL 80 IS 3 BP 245 EP 252 PG 8 WC Surgery SC Surgery GA AJ5RJ UT WOS:000337743400019 PM 24666865 ER PT J AU Berry, C Ley, EJ Margulies, DR Pruett, J Miller, C Bukur, M Palestrant, D Malinoski, D Salim, A AF Berry, Cherisse Ley, Eric J. Margulies, Daniel R. Pruett, Jessica Miller, Chad Bukur, Marko Palestrant, David Malinoski, Darren Salim, Ali TI Prospective Evaluation of Posttraumatic Vasospasm: Determining Its Clinical Significance after Traumatic Brain Injury SO AMERICAN SURGEON LA English DT Article C1 [Berry, Cherisse; Ley, Eric J.; Margulies, Daniel R.; Pruett, Jessica] Cedars Sinai Med Ctr, Dept Surg, Div Trauma & Crit Care, Los Angeles, CA 90048 USA. [Miller, Chad] Wexner Med Ctr, Dept Neurol, Div Cerebrovasc Dis & Neurocrit Care, Columbus, OH USA. [Bukur, Marko] Broward Hlth & Del Ray Med Ctr, Dept Trauma & Crit Care, Ft Lauderdale, FL USA. [Palestrant, David] Cedars Sinai Med Ctr, Dept Neurol, Div Neurocrit Care, Los Angeles, CA 90048 USA. [Malinoski, Darren] Portland VA Med Ctr, Surg Crit Care Sect, Portland, OR USA. [Salim, Ali] Brigham & Womens Hosp, Dept Surg, Div Trauma Burns & Surg Crit Care, Boston, MA 02115 USA. RP Salim, A (reprint author), Brigham & Womens Hosp, Dept Surg, Div Trauma Burns & Surg Crit Care, 75 Francis St, Boston, MA 02115 USA. EM asalim1@partners.org NR 4 TC 1 Z9 1 U1 0 U2 0 PU SOUTHEASTERN SURGICAL CONGRESS PI CUMMING PA 115 SAMARITAN DR, #200, CUMMING, GA 30040-2354 USA SN 0003-1348 EI 1555-9823 J9 AM SURGEON JI Am. Surg. PD MAR PY 2014 VL 80 IS 3 BP 310 EP 312 PG 3 WC Surgery SC Surgery GA AJ5RJ UT WOS:000337743400030 PM 24666876 ER PT J AU Paulson, D Bowen, ME Lichtenberg, PA AF Paulson, Daniel Bowen, Mary Elizabeth Lichtenberg, Peter A. TI Does Brain Reserve Protect Older Women from Vascular Depression? SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article DE Cerebrovascular burden; Education; Mood ID LATE-LIFE DEPRESSION; COGNITIVE RESERVE; RISK-FACTORS; GERIATRIC DEPRESSION; SYMPTOMS; STROKE; ADULTS; HYPOTHESIS; MORTALITY; SAMPLE AB Objectives. Brain reserve theory, typically discussed in relation to dementia, was examined with regard to late-life depression symptomatology and cerebrovascular burden (CVB) in older-old women. Method. It was predicted that in a 6-year longitudinal sample (Health and Retirement Study) of 1,355 stroke-free women aged 80 years and older, higher levels of depressive symptomatology (8-item Center for Epidemiologic Studies-Depression score) would be predicted by high CVB, less educational attainment, and the education x CVB interaction after controlling for age and cognitive functioning (Telephone Interview for Cognitive Status). A latent growth curve model was used to identify differences in depression symptomatology at baseline and over time. Logistic regression analyses were used to predict clinically significant depressive symptomatology at each wave based on CVB, education, and the education x CVB interaction. Results. Results indicate that among older women, greater educational attainment predicted fewer depression symptoms at baseline, but this advantage was partially eroded over time. The education x CVB interaction predicted clinically significant depressive symptoms at baseline when the benefits of education were most robust. Discussion. Brain reserve, characterized by educational attainment, may counterbalance the effect of high CVB with respect to depressive symptoms, thereby preserving mood in late life. These findings support the application of brain reserve theory to late-life depression. C1 [Paulson, Daniel; Lichtenberg, Peter A.] Wayne State Univ, Inst Gerontol, Detroit, MI 48202 USA. [Paulson, Daniel; Lichtenberg, Peter A.] Wayne State Univ, Dept Psychol, Detroit, MI 48202 USA. [Paulson, Daniel] Ralph H Johnson VA Med Ctr, Dept Mental Hlth, Charleston, SC USA. [Bowen, Mary Elizabeth] Vet Hlth Adm, HSR & D RR & D Ctr Excellence, Tampa, FL USA. RP Paulson, D (reprint author), Wayne State Univ, Inst Gerontol, 87 East Ferry St,226 Knapp Bldg, Detroit, MI 48202 USA. EM Paulson@wayne.edu FU Blue Cross Blue Shield of Michigan Foundation [1680.SAP]; T32 grant [T-32 AG00275-06] FX This work was generously supported by the Blue Cross Blue Shield of Michigan Foundation (1680.SAP); and by the T32 grant-supported NIH Pre-Doctoral Training Program in Aging and Urban Health at the Institute of Gerontology (T-32 AG00275-06). NR 55 TC 4 Z9 4 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5014 EI 1758-5368 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD MAR PY 2014 VL 69 IS 2 BP 157 EP 167 DI 10.1093/geronb/gbt007 PG 11 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA AJ9EG UT WOS:000338009400002 PM 23448867 ER PT J AU Hilton, J Arnaout, A Clemons, M AF Hilton, John Arnaout, Angel Clemons, Mark TI Primary endocrine therapy as an approach for patients with localized breast cancer deemed not to be surgical candidates SO CURRENT OPINION IN SUPPORTIVE AND PALLIATIVE CARE LA English DT Review DE elderly; estrogen-receptor-positive breast cancer; nonsurgical candidates; primary endocrine therapy ID ESTROGEN-RECEPTOR-ALPHA; KINASE 4/6 INHIBITOR; ANTIESTROGEN RESISTANCE; PD 0332991; NEOADJUVANT LETROZOLE; POSTMENOPAUSAL WOMEN; AROMATASE INHIBITOR; ADJUVANT TAMOXIFEN; RANDOMIZED-TRIAL; ELDERLY-WOMEN AB Purpose of review For women diagnosed with localized hormone-receptor-positive breast cancer who have a poor performance status or who have medical conditions precluding aggressive treatment with chemotherapy or surgery, primary endocrine therapy has been proposed as a therapeutic alternative. Given that society is rapidly aging overall, this subset of patients will likely become a greater proportion of the patient population seen by breast cancer specialists. Recent findings On the basis of the results from randomized trials in patients whose health does not permit surgery, it appears that tamoxifen achieves a similar overall survival compared with surgery plus tamoxifen, supporting the use of primary endocrine therapy. In the neoadjuvant setting, aromatase inhibitors appear superior to tamoxifen, suggesting that these agents may be the best choice in the primary endocrine therapy setting. In addition, new breakthroughs for the management of hormone-receptor-positive disease in the metastatic setting have recently been reported. Summary This review will discuss the rationale and evidence for primary endocrine therapy; which agents could be selected for use; and how recent advances for the management of hormone-receptor-positive disease may potentially apply to this population. C1 [Hilton, John] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Arnaout, Angel] Ottawa Gen Hosp, Dept Surg, Ottawa, ON K1H 8L6, Canada. [Arnaout, Angel; Clemons, Mark] Ottawa Hosp Res Inst, Ottawa, ON, Canada. [Clemons, Mark] Ottawa Gen Hosp, Dept Med, Div Med Oncol, Ottawa, ON K1H 8L6, Canada. RP Hilton, J (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Early Drug Dev Ctr, 450 Brookline Ave, Boston, MA 02215 USA. EM john_hilton@dfci.harvard.edu NR 38 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1751-4258 EI 1751-4266 J9 CURR OPIN SUPPORT PA JI Curr. Opin Support Palliat. Car. PD MAR PY 2014 VL 8 IS 1 BP 53 EP 58 DI 10.1097/SPC.0000000000000026 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AJ2MI UT WOS:000337489700010 PM 24299966 ER PT J AU Gorrindo, T Chevalier, L Goldfarb, E Hoeppner, BB Birnbaum, RJ AF Gorrindo, Tristan Chevalier, Lydia Goldfarb, Elizabeth Hoeppner, Bettina B. Birnbaum, Robert J. TI Autonomic Arousal and Learning in Web-Based Simulation: A Feasibility Study SO JOURNAL OF CONTINUING EDUCATION IN THE HEALTH PROFESSIONS LA English DT Article DE online; computer-based education; program planning; curriculum development; simulation; self-directed learning; continuing medical education; engagement; online learning; pedagogy; physiology ID SKIN-CONDUCTANCE RESPONSES AB Introduction Autonomic arousal is an important component of understanding learning as it is related to cognitive effort, attention, and emotional arousal. Currently, however, little is known about its relationship to online education. We conducted a study to determine the feasibility of measuring autonomic arousal and engagement in online continuing medical education (CME). Method Using the Computer Simulation Assessment Tool (CSAT) platform, health care providers were randomly assigned to either high- or low-valence versions of a Web-based simulation on risk assessment for a returning veteran. Data were collected on participants' actions within the simulation, self-reported cognitive engagement, knowledge retention, and autonomic arousal measured using galvanic skin response (GSR). Results Participants in the high-valence condition (n = 7) chose a lower percentage of critical actions (M = 79.2, SD = 4.2) than participants in the low valence (n = 8) condition (M = 83.9, SD = 3.6, t(1,14) = 2.44, p = .03). While not statistically significant, high-valence participants reported higher cognitive engagement. Participants in the high-valence condition showed a larger increase in physiologic arousal when comparing mean tonic GSR during the orientation simulation to the study simulation (high-valence mean difference = 4.21 S, SD = 1.23 vs low-valence mean difference = 1.64 S, SD = 2.32, t(1,13) = -2.62, p = .01). Discussion In addition to being consistent with previous engagement research, this experiment functioned as a feasibility study for measuring autonomic arousal in online CME. The current study provides a framework for future studies, which may use neurophysiology to identify the critical autonomic and engagement components associated with effective online learning. C1 [Gorrindo, Tristan; Birnbaum, Robert J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. [Chevalier, Lydia; Goldfarb, Elizabeth] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hoeppner, Bettina B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Addict Med, Cambridge, MA 02138 USA. RP Gorrindo, T (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 1 Bowdoin Sq,Ste 700, Boston, MA 02114 USA. EM tristan.gorrindo@mgh.harvard.edu NR 17 TC 2 Z9 2 U1 1 U2 3 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 0894-1912 EI 1554-558X J9 J CONTIN EDUC HEALTH JI J. Contin. Educ. Health Prof. PD SPR PY 2014 VL 34 SU 1 BP S17 EP S22 DI 10.1002/chp.21234 PG 6 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA AJ4FZ UT WOS:000337629500005 PM 24935879 ER PT J AU Hertzman-Miller, R Beverly, E Goodrich, A AF Hertzman-Miller, Ruth Beverly, Elizabeth Goodrich, Anne TI An Assessment of Primary Care Providers' Educational Needs Regarding Treatment for Type 2 Diabetes Mellitus SO JOURNAL OF CONTINUING EDUCATION IN THE HEALTH PROFESSIONS LA English DT Article DE gap analysis; needs assessment; mixed methods research; profession-physicians C1 [Hertzman-Miller, Ruth] Med Programs, Athens, OH USA. [Beverly, Elizabeth] Ohio Univ, Inst Diabet, Athens, OH 45701 USA. [Goodrich, Anne] Humedica Inc, Strateg Alliances, Boston, MA USA. RP Hertzman-Miller, R (reprint author), Joslin Diabet Ctr Profess Educ, 1 Joslin Pl,Rm 719, Boston, MA 02215 USA. EM ruth.hertzman-miller@joslin.harvard.edu FU Sanofi-Aventis FX The authors report funding support was given by Sanofi-Aventis for the conduct of the presently reported study. NR 4 TC 1 Z9 1 U1 0 U2 0 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 0894-1912 EI 1554-558X J9 J CONTIN EDUC HEALTH JI J. Contin. Educ. Health Prof. PD SPR PY 2014 VL 34 SU 1 BP S32 EP S33 DI 10.1002/chp.21223 PG 2 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA AJ4FZ UT WOS:000337629500008 ER PT J AU Guddati, AK Joy, PS Marak, CP AF Guddati, Achuta K. Joy, Parijat S. Marak, Creticus P. TI Dose adjustment of carboplatin in patients on hemodialysis SO MEDICAL ONCOLOGY LA English DT Article DE Carboplatin; AUC; Dose; Hemodialysis ID CELL LUNG-CANCER; DEPENDENT RENAL-INSUFFICIENCY; ADVANCED OVARIAN-CANCER; COMBINATION CHEMOTHERAPY; PHARMACOKINETIC ANALYSIS; FORMULA; DOSAGE; PACLITAXEL; CISPLATIN; ETOPOSIDE AB Carboplatin is one of the most prescribed cytotoxic drug, which is extensively used in the treatment regimens of several malignancies. The therapeutic efficiency of carboplatin has been found to correlate the area under curve (AUC). The Calvert formula has been extensively used to determine the dose of carboplatin for a fixed AUC and glomerular filtration rate (GFR). This formula has also been used in patients with end-stage renal disease on hemodialysis by assuming that the GFR is zero. This is applicable to patients who receive hemodialysis within 12-18 h after carboplatin infusion. After the first 24 h, a majority of the carboplatin is bound to proteins is not easily dialyzable and hence continues to remain in the blood stream despite repeated sessions of hemodialysis. We derive a correction factor to calculate the resultant AUC in such patients. The analysis done by using this correction factor shows that the AUC can increase by eightfold in patients who received the adjusted dose but whose hemodialysis was delayed beyond 24 h after infusion. The correction factor proposed here can also be used to calculate the dose adjustment required a priori in patients who may receive delayed hemodialysis. It is also useful to predict the AUC and estimate the resultant toxicity in such patients. C1 [Guddati, Achuta K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Internal Med, Boston, MA 02163 USA. [Joy, Parijat S.] Univ Iowa, Univ Iowa Hosp & Clin, Dept Internal Med, Iowa City, IA 52242 USA. [Marak, Creticus P.] Tahlequah City Hosp, Dept Med, Div Pulm Med, Tahlequah, OK 74464 USA. RP Guddati, AK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Internal Med, 50 Fruit St, Boston, MA 02163 USA. EM aguddati@partners.org NR 28 TC 2 Z9 2 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 EI 1559-131X J9 MED ONCOL JI Med. Oncol. PD MAR PY 2014 VL 31 IS 3 AR 848 DI 10.1007/s12032-014-0848-0 PG 5 WC Oncology SC Oncology GA AJ5MV UT WOS:000337728700014 PM 24452283 ER PT J AU Di Paolo, NC Baldwin, LK Irons, EE Papayannopoulou, T Tomlinson, S Shayakhmetov, DM AF Di Paolo, Nelson C. Baldwin, Lisa K. Irons, Eric E. Papayannopoulou, Thalia Tomlinson, Stephen Shayakhmetov, Dmitry M. TI IL-1 alpha and Complement Cooperate in Triggering Local Neutrophilic Inflammation in Response to Adenovirus and Eliminating Virus-Containing Cells SO PLOS PATHOGENS LA English DT Article ID INNATE IMMUNE-RESPONSE; IN-VIVO; GENE-TRANSFER; IMMUNOCOMPROMISED PATIENTS; INTRAVENOUS-INJECTION; STERILE INFLAMMATION; ALTERNATIVE PATHWAY; CXCR4 ANTAGONIST; MICE DEFICIENT; KUPFFER CELLS AB Inflammation is a highly coordinated host response to infection, injury, or cell stress. In most instances, the inflammatory response is pro-survival and is aimed at restoring physiological tissue homeostasis and eliminating invading pathogens, although exuberant inflammation can lead to tissue damage and death. Intravascular injection of adenovirus (Ad) results in virus accumulation in resident tissue macrophages that trigger activation of CXCL1 and CXCL2 chemokines via the IL-1 alpha-IL-1RI signaling pathway. However, the mechanistic role and functional significance of this pathway in orchestrating cellular inflammatory responses to the virus in vivo remain unclear. Resident metallophilic macrophages expressing macrophage receptor with collagenous structure (MARCO(+)) in the splenic marginal zone (MZ) play the principal role in trapping Ad from the blood. Here we show that intravascular Ad administration leads to the rapid recruitment of Ly-6G(+)7/4(+) polymorphonuclear leukocytes (PMNs) in the splenic MZ, the anatomical compartment that remains free of PMNs when these cells are purged from the bone marrow via a non-inflammatory stimulus. Furthermore, PMN recruitment in the splenic MZ resulted in elimination of virus-containing cells. IL-1a-IL-1RI signaling is only partially responsible for PMN recruitment in the MZ and requires CXCR2, but not CXCR1 signaling. We further found reduced recruitment of PMNs in the splenic MZ in complement C3-deficient mice, and that pre-treatment of IL-1 alpha-deficient, but not wild-type mice, with complement inhibitor CR2-Crry (inhibits all complement pathways at C3 activation) or CR2-fH (inhibits only the alternative complement activation pathway) prior to Ad infection, abrogates PMN recruitment to the MZ and prevents elimination of MARCO(+) macrophages from the spleen. Collectively, our study reveals a non-redundant role of the molecular factors of innate immunity - the chemokine-activating IL-1 alpha-IL-1RI-CXCR2 axis and complement - in orchestrating local inflammation and functional cooperation of PMNs and resident macrophages in the splenic MZ, which collectively contribute to limiting disseminated pathogen spread via elimination of virus-containing cells. C1 [Di Paolo, Nelson C.; Shayakhmetov, Dmitry M.] Emory Univ, Sch Med, Dept Pediat, Lowance Ctr Human Immunol, Atlanta, GA 30322 USA. [Di Paolo, Nelson C.; Shayakhmetov, Dmitry M.] Emory Univ, Sch Med, Dept Med, Lowance Ctr Human Immunol, Atlanta, GA USA. [Baldwin, Lisa K.; Irons, Eric E.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Papayannopoulou, Thalia] Univ Washington, Dept Med, Div Hematol, Seattle, WA 98195 USA. [Tomlinson, Stephen] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Tomlinson, Stephen] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Di Paolo, NC (reprint author), Emory Univ, Sch Med, Dept Pediat, Lowance Ctr Human Immunol, Atlanta, GA 30322 USA. EM dmitryshay@emory.edu FU US NIH [AI065429, CA141439, CA158179]; VA [BX001218] FX This study was supported by US NIH grants AI065429 and CA141439 to DMS, CA158179 to ST, and VA grant BX001218 to ST. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 7 Z9 7 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD MAR PY 2014 VL 10 IS 3 AR e1004035 DI 10.1371/journal.ppat.1004035 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AJ2FF UT WOS:000337470300065 PM 24651866 ER PT J AU Zhang, YJ Lenart, BA Lee, JK Chen, D Shi, P Ren, J Muehleman, C Chen, D An, HS AF Zhang, Yejia Lenart, Brett A. Lee, Joseph K. Chen, Ding Shi, Peng Ren, Jing Muehleman, Carol Chen, Di An, Howard S. TI Histological Features of Endplates of the Mammalian Spine From Mice to Men SO SPINE LA English DT Article DE endplate; intervertebral disc; mammals; human ID INTERVERTEBRAL DISC DEGENERATION; HUMAN LUMBAR DISC; SOLUTE TRANSPORT; ANIMAL-MODELS; NUTRITION; COMPRESSION; VERTEBRAE; DENSITY; WINNER AB Study Design. Histological features of the intervertebral disc (IVD)-endplate interface were analyzed. Objective. To define cartilaginous and bony vertebral endplate in commonly used laboratory animals and compare with that of the humans. Summary of Background Data. Endplates are crucial for the IVD nutrient supply: the IVDs have limited blood supply; most nutrients diffuse through endplates to nourish the discs. Various animal models of IVD and endplate degeneration have been used to study the etiology and treatments of spinal disorders. However, because humans are biped, the spine mechanics differ significantly from other mammals. Translation of animal research findings requires a characterization and comparison of the vertebral endplate in the respective species. In this study, we compared the endplate structure of laboratory animal species at the age range commonly used for modeling spine degeneration with that of an adult human. Methods. Mouse, rat, rabbit, goat, and human IVDs and the adjacent vertebral bodies were isolated from the lower lumbar spine. Tissues were stained with Alcian Blue, counterstained with hematoxylin and eosin. Results. Structure of the vertebral endplate varied significantly between the adult animal species and that of the humans. Growth plates persisted in all adult animals studied, whereas the growth plate is absent in the adult humans. In the mice and rats, the cartilaginous endplates are in continuation with the growth plates, with only a small bony center. Rabbits and goats have a bony layer between cartilaginous endplate and the growth plate. The human endplate consist of a cartilaginous layer and the bony endplate. Conclusion. Significant differences exist in histological features of the endplate across animal species and that of the humans. Consideration should be given when animal models are used to study IVD degeneration and surgical treatments. C1 [Zhang, Yejia; Lenart, Brett A.; Lee, Joseph K.; Chen, Ding; Shi, Peng; An, Howard S.] Rush Univ, Med Ctr, Dept Orthoped Surg, Chicago, IL 60612 USA. [Zhang, Yejia] Rush Univ, Med Ctr, Dept Phys Med & Rehabil, Chicago, IL 60612 USA. [Zhang, Yejia; Muehleman, Carol; Chen, Di] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA. [Zhang, Yejia] Univ Penn, Perelman Sch Med, Dept Phys Med & Rehabil, Philadelphia, PA 19104 USA. [Zhang, Yejia] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Chen, Ding] Cent S Univ, Hosp Xiangya 2, Dept Orthoped Surg, Changsha, Hunan, Peoples R China. [Ren, Jing] Qujing 1 Hosp, Dept Orthoped, Qujing, Yunnan Province, Peoples R China. RP Zhang, YJ (reprint author), Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. EM yejia.zhang@uphs.upenn.edu FU NIAMS NIH HHS [R01 AR054465, R01 AR055915]; NICHD NIH HHS [K08 HD049598] NR 25 TC 9 Z9 11 U1 4 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 EI 1528-1159 J9 SPINE JI SPINE PD MAR 1 PY 2014 VL 39 IS 5 BP E312 EP E317 DI 10.1097/BRS.0000000000000174 PG 6 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA AJ1BN UT WOS:000337390700003 PM 24365894 ER PT J AU Mhatre, SD Satyasi, V Killen, M Paddock, BE Moir, RD Saunders, AJ Marenda, DR AF Mhatre, Siddhita D. Satyasi, Vivek Killen, Mark Paddock, Brie E. Moir, Robert D. Saunders, Aleister J. Marenda, Daniel R. TI Synaptic abnormalities in a Drosophila model of Alzheimer's disease SO DISEASE MODELS & MECHANISMS LA English DT Article DE APP; Alzheimer's disease; Drosophila; BACE; Synapse; NMJ ID AMYLOID PRECURSOR PROTEIN; LARVAL NEUROMUSCULAR-JUNCTION; CYSTEINE-STRING PROTEIN; A-BETA OLIGOMERS; MOUSE MODEL; OXIDATIVE DAMAGE; DISCS-LARGE; NEURODEGENERATIVE DISEASES; MITOCHONDRIAL DYSFUNCTION; AXONAL-TRANSPORT AB Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by memory loss and decreased synaptic function. Advances in transgenic animal models of AD have facilitated our understanding of this disorder, and have aided in the development, speed and efficiency of testing potential therapeutics. Recently, we have described the characterization of a novel model of AD in the fruit fly, Drosophila melanogaster, where we expressed the human AD-associated proteins APP and BACE in the central nervous system of the fly. Here we describe synaptic defects in the larval neuromuscular junction (NMJ) in this model. Our results indicate that expression of human APP and BACE at the larval NMJ leads to defective larval locomotion behavior, decreased presynaptic connections, altered mitochondrial localization in presynaptic motor neurons and decreased postsynaptic protein levels. Treating larvae expressing APP and BACE with the.-secretase inhibitor L-685,458 suppresses the behavioral defects as well as the pre- and postsynaptic defects. We suggest that this model will be useful to assess and model the synaptic dysfunction normally associated with AD, and will also serve as a powerful in vivo tool for rapid testing of potential therapeutics for AD. C1 [Mhatre, Siddhita D.; Satyasi, Vivek; Killen, Mark; Saunders, Aleister J.; Marenda, Daniel R.] Drexel Univ, Dept Biol, Philadelphia, PA 19104 USA. [Paddock, Brie E.] Arcadia Univ, Dept Biol, Glenside, PA 19038 USA. [Moir, Robert D.] Harvard Univ, Massachusetts Gen Hosp, Genet & Aging Res Unit, MIND,Sch Med, Boston, MA 02114 USA. [Saunders, Aleister J.] Drexel Univ, Dept Biochem & Mol Biol, Coll Med, Philadelphia, PA 19104 USA. [Saunders, Aleister J.; Marenda, Daniel R.] Drexel Univ, Dept Neurobiol & Anat, Coll Med, Philadelphia, PA 19104 USA. RP Marenda, DR (reprint author), Drexel Univ, Dept Biol, Philadelphia, PA 19104 USA. EM daniel.marenda@drexel.edu FU National Institutes of Health [R01NS057295, R21 RR026074]; National Science Foundation [IOS 1256114] FX Work in the Saunders lab is supported by the National Institutes of Health, grant R01NS057295 to A.J.S.; work in the Marenda lab is supported by the National Institutes of Health, grant R21 RR026074 to D.R.M., and from the National Science Foundation IOS 1256114 to D.R.M. NR 75 TC 10 Z9 11 U1 2 U2 21 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD MAR PY 2014 VL 7 IS 3 BP 373 EP 385 DI 10.1242/dmm.012104 PG 13 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AJ4DF UT WOS:000337620300008 PM 24487408 ER PT J AU Cadoni, S Gallittu, P Sanna, S Fanari, V Porcedda, ML Erriu, M Leung, FW AF Cadoni, Sergio Gallittu, Paolo Sanna, Stefano Fanari, Viviana Porcedda, Maria L. Erriu, Matteo Leung, Felix W. TI A two-center randomized controlled trial of water-aided colonoscopy versus air insufflation colonoscopy SO ENDOSCOPY LA English DT Article ID UNSEDATED COLONOSCOPY; WARM WATER; CECAL INTUBATION; QUALITY INDICATORS; COLORECTAL-CANCER; US VETERANS; SEDATION; INFUSION; IMMERSION; EXCHANGE AB Background and study aim: Water-aided colonoscopy includes water immersion and water exchange. Several small single-center studies have suggested that the use of water rather than air insufflation during colonoscopy reduces pain on insertion. The aim of this study was to investigate whether water-aided colonoscopy is less painful than air insufflation in a large cohort of patients. Patients and methods: This was a two-center, randomized controlled trial. Consecutive patients who agreed to start colonoscopy without premedication were included. Sedation was administered on demand. Water-aided colonoscopy was performed using water immersion in the early phase of the study, and subsequently water exchange was used. The primary endpoint was cecal intubation with pain scores of <= 2 and sedation with no or <= 2mg midazolam. Secondary outcomes were pain score at discharge, cecal intubation rate and time, and adenoma detection rate (ADR). Results: A total of 672 patients were randomized to water exchange (n=338) or air insufflation (n=334). The primary endpoint was achieved in more patients in the water exchange group (83.8% vs. 62%; P<0.0005). On-demand sedation was also required less (11.5% vs. 26.0 %; P<0.0005) and mean pain score was lower (1.3 vs. 2.3; P<0.0005) in the water exchange group. The cecal intubation rates were comparable. Water exchange had a significantly higher overall ADR (25.8% vs. 19.1 %; P=0.041), proximal ADR (10.1% vs. 4.8 %; P=0.014), and proximal <10mm ADR (7.7% vs. 3.9 %; P=0.046); proximal ADR was also higher in screening-only patients in the water exchange group (18.9% vs. 7.4 %; P=0.015). No detailed analysis was possible for the air insufflation vs. water immersion comparison. Conclusion: The current results confirmed that water exchange minimized the requirement for sedation and increased the ADR. C1 [Cadoni, Sergio; Gallittu, Paolo] S Barbara Hosp, Digest Endoscopy Unit, Iglesias, Carbonia Iglesi, Italy. [Sanna, Stefano; Fanari, Viviana; Porcedda, Maria L.] NS di Bonaria Hosp, Digest Endoscopy Unit, San Gavino Monreale, Villacidro Sanl, Italy. [Erriu, Matteo] Univ Cagliari, Dept Surg, Cagliari, Italy. [Leung, Felix W.] Vet Affairs Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, North Hills, CA USA. [Leung, Felix W.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Cadoni, S (reprint author), S Barbara Hosp, Digest Endoscopy Unit, Via S Leonardo 1, I-09016 Iglesias, CI, Italy. EM cadonisergio@gmail.com OI Erriu, Matteo/0000-0002-9818-5861 NR 34 TC 18 Z9 18 U1 0 U2 5 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0013-726X EI 1438-8812 J9 ENDOSCOPY JI Endoscopy PD MAR PY 2014 VL 46 IS 3 BP 212 EP 218 DI 10.1055/s-0033-1353604 PG 7 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AI8HL UT WOS:000337152400009 PM 24218307 ER PT J AU Edlow, BL McNab, JA Witzel, T van der Kouwe, A Stevens, A Vinke, L Ebling, M Frosch, MP Schwamm, LH Greenberg, SM Wu, O Wald, LL Perl, DP Fischl, B Kinney, HC Folkerth, RD AF Edlow, B. L. McNab, J. A. Witzel, T. van der Kouwe, A. Stevens, A. Vinke, L. Ebling, M. Frosch, M. P. Schwamm, L. H. Greenberg, S. M. Wu, O. Wald, L. L. Perl, D. P. Fischl, B. Kinney, H. C. Folkerth, R. D. TI Integration of Advanced Imaging and Histopathology to Determine the Neuroanatomic Basis of Traumatic Coma and Recovery of Consciousness SO NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY LA English DT Meeting Abstract CT 115th Meeting of the British-Neuropathological-Society, Institute-of-Child-Health CY MAR 05-07, 2014 CL London, ENGLAND SP British Neuropathol Soc, Inst Child Hlth C1 [Edlow, B. L.; Schwamm, L. H.; Greenberg, S. M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Edlow, B. L.; McNab, J. A.; Witzel, T.; van der Kouwe, A.; Stevens, A.; Vinke, L.; Ebling, M.; Wu, O.; Wald, L. L.; Fischl, B.] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [McNab, J. A.] Stanford Univ, Dept Radiol, Palo Alto, CA 94305 USA. [Frosch, M. P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Perl, D. P.] Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. [Kinney, H. C.; Folkerth, R. D.] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Folkerth, R. D.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. EM bedlow@partners.org RI Witzel, Thomas/P-1402-2014; Wald, Lawrence/D-4151-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0305-1846 EI 1365-2990 J9 NEUROPATH APPL NEURO JI Neuropathol. Appl. Neurobiol. PD MAR PY 2014 VL 40 SU 1 SI SI BP 27 EP 27 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA AI9VX UT WOS:000337291600031 ER PT J AU Bashirova, AA Martin-Gayo, E Jones, DC Qi, Y Apps, R Gao, XJ Burke, PS Taylor, CJ Rogich, J Wolinsky, S Bream, JH Duggal, P Hussain, S Martinson, J Weintrob, A Kirk, GD Fellay, J Buchbinder, SP Goedert, JJ Deeks, SG Pereyra, F Trowsdale, J Lichterfeld, M Telenti, A Walker, BD Allen, RL Carrington, M Yu, XG AF Bashirova, Arman A. Martin-Gayo, Enrique Jones, Des C. Qi, Ying Apps, Richard Gao, Xiaojiang Burke, Patrick S. Taylor, Craig J. Rogich, Jerome Wolinsky, Steven Bream, Jay H. Duggal, Priya Hussain, Shehnaz Martinson, Jeremy Weintrob, Amy Kirk, Gregory D. Fellay, Jacques Buchbinder, Susan P. Goedert, James J. Deeks, Steven G. Pereyra, Florencia Trowsdale, John Lichterfeld, Mathias Telenti, Amalio Walker, Bruce D. Allen, Rachel L. Carrington, Mary Yu, Xu G. TI LILRB2 Interaction with HLA Class I Correlates with Control of HIV-1 Infection SO PLOS GENETICS LA English DT Article ID MHC CLASS-I; INHIBITORY RECEPTOR; DENDRITIC CELLS; MYELOMONOCYTIC CELLS; HOST CONTROL; MOLECULES; AIDS; COMPLEX; BINDING; ILT4 AB Natural progression of HIV-1 infection depends on genetic variation in the human major histocompatibility complex (MHC) class I locus, and the CD8(+) T cell response is thought to be a primary mechanism of this effect. However, polymorphism within the MHC may also alter innate immune activity against human immunodeficiency virus type 1 (HIV-1) by changing interactions of human leukocyte antigen (HLA) class I molecules with leukocyte immunoglobulin-like receptors (LILR), a group of immunoregulatory receptors mainly expressed on myelomonocytic cells including dendritic cells (DCs). We used previously characterized HLA allotype-specific binding capacities of LILRB1 and LILRB2 as well as data from a large cohort of HIV-1-infected individuals (N = 5126) to test whether LILR-HLA class I interactions influence viral load in HIV-1 infection. Our analyses in persons of European descent, the largest ethnic group examined, show that the effect of HLA-B alleles on HIV-1 control correlates with the binding strength between corresponding HLA-B allotypes and LILRB2 (p = 10(-2)). Moreover, overall binding strength of LILRB2 to classical HLA class I allotypes, defined by the HLA-A/B/C genotypes in each patient, positively associates with viral replication in the absence of therapy in patients of both European (p = 10(-11)-10(-9)) and African (p = 10(-5)-10(-3)) descent. This effect appears to be driven by variations in LILRB2 binding affinities to HLA-B and is independent of individual class I allelic effects that are not related to the LILRB2 function. Correspondingly, in vitro experiments suggest that strong LILRB2-HLA binding negatively affects antigen-presenting properties of DCs. Thus, we propose an impact of LILRB2 on HIV-1 disease outcomes through altered regulation of DCs by LILRB2-HLA engagement. C1 [Bashirova, Arman A.; Qi, Ying; Apps, Richard; Gao, Xiaojiang; Carrington, Mary] Leidos Biomed Res Inc, Canc & Inflammat Program, Expt Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Bashirova, Arman A.; Martin-Gayo, Enrique; Burke, Patrick S.; Rogich, Jerome; Pereyra, Florencia; Walker, Bruce D.; Carrington, Mary; Yu, Xu G.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Jones, Des C.; Trowsdale, John] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England. [Taylor, Craig J.] Addenbrookes Hosp, Tissue Typing Labs, Cambridge, England. [Wolinsky, Steven] Northwestern Univ, Sch Med, Chicago, IL USA. [Bream, Jay H.; Duggal, Priya] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Hussain, Shehnaz] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Los Angeles, CA USA. [Martinson, Jeremy] Univ Pittsburgh, Pittsburgh, PA USA. [Weintrob, Amy] USU Infect Dis Clin Res Program, Bethesda, MD USA. [Kirk, Gregory D.] Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. [Fellay, Jacques] Ecole Polytech Fed Lausanne, Sch Life Sci, Lausanne, Switzerland. [Buchbinder, Susan P.] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Goedert, James J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Deeks, Steven G.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Pereyra, Florencia] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Lichterfeld, Mathias] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Telenti, Amalio] Univ Lausanne Hosp, Inst Microbiol, Lausanne, Switzerland. [Telenti, Amalio] Univ Lausanne, Lausanne, Switzerland. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Allen, Rachel L.] Univ London, St Georges Med Sch, London, England. RP Bashirova, AA (reprint author), Leidos Biomed Res Inc, Canc & Inflammat Program, Expt Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM xyu@partners.org RI SHCS, int. coll. A/G-4083-2011; Fellay, Jacques/A-6681-2009; SHCS, all/G-4072-2011; OI Fellay, Jacques/0000-0002-8240-939X; Martinson, Jeremy/0000-0003-4673-7238; Wolinsky, Steven/0000-0002-9625-6697 FU Frederick National Laboratory for Cancer Research [HHSN261200800001E]; NIH, Frederick National Lab, Center for Cancer Research; NIAID [R01 AI087145, K24 AI069994, R24 AI067039]; UCSF/Gladstone CFAR [P30 AI027763]; UCSF CTSI [UL1 RR024131]; Center for AIDS Prevention Studies [P30 MH62246]; Bill and Melinda Gates Foundation; AIDS Healthcare Foundation; Harvard University Center for AIDS Research (CFAR), an NIH [P30 AI060354]; NIAID, NIH; NCI, NIH; NICHD, NIH; NHLBI, NIH; NIDA, NIH; NIMH, NIH; NIA, NIH; FIC, NIH; OAR, NIH; Swiss National Science Foundation; NIH/NIAID [R01 AI078799, R56 AI098484, R01 AI087452, R01 AI089339]; MRC; Wellcome Trust; AICR; NIHR Cambridge BRC; National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Heart, Lung, and Blood Institute [U01-AI-35042, UL1-RR025005, U01-AI-35043, U01-AI-35039, U01-AI-35040, U01-AI-35041] FX This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. The SCOPE cohort was supported in part by the NIAID (R01 AI087145, K24 AI069994, R24 AI067039), UCSF/Gladstone CFAR (P30 AI027763), the UCSF CTSI (UL1 RR024131), and the Center for AIDS Prevention Studies (P30 MH62246). The International HIV Controllers Study (IHCS), was funded by the Bill and Melinda Gates Foundation, the AIDS Healthcare Foundation and the Harvard University Center for AIDS Research (CFAR), an NIH funded program(P30 AI060354), which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC and OAR. Members of the International HIV Controllers Study can be found at www.hivcontrollers.org. The Swiss HIV Cohort study (www.shcs.ch) is funded by the Swiss National Science Foundation. XGY was supported by NIH/NIAID R01 AI078799, R56 AI098484, R01 AI087452 and R01 AI089339. JT and DCJ were supported by the MRC, Wellcome Trust and AICR, with partial funding from the NIHR Cambridge BRC. We thank Randy Johnson and George Nelson for helpful discussions. We are grateful to the USU Infectious Disease Clinical Research Program HIV Working Group for collecting and providing clinical data. The MACS clinical data used in this manuscript were collected at: The Johns Hopkins Bloomberg School of Public Health (Joseph Margolick); Howard Brown Health Center and Northwestern University Medical School (John Phair, Steven Wolinsky); University of California, Los Angeles (Roger Detels, Oto Martinez-Maza); University of Pittsburgh (Charles Rinaldo); and Data Analysis Center (Lisa Jacobson). The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute; and the National Heart, Lung, and Blood Institute: U01-AI-35042, UL1-RR025005 (GCRC), U01-AI-35043, U01-AI-35039, U01-AI-35040, and U01-AI-35041. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 20 Z9 20 U1 3 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2014 VL 10 IS 3 AR e1004196 DI 10.1371/journal.pgen.1004196 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AI8FM UT WOS:000337144700026 PM 24603468 ER PT J AU Gopal, GJ Kumar, A Pal, J Mukhopadhyay, G AF Gopal, Gopal Jee Kumar, Awanish Pal, Jagannath Mukhopadhyay, Gauranga TI Molecular characterization and polyclonal antibody generation against core component CagX protein of Helicobacter pylori type IV secretion system SO BIOENGINEERED LA English DT Article DE H. pylori; Cag-PAI; type IV secretion system; CagX; molecular characterization ID PATHOGENICITY ISLAND; VIRULENCE FACTORS; INFECTION; INDUCTION; TRANSLOCATION; INTERLEUKIN-8; MUTAGENESIS; STRAINS; DISEASE; SURFACE AB Gram-negative bacteria Helicobacter pylori cause gastric ulcer, duodenal cancer, and found in almost half of the world's residents. The protein responsible for this disease is secreted through type IV secretion system (TFSS) of H. pylori. TFSS is encoded by 40-kb region of chromosomal DNA known as cag-pathogenicity island (PAI). TFSS comprises of three major components: cytoplasmic/inner membrane ATPase, transmembrane core-complex and outer membranous pilli, and associated subunits. Core complex consists of CagX, CagT, CagM, and Cag3(delta) proteins as per existing knowledge. In this study, we have characterized one of the important component of core-complex forming sub-unit protein, i.e., CagX. Complete ORF of CagX except signal peptide coding region was cloned and expressed in pET28a vector. Purification of CagX protein was performed, and polyclonal anti-sera against full-length recombinant CagX were raised in rabbit model. We obtained a very specific and high titer, CagX anti-sera that were utilized to characterize endogenous CagX. Surface localization of CagX was also seen by immunofluorescence microscopy. In short for the first time a full-length CagX was characterized, and we showed that CagX is the part of high molecular weight core complex, which is important for assembly and function of H. pylori TFSS. C1 [Gopal, Gopal Jee; Pal, Jagannath; Mukhopadhyay, Gauranga] Jawaharlal Nehru Univ, Special Ctr Mol Med, New Delhi 110067, India. [Gopal, Gopal Jee] Maharaja Sayajirao Univ Baroda, Fac Sci, Dept Biochem, Vadodara, Gujarat, India. [Kumar, Awanish] Natl Inst Technol, Dept Biotechnol, Raipur, Chhattisgarh, India. [Pal, Jagannath] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Gopal, GJ (reprint author), Jawaharlal Nehru Univ, Special Ctr Mol Med, New Delhi 110067, India. EM gopaljigopal@rediffmail.com; garunga@hotmail.com OI Kumar, Awanish/0000-0001-8735-479X FU Council for Scientific and Industrial Research (CSIR); University Grant Commission (UGC), New Delhi, India FX G.J.G. acknowledges the fellowships from the Council for Scientific and Industrial Research (CSIR) and University Grant Commission (UGC), New Delhi, India. Plasmid constructs were a kind gift from Prof Haas (Max-Planck-Institut fur Biologie, Abteilung Infektionsbiologie, Tubingen, Germany). The authors are thankful to Jawaharlal Nehru University, New Delhi, India, M. S. University of Baroda, Vadodara, Gujarat, India, National Institute of Technology, Raipur (Chhattisgarh), India. G.J.G. is grateful to Prof. Rakesh Bhatnagar (School of Biotechnology, Jawaharlal Nehru University [JNU], New Delhi, India) for providing valuable advice, encouragement, and support. NR 27 TC 0 Z9 0 U1 1 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2165-5979 EI 2165-5987 J9 BIOENGINEERED JI Bioengineered PD MAR-APR PY 2014 VL 5 IS 2 BP 107 EP 113 DI 10.4161/bioe.27808 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AI5KU UT WOS:000336906200017 PM 24637488 ER PT J AU Garrido, MM AF Garrido, Melissa M. TI Propensity Scores and Palliative Care SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Letter ID MODELS C1 [Garrido, Melissa M.] James J Peters VA Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. [Garrido, Melissa M.] Icahn Sch Med Mt Sinai, Brookdale Dept Geriatr & Palliat Med, New York, NY USA. RP Garrido, MM (reprint author), 130 W Kingsbridge Rd,Room 4A-17, Bronx, NY 10468 USA. EM melissa.garrido@mssm.edu FU NIA NIH HHS [P30 AG028741] NR 4 TC 3 Z9 3 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD MAR PY 2014 VL 17 IS 3 BP 261 EP 261 DI 10.1089/jpm.2013.0587 PG 1 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AI6ZL UT WOS:000337027700004 PM 24517275 ER PT J AU Goebel, JR Ahluwalia, SC Chong, K Shreve, ST Goldzweig, CL Austin, C Asch, SM Lorenz, KA AF Goebel, Joy R. Ahluwalia, Sangeeta C. Chong, Kelly Shreve, Scott T. Goldzweig, Caroline L. Austin, Colletta Asch, Steven M. Lorenz, Karl A. TI Developing an Informatics Tool To Advance Supportive Care: The Veterans Health Care Administration Palliative Care National Clinical Template SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID SET AB Background: Increasing emphasis in performance-based payment, public reporting, and quality improvement (QI) has led to widespread interest in measuring and improving the quality of care. By 2014, hospice programs will be required to report quality data to the federal government or incur financial penalties. With this increased interest in quality reporting comes an opportunity to develop informatics tools to capture data that reflect the complex practices involved in palliative care (PC). Therefore, there is a need to disseminate information on developing tools that facilitate capturing data and fostering improved performance. The Veterans Health Care Administration, a national leader in health information technology (HIT) and PC, established the Quality Improvement Resource Center (QuIRC) to develop innovative HIT tools to standardize and improve PC practices throughout the 153 Department of Veterans Affairs (VA) medical centers nationwide. Objective: The aim of the paper is to describe the development of the Palliative Care-National Clinical Template (PC-NCT) for documenting initial PC consults. Results: Domains of quality of life provided the foundation for this template. Principles of user-centered informatics design guided development activities. A national consensus panel of PC experts prioritized quality indicators as targets for QI. An interdisciplinary team of PC providers identified desired aspects of template functionality. QuIRC balanced PC providers' desired aspects of functionality against the feasibility within the VA HIT system. Formal pilot and usability testing contributed to numerous iterations of the PC-NCT currently piloted in five geographically distributed sites. Conclusion: This paper presents a robust approach to developing an informatics tool for PC practice. Data collected via the PC-NCT will bring variations in current practice into view and assist in directing resources at "important targets'' for QI. Although the development of HIT tools to quantify PC practice is complex, there is enormous potential to improve the quality of care for patients and families facing serious illnesses. C1 [Goebel, Joy R.] Calif State Univ Long Beach, Sch Nursing, Long Beach, CA 90804 USA. [Ahluwalia, Sangeeta C.] Oregon State Univ, Sch Social & Behav Hlth Sci, Corvallis, OR 97331 USA. [Chong, Kelly; Lorenz, Karl A.] Greater Los Angeles VA Hlth Care Syst, Qual Improvement Resource Ctr, Los Angeles, CA USA. [Shreve, Scott T.] Lebanon VA Hlth Care Syst, Hosp & Palliat Care, Lebanon, PA USA. [Shreve, Scott T.] Penn State Coll Med, Lebanon, PA USA. [Goldzweig, Caroline L.; Austin, Colletta] Greater Los Angeles VA Hlth Care Syst, Clin Informat, Los Angeles, CA USA. [Asch, Steven M.] Palo Alto VA Hlth Care Syst, Palo Alto, CA USA. [Asch, Steven M.] Stanford Univ, Div Gen Med Disciplines, Palo Alto, CA 94304 USA. [Lorenz, Karl A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Goebel, JR (reprint author), Calif State Univ Long Beach, Sch Nursing, 1250 Bellflower Blvd, Long Beach, CA 90804 USA. EM joy.goebel@csulb.edu NR 19 TC 0 Z9 0 U1 0 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD MAR PY 2014 VL 17 IS 3 BP 266 EP 273 DI 10.1089/jpm.2013.0288 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AI6ZL UT WOS:000337027700007 PM 24548178 ER PT J AU Pollock, CB McDonough, S Wang, VS Lee, H Ringer, L Li, X Prandi, C Lee, RJ Feldman, AS Koltai, H Kapulnik, Y Rodriguez, OC Schlegel, R Albanese, C Yarden, RI AF Pollock, Claire B. McDonough, Sara Wang, Victor S. Lee, Hyojung Ringer, Lymor Li, Xin Prandi, Cristina Lee, Richard J. Feldman, Adam S. Koltai, Hinanit Kapulnik, Yoram Rodriguez, Olga C. Schlegel, Richard Albanese, Christopher Yarden, Ronit I. TI Strigolactone analogues induce apoptosis through activation of p38 and the stress response pathway in cancer cell lines and in conditionally reprogrammed primary prostate cancer cells SO ONCOTARGET LA English DT Article DE Plant hormone; cell cycle arrest; apoptosis; stress response; p38-MAPK ID FOXO TRANSCRIPTION FACTOR; PROTEIN-KINASE; HEPATOCELLULAR-CARCINOMA; METHYL JASMONATE; EPITHELIAL-CELLS; MAPK PATHWAYS; PROLIFERATION; ARREST; JNK; P38-ALPHA AB Strigolactones are a novel class of plant hormones produced in roots and regulate shoot and root development. We have previously shown that synthetic strigolactone analogues potently inhibit growth of breast cancer cells and breast cancer stem cells. Here we show that strigolactone analogues inhibit the growth and survival of an array of cancer-derived cell lines representing solid and non-solid cancer cells including: prostate, colon, lung, melanoma, osteosarcoma and leukemic cell lines, while normal cells were minimally affected. Treatment of cancer cells with strigolactone analogues was hallmarked by activation of the stress-related MAPKs: p38 and JNK and induction of stress-related genes; cell cycle arrest and apoptosis evident by increased percentages of cells in the sub-G1 fraction and Annexin V staining. In addition, we tested the response of patient-matched conditionally reprogrammed primary prostate normal and cancer cells. The tumor cells exhibited significantly higher sensitivity to the two most potent SL analogues with increased apoptosis confirmed by PARP1 cleavage compared to their normal counterpart cells. Thus, Strigolactone analogues are promising candidates for anticancer therapy by their ability to specifically induce cell cycle arrest, cellular stress and apoptosis in tumor cells with minimal effects on growth and survival of normal cells. C1 [Pollock, Claire B.; McDonough, Sara; Wang, Victor S.; Lee, Hyojung; Yarden, Ronit I.] Georgetown Univ, Med Ctr, Dept Human Sci, Washington, DC 20057 USA. [Pollock, Claire B.; Ringer, Lymor; Rodriguez, Olga C.; Schlegel, Richard; Albanese, Christopher; Yarden, Ronit I.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Ringer, Lymor; Rodriguez, Olga C.; Schlegel, Richard; Albanese, Christopher] Georgetown Univ, Med Ctr, Dept Pathol, Washington, DC USA. [Ringer, Lymor; Rodriguez, Olga C.; Schlegel, Richard; Albanese, Christopher] Georgetown Univ, Med Ctr, Ctr Cellular Reprogramming, Washington, DC USA. [Li, Xin] Georgetown Univ, Med Ctr, Dept Biostat Bioinformat & Biomath, Washington, DC USA. [Prandi, Cristina] Univ Turin, Dept Chem, Turin, Italy. [Lee, Richard J.; Feldman, Adam S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Koltai, Hinanit] Agr Res Org, Dept Ornamental Hort, IL-50250 Bet Dagan, Israel. [Kapulnik, Yoram] Agr Res Org, Dept Field Crops, IL-50250 Bet Dagan, Israel. [Kapulnik, Yoram] Agr Res Org, Nat Resources Inst Plant Sci, IL-50250 Bet Dagan, Israel. RP Yarden, RI (reprint author), Georgetown Univ, Med Ctr, Dept Human Sci, Washington, DC 20057 USA. EM riy2@georgetown.edu RI prandi, cristina/L-9290-2015 OI prandi, cristina/0000-0001-9510-8783 FU NIH/NCI grant [P30-CA051008]; Department of Defense Breast Program [W81XWH-11-1-0190]; BioBits Project, Regione Piemonte, Italy; SLEP (Signaling Role of Strigolactones at the interface between plants, microorganisms and the Environment); DOD pre-doctoral grant [PC101946, R01 CA129003, DOD PCRP SIDA W81XWH-13-1-0327]; CTSA pilot award FX We gratefully thank Drs. Rebecca Riggins, York Tomita and Michael Johnson (Lombardi Comprehensive Cancer Centre) for sharing reagents and helpful discussions. We would also like to thank Allison Hall for her technical assistance. Technical services were provided by the Flow Cytometry & Cell Sorting, Genomics and Epigenomics and Tissue Culture Shared Resources Shared Resources which are partially supported by NIH/NCI grant P30-CA051008.; This work was supported by the Department of Defense Breast Program W81XWH-11-1-0190 (RIY) and by the BioBits Project, Regione Piemonte, Italy (CP), by the SLEP (Signaling Role of Strigolactones at the interface between plants, microorganisms and the Environment) (CP), by a DOD pre-doctoral grant PC101946 (LR), an R01 CA129003 (CA), a DOD PCRP SIDA W81XWH-13-1-0327 (CA) and CTSA pilot award (CA). NR 43 TC 15 Z9 15 U1 1 U2 24 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR PY 2014 VL 5 IS 6 BP 1683 EP 1698 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AI6EO UT WOS:000336964000023 PM 24742967 ER PT J AU Singh, S Petrovic, D Jamnik, E Aran, S Pourjabbar, S Kave, ML Bradley, SE Choy, G Kalra, MK AF Singh, Sarabjeet Petrovic, Dean Jamnik, Ethen Aran, Shima Pourjabbar, Sarvenaz Kave, Maggie L. Bradley, Stephen E. Choy, Garry Kalra, Mannudeep K. TI Effect of Localizer Radiograph on Radiation Dose Associated With Automatic Exposure Control: Human Cadaver and Patient Study SO JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY LA English DT Article DE automatic exposure control; radiation dose reduction; CT localizer radiograph; tube current modulation ID TUBE CURRENT MODULATION; Z-AXIS MODULATION; COMPUTED-TOMOGRAPHY; CT; REDUCTION; SYSTEMS; OPTIMIZATION; ABDOMEN; PELVIS AB Purpose: To evaluate the effect of localizing radiograph on computed tomography (CT) radiation dose associated with automatic exposure control with a human cadaver and patient study. Materials and Methods: Institutional review board approved the study with a waiver of informed consent. Two chest CT image series with fixed tube current and combined longitudinal-angular automatic exposure control (AEC) were acquired in a human cadaver (64-year-old man) after each of the 8 combinations of localizer radiographs (anteroposterior [AP], AP lateral, AP-posteroanterior [PA], lateral AP, lateral PA, PA, PA-AP, and PA lateral). Applied effective milliampere second, volume CT dose index (CTDIvol) and image noise were recorded for all 24-image series. Volume CT dose indexes were also recorded in 20 patients undergoing chest and abdominal CT after PA and PA-lateral radiographs with the use of AEC. Data were analyzed using analysis of variance and linear correlation tests. Results: With AEC, the CTDIvol fluctuates with the number and projection of localizer radiographs (P < 0.0001). Lowest CTDIvol values are seen when 2 orthogonal localizer radiographs are acquired, whereas highest values are seen when single PA or AP-PA projection localizer radiographs are acquired for planning (P < 0.0001). In 20 patients, CT scanning with AEC after acquisition of 2 orthogonal projection localizer radiographs was associated with significant reduction in radiation dose compared to PA projection radiographs alone (P < 0.0001). Conclusions: When scanning with AEC, acquisition of 2 orthogonal localizer radiographs is associated with lower CTDIvol compared to a single localizer radiograph. C1 [Singh, Sarabjeet; Aran, Shima; Pourjabbar, Sarvenaz; Kave, Maggie L.; Bradley, Stephen E.; Choy, Garry; Kalra, Mannudeep K.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Petrovic, Dean; Jamnik, Ethen] Univ Ljubljana, Dept Radiol, Med Ctr, Ljubljana, Slovenia. RP Singh, S (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM ssingh6@partners.org FU Radiological Society of North America (RSNA) Research and Education Foundation's Education Scholar Grant FX This study was supported in part by Radiological Society of North America (RSNA) Research and Education Foundation's Education Scholar Grant to one of the coauthors (MKK). The data were available to all coauthors throughout the course of the study and manuscript preparation. NR 16 TC 6 Z9 6 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-8715 EI 1532-3145 J9 J COMPUT ASSIST TOMO JI J. Comput. Assist. Tomogr. PD MAR-APR PY 2014 VL 38 IS 2 BP 293 EP 298 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AI2YZ UT WOS:000336726400025 PM 24632938 ER PT J AU Butros, SR DelCarmen, MG Uppot, RN Arellano, RS AF Butros, Selim R. DelCarmen, Marcela G. Uppot, Raul N. Arellano, Ronald S. TI Image-Guided Percutaneous Thermal Ablation of Metastatic Pelvic Tumor From Gynecologic Malignancies SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID RADIOFREQUENCY ABLATION; HEPATOCELLULAR-CARCINOMA; WATER AB BACKGROUND: Image-guided percutaneous thermal ablation is a commonly performed therapeutic procedure for various tumors. Thermal ablation is not frequently used in the pelvis as a result of anatomic concerns and the potential risk of nontarget tissue injury. TECHNIQUE: Percutaneous thermal ablation is a minimally invasive procedure involving special probes inserted through the skin to the target lesion under imaging guidance. Various delivery methods of thermal ablation exist, including radiofrequency ablation, which burns tissue, and cryoablation, which freezes tissue with an ultimate goal to destroy the target tumor while minimizing damage to adjacent structures. Protective measures can be used to provide access and safe treatment delivery such as pyeloperfusion to protect the ureter with the infusion of water using a ureteral stent or hydrodissection to protect adjacent structures by displacing them away with the infusion of water using percutaneously placed needles. EXPERIENCE: The authors' experience with the technique involves thermal ablation of recurrent pelvic tumor in three patients with various gynecologic malignancies who each had a single focus of pelvic recurrence after surgical resection and radiation treatment. No residual or recurrent disease was seen at the treatment site on follow-up imaging consistent with local tumor control. CONCLUSION: Thermal ablation of metastatic or recurrent pelvic tumor is technically feasible and should be considered in selected patients with no treatment alternative. C1 [Butros, Selim R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. RP Butros, SR (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Div Abdominal Imaging & Intervent, 55 Fruit St,White 270, Boston, MA 02114 USA. EM sbutros@partners.org NR 9 TC 2 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2014 VL 123 IS 3 BP 500 EP 505 DI 10.1097/AOG.0000000000000133 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AI4BA UT WOS:000336809100004 PM 24499747 ER PT J AU Hung, KJ Tsai, AC Johnson, TRB Walensky, RP Bangsberg, DR Kerry, VB AF Hung, Kristin J. Tsai, Alexander C. Johnson, Timothy R. B. Walensky, Rochelle P. Bangsberg, David R. Kerry, Vanessa B. TI Scope of Global Health Training in US Obstetrics and Gynecology Residency Programs In Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Hung, Kristin J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Tsai, Alexander C.; Walensky, Rochelle P.; Bangsberg, David R.; Kerry, Vanessa B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tsai, Alexander C.; Walensky, Rochelle P.; Bangsberg, David R.; Kerry, Vanessa B.] Harvard Univ, Sch Med, Boston, MA USA. [Johnson, Timothy R. B.] Univ Michigan, Ann Arbor, MI 48109 USA. RP Hung, KJ (reprint author), Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RI yan, liu/A-1822-2015 OI yan, liu/0000-0001-8517-1084 FU NIAID NIH HHS [R01 AI093269]; NIMH NIH HHS [K23 MH096620] NR 6 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2014 VL 123 IS 3 BP 666 EP 667 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AI4BA UT WOS:000336809100032 PM 24553159 ER PT J AU Brent, BK Coombs, G Keshavan, MS Seidman, LJ Moran, JM Holt, DJ AF Brent, Benjamin K. Coombs, Garth Keshavan, Matcheri S. Seidman, Larry J. Moran, Joseph M. Holt, Daphne J. TI Subclinical delusional thinking predicts lateral temporal cortex responses during social reflection SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE delusions; psychosis; fMRI; lateral temporal cortex; default mode network ID MEDIAL PREFRONTAL CORTEX; DEFAULT-MODE NETWORK; SELF-REFLECTION; BRAIN-FUNCTION; FUNCTIONAL CONNECTIVITY; PERSECUTORY DELUSIONS; METACOGNITIVE EVALUATION; SCHIZOPHRENIC-PATIENTS; PSYCHOSIS PRONENESS; REALITY DISTORTION AB Neuroimaging studies have demonstrated associations between delusions in psychotic disorders and abnormalities of brain areas involved in social cognition, including medial prefrontal cortex (MPFC), posterior cingulate cortex, and lateral temporal cortex (LTC). General population studies have linked subclinical delusional thinking to impaired social cognition, raising the question of whether a specific pattern of brain activity during social perception is associated with delusional beliefs. Here, we tested the hypothesis that subclinical delusional thinking is associated with changes in neural function, while subjects made judgments about themselves or others ['social reflection' (SR)]. Neural responses during SR and non-social tasks, as well as resting-state activity, were measured using functional magnetic resonance imaging in 22 healthy subjects. Delusional thinking was measured using the Peters et al. Delusions Inventory. Delusional thinking was negatively correlated with responses of the left LTC during SR (r = -0.61, P = 0.02, Bonferroni corrected), and connectivity between the left LTC and left ventral MPFC, and was positively correlated with connectivity between the left LTC and the right middle frontal and inferior temporal cortices. Thus, delusional thinking in the general population may be associated with reduced activity and aberrant functional connectivity of cortical areas involved in SR. C1 [Brent, Benjamin K.; Keshavan, Matcheri S.; Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Coombs, Garth; Holt, Daphne J.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02114 USA. [Coombs, Garth; Seidman, Larry J.; Holt, Daphne J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Moran, Joseph M.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. RP Holt, DJ (reprint author), 149 13th St, Charlestown, MA 02129 USA. EM dholt@partners.org FU Harvard Medical School; National Institute of Mental Health [K23MH076054]; National Alliance for Research on Depression and Schizophrenia; Sidney R. Baer, Jr Foundation; Commonwealth Research Center of Massachusetts [SCDMH82101008006] FX We thank the Harvard Catalyst and Dr Heidi Thermenos for valuable statistical support throughout the study. This study was supported by Harvard Medical School's Stuart T. Hauser Clinical Research Training Program (B.K.B.) and Peter B. Livingston Fellowship (B.K.B.), the National Institute of Mental Health K23MH076054 (D.J.H.), the National Alliance for Research on Depression and Schizophrenia with the Sidney R. Baer, Jr Foundation (D.J.H.), and the Commonwealth Research Center of Massachusetts SCDMH82101008006 (L.J.S.). NR 93 TC 7 Z9 7 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 EI 1749-5024 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD MAR PY 2014 VL 9 IS 3 BP 273 EP 282 DI 10.1093/scan/nss129 PG 10 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AH9UG UT WOS:000336488300003 PM 23160817 ER PT J AU Todd, JN Florez, JC AF Todd, Jennifer N. Florez, Jose C. TI An update on the pharmacogenomics of metformin: progress, problems and potential SO PHARMACOGENOMICS LA English DT Article DE antidiabetic; biguanide; metformin; pharmacogenetics; Type 2 diabetes mellitus ID ORGANIC CATION TRANSPORTER; POLYCYSTIC-OVARY-SYNDROME; ACTIVATED PROTEIN-KINASE; GENETIC-VARIATION; DIABETES-MELLITUS; FUNCTIONAL-CHARACTERIZATION; RESPIRATORY-CHAIN; RENAL CLEARANCE; VARIANTS; POLYMORPHISMS AB The increasing prevalence of Type 2 diabetes has emphasized the need to optimize treatment regimens. Metformin, the most widely used oral agent, is recommended as first-line drug therapy by multiple professional organizations. Response to metformin varies significantly at the individual level; this heterogeneity may be explained in part by genetic factors. Understanding these underlying factors may aid with tailoring treatment for individual patients as well as with designing improved Type 2 diabetes therapies. The past 10 years have seen substantial progress in the understanding of the pharmacogenetics of metformin response. The majority of this work has focused on genes involved in the pharmacokinetics of metformin. Owing to the uncertainty surrounding its mechanism of action, studies of pharmacodynamic genetics have been relatively few; genome-wide approaches have the potential to illuminate the molecular details of metformin response. In this review we summarize current knowledge about metformin pharmacogenetics and suggest directions for future investigation. C1 [Todd, Jennifer N.] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Todd, Jennifer N.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Todd, Jennifer N.; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Todd, Jennifer N.; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. RP Florez, JC (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. EM jcflorez@partners.org FU NIH [T32 DK007260]; National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK072041, R01 DK088214]; Massachusetts General Hospital Scholars Award FX JN Todd is supported by NIH Training Grant T32 DK007260. JC Florez is supported by National Institute of Diabetes and Digestive and Kidney Diseases grants R01 DK072041 and R01 DK088214 and a Massachusetts General Hospital Scholars Award. 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 58 TC 12 Z9 13 U1 0 U2 13 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 EI 1744-8042 J9 PHARMACOGENOMICS JI Pharmacogenomics PD MAR PY 2014 VL 15 IS 4 BP 529 EP 539 DI 10.2217/PGS.14.21 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AC7IA UT WOS:000332700200020 PM 24624919 ER PT J AU Atri, A Tocco, M Hendrix, S Pejovic, V Graham, SM AF Atri, Alireza Tocco, Michael Hendrix, Suzanne Pejovic, Vojislav Graham, Stephen M. TI Cumulative Benefits of Extended-Release Memantine (28 mg, Once Daily) Across Clinical Domains in Patients With Moderate to Severe Alzheimer's Disease: An Area Under the Curve Analysis SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Atri, Alireza] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Atri, Alireza] Harvard Univ, Sch Med, Boston, MA USA. [Tocco, Michael; Graham, Stephen M.] Forest Res Inst, Jersey City, NJ USA. [Hendrix, Suzanne] Pentara Corp, Salt Lake City, UT USA. [Pejovic, Vojislav] Prescott Med Commun Grp, Chicago, IL USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S120 EP S121 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800130 ER PT J AU Beristianos, M Yaffe, K Cohen, B Byers, AL AF Beristianos, Matthew Yaffe, Kristine Cohen, Beth Byers, Amy L. TI The Impact of Late-Life PTSD on Vascular-Related Disorders SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Beristianos, Matthew; Yaffe, Kristine; Cohen, Beth; Byers, Amy L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Beristianos, Matthew; Yaffe, Kristine; Cohen, Beth; Byers, Amy L.] San Francisco VA Med Ctr, San Francisco, CA USA. 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S55 EP S55 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800049 ER PT J AU Byers, AL AF Byers, Amy L. TI Suicidal Behavior in Racially and Ethnically Diverse Older Americans SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Byers, Amy L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Byers, Amy L.] 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S125 EP S125 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800137 ER PT J AU Epstein-Lubow, G Boland, R Cheong, JA Llorente, MD AF Epstein-Lubow, Gary Boland, Robert Cheong, Josepha A. Llorente, Maria D. TI TRAINING PSYCHIATRY RESIDENTS AND FELLOWS IN QUALITY IMPROVEMENT: GERIATRIC PSYCHIATRY CAN HELP LEAD THE WAY SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Epstein-Lubow, Gary; Boland, Robert] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Cheong, Josepha A.] Univ Florida, Coll Med, Gainesville, FL USA. [Llorente, Maria D.] US Dept Vet Affairs, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S34 EP S35 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800044 ER PT J AU Fries, AE Leong, S Benson, A Streim, JE DiFilippo, S Oslin, DW AF Fries, Allison E. Leong, Shirley Benson, Amy Streim, Joel E. DiFilippo, Suzanne Oslin, David W. TI Suicidal ideation and health outcomes in an 'old-old' population SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Fries, Allison E.; Leong, Shirley; Benson, Amy; Streim, Joel E.; DiFilippo, Suzanne; Oslin, David W.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Leong, Shirley; Benson, Amy; Streim, Joel E.; DiFilippo, Suzanne; Oslin, David W.] Philadelphia VA Med Ctr, Mental Illness Res Educ & Clin Ctr VISN4, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S61 EP S62 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800057 ER PT J AU Gatchel, JR Jordan-Arthur, B Lewandowski, KE McCabe, CF Harper, DG Forester, B AF Gatchel, Jennifer R. Jordan-Arthur, Brittany Lewandowski, Kathryn E. McCabe, Cara F. Harper, David G. Forester, Brent TI Neuropsychological Function and Predictors of Cognitive Impairment in Geriatric Mood Disorders SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Gatchel, Jennifer R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gatchel, Jennifer R.; Jordan-Arthur, Brittany; Lewandowski, Kathryn E.; McCabe, Cara F.; Harper, David G.; Forester, Brent] McLean Hosp, Belmont, MA 02178 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S64 EP S65 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800061 ER PT J AU Haratz, J Zimmerman, J Leong, S Helstrom, A Benson, A DiFilippo, S Streim, JE Oslin, DW AF Haratz, Josh Zimmerman, Jacob Leong, Shirley Helstrom, Amy Benson, Amy DiFilippo, Suzanne Streim, Joel E. Oslin, David W. TI A telephone-based intervention for chronic pain in older adults enrolled in a behavioral health care management program SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Haratz, Josh] Drexel Univ Coll Med, Philadelphia, PA USA. [Zimmerman, Jacob; Leong, Shirley; Helstrom, Amy; Benson, Amy; DiFilippo, Suzanne; Streim, Joel E.; Oslin, David W.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Leong, Shirley; Helstrom, Amy; Benson, Amy; DiFilippo, Suzanne; Streim, Joel E.; Oslin, David W.] Philadelphia VA Med Ctr, VISN4 Mental Illness Res Educ & Clin Ctr, Philadelphia, PA 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S103 EP S104 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800111 ER PT J AU Kasckow, J Harvey, PD Cohen, CI Rajii, T AF Kasckow, John Harvey, Philip D. Cohen, Carl I. Rajii, Tarek TI COGNITION AND FUNCTIONING IN OLDER PATIENTS WITH SCHIZOPHRENIA: RECENT RESEARCH SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Kasckow, John] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Kasckow, John] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Cohen, Carl I.] SUNY Downstate, Brooklyn, NY USA. [Harvey, Philip D.] Univ Miami, Miami, FL USA. [Rajii, Tarek] Univ Toronto, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S8 EP S8 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800006 ER PT J AU Liptzin, B Streim, JE Colenda, CC AF Liptzin, Benjamin Streim, Joel E. Colenda, Christopher C. TI THE GERIATRIC PSYCHIATRIST AS FAMILY CAREGIVER: LESSONS LEARNED SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Liptzin, Benjamin] Baystate Med Ctr, Springfield, MA USA. [Liptzin, Benjamin] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Colenda, Christopher C.] W Virginia Univ, Robert C Byrd Hlth Sci Ctr, Morgantown, WV 26506 USA. [Streim, Joel E.] Univ Penn, Sch Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Streim, Joel E.] Philadelphia VA Med Ctr, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S33 EP S33 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800042 ER PT J AU Mathur, N Leong, S DiLeone, BA Casares, J Streim, JE Oslin, DW DiFilippo, S AF Mathur, Nivedita Leong, Shirley DiLeone, Brooke A. Casares, Jose Streim, Joel E. Oslin, David W. DiFilippo, Suzanne TI Disparity in Antidepressant Prescription between African American and Caucasian Elderly Veterans: A Retrospective Descriptive Study SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Mathur, Nivedita; Streim, Joel E.; Oslin, David W.; DiFilippo, Suzanne] Univ Penn, Philadelphia, PA 19104 USA. [Mathur, Nivedita; Leong, Shirley; DiLeone, Brooke A.; Casares, Jose; Streim, Joel E.; Oslin, David W.; DiFilippo, Suzanne] Philadelphia VA Med Ctr, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S90 EP S91 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800097 ER PT J AU Mintzer, J Steinberg, E AF Mintzer, Jacobo Steinberg, Ellen TI Elder courts: transforming a crisis into a therapeutic opportunity SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Steinberg, Ellen] Charleston Cty Magistrate Court, Charleston, SC USA. [Mintzer, Jacobo] Roper St Francis Healthcare, Charleston, SC 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 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S143 EP S143 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800160 ER PT J AU Streim, JE Boustani, M Unutzer, J Oslin, DW AF Streim, Joel E. Boustani, Malaz Unutzer, Jurgen Oslin, David W. TI IMPLEMENTATION OF INTEGRATED COLLABORATIVE GERIATRIC MENTAL HEALTH CARE MODELS: WHAT HAVE WE LEARNED FROM A DECADE OF EXPERIENCE? SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL 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. [Boustani, Malaz] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Unutzer, Jurgen] Univ Washington, Sch Med, Seattle, WA 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S18 EP S18 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800020 ER PT J AU Streim, JE Liptzin, B Chung, H Rosen, J AF Streim, Joel E. Liptzin, Benjamin Chung, Henry Rosen, Jules TI EARLY EXPERIENCES WITH IMPLEMENTATION OF ACCOUNTABLE CARE ORGANIZATIONS (ACOS): HOW ARE GERIATRIC MENTAL HEALTH SERVICES PROVIDED? SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Streim, Joel E.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Streim, Joel E.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Liptzin, Benjamin] Baystate Med Ctr, Springfield, MA USA. [Liptzin, Benjamin] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Chung, Henry] Albert Einstein Coll Med, New York, NY USA. [Chung, Henry] Montefiore Care Management Co, New York, NY USA. [Rosen, Jules] Univ Colorado, Sch Med, Denver, CO 80202 USA. [Rosen, Jules] Colorado West Mental Hlth, Frisco, CO USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S12 EP S13 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800012 ER PT J AU Wang, LY Murphy, RR Robinson, G Fredrickson, KR Thielke, SM Tsuang, DW Borson, S AF Wang, Lucy Y. Murphy, Richard R. Robinson, Gayle Fredrickson, Kristine R. Thielke, Stephen M. Tsuang, Debby W. Borson, Soo TI Telemedicine Adaptation of a Dementia Care Shared Medical Visit Model SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Wang, Lucy Y.; Murphy, Richard R.] VA Puget Sound Hlth Care Syst, MIRECC, Seattle, WA USA. [Wang, Lucy Y.; Thielke, Stephen M.; Tsuang, Debby W.; Borson, Soo] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Murphy, Richard R.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. [Robinson, Gayle; Fredrickson, Kristine R.; Thielke, Stephen M.; Tsuang, Debby W.] VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S128 EP S128 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800141 ER PT J AU Wiechers, I Ruderman, L Levy, I AF Wiechers, Ilse Ruderman, Lital Levy, Ifat TI Does Patient Age Affect Physician Decision Making Under Varying Risk and Ambiguity? SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-for-Geriatric-Psychiatry (AAGP) CY MAR, 2014 CL Orlando, FL SP Amer Assoc Geriatr Psychiat C1 [Wiechers, Ilse] Yale Univ, Sch Med, US Dept Vet Affairs, RWJF Clin Scholars Program, New Haven, CT USA. [Ruderman, Lital; Levy, Ifat] Yale Univ, Sch Med, New Haven, CT USA. [Levy, Ifat] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2014 VL 22 IS 3 SU S BP S98 EP S98 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AH4FE UT WOS:000336081800106 ER PT J AU Ghobrial, IM Witzig, TE Gertz, M LaPlant, B Hayman, S Camoriano, J Lacy, M Bergsagel, PL Chuma, S DeAngelo, D Treon, SP AF Ghobrial, Irene M. Witzig, Thomas E. Gertz, Morie LaPlant, Betsy Hayman, Suzanne Camoriano, John Lacy, Martha Bergsagel, P. Leif Chuma, Stacey DeAngelo, Daniel Treon, Steven P. TI Long-term results of the phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or refractory Waldenstrom Macroglobulinemia SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID MULTIPLE-MYELOMA CELLS; CONSENSUS PANEL RECOMMENDATIONS; EXTENDED RITUXIMAB THERAPY; 2ND INTERNATIONAL WORKSHOP; MAMMALIAN TARGET; SYNERGISTIC ACTIVITY; CANCER-THERAPY; MYD88 L265P; RAPAMYCIN; UPDATE AB Everolimus is an oral raptor mTOR inhibitor and has shown activity in patients with Waldenstrom's macroglobulinemia (WM). This study examines a large cohort of patients with relapsed/refractory WM with long-term follow up for survival. Patients were eligible if they had measurable disease, a platelet count > 75,000 x 10(6)/L, an absolute neutrophil count > 1,000 x 10(6)/L. Patients received everolimus 10 mg PO daily and were evaluated monthly. A success was defined as a complete or partial response (PR); minor responses (MR) were recorded and considered to be of clinical benefit. Sixty patients were enrolled and treated. The overall response rate (ORR) was 50% (all PR); the clinical benefit rate including MR or better was 73% (95% CI: 60-84%) with 23% MR. The median time to response for patients who achieved PR was 2 months (range, 1-26). The median duration of response has not been reached and median progression-free survival (PFS) was 21 months. Grade 3 or higher toxicities (at least possibly related to everolimus) were observed in 67% of patients. The most common grade 3 or 4 toxicities were anemia (27%), leukopenia (22%), and thrombocytopenia (20%). Other nonhematological toxicities were diarrhea (5%), fatigue (8%), stomatitis (8%) and pulmonary toxicity (5%). Everolimus has a high single-agent activity of 73% including MR, with a progression free survival of 21 months, indicating that this agent is active in relapsed/refractory WM. Am. J. Hematol. 89:237-242, 2014. (c) 2013 Wiley Periodicals, Inc C1 [Ghobrial, Irene M.; Chuma, Stacey; DeAngelo, Daniel; Treon, Steven P.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Witzig, Thomas E.; Gertz, Morie; LaPlant, Betsy; Hayman, Suzanne; Camoriano, John; Lacy, Martha] Mayo Clin, Coll Med, Rochester, MN USA. [Witzig, Thomas E.; Gertz, Morie; LaPlant, Betsy; Hayman, Suzanne; Camoriano, John; Lacy, Martha] Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. [Bergsagel, P. Leif] Mayo Clin, Coll Med, Scottsdale, AZ USA. [Bergsagel, P. Leif] Mayo Fdn, Scottsdale, AZ USA. RP Treon, SP (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM steven_treon@dfci.harvard.edu FU Novartis Inc, International Waldenstrom Macroglobulinemia Foundation [1R01FD003743] FX Contract grant sponsor: Novartis Inc, International Waldenstrom Macroglobulinemia Foundation; Contract grant number: 1R01FD003743. NR 48 TC 24 Z9 24 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD MAR PY 2014 VL 89 IS 3 BP 237 EP 242 DI 10.1002/ajh.23620 PG 6 WC Hematology SC Hematology GA AB7AL UT WOS:000331941600001 PM 24716234 ER PT J AU Castillo, JJ Winer, ES Olszewski, AJ AF Castillo, Jorge J. Winer, Eric S. Olszewski, Adam J. TI Sites of extranodal involvement are prognostic in patients with diffuse large B-cell lymphoma in the rituximab era: An analysis of the Surveillance, Epidemiology and End Results database SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID NON-HODGKINS-LYMPHOMA; PRIMARY BONE LYMPHOMA; CLINICOPATHOLOGICAL FEATURES; RACIAL-DIFFERENCES; CLINICAL-FEATURES; WALDEYERS RING; PRIMARY BREAST; ADULT PATIENTS; OUTCOMES; SURVIVAL AB Approximately a third of the patients with diffuse large B-cell lymphoma present with extranodal involvement. Our study aims to identify primary extranodal sites of disease associated with prognosis in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era. A secondary objective is to describe epidemiological and clinical characteristics of patients with extranodal DLBCL. We included adult patients from the Surveillance, Epidemiology and End Results (SEER) database (2004-2009) in whom DLBCL was the first malignancy diagnosed. Extranodal primary sites were divided into 12 groups according to the topography code reported by SEER. Multivariate overall survival (OS) analyses were performed using Cox proportional-hazard regression models adjusted for age, sex, race, and stage. From a total of 25,992 adult DLBCL patients included in our analysis, 32% presented with extranodal primary sites. Gastrointestinal tract (34%), head/neck (H & N; 14%), and skin/soft tissue (11%) were the most common. In comparison with nodal DLBCL, patients with extranodal involvement were older (with exception of skeletal sites) and presented with earlier stages. In the multivariate analysis, sites associated with worse OS rates were gastrointestinal (Hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.15-1.33; P <0.001), pulmonary (HR 1.59, 95% CI 1.38-1.83; P <0.001), and liver/pancreas (HR 1.58, 95% CI 1.35-1.85; P <0.001), whereas H&N was associated with better survival (HR 0.79, 95% CI 0.70-0.89; P <0.001). In this population-based study, primary extranodal sites of involvement are associated with distinct outcomes in patients with DLBCL. Gastrointestinal, pulmonary, and liver/pancreas sites had a significant worse outcome than nodal sites. Am. J. Hematol. 89:310-314, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Castillo, Jorge J.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Winer, Eric S.] Rhode Isl Hosp, Div Hematol & Oncol, Providence, RI USA. [Winer, Eric S.] Miriam Hosp, Providence, RI 02906 USA. [Olszewski, Adam J.] Brown Univ, Mem Hosp Rhode Isl, Div Hematol & Oncol, Pawtucket, RI 02860 USA. RP Castillo, JJ (reprint author), 450 Brookline Ave,M221, Boston, MA 02215 USA. EM jorgej_castillo@dfci.harvard.edu OI Olszewski, Adam/0000-0002-6472-6658; Castillo, Jorge/0000-0001-9490-7532 NR 31 TC 16 Z9 17 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD MAR PY 2014 VL 89 IS 3 BP 310 EP 314 DI 10.1002/ajh.23638 PG 5 WC Hematology SC Hematology GA AB7AL UT WOS:000331941600013 PM 24273125 ER PT J AU Widemann, BC Acosta, MT Ammoun, S Belzberg, AJ Bernards, A Blakeley, J Bretscher, A Cichowski, K Clapp, DW Dombi, E Evans, GD Ferner, R Fernandez-Valle, C Fisher, MJ Giovannini, M Gutmann, DH Hanemann, CO Hennigan, R Huson, S Ingram, D Kissil, J Korf, BR Legius, E Packer, RJ McClatchey, AI McCormick, F North, K Pehrsson, M Plotkin, SR Ramesh, V Ratner, N Schirmer, S Sherman, L Schorry, E Stevenson, D Stewart, DR Ullrich, N Bakker, AC Morrison, H AF Widemann, Brigitte C. Acosta, Maria T. Ammoun, Sylvia Belzberg, Allan J. Bernards, Andre Blakeley, Jaishri Bretscher, Antony Cichowski, Karen Clapp, D. Wade Dombi, Eva Evans, Gareth D. Ferner, Rosalie Fernandez-Valle, Cristina Fisher, Michael J. Giovannini, Marco Gutmann, David H. Hanemann, C. Oliver Hennigan, Robert Huson, Susan Ingram, David Kissil, Joe Korf, Bruce R. Legius, Eric Packer, Roger J. McClatchey, Andrea I. McCormick, Frank North, Kathryn Pehrsson, Minja Plotkin, Scott R. Ramesh, Vijaya Ratner, Nancy Schirmer, Susann Sherman, Larry Schorry, Elizabeth Stevenson, David Stewart, Douglas R. Ullrich, Nicole Bakker, Annette C. Morrison, Helen TI CTF Meeting 2012: Translation of the Basic Understanding of the Biology and Genetics of NF1, NF2, and Schwannomatosis Toward the Development of Effective Therapies SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE neurofibromatosis type 1; neurofibromatosis type 2; NF1; NF2; schwannomatosis; tumor suppressor; SMARCB1; merlin neurofibromin; preclinical models ID HISTONE DEACETYLASE INHIBITOR; NEUROFIBROMATOSIS TYPE-2; VESTIBULAR SCHWANNOMAS; FAMILIAL SCHWANNOMATOSIS; SPORADIC SCHWANNOMATOSIS; RETROSPECTIVE ANALYSIS; MULTIPLE MENINGIOMAS; DIAGNOSTIC-CRITERIA; SMARCB1 MUTATIONS; CLINICAL ARTICLE AB The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a state-of-the-field for NF research in 2012. (c) 2014 Wiley Periodicals, Inc. C1 [Widemann, Brigitte C.; Dombi, Eva] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Acosta, Maria T.; Packer, Roger J.] Gilbert NF Inst, Washington, DC USA. [Ammoun, Sylvia; Hanemann, C. Oliver] Univ Plymouth, Peninsula Sch Med, Plymouth PL4 8AA, Devon, England. [Ammoun, Sylvia; Hanemann, C. Oliver] Univ Plymouth, Peninsula Sch Dent, Plymouth PL4 8AA, Devon, England. [Belzberg, Allan J.; Blakeley, Jaishri] Johns Hopkins Univ, Baltimore, MD USA. [Bernards, Andre; McClatchey, Andrea I.; Plotkin, Scott R.; Ramesh, Vijaya] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Bernards, Andre; McClatchey, Andrea I.; Plotkin, Scott R.; Ramesh, Vijaya] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA. [Bretscher, Antony] Cornell Univ, New York, NY 10021 USA. [Cichowski, Karen] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Clapp, D. Wade; Ingram, David] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Evans, Gareth D.; Huson, Susan] Univ Manchester, St Marys Hosp, Manchester M13 0JH, Lancs, England. [Ferner, Rosalie] Guys & St Thomas NHS Fdn Trust, London, England. [Ferner, Rosalie] Kings Coll London, Dept Clin Neurosci, London, England. [Fernandez-Valle, Cristina] Univ Cent Florida, Orlando, FL 32816 USA. [Fisher, Michael J.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Giovannini, Marco] Univ So Calif, House Res Inst, Los Angeles, CA USA. [Gutmann, David H.] Washington Univ, Sch Med, St Louis, MO USA. [Hennigan, Robert; Ratner, Nancy; Schorry, Elizabeth] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Kissil, Joe] Scripps Res Inst Florida, Jupiter, FL USA. [Korf, Bruce R.] Univ Alabama Birmingham, Birmingham, AL USA. [Legius, Eric] Catholic Univ Louvain, B-3000 Louvain, Belgium. [McCormick, Frank] Univ Calif San Francisco, San Francisco, CA 94143 USA. [North, Kathryn] Childrens Hosp, Westmead, NSW, Australia. [Pehrsson, Minja] Biomed Helsinki, Helsinki, Finland. [Schirmer, Susann; Morrison, Helen] Leibniz Inst Age Res, Jena, Germany. [Sherman, Larry] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Stevenson, David] Univ Utah, Salt Lake City, UT USA. [Stewart, Douglas R.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Ullrich, Nicole] Childrens Hosp, Boston, MA 02115 USA. [Bakker, Annette C.] Childrens Tumor Fdn, New York, NY 10005 USA. RP Bakker, AC (reprint author), Childrens Tumor Fdn, 95 Pine St, New York, NY 10005 USA. EM widemanb@mail.nih.gov; abakker@ctf.org RI North, Kathryn/K-6476-2012; Morrison, Helen/B-3984-2017; OI North, Kathryn/0000-0003-0841-8009; Morrison, Helen/0000-0003-4938-1409; Hanemann, Clemens Oliver/0000-0002-1951-1025; Evans, Gareth/0000-0002-8482-5784 FU National Institutes of Health Grant Award [1R13NS070505-01]; Center for Cancer Research; National Cancer Institute FX Grant sponsor: National Institutes of Health Grant Award; Grant number: 1R13NS070505-01; Grant sponsor: Center for Cancer Research; Grant sponsor: National Cancer Institute. NR 70 TC 4 Z9 4 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAR PY 2014 VL 164 IS 3 BP 563 EP 578 DI 10.1002/ajmg.a.36312 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA AB7NZ UT WOS:000331978700001 PM 24443315 ER PT J AU Ting, CK Johnson, KB Teng, WN Synoid, ND LaPierre, C Yu, L Westenskow, DR AF Ting, Chien-Kun Johnson, Ken B. Teng, Wei-Nung Synoid, Noah D. LaPierre, Cris Yu, Lu Westenskow, Dwayne R. TI Response Surface Model Predictions of Wake- Up Time During Scoliosis Surgery SO ANESTHESIA AND ANALGESIA LA English DT Article ID ALVEOLAR ANESTHETIC CONCENTRATION; PROPOFOL-REMIFENTANIL ANESTHESIA; SEVOFLURANE REQUIREMENTS; UP TEST; INHALATION ANESTHESIA; CONCENTRATION-AWAKE; CONTROLLED INFUSION; SYSTEM MODEL; FENTANYL; DESFLURANE AB BACKGROUND: With the use of previously published data, new sevoflurane-remifentanil interaction models of various degrees of sedation were created and adapted to desflurane-fentanyl by using minimal alveolar concentration and opioid equivalencies. These models were used to predict return of responsiveness in patients undergoing scoliosis surgery during a wake-up test. Our hypothesis was that one of the interaction models would accurately predict return of responsiveness during a wake-up test. METHODS: Three new sevoflurane-remifentanil interaction models were constructed from previous observations in volunteers by using the Observer's Assessment of Alertness/Sedation (OAA/S) scores. These models included predictions of OAA/S<2 (unresponsive), OAA/S< 3, and OAA/S<4 (sedation). Twenty-three patients scheduled for scoliosis surgery received a fentanyl-desflurane anesthetic. With the use of published pharmacokinetic models, predictions of fentanyl and desflurane effect-site concentrations were recorded throughout surgery and converted to equivalent remifentanil and sevoflurane effect-site concentrations. Data were recorded every 10 seconds from the time when desflurane was turned off until 10 minutes after the patients responded by moving their hands and toes. Model predictions were compared with observations with graphical and temporal analyses. RESULTS: The average difference between the time when a patient first responded and the time when the model predicted that there was a 50% probability that the patient would respond were -2.6 3.6 minutes (mean +/- SD) for the OAA/S<2 model, 2.8 +/- 5.6 minutes for the OAA/S<3 model and 52.6 +/- 32.3 minutes for the OAA/S<4 model. CONCLUSIONS: The results confirmed our study hypothesis; a sevoflurane-remifentanil interaction model built from observations in volunteers and adapted to desflurane and fentanyl accurately predicted patient response during a wake-up test. These results were similar to our previous study comparing model predictions and patient observations after a sevoflurane-remifentanil/fentanyl anesthetic. The OAA/S <2 model most accurately predicted the time patients would respond by moving their fingers and toes. This model may help anesthesiologists better predict return of responsiveness during a wake-up test in patients undergoing spine surgery. C1 [Ting, Chien-Kun; Teng, Wei-Nung] Taipei Vet Gen Hosp, Dept Anesthesiol, Taipei, Taiwan. [Ting, Chien-Kun; Teng, Wei-Nung] Natl Yang Ming Univ, Taipei 112, Taiwan. [Johnson, Ken B.; Synoid, Noah D.; Westenskow, Dwayne R.] Univ Utah Sch Med, Dept Anesthesiol, Salt Lake City, UT USA. [Johnson, Ken B.; Westenskow, Dwayne R.] Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA. [LaPierre, Cris] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. [LaPierre, Cris] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Yu, Lu] China Med Univ, Dept Biomed Engn, Coll Basic Med Sci, Shenyang, Liaoning, Peoples R China. RP Ting, CK (reprint author), Taipei Vet Gen Hosp, Dept Anesthesiol, 201,Sect 2,Shi Pai Rd, Taipei, Taiwan. EM ckting2@gmail.com RI Ting, Chien-Kun/C-1389-2012 OI Ting, Chien-Kun/0000-0002-3156-8139 NR 41 TC 6 Z9 6 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 EI 1526-7598 J9 ANESTH ANALG JI Anesth. Analg. PD MAR PY 2014 VL 118 IS 3 BP 546 EP 553 DI 10.1213/ANE.0000000000000094 PG 8 WC Anesthesiology SC Anesthesiology GA AG4NG UT WOS:000335396200012 PM 24557102 ER PT J AU Ge, R Pejo, E Gallin, H Jeffrey, S Cotten, JF Raines, DE AF Ge, Rile Pejo, Ervin Gallin, Hilary Jeffrey, Spencer Cotten, Joseph F. Raines, Douglas E. TI The Pharmacology of Cyclopropyl-Methoxycarbonyl Metomidate: A Comparison with Propofol SO ANESTHESIA AND ANALGESIA LA English DT Article ID MULTIPLE TRAUMA PATIENTS; ADRENOCORTICAL SUPPRESSION; ETOMIDATE ANALOG; PROTEIN-BINDING; IN-VIVO; ANESTHESIA; MAINTENANCE; INHIBITION; METABOLITE; INFUSIONS AB BACKGROUND: Cyclopropyl-methoxycarbonyl metomidate (CPMM) is a soft etomidate analogue currently being developed as a propofol alternative for anesthetic induction and maintenance. METHODS: We compared the potencies of CPMM and propofol by assessing their abilities to directly activate (1)(L264T)(32) gamma-aminobutyric acid type A (GABA(A)) receptors and induce loss of righting reflexes in tadpoles. We also measured the rates of encephalographic recovery in rats after CPMM and propofol infusions ranging in duration from 5 to 120 minutes. RESULTS: CPMM and propofol activate GABA(A) receptors and induce loss of righting reflexes in tadpoles with respective 50% effective concentrations (EC50s) of 3.8 0.4 and 3.9 +/- 0.2 M (GABA(A) receptor) and 2.6 +/- 0.19 and 1.3 +/- 0.04 M (tadpole). Encephalographic recovery after prolonged infusion was faster with CPMM and lacked propofol's context sensitivity. CONCLUSION: CPMM and propofol have similar potencies in GABA(A) receptors and tadpoles; however, CPMM provides more rapid and predictable recovery than propofol, particularly after prolonged infusion. C1 [Ge, Rile] Boston Childrens Hosp, Dept Anesthesia Perioperat & Pain Med, Boston, MA USA. [Pejo, Ervin; Jeffrey, Spencer; Cotten, Joseph F.; Raines, Douglas E.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Gallin, Hilary] Washington Univ Sch Med, St Louis, MO USA. RP Raines, DE (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM draines@partners.org FU National Institutes of Health, Bethesda, MD [R01-GM087316]; Department of Anesthesia, Critical Care & Pain Medicine at the Massachusetts General Hospital; [K08-GM083216] FX This research was supported by grants to DER (R01-GM087316 from the National Institutes of Health, Bethesda, MD) and JFC (K08-GM083216), and by the Department of Anesthesia, Critical Care & Pain Medicine at the Massachusetts General Hospital. NR 19 TC 8 Z9 8 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD MAR PY 2014 VL 118 IS 3 BP 563 EP 567 DI 10.1213/ANE.0000000000000069 PG 5 WC Anesthesiology SC Anesthesiology GA AG4NG UT WOS:000335396200014 PM 24557104 ER PT J AU El-Orbany, M Ali, HH Baraka, A Salem, MR AF El-Orbany, Mohammad Ali, Hassan H. Baraka, Anis Salem, M. Ramez TI Residual Neuromuscular Block Should, and Can, Be a "Never Event" SO ANESTHESIA AND ANALGESIA LA English DT Letter ID CLINICAL RECOVERY C1 [El-Orbany, Mohammad] Med Coll Wisconsin, Dept Anesthesiol, Milwaukee, WI 53226 USA. [Ali, Hassan H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesiol, Boston, MA USA. [Baraka, Anis] Amer Univ Beirut, Dept Anesthesiol, Beirut, Lebanon. [Salem, M. Ramez] Advocate Illinois Masonic Med Ctr, Dept Anesthesiol, Chicago, IL USA. RP El-Orbany, M (reprint author), Med Coll Wisconsin, Dept Anesthesiol, Milwaukee, WI 53226 USA. EM elorbany@mcw.edu NR 9 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 EI 1526-7598 J9 ANESTH ANALG JI Anesth. Analg. PD MAR PY 2014 VL 118 IS 3 BP 691 EP 691 DI 10.1213/ANE.0000000000000090 PG 1 WC Anesthesiology SC Anesthesiology GA AG4NG UT WOS:000335396200035 PM 24557116 ER PT J AU Arriaga, AF Gawande, AA Raemer, DB Jones, DB Smink, DS Weinstock, P Dwyer, K Lipsitz, SR Peyre, S Pawlowski, JB Muret-Wagstaff, S Gee, D Gordon, JA Cooper, JB Berry, WR AF Arriaga, Alexander F. Gawande, Atul A. Raemer, Daniel B. Jones, Daniel B. Smink, Douglas S. Weinstock, Peter Dwyer, Kathy Lipsitz, Stuart R. Peyre, Sarah Pawlowski, John B. Muret-Wagstaff, Sharon Gee, Denise Gordon, James A. Cooper, Jeffrey B. Berry, William R. CA Harvard Surg Safety Collaborative TI Pilot Testing of a Model for Insurer-Driven, Large-Scale Multicenter Simulation Training for Operating Room Teams SO ANNALS OF SURGERY LA English DT Article DE medical simulation; operating room teamwork training; patient safety ID CRISIS RESOURCE-MANAGEMENT; SURGICAL SAFETY CHECKLIST; 2000 INCIDENT REPORTS; CLINICAL-PERFORMANCE; NONTECHNICAL SKILLS; TEACHING HOSPITALS; MALPRACTICE CLAIMS; ANESTHETIC CRISIS; CARDIAC-SURGERY; PATIENT SAFETY AB Objective: To test the feasibility of implementing a standardized teamwork training program with full operating room teams in multiple institutions, driven by malpractice insurer support and incentives. Background: Failures in intraoperative teamwork are among the leading causes of preventable patient injury and death in surgical patients. Teamwork training, particularly using simulation, can be an effective intervention but is difficult to scale. Methods: A malpractice insurer convened a collaborative with 4 Harvard-affiliated simulation programs to develop a standardized operating room teamwork training curriculum, including principles of communication, assertiveness, and use of the World Health Organization Surgical Safety Checklist. Participant teams were compensated for lost operative time via malpractice premium discounts, continuing education credits, and compensation for lost wages. The course was delivered through a simulation program involving the management of intraoperative emergency scenarios. Participants were surveyed for their perceptions of the program and of its impact on clinical practice. Results: A total of 221 active operating room staff members participated in the program. Each team contained at least 1 attending surgeon, 1 attending anesthesiologist, and 1 operating room nurse (mean size per team: 7 2 participants). No study dates were cancelled because of lack of attendance. The survey response rate was 99% (218/221). Overall, the vast majority of participants found the scenarios realistic [94% (95% confidence interval: 90.9%, 97.2%)], appropriately challenging [95.4% (92.6%, 98.2%)], relevant to their practice [96.3% (93.8%, 98.8%)], and found the training would help them provide safer patient care [92.6% (89.1%, 96.1%)]. Surgeons reported their greatest personal deficit as communication skills. Operating room nurses and anesthesiologists reported a greater need than surgeons to work on personal assertiveness. Conclusions: A standardized multicenter team training program involving full operative teams is feasible with high-fidelity simulation and modest compensation for lost time. The vast majority of the multidisciplinary participants believed the course to have had a meaningful impact on their approach to clinical practice. C1 [Arriaga, Alexander F.; Gawande, Atul A.; Smink, Douglas S.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Arriaga, Alexander F.] Brigham & Womens Hosp, Dept Anesthesiol Pain & Perioperat Med, Boston, MA 02115 USA. [Arriaga, Alexander F.; Gawande, Atul A.; Berry, William R.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Arriaga, Alexander F.; Gawande, Atul A.; Lipsitz, Stuart R.; Berry, William R.] Ariadne Labs, Boston, MA USA. [Arriaga, Alexander F.; Gawande, Atul A.; Smink, Douglas S.; Lipsitz, Stuart R.; Berry, William R.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Raemer, Daniel B.; Cooper, Jeffrey B.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Raemer, Daniel B.; Gee, Denise; Cooper, Jeffrey B.] Ctr Med Simulat, Cambridge, MA USA. [Jones, Daniel B.] Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA. [Jones, Daniel B.; Pawlowski, John B.; Muret-Wagstaff, Sharon] Beth Israel Deaconess Med Ctr, Carl J Shapiro Simulat & Skills Ctr, Boston, MA 02215 USA. [Smink, Douglas S.] Brigham & Womens Hosp, STRATUS Ctr Med Simulat, Boston, MA 02115 USA. [Weinstock, Peter] Boston Childrens Hosp, Dept Anesthesia, Div Crit Care Med, Boston, MA USA. [Weinstock, Peter] Boston Childrens Hosp, Simulator Program, Boston, MA USA. [Dwyer, Kathy] Harvard Med Inst CRICO RMF, Risk Management Fdn, Cambridge, MA USA. [Lipsitz, Stuart R.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Peyre, Sarah] Univ Rochester, Dept Surg, Rochester, NY USA. [Pawlowski, John B.; Muret-Wagstaff, Sharon] Beth Israel Deaconess Med Ctr, Dept Anesthesia & Crit Care, Boston, MA 02215 USA. [Gee, Denise] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Gordon, James A.] Harvard Univ, Sch Med, Gilbert Program Med Simulat, Boston, MA USA. [Gordon, James A.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Arriaga, AF (reprint author), Harvard Univ, Sch Publ Hlth, 677 Huntington Ave, Boston, MA 02115 USA. EM wberry@hsph.harvard.edu FU Risk Management Foundation of the Harvard Medical Institutions (CRICO/RMF); United States Army Medical Research Acquisition [W81XWH-09-2-001] FX This study was supported by a grant from the Risk Management Foundation of the Harvard Medical Institutions (CRICO/RMF). Kathy Dwyer is a senior program director and William R. Berry is the associate medical director for CRICO/RMF. Jeffrey B. Cooper is the executive director for the Center for Medical Simulation, a nonprofit research and education organization that provides fee for service programs of the type described in this report. James A. Gordon is supported by contract W81XWH-09-2-001 under a cooperative agreement issued by the United States Army Medical Research Acquisition. No other disclosures relevant to the work were made by the remaining authors. NR 85 TC 24 Z9 24 U1 6 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD MAR PY 2014 VL 259 IS 3 BP 403 EP 410 DI 10.1097/SLA.0000000000000342 PG 8 WC Surgery SC Surgery GA AH6NQ UT WOS:000336248000018 PM 24263327 ER PT J AU Fernandez-del Castillo, CF Thayer, SP Ferrone, CR Wargo, J AF Fernandez-del Castillo, Carlos F. Thayer, Sarah P. Ferrone, Cristina R. Wargo, Jennifer TI Surgery for Small and Asymptomatic Branch-Duct IPMNs SO ANNALS OF SURGERY LA English DT Letter ID NEOPLASMS C1 [Fernandez-del Castillo, Carlos F.; Thayer, Sarah P.; Ferrone, Cristina R.; Wargo, Jennifer] Massachusetts Gen Hosp, Pancreas & Biliary Surg Program, Boston, MA 02114 USA. RP Fernandez-del Castillo, CF (reprint author), Massachusetts Gen Hosp, Pancreas & Biliary Surg Program, Boston, MA 02114 USA. EM cfernandez@partners.org NR 4 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD MAR PY 2014 VL 259 IS 3 BP E47 EP E47 DI 10.1097/SLA.0000000000000270 PG 1 WC Surgery SC Surgery GA AH6NQ UT WOS:000336248000008 PM 24096750 ER PT J AU Carillo, S Zhang, Y Fay, R Angioi, M Vincent, J Sutradhor, SC Ahmed, A Pitt, B Zannad, F AF Carillo, Sylvain Zhang, Yan Fay, Renaud Angioi, Michael Vincent, John Sutradhor, Santosh C. Ahmed, Ali Pitt, Bertram Zannad, Faiez TI Heart failure with systolic dysfunction complicating acute myocardial infarction - differential outcomes but similar eplerenone efficacy by ST-segment or non-ST-segment elevation: A post hoc substudy of the EPHESUS trial SO ARCHIVES OF CARDIOVASCULAR DISEASES LA English DT Article DE NSTEMI; STEMI; Heart failure; Eplerenone ID ACUTE CORONARY SYNDROMES; PRACTICE GUIDELINES COMMITTEE; LEFT-VENTRICULAR DYSFUNCTION; ASSOCIATION TASK-FORCE; MEDITERRANEAN BASIN; ACC/AHA GUIDELINES; HOSPITAL MORTALITY; NATIONAL REGISTRY; AMERICAN-COLLEGE; UNSTABLE ANGINA AB Background. - Differential outcomes in patients with acute systolic heart failure (HF) complicating acute myocardial infarction (AMI) and the efficacy of mineralocorticoid receptor antagonists according to non-ST-segment and ST-segment elevation myocardial infarction (NSTEMI, STEM!) status has not been specifically investigated. Methods. - In the EPHESUS study, 6632 patients with acute HF and left ventricular ejection fraction <40% were randomized 3-14 days post-AMI (median 7.3+/-3.0 days) to receive eplerenone (n=3319) or placebo (n=3313). Among them, 6392 patients with available data on baseline ST-segment status (4634 STEMI; 1758 NSTEMI) were compared using a Cox model analysis stratified according to quintiles of propensity score (PS), taking into account major baseline risk factors, including revascularization. Results. - STEMI and NSTEMI patients differed significantly across a large variety of baseline characteristics. During 30 months of follow-up, all-cause death occurred in 19% and 13% (P<0.0001), cardiovascular death in 16% and 12% (P<0.0001), cardiovascular death and hospitalization in 33% and 26% (P<0.0001) and death from progression of HF in 5% and 3% (P<0.0001) of unadjusted NSTEMI and STEMI patients, respectively. After Cox model PS adjustment without revascularization, NSTEMI status still proved to be a risk factor for all-cause death, cardiovascular death and death from progression of HE After Cox model PS adjustment including revascularization, none of the outcomes differed between STEMI and NSTEMI patients. Eplerenone morbidity and mortality benefits were consistent in the STEMI and NSTEMI subgroups. Conclusion. - In patients with acute systolic HF complicating AMI, eplerenone improves outcomes equally in STEMI and NSTEMI patients. Worse outcomes associated with NSTEMI could be explained by more co-morbidities, less aggressive therapies and, mainly, less frequent revascularization. (C) 2014 Elsevier Masson SAS. All rights reserved. C1 [Carillo, Sylvain; Fay, Renaud; Zannad, Faiez] CHU Nancy, CIC9501, Inst Lorrain Coeur & Vaisseaux, Inserm U961, F-54500 Vandoeuvre Les Nancy, France. [Zhang, Yan; Ahmed, Ali] Univ Alabama Birmingham, Birmingham & VA Med Ctr, Birmingham, AL USA. [Angioi, Michael] Clin Louis Pasteur, F-54270 Esseys Les Nancy, France. [Vincent, John; Sutradhor, Santosh C.] Pfizer Inc, New York, NY USA. [Pitt, Bertram] Univ Michigan, Ann Arbor, MI 48109 USA. RP Carillo, S (reprint author), CHU Nancy, CIC9501, Inst Lorrain Coeur & Vaisseaux, Inserm U961, 2 Ave Morvan, F-54500 Vandoeuvre Les Nancy, France. EM s.carillo@chu-nancy.fr FU Novartis; Medtronic; Forrest Laboratories; BG Medicine; Roche Diagnostics FX Sylvain Carillo, Renaud Fay and Mickael Angioi: none. Yan Zhang: affiliation with UAB. John Vincent and Santosh C. Sutradhor: Pfizer Inc. employees. Ali Ahmed: affiliation with UAB and VA. Bertram Pitt: consultant for Pfizer, Merck, Novartis, Bayer, Takeda, AstraZeneca, Lilly, BMS, BG Medicine (stock options), Relypsa (stock options), Cytopherx, Amorcyte, Aurasence (stock options) and Ardelyx; grants from Novartis, Medtronic and Forrest Laboratories. Faiez Zannad: grants to institution from BG Medicine and Roche Diagnostics; consultant/member of steering committees, event committees and data safety monitoring boards for Bayer, Biomerieux, Biotronik, Boston Scientific, CVCT, Novartis, Pfizer, Resmed, Servier and Takeda. NR 38 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 1875-2136 EI 1875-2128 J9 ARCH CARDIOVASC DIS JI Arch. Cardiovasc. Dis. PD MAR PY 2014 VL 107 IS 3 BP 149 EP 157 DI 10.1016/j.acvd.2014.01.010 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AH7XA UT WOS:000336347500002 PM 24630753 ER PT J AU Hegde, M Lowenstein, DH AF Hegde, Manu Lowenstein, Daniel H. TI The search for circulating epilepsy biomarkers SO BIOMARKERS IN MEDICINE LA English DT Article DE autoantibodies; biomarkers; blood; cerebrospinal fluid; epilepsy center dot epileptogenesis; inflammation; pharmacoresistance ID TEMPORAL-LOBE EPILEPSY; PYRIDOXINE-DEPENDENT EPILEPSY; NMDA RECEPTOR ENCEPHALITIS; STEVENS-JOHNSON-SYNDROME; ALPHA-AMINOADIPIC SEMIALDEHYDE; GLUTAMIC-ACID DECARBOXYLASE; TUBEROUS SCLEROSIS COMPLEX; IMMATURE RAT MODEL; DYSPLASIA TYPE IIB; STATUS EPILEPTICUS AB Few would experience greater benefit from the development of biomarkers than those who suffer from epilepsy. Both the timing of individual seizures and the overall course of the disease are highly unpredictable, and the associated morbidity is considerable. Thus, there is an urgent need to develop biomarkers that can predict the progression of epilepsy and treatment response. Doing so may also shed light on the mechanisms of epileptogenesis and pharmacoresistance, which remain elusive despite decades of study. However, recent advances suggest the possible identification of circulating epilepsy biomarkers - accessible in blood, cerebrospinal fluid or urine. In this review, we focus on advances in several areas: neuroimmunology and inflammation; neurological viral infection; exemplary pediatric syndromes; and the genetics of pharmacoresistance, as relevant to epilepsy. These are fertile areas of study with great potential to yield accessible epilepsy biomarkers. C1 [Hegde, Manu; Lowenstein, Daniel H.] Univ Calif San Francisco, Dept Neurol, UCSF Epilepsy Ctr, San Francisco, CA 94143 USA. [Hegde, Manu] San Francisco VA Med Ctr, Epilepsy Ctr Excellence, San Francisco, CA 94121 USA. RP Hegde, M (reprint author), Univ Calif San Francisco, Dept Neurol, UCSF Epilepsy Ctr, 521 Parnassus Ave C-440, San Francisco, CA 94143 USA. EM manu.hegde@ucsf.edu NR 99 TC 10 Z9 11 U1 0 U2 8 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 EI 1752-0371 J9 BIOMARK MED JI Biomark. Med. PD MAR PY 2014 VL 8 IS 3 BP 413 EP 427 DI 10.2217/BMM.13.142 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AE4RN UT WOS:000333970700018 PM 24712433 ER PT J AU Qian, J Payabvash, S Kemmling, A Lev, MH Schwamm, LH Betensky, RA AF Qian, Jing Payabvash, Seyedmehdi Kemmling, Andre Lev, Michael H. Schwamm, Lee H. Betensky, Rebecca A. TI Variable Selection and Prediction Using a Nested, Matched Case-Control Study: Application to Hospital Acquired Pneumonia in Stroke Patients SO BIOMETRICS LA English DT Article DE AUC; Cerebral infarction; Conditional logistic regression; Elastic net; Lasso; Penalized likelihood; ROC analysis ID GENOME-WIDE ASSOCIATION; LOGISTIC-REGRESSION; LASSO; CLASSIFICATION; MRI AB Matched case-control designs are commonly used in epidemiologic studies for increased efficiency. These designs have recently been introduced to the setting of modern imaging and genomic studies, which are characterized by high-dimensional covariates. However, appropriate statistical analyses that adjust for the matching have not been widely adopted. A matched case-control study of 430 acute ischemic stroke patients was conducted at Massachusetts General Hospital (MGH) in order to identify specific brain regions of acute infarction that are associated with hospital acquired pneumonia (HAP) in these patients. There are 138 brain regions in which infarction was measured, which introduce nearly 10,000 two-way interactions, and challenge the statistical analysis. We investigate penalized conditional and unconditional logistic regression approaches to this variable selection problem that properly differentiate between selection of main effects and of interactions, and that acknowledge the matching. This neuroimaging study was nested within a larger prospective study of HAP in 1915 stroke patients at MGH, which recorded clinical variables, but did not include neuroimaging. We demonstrate how the larger study, in conjunction with the nested, matched study, affords us the capability to derive a score for prediction of HAP in future stroke patients based on imaging and clinical features. We evaluate the proposed methods in simulation studies and we apply them to the MGH HAP study. C1 [Qian, Jing] Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. [Qian, Jing; Betensky, Rebecca A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Payabvash, Seyedmehdi; Kemmling, Andre; Lev, Michael H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Qian, J (reprint author), Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. EM qian@schoolph.umass.edu OI Schwamm, Lee/0000-0003-0592-9145 FU Harvard NeuroDiscovery Center; Harvard Catalyst [8UL1TR000170]; NIH [R01-CA075971] FX The authors are grateful to the editor, the associate editor, and two anonymous referees for their valuable comments. This research was supported in part by the Harvard NeuroDiscovery Center, the Harvard Catalyst (8UL1TR000170), NIH grant R01-CA075971. NR 25 TC 4 Z9 5 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD MAR PY 2014 VL 70 IS 1 BP 153 EP 163 DI 10.1111/biom.12113 PG 11 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA AC4BS UT WOS:000332466200003 PM 24320930 ER PT J AU Fadlallah, A Atallah, M Cherfan, G Awwad, ST Syed, ZA Melki, SA AF Fadlallah, Ali Atallah, Marwan Cherfan, George Awwad, Shady T. Syed, Zeba A. Melki, Samir A. TI Gamma-Irradiated Corneas as Carriers for the Boston Type 1 Keratoprosthesis: Advantages and Outcomes in a Surgical Mission Setting SO CORNEA LA English DT Article DE keratoprosthesis; gamma-irradiation; Beirut ID SURGERY AB Purpose:The Boston keratoprosthesis (KPro) is the most commonly used KPro worldwide. There are limited data on the outcomes when irradiated corneas are used as KPro carriers. We report a retrospective analysis of corneal transplantations performed in a regular surgical mission setting in Beirut, Lebanon, using the Boston KPro type 1 and gamma-irradiated carrier corneas, and we describe visual outcomes, complications, and retention percentage.Methods:We conducted a retrospective analysis of 17 consecutive eyes from 16 patients who underwent Boston KPro type 1 implantation at the Beirut Eye Specialist Hospital between December 2010 and July 2012. Patient medical records were reviewed for preoperative, intraoperative, and postoperative details.Results:Postoperatively, 9 (52.9%), 5 (29.4%), and 2 (11.7%) eyes had a corrected visual acuity of 20/400 or better, 20/100 or better, and 20/40 or better, respectively, at the most recent follow-up visit. A total of 16 eyes (94.1%) improved in corrected visual acuity over the course of follow-up. Overall, 13 eyes (76.4%) developed at least 1 complication after surgery. Retroprosthetic membrane formation was the most common complication, occurring in 10 eyes (58.8%). Neither infectious keratitis nor corneal stromal necrosis was noted during the follow-up period. The retention percentage was 94.1%.Conclusions:The visual acuity outcomes, incidence of complications, and retention percentage of the KPro using gamma-irradiated carrier corneas are comparable with the outcomes of KPro implantation reported in the literature using fresh grafts as carriers. KPro with irradiated corneal carrier grafts seems to be an effective option to increase the supply of transplantation suitable corneas in remote areas, where fresh corneal grafts may be scarce. C1 [Fadlallah, Ali; Cherfan, George; Melki, Samir A.] Beirut Eye Specialist Hosp, Beirut, Lebanon. [Fadlallah, Ali; Atallah, Marwan] St Joseph Univ, Fac Med, Beirut, Lebanon. [Fadlallah, Ali; Atallah, Marwan] Univ Paris 04, UPMC, Paris, France. [Awwad, Shady T.] Amer Univ Beirut, Med Ctr, Opthalmol Dept, Beirut, Lebanon. [Syed, Zeba A.; Melki, Samir A.] Harvard Univ, Sch Med, Boston, MA USA. [Melki, Samir A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Melki, SA (reprint author), Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv, 243 Charles St, Boston, MA 02114 USA. EM samir_melki@meei.harvard.edu NR 13 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 EI 1536-4798 J9 CORNEA JI Cornea PD MAR PY 2014 VL 33 IS 3 BP 235 EP 239 DI 10.1097/ICO.0000000000000065 PG 5 WC Ophthalmology SC Ophthalmology GA AB1DD UT WOS:000331530700004 PM 24457451 ER PT J AU Fava, M Ball, S Nelson, JC Sparks, J Konechnik, T Classi, P Dube, S Thase, ME AF Fava, Maurizio Ball, Susan Nelson, J. Craig Sparks, JonDavid Konechnik, Thomas Classi, Peter Dube, Sanjay Thase, Michael E. TI CLINICAL RELEVANCE OF FATIGUE AS A RESIDUAL SYMPTOM IN MAJOR DEPRESSIVE DISORDER SO DEPRESSION AND ANXIETY LA English DT Review DE residual symptoms; fatigue; major depressive disorder; functioning; remission ID SEROTONIN REUPTAKE INHIBITORS; STAR-ASTERISK-D; SELECTIVE SEROTONIN; DOUBLE-BLIND; CATECHOLAMINE DEPLETION; ANTIDEPRESSANT ACTION; PARTIAL RESPONDERS; PHYSICAL SYMPTOMS; PARTIAL REMISSION; SLEEPINESS AB Residual symptoms of major depressive disorder (MDD) following treatment are increasingly recognized as having a negative impact on the patient because of their association with lack of remission, poorer psychosocial functioning, and a more chronic course of depression. Although the effects of specific residual symptoms have not been as systematically studied, several symptoms, including fatigue, sleep disturbance, anxiety, and concentration difficulties, commonly occur as part of the residual state in MDD. In particular, the relatively high prevalence of residual fatigue suggests that this symptom is not being adequately addressed by standard antidepressant therapies. A review of the clinical relevance of residual fatigue was undertaken, using the published literature with respect to its assessment, neurobiology, and treatment implications. The findings of this review suggest that fatigue is highly prevalent as a residual symptom; its response to treatment is relatively poor or delayed; and the presence of residual fatigue is highly predictive of inability to achieve remission with treatment as well as impaired psychosocial functioning. Recognition of the significant consequences of residual fatigue should reinforce the need for further therapeutic interventions to help reduce the impact of this symptom of MDD. C1 [Fava, Maurizio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Ball, Susan; Sparks, JonDavid; Konechnik, Thomas; Classi, Peter] Lilly Res Labs, Indianapolis, IN USA. [Ball, Susan; Dube, Sanjay] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [Nelson, J. Craig] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Dube, Sanjay] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA 15260 USA. [Thase, Michael E.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Fava, M (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program, 55 Fruit St,Bulfinch 351, Boston, MA 02114 USA. EM mfava@partners.org NR 61 TC 24 Z9 24 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD MAR PY 2014 VL 31 IS 3 BP 250 EP 257 DI 10.1002/da.22199 PG 8 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA AC3AE UT WOS:000332386600009 PM 24115209 ER PT J AU Mueller, B Ahnert, P Burkhardt, J Brauer, J Czepezauer, I Quente, E Boltze, J Wilcke, A Kirsten, H AF Mueller, B. Ahnert, P. Burkhardt, J. Brauer, J. Czepezauer, I. Quente, E. Boltze, J. Wilcke, A. Kirsten, H. TI Genetic risk variants for dyslexia on chromosome 18 in a German cohort SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Chromosome 18; dyslexia; genetic association studies; genetic predisposition to disease; German primary school students; linkage disequilibrium; quantitative association study; replication study; single nucleotide polymorphism ID DEVELOPMENTAL DYSLEXIA; LINKAGE ANALYSES; GENOMEWIDE SCAN; BLOOD-PRESSURE; LOCUS; ASSOCIATION; DISABILITIES; SAMPLE; TRAIT AB Dyslexia is characterized by impaired reading and spelling. The disorder has a prevalence of about 5% in Germany, and a strong hereditary component. Several loci are thought to be involved in the development of dyslexia. Scerri et al. identified eight potential dyslexia-associated single nucleotide polymorphisms (SNPs) in seven genes on chromosome 18 in an English-speaking population. Here, we present an association analysis that explores the relevance of these SNPs in a German population comprising 388 dyslexia cases and 364 control cases. In case-control analysis, three nominal SNP associations were replicated. The major alleles of NEDD4L-rs12606138 and NEDD4L-rs8094327 were risk associated [odds ratio (OR)=1.35, 95% confidence interval (CI)=1.0-1.7, P-value=0.017 and OR=1.39, 95% CI=1.1-1.7, P-value=0.007, respectively], and both SNPs were in strong linkage disequilibrium (r(2)=0.95). For MYO5B-rs555879, the minor allele was risk associated (OR=1.31, 95% CI=1.1-1.6, P-value=0.011). The combined analysis of SNP sets using set enrichment analysis revealed a study-wide significant association for three SNPs with susceptibility for dyslexia. In summary, our results substantiate genetic markers in NEDD4L and MYO5B as risk factors for dyslexia and provide first evidence that the relevance of these markers is not restricted to the English language. C1 [Mueller, B.; Czepezauer, I.; Quente, E.; Boltze, J.; Wilcke, A.; Kirsten, H.] Fraunhofer Inst Cell Therapy & Immunol, Dept Cell Therapy, D-04103 Leipzig, Germany. [Ahnert, P.; Kirsten, H.] Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany. [Ahnert, P.; Kirsten, H.] Univ Leipzig, LIFE Ctr, Leipzig Interdisciplinary Res Cluster Genet Facto, D-04109 Leipzig, Germany. [Burkhardt, J.; Boltze, J.; Wilcke, A.; Kirsten, H.] Univ Leipzig, Translat Ctr Regenerat Med TRM, D-04109 Leipzig, Germany. [Brauer, J.] Max Planck Inst Human Cognit & Brain Sci, Dept Neuropsychol, Leipzig, Germany. [Boltze, J.] Massachusetts Gen Hosp, Stroke & Neuro Vasc Regulat Lab, Boston, MA 02114 USA. [Boltze, J.] Harvard Univ, Sch Med, Boston, MA USA. RP Mueller, B (reprint author), Fraunhofer Inst Cell Therapy & Immunol, Dept Cell Therapy, Perlickstr 1, D-04103 Leipzig, Germany. EM bent.mueller@izi.fraunhofer.de RI Ahnert, Peter/I-8150-2015; OI Ahnert, Peter/0000-0002-1771-0856; Muller, Bent/0000-0001-8308-6193 FU Federal Ministry of Education and Research [BMBF 1315883]; Leipzig Interdisciplinary Research Cluster of Genetic Factors, Clinical Phenotypes and Environment (LIFE Center, Universitat Leipzig); European Union; European Regional Development Fund (ERFD); European Social Fund; Free State of Saxony; Max-Planck Society; Fraunhofer Society program ('Pakt fur Forschung und Innovation', project 'LEGASCREEN') FX E.Q., J.Bu., H.K. and A.W. received funding from the Federal Ministry of Education and Research (BMBF 1315883). P.A. and H.K. were funded by the Leipzig Interdisciplinary Research Cluster of Genetic Factors, Clinical Phenotypes and Environment (LIFE Center, Universitat Leipzig). LIFE is funded by means of the European Union, by the European Regional Development Fund (ERFD), the European Social Fund and by means of the Free State of Saxony within the framework of the excellence initiative. Finally, B.M., J.Bo., J.Br., H.K., I.C. and A.W. received funding from the joint Max-Planck Society and Fraunhofer Society program ('Pakt fur Forschung und Innovation', project 'LEGASCREEN'). The authors declare no conflict of interest. NR 35 TC 3 Z9 3 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD MAR PY 2014 VL 13 IS 3 BP 350 EP 356 DI 10.1111/gbb.12118 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA AB8ND UT WOS:000332046400010 PM 24373531 ER PT J AU Dogliotti, A Paolasso, E Giugliano, RP AF Dogliotti, Ariel Paolasso, Ernesto Giugliano, Robert P. TI Current and new oral antithrombotics in nonvalvular atrial fibrillation: a network meta-analysis of 79 808 patients SO HEART LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; STROKE PREVENTION; DABIGATRAN ETEXILATE; SECONDARY PREVENTION; ANTICOAGULANT DRUGS; ELDERLY-PATIENTS; DOSE WARFARIN; ASPIRIN; RIVAROXABAN; APIXABAN AB Background Antithrombotic therapy reduces stroke, embolism and mortality in patients with atrial fibrillation (AF); however, meta-analyses have focused on pairwise comparisons of treatments. Objective To synthesise the evidence from trials using a multiple treatment comparison methods thereby permitting a broader comparison across multiple therapies. Design, setting, patients Randomised controlled trials in patients with AF of antithrombotics were identified from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials through May 2012. We performed a random-effects model within a Bayesian framework using Markov Chain Monte Carlo simulation to calculate pooled OR and 95% credibility intervals (CrI). We also ranked therapies by their likelihood of leading to the best results for the outcomes. Main outcome measure Multiple endpoints including stroke, embolism, death and bleeding. Results We identified 20 studies with 79808 patients allocated to 8 treatments: ASA, ASA plus clopidogrel, vitamin K antagonists (VKAs), dabigatran 110mg, dabigatran 150mg, rivaroxaban, apixaban or placebo/control. Compared with placebo/control, dabigatran 150mg was associated with the lowest risk of stroke (OR=0.25, 0.15-0.43), the composite of ischaemic stroke or systemic embolism (OR=0.26, 0.12-0.54) and mortality (OR=0.53, 0.28-0.88). ASA plus clopidogrel was associated with the highest risk of major bleeding (OR=3.65, 1.22-13.56). In simulated comparisons, the novel oral anticoagulants ranked better than VKA or antiplatelet therapies for prevention of stroke, ischaemic stroke or systemic embolism and mortality. Conclusions In this network meta-analysis, novel oral anticoagulants were the most promising treatments to reduce stroke, stroke or systemic embolism, and all-cause mortality in patients with AF. C1 [Dogliotti, Ariel] Grp Orono, Unidad Epidemiol Clin & Estadist, Rosario, Santa Fe, Argentina. [Dogliotti, Ariel; Paolasso, Ernesto] Inst Cardiovasc Rosario, Rosario, Santa Fe, Argentina. [Paolasso, Ernesto] Inst Invest Clin, Rosario, Santa Fe, Argentina. [Giugliano, Robert P.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Giugliano, RP (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, TIMI Study Grp, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. EM rgiugliano@partners.org FU Johnson Johnson; Daiichi-Sankyo FX Robert Giugliano: Dr Giugliano is a member of the TIMI Study Group, which has received research grant support from Johnson & Johnson and from Daiichi-Sankyo related to clinical trials of anticoagulants. Dr Giugliano has received honoraria for consultation/lectures from Bristol-Myers Squibb, Daiichi-Sankyo and Johnson & Johnson. NR 50 TC 26 Z9 26 U1 0 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 EI 1468-201X J9 HEART JI Heart PD MAR 1 PY 2014 VL 100 IS 5 BP 396 EP 405 DI 10.1136/heartjnl-2013-304347 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AB8DV UT WOS:000332021200011 PM 24009224 ER PT J AU Sondhi, D Scott, EC Chen, A Hackett, NR Wong, AMS Kubiak, A Nelvagal, HR Pearse, Y Cotman, SL Cooper, JD Crystal, RG AF Sondhi, Dolan Scott, Emma C. Chen, Alvin Hackett, Neil R. Wong, Andrew M. S. Kubiak, Agnieszka Nelvagal, Hemanth R. Pearse, Yewande Cotman, Susan L. Cooper, Jonathan D. Crystal, Ronald G. TI Partial Correction of the CNS Lysosomal Storage Defect in a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis by Neonatal CNS Administration of an Adeno-Associated Virus Serotype rh. 10 Vector Expressing the Human CLN3 Gene SO HUMAN GENE THERAPY LA English DT Article ID UNDERLYING BATTEN-DISEASE; KNOCK-IN MICE; GLIAL ACTIVATION; THERAPY; BRAIN; PROTEIN; AUTOPHAGY; PATHOLOGY; JNCL; NEURODEGENERATION AB Juvenile neuronal ceroid lipofuscinosis (JNCL or CLN3 disease) is an autosomal recessive lysosomal storage disease resulting from mutations in the CLN3 gene that encodes a lysosomal membrane protein. The disease primarily affects the brain with widespread intralysosomal accumulation of autofluorescent material and fibrillary gliosis, as well as the loss of specific neuronal populations. As an experimental treatment for the CNS manifestations of JNCL, we have developed a serotype rh.10 adeno-associated virus vector expressing the human CLN3 cDNA (AAVrh.10hCLN3). We hypothesized that administration of AAVrh.10hCLN3 to the Cln3(ex7/8) knock-in mouse model of JNCL would reverse the lysosomal storage defect, as well as have a therapeutic effect on gliosis and neuron loss. Newborn Cln3(ex7/8) mice were administered 3x10(10) genome copies of AAVrh.10hCLN3 to the brain, with control groups including untreated Cln3(ex7/8) mice and wild-type littermate mice. After 18 months, CLN3 transgene expression was detected in various locations throughout the brain, particularly in the hippocampus and deep anterior cortical regions. Changes in the CNS neuronal lysosomal accumulation of storage material were assessed by immunodetection of subunit C of ATP synthase, luxol fast blue staining, and periodic acid-Schiff staining. For all parameters, Cln3(ex7/8) mice exhibited abnormal lysosomal accumulation, but AAVrh.10hCLN3 administration resulted in significant reductions in storage material burden. There was also a significant decrease in gliosis in AAVrh.10hCLN3-treated Cln3(ex7/8) mice, and a trend toward improved neuron counts, compared with their untreated counterparts. These data demonstrate that AAVrh.10 delivery of a wild-type cDNA to the CNS is not harmful and instead provides a partial correction of the neurological lysosomal storage defect of a disease caused by a lysosomal membrane protein, indicating that this may be an effective therapeutic strategy for JNCL and other diseases in this category. C1 [Sondhi, Dolan; Scott, Emma C.; Chen, Alvin; Hackett, Neil R.; Crystal, Ronald G.] Cornell Univ, Weill Med Coll, Dept Med Genet, New York, NY 10065 USA. [Wong, Andrew M. S.; Kubiak, Agnieszka; Nelvagal, Hemanth R.; Pearse, Yewande; Cooper, Jonathan D.] Kings Coll London, Ctr Cellular Basis Behav, Dept Neurosci, London SE5 9NU, England. [Wong, Andrew M. S.; Kubiak, Agnieszka; Nelvagal, Hemanth R.; Pearse, Yewande; Cooper, Jonathan D.] Kings Coll London, Inst Psychiat, Kings Hlth Partners Ctr Neurodegenerat Res, London SE5 9NU, England. [Cotman, Susan L.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Crystal, RG (reprint author), Cornell Univ, Weill Med Coll, Dept Med Genet, 1300 York Ave,Box 164, New York, NY 10065 USA. EM geneticmedicine@med.cornell.edu FU National Contest for Life-Stiftung; Natalie Fund; DEM-CHILD; European Community [281234]; National Institutes of Health (National Institute of Neurological Disorders Stroke) [R01-NS073813]; Dubai-Harvard Foundation for Medical Research FX We thank Benjamin Van de Graaf and Scott H. Coppel for technical assistance and N. Mohamed and D. N. McCarthy for help in preparing this article. The studies were supported, in part, by National Contest for Life-Stiftung, The Natalie Fund, and DEM-CHILD funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under Grant Agreement No. 281234. S. L. C. is supported by the National Institutes of Health (National Institute of Neurological Disorders & Stroke; R01-NS073813) and the Dubai-Harvard Foundation for Medical Research. NR 63 TC 10 Z9 10 U1 0 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 EI 1557-7422 J9 HUM GENE THER JI Hum. Gene Ther. PD MAR 1 PY 2014 VL 25 IS 3 BP 223 EP 239 DI 10.1089/hum.2012.253 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA AC8FE UT WOS:000332768100009 PM 24372003 ER PT J AU Kramer, J Rubin, A Coster, W Helmuth, E Hermos, J Rosenbloom, D Moed, R Dooley, M Kao, YC Liljenquist, K Brief, D Enggasser, J Keane, T Roy, M Lachowicz, M AF Kramer, Jessica Rubin, Amy Coster, Wendy Helmuth, Eric Hermos, John Rosenbloom, David Moed, Rich Dooley, Meghan Kao, Ying-Chia Liljenquist, Kendra Brief, Deborah Enggasser, Justin Keane, Terence Roy, Monica Lachowicz, Mark TI Strategies to address participant misrepresentation for eligibility in Web-based research SO INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH LA English DT Article DE Internet data collection; World Wide Web data collection; sampling methods; recruitment and enrollment methods; participant misrepresentation ID ALCOHOL-USE; PEDI-CAT; INTERNET; CARE AB Emerging methodological research suggests that the World Wide Web (Web) is an appropriate venue for survey data collection, and a promising area for delivering behavioral intervention. However, the use of the Web for research raises concerns regarding sample validity, particularly when the Web is used for recruitment and enrollment. The purpose of this paper is to describe the challenges experienced in two different Web-based studies in which participant misrepresentation threatened sample validity: a survey study and an online intervention study. The lessons learned from these experiences generated three types of strategies researchers can use to reduce the likelihood of participant misrepresentation for eligibility in Web-based research. Examples of procedural/design strategies, technical/software strategies and data analytic strategies are provided along with the methodological strengths and limitations of specific strategies. The discussion includes a series of considerations to guide researchers in the selection of strategies that may be most appropriate given the aims, resources and target population of their studies. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Kramer, Jessica; Coster, Wendy; Dooley, Meghan; Kao, Ying-Chia; Liljenquist, Kendra] Boston Univ, Dept Occupat Therapy, Boston, MA 02215 USA. [Rubin, Amy; Hermos, John] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Helmuth, Eric; Rosenbloom, David] Boston Univ, Dept Hlth Policy & Management, Boston, MA 02215 USA. [Brief, Deborah; Enggasser, Justin; Keane, Terence; Roy, Monica; Lachowicz, Mark] VA Boston Healthcare Syst, Boston, MA USA. RP Kramer, J (reprint author), Boston Univ, Dept Occupat Therapy, 635 Commonwealth Ave SAR 503, Boston, MA 02215 USA. EM kramerj@bu.edu FU NIAAA NIH HHS [RC1 AA019248]; NICHD NIH HHS [R21 HD065281] NR 19 TC 11 Z9 11 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1049-8931 EI 1557-0657 J9 INT J METH PSYCH RES JI Int. J. Methods Psychiatr. Res. PD MAR PY 2014 VL 23 IS 1 BP 120 EP 129 DI 10.1002/mpr.1415 PG 10 WC Psychiatry SC Psychiatry GA AD1QZ UT WOS:000333009800011 PM 24431134 ER PT J AU Yehia, BR French, B Fleishman, JA Metlay, JP Berry, SA Korthuis, PT Agwu, AL Gebo, KA AF Yehia, Baligh R. French, Benjamin Fleishman, John A. Metlay, Joshua P. Berry, Stephen A. Korthuis, P. Todd Agwu, Allison L. Gebo, Kelly A. CA HIV Res Network TI Retention in Care Is More Strongly Associated With Viral Suppression in HIV-Infected Patients With Lower Versus Higher CD4 Counts SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV disease severity; viral suppression; engagement in care; retention in care; retention measures; CD4 count ID ACTIVE ANTIRETROVIRAL THERAPY; MEDICAL-CARE; ADHERENCE; COHORT; PREDICTORS; PREVENTION; SURVIVAL; OUTCOMES; FAILURE; CLINICS AB Background: Retention in care is important for all HIV-infected patients, but may be more important for people with advanced HIV disease. We evaluated whether the association between retention in care and viral suppression differed by HIV disease severity. Methods: A repeated cross-sectional analysis (2006-2011) involving 35,433 adults at 18 US HIV clinics. Multivariable logistic regression models examined associations between retention measures [Health Resources and Services Administration (HRSA) retention measure, 6-month gap, and 3-month visit constancy] and viral suppression (HIV-1 RNA <= 400 copies/mL) for HIV disease severity groups defined by CD4 counts: <= 200, 201-350, 351-500, and >500 cells per cubic millimeter. Results: Overall, patients met the HRSA measure in 84% of person-years, did not have a 6-month gap in 76%, and had visits in all 4 quarters in 37%; patients achieved viral suppression in 72% of person-years. The association between retention in care and viral suppression differed by disease severity, and was strongest for patients with lower CD4 counts: <= 200 [adjusted odds ratio (AOR) = 2.33, 95% confidence interval (CI): 2.16 to 2.51], 201-350 (AOR = 1.96, CI: 1.81 to 2.12), 351-500 (AOR = 1.65, CI: 1.53 to 1.78), and >500 cells per cubic millimeter (AOR = 1.22, CI: 1.14 to 1.30) using the HRSA retention measure as a representative example. Conclusions: This is one of the first studies to report the impact of HIV disease severity on retention in care and viral suppression, demonstrating that retention in care is more strongly associated with viral suppression in patients with lower CD4 counts. These results have important implications for improving the health of patients with advanced HIV disease and for test and treat approaches to HIV prevention. C1 [Yehia, Baligh R.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Yehia, Baligh R.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Yehia, Baligh R.] Philadelphia Vet Affairs Ctr Hlth Equ Res & Promo, Philadelphia, PA USA. [French, Benjamin] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Fleishman, John A.] Agcy Healthcare Res & Qual, Ctr Financing Access & Cost Trends, Rockville, MD USA. [Metlay, Joshua P.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Berry, Stephen A.; Agwu, Allison L.; Gebo, Kelly A.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Korthuis, P. Todd] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. RP Yehia, BR (reprint author), Univ Penn, Dept Med, Perelman Sch Med, 1021 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM byehia@upenn.edu FU Agency for Healthcare Research and Quality [HHSA290201100007C]; National Institutes of Health [K23-MH097647] FX Supported by the Agency for Healthcare Research and Quality (HHSA290201100007C) and the National Institutes of Health (K23-MH097647 to B.R.Y.). NR 34 TC 21 Z9 21 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD MAR 1 PY 2014 VL 65 IS 3 BP 333 EP 339 DI 10.1097/QAI.0000000000000023 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AH0DL UT WOS:000335789200023 PM 24129370 ER PT J AU Marks, KM Kitch, D Chung, RT Hadigan, C Andersen, J Tien, P Luetkemeyer, A Alston-Smith, B Glesby, MJ AF Marks, Kristen M. Kitch, Douglas Chung, Raymond T. Hadigan, Colleen Andersen, Janet Tien, Phyllis Luetkemeyer, Annie Alston-Smith, Beverly Glesby, Marshall J. CA A5239 Team TI Pilot Study of Pioglitazone Before HCV Retreatment in HIV/HCV Genotype 1-Infected Subjects With Insulin Resistance and Previous Nonresponse to Peginterferon and Ribavirin Therapy: A5239 SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE metabolic; hepatitis C; nonresponder; pegylated interferon; insulin resistance; HIV ID HEPATITIS-C VIRUS; ALPHA-2A PLUS RIBAVIRIN; VIROLOGICAL RESPONSE; COINFECTED PATIENTS; NONALCOHOLIC STEATOHEPATITIS; ANTIRETROVIRAL THERAPY; INFECTED PATIENTS; HIV; STEATOSIS; METFORMIN AB Insulin resistance is associated with nonresponse to hepatitis C virus (HCV) treatment. In this multicenter, single-arm pilot study, adult, HIV/HCV genotype 1-coinfected previous nonresponders to peginterferon/ribavirin (PegIFN/RBV) with homeostatic model assessment of insulin resistance >2.5 were treated with pioglitazone (PIO) for 24 weeks followed by PegIFN/RBV/PIO. Three of 19 subjects (15.8%) achieved undetectable HCV RNA at week 24 of PegIFN/RBV/PIO, which was not significantly different than the historical null rate of 10% (P = 0.29, lower limit of the exact 1-sided 90% confidence interval 5.9%). Over the 24 weeks of PIO monotherapy, alanine aminotransferase and aspartate aminotransferase declined significantly and correlated with improved metabolic parameters. C1 [Marks, Kristen M.; Glesby, Marshall J.] Weill Cornell Med Coll, Div Infect Dis, New York, NY 10065 USA. [Kitch, Douglas; Andersen, Janet] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Div, Boston, MA USA. [Hadigan, Colleen; Alston-Smith, Beverly] NIAID, NIH, Bethesda, MD 20892 USA. [Tien, Phyllis] Univ Calif San Francisco, Sch Med, Div Infect Dis, San Francisco, CA USA. [Tien, Phyllis] Dept Vet Affairs, Med Serv, San Francisco, CA USA. [Luetkemeyer, Annie] Univ Calif San Francisco, San Francisco Gen Hosp, Div HIV AIDS, San Francisco, CA USA. RP Marks, KM (reprint author), Weill Cornell Med Coll, Div Infect Dis, 525 East 68th St,F24, New York, NY 10065 USA. EM markskr@med.cornell.edu FU National Institute of Allergy and Infectious Diseases [UM1AI068636]; National Institute of Mental Health, National Institute of Dental and Craniofacial Research; Roche (Genentech); Takeda Pharmaceuticals, USA, Inc.; AACTG/ACTG Statistical and Data Management Center [1 UM1 AI068634, 5 U01 AI38855]; Intramural National Institute of Allergy and Infectious Diseases support [NIH DK078772, K24 AI078884, U01 AI069502]; Roche Laboratories; Bristol-Myers Squibb; Gilead; Vertex Pharmaceuticals; Pfizer; Gilead Sciences; SIGA Technologies; Boehringer Ingelheim; CTU [U01 AI69419, 5UO1 AI069502-07, UM1AI069532, UM1 AI069511, AI69501, AI 069471, UM1-AI069503, IU0IAI69472]; CTSCs from the National Center for Advancing Translational Sciences component of the National Institutes of Health (NIH) [UL1 TR000457, UL1TR000439]; National Center for Advancing Translational Sciences (Virginia Commonwealth University) [UL1TR000058] FX Supported by Award Number UM1AI068636 from the National Institute of Allergy and Infectious Diseases and supported by National Institute of Mental Health, National Institute of Dental and Craniofacial Research. This research was also supported by Roche (Genentech) and Takeda Pharmaceuticals, USA, Inc. Other grant support included 1 UM1 AI068634 and 5 U01 AI38855 to AACTG/ACTG Statistical and Data Management Center; Intramural National Institute of Allergy and Infectious Diseases support (C. H.); NIH DK078772 (R. T. C.); K24 AI078884 (M. G.), U01 AI069502 (A. L.). R. T. C. received research funding from Roche Laboratories. A. L. has received research grant support to University of California San Francisco from Bristol-Myers Squibb, Gilead, and Vertex Pharmaceuticals. M.J.G. has received research support from Pfizer to Weill Cornell Medical College and has served as a consultant to Gilead Sciences, SIGA Technologies, and Pfizer. K. M. M. has received research support to Weill Cornell Medical College from Bristol-Myers Squibb, Vertex Pharmaceuticals, Janssen Pharmaceuticals, Boehringer Ingelheim, and Gilead and has received honoraria for lectures from Boehringer Ingelheim and Bristol-Myers Squibb. Also supported in part by CTU grants, including U01 AI69419 [Cornell (Site 7804)], 5UO1 AI069502-07 [University of California San Francisco AIDS CRS (Site 801)], UM1AI069532 [New York University/NYC HHC at Bellevue Hospital Center (Site 401)], UM1 AI069511 [University of Rochester (Site 1101)], AI69501 [MetroHealth Medical Center (Site 2503)], AI 069471 [Northwestern University (A2701)], UM1-AI069503 [Virginia Commonwealth University (Site 31475)], and Massachusetts General Hospital (Site 101) CTU Grant IU0IAI69472. Also supported in part by grants funded by site CTSCs, including UL1 TR000457 (Cornell CTSC), UL1TR000439 from the National Center for Advancing Translational Sciences component of the National Institutes of Health (NIH) and NIH roadmap for Medical Research (Clinical and Translational Science Collaborative of Cleveland), UL1TR000058 from the National Center for Advancing Translational Sciences (Virginia Commonwealth University). NR 19 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD MAR 1 PY 2014 VL 65 IS 3 BP 345 EP 349 DI 10.1097/QAI.0000000000000073 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AH0DL UT WOS:000335789200025 PM 24525470 ER PT J AU Desmonde, S Essanin, JB Aka, AE Messou, E Amorissani-Folquet, M Rondeau, V Ciaranello, A Leroy, V AF Desmonde, Sophie Essanin, Jean-Bosco Aka, Addi E. Messou, Eugene Amorissani-Folquet, Madeleine Rondeau, Virginie Ciaranello, Andrea Leroy, Valeriane TI Morbidity and Health care Resource Utilization in HIV-Infected Children After Antiretroviral Therapy Initiation in Cote d'Ivoire, 2004-2009 SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE morbidity; HIV; antiretroviral therapy; health care resource utilization; children; West Africa ID MALARIA-ENDEMIC AREA; FOLLOW-UP; COTRIMOXAZOLE PROPHYLAXIS; HIV-1-INFECTED CHILDREN; HOSPITAL ADMISSIONS; TREATMENT PROGRAM; ZAMBIAN CHILDREN; LIMITED SETTINGS; WEST-AFRICA; ABIDJAN AB Background: We describe severe morbidity and health care resource utilization (HCRU) among HIV-infected children on antiretroviral therapy (ART) in Abidjan, Cote d ' Ivoire. Methods: All HIV-infected children enrolled in an HIV-care program (2004-2009) were eligible for ART initiation until database closeout, death, ART interruption, or loss to follow-up. We calculated incidence rates (IRs) of density per 100 child-years (CYs) for severe morbidity, HCRU (outpatient care and inpatient care), and associated factors using frailty models with a Weibull distribution. Results: Of 332 children with a median age of 5.7 years and median follow-up of 2.5 years, 65.4% were severely immunodeficient by World Health Organization (WHO) criteria, and all received cotrimoxazole prophylaxis. We recorded 464 clinical events in 228 children; the overall IR was 57.6/100 CYs [95% confidence interval (CI): 52.1 to 62.5]. Severe morbidity was more frequent in children on protease inhibitor (PI)-based ART compared to those on other regimens [adjusted hazards ratio (aHR): 1.83; 95% CI: 1.35 to 2.47] and to those moderately/severely immunodeficient compared to those not (aHR: 1.57; 95% CI: 1.13 to 2.18 and aHR: 2.53; 95% CI: 1.81 to 3.55, respectively). Of the 464 events, 371 (80%) led to outpatient care (IR: 45.6/100 CYs) and 164 (35%) to inpatient care (IR: 20.2/100 CYs). In adjusted analyses, outpatient care was significantly less frequent in children older than 10 years compared with children younger than 2 years (aHR: 0.49; 95% CI: 0.31 to 0.78) and in those living furthest from clinics compared with those living closest (aHR: 0.65; 95% CI: 0.47 to 0.90). Both inpatient and outpatient HCRU were negatively associated with cotrimoxazole prophylaxis. Conclusions: Despite ART, HIV-infected children still require substantial utilization of health care services. C1 [Desmonde, Sophie; Rondeau, Virginie; Leroy, Valeriane] Ctr INSERM U897, Bordeaux, France. [Desmonde, Sophie; Rondeau, Virginie; Leroy, Valeriane] Univ Bordeaux, ISPED, Ctr INSERM U897, Bordeaux, France. [Essanin, Jean-Bosco; Amorissani-Folquet, Madeleine] Univ Cocody, Abidjan, Cote Ivoire. [Aka, Addi E.; Messou, Eugene] ACONDA, CePReF, Abidjan, Cote Ivoire. [Amorissani-Folquet, Madeleine] Cocody Univ Hosp, Dept Pediat, Abidjan, Cote Ivoire. [Ciaranello, Andrea] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Desmonde, S (reprint author), INSERM, U897, ISPED, F-33076 Bordeaux, France. EM sophie.desmonde@isped.u-bordeaux2.fr RI Leroy, Valeriane/F-8129-2013; rondeau, virginie/E-4192-2014 OI Leroy, Valeriane/0000-0003-3542-8616; rondeau, virginie/0000-0001-7109-4831 FU National Cancer Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Allergy and Infectious Diseases (NIAID) of the US National Institutes of Health [U01AI069919, R01 A1058736, R01AI05873, K01AI078754]; International Maternal Pediatric Adolescent AIDS Clinical Trials network; NIAID [U01 AI068632]; NICHD; National Institute of Mental Health [AI068632]; United States President's Emergency Plan for AIDS Relief, through the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC; French GIP ESTHER; Cote d'Ivoire Ministry of Public Health FX Supported in part by the National Cancer Institute, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Allergy and Infectious Diseases (NIAID) of the US National Institutes of Health, Grants U01AI069919 (Epidemiologic Databases to Evaluate AIDS, West Africa), R01 A1058736, R01AI05873, and K01AI078754, and the International Maternal Pediatric Adolescent AIDS Clinical Trials network (A. C.). Overall support for International Maternal Pediatric Adolescent AIDS Clinical Trials was provided by the NIAID Grant U01 AI068632, the NICHD, and the National Institute of Mental Health Grant AI068632. S. D. is a fellow of the Ecole des Hautes Etudes en Sante Publique, Rennes, France. The Aconda program was funded by the United States President's Emergency Plan for AIDS Relief, through the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC, with additional support from the French GIP ESTHER and the Cote d'Ivoire Ministry of Public Health. NR 46 TC 2 Z9 2 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD MAR 1 PY 2014 VL 65 IS 3 BP E95 EP E103 DI 10.1097/QAI.0b013e3182a4ea6f PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AH0DL UT WOS:000335789200001 PM 24525473 ER PT J AU Thrift, AP Kramer, JR Alsarraj, A El-Serag, HB AF Thrift, Aaron P. Kramer, Jennifer R. Alsarraj, Abeer El-Serag, Hashem B. TI Fat Mass by Bioelectrical Impedance Analysis is not Associated With Increased Risk of Barrett Esophagus SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article DE Barrett esophagus; obesity; bioelectrical impedance analysis; risk factors ID APPENDICULAR BODY-COMPOSITION; BIOIMPEDANCE ANALYSIS; GENERAL-POPULATION; ABDOMINAL OBESITY; INDEX; ADIPOSITY; ACCURACY; ADENOCARCINOMA; METAANALYSIS; ADULTS AB Goal:To evaluate whether the association between obesity and Barrett esophagus (BE) is due to total body fatness, abdominal obesity, or both.Background:BE risk seems to be more strongly related to central obesity than total obesity. However, no studies have investigated the association between total obesity and BE using direct measures of total body fatness.Study:We conducted a case-control study among patients scheduled for elective esophagogastroduodenoscopy, and a sample of patients eligible for screening colonoscopy recruited from primary care clinics. BE cases were patients with specialized intestinal metaplasia, whereas controls had no endoscopic or histopathologic BE. All patients underwent a study esophagogastroduodenoscopy and had body measurements taken. Fat mass and fat-free mass were estimated from bioelectrical impedance analysis (BIA). We calculated odds ratios (OR) and 95% confidence intervals (95% CI) using multivariable logistic regression.Results:There were 70 BE cases, 229 endoscopy controls, and 118 primary care controls. BMI and BIA-derived fat mass were highly correlated; however, we found no association between BMI, fat mass, and BE (vs. all controls: BMI, OR/1 SD=1.01; 95% CI, 0.76-1.34; fat mass, OR=1.02; 95% CI, 0.77-1.36). Waist-to-hip ratio was significantly associated with increased BE risk (vs. all controls: OR/1 SD=1.45; 95% CI, 1.03-2.04). We found similar results when we analyzed the control groups separately.Conclusion:Waist-to-hip ratio, but not fat mass or BMI, was associated with increased BE risk. This study provides strong evidence that BE is related to body size and composition through central adiposity and not through total body fatness. C1 [Thrift, Aaron P.] Queensland Inst Med Res, Dept Populat Hlth, Brisbane, Qld 4006, Australia. [Kramer, Jennifer R.; Alsarraj, Abeer; El-Serag, Hashem B.] Baylor Coll Med, Houston VA HSR&D Ctr Excellence, Houston, TX 77030 USA. [El-Serag, Hashem B.] Baylor Coll Med, Dept Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Kramer, Jennifer R.] Baylor Coll Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [El-Serag, Hashem B.] Baylor Coll Med, Dept Med, Sect Gastroenterol & Hepatol, Houston, TX 77030 USA. RP El-Serag, HB (reprint author), Houston Vet Affairs Med Ctr, 2002 Holcombe Blvd 152, Houston, TX 77030 USA. EM hasheme@bcm.edu FU NIH [NCI R01 116845]; Houston VA, HSR&D Center of Excellence [HFP90-020]; Texas Digestive Disease Center NIH [DK58338]; NIDDK [K24-04-107] FX Supported in part by NIH grant NCI R01 116845, the Houston VA, HSR&D Center of Excellence (HFP90-020), and the Texas Digestive Disease Center NIH, DK58338. H.B.E.-S. is also supported by NIDDK K24-04-107. NR 28 TC 8 Z9 8 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-0790 EI 1539-2031 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD MAR PY 2014 VL 48 IS 3 BP 218 EP 223 DI 10.1097/MCG.0b013e31829ae98c PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AF7UU UT WOS:000334921100004 PM 23842216 ER PT J AU Jin, J Machado, ER Yu, H Zhang, X Lu, Z Li, Y Lopes-Virella, MF Kirkwood, KL Huang, Y AF Jin, J. Machado, E. R. Yu, H. Zhang, X. Lu, Z. Li, Y. Lopes-Virella, M. F. Kirkwood, K. L. Huang, Y. TI Simvastatin Inhibits LPS-induced Alveolar Bone Loss during Metabolic Syndrome SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE lipopolysaccharide; inflammation obesity; periodontal disease; statin; insulin resistance ID PERIODONTAL-DISEASE; STATIN THERAPY; CARDIOVASCULAR-DISEASE; TNF-ALPHA; OBESITY; INFLAMMATION; ASSOCIATION; METAANALYSIS; ARTHRITIS; MICE AB Studies in recent years have shown a positive relationship between metabolic syndrome (MS) and periodontal disease (PD). Given that patients with MS take statins to reduce cholesterol, and statins also have anti-inflammatory effects, it is important to determine if statin intake hinders the progression of MS-associated PD. In this study, PD was induced in Zucker fat rats (ZFRs), an animal model for MS, and in control lean rats by periodontal injection of Aggregatibacter actinomycetemcomitans lipopolysaccharide (LPS), while simvastatin was given to some of the rats via gavage. After 4 wk of treatment, alveolar bone loss was determined by micro-computed tomography. To explore the underlying mechanisms, we determined the effect of simvastatin on tissue inflammation and the expression of molecules involved in osteoclastogenesis. Results showed that while bone loss was increased by LPS in both ZFRs and the control lean rats, it was significantly more in the former than the latter. Simvastatin effectively alleviated bone loss in both ZFRs and the control rats. Results also showed that LPS stimulated leukocyte tissue infiltration and expression of molecules for osteoclastogenesis, but simvastatin significantly modulated the stimulation. This study demonstrated that simvastatin inhibited LPS-induced alveolar bone loss and periodontal tissue inflammation in rats with MS. C1 [Jin, J.; Zhang, X.; Lu, Z.; Li, Y.; Lopes-Virella, M. F.; Huang, Y.] Med Univ S Carolina, Coll Med, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. [Lopes-Virella, M. F.; Huang, Y.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Machado, E. R.; Yu, H.; Kirkwood, K. L.] Med Univ S Carolina, Coll Dent Med, Dept Craniofacial Biol, Charleston, SC 29425 USA. [Machado, E. R.; Yu, H.; Kirkwood, K. L.] Med Univ S Carolina, Coll Dent Med, Ctr Oral Hlth Res, Charleston, SC 29425 USA. [Jin, J.] Guilin Med Univ, Affiliated Hosp, Lab Hepatobiliary & Pancreat Surg, Guilin 541001, Guangxi, Peoples R China. RP Huang, Y (reprint author), Med Univ S Carolina, Coll Med, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. EM huangyan@musc.edu FU National Institutes of Health [DE016353]; Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs; National Institute of General Medical Sciences of the National Institutes of Health [P30103331] FX This work was supported by National Institutes of Health grant DE016353 and by the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs (to Y.H.). Research reported in this publication was also supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P30103331. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 30 TC 8 Z9 9 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD MAR PY 2014 VL 93 IS 3 BP 294 EP 299 DI 10.1177/0022034513516980 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AA9SM UT WOS:000331433200013 PM 24352501 ER PT J AU Nunn, ME Fish, MD Garcia, RI Kaye, EK Figueroa, R Gohel, A Ito, M Lee, HJ Williams, DE Miyamoto, T AF Nunn, M. E. Fish, M. D. Garcia, R. I. Kaye, E. K. Figueroa, R. Gohel, A. Ito, M. Lee, H. J. Williams, D. E. Miyamoto, T. TI Response to Letter to the Editor, "Retained Asymptomatic Third Molars and Risk for Second Molar Pathology" SO JOURNAL OF DENTAL RESEARCH LA English DT Letter C1 [Nunn, M. E.; Miyamoto, T.] Creighton Univ, Sch Dent, Dept Periodontol, Omaha, NE 68178 USA. [Fish, M. D.; Garcia, R. I.; Kaye, E. K.] Boston Univ, Henry M Goldman Sch Dent Med, Dept Hlth Policy & Hlth Serv Res, Boston, MA 02215 USA. [Garcia, R. I.] VA Boston Healthcare Syst, Boston, MA USA. [Figueroa, R.] Boston Univ, Henry M Goldman Sch Dent Med, Dept Oral & Maxillofacial Surg, Boston, MA 02215 USA. [Gohel, A.] Boston Univ, Henry M Goldman Sch Dent Med, Dept Oral & Maxillofacial Radiol, Boston, MA 02215 USA. [Ito, M.] Nihon Univ, Sch Dent Matsudo, Dept Removable Prosthodont, Chiba, Japan. [Lee, H. J.] Seoul Natl Univ, Bundang Hosp, Dept Periodontol, Songnam, South Korea. [Williams, D. E.] Creighton Univ, Sch Dent, Dept Oral & Maxillofacial Surg, Omaha, NE 68178 USA. RP Nunn, ME (reprint author), Creighton Univ, Sch Dent, Dept Periodontol, Omaha, NE 68178 USA. EM nunn@creighton.edu FU NIDCR NIH HHS [R01 DE019656, K24 DE000419] NR 5 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 EI 1544-0591 J9 J DENT RES JI J. Dent. Res. PD MAR PY 2014 VL 93 IS 3 BP 320 EP 321 DI 10.1177/0022034513520327 PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AA9SM UT WOS:000331433200018 PM 24554649 ER PT J AU Zhao, PC Hou, LF Farley, K Sundrud, MS Remold-O'Donnell, E AF Zhao, Picheng Hou, Lifei Farley, Kalamo Sundrud, Mark S. Remold-O'Donnell, Eileen TI SerpinB1 regulates homeostatic expansion of IL-17(+) gamma delta and CD4(+)Th17 cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE lymphocytes; population size; cell proliferation; inflammation; cytokine regulation ID SERINE-PROTEASE INHIBITORS; T-CELLS; INFLUENZA-A; TRANSCRIPTION FACTOR; INTERFERON-GAMMA; INFECTION; IDENTIFICATION; LYMPHOCYTES; MECHANISM; INFLAMMATION AB Gene-deleted mice show that serpinB1 serves as an endogenous restraint to limit untoward expansion of lymphocytes with a Th17 phenotype. SerpinB1 is an endogenous inhibitor of serine proteases recognized for its anti-inflammatory and host-protective properties. Although loss of serpinB1 in mice does not result in gross immune deregulation, serpinb1a(-/-) mice display increased mortality and inflammation-associated morbidity upon challenge with influenza virus. Here, we show that IL-17A(+) and CD4(+) Th17 cells are already expanded in the lungs of serpinb1a(-/-) mice at steady-state. Both and (+) CD4(+) CCR6(+) T cells isolated from the lungs of naive serpinb1a(-/-) mice displayed a skewed transcriptional profile relative to WT cells, including increased Th17 signature transcripts [Il17a, l17f, and Rorc (RORt)] and decreased Th1 signature transcripts [Ifng, Cxcr3, and Tbx21 (T-bet)] in T cells. In addition to the lung, IL-17A(+) and CD4(+) Th17 cells were increased in the spleen of naive serpinb1a(-/-) mice, despite normal and T cell development in the thymus. Within the T cell compartment, loss of serpinb1a prompted selective expansion of V4(+) and V6/V1(+) cells, which also displayed elevated expression of the proliferating cell nuclear antigen, Ki-67, and IL-17A. Given that serpinb1a is preferentially expressed in WT IL-17A(+) and CD4(+) Th17 cell subsets vis-a-vis other T cell lineages, our findings reveal a novel function of serpinB1 in limiting untoward expansion of lymphocytes with a Th17 phenotype. C1 [Zhao, Picheng; Hou, Lifei; Farley, Kalamo; Remold-O'Donnell, Eileen] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Remold-O'Donnell, Eileen] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Zhao, Picheng; Hou, Lifei; Farley, Kalamo; Remold-O'Donnell, Eileen] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Sundrud, Mark S.] Tempero Pharmaceut, Discovery Biol, Cambridge, MA USA. RP Remold-O'Donnell, E (reprint author), Boston Childrens Hosp, 3 Blackfan Circle, Boston, MA 02115 USA. EM eileen.remold-odonnell@childrens.harvard.edu RI ZHAO, PICHENG/G-3737-2014 FU Pilot Award of the GlaxoSmithKline/Immune Disease Institute Research Alliance; National Heart, Lung, and Blood Institute, U.S. National Institutes of Health, Bethesda, MD, USA [HL-066548] FX This work was supported by a Pilot Award of the GlaxoSmithKline/Immune Disease Institute Research Alliance and by grant HL-066548 from the National Heart, Lung, and Blood Institute, U.S. National Institutes of Health, Bethesda, MD, USA. We thank Kevan L. Hartshorn and Mitchell White (Boston Medical Center, Boston, MA, USA) for providing virus; Robert Tigelaar and Julie Lewis (Yale University School of Medicine, New Haven, CT, USA) for 17D1 antibodies; Natasha Barteneva PCMM Flow Cytometry Core Facility, Boston, MA, USA] for guidance in cell sorting; and Scott Davis (Tempero Pharmaceuticals, Cambridge, MA, USA) for technical support with microarray data analyses. We thank Jessica Cooley for figure preparation and Fauve Dela Cruz for maintaining the mouse colony. NR 43 TC 10 Z9 12 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 EI 1938-3673 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD MAR PY 2014 VL 95 IS 3 BP 521 EP 530 DI 10.1189/jlb.0613331 PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA AG3MU UT WOS:000335324400015 PM 24249741 ER PT J AU Crabtree, D Dodson, M Ouyang, XS Boyer-Guittaut, M Liang, QL Ballestas, ME Fineberg, N Zhang, JH AF Crabtree, Donna Dodson, Matthew Ouyang, Xiaosen Boyer-Guittaut, Michael Liang, Qiuli Ballestas, Mary E. Fineberg, Naomi Zhang, Jianhua TI Over-expression of an inactive mutant cathepsin D increases endogenous alpha-synuclein and cathepsin B activity in SH-SY5Y cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE autophagy; cathepsin D; lysosome; alpha-synuclein ID CHAPERONE-MEDIATED AUTOPHAGY; FAMILIAL PARKINSONS-DISEASE; LYSOSOMAL STORAGE; IN-VIVO; MACROAUTOPHAGY; DEGRADATION; AGGREGATION; DUPLICATION; TOXICITY; NEURONS AB Parkinson's disease is a neurodegenerative movement disorder. The histopathology of Parkinson's disease comprises proteinaceous inclusions known as Lewy bodies, which contains aggregated -synuclein. Cathepsin D (CD) is a lysosomal protease previously demonstrated to cleave -synuclein and decrease its toxicity in both cell lines and mouse brains in vivo. Here, we show that pharmacological inhibition of CD, or introduction of catalytically inactive mutant CD, resulted in decreased CD activity and increased cathepsin B activity, suggesting a possible compensatory response to inhibition of CD activity. However, this increased cathepsin B activity was not sufficient to maintain -synuclein degradation, as evidenced by the accumulation of endogenous -synuclein. Interestingly, the levels of LC3, LAMP1, and LAMP2, proteins involved in autophagy-lysosomal activities, as well as total lysosomal mass as assessed by LysoTracker flow cytometry, were unchanged. Neither autophagic flux nor proteasomal activities differs between cells over-expressing wild-type versus mutant CD. These observations point to a critical regulatory role for that endogenous CD activity in dopaminergic cells in -synuclein homeostasis which cannot be compensated for by increased Cathepsin B. These data support the potential need to enhance CD function in order to attenuate -synuclein accumulation as a therapeutic strategy against development of synucleinopathy. C1 [Crabtree, Donna; Dodson, Matthew; Ouyang, Xiaosen; Boyer-Guittaut, Michael; Liang, Qiuli; Zhang, Jianhua] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Dodson, Matthew; Ouyang, Xiaosen; Boyer-Guittaut, Michael; Liang, Qiuli; Zhang, Jianhua] Univ Alabama Birmingham, Ctr Free Rad Biol, Birmingham, AL 35294 USA. [Ouyang, Xiaosen; Liang, Qiuli; Zhang, Jianhua] Birmingham VA Med Ctr, Dept Vet Affairs, Birmingham, AL USA. [Boyer-Guittaut, Michael] Univ Franche Comte, Biochim Lab, UFR Sci & Tech, F-25030 Besancon, France. [Ballestas, Mary E.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL 35294 USA. [Fineberg, Naomi] UAB Sch Publ Hlth, Dept Biostat, Birmingham, AL USA. RP Zhang, JH (reprint author), Univ Alabama Birmingham, Dept Pathol, BMRII 534,901 19th St S, Birmingham, AL 35294 USA. EM zhanja@uab.edu OI Ballestas, Mary/0000-0003-0660-9477; Zhang, Jianhua/0000-0002-2128-9574 FU Michael J Fox Foundation [NIHR01-NS064090]; VA merit award; UAB Neuroscience NINDS Protein Interaction Core C [NINDSP30-NS047466]; NIH [P30 AR48311] FX We are grateful to Dr Aimee Landar, Ms Stephanie Wall, Victor Darley-Usmar and members of the Zhang laboratory for technical help and discussions. This study was supported by Michael J Fox Foundation, NIHR01-NS064090 and a VA merit award (to JZ), NINDSP30-NS047466 (UAB Neuroscience NINDS Protein Interaction Core C), and NIH P30 grant #P30 AR48311 (RDCC-APCC core). The authors have no conflict of interest to declare. NR 33 TC 14 Z9 14 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD MAR PY 2014 VL 128 IS 6 BP 950 EP 961 DI 10.1111/jnc.12497 PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AC2PV UT WOS:000332347300016 PM 24138030 ER PT J AU Pietersen, CY Mauney, SA Kim, SS Lim, MP Rooney, RJ Goldstein, JM Petryshen, TL Seidman, LJ Shenton, ME McCarley, RW Sonntag, KC Woo, TUW AF Pietersen, Charmaine Y. Mauney, Sarah A. Kim, Susie S. Lim, Maribel P. Rooney, Robert J. Goldstein, Jill M. Petryshen, Tracey L. Seidman, Larry J. Shenton, Martha E. McCarley, Robert W. Sonntag, Kai-C. Woo, Tsung-Ung W. TI Molecular Profiles of Pyramidal Neurons in the Superior Temporal Cortex in Schizophrenia SO JOURNAL OF NEUROGENETICS LA English DT Article DE cerebral cortex; gene expression profiling; laser-capture microdissection; microRNA; schizophrenia ID CHONDROITIN SULFATE PROTEOGLYCANS; LASER-CAPTURE MICRODISSECTION; DENDRITIC SPINE DENSITY; GROWTH-FACTOR-BETA; REAL-TIME PCR; GRAY-MATTER ABNORMALITIES; PREFRONTAL CORTEX; EXTRACELLULAR-MATRIX; MICRORNA EXPRESSION; SYMPATHETIC NEURONS AB Disrupted synchronized oscillatory firing of pyramidal neuronal networks in the cerebral cortex in the gamma frequency band (i.e., 30-100 Hz) mediates many of the cognitive deficits and symptoms of schizophrenia. In fact, the density of dendritic spines and the average somal area of pyramidal neurons in layer 3 of the cerebral cortex, which mediate both long-range (associational) and local (intrinsic) corticocortical connections, are decreased in subjects with this illness. To explore the molecular pathophysiology of pyramidal neuronal dysfunction, we extracted ribonucleic acid (RNA) from laser-captured pyramidal neurons from layer 3 of Brodmann's area 42 of the superior temporal gyrus (STG) from postmortem brains from schizophrenia and normal control subjects. We then profiled the messenger RNA (mRNA) expression of these neurons, using microarray technology. We identified 1331 mRNAs that were differentially expressed in schizophrenia, including genes that belong to the transforming growth factor beta (TGF-beta) and the bone morphogenetic proteins (BMPs) signaling pathways. Disturbances of these signaling mechanisms may in part contribute to the altered expression of other genes found to be differentially expressed in this study, such as those that regulate extracellular matrix (ECM), apoptosis, and cytoskeletal and synaptic plasticity. In addition, we identified 10 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of their predicted gene targets revealed signaling pathways and gene networks that were found by microarray to be dysregulated, raising an interesting possibility that dysfunction of pyramidal neurons in schizophrenia may in part be mediated by a concerted dysregulation of gene network functions as a result of the altered expression of a relatively small number of miRNAs. Taken together, findings of this study provide a neurobiological framework within which specific hypotheses about the molecular mechanisms of pyramidal cell dysfunction in schizophrenia can be formulated. C1 [Pietersen, Charmaine Y.; Mauney, Sarah A.; Kim, Susie S.; Lim, Maribel P.; Woo, Tsung-Ung W.] McLean Hosp, Lab Cellular Neuropathol, Belmont, MA 02478 USA. [Pietersen, Charmaine Y.; McCarley, Robert W.; Sonntag, Kai-C.; Woo, Tsung-Ung W.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Rooney, Robert J.] Genome Explorat Inc, Memphis, TN USA. [Goldstein, Jill M.; Shenton, Martha E.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Petryshen, Tracey L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Seidman, Larry J.; McCarley, Robert W.; Woo, Tsung-Ung W.] Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA 02215 USA. [McCarley, Robert W.] Vet Affairs Boston Healthcare Syst, Dept Psychiat, Brockton, MA USA. [Sonntag, Kai-C.] McLean Hosp, Dept Psychiat, Belmont, MA 02478 USA. RP Woo, TUW (reprint author), McLean Hosp, Mailman Res Ctr, Room 303E,115 Mill St, Belmont, MA 02478 USA. EM wwoo@hms.harvard.edu RI McCarley, Robert/N-5562-2014 OI McCarley, Robert/0000-0001-5705-7495 FU National Institutes of Health [P50MH080272, R01MH076060] FX This study was supported by grants P50MH080272 (Boston CIDAR: Vulnerability to Progression in Schizophrenia) and R01MH076060 from the National Institutes of Health. NR 111 TC 23 Z9 24 U1 1 U2 10 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0167-7063 EI 1563-5260 J9 J NEUROGENET JI J. Neurogenet. PD MAR-JUN PY 2014 VL 28 IS 1-2 SI SI BP 53 EP 69 DI 10.3109/01677063.2014.882918 PG 17 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA AH8SR UT WOS:000336409000005 PM 24702465 ER PT J AU Pietersen, CY Mauney, SA Kim, SS Passeri, E Lim, MP Rooney, RJ Goldstein, JM Petreyshen, TL Seidman, LJ Shenton, ME Mccarley, RW Sonntag, KC Woo, TUW AF Pietersen, Charmaine Y. Mauney, Sarah A. Kim, Susie S. Passeri, Eleonora Lim, Maribel P. Rooney, Robert J. Goldstein, Jill M. Petreyshen, Tracey L. Seidman, Larry J. Shenton, Martha E. Mccarley, Robert W. Sonntag, Kai-C. Woo, Tsung-Ung W. TI Molecular Profiles of Parvalbumin-Immunoreactive Neurons in the Superior Temporal Cortex in Schizophrenia SO JOURNAL OF NEUROGENETICS LA English DT Article DE cerebral cortex; gene expression profiling; laser capture microdissection; microRNA ID ADULT NERVOUS-SYSTEM; LASER-CAPTURE MICRODISSECTION; PREFRONTAL CORTEX; SYNAPTIC PLASTICITY; BIPOLAR DISORDER; OXIDATIVE STRESS; EXPRESSION PROFILES; MICRORNA EXPRESSION; GLUTATHIONE DEFICIT; NMDA RECEPTORS AB Dysregulation of pyramidal cell network function by the soma- and axon-targeting inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) represents a core pathophysiological feature of schizophrenia. In order to gain insight into the molecular basis of their functional impairment, we used laser capture microdissection (LCM) to isolate PV-immunolabeled neurons from layer 3 of Brodmann's area 42 of the superior temporal gyrus (STG) from postmortem schizophrenia and normal control brains. We then extracted ribonucleic acid (RNA) from these neurons and determined their messenger RNA (mRNA) expression profile using the Affymetrix platform of microarray technology. Seven hundred thirty-nine mRNA transcripts were found to be differentially expressed in PV neurons in subjects with schizophrenia, including genes associated with WNT (wingless-type), NOTCH, and PGE(2) (prostaglandin E-2) signaling, in addition to genes that regulate cell cycle and apoptosis. Of these 739 genes, only 89 (12%) were also differentially expressed in pyramidal neurons, as described in the accompanying paper, suggesting that the molecular pathophysiology of schizophrenia appears to be predominantly neuronal type specific. In addition, we identified 15 microRNAs (miRNAs) that were differentially expressed in schizophrenia; enrichment analysis of the predicted targets of these miRNAs included the signaling pathways found by microarray to be dysregulated in schizophrenia. Taken together, findings of this study provide a neurobiological framework within which hypotheses of the molecular mechanisms that underlie the dysfunction of PV neurons in schizophrenia can be generated and experimentally explored and, as such, may ultimately inform the conceptualization of rational targeted molecular intervention for this debilitating disorder. C1 [Pietersen, Charmaine Y.; Mauney, Sarah A.; Kim, Susie S.; Passeri, Eleonora; Lim, Maribel P.; Woo, Tsung-Ung W.] McLean Hosp, Lab Cellular Neuropathol, Belmont, MA 02478 USA. [Pietersen, Charmaine Y.; Passeri, Eleonora; Mccarley, Robert W.; Sonntag, Kai-C.; Woo, Tsung-Ung W.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Rooney, Robert J.] Genome Explorat Inc, Memphis, TN USA. [Goldstein, Jill M.; Shenton, Martha E.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Petreyshen, Tracey L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Seidman, Larry J.; Mccarley, Robert W.; Woo, Tsung-Ung W.] Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA 02215 USA. [Mccarley, Robert W.] Vet Affairs Boston Healthcare Syst, Dept Psychiat, Brockton, MA USA. [Sonntag, Kai-C.] McLean Hosp, Dept Psychiat, Belmont, MA 02478 USA. RP Woo, TUW (reprint author), McLean Hosp, Mailman Res Ctr, Room 303E,115 Mill St, Belmont, MA 02478 USA. EM wwoo@hms.harvard.edu RI McCarley, Robert/N-5562-2014 OI McCarley, Robert/0000-0001-5705-7495 FU National Institutes of Health [P50MH080272, R01MH076060] FX This study was supported by grants P50MH080272 (Boston CIDAR: Vulnerability to Progression in Schizophrenia) and R01MH076060 from the National Institutes of Health. NR 106 TC 17 Z9 17 U1 1 U2 11 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0167-7063 EI 1563-5260 J9 J NEUROGENET JI J. Neurogenet. PD MAR-JUN PY 2014 VL 28 IS 1-2 SI SI BP 70 EP 85 DI 10.3109/01677063.2013.878339 PG 16 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA AH8SR UT WOS:000336409000006 PM 24628518 ER PT J AU Petrie, EC Cross, DJ Yarnykh, VL Richards, T Martin, NM Pagulayan, K Hoff, D Hart, K Mayer, C Tarabochia, M Raskind, MA Minoshima, S Peskind, ER AF Petrie, Eric C. Cross, Donna J. Yarnykh, Vasily L. Richards, Todd Martin, Nathalie M. Pagulayan, Kathleen Hoff, David Hart, Kim Mayer, Cynthia Tarabochia, Matthew Raskind, Murray A. Minoshima, Satoshi Peskind, Elaine R. TI Neuroimaging, Behavioral, and Psychological Sequelae of Repetitive Combined Blast/ Impact Mild Traumatic Brain Injury in Iraq and Afghanistan War Veterans SO JOURNAL OF NEUROTRAUMA LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; WHITE-MATTER; AXONAL INJURY; MULTIPLE-SCLEROSIS; DIFFUSION MRI; STEADY-STATE; HEAD-INJURY; FDG-PET; IMAGES; ENCEPHALOPATHY C1 [Petrie, Eric C.; Pagulayan, Kathleen; Hoff, David; Hart, Kim; Mayer, Cynthia; Tarabochia, Matthew; Raskind, Murray A.; Peskind, Elaine R.] VA Puget Sound, MIRECC, Vet Affairs VA Northwest Network VISN 20, Seattle, WA 98108 USA. [Petrie, Eric C.; Pagulayan, Kathleen; Raskind, Murray A.; Peskind, Elaine R.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Petrie, Eric C.; Cross, Donna J.; Yarnykh, Vasily L.; Richards, Todd; Martin, Nathalie M.; Minoshima, Satoshi] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. RP Petrie, EC (reprint author), VA Puget Sound, MIRECC, 1660 S Columbian Way,Mail Code S-116, Seattle, WA 98108 USA. EM epetrie@uw.edu RI Yarnykh, Vasily/G-8757-2016; Yarnykh, Vasiliy/N-7635-2014 OI Yarnykh, Vasily/0000-0002-1583-8979; FU Department of Veterans Affairs Rehabilitation Research and Development Service [B77421]; VA Clinical Science Research and Development CAREER development award [TK2 CX000516]; VA Northwest Network MIRECC; National Institute of Health [AG05136, 5K08AG23670, R21EB009908] FX This material is based on work supported, in part, by the Department of Veterans Affairs Rehabilitation Research and Development Service (B77421), VA Clinical Science Research and Development CAREER development award TK2 CX000516, and VA Northwest Network MIRECC; National Institute of Health grants AG05136, 5K08AG23670, and R21EB009908; and an anonymous foundation. NR 71 TC 36 Z9 36 U1 5 U2 17 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD MAR 1 PY 2014 VL 31 IS 5 BP 425 EP 436 DI 10.1089/NEU.2013.2952 PG 12 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AB4ZV UT WOS:000331799600241 PM 24102309 ER PT J AU Hook, GR Yu, J Sipes, N Pierschbacher, MD Hook, V Kindy, MS AF Hook, Gregory R. Yu, Jin Sipes, Nancy Pierschbacher, Michael D. Hook, Vivian Kindy, Mark S. TI The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE cathepsin B; cysteine protease inhibitor; motor function; traumatic brain injury ID CELL-FREE DNA; ALZHEIMERS-DISEASE; MITOCHONDRIAL-DNA; PREDICTIVE MARKER; RAT-BRAIN; DAMAGE; REPAIR; NEUROTRAUMA; RADIATION; NUCLEAR AB There are currently no effective therapeutic agents for traumatic brain injury (TBI), but drug treatments for TBI can be developed by validation of new drug targets and demonstration that compounds directed to such targets are efficacious in TBI animal models using a clinically relevant route of drug administration. The cysteine protease, cathepsin B, has been implicated in mediating TBI, but it has not been validated by gene knockout (KO) studies. Therefore, this investigation evaluated mice with deletion of the cathepsin B gene receiving controlled cortical impact TBI trauma. Results indicated that KO of the cathepsin B gene resulted in amelioration of TBI, shown by significant improvement in motor dysfunction, reduced brain lesion volume, greater neuronal density in brain, and lack of increased proapoptotic Bax levels. Notably, oral administration of the small-molecule cysteine protease inhibitor, E64d, immediately after TBI resulted in recovery of TBI-mediated motor dysfunction and reduced the increase in cathepsin B activity induced by TBI. E64d outcomes were as effective as cathepsin B gene deletion for improving TBI. E64d treatment was effective even when administered 8h after injury, indicating a clinically plausible time period for acute therapeutic intervention. These data demonstrate that a cysteine protease inhibitor can be orally efficacious in a TBI animal model when administered at a clinically relevant time point post-trauma, and that E64d-mediated improvement of TBI is primarily the result of inhibition of cathepsin B activity. These results validate cathepsin B as a new TBI therapeutic target. C1 [Hook, Gregory R.; Sipes, Nancy; Pierschbacher, Michael D.] Amer Life Sci Pharmaceut, San Diego, CA USA. [Yu, Jin; Kindy, Mark S.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Yu, Jin; Kindy, Mark S.] Appl Neurotechnol Inc, Charleston, SC USA. [Hook, Vivian] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Kindy, Mark S.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Kindy, MS (reprint author), Med Univ S Carolina, Dept Neurosci, 173 Ashley Ave,BSB 403, Charleston, SC 29425 USA. EM kindyms@musc.edu FU NIH [R44AG032784, 5R01ES016774-02]; VA Merit Review [1I01RX000331-01] FX The authors thank Christoph Peters, MD, of Albert Ludwig University (Freiburg, Germany) for providing the cathepsin B-deficient mice and Lawrence Marshall, MD, for reviewing the manuscript. This work was supported, in part, by NIH grants R44AG032784 (to American Life Science Pharmaceuticals; ALSP) and 5R01ES016774-02 (to M. S. K.) and VA Merit Review 1I01RX000331-01 (to M.S.K.). NR 31 TC 9 Z9 9 U1 0 U2 8 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD MAR 1 PY 2014 VL 31 IS 5 BP 515 EP 529 DI 10.1089/NEU.2013.2944 PG 15 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AB4ZV UT WOS:000331799600250 PM 24083575 ER PT J AU Neuhaus, V Bot, AGJ Guitton, TG Ring, DC AF Neuhaus, Valentin Bot, Arjan G. J. Guitton, Thierry G. Ring, David C. TI Scapula Fractures: Interobserver Reliability of Classification and Treatment SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Article DE OTA; AO fracture classification; New International Classification for Scapular Fractures; reliability; scapula ID DISPLACED CLAVICLE FRACTURES AB Objectives:There is substantial variation in the classification and management of scapula fractures. The first purpose of this study was to analyze the interobserver reliability of the OTA/AO classification and the New International Classification for Scapula Fractures. The second purpose was to assess the proportion of agreement among orthopaedic surgeons on operative or nonoperative treatment.Design:Web-based reliability study.Setting:Independent orthopaedic surgeons from several countries were invited to classify scapular fractures in an online survey.Participants:One hundred three orthopaedic surgeons evaluated 35 movies of three-dimensional computerized tomography reconstruction of selected scapular fractures, representing a full spectrum of fracture patterns.Main Outcome Measurements:Fleiss kappa () was used to assess the reliability of agreement between the surgeons.Results:The overall agreement on the OTA/AO classification was moderate for the types (A, B, and C, = 0.54) with a 71% proportion of rater agreement (PA) and for the 9 groups (A1 to C3, = 0.47) with a 57% PA. For the New International Classification, the agreement about the intraarticular extension of the fracture (Fossa (F), = 0.79) was substantial and the agreement about a fractured body (Body (B), = 0.57) or process was moderate (Process (P), = 0.53); however, PAs were more than 81%. The agreement on the treatment recommendation was moderate ( = 0.57) with a 73% PA.Conclusions:The New International Classification was more reliable. Body and process fractures generated more disagreement than intraarticular fractures and need further clear definitions. C1 [Neuhaus, Valentin; Bot, Arjan G. J.; Guitton, Thierry G.; Ring, David C.] Massachusetts Gen Hosp, Orthopaed Hand Serv, Boston, MA 02114 USA. RP Ring, DC (reprint author), Massachusetts Gen Hosp, Yawkey Ctr, Orthopaed Hand Serv, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org RI Fernandes, C/F-9839-2012; OI adolfsson, lars/0000-0001-7873-3093; Neuhaus, Valentin/0000-0003-4012-5628; Fernandes, C/0000-0003-0146-6091; Guitton, Thierry/0000-0002-2599-1985; Gummerson, Nigel/0000-0002-5727-8041; Streubel, Philipp/0000-0002-4585-1779 FU Bangerter Foundation Switzerland; VSB fonds; Beurs Prins Bernhard Cultuur fonds; beurs/Banning-de Jong fonds; Stichting Anna fonds, the Netherlands FX V. Neuhaus has received a grant from the Bangerter Foundation Switzerland. A. G. J. Bot has received grants from VSB fonds, Beurs Prins Bernhard Cultuur fonds, beurs/Banning-de Jong fonds, Stichting Anna fonds, the Netherlands. T. G. Guitton had no conflicts of interest. D. C. Ring has no conflicts related to this research. NR 20 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-5339 EI 1531-2291 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD MAR PY 2014 VL 28 IS 3 BP 124 EP 129 DI 10.1097/BOT.0b013e31829673e2 PG 6 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA AG3MZ UT WOS:000335324900006 PM 23629469 ER PT J AU Grigoryan, KV Javedan, H Rudolph, JL AF Grigoryan, Konstantin V. Javedan, Houman Rudolph, James L. TI Orthogeriatric Care Models and Outcomes in Hip Fracture Patients: A Systematic Review and Meta-Analysis SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Review DE hip fracture; geriatrics; orthopaedic surgery; aged; mortality; meta-analysis ID RANDOMIZED CONTROLLED-TRIAL; OLDER-ADULTS; GERIATRIC CONSULTATION; INTERVENTION; MANAGEMENT; MORTALITY; DELIRIUM; STANDARD; RECOVERY; PROGRAM AB Objectives:Hip fractures are common, morbid, and costly health events that threaten independence and function of older patients. The purpose of this systematic review and meta-analysis was to determine if orthogeriatric collaboration models improve outcomes.Data sources:Articles in English and Spanish languages were searched in the electronic databases including MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, and the Cochrane Registry from 1992 to 2012.Study selection:Studies were included if they described an inpatient multidisciplinary approach to hip fracture management involving an orthopaedic surgeon and a geriatrician. Studies were grouped into 3 following categories: routine geriatric consultation, geriatric ward with orthopaedic consultation, and shared care. After independent review of 1480 citations by 2 authors, 18 studies (9094 patients) were identified as meeting the inclusion criteria.Data extraction:In-hospital mortality, length of stay, and long-term mortality outcomes were collected.Data synthesis:A random effects model meta-analysis determined whether orthogeriatric collaboration was associated with improved outcomes. The overall meta-analysis found that orthogeriatric collaboration was associated with a significant reduction of in-hospital mortality [relative risk 0.60; 95% confidence interval (95% CI), 0.43-0.84) and long-term mortality (relative risk 0.83; 95% CI, 0.74-0.94). Length of stay (standardized mean difference -0.25; 95% CI, -0.44 to -0.05) was significantly reduced, particularly in the shared care model (standardized mean difference -0.61; 95% CI, -0.95 to -0.28), but heterogeneity limited this interpretation. Other variables such as time to surgery, delirium, and functional status were measured infrequently.Conclusions:This meta-analysis supports orthogeriatric collaboration to improve mortality after hip repair. Further study is needed to determine the best model of orthogeriatric collaboration and if these partnerships improve functional outcomes. C1 [Grigoryan, Konstantin V.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Javedan, Houman; Rudolph, James L.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Rudolph, James L.] VA Boston Healthcare Syst, GRECC, Boston, MA 02130 USA. RP Rudolph, JL (reprint author), VA Boston Healthcare Syst, GRECC, 150 S Huntington Ave, Boston, MA 02130 USA. EM jrudolph@partners.org FU NIH [1T35AG038027-02]; VA Rehabilitation Research and Development Career Development Award FX Support for this research was made possible through NIH grant #: 1T35AG038027-02. Dr J. L. Rudolph is supported by a VA Rehabilitation Research and Development Career Development Award. NR 33 TC 52 Z9 53 U1 5 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-5339 EI 1531-2291 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD MAR PY 2014 VL 28 IS 3 BP E49 EP E55 DI 10.1097/BOT.0b013e3182a5a045 PG 7 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA AG3MZ UT WOS:000335324900002 PM 23912859 ER PT J AU Janne, PA Cohen, RB Laird, AD Mace, S Engelman, JA Ruiz-Soto, R Rockich, K Xu, JB Shapiro, GI Martinez, P Felip, E AF Jaenne, Pasi A. Cohen, Roger B. Laird, A. Douglas Mace, Sandrine Engelman, Jeffrey A. Ruiz-Soto, Rodrigo Rockich, Kevin Xu, Jianbo Shapiro, Geoffrey I. Martinez, Pablo Felip, Enriqueta TI Phase I Safety and Pharmacokinetic Study of the PI3K/mTOR Inhibitor SAR245409 ( XL765) in Combination with Erlotinib in Patients with Advanced Solid Tumors SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE PI3K; mammalian target of rapamycin inhibitor; Epidermal growth factor receptor inhibitor; Pharmacokinetics; Pharmacodynamics; Advanced solid tumors ID PHOSPHOINOSITIDE 3-KINASE PATHWAY; PI3K INHIBITION; LUNG-CANCER; RESISTANCE; EGFR; GEFITINIB; GROWTH; KINASE; CELLS AB Introduction: The primary objectives of this phase I study were to evaluate the safety and maximum tolerated dose (MTD) of SAR245409, a pan-class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin inhibitor, combined with erlotinib in patients with advanced solid tumors. Methods: Forty-six patients with advanced solid tumors were enrolled. Patients with lung cancer (n = 37) had received an epidermal growth factor receptor (EGFR) inhibitor before study entry. SAR245409 30, 50, 70, or 90 mg once daily (QD) or 20 or 30 mg twice daily (BID) was administered, in combination with erlotinib 100 mg QD, in 28-day cycles. Dose escalation of SAR245409 followed a standard 3 + 3 design. Patients were evaluated for adverse events (AEs). Additional evaluations included pharmacokinetics, pharmacodynamic effects on PI3K and EGFR/mitogen-activated protein kinase signaling pathways in tumor and skin samples, and tumor response. Results: The MTDs of SAR245409, in combination with erlotinib 100 mg QD, were 70 mg QD and 20 mg BID. The most frequently reported treatment-related AEs (any grade) were diarrhea (35%), rash (35%), and nausea (28%). No treatment-related AE occurred at grade 3/4 in more than one patient (2.2%). No major pharmacokinetic interaction between SAR245409 and erlotinib was noted. Suppression of PI3K and EGFR/mitogen-activated protein kinase signaling pathway biomarkers was observed in skin and tumor samples. Stable disease was the best overall response reported, occurring in 12 of 32 (37.5%) evaluable patients. Conclusion: MTDs of SAR245409 and erlotinib were below the single-agent doses of either agent, despite the lack of major pharmacokinetic interaction. C1 [Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02215 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA. [Cohen, Roger B.] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. [Laird, A. Douglas] Exelixis Inc, Translat Med, San Francisco, CA USA. [Mace, Sandrine] Sanofi, Translat & Expt Med, Vitry Sur Seine, France. [Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Ctr Thorac Ctr, Charlestown, MA USA. [Ruiz-Soto, Rodrigo] Sanofi, Clin Dev Oncol, Cambridge, MA USA. [Rockich, Kevin] Sanofi, Pharmacokinet Modeling & Simulat, Cambridge, MA USA. [Xu, Jianbo] Sanofi, Biostat & Programming, Cambridge, MA USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02115 USA. [Martinez, Pablo; Felip, Enriqueta] Vall Debron Univ Hosp, Dept Med Oncol, Barcelona, Spain. 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 Sanofi FX The authors thank participating patients and their families as well as Art DeCillis (VP Medical Affairs and Clinical Research, Exelixis) and the clinical research team at Exelixis who initiated this trial. In addition, the authors thank Bin Wu (Sanofi), Linh Nguyen, Frauke Bentzien, Belinda Cancilla, and Valentina Vysotskaia (Exelixis) for their contributions to PK, pharmacodynamic, and molecular profiling analyses and Coumaran Egile (Sanofi) for his contribution to this work. This study was funded by Sanofi. Editorial assistance in the form of medical writing services was provided by Melissa Purves and Simone Blagg of MediTech Media, funded by Sanofi. NR 23 TC 14 Z9 15 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD MAR PY 2014 VL 9 IS 3 BP 316 EP 323 DI 10.1097/JTO.0000000000000088 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AB1EO UT WOS:000331534500011 PM 24496004 ER PT J AU Lehavot, K Katon, JG Williams, EC Nelson, KM Gardella, CM Reiber, GE Simpson, TL AF Lehavot, Keren Katon, Jodie G. Williams, Emily C. Nelson, Karin M. Gardella, Carolyn M. Reiber, Gayle E. Simpson, Tracy L. TI Sexual Behaviors and Sexually Transmitted Infections in a Nationally Representative Sample of Women Veterans and Nonveterans SO JOURNAL OF WOMENS HEALTH LA English DT Article ID HUMAN-PAPILLOMAVIRUS INFECTION; SIMPLEX-VIRUS TYPE-2; UNITED-STATES; HEALTH-CARE; CHLAMYDIAL INFECTION; MINORITY VETERANS; RISK BEHAVIOR; US MILITARY; CONDOM USE; GONORRHEA AB Background: Women veterans are a growing population with unique characteristics and documented health disparities. Few studies have examined their sexual behaviors and rates of sexually transmitted infections (STIs), and none have compared women veterans to nonveterans to identify potential sexual health disparities. Methods: We used data from the 1999-2010 National Health and Nutrition Examination Survey, a nationally representative U.S. survey. We compared lifetime sexual history (age at first intercourse, number of partners), sexual activity in the last year, and STIs between women veterans (n=151) and nonveterans (n=8738), adjusting for age, race/ethnicity, education, marital status, binge drinking, and survey year. Results: Compared to nonveterans, women veterans reported a younger age at first intercourse and a greater number of female and male lifetime sexual partners, and they were more likely to have ever had sex with a woman. They were also more likely than nonveterans to have genital herpes and genital warts. Conclusions: Women veterans reported higher rates of sexual activity and STIs than nonveterans. Future research is needed to assess high-risk behaviors and determine what factors may underlie these associations. Providers should ensure thorough screening and intervention services are provided for this growing population. C1 [Lehavot, Keren; Simpson, Tracy L.] VA Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Lehavot, Keren; Simpson, Tracy L.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Katon, Jodie G.; Williams, Emily C.; Nelson, Karin M.; Reiber, Gayle E.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev HSR&D, Seattle, WA 98108 USA. [Katon, Jodie G.] Dept Vet Affairs, VA Off Womens Hlth Serv, Washington, DC USA. [Katon, Jodie G.; Williams, Emily C.; Reiber, Gayle E.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Nelson, Karin M.] Univ Washington, Dept Med, Seattle, WA USA. [Gardella, Carolyn M.] VA Puget Sound Hlth Care Syst, Gynecol Serv, Seattle, WA 98108 USA. [Gardella, Carolyn M.] Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Simpson, Tracy L.] VA Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA 98108 USA. RP Lehavot, K (reprint author), VA Puget Sound Hlth Care Syst, MIRECC, 1660 S Columbian Way S-116 POC, Seattle, WA 98108 USA. EM klehavot@uw.edu FU Associated Health Postdoctoral Fellowship [TPP 61-026]; Career Development Award [CDA 12-276]; Senior Career Scientist Award grant [RCS 98-353]; National Institute of Mental Health [R25 MH080916-01A2]; Department of Veterans Affairs, Health Services Research & Development Service, Quality Enhancement Research Initiative (QUERI) FX This material is the result of work supported by resources from the U.S. Department of Veterans Affairs Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment (K.L.), Associated Health Postdoctoral Fellowship (J.K., no. TPP 61-026), Career Development Award (E.W., CDA 12-276), Senior Career Scientist Award grant (G.R., no. RCS 98-353), and the VA Puget Sound Health Care System, Seattle, Washington. EW is an investigator with the Implementation Research Institute (IRI) at the George Warren Brown School of Social Work at Washington University in St. Louis. IRI is supported through an award from the National Institute of Mental Health (R25 MH080916-01A2) and the Department of Veterans Affairs, Health Services Research & Development Service, Quality Enhancement Research Initiative (QUERI). The authors would like to thank Jeff Rodenbaugh for managing the data. The views expressed in this article are those of the authors and do not represent the views of the Department of Veterans Affairs or the United States government. NR 47 TC 7 Z9 7 U1 1 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD MAR 1 PY 2014 VL 23 IS 3 BP 246 EP 252 DI 10.1089/jwh.2013.4327 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA AC4BQ UT WOS:000332466000010 PM 24328438 ER PT J AU Whiteman, KR Johnson, HA Mayo, MF Audette, CA Carrigan, CN LaBelle, A Zukerberg, L Lambert, JM Lutz, RJ AF Whiteman, Kathleen R. Johnson, Holly A. Mayo, Michele F. Audette, Charlene A. Carrigan, Christina N. LaBelle, Alyssa Zukerberg, Lawrence Lambert, John M. Lutz, Robert J. TI Lorvotuzumab mertansine, a CD56-targeting antibody-drug conjugate with potent antitumor activity against small cell lung cancer in human xenograft models SO MABS LA English DT Article DE small cell lung cancer; CD56; antibody-drug conjugate; ADC; maytansinoid; combination therapy; xenografts ID ADHESION MOLECULES; ANTICANCER DRUGS; IN-VITRO; CISPLATIN; EXPRESSION; CARCINOMA; ETOPOSIDE; PACLITAXEL; NCAM; IMMUNOCONJUGATE AB Lorvotuzumab mertansine (LM) is an antibody-drug conjugate composed of a humanized anti-CD56 antibody, lorvotuzumab, linked via a cleavable disulfide linker to the tubulin-binding maytansinoid DM1. CD56 is expressed on most small cell lung cancers (SCLC), providing a promising therapeutic target for treatment of this aggressive cancer, which has a poor five-year survival rate of only 5-10%. We performed immunohistochemical staining on SCLC tumor microarrays, which confirmed that CD56 is expressed at high levels on most (similar to 74%) SCLC tumors. Conjugation of lorvotuzumab with DM1 did not alter its specific binding to cells and LM demonstrated potent target-dependent cytotoxicity against CD56-positive SCLC cells in vitro. The anti-tumor activity of LM was evaluated against SCLC xenograft models in mice, both as monotherapy and in combination with platinum/etoposide and paclitaxel/carboplatin. Dose-dependent and antigen-specific anti-tumor activity of LM monotherapy was demonstrated at doses as low as 3 mg/kg. LM was highly active in combination with standard-of-care platinum/etoposide therapies, even in relatively resistant xenograft models. LM demonstrated outstanding anti-tumor activity in combination with carboplatin/etoposide, with superior activity over chemotherapy alone when LM was used in combinations at significantly reduced doses (6-fold below the minimally efficacious dose for LM monotherapy). The combination of LM with carboplatin/paclitaxel was also highly active. This study provides the rationale for clinical evaluation of LM as a promising novel targeted therapy for SCLC, both as monotherapy and in combination with chemotherapy. C1 [Whiteman, Kathleen R.; Johnson, Holly A.; Mayo, Michele F.; Audette, Charlene A.; Carrigan, Christina N.; LaBelle, Alyssa; Lambert, John M.; Lutz, Robert J.] ImmunoGen Inc, Waltham, MA 02451 USA. [Zukerberg, Lawrence] Harvard Univ, Sch Med, Boston, MA USA. [Zukerberg, Lawrence] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Whiteman, KR (reprint author), ImmunoGen Inc, Waltham, MA 02451 USA. EM kathleen.whiteman@immunogen.com NR 47 TC 17 Z9 17 U1 0 U2 17 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1942-0862 EI 1942-0870 J9 MABS-AUSTIN JI mAbs PD MAR-APR PY 2014 VL 6 IS 2 BP 556 EP 566 DI 10.4161/mabs.27756 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AH6HL UT WOS:000336231200022 PM 24492307 ER PT J AU Ploumis, A Christodoulou, P Wood, KB Varvarousis, D Sarni, JL Beris, A AF Ploumis, Avraam Christodoulou, Pavlos Wood, Kirkham B. Varvarousis, Dimitrios Sarni, James L. Beris, Alexander TI Original Research Article Caudal vs Transforaminal Epidural Steroid Injections as Short-Term ( 6 Months) Pain Relief in Lumbar Spinal Stenosis Patients with Sciatica SO PAIN MEDICINE LA English DT Article DE Injections; Transforaminal; Caudal; Stenosis ID MEDICINE PRACTICE GUIDELINES; RADICULAR PAIN; EFFICACY; BLIND; MANAGEMENT; HERNIATION AB ObjectiveThe aim of this study is to evaluate prospectively the efficacy of caudal epidural steroid injection (CESI) and transforaminal epidural steroid injection (TFESI) in lumbar spinal stenosis patients with sciatic pain. DesignProspective clinical study. Setting and PatientsThirty-one patients (average age 62 years) from two hospitals, with single dermotomal distribution of sciatic pain due to spinal stenosis were included in the study. InterventionsPatients underwent epidural steroid injections done by the same injectionist. Eleven patients from one hospital were included in the CESI group, while the TFESI group consisted of 20 comparable patients from the second site. Outcome MeasuresPrimary outcome measure was the complete relief or at least 50% reduction of pain (visual analog scale [VAS]) at 6 months postinjection. Secondary outcome measures were the improvement of function (of at least 15 points of Oswestry Disability Index [ODI]) at 6 months and the changes of VAS and ODI and at 2 weeks, at 3 months, and at 6 months postinjection. ResultsA significantly greater number of stenosis patients showed pain relief at 6 months postinjection with TFSI (90%) than with CESI (54.54%). All patients with TFSI showed improvement of function at 6 months while only three (27.27%) patients with caudal epidural improved functionally. Out of the total 31 patients, two patients from group A underwent a second CESI at 15 days postinjection and decompressive spine surgery between 3 and 6 months postinjection. ConclusionsThe effectiveness of transforaminal steroid injection for the stenosis patients with sciatica was superior to caudal at 6 months postinjection. C1 [Ploumis, Avraam; Varvarousis, Dimitrios; Beris, Alexander] Univ Hosp Ioannina, Dept Orthopaed Surg, Ioannina, Greece. [Ploumis, Avraam; Varvarousis, Dimitrios; Beris, Alexander] Univ Hosp Ioannina, Dept Rehabil, Ioannina, Greece. [Ploumis, Avraam; Christodoulou, Pavlos] 424 Gen Army Hosp, Dept Orthopaed, Thessaloniki, Greece. [Ploumis, Avraam; Wood, Kirkham B.; Sarni, James L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed, Boston, MA USA. RP Ploumis, A (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Yawkey 3-3a, Boston, MA 02114 USA. EM aploumis@cc.uoi.gr NR 22 TC 8 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-2375 EI 1526-4637 J9 PAIN MED JI Pain Med. PD MAR PY 2014 VL 15 IS 3 BP 379 EP 385 DI 10.1111/pme.12318 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AC2GU UT WOS:000332318600005 PM 24341966 ER PT J AU Frank, JW Bair, MJ Becker, WC Krebs, EE Liebschutz, JM Alford, DP AF Frank, Joseph W. Bair, Matthew J. Becker, William C. Krebs, Erin E. Liebschutz, Jane M. Alford, Daniel P. TI Update in Pain Medicine for Primary Care Providers: A Narrative Review, 2010-2012 SO PAIN MEDICINE LA English DT Review DE Pain Management; Primary Care; Interventional; Opioids; Neuropathic Pain; Exercise; Psychotherapy; Physical Therapy ID LOW-BACK-PAIN; RANDOMIZED CONTROLLED-TRIAL; NEUROPATHIC PAIN; STEPPED CARE; MANAGEMENT; YOGA; INTERVENTIONS; METAANALYSIS; POPULATION; PREVALENCE AB ObjectiveThis manuscript reviews peer-reviewed literature published from 2010-2012 relevant to the management of chronic pain in the primary care setting. DesignNarrative review of peer-reviewed literature. MethodsWe searched MEDLINE, PubMed, and reference lists and queried expert contacts for English-language studies related to the management of chronic noncancer pain in adult patients in primary care settings. One investigator reviewed all eligible studies for relevance, and 47 studies were reviewed by all authors and rated according to their impact on 1) primary care clinical practice, 2) policy, 3) research, and 4) quality of study methods. Through iterative discussion, nine articles were selected for detailed review and discussion. ResultsWe present articles in six topic areas: interventional pain management; opioid dose and risk of overdose death; neuropathic pain; yoga for chronic low back pain; cognitive behavioral therapy; and systematic approaches to treating back pain. We discuss implications for pain management in primary care. ConclusionsThere is growing evidence for the risks, benefits, and limitations of the multiple modalities available to primary care providers for the management of chronic pain. The dissemination and implementation of the evidence from these studies as well as novel system-level interventions warrant additional study and support from clinicians, educators, and policy makers. C1 [Frank, Joseph W.] Univ Colorado, Sch Med, Div Gen Internal Med, Denver VA Med Ctr, Aurora, CO 80045 USA. [Bair, Matthew J.] Indiana Univ, Sch Med, Roudebush VA Med Ctr, Indianapolis, IN USA. [Becker, William C.] Yale Univ, Sch Med, VA Connecticut Healthcare Syst, New Haven, CT USA. [Krebs, Erin E.] Univ Minnesota, Sch Med, Minneapolis VA Med Ctr, Minneapolis, MN 55455 USA. [Liebschutz, Jane M.; Alford, Daniel P.] Boston Univ, Sch Med, Boston Med Ctr, Boston, MA 02118 USA. [Liebschutz, Jane M.] Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Frank, JW (reprint author), Univ Colorado, Sch Med, Div Gen Internal Med, 8th Floor,Acad Off 1,Mailstop B180, Aurora, CO 80045 USA. EM joseph.frank@ucdenver.edu FU an institutional National Research Service Award [T32HP10251]; VA HSR&D Research Career Development Awards FX All authors are members of the Society of General Internal Medicine's Pain Medicine Interest Group. This article derives from the presentation "Update in Pain Medicine" at the 36th annual meeting of SGIM in April 2013 in Denver, Colorado. Dr. Frank was supported by an institutional National Research Service Award (T32HP10251). Drs. Becker and Krebs are supported by VA HSR&D Research Career Development Awards. NR 34 TC 3 Z9 3 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-2375 EI 1526-4637 J9 PAIN MED JI Pain Med. PD MAR PY 2014 VL 15 IS 3 BP 425 EP 431 DI 10.1111/pme.12337 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AC2GU UT WOS:000332318600010 PM 24423083 ER PT J AU Giblin, K Newmark, JL Brenner, GJ Wainger, BJ AF Giblin, Kathryn Newmark, Jordan L. Brenner, Gary J. Wainger, Brian J. TI Headache Plus: Trigeminal and Autonomic Features in a Case of Cervicogenic Headache Responsive to Third Occipital Nerve Radiofrequency Ablation SO PAIN MEDICINE LA English DT Article DE Cervicogenic Headache; Trigeminal Autonomic Cephalgia; Radiofrequency Ablation; Third Occipital Nerve ID ZYGAPOPHYSEAL-JOINT PAIN; HEMICRANIA CONTINUA; CLUSTER HEADACHE; DIAGNOSTIC-CRITERIA; DOUBLE-BLIND; ATTACKS; ACTIVATION; INJECTION; NEUROTOMY AB ObjectiveTo describe a case of cervicogenic headache with associated autonomic features and pain in a trigeminal distribution, all of which responded to third occipital nerve radiofrequency ablation. DesignSingle case report. SettingMassachusetts General Hospital Center for Pain Medicine. PatientsA 38-year-old woman with history of migraines and motor vehicle accident. InterventionsRight third occipital nerve diagnostic blocks and radiofrequency lesioning. Outcome MeasuresPain reduction; physical findings, including periorbital and mandibular facial swelling, tearing, conjunctival injection, and allodynia; and use of opioid and non-opioid pain medicines. ResultsThe patient had complete relief of her pain and autonomic symptoms, and was able to stop all pain medications following a dedicated third occipital nerve lesioning. ConclusionsThis case illustrates the diagnostic and therapeutic complexity of cervicogenic headache and the overlap with other headache types, including trigeminal autonomic cephalgias and migraine. It represents a unique proof of principle in that not only trigeminal nerve pain but also presumed neurogenic inflammation can be relieved by blockade of cervical nociceptive inputs. Further investigation into shared mechanisms of headache pathogenesis is warranted. C1 [Giblin, Kathryn; Newmark, Jordan L.; Brenner, Gary J.; Wainger, Brian J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Brenner, GJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, WACC 340, Boston, MA 02114 USA. EM gjbrenner@partners.org NR 33 TC 2 Z9 2 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-2375 EI 1526-4637 J9 PAIN MED JI Pain Med. PD MAR PY 2014 VL 15 IS 3 BP 473 EP 478 DI 10.1111/pme.12334 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA AC2GU UT WOS:000332318600016 PM 24401103 ER PT J AU Hagen, CE Lauwers, GY Mino-Kenudson, M AF Hagen, Catherine E. Lauwers, Gregory Y. Mino-Kenudson, Mari TI Barrett esophagus: Diagnostic challenges SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Article DE Esophageal adenocarcinoma; Intestinal metaplasia; Crypt dysplasia; Foveolar dysplasia; Carditis ID ENDOSCOPIC MUCOSAL RESECTION; LOW-GRADE DYSPLASIA; P53 PROTEIN EXPRESSION; INTESTINAL METAPLASIA; GASTROESOPHAGEAL JUNCTION; DISTAL ESOPHAGUS; MULTILAYERED EPITHELIUM; NEOPLASTIC PROGRESSION; COLUMNAR EPITHELIUM; DISEASE PROGRESSION AB The incidence of esophageal adenocarcinoma and associated mortality has risen dramatically over the past several decades, and, thus, it is increasingly important to understand its pathogenesis and risk factors. Barrett esophagus is the established precursor to esophageal adenocarcinoma that progresses through a metaplasia-dysplasia-carcinoma sequence. Its risk of transforming to carcinoma is not as high as previously reported and there appears to be a biological heterogeneity among patients with this disease. The overall prevalence of Barrett esophagus in the United States ranges from 1% to 25% and is closer to 5% in patients with gastroesophageal reflux disease. Because of the frequency of Barrett esophagus and associated implications, it is important for the practicing pathologist to have a thorough understanding of this disease and its diagnostic pitfalls. In this review, we will discuss issues associated with the diagnosis of Barrett esophagus, including the definition of Barrett esophagus and its distinction from carditis with intestinal metaplasia. We will also discuss challenges in the grading of dysplasia and new variants of dysplasia, including crypt dysplasia and foveolar-type dysplasia. Finally, we will touch upon the evaluation of dysplasia in endoscopic mucosal resection specimens. (C) 2014 Elsevier Inc. All rights reserved. C1 [Hagen, Catherine E.; Lauwers, Gregory Y.; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hagen, Catherine E.; Lauwers, Gregory Y.; Mino-Kenudson, Mari] Harvard Univ, Sch Med, Boston, MA USA. RP Mino-Kenudson, M (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 122, Boston, MA 02114 USA. EM mminokenudson@partners.org OI Hagen, Catherine/0000-0002-1867-4957 NR 76 TC 2 Z9 3 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0740-2570 EI 1930-1111 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD MAR PY 2014 VL 31 IS 2 BP 100 EP 113 DI 10.1053/j.semdp.2014.02.005 PG 14 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA AH9MR UT WOS:000336467000002 PM 24815936 ER PT J AU Baltarowich, OH Di Salvo, DN Scoutt, LM Brown, DL Cox, CW DiPietro, MA Glazer, DI Hamper, UM Manning, MA Nazarian, LN Neutze, JA Romero, M Stephenson, JW Dubinsky, TJ AF Baltarowich, Oksana H. Di Salvo, Donald N. Scoutt, Leslie M. Brown, Douglas L. Cox, Christian W. DiPietro, Michael A. Glazer, Daniel I. Hamper, Ulrike M. Manning, Maria A. Nazarian, Levon N. Neutze, Janet A. Romero, Miriam Stephenson, Jason W. Dubinsky, Theodore J. TI National Ultrasound Curriculum for Medical Students SO ULTRASOUND QUARTERLY LA English DT Article DE ultrasound; curriculum; medical student; medical student education; medical school curriculum; diagnostic ultrasound ID SONOGRAPHY AB Ultrasound (US) is an extremely useful diagnostic imaging modality because of its real-time capability, noninvasiveness, portability, and relatively low cost. It carries none of the potential risks of ionizing radiation exposure or intravenous contrast administration. For these reasons, numerous medical specialties now rely on US not only for diagnosis and guidance for procedures, but also as an extension of the physical examination. In addition, many medical school educators recognize the usefulness of this technique as an aid to teaching anatomy, physiology, pathology, and physical diagnosis. Radiologists are especially interested in teaching medical students the appropriate use of US in clinical practice. Educators who recognize the power of this tool have sought to incorporate it into the medical school curriculum. The basic question that educators should ask themselves is: What should a student graduating from medical school know about US? To aid them in answering this question, US specialists from the Society of Radiologists in Ultrasound and the Alliance of Medical School Educators in Radiology have collaborated in the design of a US curriculum for medical students. The implementation of such a curriculum will vary from institution to institution, depending on the resources of the medical school and space in the overall curriculum. Two different examples of how US can be incorporated vertically or horizontally into a curriculum are described, along with an explanation as to how this curriculum satisfies the Accreditation Council for Graduate Medical Education competencies, modified for the education of our future physicians. C1 [Baltarowich, Oksana H.; Nazarian, Levon N.] Jefferson Ultrasound Radiol & Educ Inst, Dept Radiol, Philadelphia, PA USA. [Baltarowich, Oksana H.; Nazarian, Levon N.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Di Salvo, Donald N.] Harvard Univ, Sch Med, Boston, MA USA. [Di Salvo, Donald N.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Scoutt, Leslie M.] Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT 06510 USA. [Brown, Douglas L.] Mayo Clin, Coll Med, Rochester, MN USA. [Brown, Douglas L.] Mayo Clin, Rochester, MN USA. [Cox, Christian W.] Univ Colorado, Sch Med, Rocky Vista Univ, Coll Osteopath Med, Denver, CO USA. [Cox, Christian W.] Natl Jewish Hlth, Denver, CO USA. [DiPietro, Michael A.] CS Mott Childrens Hosp, Ann Arbor, MI USA. [DiPietro, Michael A.; Glazer, Daniel I.] Univ Michigan, Ann Arbor, MI 48109 USA. [Hamper, Ulrike M.] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21218 USA. [Manning, Maria A.] Univ Maryland, Sch Med, Dept Radiol, Baltimore, MD 21201 USA. [Nazarian, Levon N.] Thomas Jefferson Univ, Dept Radiol, Philadelphia, PA 19107 USA. [Neutze, Janet A.] Penn State Hershey Med Ctr, Hershey, PA USA. [Romero, Miriam] Univ So Calif, Keck Sch Med, Dept Radiol, Los Angeles, CA 90033 USA. [Stephenson, Jason W.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Radiol, Madison, WI USA. [Dubinsky, Theodore J.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. RP Baltarowich, OH (reprint author), Thomas Jefferson Univ, Dept Radiol, Jefferson Ultrasound Radiol & Educ Inst, 132 S 10th St,Suite 763D, Philadelphia, PA 19107 USA. EM oksana.baltarowich@jefferson.edu RI Neutze, Janet/B-6123-2015 OI Neutze, Janet/0000-0001-5870-8798 NR 17 TC 16 Z9 17 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-8771 EI 1536-0253 J9 ULTRASOUND Q JI Ultrasound Q. PD MAR PY 2014 VL 30 IS 1 BP 13 EP 19 DI 10.1097/RUQ.0000000000000066 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AH2UZ UT WOS:000335978500004 PM 24901774 ER PT J AU Lalwani, N Dubinsky, T Javitt, MC Gaffney, DK Glanc, P Elshaikh, MA Kim, YB Lee, LJ Pannu, HK Royal, HD Shipp, TD Siegel, CL Simpson, L Wahl, AO Wolfson, AH Zelop, CM AF Lalwani, Neeraj Dubinsky, Theodore Javitt, Marcia C. Gaffney, David K. Glanc, Phyllis Elshaikh, Mohamed A. Kim, Young Bae Lee, Larissa J. Pannu, Harpreet K. Royal, Henry D. Shipp, Thomas D. Siegel, Cary Lynn Simpson, Lynn Wahl, Andrew O. Wolfson, Aaron H. Zelop, Carolyn M. TI ACR Appropriateness Criteria\Pretreatment Evaluation and Follow-Up of Endometrial Cancer SO ULTRASOUND QUARTERLY LA English DT Article DE appropriateness criteria; endometrial cancer; staging; imaging; recurrence; treatment response ID LYMPH-NODE METASTASIS; APPARENT DIFFUSION-COEFFICIENT; POSITRON-EMISSION-TOMOGRAPHY; TRANSVAGINAL SONOGRAPHY; MYOMETRIAL INVASION; PREOPERATIVE ASSESSMENT; DIAGNOSTIC-ACCURACY; CERVICAL INVASION; DEEP MYOMETRIAL; CLINICAL IMPACT AB Endometrial cancer is the most common gynecologic and the fourth most common malignancy in women in the United States. Cross-sectional imaging plays a vital role in pretreatment assessment of endometrial cancers and should be viewed as a complementary tool for surgical evaluation and planning of these patients. Although transvaginal US remains the preferred examination for the screening purposes, MRI has emerged as the modality of choice for the staging of endometrial cancer and imaging assessment of recurrence or treatment response. A combination of dynamic contrast-enhanced and diffusion weighted MRI provides the highest accuracy for the staging. Both CT and MRI perform equivalently for assessing nodal involvement or distant metastasis. PET-CT is more appropriate for assessing lymphadenopathy in high-grade FDG-avid tumors or for clinically suspected recurrence after treatment. An appropriate use and guidelines of imaging techniques in diagnosis, staging, and detection of endometrial cancer and treatment of recurrent disease are reviewed. The American College of Radiology Appropriateness Criteria((R)) are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. C1 [Lalwani, Neeraj; Dubinsky, Theodore] Univ Washington, Sch Med, Seattle, WA 98104 USA. [Javitt, Marcia C.] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. [Gaffney, David K.] Univ Utah, Med Ctr, Salt Lake City, UT USA. [Glanc, Phyllis] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Elshaikh, Mohamed A.] Henry Ford Hlth Syst, Detroit, MI USA. [Kim, Young Bae] Tufts Med Ctr, Soc Gynecol Oncologists, Boston, MA USA. [Lee, Larissa J.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Pannu, Harpreet K.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Royal, Henry D.] Washington Univ, Med Ctr, Mallinckrodt Inst Radiol, Soc Nucl Med & Mol Imaging, St Louis, MO 63110 USA. [Shipp, Thomas D.] Brigham & Womens Hosp, Amer Coll Obstet & Gynecol, Boston, MA 02115 USA. [Siegel, Cary Lynn] Washington Univ, Med Ctr, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. [Simpson, Lynn] Columbia Univ, Amer Coll Obstet & Gynecol, New York, NY USA. [Wahl, Andrew O.] Univ Nebraska Med Ctr, Omaha, NE USA. [Wolfson, Aaron H.] Univ Miami, Miami, FL USA. [Zelop, Carolyn M.] Valley Hosp, Amer Coll Obstet & Gynecol, Ridgewood, NJ USA. RP Lalwani, N (reprint author), Univ Washington, Dept Radiol Body Imaging, Box 359728,325 9th Ave, Seattle, WA 98104 USA. EM neerajl@u.washington.edu NR 64 TC 5 Z9 5 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-8771 EI 1536-0253 J9 ULTRASOUND Q JI Ultrasound Q. PD MAR PY 2014 VL 30 IS 1 BP 21 EP 28 DI 10.1097/RUQ.0000000000000068 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AH2UZ UT WOS:000335978500005 PM 24901775 ER PT J AU Bei, M AF Bei, M. TI KCNHI2 AND KCNJ8 INTERACTIVELY REGULATE SKIN WOUND HEALING AND REGENERATION SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Bei, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bei, M.] Shriners Burns Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1067-1927 EI 1524-475X J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR PY 2014 VL 22 IS 2 BP A31 EP A31 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA AC9DV UT WOS:000332835400018 ER PT J AU Bouldin, EL Littman, AJ Rice, K Reiber, GE AF Bouldin, E. L. Littman, A. J. Rice, K. Reiber, G. E. TI RURAL RESIDENCE, DUAL USE, AND CHRONIC WOUND OUTCOMES AMONG VETERANS SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Bouldin, E. L.; Littman, A. J.; Reiber, G. E.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Bouldin, E. L.; Littman, A. J.; Rice, K.; Reiber, G. E.] Univ Washington, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1067-1927 EI 1524-475X J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR PY 2014 VL 22 IS 2 BP A33 EP A33 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA AC9DV UT WOS:000332835400024 ER PT J AU Hu, MS Januszyk, M Hong, WX Walmsley, GG Colwell, A McArdle, A Zielins, E Chung, MT Gurtner, GC Longaker, MT Lorenz, HP AF Hu, M. S. Januszyk, M. Hong, W. X. Walmsley, G. G. Colwell, A. McArdle, A. Zielins, E. Chung, M. T. Gurtner, G. C. Longaker, M. T. Lorenz, H. P. TI GENE EXPRESSION PATHWAY ANALYSIS OF FETAL SKIN AND WOUNDS SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Hu, M. S.; Januszyk, M.; Hong, W. X.; Walmsley, G. G.; McArdle, A.; Zielins, E.; Chung, M. T.; Gurtner, G. C.; Longaker, M. T.; Lorenz, H. P.] Stanford Univ, Palo Alto, CA 94304 USA. [Hu, M. S.] Univ Hawaii, Honolulu, HI 96822 USA. [Colwell, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1067-1927 EI 1524-475X J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR PY 2014 VL 22 IS 2 BP A46 EP A46 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA AC9DV UT WOS:000332835400075 ER PT J AU Mattoo, H Della-Torre, E Mahajan, VS Stone, JH Pillai, S AF Mattoo, H. Della-Torre, E. Mahajan, V. S. Stone, J. H. Pillai, S. TI Circulating Th2 memory cells in IgG4-related disease are restricted to a defined subset of subjects with atopy SO ALLERGY LA English DT Article ID REGULATORY IMMUNE-REACTIONS; LACRIMAL GLAND ENLARGEMENT; PANCREATITIS C1 [Mattoo, H.; Della-Torre, E.; Mahajan, V. S.; Pillai, S.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02129 USA. [Della-Torre, E.] Univ Vita Salute San Raffaele, Sch Med, Unit Med & Clin Immunol, Milan, Italy. [Stone, J. H.] Massachusetts Gen Hosp, Ctr Rheumatol Allergy & Immunol, Boston, MA 02129 USA. RP Pillai, S (reprint author), Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Res, 149,13th St, Boston, MA 02129 USA. EM jhstone@partners.org; pillai@helix.mgh.harvard.edu OI Della Torre, Emanuel/0000-0002-9192-4270 FU NIH [AI 064930, AI 076505] FX This study was funded by grants AI 064930 and AI 076505 from the NIH to SP. NR 8 TC 25 Z9 26 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-4538 EI 1398-9995 J9 ALLERGY JI Allergy PD MAR PY 2014 VL 69 IS 3 BP 399 EP 402 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA AA8PW UT WOS:000331358400015 PM 24382311 ER PT J AU Gordon, KB Kimball, AB Chau, D Viswanathan, HN Li, J Revicki, DA Kricorian, G Ortmeier, BG AF Gordon, K. B. Kimball, A. B. Chau, D. Viswanathan, H. N. Li, J. Revicki, D. A. Kricorian, G. Ortmeier, B. G. TI Impact of brodalumab treatment on psoriasis symptoms and health-related quality of life: use of a novel patient-reported outcome measure, the Psoriasis Symptom Inventory SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article ID PHASE-II; PREVALENCE C1 [Gordon, K. B.] Northwestern Univ, Dept Dermatol, Feinberg Sch Med, Chicago, IL 60611 USA. [Kimball, A. B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Chau, D.; Viswanathan, H. N.; Li, J.; Kricorian, G.; Ortmeier, B. G.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Revicki, D. A.] UnitedBioSource Corp, Bethesda, MD USA. RP Gordon, KB (reprint author), Northwestern Univ, Dept Dermatol, Feinberg Sch Med, 676 N St Clair St,Suite 1600, Chicago, IL 60611 USA. EM Kenneth-gordon@northwestern.edu FU Amgen Inc. FX Funding for this study and for manuscript development was provided by Amgen Inc. NR 19 TC 10 Z9 10 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD MAR PY 2014 VL 170 IS 3 BP 705 EP 715 PG 11 WC Dermatology SC Dermatology GA AC5UJ UT WOS:000332586100023 PM 24079852 ER PT J AU Mehta, SJ Asch, DA AF Mehta, Shivan J. Asch, David A. TI When are effective medications just too expensive? SO CLEVELAND CLINIC JOURNAL OF MEDICINE LA English DT Editorial Material ID COST C1 [Mehta, Shivan J.] Univ Penn, Perelman Sch Med, Div Gastroenterol, Philadelphia, PA 19104 USA. [Mehta, Shivan J.; Asch, David A.] Univ Penn, Ctr Hlth Care Innovat, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Mehta, SJ (reprint author), Univ Penn, Perelman Sch Med, 1133 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM shivan.mehta@uphs.upenn.edu OI Asch, David/0000-0002-7970-286X NR 9 TC 1 Z9 1 U1 1 U2 1 PU CLEVELAND CLINIC PI CLEVELAND PA 9500 EUCLID AVE, CLEVELAND, OH 44106 USA SN 0891-1150 EI 1939-2869 J9 CLEV CLIN J MED JI Clevel. Clin. J. Med. PD MAR PY 2014 VL 81 IS 3 BP 173 EP 175 DI 10.3949/ccjm.81a.14010 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AH1WA UT WOS:000335911200008 PM 24591472 ER PT J AU Frech, T Redd, D Rhiannon, J Murtaugh, M Zeng, Q AF Frech, T. Redd, D. Rhiannon, J. Murtaugh, M. Zeng, Q. TI INFORMATICS CAN IDENTIFY SYSTEMIC SCLEROSIS PATIENTS AT RISK FOR SCLERODERMA RENAL CRISIS SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Frech, T.; Redd, D.; Murtaugh, M.; Zeng, Q.] Univ Utah, Salt Lake VAMC, Salt Lake City, UT USA. [Rhiannon, J.] Denver VAMC, Denver, CO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD MAR-APR PY 2014 VL 32 IS 2 SU 81 BP S115 EP S116 PG 2 WC Rheumatology SC Rheumatology GA AH2FH UT WOS:000335936400308 ER PT J AU Ghassemi, P Lagares, D Tremblay, C Blati, M Baron, M Tager, A Kapoor, M AF Ghassemi, P. Lagares, D. Tremblay, C. Blati, M. Baron, M. Tager, A. Kapoor, M. TI EPHRIN B2 IS OVEREXPRESSED IN HUMAN SCLERODERMA SKIN AND MEDIATES FIBROBLAST TO MYOFIBROBLAST DIFFERENTIATION, AND INDUCES FIBROSIS IN MICE SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Ghassemi, P.; Tremblay, C.; Blati, M.; Kapoor, M.] Univ Montreal, Montreal, PQ, Canada. [Lagares, D.; Tager, A.] McGill Univ, Montreal, PQ, Canada. [Baron, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD MAR-APR PY 2014 VL 32 IS 2 SU 81 BP S14 EP S15 PG 2 WC Rheumatology SC Rheumatology GA AH2FH UT WOS:000335936400026 ER PT J AU Khanna, D Gladue, H Fitzgerald, J Channick, R Chung, L Distler, O Furst, D Hachulla, E Humbert, M Langelben, D Mathai, S Saggars, R Visovatti, S McLaughlin, V AF Khanna, D. Gladue, H. Fitzgerald, J. Channick, R. Chung, L. Distler, O. Furst, D. Hachulla, E. Humbert, M. Langelben, D. Mathai, S. Saggars, R. Visovatti, S. McLaughlin, V. TI RECOMMENDATIONS FOR SCREENING AND DETECTION OF CONNECTIVE-TISSUE DISEASE ASSOCIATED PULMONARY ARTERIAL HYPERTENSION SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract C1 [Khanna, D.; Gladue, H.; Visovatti, S.; McLaughlin, V.] Univ Michigan, Ann Arbor, MI 48109 USA. [Fitzgerald, J.; Furst, D.] Univ Calif Los Angeles, Los Angeles, CA USA. [Channick, R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chung, L.] Stanford Univ, Palo Alto, CA 94304 USA. [Distler, O.] Univ Zurich, Zurich, Switzerland. [Hachulla, E.] Univ Hosp Lille, Lille, France. [Humbert, M.] Univ S Paris, Paris, France. [Langelben, D.] McGill Univ, Montreal, PQ, Canada. [Mathai, S.] Johns Hopkins Univ, Baltimore, MD USA. [Saggars, R.] St Joseph Hosp, Phoenix, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD MAR-APR PY 2014 VL 32 IS 2 SU 81 BP S20 EP S20 PG 1 WC Rheumatology SC Rheumatology GA AH2FH UT WOS:000335936400039 ER PT J AU Bernal-Mizrachi, E Kulkarni, RN Scott, DK Mauvais-Jarvis, F Stewart, AF Garcia-Ocana, A AF Bernal-Mizrachi, Ernesto Kulkarni, Rohit N. Scott, Donald K. Mauvais-Jarvis, Franck Stewart, Andrew F. Garcia-Ocana, Adolfo TI Human beta-Cell Proliferation and Intracellular Signaling Part 2: Still Driving in the Dark Without a Road Map SO DIABETES LA English DT Article ID HUMAN PANCREATIC-ISLETS; ESTROGEN-RECEPTOR-ALPHA; INDUCED GENE-EXPRESSION; INSULIN-SECRETION; GROWTH-FACTOR; GLUCOSE-HOMEOSTASIS; DIABETES-MELLITUS; IN-VIVO; MOUSE PANCREAS; ADIPOSE-TISSUE C1 [Bernal-Mizrachi, Ernesto] Univ Michigan, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 USA. [Bernal-Mizrachi, Ernesto] US Dept Vet Affairs Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Kulkarni, Rohit N.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Scott, Donald K.; Stewart, Andrew F.; Garcia-Ocana, Adolfo] Icahn Sch Med Mt Sinai, Diabet Obes & Metab Inst, New York, NY USA. [Mauvais-Jarvis, Franck] Tulane Univ, Sch Med, Div Endocrinol & Metab, New Orleans, LA 70112 USA. [Mauvais-Jarvis, Franck] Hlth Sci Ctr, New Orleans, LA USA. [Garcia-Ocana, Adolfo] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY USA. RP Bernal-Mizrachi, E (reprint author), Univ Michigan, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 USA. EM ebernal@med.umich.edu; adolfo.g.ocana@mssm.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK084236, DK073716]; Juvenile Diabetes Research Foundation (JDRF) [46-2010-758]; NIDDK [DK067536, DK055523, DK065149, DK069362, DK074970, HD044405, DK77096, DK67351]; Harvard Stem Cell Institute; JDRF/Sanofi Strategic Alliance; AstraZeneca; American Diabetes Association [7-11-BS-128]; JDRF [17-2011-598, 1-2006-837, 1-2008-39, 34-2008-630, 47-2012-750]; March of Dimes [6-FY07-678]; NIDDK Beta Cell Biology Consortium [U01 DK089538, DK55023] FX The authors wish to thank the funding agencies for their essential contribution to this work, which was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants DK084236 and DK073716 and the Juvenile Diabetes Research Foundation (JDRF) International grant 46-2010-758 to E.B.-.M.; NIDDK grants DK067536 and DK055523, the Harvard Stem Cell Institute, the JDRF/Sanofi Strategic Alliance, and AstraZeneca to R.N.K.; NIDDK grant DK065149, American Diabetes Association grant 7-11-BS-128, and JDRF grant 17-2011-598 to D.K.S.; NIDDK grants DK069362, DK074970, and HD044405, JDRF grant 1-2006-837, and the March of Dimes grant 6-FY07-678 to F.M.-.J.; the NIDDK Beta Cell Biology Consortium grants U01 DK089538 and DK55023, JDRF grants 1-2008-39, 17-2011-598, and 34-2008-630 to A.F.S.; and NIDDK grants DK77096 and DK67351 and JDRF grant 47-2012-750 to A.G.-O. NR 94 TC 48 Z9 48 U1 0 U2 10 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD MAR PY 2014 VL 63 IS 3 BP 819 EP 831 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB2HQ UT WOS:000331614200001 PM 24556859 ER PT J AU Mezza, T Muscogiuri, G Sorice, GP Clemente, G Hu, J Pontecorvi, A Holst, JJ Giaccari, A Kulkarni, RN AF Mezza, Teresa Muscogiuri, Giovanna Sorice, Gian Pio Clemente, Gennaro Hu, Jiang Pontecorvi, Alfredo Holst, Jens J. Giaccari, Andrea Kulkarni, Rohit N. TI Insulin Resistance Alters Islet Morphology in Nondiabetic Humans SO DIABETES LA English DT Article ID GLUCAGON-LIKE PEPTIDE-1; BETA-CELL MASS; GASTRIC-INHIBITORY POLYPEPTIDE; PARTIAL PANCREATECTOMY; IN-VIVO; GLUCOSE; SECRETION; HYPERPLASIA; EXPRESSION; APOPTOSIS C1 [Mezza, Teresa; Hu, Jiang; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Med,Brigham & Womens Hosp, Boston, MA 02115 USA. [Mezza, Teresa; Muscogiuri, Giovanna; Sorice, Gian Pio; Pontecorvi, Alfredo; Giaccari, Andrea] Univ Cattolica Sacro Cuore, Div Endocrinol & Metab Dis, Rome, Italy. [Clemente, Gennaro] Univ Cattolica Sacro Cuore, Dept Surg, Rome, Italy. [Holst, Jens J.] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Dept Biomed Sci, Panum Inst, DK-1168 Copenhagen, Denmark. [Giaccari, Andrea] Fdn Don C Gnocchi, Milan, Italy. RP Giaccari, A (reprint author), Univ Cattolica Sacro Cuore, Div Endocrinol & Metab Dis, Rome, Italy. EM giaccari@rm.unicatt.it; rohit.kulkarni@joslin.harvard.edu OI Mezza, Teresa/0000-0001-5407-9576 FU Universita Cattolica del Sacro Cuore (Fondi Ateneo Linea D.3.2 Sindrome Metabolica); Italian Ministry of Education, University and Research [2010JS3PMZ_011]; Fondazione Don Gnocchi; European Association for the Study of Diabetes; Societa Italiana di Diabetologia; Laboratori Guidotti; National Institutes of Health [R01-DK-67536] FX This study was supported by grants to A.G. from Universita Cattolica del Sacro Cuore (Fondi Ateneo Linea D.3.2 Sindrome Metabolica), from the Italian Ministry of Education, University and Research (PRIN 2010JS3PMZ_011) and from Fondazione Don Gnocchi. T.M. is the recipient of the Albert Reynolds Travel Fellowship by the European Association for the Study of Diabetes and the Fellowship Prize by the Societa Italiana di Diabetologia. G.P.S. is the recipient of a fellowship from Laboratori Guidotti. Some of the reagents used in the study were supported by National Institutes of Health grant R01-DK-67536 to R.N.K. NR 47 TC 48 Z9 48 U1 2 U2 10 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD MAR PY 2014 VL 63 IS 3 BP 994 EP 1007 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB2HQ UT WOS:000331614200020 PM 24215793 ER PT J AU Bhama, PK Weinberg, JS Lindsay, RW Hohman, MH Cheney, ML Hadlock, TA AF Bhama, Prabhat K. Weinberg, Julie S. Lindsay, Robin W. Hohman, Marc H. Cheney, Mack L. Hadlock, Tessa A. TI Objective Outcomes Analysis Following Microvascular Gracilis Transfer for Facial Reanimation A Review of 10 Years' Experience SO JAMA FACIAL PLASTIC SURGERY LA English DT Article ID PARALYSIS; NERVE AB IMPORTANCE Objective assessment of smile outcome after microvascular free gracilis transfer is challenging, and quantification of smile outcomes in the literature is inconsistent. OBJECTIVE To report objective excursion and symmetry outcomes from a series of free gracilis cases and investigate the predictive value of intraoperative measurements on final outcomes. DESIGN, SETTING, AND PARTICIPANTS A retrospective medical chart review was undertaken of all patients who underwent microvascular free gracilis transfer for smile at our institution over the past 10 years. MAIN OUTCOMES AND MEASURES Outcome measures included the following: smile excursion, angle of smile with respect to the vertical midline, and facial symmetry during repose and with smile. Measurements were obtained using an automated tool for assessment of facial landmarks (FACE-Gram). An exhaustive set of intraoperative parameters including degree of recoil of the gracilis muscle following harvest, the degree to which the muscle foreshortened during stimulation of the obturator nerve, final stretched length of the inset muscle, surgeon assessment of neurorrhaphy and pulse pressure, ischemia time, number of sutures used during neurorrhaphy, nerve used to innervate the flap, and surgeon assessment of oral commissure overcorrection were recorded and placed into a linear regression model to investigate correlations with smile. RESULTS From March 2003 to March 2013, 154 microvascular free gracilis transfers were performed for facial reanimation at our institution, 14 (9%) of which were deemed failures. Of the remaining 140 flaps, 127 fulfilled inclusion criteria and constituted the study cohort. Smile excursion, angle excursion, and symmetry of the oral commissure at repose and with smile all improved following gracilis free flap (P < .05). Associations between selected outcomes measures and intraoperative gracilis measurements were identified. CONCLUSIONS AND RELEVANCE Facial reanimation using free gracilis transfer results in quantifiable improvements in oral commissure excursion and facial symmetry both at rest and with smiling. Associations between contractility and internal recoil of the flap and final outcome were identified. C1 [Bhama, Prabhat K.; Weinberg, Julie S.; Lindsay, Robin W.; Cheney, Mack L.; Hadlock, Tessa A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Div Facial Plast & Reconstruct Surg,Dept Otolaryn, Boston, MA 02114 USA. [Bhama, Prabhat K.] Harvard Univ, Sch Publ Hlth, Boston, MA 02114 USA. [Hohman, Marc H.] Madigan Army Med Ctr, Tacoma, WA 98431 USA. RP Bhama, PK (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Publ Hlth,Sch Med, Div Facial Plast & Reconstruct Surg,Dept Otolaryn, 243 Charles St, Boston, MA 02114 USA. EM pbhama@gmail.com FU National Institutes of Health (NIH) [R01NS071067] FX This research was supported by grant R01NS071067 from the National Institutes of Health (NIH). NR 8 TC 17 Z9 17 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6076 EI 2168-6092 J9 JAMA FACIAL PLAST SU JI JAMA Facial Plast. Surg. PD MAR-APR PY 2014 VL 16 IS 2 BP 85 EP 92 DI 10.1001/jamafacial.2013.2463 PG 8 WC Surgery SC Surgery GA AH2OX UT WOS:000335961900003 PM 24481538 ER PT J AU Herr, MW Emerick, KS Deschler, DG AF Herr, Marc W. Emerick, Kevin S. Deschler, Daniel G. TI The Supraclavicular Artery Flap for Head and Neck Reconstruction SO JAMA FACIAL PLASTIC SURGERY LA English DT Article ID ISLAND FLAP; CERVICOHUMERAL FLAP; CONTRACTURES; EXPERIENCE AB IMPORTANCE This study demonstrates the versatility of the supraclavicular artery (SCA) flap in head and neck reconstruction and offers technical highlights to improve the efficiency of flap harvest. OBJECTIVES To report our series of diverse reconstructions utilizing the SCA flap and to highlight several technical aspects of flap harvest that make the procedure more safe, reliable, and efficient. DESIGN, SETTING, AND PARTICIPANTS A retrospective review was conducted from July 2011 to December 2012 on all patients who had undergone SCA flap reconstruction of a head and neck defect at a tertiary referral center. The average follow-up time was 8 months. INTERVENTION OR EXPOSURE Supraclavicular artery flap reconstruction of defects at various head and neck subsites. MAIN OUTCOME AND MEASURE Reconstructive outcomes and complications were assessed and cases were reviewed to identify key aspects of flap harvest. RESULTS Twenty-four SCA flaps were performed on defects at multiple head and neck subsites. Several technical modifications were developed to increase the safety and efficiency of flap harvest. Complications were typically self-limited and were successfully managed nonsurgically. CONCLUSIONS AND RELEVANCE The SCA flap is a versatile and reliable reconstructive option for head and neck defects. There are 4 key steps to making the harvest of this flap safe, reliable, and efficient. C1 [Herr, Marc W.; Emerick, Kevin S.; Deschler, Daniel G.] Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Div Head & Neck Surg, Boston, MA 02114 USA. RP Herr, MW (reprint author), Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Div Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM marc.w.herr@gmail.com NR 24 TC 7 Z9 7 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6076 EI 2168-6092 J9 JAMA FACIAL PLAST SU JI JAMA Facial Plast. Surg. PD MAR-APR PY 2014 VL 16 IS 2 BP 127 EP 132 DI 10.1001/jamafacial.2013.2170 PG 6 WC Surgery SC Surgery GA AH2OX UT WOS:000335961900009 PM 24370537 ER PT J AU Kleiss, IJ Knox, CJ Malo, JS Marres, HAM Hadlock, TA Heaton, JT AF Kleiss, Ingrid J. Knox, Christopher J. Malo, Juan S. Marres, Henri A. M. Hadlock, Tessa A. Heaton, James T. TI Whisking Recovery After Automated Mechanical Stimulation During Facial Nerve Regeneration SO JAMA FACIAL PLASTIC SURGERY LA English DT Article ID IMPROVES FUNCTIONAL RECOVERY; RAT SKELETAL-MUSCLE; MANUAL STIMULATION; PERIPHERAL-NERVE; ELECTRICAL-STIMULATION; MOTOR FUNCTION; CRUSH LESION; INJURY; MOVEMENTS; REPAIR AB IMPORTANCE Recovery from facial nerve transection is typically poor, but daily mechanical stimulation of the face in rats has been reported to remarkably enhance functional recovery after facial nerve transection and suture repair. This phenomenon needs additional investigation because of its important clinical implications. OBJECTIVE To determine whether automated mechanical stimulation of the whisker pad improves whisking recovery after facial nerve transection and repair in a rat model. DESIGN AND SETTING Sixty-one rats underwent unilateral facial nerve transection and suture repair and were randomized into 8 groups. Six groups received daily automated whisker or whisker pad mechanical stimulation including 0.5-, 1.5-, and 8.0-Hz patterns. Two control groups received restraint without stimulation. Treatment started on postoperative day 8, occurred 5 days per week, and lasted throughout 15 weeks of recovery. Whisking amplitude, velocity, and acceleration were quantified weekly for 15 weeks. INTERVENTIONS Unilateral facial nerve transection, suture repair, and, for 6 groups, daily automated whisker or whisker pad mechanical stimulation. MAIN OUTCOMES AND MEASURES Quantification of whisking amplitude, velocity, and acceleration. RESULTS Rats receiving the low frequencies of stimulation of the whiskers or whisker pad did not demonstrate enhanced whisking recovery, and rats receiving stimulation at 8.0 Hz showed significantly worse whisking recovery compared with controls and previously published groups receiving lower dose manual stimulation. CONCLUSIONS AND RELEVANCE Although daily manual whisker pad stimulation has been shown to enhance whisking recovery, rats in this study did not demonstrate improved whisking recovery after automated mechanical stimulation across a wide range of driving frequencies. Moreover, faster stimulation (8.0 Hz) was actually detrimental to recovery. Further work is needed to understand the relationship between stimulation patterns and the physiologic mechanisms underlying improved or worsened functional outcomes after facial nerve transection and repair. C1 [Kleiss, Ingrid J.; Knox, Christopher J.; Malo, Juan S.; Hadlock, Tessa A.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. [Heaton, James T.] Massachusetts Gen Hosp, Dept Surg, 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 FU National Institutes of Health [R01NS071067] FX This study was funded by grant R01NS071067 from the National Institutes of Health (Drs Hadlock and Heaton). NR 35 TC 1 Z9 1 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6076 EI 2168-6092 J9 JAMA FACIAL PLAST SU JI JAMA Facial Plast. Surg. PD MAR-APR PY 2014 VL 16 IS 2 BP 133 EP 139 DI 10.1001/jamafacial.2013.2217 PG 7 WC Surgery SC Surgery GA AH2OX UT WOS:000335961900010 PM 24407357 ER PT J AU Haller, JF Cavallaro, P Hernandez, NJ Dolat, L Soscia, SJ Welti, R Grabowski, GA Fitzgerald, ML Freeman, MW AF Haller, Jorge F. Cavallaro, Paul Hernandez, Nicholas J. Dolat, Lee Soscia, Stephanie J. Welti, Ruth Grabowski, Gregory A. Fitzgerald, Michael L. Freeman, Mason W. TI Endogenous beta-glucocerebrosidase activity in Abca12(-/-) epidermis elevates ceramide levels after topical lipid application but does not restore barrier function SO JOURNAL OF LIPID RESEARCH LA English DT Article DE glucosylceramide; harlequin ichthyosis; skin permeability barrier; ABCA12 antibody ID STRATUM-CORNEUM CERAMIDES; HARLEQUIN ICHTHYOSIS; PERMEABILITY BARRIER; GLUCOSYLCERAMIDE SYNTHASE; GAUCHER-DISEASE; KERATINOCYTE DIFFERENTIATION; IMPROVED INHIBITORS; SKIN; MICE; MUTATIONS AB ABCA12 mutations disrupt the skin barrier and cause harlequin ichthyosis. We previously showed Abca12(-/-) skin has increased glucosylceramide (GlcCer) and correspondingly lower amounts of ceramide (Cer). To examine why loss of ABCA12 leads to accumulation of GlcCer, de novo sphingolipid synthesis was assayed using [C-14] serine labeling in ex vivo skin cultures. A defect was found in beta-glucocerebrosidase (GCase) processing of newly synthesized GlcCer species. This was not due to a decline in GCase function. Abca12(-/-) epidermis had 5-fold more GCase protein (n = 4, P < 0.01), and a 5-fold increase in GCase activity (n = 3, P < 0.05). As with Abca12(+/+) epidermis, immunostaining in null skin showed a typical interstitial distribution of the GCase protein in the Abca12(-/-) stratum corneum. Hence, we tested whether the block in GlcCer conversion could be circumvented by topically providing GlcCer. This approach restored up to 15% of the lost Cer products of GCase activity in the Abca12(-/-) epidermis. However, this level of barrier ceramide replacement did not significantly reduce trans-epidermal water loss function.(jlr) Our results indicate loss of ABCA12 function results in a failure of precursor GlcCer substrate to productively interact with an intact GCase enzyme, and they support a model of ABCA12 function that is critical for transporting GlcCer into lamellar bodies. C1 [Haller, Jorge F.; Cavallaro, Paul; Hernandez, Nicholas J.; Dolat, Lee; Soscia, Stephanie J.; Fitzgerald, Michael L.; Freeman, Mason W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lipid Metab Unit, Boston, MA 02114 USA. [Haller, Jorge F.; Cavallaro, Paul; Hernandez, Nicholas J.; Dolat, Lee; Soscia, Stephanie J.; Fitzgerald, Michael L.; Freeman, Mason W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Welti, Ruth] Kansas State Univ, Kansas Lipid Res Ctr, Manhattan, KS 66506 USA. [Grabowski, Gregory A.] Childrens Hosp Res Fdn, Div & Program Human Genet, Cincinnati, OH 45229 USA. RP Fitzgerald, ML (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lipid Metab Unit, Boston, MA 02114 USA. EM mfitzgerald@ccib.mgh.harvard.edu; mfreeman@ccib.mgh.harvard.edu FU National Institutes of Health [RR020345, RR020345-04S1, HL112661, HL101274, P20 RR16475]; National Science Foundation [MCB 0455318, DBI 0521587]; EPSCoR [EPS-0236913]; State of Kansas through Kansas Technology Enterprise Corporation and Kansas State University FX This work was supported by National Institutes of Health Grants RR020345 (M.W.F.), RR020345-04S1 (M.W.F.), HL112661 (M.L.F.), and HL101274 (M.L.F.). The Kansas Lipidomics Research Center was supported by National Science Foundation Grants MCB 0455318 and DBI 0521587; by EPSCoR Grant EPS-0236913 with matching support from the State of Kansas through Kansas Technology Enterprise Corporation and Kansas State University; and by National Institutes of Health Grant P20 RR16475. NR 42 TC 2 Z9 2 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 EI 1539-7262 J9 J LIPID RES JI J. Lipid Res. PD MAR PY 2014 VL 55 IS 3 BP 493 EP 503 DI 10.1194/jlr.M044941 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AH8YX UT WOS:000336425300013 PM 24293640 ER PT J AU Goodman, J Chenausky, K AF Goodman, Janice Chenausky, Kerry TI CALM Pregnancy: Results of a Pilot Study of Mindfulness-Based Cognitive Therapy for Perinatal Anxiety SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Goodman, Janice] Massachusetts Gen Hosp, Inst Hlth Profess, Sch Nursing, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2014 VL 63 IS 2 BP E61 EP E61 PG 1 WC Nursing SC Nursing GA AE6JP UT WOS:000334098000170 ER PT J AU Gray-Miceli, D Ratcliffe, S Thomasson, A AF Gray-Miceli, Deanna Ratcliffe, Sarah Thomasson, Arwin TI Patient Level Risk Factors to Assess in Older Adult Fallers with Orthostatic Hypotension SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Gray-Miceli, Deanna] Rutgers State Univ, Coll Nursing, Piscataway, NJ 08855 USA. [Ratcliffe, Sarah] Univ Penn, Sch Med & Biostat, Philadelphia, PA 19104 USA. [Thomasson, Arwin] Ctr Hlth Equ Res & Promot, Philadelphia VA 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 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2014 VL 63 IS 2 BP E7 EP E8 PG 2 WC Nursing SC Nursing GA AE6JP UT WOS:000334098000019 ER PT J AU Kutney-Lee, A Brennan, C Meterko, M Ersek, M AF Kutney-Lee, Ann Brennan, Caitlin Meterko, Mark Ersek, Mary TI Organization of Nursing and Quality of Care for Veterans at the End of Life SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Kutney-Lee, Ann] Univ Penn, Philadelphia, PA 19104 USA. [Brennan, Caitlin] NIH, Ctr Clin, Bethesda, MD USA. [Meterko, Mark] VA Boston Healthcare Syst, Boston, MA USA. [Ersek, Mary] Univ Penn, Philadelphia VA Med Ctr, Philadelphia, PA 19104 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 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2014 VL 63 IS 2 BP E129 EP E129 PG 1 WC Nursing SC Nursing GA AE6JP UT WOS:000334098000355 ER PT J AU Malley, A Kenner, C Kim, T Blakeney, B AF Malley, Ann Kenner, Carole Kim, Tiffany Blakeney, Barbara TI Nursing's Contribution To Transitions in Care SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Malley, Ann; Blakeney, Barbara] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kenner, Carole; Kim, Tiffany] Northeastern Univ, 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 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2014 VL 63 IS 2 BP E121 EP E121 PG 1 WC Nursing SC Nursing GA AE6JP UT WOS:000334098000334 ER PT J AU Mataoui, FZ Sheldon, LK Cooley, M AF Mataoui, Fatma Zohra Sheldon, Lisa Kennedy Cooley, Mary TI What are the Barriers to BRCA1/2 Testing Among Women at High-risk for Breast and Ovarian Cancer? A Systematic Review SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Mataoui, Fatma Zohra] Univ Massachusetts, Amherst, MA 01003 USA. [Sheldon, Lisa Kennedy] Univ Massachusetts Boston, Boston, MA USA. [Cooley, Mary] Univ Massachusetts Boston, Dana Farber Canc Inst, 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 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2014 VL 63 IS 2 BP E112 EP E112 PG 1 WC Nursing SC Nursing GA AE6JP UT WOS:000334098000309 ER PT J AU Moriarty, H Winter, L Robinson, K Piersol, C Vause-Earland, T Iacavone, D True, G Hodgson, N Holbert, L Newhart, B Fishman, D AF Moriarty, Helene Winter, Laraine Robinson, Keith Piersol, Catherine Vause-Earland, Tracey Iacavone, Dolores True, Gala Hodgson, Nancy Holbert, Laura Newhart, Brian Fishman, Deborah TI Challenges in Mental Health Predictors of Community Reintegration in Military Veterans with Mild to Moderate Traumatic Brain Injury SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Moriarty, Helene] Villanova Univ, Coll Nursing, Villanova, PA 19085 USA. [Winter, Laraine; Robinson, Keith; Iacavone, Dolores; True, Gala; Holbert, Laura; Newhart, Brian; Fishman, Deborah] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Piersol, Catherine; Vause-Earland, Tracey] Thomas Jefferson Univ, Sch Hlth Profess, Philadelphia, PA USA. [Hodgson, Nancy] Johns Hopkins Univ, Sch Nursing, Baltimore, MD 21218 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 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2014 VL 63 IS 2 BP E71 EP E72 PG 2 WC Nursing SC Nursing GA AE6JP UT WOS:000334098000199 ER PT J AU Moriarty, H Winter, L Piersol, C Vause-Earland, T Robinson, K Lacavone, D True, G Holbert, L Newhart, B Hodgson, N Fishman, D AF Moriarty, Helene Winter, Laraine Piersol, Catherine Vause-Earland, Tracey Robinson, Keith Lacavone, Dolores True, Gala Holbert, Laura Newhart, Brian Hodgson, Nancy Fishman, Deborah TI Using Dyadic Analyses with Veterans with Traumatic Brain Injury and their Family Members: Implications for Family Relationships SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Moriarty, Helene] Villanova Univ, Coll Nursing, Villanova, PA 19085 USA. [Winter, Laraine; Robinson, Keith; Lacavone, Dolores; Holbert, Laura; Newhart, Brian; Fishman, Deborah] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Piersol, Catherine; Vause-Earland, Tracey] Thomas Jefferson Univ, Sch Hlth Profess, Philadelphia, PA USA. [True, Gala] CHERP, Philadelphia VA Med Ctr, Philadelphia, PA USA. [Hodgson, Nancy] Johns Hopkins Univ, Sch Nursing, Baltimore, MD 21218 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 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2014 VL 63 IS 2 BP E11 EP E12 PG 2 WC Nursing SC Nursing GA AE6JP UT WOS:000334098000030 ER PT J AU Mosadegh, S Farnum, K Kline, N AF Mosadegh, Sara Farnum, Karen Kline, Nancy TI The Red Bag Review: A Medication Reconciliation Initiative SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Mosadegh, Sara; Farnum, Karen] Northeastern Univ, Boston, MA USA. [Kline, Nancy] Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA 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 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2014 VL 63 IS 2 BP E38 EP E38 PG 1 WC Nursing SC Nursing GA AE6JP UT WOS:000334098000107 ER PT J AU Poghosyan, H Joseph, J Bell, J Cooley, M AF Poghosyan, Hermine Joseph, Jill Bell, Janice Cooley, Mary TI The Association Between Having a First-degree Family History of Cancer and Smoking Status SO NURSING RESEARCH LA English DT Meeting Abstract C1 [Poghosyan, Hermine] Univ Massachusetts Boston, Boston, MA USA. [Joseph, Jill; Bell, Janice] Univ Calif Davis, Davis, CA USA. [Cooley, Mary] Dana Farber Canc Inst, 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 0029-6562 EI 1538-9847 J9 NURS RES JI Nurs. Res. PD MAR-APR PY 2014 VL 63 IS 2 BP E71 EP E71 PG 1 WC Nursing SC Nursing GA AE6JP UT WOS:000334098000198 ER PT J AU Stetler, RA Leak, RK Gan, Y Li, PY Zhang, F Hu, XM Jing, Z Chen, J Zigmond, MJ Gao, YQ AF Stetler, R. Anne Leak, Rehana K. Gan, Yu Li, Peiying Zhang, Feng Hu, Xiaoming Jing, Zheng Chen, Jun Zigmond, Michael J. Gao, Yanqin TI Preconditioning provides neuroprotection in models of CNS disease: Paradigms and clinical significance SO PROGRESS IN NEUROBIOLOGY LA English DT Review DE Preconditioning; Neuroprotection; Ischemia; Traumatic brain injury ID FOCAL CEREBRAL-ISCHEMIA; TRAUMATIC BRAIN-INJURY; METHYL-D-ASPARTATE; OXYGEN-GLUCOSE DEPRIVATION; MESENCHYMAL STEM-CELLS; K-ATP CHANNEL; HYPOTHERMIC CIRCULATORY ARREST; SENSITIVE POTASSIUM CHANNELS; NEONATAL HYPOXIA-ISCHEMIA; CEREBELLAR GRANULE CELLS AB Preconditioning is a phenomenon in which brief episodes of a sublethal insult induce robust protection against subsequent lethal injuries. Preconditioning has been observed in multiple organisms and can occur in the brain as well as other tissues. Extensive animal studies suggest that the brain can be preconditioned to resist acute injuries, such as ischemic stroke, neonatal hypoxia/ischemia, surgical brain injury, trauma, and agents that are used in models of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Effective preconditioning stimuli are numerous and diverse, ranging from transient ischemia, hypoxia, hyperbaric oxygen, hypothermia and hyperthermia, to exposure to neurotoxins and pharmacological agents. The phenomenon of "cross-tolerance," in which a sublethal stress protects against a different type of injury, suggests that different preconditioning stimuli may confer protection against a wide range of injuries. Research conducted over the past few decades indicates that brain preconditioning is complex, involving multiple effectors such as metabolic inhibition, activation of extra- and intracellular defense mechanisms, a shift in the neuronal excitatory/inhibitory balance, and reduction in inflammatory sequelae. An improved understanding of brain preconditioning should help us identify innovative therapeutic strategies that prevent or at least reduce neuronal damage in susceptible patients. In this review, we focus on the experimental evidence of preconditioning in the brain and systematically survey the models used to develop paradigms for neuroprotection, and then discuss the clinical potential of brain preconditioning. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Stetler, R. Anne; Gan, Yu; Li, Peiying; Zhang, Feng; Chen, Jun; Zigmond, Michael J.; Gao, Yanqin] Fudan Univ, Shanghai Med Coll, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China. [Stetler, R. Anne; Gan, Yu; Li, Peiying; Zhang, Feng; Chen, Jun; Zigmond, Michael J.; Gao, Yanqin] Fudan Univ, Shanghai Med Coll, Inst Brain Sci, Shanghai 200032, Peoples R China. [Stetler, R. Anne; Gan, Yu; Li, Peiying; Zhang, Feng; Hu, Xiaoming; Jing, Zheng; Chen, Jun; Zigmond, Michael J.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. [Stetler, R. Anne; Gan, Yu; Li, Peiying; Zhang, Feng; Hu, Xiaoming; Jing, Zheng; Chen, Jun; Zigmond, Michael J.] Univ Pittsburgh, Sch Med, Ctr Cerebrovasc Dis Res, Pittsburgh, PA 15213 USA. [Leak, Rehana K.] Duquesne Univ, Mylan Sch Pharm, Div Pharmaceut Sci, Pittsburgh, PA 15282 USA. [Stetler, R. Anne; Zhang, Feng; Hu, Xiaoming; Jing, Zheng; Chen, Jun] Vet Affairs Pittsburgh Hlth Care Syst, Educ & Clin Ctr, Pittsburgh, PA 15261 USA. RP Gao, YQ (reprint author), Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China. EM yqgao@shmu.edu.cn RI Gao, Yanqin/I-6790-2016; OI Gao, Yanqin/0000-0002-4915-9819; Leak, Rehana/0000-0003-2817-7417 FU National Institutes of Health/NINDS [NS36736, NS43802, NS56118, NS45048, NS070825]; VA Merit Review Grant; Chinese Natural Science Foundation [81020108021, 81171149, 81371306, 30870794, 81228008, 81271276]; VA Career Scientist Award; RK Mellon Endowed Chair from the University of Pittsburgh Medical Center; Changjiang Chair Professorship from the Chinese Ministry of Education; International Distinguished Professorship from the Chinese Ministry of Education [MS2011FDDX025] FX This work was supported by National Institutes of Health/NINDS Grants NS36736, NS43802, NS56118, and NS45048 (to JC) and NS070825 (to MZ and JC), the VA Merit Review Grant (to JC), and Chinese Natural Science Foundation grants 81020108021, 81171149, 81371306 and 30870794 (to YG); 81228008 (to JC); 81271276 (to FZ). J.C. is a recipient of the VA Career Scientist Award, the RK Mellon Endowed Chair from the University of Pittsburgh Medical Center, and the Changjiang Chair Professorship from the Chinese Ministry of Education. M.Z. is the recipient of the International Distinguished Professorship from the Chinese Ministry of Education (MS2011FDDX025). We thank Ms. Carol Culver for excellent editorial assistance and Ms. Pat Strickler for secretarial support. NR 415 TC 55 Z9 58 U1 4 U2 38 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD MAR PY 2014 VL 114 BP 58 EP 83 DI 10.1016/j.pneurobio.2013.11.005 PG 26 WC Neurosciences SC Neurosciences & Neurology GA AH1JQ UT WOS:000335876800004 PM 24389580 ER PT J AU Ellingson, LD Koltyn, KF Kim, JS Cook, DB AF Ellingson, Laura D. Koltyn, Kelli F. Kim, Jee-Seon Cook, Dane B. TI Does exercise induce hypoalgesia through conditioned pain modulation? SO PSYCHOPHYSIOLOGY LA English DT Article ID NOXIOUS INHIBITORY CONTROLS; BLOOD-PRESSURE; PHYSICAL-ACTIVITY; FIBROMYALGIA SYNDROME; ISOMETRIC-EXERCISE; UNITED-STATES; MUSCLE PAIN; ACCELEROMETER; ANALGESIA; MECHANISMS C1 [Ellingson, Laura D.; Cook, Dane B.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Ellingson, Laura D.; Koltyn, Kelli F.; Cook, Dane B.] Univ Wisconsin, Dept Kinesiol, Madison, WI 53706 USA. [Kim, Jee-Seon] Univ Wisconsin, Dept Educ Psychol, Madison, WI 53706 USA. RP Cook, DB (reprint author), Univ Wisconsin, Dept Kinesiol, 2000 Observ Dr, Madison, WI 53706 USA. EM dcook@education.wisc.edu NR 48 TC 16 Z9 17 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD MAR PY 2014 VL 51 IS 3 BP 267 EP 276 PG 10 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA AA8OZ UT WOS:000331356100006 PM 24354707 ER PT J AU Desai, NS Saboo, SS Khandelwal, A Ricci, JA AF Desai, Naman S. Saboo, Sachin S. Khandelwal, Ashish Ricci, Joseph A. TI Pneumosinus Dilatans: Is It More Than an Aesthetic Concern? SO JOURNAL OF CRANIOFACIAL SURGERY LA English DT Article DE Pneumosinus dilatans; paranasal sinuses; meningioma; arachnoid cyst; orbital tumor ID FRONTAL-SINUS; ETIOLOGY; MENINGIOMAS; PRESSURE; SIGN AB Background Pneumosinus dilatans (PD) is a pathologic condition involving the hyperaeration of one or several of the paranasal sinuses that can lead to significant deformation of the overlying bone. Although the presenting complaint of patients with PD is most commonly aesthetic in nature, the condition has also been associated with intracranial tumors and several other serious conditions. Materials and Methods A meta-analysis of all available clinical publications on the subject of PD was conducted. Patients were categorized on the basis of their sinus involvement. Associated conditions were also identified and categorized. The resulting data were used to further characterize the condition and describe previously unreported associations between PD and other conditions. Results To date, a total of 123 cases of PD have been reported. The frontal sinus was the most commonly involved (63%), followed by the sphenoid sinus (24%), maxillary sinus (20%), and ethmoid sinus (19%). Of patients with symptomatic PD of the frontal sinus, 25% had intracranial pathology (meningioma or arachnoid cyst or orbital tumor). Patients with sphenoid PD had an 83% chance of having associated diagnosis of visual loss, meningioma, or arachnoid cyst, whereas patients with ethmoid PD had 83% chance of having associated diagnosis of exophthalmos, vision loss, or arachnoid cyst. Conclusions Although the presenting complaint of patients with PD is most commonly aesthetic in nature, a significant percentage may have an associated diagnosis. Health care providers must be able to recognize the condition and carry out the appropriate clinical evaluation to avoid missing an associated diagnosis. C1 [Desai, Naman S.; Saboo, Sachin S.; Khandelwal, Ashish] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Desai, Naman S.; Saboo, Sachin S.; Khandelwal, Ashish; Ricci, Joseph A.] Harvard Univ, Sch Med, Boston, MA USA. [Ricci, Joseph A.] Massachusetts Gen Hosp, Dept Surg, Div Plast Surg, Boston, MA 02114 USA. RP Ricci, JA (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Plast Surg, WACC 435,55 Fruit St, Boston, MA 02114 USA. EM jaricci@partners.org NR 23 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1049-2275 EI 1536-3732 J9 J CRANIOFAC SURG JI J. Craniofac. Surg. PD MAR PY 2014 VL 25 IS 2 BP 418 EP 421 DI 10.1097/SCS.0000000000000694 PG 4 WC Surgery SC Surgery GA AG4IB UT WOS:000335381800067 PM 24561372 ER PT J AU Doumit, GD Junewicz, A Yaremchuk, M AF Doumit, Gaby D. Junewicz, Alexandra Yaremchuk, Michael TI The Temporoparietal Adipofascial Flap for the Correction of Recurrent Idiopathic Enophthalmos SO JOURNAL OF CRANIOFACIAL SURGERY LA English DT Article DE Temporoparietal adipofascial flap; enophthalmos ID ORBITAL RECONSTRUCTION AB Enophthalmos, the posterior displacement of a normal-size ocular globe relative to the orbital cavity, is usually repaired using autogenous grafts or alloplastic materials. We present the case of a 40-year-old man with bilateral idiopathic enophthalmos whose symptoms recurred 8 years after initial successful surgical repair. We describe the successful and safe use of a bilateral temporoparietal adipofascial flap in the treatment of recurrent idiopathic enophthalmos. C1 [Doumit, Gaby D.; Junewicz, Alexandra] Cleveland Clin, Dept Plast Surg, Inst Dermatol & Plast Surg, Cleveland, OH 44195 USA. [Yaremchuk, Michael] Massachusetts Gen Hosp, Dept Surg, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. RP Doumit, GD (reprint author), Cleveland Clin, Dept Plast Surg, Inst Dermatol & Plast Surg, 9500 Euclid Ave,Suite A60, Cleveland, OH 44195 USA. EM doumitg@ccf.org NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1049-2275 EI 1536-3732 J9 J CRANIOFAC SURG JI J. Craniofac. Surg. PD MAR PY 2014 VL 25 IS 2 BP 676 EP 678 DI 10.1097/SCS.0000000000000490 PG 3 WC Surgery SC Surgery GA AG4IB UT WOS:000335381800142 PM 24621720 ER PT J AU Kadayifci, A Atar, M Parlar, S Balkan, A Koruk, I Koruk, M AF Kadayifci, Abdurrahman Atar, Mustafa Parlar, Serap Balkan, Ayhan Koruk, Irfan Koruk, Mehmet TI Transnasal Endoscopy is Preferred by Transoral Endoscopy Experienced Patients SO JOURNAL OF GASTROINTESTINAL AND LIVER DISEASES LA English DT Article DE Transnasal endoscopy; ultrathin endoscope; unsedated endoscopy; tolerability ID UPPER GASTROINTESTINAL ENDOSCOPY; UNSEDATED TRANSNASAL; RANDOMIZED-TRIAL; CONVENTIONAL EGD; OLDER PATIENTS; ESOPHAGOGASTRODUODENOSCOPY; SEDATION; ACCEPTABILITY AB Background & Aims: Both unsedated transoral endoscopy (TOE) and sedated TOE have some drawbacks in clinical practice. Unsedated transnasal endoscopy (TNE) has been suggested as an alternative to both methods. This study aimed to determine the advantages of TNE in patients who have previously undergone unsedated conventional TOE. Methods: Patients who had received an unsedated TOE in the last 12 months and were scheduled for a second upper endoscopy were included. They were randomized to undergo either unsedated TOE, using a standard endoscope, or unsedated TNE, using an ultrathin endoscope. Post-procedure, patients were asked to complete a questionnaire to assess pain, discomfort and acceptability of the procedure, and to compare the current procedure with their previous unsedated TOE. Endoscope insertion rate, procedure duration, and side-effects were recorded. Results: Each group included 50 patients. With the exception of nasal pain, the tolerability and acceptance were significantly greater in the unsedated TNE group. Significantly more TNE patients (82%) found the current endoscopic procedure to be better than their previous TOE when compared with patients who had received a second TOE (12%). A repeat procedure was significantly more acceptable for TNE patients when compared to the TOE group (68% vs.16%). The duration of endoscopy was significantly shorter in TOE than in TNE (p<0.05). Endoscope insertion failed in 4% and mild epistaxis was observed in 4% of TNE patients. Conclusion: Unsedated TNE was better tolerated in endoscopy experienced patients when compared with unsedated TOE. The majority of patients found TNE more acceptable and preferable to TOE, suggesting that TNE should become a more common practice in clinics when applicable. C1 [Kadayifci, Abdurrahman; Balkan, Ayhan; Koruk, Irfan; Koruk, Mehmet] Gaziantep Univ, Div Gastroenterol, Fac Med, Gaziantep, Turkey. [Atar, Mustafa] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol, Boston, MA USA. [Parlar, Serap] Gaziantep Univ, Dept Internal Med Nursing, Fac Hlth Sci, Gaziantep, Turkey. RP Kadayifci, A (reprint author), Massachusetts Gen Hosp, 3-H GI Associates,Zero Emerson Pl,Blossom St, Boston, MA 02114 USA. EM akadayifci@mgh.harvard.edu NR 27 TC 3 Z9 3 U1 1 U2 3 PU MEDICAL UNIV PRESS PI CLUJ-NAPOCA PA 3RD MEDICAL CLINIC, STR CROITORILOR NO 19-21, CLUJ-NAPOCA, 400162, ROMANIA SN 1841-8724 EI 1842-1121 J9 J GASTROINTEST LIVER JI J. Gastrointest. Liver Dis. PD MAR PY 2014 VL 23 IS 1 BP 27 EP 31 PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AH1JY UT WOS:000335877600008 PM 24689093 ER PT J AU Peraino, JS Zhang, HP Rajasekera, PV Wei, M Madsen, JC Sachs, DH Huang, CA Wang, ZR AF Peraino, Jaclyn Stromp Zhang, Huiping Rajasekera, Priyani V. Wei, Min Madsen, Joren C. Sachs, David H. Huang, Christene A. Wang, Zhirui TI Diphtheria toxin-based bivalent human IL-2 fusion toxin with improved efficacy for targeting human CD25(+) cells SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Human IL-2; Diphtheria toxin; Fusion toxin; Regulatory T cell; Pichia pastoris expression ID REGULATORY T-CELLS; YEAST PICHIA-PASTORIS; DENILEUKIN DIFTITOX; PORCINE CTLA-4; IMMUNOTOXIN; EXPRESSION; PURIFICATION; MELANOMA; DELIVERY; CYTOSOL AB Regulatory T cells (Treg) constitute a major inhibitory cell population which suppresses immune responses. Thus, Treg have proven to be key players in the induction of transplantation tolerance, protection from autoimmune disease and prevention of the development of effective anti-tumor immune reactions. Treg express high levels of the high affinity interleukin-2 receptor (IL-2R) consisting of IL-2R alpha. (CD25) together with IL-2R beta (CD122) and the common gamma-chain (CD132). An effective reagent capable of depleting Treg in vivo would facilitate better cancer treatment and allow mechanistic studies of the role of Treg in transplantation tolerance and the development of autoimmune disease. In this study, we have developed a novel bivalent human IL-2 fusion toxin along with an Ontak (R)-like monovalent human IL-2 fusion toxin and compared the functional ability of these reagents in vitro. Here we show that genetically linking two human IL-2 domains in tandem, thereby generating a bivalent fusion toxin, results in significantly improved capacity in targeting human CD25(+) cells in vitro. Binding analysis by flow cytometry showed that the bivalent human IL-2 fusion toxin has notably increased affinity for human CD25(+) cells. In vitro functional analysis demonstrated that the bivalent isoform has an increased potency of approximately 2 logs in inhibiting cellular proliferation and protein synthesis in human CD25(+) cells compared to the monovalent human IL-2 fusion toxin. Additionally, we performed two inhibition assays in order to verify that the fusion toxins target the cells specifically through binding of the human IL-2 domain of the fusion toxin to the human IL-2 receptor on the cell surface. These results demonstrated that 1) both monovalent and bivalent human IL-2 fusion toxins are capable of blocking the binding of biotinylated human IL-2 to human CD25 by flow cytometry; and 2) human IL-2 blocked the fusion toxins from inhibiting protein synthesis and cellular proliferation in vitro, thus confirming that the human IL-2 fusion toxins target the cells specifically through binding to the human IL-2 receptor. We believe that the bivalent human IL-2 fusion toxin will be a more potent, and therefore, more optimal agent than the current clinically-used monovalent fusion toxin (denileukin diftitox, Ontak (R)) for in vivo depletion of Treg. (C) 2014 Elsevier B.V. All rights reserved. C1 [Peraino, Jaclyn Stromp; Zhang, Huiping; Rajasekera, Priyani V.; Wei, Min; Madsen, Joren C.; Sachs, David H.; Huang, Christene A.; Wang, Zhirui] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. [Peraino, Jaclyn Stromp; Zhang, Huiping; Rajasekera, Priyani V.; Wei, Min; Madsen, Joren C.; Sachs, David H.; Huang, Christene A.; Wang, Zhirui] Harvard Univ, Sch Med, Boston, MA USA. [Peraino, Jaclyn Stromp; Zhang, Huiping; Rajasekera, Priyani V.; Wei, Min; Sachs, David H.; Huang, Christene A.; Wang, Zhirui] MGH DF HCC Recombinant Prot Express & Purificat C, Boston, MA USA. RP Wang, ZR (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Bldg 149-6113,13th St, Boston, MA 02129 USA. EM zhirui.wang@tbrc.mgh.harvard.edu FU Dana Farber/Harvard Cancer Center FX The work was supported in part by a Dana Farber/Harvard Cancer Center Core development grant. We would like to thank Angimmune LLC for kindly providing the diphtheria toxin resistant yeast Pichia pastoris strain and the codon-optimized DT390 DNA. We would like to thank Dr. Robert Harrison for generously providing the HUT 102/6TG cell line. We would like to thank Edward Harrington for technical assistance, and Dr. Bob Hawley and Sharon Germana for their intensive manuscript review. NR 21 TC 2 Z9 2 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD MAR PY 2014 VL 405 BP 57 EP 66 DI 10.1016/j.jim.2014.01.008 PG 10 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA AG7PA UT WOS:000335608900007 PM 24462799 ER PT J AU Wellinghoff, MA Bunchman, AM Dean, JC AF Wellinghoff, Molly A. Bunchman, Alison M. Dean, Jesse C. TI Gradual mechanics-dependent adaptation of medial gastrocnemius activity during human walking SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE dual-task walking; locomotion; motor adaptation; muscle activity ID MUSCLE-ACTIVITY; STEP FREQUENCY; PROLONGED WALKING; TENDON VIBRATION; MOTOR ADAPTATION; DOWNHILL WALKING; ACHILLES-TENDON; UPHILL WALKING; HUMAN MOVEMENT; SOLEUS MUSCLE AB While performing a simple bouncing task, humans modify their preferred movement period and pattern of plantarflexor activity in response to changes in system mechanics. Over time, the preferred movement pattern gradually adapts toward the resonant frequency. The purpose of the present experiments was to determine whether humans undergo a similar process of gradually adapting their stride period and plantarflexor activity after a change in mechanical demand while walking. Participants walked on a treadmill while we measured stride period and plantarflexor activity (medial gastrocnemius and soleus). Plantarflexor activity during stance was divided into a storage phase (30-65% stance) and a return phase (65-100% stance) based on when the Achilles tendon has previously been shown to store and return mechanical energy. Participants walked either on constant inclines (0%, 1%, 5%, 9%) or on a variable incline (0-1%) for which they were unaware of the incline changes. For variable-incline trials, participants walked under both single-task and dual-task conditions in order to vary the cognitive load. Both stride period and plantarflexor activity increased at steeper inclines. During single-task walking, small changes in incline were followed by gradual adaptation of storage-phase medial gastrocnemius activity. However, this adaptation was not present during dual-task walking, indicating some level of cognitive involvement. The observed adaptation may be the result of using afferent feedback in order to optimize the contractile conditions of the plantarflexors during the stance phase. Such adaptation could serve to improve metabolic economy but may be limited in clinical populations with disrupted proprioception. C1 [Wellinghoff, Molly A.; Bunchman, Alison M.; Dean, Jesse C.] Med Univ S Carolina, Div Phys Therapy, Coll Hlth Profess, Charleston, SC 29425 USA. [Dean, Jesse C.] Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC USA. RP Dean, JC (reprint author), 77 President St,MSC700, Charleston, SC 29425 USA. EM deaje@musc.edu OI Dean, Jesse/0000-0003-2034-4217 FU Department of Veterans Affairs, Office of Research and Development, Rehabilitation Research and Development Service [1IK2RX000750-01A1]; National Institute of Child Health and Human Development [1R21 HD-064964-01A1] FX This study was partially supported by the Department of Veterans Affairs, Office of Research and Development, Rehabilitation Research and Development Service through Grant 1IK2RX000750-01A1. This study was also partially supported by the National Institute of Child Health and Human Development through Grant 1R21 HD-064964-01A1. NR 62 TC 1 Z9 1 U1 1 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD MAR PY 2014 VL 111 IS 5 BP 1120 EP 1131 DI 10.1152/jn.00251.2013 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA AG8LM UT WOS:000335669900022 PM 24335207 ER PT J AU Li, PY Tsai, TY Li, JS Wang, SB Zhang, Y Kwon, YM Rubash, HE Li, GA AF Li, Pingyue Tsai, Tsung-Yuan Li, Jing-Sheng Wang, Shaobai Zhang, Yu Kwon, Young-Min Rubash, Harry E. Li, Guoan TI Gender analysis of the anterior femoral condyle geometry of the knee SO KNEE LA English DT Article DE Anterior femoral condyle; TKA; Gender-specific knee ID ANATOMIC VARIATIONS; FEMALE KNEE; ARTHROPLASTY; DESIGN; STIFFNESS AB Background: No study has used 3-D anatomic knee models to investigate the gender differences in anterior femoral condyles. Therefore, this study aims to determine the morphologic differences between genders in anterior femoral condyles of the knees using 3-D anatomic knee models. Methods: Ninety-six male and sixty-five female 3D anatomic knee models were used to measure lateral and medial anterior condyle heights, anterior trochlear groove heights, and anterior condyle width, which were normalized by the anterior-posterior and medial-lateral dimensions of the knee, respectively. The shape of anterior condyle groove was also analyzed. Results: The mean lateral anterior condyle height, medial anterior condyle height and anterior condyle width of females were 6.6 +/- 1.8 mm, 2.0 +/- 2.3 mm, and 44.7 +/- 4.2 mm, respectively. These data were significantly smaller (p < 0.05) than those of males (7.7 +/- 1.8 mm, 2.9 +/- 2.0 mm and 50.0 +/- 3.4 mm). However, after normalizing by the femur size, the aspect ratios had no gender differences. Both the ranges of lateral and medial condyle of females were significantly smaller than those of males, and the geometry curve of anterior condyle was different between genders. Conclusion: Although the gender differences in anterior femoral condyle sizes no longer existed after normalization with the femur size, the shape and the peak position of anterior condyle groove still have gender differences. The data may have important implications on the current debate of gender-specific TKAs. (C) 2013 Elsevier B.V. All rights reserved. C1 [Li, Pingyue; Tsai, Tsung-Yuan; Li, Jing-Sheng; Wang, Shaobai; Kwon, Young-Min; Rubash, Harry E.; Li, Guoan] Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, Boston, MA 02114 USA. [Li, Pingyue; Tsai, Tsung-Yuan; Li, Jing-Sheng; Wang, Shaobai; Kwon, Young-Min; Rubash, Harry E.; Li, Guoan] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Li, Pingyue; Zhang, Yu] Guangzhou Mil Command, Guangzhou Gen Hosp, Dept Orthopaed Surg, Guangzhou 510010, Guangdong, Peoples R China. RP Li, GA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg,Bioengn Lab, 55 Fruit St,GRJ-1215, Boston, MA 02114 USA. EM gli1@partners.org OI Tsai, Tsung-Yuan/0000-0003-1522-2987 NR 22 TC 3 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0968-0160 EI 1873-5800 J9 KNEE JI Knee PD MAR PY 2014 VL 21 IS 2 BP 529 EP 533 DI 10.1016/j.knee.2013.12.001 PG 5 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA AG7SS UT WOS:000335619500036 PM 24462107 ER PT J AU Wang, W Tsai, TY Yue, B Kwon, YM Li, G AF Wang, Wei Tsai, Tsung-Yuan Yue, Bin Kwon, Young-Min Li, Guoan TI Posterior femoral condylar offsets of a Chinese population SO KNEE LA English DT Article DE Knee; Knee replacement; Arthroplasty; Posterior condylar offset; Posterior condylar offset ratio ID TOTAL KNEE ARTHROPLASTY; FLEXION; RANGE; KINEMATICS; DESIGN; MOTION; JOINTS; REPLACEMENT; PROSTHESES; PARAMETER AB Background: The effect of posterior condylar offset (PCO) on maximal flexion of the knee after TKA is controversial. Another parameter, the posterior condylar offset ratio (PCOR), has been recently introduced to describe the posterior condylar geometry. This study measured the posterior femoral condyle geometry of a Chinese population and compared with those of a Western population published in the literature. Methods: We measured the PCO and PCOR of 100 Chinese knees (50 males, 50 females). The distances from the anterior and posterior femoral shaft cortex line to the most posterior femoral condyle tangent line were defined as the anterior-posterior dimension (ACP) and posterior condylar offset (PCO). The PCOR was calculated as PCO/ACP. The measured PCO and PCOR were compared to those of a Western population reported in the literature. Results: The PCOs were 25.80 +/- 2.71 and 2732 +/- 234 mm for the Chinese females and males, respectively, where the PCO of the females was significantly smaller than that of the males (p < 0.05). The PCORs were 0.47 +/- 0.04 and 0.46 +/- 0.03 for the Chinese females and males, respectively, where the PCORs were similar among the Chinese males and females (p > 0.05). Conclusions: While the PCO of the Chinese females was smaller than that of the males, their PCORs were similar. Compared to the data of a Western population reported in literature, the PCO of the Chinese population is significantly smaller, but the PCOR is significantly larger. (c) 2013 Elsevier B.V. All rights reserved. C1 [Wang, Wei; Tsai, Tsung-Yuan; Kwon, Young-Min; Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, Boston, MA 02114 USA. [Wang, Wei] Xi An Jiao Tong Univ, Dept Orthopaed Surg, Affiliated Hosp 2, Sch Med, Xian 710049, Shaanxi Provinc, Peoples R China. [Yue, Bin] Shanghai Ninth Peoples Hosp, Dept Orthopaed Surg, Shanghai, Peoples R China. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org OI Tsai, Tsung-Yuan/0000-0003-1522-2987 FU Department of Orthpaedic Surgery of Massachusetts General Hospital; Interdisciplinary Research Fund of Xi'an Jiaotong University [8143027] FX The support of the Department of Orthpaedic Surgery of Massachusetts General Hospital and the Interdisciplinary Research Fund of Xi'an Jiaotong University (no. 8143027) was greatly appreciated. NR 30 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0968-0160 EI 1873-5800 J9 KNEE JI Knee PD MAR PY 2014 VL 21 IS 2 BP 553 EP 556 DI 10.1016/j.knee.2013.03.010 PG 4 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA AG7SS UT WOS:000335619500041 PM 23587633 ER PT J AU Blashill, AJ Safren, SA AF Blashill, Aaron J. Safren, Steven A. TI Sexual Orientation and Anabolic-Androgenic Steroids in US Adolescent Boys SO PEDIATRICS LA English DT Article DE sexual orientation; anabolic-androgenic steroids; adolescents; boys ID PROBLEM BEHAVIORS; DOPING AGENTS; MENTAL-HEALTH; DRUG-USE; MINORITY; ABUSE; GAY; VICTIMIZATION; METAANALYSIS; SUICIDALITY AB OBJECTIVES:We compared the lifetime prevalence of anabolic-androgenic steroid (AAS) misuse among sexual minority versus heterosexual US adolescent boys, and secondarily, sought to explore possible intermediate variables that may explain prevalence differences.METHODS:Participants were 17250 adolescent boys taken from a pooled data set of the 14 jurisdictions from the 2005 and 2007 Youth Risk Behavior Surveys that assessed sexual orientation. Data were analyzed for overall prevalence of AAS misuse and possible intermediary risk factors.RESULTS:Sexual minority adolescent boys were at an increased odds of 5.8 (95% confidence interval 4.1-8.2) to report a lifetime prevalence of AAS (21% vs 4%) compared with their heterosexual counterparts, P < .001. Exploratory analyses suggested that increased depressive symptoms/suicidality, victimization, and substance use contributed to this disparity.CONCLUSIONS:This is the first known study to test and find substantial health disparities in the prevalence of AAS misuse as a function of sexual orientation. Prevention and intervention efforts are needed for sexual minority adolescent boys. C1 [Blashill, Aaron J.; Safren, Steven A.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp,Fenway Inst, Boston, MA 02115 USA. RP Blashill, AJ (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM ablashill@mgh.harvard.edu FU Center for Population Research in LGBT Health at The Fenway Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development [R21HD051178]; National Institutes of Health (NIH) FX Supported by The Center for Population Research in LGBT Health at The Fenway Institute and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development under award R21HD051178. Investigator time was supported by K23MH096647 (Dr Blashill) and K24MH094214 (Dr Safren). Funded by the National Institutes of Health (NIH). NR 42 TC 13 Z9 13 U1 3 U2 10 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD MAR PY 2014 VL 133 IS 3 BP 469 EP 475 DI 10.1542/peds.2013-2768 PG 7 WC Pediatrics SC Pediatrics GA AG3PB UT WOS:000335330700015 PM 24488735 ER PT J AU Lavelle, TA Weinstein, MC Newhouse, JP Munir, K Kuhlthau, KA Prosser, LA AF Lavelle, Tara A. Weinstein, Milton C. Newhouse, Joseph P. Munir, Kerim Kuhlthau, Karen A. Prosser, Lisa A. TI Economic Burden of Childhood Autism Spectrum Disorders SO PEDIATRICS LA English DT Article DE cost of illness; health economics; autism spectrum disorder ID HEALTH-CARE EXPENDITURES; CHILDREN; COSTS; SERVICES; DIAGNOSIS; MEDICAID; PROFILE; IMPACT; US AB OBJECTIVE:To estimate the associations between autism spectrum disorder (ASD) diagnoses and service use, caregiver time, and cost outcomes.METHODS:We used national data from the Medical Expenditure Panel Survey linked to the National Health Interview Survey and a study-specific survey to estimate the annual utilization and costs for health care, school, ASD-related therapy, family-coordinated services, as well as caregiver time in children aged 3 to 17 years, with and without parent-reported ASD. Regression analyses estimated the association between ASD diagnosis and cost, controlling for child gender, age, race/ethnicity, insurance status, household income, country region and urban/rural classification, and non-ASD-related illnesses.RESULTS:Children with parent-reported ASD had higher levels of health care office visits and prescription drug use compared with children without ASD (P < .05). A greater proportion of children in the ASD group used special educational services (76% vs 7% in the control group, P < .05). After adjusting for child demographic characteristics and non-ASD-associated illnesses, ASD was associated with $3020 (95% confidence interval [CI]: $1017-$4259) higher health care costs and $14061 (95% CI: $4390-$24302) higher aggregate non-health care costs, including $8610 (95% CI: $6595-$10421) higher school costs. In adjusted analyses, parents who reported that their child had ASD did not have significantly higher out-of-pocket costs or spend more time on caregiving activities compared with control parents.CONCLUSIONS:The economic burden associated with ASD is substantial and can be measured across multiple sectors of our society. Previous analyses that focused on health care underestimated this economic burden, particularly for school systems. C1 [Lavelle, Tara A.] Harvard Univ, PhD Program Hlth Policy, Cambridge, MA 02138 USA. [Weinstein, Milton C.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Newhouse, Joseph P.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Munir, Kerim] Boston Childrens Hosp, Div Dev Med, Boston, MA USA. [Kuhlthau, Karen A.] Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Res & Policy, Boston, MA 02114 USA. [Prosser, Lisa A.] Univ Michigan Hlth Syst, Div Gen Pediat, Child Hlth Evaluat & Res Unit, Ann Arbor, MI USA. RP Lavelle, TA (reprint author), RAND Corp, 1200 South Hayes St, Arlington, VA 22202 USA. EM tlavelle@rand.org RI Munir, Kerim/D-6910-2015 OI Munir, Kerim/0000-0002-2404-1806 FU National Institute of Mental Health [5T32MH019733-18]; Harvard University's Center for American Political Studies; National Institute of Mental Health Research Training Program in Mental Health and Developmental Disabilities at Boston Children's Hospital [R25 MH071286]; National Institute for Nursing Research [7-R01-NR-011880-03]; Harvard University Graduate School of Arts and Sciences; Nancy Lurie Marks Foundation FX Funding for this study was provided by the National Institute of Mental Health (5T32MH019733-18), Harvard University's Center for American Political Studies, the National Institute of Mental Health Research Training Program in Mental Health and Developmental Disabilities at Boston Children's Hospital (R25 MH071286), National Institute for Nursing Research (7-R01-NR-011880-03), Harvard University Graduate School of Arts and Sciences, and the Nancy Lurie Marks Foundation. NR 48 TC 34 Z9 34 U1 7 U2 26 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD MAR PY 2014 VL 133 IS 3 BP E520 EP E529 DI 10.1542/peds.2013-0763 PG 10 WC Pediatrics SC Pediatrics GA AG3PB UT WOS:000335330700025 PM 24515505 ER PT J AU Vacas-Jacques, P Linnes, J Young, A Gerrard, V Gomez-Marquez, J AF Vacas-Jacques, Paulino Linnes, Jacqueline Young, Anna Gerrard, Victoria Gomez-Marquez, Jose TI Portable digital lock-in instrument to determine chemical constituents with single-color absorption measurements for Global Health Initiatives SO REVIEW OF SCIENTIFIC INSTRUMENTS LA English DT Article ID LOW-COST AB Innovations in international health require the use of state-of-the-art technology to enable clinical chemistry for diagnostics of bodily fluids. We propose the implementation of a portable and affordable lock-in amplifier-based instrument that employs digital technology to perform biochemical diagnostics on blood, urine, and other fluids. The digital instrument is composed of light source and optoelectronic sensor, lock-in detection electronics, microcontroller unit, and user interface components working with either power supply or batteries. The instrument performs lock-in detection provided that three conditions are met. First, the optoelectronic signal of interest needs be encoded in the envelope of an amplitude-modulated waveform. Second, the reference signal required in the demodulation channel has to be frequency and phase locked with respect to the optoelectronic carrier signal. Third, the reference signal should be conditioned appropriately. We present three approaches to condition the signal appropriately: high-pass filtering the reference signal, precise offset tuning the reference level by low-pass filtering, and by using a voltage divider network. We assess the performance of the lock-in instrument by comparing it to a benchmark device and by determining protein concentration with single-color absorption measurements. We validate the concentration values obtained with the proposed instrument using chemical concentration measurements. Finally, we demonstrate that accurate retrieval of phase information can be achieved by using the same instrument. (C) 2014 AIP Publishing LLC. C1 [Vacas-Jacques, Paulino; Linnes, Jacqueline; Young, Anna; Gerrard, Victoria; Gomez-Marquez, Jose] SUTD MIT Int Design Ctr, Little Devices Grp, Cambridge, MA 02139 USA. [Vacas-Jacques, Paulino] Wellman Ctr Photomed, Boston, MA 02114 USA. [Vacas-Jacques, Paulino] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Linnes, Jacqueline] Boston Univ, Biomed Engn Dept, Boston, MA 02215 USA. [Gerrard, Victoria] Singapore Univ Technol & Design, Opportun Lab, Singapore 138682, Singapore. RP Vacas-Jacques, P (reprint author), SUTD MIT Int Design Ctr, Little Devices Grp, Cambridge, MA 02139 USA. RI Linnes, Jacqueline/D-3964-2016 OI Linnes, Jacqueline/0000-0003-4962-0908 NR 16 TC 1 Z9 1 U1 0 U2 10 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0034-6748 EI 1089-7623 J9 REV SCI INSTRUM JI Rev. Sci. Instrum. PD MAR PY 2014 VL 85 IS 3 AR 033103 DI 10.1063/1.4867097 PG 7 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA AH1ZL UT WOS:000335920400004 PM 24689560 ER PT J AU Pessler, F Ogdie, AR Mayer, CT Kretzschmar, WW Dai, L Elsaman, AM Einhorn, E Krenn, V Schumacher, HR AF Pessler, Frank Ogdie, Alexis R. Mayer, Christian T. Kretzschmar, Warren W. Dai, Lie Elsaman, Ahmed M. Einhorn, Eugene Krenn, Veit Schumacher, H. Ralph TI Amyloid arthropathy associated with multiple myeloma: polyarthritis without synovial infiltration of CD20+or CD38+cells SO AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS LA English DT Article DE Amyloidosis; arthritis; B cells; multiple myeloma; plasma cells; synovitis ID WAR-VETERANS-ILLNESS; JOINT PAIN; DISEASE; ARTHRITIS AB Objectives: To describe histological, immunohistochemical and ultrastructural features of synovial biopsies of amyloid arthropathy associated with multiple myeloma (MM). Methods: Synovial biopsies from affected joints of two patients with MM and amyloid arthropathy were examined with light and electron microscopy, and immunohistochemically for expression of CD3, CD8, CD20, CD38, CD68, Ki-67 and vWF. Results were compared to values from osteoarthritis (OA, n=26), rheumatoid arthritis (RA, n=24) and normal (n=15) synovial membranes. Results: There was no or only mild lining hyperplasia. Vascular density was not elevated, and there were few Ki-67+ proliferating cells in the stroma. The Krenn synovitis score classified one specimen as "low-grade'' and one as "high-grade'' synovitis. CD68+ and CD3+ cells were the predominant mononuclear inflammatory cells, whereas CD20+ and CD38+ cells were absent from both synovial membrane and synovial fluid sediment. Electron microscopy demonstrated amyloid phagocytosis by synovial macrophages. In hierarchical clustering the two amyloid arthropathy specimens were more closely related to OA than to RA or normal synovium. Conclusions: This first detailed immunohistological analysis of MM-associated amyloid arthropathy suggests that it is a chronic synovitis that evolves despite the loss of humoral immunity seen in advanced MM. Instead, amyloid phagocytosis by synovial macrophages likely triggers and perpetuates local disease. C1 [Pessler, Frank; Mayer, Christian T.] TWINCORE Ctr Expt & Clin Infect Res, D-30625 Hannover, Germany. [Pessler, Frank; Elsaman, Ahmed M.] Helmholtz Ctr Infect Res, Braunschweig, Germany. [Ogdie, Alexis R.; Dai, Lie; Schumacher, H. Ralph] Univ Penn, Div Rheumatol, Philadelphia, PA 19104 USA. [Kretzschmar, Warren W.] Wellcome Trust Ctr Human Genet, Oxford, England. [Dai, Lie] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Rheumatol, Guangzhou 510275, Guangdong, Peoples R China. [Elsaman, Ahmed M.] Sohag Univ, Dept Rheumatol & Rehabil, Sohag, Egypt. [Einhorn, Eugene] Philadelphia VA Med Ctr, Dept Pathol, Philadelphia, PA USA. [Krenn, Veit] Ctr Histol Cytol & Mol Diagnost, Trier, Germany. [Schumacher, H. Ralph] Philadelphia VA Med Ctr, Div Rheumatol, Philadelphia, PA USA. RP Pessler, F (reprint author), TWINCORE Ctr Expt & Clin Infect Res, Feodor Lynen Str 7-9, D-30625 Hannover, Germany. EM frank.pessler@twincore.de OI Kretzschmar, Warren/0000-0002-2575-0807; Ogdie, Alexis/0000-0002-4639-0775 FU American College of Rheumatology/Research; Education Foundation Health Professional Graduate Student Research Preceptorship award; Wellcome Trust [09730/Z/11/Z]; German-Egyptian Scientific Projects (GESP) from the German Academic Exchange Service (DAAD) [51309219]; Ministry of Higher Education and Scientific Research of the Arab Republic of Egypt; Helmholtz Association FX C. T. Mayer was supported by an American College of Rheumatology/Research and Education Foundation Health Professional Graduate Student Research Preceptorship award. WWK is supported by a Wellcome Trust studentship (09730/Z/11/Z). AME was supported by German-Egyptian Scientific Projects (GESP) grant no. 51309219 from the German Academic Exchange Service (DAAD) and the Ministry of Higher Education and Scientific Research of the Arab Republic of Egypt. The study was supported in part by funds from the Helmholtz Association (Programs in Infection and Immunity and in Individualized Medicine, iMed). The study was approved by the Institutional Review Board of the Philadelphia VA Medical Center as part of a larger study of synovial histopathology. The need to obtain informed consent was waived due to the use of anonymized data. NR 21 TC 1 Z9 2 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1350-6129 EI 1744-2818 J9 AMYLOID JI Amyloid-J. Protein Fold. Disord. PD MAR PY 2014 VL 21 IS 1 BP 28 EP 34 DI 10.3109/13506129.2013.862229 PG 7 WC Biochemistry & Molecular Biology; Medicine, General & Internal; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; General & Internal Medicine; Research & Experimental Medicine GA AG9UB UT WOS:000335764200005 PM 24286442 ER PT J AU Tan, ASL Gibson, L Zafar, HM Gray, SW Hornik, RC Armstrong, K AF Tan, Andy S. L. Gibson, Laura Zafar, Hanna M. Gray, Stacy W. Hornik, Robert C. Armstrong, Katrina TI Associations between Cancer-Related Information Seeking and Receiving PET Imaging for Routine Cancer Surveillance-An Analysis of Longitudinal Survey Data SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; BREAST-CANCER; MAXIMUM-LIKELIHOOD; COLORECTAL-CANCER; MISSING DATA; CLINICAL-ONCOLOGY; AMERICAN-SOCIETY; FOLLOW-UP; FDG PET; CARE AB Background: Routine cancer surveillance with positron emission tomography (PET) is not recommended for most patients who have completed curative treatment for cancer. Yet, recent trends suggest that PET is increasingly used for follow-up among patients with cancer. This study investigates whether informationseeking behaviors predicted self-reported utilization of PET for routine surveillance in patients with colorectal, breast, and prostate cancer. Methods: We conducted annual surveys for 3 years in a cohort of Pennsylvania cancer survivors diagnosed with colorectal, breast, or prostate cancer in 2005. The outcome was self-reported PET receipt for routine surveillance among 944 patients diagnosed with nonmetastatic disease (stages 0-III). Predictors included cancer-related information seeking from nonmedical sources and providers. Weighted multiple logistic regression analyses were performed. Results: In this population, 11% of patients reported receiving at least one PET scan for routine follow-up in a 12-month period several years after diagnosis. Seeking cancer-related information from nonmedical sources was associated with higher odds of subsequent reported PET use [OR, 3.7; 95% confidence interval (CI), 1.112.1; P 0.032], after adjusting for potential confounders. Patient engagement with physicians about cancerrelated information was not a significant predictor. Conclusions: Overall reported PET utilization for routine surveillance of colorectal, breast, and prostate cancer is low. However, we found a significant association with information seeking from nonmedical sources but not from providers. Impact: Exposure to cancer-related information through mass media and lay interpersonal sources may be driving inappropriate utilization of high-cost advanced imaging procedures. These findings have important implications for cancer survivors, healthcare providers, and health policy. C1 [Tan, Andy S. L.; Gibson, Laura; Hornik, Robert C.] Univ Penn, Annenberg Sch Commun, Ctr Excellence Canc Commun Res, Philadelphia, PA 19104 USA. [Zafar, Hanna M.] Hosp Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Gray, Stacy W.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Ctr Community Based Res, Boston, MA 02115 USA. [Armstrong, Katrina] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Tan, ASL (reprint author), Univ Penn, Annenberg Sch Commun, 3620 Walnut St, Philadelphia, PA 19104 USA. EM andytan@alumni.upenn.edu OI Tan, Andy/0000-0001-6459-6171; Hornik, Robert/0000-0002-2148-8805 FU National Cancer Institute [P50CA095856, P20CA095856]; L.Gibson [P20CA095856] FX This work was supported by the National Cancer Institute grant nos. P50CA095856 (to R.C.Hornik) and P20CA095856 (to R.C.Hornik and K.Armstrong).A.S.L.Tan and L.Gibson were supported for this work by P20CA095856.; The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.Section 1734 solely to indicate this fact. NR 49 TC 1 Z9 1 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2014 VL 23 IS 3 BP 481 EP 489 DI 10.1158/1055-9965.EPI-13-0999 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AG0ZO UT WOS:000335144700014 PM 24550351 ER PT J AU Buys, E Sips, P AF Buys, Emmanuel Sips, Patrick TI New insights into the role of soluble guanylate cyclase in blood pressure regulation SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE hypertension; soluble guanylate cyclase; nitric oxide; redox; vasodilation ID PULMONARY ARTERIAL-HYPERTENSION; CYCLIC GUANOSINE-MONOPHOSPHATE; H-NOX DOMAIN; NITRIC-OXIDE; CARBON-MONOXIDE; ENDOTHELIAL DYSFUNCTION; S-NITROSYLATION; TUBULOGLOMERULAR FEEDBACK; CARDIOVASCULAR-RESPONSES; NITROSATIVE STRESS AB Purpose of review Nitric oxide (NO)-soluble guanylate cyclase (sGC)-dependent signaling mechanisms have a profound effect on the regulation of blood pressure (BP). In this review, we will discuss recent findings in the field that support the importance of sGC in the development of hypertension. Recent findings The importance of sGC in BP regulation was highlighted by studies using genetically modified animal models, chemical stimulators/activators and inhibitors of the NO/sGC signaling pathway, and genetic association studies in humans. Many studies further support the role of NO/sGC in vasodilation and vascular dysfunction, which is underscored by the early clinical success of synthetic sGC stimulators for the treatment of pulmonary hypertension. Recent work has uncovered more details about the structural basis of sGC activation, enabling the development of more potent and efficient modulators of sGC activity. Finally, the mechanisms involved in the modulation of sGC by signaling gases other than NO, as well as the influence of redox signaling on sGC, have been the subject of several interesting studies. sGC is fast becoming an interesting therapeutic target for the treatment of vascular dysfunction and hypertension, with novel sGC stimulating/activating compounds as promising clinical treatment options. C1 [Buys, Emmanuel] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Sips, Patrick] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med, Boston, MA 02115 USA. RP Sips, P (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St,Thorn 1123, Boston, MA 02115 USA. EM psips@partners.org OI Sips, Patrick/0000-0001-9241-5980 FU NIH [R01 EY022746-01, R01 HL113933-01A1, R01-HL110378-01A1, U54 NS079201-02]; American Heart Association [10SDG2610313] FX E.B. was supported by NIH grants R01 EY022746-01, R01 HL113933-01A1, and R01-HL110378-01A1, and by a Scientist Development Grant from the American Heart Association 10SDG2610313. P. S. received support from NIH grant U54 NS079201-02. NR 73 TC 6 Z9 7 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 EI 1473-6543 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD MAR PY 2014 VL 23 IS 2 BP 135 EP 142 DI 10.1097/01.mnh.0000441048.91041.3a PG 8 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA AG1FF UT WOS:000335159800007 PM 24419369 ER PT J AU Belayev, LY Palevsky, PM AF Belayev, Linda Y. Palevsky, Paul M. TI The link between acute kidney injury and chronic kidney disease SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE chronic kidney disease; epidemiology; acute kidney injury ID ACUTE-RENAL-FAILURE; ACUTE TUBULAR-NECROSIS; CHRONIC DIALYSIS; FOLLOW-UP; RISK; PROGRESSION; DEATH; OUTCOMES; INCREASES; FIBROSIS AB Purpose of review It has been argued that the existing epidemiologic data are insufficient to establish a causal link between acute kidney injury (AKI) and subsequent development or progression of chronic kidney disease (CKD), especially given that risk factors for the development of AKI overlap with those for progressive CKD. Recent findings Multiple studies published over the past 5 years have demonstrated a strong epidemiologic association between episodes of AKI and subsequent development or progression of CKD, including evidence that severity of AKI and repeated episodes of AKI are associated with increased risk of CKD. In addition, animal models have provided evidence for a biological basis linking episodes of AKI with CKD. The preponderance of data support a causal link between episodes of AKI and subsequent development or progression of CKD. C1 [Belayev, Linda Y.; Palevsky, Paul M.] Univ Pittsburgh, Sch Med, Renal Electrolyte Div, Pittsburgh, PA USA. [Palevsky, Paul M.] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA 15240 USA. RP Palevsky, PM (reprint author), VA Pittsburgh Healthcare Syst, Room 7E123 111F U,Univ Dr, Pittsburgh, PA 15240 USA. EM Palevsky@pitt.edu OI Palevsky, Paul/0000-0002-7334-5400 FU NIDDK NIH HHS [T32 DK061296] NR 35 TC 17 Z9 18 U1 3 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 EI 1473-6543 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD MAR PY 2014 VL 23 IS 2 BP 149 EP 154 DI 10.1097/01.mnh.0000441051.36783.f3 PG 6 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA AG1FF UT WOS:000335159800009 PM 24384553 ER PT J AU Bhan, I AF Bhan, Ishir TI Phosphate management in chronic kidney disease SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE phosphate binders; hyperphosphatemia; mineral and bone disease; chronic kidney disease ID CALCIUM ACETATE/MAGNESIUM CARBONATE; INCIDENT HEMODIALYSIS-PATIENTS; RANDOMIZED CLINICAL-TRIAL; STAGE RENAL-DISEASE; MAINTENANCE HEMODIALYSIS; SEVELAMER-HYDROCHLORIDE; LANTHANUM CARBONATE; PHOSPHORUS BINDERS; SERUM PHOSPHATE; HYPERPHOSPHATEMIA AB Purpose of review The review focuses on the rationale and evidence behind management strategies for hyperphosphatemia in patients with chronic kidney disease (CKD). Recent findings Optimal management of phosphate in CKD remains an area of uncertainty, but multiple studies now point to a clinical benefit from the use of phosphate binders. Evidence of improved survival is particularly strong with sevelamer, though it remains unclear whether the absence of calcium or other properties of sevelamer are responsible for this relationship. Newer agents, such as iron-based binders or niacin compounds to inhibit phosphorus absorption, may have additional benefits which will be better defined with additional experience. A reduced pill count may be a particularly beneficial characteristic of newer agents, and has been associated with improved response to therapy. Increased use of frequent, nocturnal hemodialysis is an additional tool to help ameliorate phosphate control. Data on the reduction of fibroblast growth factor 23 through use of phosphate binders remain weak. An improved understanding of phosphate regulation and the development of new therapeutic agents have reinvigorated a once stagnant field, but significant changes to practice cannot yet be justified. There is increasing support for using sevelamer in place of calcium-based binders, though economic practicability remains challenging. C1 [Bhan, Ishir] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. RP Bhan, I (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 39 TC 2 Z9 2 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 EI 1473-6543 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD MAR PY 2014 VL 23 IS 2 BP 174 EP 179 DI 10.1097/01.mnh.0000441155.47696.41 PG 6 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA AG1FF UT WOS:000335159800013 PM 24445424 ER PT J AU Naylor, MG Cardenas, VA Tosun, D Schuff, N Weiner, M Schwartzman, A AF Naylor, Melissa G. Cardenas, Valerie A. Tosun, Duygu Schuff, Norbert Weiner, Michael Schwartzman, Armin TI Voxelwise multivariate analysis of multimodality magnetic resonance imaging SO HUMAN BRAIN MAPPING LA English DT Article DE multiple comparisons; diffusion tensor imaging; structural magnetic resonance imaging; multivariate analysis; Alzheimer's disease; perfusion weighted magnetic resonance imaging; multimodality imaging ID CANONICAL CORRELATION-ANALYSIS; ALZHEIMERS-DISEASE; REGRESSION AB Most brain magnetic resonance imaging (MRI) studies concentrate on a single MRI contrast or modality, frequently structural MRI. By performing an integrated analysis of several modalities, such as structural, perfusion-weighted, and diffusion-weighted MRI, new insights may be attained to better understand the underlying processes of brain diseases. We compare two voxelwise approaches: (1) fitting multiple univariate models, one for each outcome and then adjusting for multiple comparisons among the outcomes and (2) fitting a multivariate model. In both cases, adjustment for multiple comparisons is performed over all voxels jointly to account for the search over the brain. The multivariate model is able to account for the multiple comparisons over outcomes without assuming independence because the covariance structure between modalities is estimated. Simulations show that the multivariate approach is more powerful when the outcomes are correlated and, even when the outcomes are independent, the multivariate approach is just as powerful or more powerful when at least two outcomes are dependent on predictors in the model. However, multiple univariate regressions with Bonferroni correction remain a desirable alternative in some circumstances. To illustrate the power of each approach, we analyze a case control study of Alzheimer's disease, in which data from three MRI modalities are available. Hum Brain Mapp 35:831-846, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Naylor, Melissa G.; Schwartzman, Armin] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Naylor, Melissa G.] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. [Cardenas, Valerie A.; Tosun, Duygu; Schuff, Norbert; Weiner, Michael] Dept Vet Affairs Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA USA. [Cardenas, Valerie A.; Tosun, Duygu; Schuff, Norbert; Weiner, Michael] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Schwartzman, Armin] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Naylor, MG (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM mgn@uchicago.edu OI Schwartzman, Armin/0000-0001-5335-1611 FU National Institute of Health [T32 MH017119, U01 HL089856, R01 MH081862, R01 MH087590, R21EB013795, R01 CA157528]; NIH [R03EB008136, P41EB015904, P50AG023501, P01AG19724] FX Contract grant sponsor: National Institute of Health; Contract grant numbers: T32 MH017119, U01 HL089856, R01 MH081862, R01 MH087590, R21EB013795, and R01 CA157528; Contract grant sponsor: NIH, administered by the Northern California Institute for Research and Education, with resources of the Veterans Affairs Medical Center, San Francisco, California; Contract grant numbers: R03EB008136, P41EB015904, P50AG023501, and P01AG19724. NR 25 TC 5 Z9 5 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD MAR PY 2014 VL 35 IS 3 BP 831 EP 846 DI 10.1002/hbm.22217 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AF0IW UT WOS:000334398500008 PM 23408378 ER PT J AU Ward, AM Schultz, AP Huijbers, W Van Dijk, KRA Hedden, T Sperling, RA AF Ward, Andrew M. Schultz, Aaron P. Huijbers, Willem Van Dijk, Koene R. A. Hedden, Trey Sperling, Reisa A. TI The parahippocampal gyrus links the default-mode cortical network with the medial temporal lobe memory system SO HUMAN BRAIN MAPPING LA English DT Article DE brain networks; functional connectivity; human; Magnetic Resonance Imaging; young adult; brain mapping; resting state; physiology; MTL; Mediation ID INTRINSIC FUNCTIONAL CONNECTIVITY; RESTING-STATE NETWORKS; INDEPENDENT COMPONENT ANALYSIS; MILD COGNITIVE IMPAIRMENT; FALSE DISCOVERY RATE; ALZHEIMERS-DISEASE; HUMAN BRAIN; RECOGNITION MEMORY; HIPPOCAMPAL-FORMATION; SENSORY STIMULATION AB The default-mode network (DMN) is a distributed functional-anatomic network implicated in supporting memory. Current resting-state functional connectivity studies in humans remain divided on the exact involvement of medial temporal lobe (MTL) in this network at rest. Notably, it is unclear to what extent the MTL regions involved in successful memory encoding are connected to the cortical nodes of the DMN during resting state. Our findings using functional connectivity MRI analyses of resting-state data indicate that the parahippocampal gyrus (PHG) is the primary hub of the DMN in the MTL during resting state. Also, connectivity of the PHG is distinct from connectivity of hippocampal regions identified by an associative memory-encoding task. We confirmed that several hippocampal encoding regions lack significant functional connectivity with cortical DMN nodes during resting state. Additionally, a mediation analysis showed that resting-state connectivity between the hippocampus and posterior cingulate cortex-a major hub of the DMN-is indirect and mediated by the PHG. Our findings support the hypothesis that the MTL memory system represents a functional subnetwork that relates to the cortical nodes of the DMN through parahippocampal functional connections. Hum Brain Mapp 35:1061-1073, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Ward, Andrew M.; Huijbers, Willem; Sperling, Reisa A.] Harvard Univ, Sch Med, Dept Neurol, Brigham & Womens Hosp, Boston, MA 02115 USA. [Ward, Andrew M.; Schultz, Aaron P.; Huijbers, Willem; Sperling, Reisa A.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Ward, Andrew M.; Schultz, Aaron P.; Huijbers, Willem; Van Dijk, Koene R. A.; Hedden, Trey; Sperling, Reisa A.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Van Dijk, Koene R. A.; Hedden, Trey] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Van Dijk, Koene R. A.] Harvard Univ, Dept Psychol, Ctr Brain Sci, Cambridge, MA 02138 USA. [Sperling, Reisa A.] Ctr Alzheimer Res & Treatment, Boston, MA USA. RP Sperling, RA (reprint author), Sperling, 221 Longwood Ave, Boston, MA 02115 USA. EM rsperling@rics.bwh.harvard.edu RI Van Dijk, Koene/G-3317-2012; OI Van Dijk, Koene/0000-0001-6137-4282; Ward, Andrew/0000-0001-6948-4814 FU NIA [AG027435, P01AG036694, P50 AG005134, K24 AG035007, NS002189, K01 AG040197]; European Molecular Biology Organization [ALTF 318-2011]; Fidelity Medical Foundation; Harvard NeuroDiscovery Center; American Health Assistance Foundation FX Contract grant sponsor: NIA; Contract grant numbers: AG027435, P01AG036694, P50 AG005134, K24 AG035007, NS002189, K01 AG040197; Contract grant sponsor: the European Molecular Biology Organization; Contract grant number: ALTF 318-2011 ( W. H.); Contract grant sponsor: the Fidelity Medical Foundation; the Harvard NeuroDiscovery Center; and the American Health Assistance Foundation. NR 104 TC 49 Z9 49 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD MAR PY 2014 VL 35 IS 3 BP 1061 EP 1073 DI 10.1002/hbm.22234 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AF0IW UT WOS:000334398500025 PM 23404748 ER PT J AU Leritz, EC Shepel, J Williams, VJ Lipsitz, LA McGlinchey, RE Milberg, WP Salat, DH AF Leritz, Elizabeth C. Shepel, Juli Williams, Victoria J. Lipsitz, Lewis A. McGlinchey, Regina E. Milberg, William P. Salat, David H. TI Associations between T-1 white matter lesion volume and regional white matter microstructure in aging SO HUMAN BRAIN MAPPING LA English DT Article DE white matter lesions; diffusion tensor imaging; aging; white matter microstructure ID HUMAN CEREBRAL-CORTEX; MAGNETIC-RESONANCE IMAGES; SURFACE-BASED ANALYSIS; DIFFUSION TENSOR MRI; HEALTHY OLDER-ADULTS; MULTIPLE-SCLEROSIS; ALZHEIMERS-DISEASE; BLOOD-PRESSURE; NEUROPSYCHOLOGICAL IMPAIRMENT; COGNITIVE IMPAIRMENT AB White matter lesions, typically manifesting as regions of signal intensity abnormality (WMSA) on MRI, increase in frequency with age. However, the role of this damage in cognitive decline and disease is still not clear, as lesion volume has only loosely been associated with clinical status. Diffusion tensor imaging (DTI) has been used to examine the quantitative microstructural integrity of white matter, and has applications in the examination of subtle changes to tissue that appear visually normal on conventional imaging. The primary goal of this study was to determine whether major macrostructural white matter damage, (total WMSA volume), is associated with microstructural integrity of normal appearing white matter, and if these macrostructural changes fully account for microstructural changes. Imaging was performed in 126 nondemented individuals, ages 43-85 years, with no history of cerebrovascular disease. Controlling for age, greater WMSA volume was associated with decreased fractional anisotropy (FA) in widespread brain regions. Patterns were similar for FA and radial diffusivity but in contrast, WMSA was associated with axial diffusivity in fewer areas. Age was associated with FA in several regions, and many of these effects remained even when controlling for WMSA volume, suggesting the etiology of WMSAs does not fully account for all age-associated white matter deterioration. These results provide evidence that WMSA volume is associated with the integrity of normal-appearing white matter. In addition, our results suggest that overt lesions may not account for the association of increasing age with decreased white matter tissue integrity. Hum Brain Mapp 35:1085-1100, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Leritz, Elizabeth C.; Shepel, Juli; Williams, Victoria J.; McGlinchey, Regina E.; Milberg, William P.; Salat, David H.] VA Boston Healthcare Syst, GRECC, Boston, MA USA. [Leritz, Elizabeth C.; Shepel, Juli; Williams, Victoria J.; McGlinchey, Regina E.; Milberg, William P.; Salat, David H.] VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr NeRVe, Boston, MA USA. [Leritz, Elizabeth C.; Shepel, Juli; Williams, Victoria J.; McGlinchey, Regina E.; Milberg, William P.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Leritz, Elizabeth C.; McGlinchey, Regina E.; Milberg, William P.; Salat, David H.] Harvard Univ, Sch Med, Boston, MA USA. [Leritz, Elizabeth C.; Shepel, Juli; Williams, Victoria J.; Salat, David H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Lipsitz, Lewis A.] Beth Israel Deaconness Med Ctr, Boston, MA USA. RP Leritz, EC (reprint author), 150 South Huntington Ave,GRECC 182 JP, Boston, MA 02130 USA. EM bleritz@nmr.mgh.harvard.edu RI McGlinchey, Regina/R-1971-2016 FU National Institute of Neurologic Disorders and Stroke [K23NS062148]; National Institute of Nursing Research [R01NR010827]; National Institute on Aging [P60AG08812, P01AG004390]; Medical Research Service VA FX Contract grant sponsor: National Institute of Neurologic Disorders and Stroke; Contract grant number: K23NS062148; Contract grant sponsor: National Institute of Nursing Research; Contract grant number: R01NR010827; Contract grant sponsor: National Institute on Aging; Contract grant number: P60AG08812 and P01AG004390; Contract grant sponsor: Medical Research Service VA (Merit Review Awards to W.M. and R.McG.). NR 93 TC 15 Z9 16 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD MAR PY 2014 VL 35 IS 3 BP 1085 EP 1100 DI 10.1002/hbm.22236 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AF0IW UT WOS:000334398500027 PM 23362153 ER PT J AU Chan, NK Abdullah, KG Lubelski, D Steinmetz, MP Benzel, EC Shin, JH Mroz, TE AF Chan, N. K. Abdullah, K. G. Lubelski, D. Steinmetz, M. P. Benzel, E. C. Shin, J. H. Mroz, T. E. TI Stereotactic radiosurgery for metastatic spine tumors SO JOURNAL OF NEUROSURGICAL SCIENCES LA English DT Review DE Spinal cord neoplasms, radiotherapy; Radiosurgery; Spinal neoplasms, secondary; Spinal neoplasms, surgery ID INTENSITY-MODULATED RADIOTHERAPY; ONCOLOGY STUDY-GROUP; CORD COMPRESSION; BODY RADIOTHERAPY; CYBERKNIFE RADIOSURGERY; CLINICAL-EXPERIENCE; RADIATION-THERAPY; PARASPINAL TUMORS; SINGLE-SESSION; PAIN-CONTROL AB Spinal metastases invariably affect the majority of patients with cancer. Many will develop symptoms related to pain and disability from epidural spinal cord compression as well as pathologic fracture of the vertebrae. With the emergence of targeted systemic therapies and a better understanding of cancer biology, patients are living longer with bony metastases. This poses particular challenges, as palliation of pain and maintenance of local tumor control are paramount to quality of life and overall functional independence for these patients. Stereotactic radiosurgery (SRS) has emerged as a potent primary standalone and adjuvant treatment option for spinal metastases. To date, the primary indications for SRS include 1) upfront standalone treatment for painful bony metastases in the oligometastatic patient, 2) standalone or post-operative treatment following progression or recurrence of local disease despite previous conventional external beam radiation therapy (cEBRT), and 3) following surgery during which epidural disease is decompressed and the spine stabilized when indicated. SRS has demonstrated a significant advantage over cEBRT for tumors traditionally regarded as relatively radioresistant such as sarcoma, melanoma, renal cell carcinoma, non-small cell lung cancer and colon carcinoma.9 The radiobiological advantage of increased tumoricidal dose delivery and spinal cord dose sparing in SRS have made this a powerful treatment alternative to cEBRT particularly within the context of re-irradiation. Given the limitations of spinal cord dose constraints, surgery is still the first-line therapy in patients with high-grade epidural spinal cord compression (ESCC). Epidural compression can be treated with SRS, however this risks radiation-induced myelopathy and challenges the safety of effective dose delivery at the du-ral margin.(11) With increasing dose, radiation-induced vertebral fracture is the most serious and prevalent side effect of SRS.(53) An overview of SRS, including the most common indications, complications, and outcomes for spinal metastases are presented here. C1 [Chan, N. K.; Abdullah, K. G.; Lubelski, D.; Benzel, E. C.; Mroz, T. E.] Cleveland Clin, Ctr Spine Hlth, Cleveland, OH 44195 USA. [Chan, N. K.; Abdullah, K. G.; Lubelski, D.; Benzel, E. C.; Mroz, T. E.] Cleveland Clin, Dept Neurol Surg, Cleveland, OH 44195 USA. [Chan, N. K.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Abdullah, K. G.; Lubelski, D.; Benzel, E. C.; Mroz, T. E.] Cleveland Clin, Lerner Coll Med, Cleveland, OH 44195 USA. [Abdullah, K. G.] MetroHlth Med Ctr, Dept Neurosurg, Cleveland, OH USA. [Steinmetz, M. P.] Hosp Univ Penn, Dept Neurosurg, Philadelphia, PA 19104 USA. [Shin, J. H.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Mroz, TE (reprint author), Cleveland Clin, Dept Orthoped, Ctr Spine Hlth, 9500 Euclid Ave,S-40, Cleveland, OH 44195 USA. EM mrozt@ccf.org NR 53 TC 4 Z9 4 U1 1 U2 2 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0390-5616 EI 1827-1855 J9 J NEUROSURG SCI JI J. Neurosurg. Sci. PD MAR PY 2014 VL 58 IS 1 BP 37 EP 44 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AG4CK UT WOS:000335366600006 PM 24614791 ER PT J AU Pagoto, SL Schneider, KL Oleski, J Smith, B Bauman, M AF Pagoto, Sherry L. Schneider, Kristin L. Oleski, Jessica Smith, Brian Bauman, Michael TI The Adoption and Spread of a Core-Strengthening Exercise Through an Online Social Network SO JOURNAL OF PHYSICAL ACTIVITY & HEALTH LA English DT Article DE Twitter; exercise; social networks ID PHYSICAL-ACTIVITY; CONTROLLED-TRIAL; UNITED-STATES; PREVALENCE; SUPPORT; ADULTS AB Background: The present feasibility study describes engagement and spread of a Twitter-based core-strengthening challenge. Methods: A challenge that entailed completing a core-strengthening exercise using a hashtag (#PlankADay) was circulated via Twitter. This study surveyed users who joined during the first 2 months of the challenge to describe their characteristics, including social support for exercise and to what extent they invited others to join. The study continued to track total users for 10 months. Results: Of 407 individuals who joined in the first 2 months, 105 completed surveys. Among these, 81% were female and 86% white and mean age was 35.8. 72% participated for at least 1 month and 47% participated for at least 2 months. Survey participants reported that the challenge increased their enjoyment of abdominal exercise. Of the 68% of participants who invited others to participate, 28% recruited none, 66% recruited 1-5 users, and 6% recruited 10 or more users. Participants reported that online friends provided as much positive social support for exercise as family and in-person friends. In 14 months, 4941 users produced 76,746 tweets and mean total tweets per user was 15.86 (SD = 75.34; range = 1-2888). Conclusion: Online social networks may be a promising mechanism to spread brief exercise behaviors. C1 [Pagoto, Sherry L.; Schneider, Kristin L.; Oleski, Jessica] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. [Smith, Brian] Boston Univ, Sch Med, Dept Med, VA Boston Healthcare Syst, Boston, MA 02118 USA. [Bauman, Michael] MB Financial Grp, Macomb, MI USA. RP Pagoto, SL (reprint author), Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. NR 14 TC 8 Z9 8 U1 1 U2 10 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1543-3080 EI 1543-5474 J9 J PHYS ACT HEALTH JI J. Phys. Act. Health PD MAR PY 2014 VL 11 IS 3 BP 648 EP 653 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AF8RQ UT WOS:000334983700024 PM 23416874 ER PT J AU Rosen, AK Chen, Q Shin, MH O'Brien, W Shwartz, M Mull, HJ Cevasco, M Borzecki, AM AF Rosen, Amy K. Chen, Qi Shin, Marlena H. O'Brien, William Shwartz, Michael Mull, Hillary J. Cevasco, Marisa Borzecki, Ann M. TI Medical and Surgical Readmissions in the Veterans Health Administration What Proportion are Related to the Index Hospitalization? SO MEDICAL CARE LA English DT Article DE readmission; quality of care; unplanned readmission; clinically related readmission; quality improvement ID QUALITY-OF-CARE; FEE-FOR-SERVICE; COLORECTAL SURGERY; PATIENT SAFETY; HEART-FAILURE; RISK-FACTORS; RATES; PROGRAM; ASSOCIATION; MORTALITY AB Background: Readmissions are an attractive quality measure because they offer a broad view of quality beyond the index hospitalization. However, the extent to which medical or surgical readmissions reflect quality of care is largely unknown, because of the complexity of factors related to readmission. Identifying those readmissions that are clinically related to the index hospitalization is an important first step in closing this knowledge gap. Objectives: The aims of this study were to examine unplanned readmissions in the Veterans Health Administration, identify clinically related versus unrelated unplanned readmissions, and compare the leading reasons for unplanned readmission between medical and surgical discharges. Methods: We classified 2,069,804 Veterans Health Administration hospital discharges (Fiscal Years 2003-2007) into medical/surgical index discharges with/without readmissions per their diagnosis-related groups. Our outcome variable was "all-cause" 30-day unplanned readmission. We compared medical and surgical unplanned readmissions (n=217,767) on demographics, clinical characteristics, and readmission reasons using descriptive statistics. Results: Among all unplanned readmissions, 41.5% were identified as clinically related. Not surprisingly, heart failure (10.2%) and chronic obstructive pulmonary disease (6.5%) were the top 2 reasons for clinically related readmissions among medical discharges; postoperative complications (ie, complications of surgical procedures and medical care or complications of devices) accounted for 70.5% of clinically related readmissions among surgical discharges. Conclusions: Although almost 42% of unplanned readmissions were identified as clinically related, the majority of unplanned readmissions were unrelated to the index hospitalization. Quality improvement interventions targeted at processes of care associated with the index hospitalization are likely to be most effective in reducing clinically related readmissions. It is less clear how to reduce nonclinically related readmissions; these may involve broader factors than inpatient care. C1 [Rosen, Amy K.; Chen, Qi; Shin, Marlena H.; O'Brien, William; Shwartz, Michael; Mull, Hillary J.; Borzecki, Ann M.] Boston Univ, Sch Med, Ctr Healthcare Org & Implementat Res CHOIR, Boston, MA 02118 USA. [Rosen, Amy K.; Mull, Hillary J.] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. [Shwartz, Michael] Boston Univ, Sch Management, Dept Operat & Technol Management, Boston, MA 02215 USA. [Cevasco, Marisa] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Borzecki, Ann M.] Ctr Healthcare Org & Implementat Res CHOIR, Bedford, MA USA. [Borzecki, Ann M.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Borzecki, Ann M.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02215 USA. RP Rosen, AK (reprint author), VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, 150 S Huntington Ave 152 M, Boston, MA 02130 USA. EM akrosen@bu.edu FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development, SDR [07-002] FX Supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development, SDR #07-002. NR 42 TC 7 Z9 7 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD MAR PY 2014 VL 52 IS 3 BP 243 EP 249 DI 10.1097/MLR.0000000000000081 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AG3NW UT WOS:000335327400010 PM 24374424 ER PT J AU Lamont, EB Lan, L AF Lamont, Elizabeth B. Lan, Lan TI Sensitivity of Medicare Claims Data for Measuring Use of Standard Multiagent Chemotherapy Regimens SO MEDICAL CARE LA English DT Article DE comparative effectiveness research; elderly; chemotherapy; Medicare; cancer ID LEUKEMIA GROUP-B; CELL LUNG-CANCER; RADIATION-THERAPY; BREAST-CANCER; TRIALS; COMBINATION; PACLITAXEL; CISPLATIN; ETOPOSIDE; OLDER AB Purpose: We sought to determine the accuracy with which Medicare billing data documents elderly Medicare cancer patients' receipt of common multiagent chemotherapy regimens. Methods: We merged gold-standard clinical trial data from 406 elderly cancer patients known to be treated on 1 of 6 Cancer and Leukemia Group B (CALGB) breast, colorectal, and lung cancer trials (trial numbers; 9344, 9730, 9235,9732, 80203, 89803) with their Medicare claims data from Centers for Medicare and Medicaid Services (CMS). Comparing CMS chemotherapy codes to gold-standard CALGB treatment data, we estimated Medicare data's sensitivity at measuring the correct drugs and schedule for each of the multiagent chemotherapy regimens. Results: Overall 92% (375/406) of CALGB patients had contemporaneous CMS claims indicating receipt of chemotherapy. The overall sensitivity of CMS ambulatory claims for documenting treatment with the correct drugs and on the correct schedule (ie, all drugs had to be billed on the same day) for the 5 common multiagent chemotherapy regimens was 78% (275/354) for those potentially treated in the ambulatory setting. The sensitivity was similar for all treatment regimens: carboplatin and paclitaxel 83%, 5-fluorouracil and leucovorin 80%, fluorouracil, leucovorin, and irinotecan (FOLFIRI) 76%, doxorubicin and cyclophosphamide 75%, and cisplatin and etoposide 75%. Conclusions: We correctly identified at least 3-quarters of elderly Medicare cancer patients treated on a clinical trial with standard first-line multiagent chemotherapy regimens in the ambulatory setting by applying coding algorithms to their CMS claims. The algorithms may be useful in identifying cohorts of elderly Medicare patients for observational studies of the comparative effectiveness of standard multiagent chemotherapy regimens. C1 [Lamont, Elizabeth B.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp,Canc Ctr, Boston, MA 02115 USA. [Lamont, Elizabeth B.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Massachusetts Gen Hosp,Canc Ctr, Boston, MA 02115 USA. [Lan, Lan] Duke Univ, Dept Biostat, Durham, NC USA. RP Lamont, EB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180A Longwood Ave, Boston, MA 02115 USA. EM lamont@hcp.med.harvard.edu FU National Cancer Institute [CA132900, CA33601] FX Supported by grants from the National Cancer Institute: CA132900 (Lamont) and CA33601 (CALGB Statistics Center). NR 18 TC 6 Z9 6 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD MAR PY 2014 VL 52 IS 3 BP E15 EP E20 DI 10.1097/MLR.0b013e31824e342f PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AG3NW UT WOS:000335327400001 PM 22410411 ER PT J AU DeSalvo, MN Douw, L Tanaka, N Reinsberger, C Stufflebeam, SM AF DeSalvo, Matthew N. Douw, Linda Tanaka, Naoaki Reinsberger, Claus Stufflebeam, Steven M. TI Altered Structural Connectome in Temporal Lobe Epilepsy SO RADIOLOGY LA English DT Article ID GRAPH-THEORETICAL ANALYSIS; SURFACE-BASED ANALYSIS; NETWORKS; BRAIN; CONNECTIVITY; SYSTEM AB Purpose: To study differences in the whole-brain structural connectomes of patients with left temporal lobe epilepsy (TLE) and healthy control subjects. Materials and Methods: This study was approved by the institutional review board, and all individuals gave signed informed consent. Sixty-direction diffusion-tensor imaging and magnetization-prepared rapid acquisition gradient-echo (MP-RAGE) magnetic resonance imaging volumes were analyzed in 24 patients with left TLE and in 24 healthy control subjects. MP-RAGE volumes were segmented into 1015 regions of interest (ROIs) spanning the entire brain. Deterministic white matter tractography was performed after voxelwise tensor calculation. Weighted structural connectivity matrices were generated by using the pairwise density of connecting fibers between ROIs. Graph theoretical measures of connectivity networks were compared between groups by using linear models with permutation testing. Results: Patients with TLE had 22%-45% reduced (P <.01) distant connectivity in the medial orbitofrontal cortex, temporal cortex, posterior cingulate cortex, and precuneus, compared with that in healthy subjects. However, local connectivity, as measured by means of network efficiency, was increased by 85%-270% (P <.01) in the medial and lateral frontal cortices, insular cortex, posterior cingulate cortex, precuneus, and occipital cortex in patients with TLE as compared with healthy subjects. Conclusion: This study suggests that TLE involves altered structural connectivity in a network that reaches beyond the temporal lobe, especially in the default mode network. (C) RSNA, 2013 C1 [DeSalvo, Matthew N.; Douw, Linda; Tanaka, Naoaki; Stufflebeam, Steven M.] Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [DeSalvo, Matthew N.; Douw, Linda; Tanaka, Naoaki; Stufflebeam, Steven M.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. [Reinsberger, Claus] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. RP Stufflebeam, SM (reprint author), Athinoula Martinos Ctr Biomed Imaging, 149 Thirteenth St,Suite 2301, Charlestown, MA 02129 USA. EM sms@nmr.mgh.harvard.edu FU National Institutes of Health [P41-RR14075, R01-NS037462, R0-1NS069696, 5R01-NS060918] FX This research was supported by the National Institutes of Health (grants P41-RR14075, R01-NS037462, R0-1NS069696, and 5R01-NS060918). NR 25 TC 24 Z9 24 U1 2 U2 5 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAR PY 2014 VL 270 IS 3 BP 842 EP 848 DI 10.1148/radiol.13131044 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AG0WQ UT WOS:000335136800022 PM 24475828 ER PT J AU Growdon, WB Byron, V DiGloria, C Borger, DR Foster, R Winslow, J Chenna, A Sperinde, J Rueda, BR AF Growdon, Whitfield B. Byron, Virginia DiGloria, Celeste Borger, Darrell R. Foster, Rosemary Winslow, John Chenna, Ahmed Sperinde, Jeffrey Rueda, Bo R. TI HER2 Over-Expressing High Grade Endometrial Cancer Expresses High Levels of p95HER2 Variant SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Growdon, Whitfield B.; Byron, Virginia; DiGloria, Celeste; Borger, Darrell R.; Foster, Rosemary; Rueda, Bo R.] Massachusetts Gen Hosp, Vincent Dept Obstet Gynecol & Reprod Biol, Boston, MA 02114 USA. [Winslow, John; Chenna, Ahmed; Sperinde, Jeffrey] Monogram Biosci, LabCorps Specialty Testing Grp, San Francisco, CA USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 94A EP 95A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813001056 ER PT J AU Tanwar, PS Kaneko-Tarui, T Teixeira, JM AF Tanwar, Pradeep S. Kaneko-Tarui, Tomoko Teixeira, Jose M. TI Constitutive Wnt/B-Catenin Signaling in Mice in the Absence of Mullerian Inhibiting Substance/AntiMulleiran Hormone Signaling Leads to the Development of a Polycystic Ovary Phenotype SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Tanwar, Pradeep S.; Kaneko-Tarui, Tomoko] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA USA. [Teixeira, Jose M.] Michigan State Univ, Coll Human Med, Grand Rapids, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 125A EP 126A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813001144 ER PT J AU Guseh, S Ecker, J Kaimal, A AF Guseh, Stephanie Ecker, Jeffrey Kaimal, Anjali TI Appropriate and Timely Betamethasone Administration: Can We Do Better? SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Guseh, Stephanie; Kaimal, Anjali] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Ecker, Jeffrey] Massachusetts Gen Hosp, Vincent Obstet & Gynecol Dept, Div Maternal Fetal Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 159A EP 160A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813001246 ER PT J AU Pastore, L Silverman, L Manichaikhul, A Wang, X Finkelstein, J AF Pastore, L. Silverman, L. Manichaikhul, A. Wang, X. Finkelstein, J. TI FMR1 CGG Repeat Length Variation by Race-Ethnicity in Females with Normal Fertility SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Pastore, L.; Silverman, L.; Manichaikhul, A.; Wang, X.] Univ Virginia, Charlottesville, VA 22903 USA. [Finkelstein, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 202A EP 202A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813002055 ER PT J AU Styer, AK Karmon, A Guo, L Foster, R DiGloria, C Rueda, BR AF Styer, Aaron K. Karmon, Anatte Guo, Lankai Foster, Rosemary DiGloria, Celeste Rueda, Bo R. TI Defining Ethnic Specific MicroRNA Expression Signatures and Clinical Characteristics of Uterine Fibroids SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Styer, Aaron K.; Karmon, Anatte; Guo, Lankai; Foster, Rosemary; DiGloria, Celeste; Rueda, Bo R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Dept Obstet & Gynecol,Vincent Ctr Reprod, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 317A EP 317A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003063 ER PT J AU Phillippe, M Oppenheimer, K Sweet, LM AF Phillippe, Mark Oppenheimer, Karen Sweet, Leigh M. TI The Synergistic Innate Immune Response to Bacterial and Viral PAMPs by the Pregnant Mouse Uterus SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Phillippe, Mark] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Oppenheimer, Karen; Sweet, Leigh M.] Univ Vermont, Burlington, VT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 336A EP 337A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003121 ER PT J AU Veal, CT Berk, T Phillippe, M AF Veal, Christopher T. Berk, Tucker Phillippe, Mark TI Expression of Functional TLRs in Human Uterine Myocytes SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Veal, Christopher T.; Berk, Tucker; Phillippe, Mark] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Veal, Christopher T.] Univ Vermont, Coll Med, Burlington, VT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 381A EP 381A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003249 ER PT J AU Rana, S Rajakumar, A Geahchan, C Cerdeira, ASA Salahuddin, S Burke, S George, E Granger, JP Karumanchi, SA AF Rana, Sarosh Rajakumar, Augustine Geahchan, Carl Cerdeira, Ana Sofi A. Salahuddin, Saira Burke, Suzanne George, Eric Granger, Joey P. Karumanchi, S. Ananth TI Ouabain Downregulates sFlt1 Production by Inhibiting HSP27 Dependent HIF1 Expression SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Rana, Sarosh; Rajakumar, Augustine; Geahchan, Carl; Cerdeira, Ana Sofi A.; Salahuddin, Saira; Burke, Suzanne; Karumanchi, S. Ananth] BIDMC, Boston, MA USA. [George, Eric; Granger, Joey P.] Univ Mississippi, Med Ctr, Jackson, MS USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 396A EP 396A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003294 ER PT J AU Wang, N Satirapod, C Ohguchi, Y Tilly, JL AF Wang, Ning Satirapod, Chonthicha Ohguchi, Yasuyo Tilly, Jonathan L. TI Oocytes Generated during Adulthood Contribute to Natural Fertility in Mice SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Wang, Ning; Satirapod, Chonthicha; Ohguchi, Yasuyo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept OB GYN, Boston, MA USA. [Tilly, Jonathan L.] Northeastern Univ, Dept Biol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2014 VL 21 IS 3 SU S BP 416A EP 417A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AE2OO UT WOS:000333813003353 ER PT J AU Safren, SA Gonzalez, JS Wexler, DJ Psaros, C Delahanty, LM Blashill, AJ Margolina, AI Cagliero, E AF Safren, Steven A. Gonzalez, Jeffrey S. Wexler, Deborah J. Psaros, Christina Delahanty, Linda M. Blashill, Aaron J. Margolina, Aleksandra I. Cagliero, Enrico TI A Randomized Controlled Trial of Cognitive Behavioral Therapy for Adherence and Depression (CBT-AD) in Patients With Uncontrolled Type 2 Diabetes SO DIABETES CARE LA English DT Article ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; MEDICATION ADHERENCE; COLLABORATIVE CARE; GLYCEMIC CONTROL; SELF-CARE; DSM-IV; MELLITUS; METAANALYSIS; MANAGEMENT; MORTALITY AB OBJECTIVETo test cognitive behavioral therapy for adherence and depression (CBT-AD) in type 2 diabetes. We hypothesized that CBT-AD would improve adherence; depression; and, secondarily, hemoglobin A(1c) (A1C).RESEARCH DESIGN AND METHODSEighty-seven adults with unipolar depression and uncontrolled type 2 diabetes received enhanced treatment as usual (ETAU), including medication adherence, self-monitoring of blood glucose (SMBG), and lifestyle counseling; a provider letter documented psychiatric diagnoses. Those randomized to the intervention arm also received 9-11 sessions of CBT-AD.RESULTSImmediately after acute treatment (4 months), adjusting for baseline, CBT-AD had 20.7 percentage points greater oral medication adherence on electronic pill cap (95% CI -31.14 to -10.22, P = 0.000); 30.2 percentage points greater SMBG adherence through glucometer downloads (95% CI -42.95 to -17.37, P = 0.000); 6.44 points lower depression scores on the Montgomery-Asberg Depression Rating Scale (95% CI 2.33-10.56, P = 0.002); 0.74 points lower on the Clinical Global Impression (95% CI 0.16-1.32, P = 0.01); and 0.72 units lower A1C (95% CI 0.29-1.15, P = 0.001) relative to ETAU. Analyses of 4-, 8-, and 12-month follow-up time points indicated that CBT-AD maintained 24.3 percentage points higher medication adherence (95% CI -38.2 to -10.3, P = 0.001); 16.9 percentage points greater SMBG adherence (95% CI -33.3 to -0.5, P = 0.043); and 0.63 units lower A1C (95% CI 0.06-1.2, P = 0.03) after acute treatment ended. For depression, there was some evidence of continued improvement posttreatment, but no between-group differences.CONCLUSIONSCBT-AD is an effective intervention for adherence, depression, and glycemic control, with enduring and clinically meaningful benefits for diabetes self-management and glycemic control in adults with type 2 diabetes and depression. C1 [Safren, Steven A.; Psaros, Christina; Blashill, Aaron J.; Margolina, Aleksandra I.] Massachusetts Gen Hosp, Dept Psychiat, Behav Med Serv, Boston, MA 02114 USA. [Safren, Steven A.; Wexler, Deborah J.; Psaros, Christina; Delahanty, Linda M.; Blashill, Aaron J.; Margolina, Aleksandra I.; Cagliero, Enrico] Harvard Univ, Sch Med, Boston, MA USA. [Gonzalez, Jeffrey S.] Yeshiva Univ, Ferkauf Grad Sch Psychol, Bronx, NY USA. [Gonzalez, Jeffrey S.] Yeshiva Univ, Albert Einstein Coll Med, Diabet Res Ctr, Bronx, NY USA. [Wexler, Deborah J.; Delahanty, Linda M.; Cagliero, Enrico] Massachusetts Gen Hosp, Dept Med, MGH Diabet Ctr, Boston, MA 02114 USA. RP Safren, SA (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Behav Med Serv, Boston, MA 02114 USA. EM ssafren@partners.org FU National Institute of Mental Health [R01-MH-078571]; Harvard Catalyst, Harvard Clinical and Translational Science Center; National Institutes of Health [1UL1-RR-025758-03]; National Institute of Diabetes and Digestive and Kidney Diseases Career Development Award [K23-DK-080228]; [DK-020541]; [1K23-MH-096647] FX This project was supported by National Institute of Mental Health grant R01-MH-078571 (principal investigator: S. A. S.). Additional support came from the Harvard Catalyst, Harvard Clinical and Translational Science Center, by National Institutes of Health grant 1UL1-RR-025758-03 for a portion of the nurse and dietitian study visits. J.S.G. is partially supported by grant DK-020541. D.J.W. was supported by a National Institute of Diabetes and Digestive and Kidney Diseases Career Development Award (K23-DK-080228). A.J.B. is supported by grant 1K23-MH-096647. NR 39 TC 43 Z9 44 U1 6 U2 33 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2014 VL 37 IS 3 BP 625 EP 633 DI 10.2337/dc13-0816 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB3RT UT WOS:000331708600015 PM 24170758 ER PT J AU Kim, C Cleary, PA Cowie, CC Braffett, BH Dunn, RL Larkin, ME Gatcomb, PM Wessells, HB Nathan, DM Sarma, AV AF Kim, Catherine Cleary, Patricia A. Cowie, Catherine C. Braffett, Barbara H. Dunn, Rodney L. Larkin, Mary E. Gatcomb, Patricia M. Wessells, Hunter B. Nathan, David M. Sarma, Aruna V. CA DCCT EDIC Res Grp TI Effect of Glycemic Treatment and Microvascular Complications on Menopause in Women With Type 1 Diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort SO DIABETES CARE LA English DT Article ID PREMATURE OVARIAN FAILURE; ANTI-MULLERIAN HORMONE; INHIBIN B LEVELS; MELLITUS; TRIAL; EPIDEMIOLOGY; AUTOIMMUNITY; DYSFUNCTION; THERAPY; HISTORY AB OBJECTIVEWe examined the impact of intensive versus conventional diabetes treatment upon menopause among women with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT), a randomized controlled trial of intensive diabetes treatment, and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) study.RESEARCH DESIGN AND METHODSIn a secondary analysis of women in the DCCT/EDIC (n = 657), outcomes were the cumulative incidences of natural menopause and surgical menopause. Cox regression analyses were used to examine associations with treatment group, time-varying estimates of hemoglobin A(1c) (HbA(1c)), insulin dosage, BMI, and microvascular complications (retinopathy, nephropathy, and neuropathy).RESULTSBy EDIC year 18, after an average of 28 years of follow-up, 240 (38%) women had experienced natural menopause and 115 (18%) women had experienced surgical menopause. Age at natural menopause was similar in the intensive versus conventional groups (49.9 vs. 49.0 years; P = 0.28), and age at surgical menopause was similar in the intensive versus conventional groups (40.8 vs. 42.0 years; P = 0.31). In multivariable models, treatment group, HbA(1c), and microvascular complications were not associated with risk of natural or surgical menopause. Each 10 unit/day increase in insulin dosage decreased risk of natural menopause (hazard ratio [HR] 0.91, 95% CI 0.75-0.98) and each kg/m(2) increase in BMI increased risk of surgical menopause (HR 1.08, 95% CI 1.00-1.16).CONCLUSIONSIn the DCCT/EDIC, intensive versus conventional treatment group and HbA(1c) level were not associated with menopause risk. Greater insulin dose was associated with lower menopause risk. C1 [Kim, Catherine] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. [Kim, Catherine] Univ Michigan, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA. [Cleary, Patricia A.; Braffett, Barbara H.] George Washington Univ, Biostat Ctr, Rockville, MD USA. [Cowie, Catherine C.] Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. [Dunn, Rodney L.; Sarma, Aruna V.] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. [Larkin, Mary E.; Nathan, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Diabet, Boston, MA USA. [Gatcomb, Patricia M.] Yale Univ, Dept Med, New Haven, CT 06520 USA. [Wessells, Hunter B.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. RP Kim, C (reprint author), Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. EM cathkim@umich.edu FU Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases [U01-DK-094176, U01-DK-094157]; National Eye Institute; National Institute of Neurological Disorders and Stroke; Genetic Clinical Research Centers Program; Clinical and Translational Science Center Program, Bethesda, MD; U01 Cooperative Agreement; [R01-DK-083297] FX The DCCT/EDIC has been supported by U01 Cooperative Agreement grants (1982-93, 2011-2016) and contracts (1982-2011) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (current grant numbers U01-DK-094176 and U01-DK-094157) and through support by the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the Genetic Clinical Research Centers Program (1993-2007), and the Clinical and Translational Science Center Program (2006-present), Bethesda, MD. Additional support for C. K. was provided by R01-DK-083297. NR 20 TC 8 Z9 8 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2014 VL 37 IS 3 BP 701 EP 708 DI 10.2337/dc13-1746 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB3RT UT WOS:000331708600025 PM 24170751 ER PT J AU Novak, V Milberg, W Hao, Y Munshi, M Novak, P Galica, A Manor, B Roberson, P Craft, S Abduljalil, A AF Novak, Vera Milberg, William Hao, Ying Munshi, Medha Novak, Peter Galica, Andrew Manor, Bradley Roberson, Paula Craft, Suzanne Abduljalil, Amir TI Enhancement of Vasoreactivity and Cognition by Intranasal Insulin in Type 2 Diabetes SO DIABETES CARE LA English DT Article ID CEREBRAL-BLOOD-FLOW; IMPAIRED OLDER-ADULTS; BRAIN; MEMORY; HYPERINTENSITIES; PRESSURE; MELLITUS; DELIVERY; DISEASE; ATROPHY AB OBJECTIVETo determine acute effects of intranasal insulin on regional cerebral perfusion and cognition in older adults with type 2 diabetes mellitus (DM).RESEARCH DESIGN AND METHODSThis was a proof-of-concept, randomized, double-blind, placebo-controlled intervention evaluating the effects of a single 40-IU dose of insulin or saline on vasoreactivity and cognition in 15 DM and 14 control subjects. Measurements included regional perfusion, vasodilatation to hypercapnia with 3-Tesla MRI, and neuropsychological evaluation.RESULTSIntranasal insulin administration was well tolerated and did not affect systemic glucose levels. No serious adverse events were reported. Across all subjects, intranasal insulin improved visuospatial memory (P 0.05). In the DM group, an increase of perfusion after insulin administration was greater in the insular cortex compared with the control group (P = 0.0003). Cognitive performance after insulin administration was related to regional vasoreactivity. Improvements of visuospatial memory after insulin administration in the DM group (R-adjusted(2) = 0.44, P = 0.0098) and in the verbal fluency test in the control group (R-adjusted(2) = 0.64, P = 0.0087) were correlated with vasodilatation in the middle cerebral artery territory.CONCLUSIONSIntranasal insulin administration appears safe, does not affect systemic glucose control, and may provide acute improvements of cognitive function in patients with type 2 DM, potentially through vasoreactivity mechanisms. Intranasal insulin-induced changes in cognitive function may be related to vasodilatation in the anterior brain regions, such as insular cortex that regulates attention-related task performance. Larger studies are warranted to identify long-term effects and predictors of positive cognitive response to intranasal insulin therapy. C1 [Novak, Vera; Hao, Ying; Munshi, Medha; Galica, Andrew; Manor, Bradley] Harvard Univ, Sch Med, Dept Neurol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Milberg, William] VA Boston Healthcare, Boston Div, New England Geriatr Res Educ & Clin Ctr, Boston, MA USA. [Milberg, William] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Hao, Ying] Peking Univ, Acad Adv Interdisciplinary Studies, Beijing 100871, Peoples R China. [Munshi, Medha] Joslin Diabet Ctr, Boston, MA 02215 USA. [Novak, Peter] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. [Roberson, Paula] Univ Arkansas Med Sci, Dept Biostat, Little Rock, AR 72205 USA. [Craft, Suzanne] Wake Forest Univ, Bowman Gray Sch Med, Div Gerontol & Geriatr Med, Winston Salem, NC USA. [Abduljalil, Amir] Ohio State Univ, Dept Radiol, Columbus, OH 43210 USA. RP Novak, V (reprint author), Harvard Univ, Sch Med, Dept Neurol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. EM vnovak@bidmc.harvard.edu FU National Institutes of Health (NIH)-National Institute of Diabetes and Digestive and Kidney Diseases [5R21-DK-084463-02]; NIH-National Institute on Aging (NIA) [1R01-AG-0287601-A2]; China Scholarship Council [201206010220]; NIH-NIA [R01-AG-027415]; Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH) [1KL2RR025757-04, 8KL2TR000168-05, 8UL1TR000170-05]; Translational Research Center for Traumatic Brain Injury (TBI) and Stress Disorders (TRACTS); VA Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence [B6796-C]; VA Merit Review Award; Harvard Catalyst; Harvard University FX V.N. has received grants from the National Institutes of Health (NIH)-National Institute of Diabetes and Digestive and Kidney Diseases (5R21-DK-084463-02) and the NIH-National Institute on Aging (NIA) (1R01-AG-0287601-A2) related to this study, and V.N., M.M., P.N., A.G., B.M., P.R., and S.C. received salaries from these grants. Y.H. received grant support from the China Scholarship Council (201206010220). S.C. has received a grant from the NIH-NIA (R01-AG-027415). B.M. received a KL2 Medical Research Investigator Training (MeRIT) award (1KL2RR025757-04) from the Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH award 8KL2TR000168-05). W.M. was also supported by the Translational Research Center for Traumatic Brain Injury (TBI) and Stress Disorders (TRACTS), a VA Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (B6796-C), and VA Merit Review Award to Regina McGlinchey. This work was conducted with support from Harvard Catalyst, the Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH award 8UL1TR000170-05 and financial contributions from Harvard University and its affiliated academic health care centers). NR 36 TC 29 Z9 35 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 MAR PY 2014 VL 37 IS 3 BP 751 EP 759 DI 10.2337/dc13-1672 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB3RT UT WOS:000331708600031 PM 24101698 ER PT J AU Nadeau, KJ Mather, KJ Arslanian, SA Buchanan, TA Caprio, S Edelstein, SL Ehrmann, DA Savage, PJ Kahn, SE Mokhlesi, B Van Cauter, E Montgomery, BK Palmer, J Utzschneider, K Mather, KJ Chisholm, R Hannon, T Nadeau, KJ Zeitler, P Arslanian, SA Caprio, S Buchanan, TA Xiang, A Edelstein, SL Lachin, JM Savage, PJ AF Nadeau, Kristen J. Mather, Kieren J. Arslanian, Silva A. Buchanan, Thomas A. Caprio, Sonia Edelstein, Sharon L. Ehrmann, David A. Savage, Peter J. Kahn, Steven E. Mokhlesi, Babak Van Cauter, Eve Montgomery, Brenda K. Palmer, Jerry Utzschneider, Kristina Mather, Kieren J. Chisholm, Robin Hannon, Tamara Nadeau, Kristen J. Zeitler, Phil Arslanian, Silva A. Caprio, Sonia Buchanan, Thomas A. Xiang, Anny Edelstein, Sharon L. Lachin, John M. Savage, Peter J. CA RISE Consortium TI Restoring Insulin Secretion (RISE): Design of Studies of beta-Cell Preservation in Prediabetes and Early Type 2 Diabetes Across the Life Span SO DIABETES CARE LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; STYLE INTERVENTION; GLYCEMIC CONTROL; POSTPRANDIAL HYPERGLYCEMIA; PREVENTION PROGRAM; BARIATRIC SURGERY; CONTROLLED-TRIAL; HISPANIC WOMEN; FOLLOW-UP; METFORMIN AB OBJECTIVEThe Restoring Insulin Secretion (RISE) Consortium is testing interventions designed to preserve or improve -cell function in prediabetes or early type 2 diabetes.RESEARCH DESIGN AND METHODS-Cell function is measured using hyperglycemic clamps and oral glucose tolerance tests (OGTTs). The adult medication protocol randomizes participants to 12 months of placebo, metformin alone, liraglutide plus metformin, or insulin (3 months) followed by metformin (9 months). The pediatric medication protocol randomizes participants to metformin or insulin followed by metformin. The adult surgical protocol randomizes participants to gastric banding or metformin (24 months). Adult medication protocol inclusion criteria include fasting plasma glucose 95-125 mg/dL (5.3-6.9 mmol/L), OGTT 2-h glucose 140 mg/dL (7.8 mmol/L), HbA(1c) 5.8-7.0% (40-53 mmol/mol), and BMI 25-40 kg/m(2). Adult surgical protocol criteria are similar, except for fasting plasma glucose 90 mg/dL (5.0 mmol/L), BMI 30-40 kg/m(2), HbA(1c) <7.0% (<53 mmol/mol), and diabetes duration <12 months. Pediatric inclusion criteria include fasting plasma glucose 90 mg/dL (5.0 mmol/L), 2-h glucose 140 mg/dL (7.8 mmol/L), HbA(1c) 8.0% (64 mmol/mol), BMI >85th percentile and 50 kg/m(2), 10-19 years of age, and diabetes <6 months.RESULTSPrimary outcomes are clamp-derived glucose-stimulated C-peptide secretion and maximal C-peptide response to arginine during hyperglycemia. Measurements are made at baseline, after 12 months on treatment, and 3 months after treatment withdrawal (medication protocols) or 24 months postintervention (surgery protocol). OGTT-derived measures are also obtained at these time points.CONCLUSIONSRISE is determining whether medication or surgical intervention strategies can mitigate progressive -cell dysfunction in adults and youth with prediabetes or early type 2 diabetes. C1 [Nadeau, Kristen J.; Mather, Kieren J.; Chisholm, Robin; Hannon, Tamara] Univ Colorado Denver, Denver, CO 80202 USA. [Nadeau, Kristen J.; Mather, Kieren J.; Chisholm, Robin; Hannon, Tamara] Childrens Hosp Colorado, Colorado Springs, CO USA. [Mather, Kieren J.; Montgomery, Brenda K.; Palmer, Jerry; Utzschneider, Kristina] Indiana Univ, Sch Med, Bloomington, IN 47405 USA. [Arslanian, Silva A.; Nadeau, Kristen J.; Zeitler, Phil] Univ Pittsburgh, Med Ctr, Childrens Hosp Pittsburgh, Pittsburgh, PA 15260 USA. [Buchanan, Thomas A.; Caprio, Sonia] Univ So Calif, Keck Sch Med, Los Angeles, CA 90089 USA. [Caprio, Sonia; Arslanian, Silva A.] Yale Univ, Dept Pediat, New Haven, CT 06520 USA. [Edelstein, Sharon L.; Buchanan, Thomas A.; Xiang, Anny; Edelstein, Sharon L.; Lachin, John M.; Savage, Peter J.] George Washington Univ, Ctr Biostat, Washington, DC 20052 USA. [Ehrmann, David A.] Univ Chicago, Clin Res Ctr, Chicago, IL 60637 USA. [Savage, Peter J.; Kahn, Steven E.; Mokhlesi, Babak; Van Cauter, Eve] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Savage, Peter J.; Kahn, Steven E.; Mokhlesi, Babak; Van Cauter, Eve] Univ Washington, Seattle, WA 98195 USA. [Caprio, Sonia] Kaiser Permanente So Calif, Los Angeles, CA USA. RP Edelstein, SL (reprint author), Univ Colorado Denver, Denver, CO 80202 USA. EM rise@bsc.gwu.edu FU NIDDK [Chicago DK-094431, Denver DK-094467, Indiana DK-094438, Los Angeles DK-094430, Seattle DK-09440]; Department of Veterans Affairs FX RISE is supported by grants from the NIDDK (Chicago DK-094431, Denver DK-094467, Indiana DK-094438, Los Angeles DK-094430, and Seattle DK-09440) and the Department of Veterans Affairs. NR 41 TC 8 Z9 8 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2014 VL 37 IS 3 BP 780 EP 788 DI 10.2337/dc13-1879 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AB3RT UT WOS:000331708600035 ER PT J AU Alkire, BC Juliano, AF Hartnick, CJ AF Alkire, Blake C. Juliano, Amy F. Hartnick, Christopher J. TI Neck Mass in an Adolescent Male SO JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Editorial Material ID PYRIFORM SINUS FISTULA; BRANCHIAL ANOMALIES; IMAGING FINDINGS; MANAGEMENT; INFECTION C1 [Alkire, Blake C.; Juliano, Amy F.; Hartnick, Christopher J.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. RP Hartnick, CJ (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM christopher_hartnick@meei.harvard.edu NR 10 TC 0 Z9 0 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6181 EI 2168-619X J9 JAMA OTOLARYNGOL JI JAMA Otolaryngol-Head Neck Surg. PD MAR PY 2014 VL 140 IS 3 BP 275 EP 276 DI 10.1001/jamaoto.2013.6230 PG 2 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AF4HQ UT WOS:000334673000019 PM 24408774 ER PT J AU Balentine, CJ Naik, AD Robinson, CN Petersen, NJ Chen, GJ Berger, DH Anaya, DA AF Balentine, Courtney J. Naik, Aanand D. Robinson, Celia N. Petersen, Nancy J. Chen, G. John Berger, David H. Anaya, Daniel A. TI Association of High-Volume Hospitals With Greater Likelihood of Discharge to Home Following Colorectal Surgery SO JAMA SURGERY LA English DT Article ID QUALITY-OF-CARE; INPATIENT SURGERY; UNITED-STATES; MORTALITY; COMPLICATIONS; OUTCOMES; CANCER; IMPACT; COLECTOMY; SURVIVAL AB IMPORTANCE Discharge disposition is a patient-centered quality metric that reflects differences in quality of life and recovery following surgery. The effect of hospital volume on quality of recovery measured by rates of successful discharge to home remains unclear. OBJECTIVE To test the hypothesis that patients having colorectal surgery at high-volume hospitals would more likely be discharged to home rather than discharged to skilled rehabilitation facilities to complete recovery. DESIGN, SETTING, AND PARTICIPANTS Longitudinal analysis of 2008 hospital inpatient data to identify patients undergoing colorectal surgery who survived to discharge. The setting was the Nationwide Inpatient Sample, the largest all-payer inpatient care database, containing data from more than 1000 hospitals. Participants were 280 644 patients (>= 18 years) who underwent colorectal resections for benign or malignant disease and survived to discharge. MAIN OUTCOMES AND MEASURES The primary end point was discharge to home (with or without home health care) vs discharge to skilled facilities (skilled nursing, short-term recovery, or rehabilitation hospitals or other institutions). The secondary end point was discharge to home with home health care rather than to a skilled facility for patients with postdischarge care needs. Multiple logistic regression using robust standard errors was used to compute the odds ratios of each outcome based on hospital volume, while adjusting for other important variables. RESULTS The odds of discharge to home vs discharge to skilled facilities were significantly greater in high-volume hospitals compared with low-volume hospitals (odds ratio, 2.09; 95% CI, 1.70-2.56), with an absolute increase of 9%. For patients with postdischarge care needs, high-volume hospitals were less likely than low-volume hospitals to use skilled facilities rather than home health care (odds ratio, 0.35; 95% CI, 0.27-0.45), with an absolute difference of 10%. CONCLUSIONS AND RELEVANCE Patients having colorectal surgery at high-volume hospitals are significantly more likely to recover and return home after surgery than individuals having operations at low-volume hospitals. This study is the first step in a process of identifying which features of high-volume hospitals contribute toward desirable outcomes. Efforts to identify the reasons for improved recovery at high-volume hospitals can help lower-volume hospitals adopt beneficial practices. C1 [Balentine, Courtney J.; Naik, Aanand D.; Petersen, Nancy J.; Chen, G. John; Berger, David H.; Anaya, Daniel A.] Michael E DeBakey VA Med Ctr, Hlth Serv Res & Dev Ctr Excellence, Houston, TX 77030 USA. [Balentine, Courtney J.; Robinson, Celia N.; Berger, David H.; Anaya, Daniel A.] DeBakey Vet Affairs Med Ctr, Houston, TX USA. [Balentine, Courtney J.; Berger, David H.; Anaya, Daniel A.] Baylor Coll Med, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [Naik, Aanand D.; Chen, G. John] Baylor Coll Med, Dept Med, Div Geriatr, Houston, TX 77030 USA. [Naik, Aanand D.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. RP Anaya, DA (reprint author), Michael E DeBakey VA Med Ctr, Hlth Serv Res & Dev Ctr Excellence, Room 152,2002 Holcombe Blvd, Houston, TX 77030 USA. EM danaya@bcm.edu FU National Institute on Aging [K23AG027144]; Doris Duke Charitable Foundation Clinical Scientist Development Award; Baylor College of Medicine Comprehensive Cancer Training Program Grant Cancer Prevention & Research Institute of Texas [101499] FX Dr Naik is supported by grant K23AG027144 from the National Institute on Aging and by a Doris Duke Charitable Foundation Clinical Scientist Development Award. Dr Robinson has received support from Baylor College of Medicine Comprehensive Cancer Training Program Grant Cancer Prevention & Research Institute of Texas, Research Project 101499. No other disclosures were reported. NR 26 TC 15 Z9 15 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD MAR PY 2014 VL 149 IS 3 BP 244 EP 251 DI 10.1001/jamasurg.2013.3838 PG 8 WC Surgery SC Surgery GA AF3JX UT WOS:000334609400007 PM 24430092 ER PT J AU Brinton, LA Cook, MB McCormack, V Johnson, KC Olsson, H Casagrande, JT Cooke, R Falk, RT Gapstur, SM Gaudet, MM Gaziano, JM Gkiokas, G Guenel, P Henderson, BE Hollenbeck, A Hsing, AW Kolonel, LN Isaacs, C Lubin, JH Michels, KB Negri, E Parisi, D Petridou, ET Pike, MC Riboli, E Sesso, HD Snyder, K Swerdlow, AJ Trichopoulos, D Ursin, G van den Brandt, PA Van Den Eeden, SK Weiderpass, E Willett, WC Ewertz, M Thomas, DB AF Brinton, Louise A. Cook, Michael B. McCormack, Valerie Johnson, Kenneth C. Olsson, Hakan Casagrande, John T. Cooke, Rosie Falk, Roni T. Gapstur, Susan M. Gaudet, Mia M. Gaziano, J. Michael Gkiokas, Georgios Guenel, Pascal Henderson, Brian E. Hollenbeck, Albert Hsing, Ann W. Kolonel, Laurence N. Isaacs, Claudine Lubin, Jay H. Michels, Karin B. Negri, Eva Parisi, Dominick Petridou, Eleni Th. Pike, Malcolm C. Riboli, Elio Sesso, Howard D. Snyder, Kirk Swerdlow, Anthony J. Trichopoulos, Dimitrios Ursin, Giske van den Brandt, Piet A. Van Den Eeden, Stephen K. Weiderpass, Elisabete Willett, Walter C. Ewertz, Marianne Thomas, David B. CA European Rare Canc Study Grp TI Anthropometric and Hormonal Risk Factors for Male Breast Cancer: Male Breast Cancer Pooling Project Results SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BASE-LINE CHARACTERISTICS; KLINEFELTER-SYNDROME; PROSTATE-CANCER; MEN; COHORT; EPIDEMIOLOGY; NUTRITION; HEALTH; TESTOSTERONE; MORTALITY AB The etiology of male breast cancer is poorly understood, partly because of its relative rarity. Although genetic factors are involved, less is known regarding the role of anthropometric and hormonally related risk factors. In the Male Breast Cancer Pooling Project, a consortium of 11 casecontrol and 10 cohort investigations involving 2405 case patients (n 1190 from casecontrol and n 1215 from cohort studies) and 52013 control subjects, individual participant data were harmonized and pooled. Unconditional logistic regression generated study designspecific (casecontrol/cohort) odds ratios (ORs) and 95% confidence intervals (CIs), with exposure estimates combined using fixed effects meta-analysis. All statistical tests were two-sided. Risk was statistically significantly associated with weight (highest/lowest tertile: OR 1.36; 95% CI 1.18 to 1.57), height (OR 1.18; 95% CI 1.01 to 1.38), and body mass index (BMI; OR 1.30; 95% CI 1.12 to 1.51), with evidence that recent rather than distant BMI was the strongest predictor. Klinefelter syndrome (OR 24.7; 95% CI 8.94 to 68.4) and gynecomastia (OR 9.78; 95% CI 7.52 to 12.7) were also statistically significantly associated with risk, relations that were independent of BMI. Diabetes also emerged as an independent risk factor (OR 1.19; 95% CI 1.04 to 1.37). There were also suggestive relations with cryptorchidism (OR 2.18; 95% CI 0.96 to 4.94) and orchitis (OR 1.43; 95% CI 1.02 to 1.99). Although age at onset of puberty and histories of infertility were unrelated to risk, never having had children was statistically significantly related (OR 1.29; 95% CI 1.01 to 1.66). Among individuals diagnosed at older ages, a history of fractures was statistically significantly related (OR 1.41; 95% CI 1.07 to 1.86). Consistent findings across casecontrol and cohort investigations, complemented by pooled analyses, indicated important roles for anthropometric and hormonal risk factors in the etiology of male breast cancer. Further investigation should focus on potential roles of endogenous hormones. C1 [Brinton, Louise A.; Cook, Michael B.; Falk, Roni T.; Lubin, Jay H.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [McCormack, Valerie] Int Agcy Res Canc, Sect Environm & Radiat, F-69372 Lyon, France. [Johnson, Kenneth C.] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON, Canada. [Olsson, Hakan] Lund Univ, Dept Oncol, Lund, Sweden. [Casagrande, John T.; Henderson, Brian E.; Pike, Malcolm C.; Ursin, Giske] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Cooke, Rosie; Swerdlow, Anthony J.] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Gapstur, Susan M.; Gaudet, Mia M.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Michels, Karin B.] Brigham & Womens Hosp, Obstet & Gynecol Epidemiol Ctr, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Sesso, Howard D.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Sesso, Howard D.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, MAVERIC, Boston, MA USA. [Gkiokas, Georgios] Aretaie Univ Hosp, Dept Surg, Athens, Greece. [Guenel, Pascal] Univ Paris Sud, INSERM, Ctr Res Epidemiol & Populat Hlth, U1018, Villejuif, France. [Hollenbeck, Albert] AARP, AARP Res, Washington, DC USA. [Hsing, Ann W.] Canc Prevent Inst Calif, Fremont, CA USA. [Hsing, Ann W.] Stanford Univ, Div Epidemiol, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. [Hsing, Ann W.] Stanford Univ, Stanford Canc Inst, Stanford Sch Med, Stanford, CA USA. [Kolonel, Laurence N.] Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA. [Isaacs, Claudine] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Michels, Karin B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Michels, Karin B.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Negri, Eva; Trichopoulos, Dimitrios] Ist Richerche Farmacol, Milan, Italy. [Parisi, Dominick; Snyder, Kirk] IMS Inc, Rockville, MD USA. [Petridou, Eleni Th.] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Sesso, Howard D.] Inst Canc Res, Div Prevent Med, London SW3 6JB, England. [Sesso, Howard D.] Inst Canc Res, Div Aging, London SW3 6JB, England. [Swerdlow, Anthony J.] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England. [Ursin, Giske; Weiderpass, Elisabete] Canc Registry Norway, Oslo, Norway. [Ursin, Giske] Univ Oslo, Inst Basic Med Sci, Dept Nutr, Oslo, Norway. [van den Brandt, Piet A.] Maastricht Univ, Dept Epidemiol, Maastricht, Netherlands. [Van Den Eeden, Stephen K.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Weiderpass, Elisabete] Arct Univ Norway, Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Weiderpass, Elisabete] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Weiderpass, Elisabete] Samfundet Folkhalsan, Helsinki, Finland. [Ewertz, Marianne] Univ Southern Denmark, Inst Clin Res, Odense Univ Hosp, Dept Oncol, Odense, Denmark. [Thomas, David B.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. RP Brinton, LA (reprint author), NCI, NIH, Hormonal & Reprod Epidemiol Branch, 9609 Med Ctr Dr,Rm 7-E102,MSC 9774, Bethesda, MD 20892 USA. EM brinton@nih.gov RI Brinton, Louise/G-7486-2015; Cook, Michael/A-5641-2009; Weiderpass, Elisabete/M-4029-2016 OI Brinton, Louise/0000-0003-3853-8562; Cook, Michael/0000-0002-0533-7302; Weiderpass, Elisabete/0000-0003-2237-0128 FU European Research Council [ERC-2011-294576]; National Institutes of Health, Bethesda, Maryland; Institute of Cancer Research acknowledges National Health Service; Deutsche Krebshilfe; Deutsches Krebsforschungszentrum; Federal Ministry of Education and Research Germany; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane and Vasterbotten; Cancer Research UK; UK Medical Research Council; Danish Cancer Society; Italian Association for Research on Cancer; National Research Council Italy; HuGeF Foundation, Torino, Italy; ISCIII RT ICC Red Tematica de Investigacion Cooperativa en Cancer, Spain [R06/0020]; Hellenic Health Foundation; Stavros Niarchos Foundation; Hellenic Ministry of Health and Social Solidarity FX This research was funded in part by intramural funds from the National Institutes of Health, Bethesda, Maryland. The Swedish Case-Control Study acknowledges the support of the European Research Council Advanced Grant ERC-2011-294576. The Institute of Cancer Research acknowledges National Health Service funding to the National Institute for Health Research Biomedical Research Centre. The principle investigators and funders corresponding to each of the EPIC centers that contributed cases were Heiner Boeing, Rudolph Kaaks (Germany); Goran Hallmans, Jonas Manjer (Sweden); Timothy Key, Nick Wareham (UK); Kim Overvad, Anne Tjonneland (Denmark); Domenico Palli, Paolo Vineis, Rosario Tumino (Italy); Maria Jose Sanchez (Spain); Antonia Trichopoulou (Greece); from the Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and the Federal Ministry of Education and Research Germany; the Swedish Cancer Society, Swedish Scientific Council and the Regional Government of Skane and Vasterbotten; Cancer Research UK and the UK Medical Research Council; Danish Cancer Society; Italian Association for Research on Cancer, National Research Council Italy, and HuGeF Foundation, Torino, Italy; ISCIII RT ICC Red Tematica de Investigacion Cooperativa en Cancer (R06/0020) Spain; Hellenic Health Foundation, the Stavros Niarchos Foundation and the Hellenic Ministry of Health and Social Solidarity. NR 53 TC 28 Z9 28 U1 1 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD MAR PY 2014 VL 106 IS 3 AR djt465 DI 10.1093/jnci/djt465 PG 11 WC Oncology SC Oncology GA AF4NY UT WOS:000334691200012 PM 24552677 ER PT J AU Borges, S Chen, YF Laughren, TP Temple, R Patel, HD David, PA Mathis, M Unger, E Yang, PL Khin, NA AF Borges, Silvana Chen, Yeh-Fong Laughren, Thomas P. Temple, Robert Patel, Hiren D. David, Paul A. Mathis, Mitchell Unger, Ellis Yang, Peiling Khin, Ni A. TI Review of Maintenance Trials for Major Depressive Disorder: A 25-Year Perspective From the US Food and Drug Administration SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Review ID RELAPSE PREVENTION; RESIDUAL SYMPTOMS; METAANALYSIS; ANTIDEPRESSANTS; RECURRENCE; REMISSION; RECOVERY AB Objective: The maintenance efficacy of antidepressants is usually assessed in postmarketing studies with a randomized withdrawal design. This report explores differences in relapse rates, trial characteristics, and success rates in maintenance efficacy studies submitted to the US Food and Drug Administration (FDA) over a 25-year period. Data Sources: Clinical data from all maintenance trials with antidepressants submitted to FDA between 1987 and 2012. Study Selection: Efficacy data were compiled from 15 maintenance clinical trials in adults diagnosed with major depressive disorder according to DSM-III or DSM-IV criteria. Data Extraction: Trial characteristics, relapse rates, and time to relapse in each study were examined. Results: Relapse rates were significantly lower (P <.05) in the drug arm than in the placebo arm in every study, with a mean relapse rate difference of 18% and an average percent reduction in relapse rate of 52% compared to placebo. Only 6% of the relapse events occurred in the first 2 weeks of the doubleblind phase. The separation between treatment arms continued to increase throughout the double-blind phase only in the trial with longest response stabilization period. Conclusions: Antidepressant maintenance trials have a high rate of success, indicating a benefit of continuing drug treatment after initial response to an antidepressant. This benefit appears to result mainly from a decreased rate of recurrent depression rather than from an effect of drug withdrawal in the placebo groups. C1 [Borges, Silvana; Patel, Hiren D.; David, Paul A.; Mathis, Mitchell] Food & Drug Adm 1, Div Psychiat Prod, Off New Drugs, Silver Spring, MD 20993 USA. [Temple, Robert] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Laughren, Thomas P.] Massachusetts Gen Hosp, Clin Trials Network & Inst, Boston, MA USA. [Laughren, Thomas P.] NIMH, Bethesda, MD 20892 USA. RP Borges, S (reprint author), Food & Drug Adm, Div Psychiat Prod, 10903 New Hampshire Ave,Bldg 22,Rm 4159, Silver Spring, MD 20993 USA. EM silvana.borges@fda.hhs.gov NR 24 TC 17 Z9 17 U1 4 U2 11 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD MAR PY 2014 VL 75 IS 3 BP 205 EP 214 DI 10.4088/JCP.13r08722 PG 10 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AF0RP UT WOS:000334422000005 PM 24717376 ER PT J AU Yucel, MA Selb, J Cooper, RJ Boas, DA AF Yuecel, Meryem A. Selb, Juliette Cooper, Robert J. Boas, David A. TI Targeted principle component analysis: A new motion artifact correction approach for near-infrared spectroscopy SO JOURNAL OF INNOVATIVE OPTICAL HEALTH SCIENCES LA English DT Article DE Wavelet; spline; collodion-fixed fiber ID CEREBRAL OXYGENATION; BRAIN; TOPOGRAPHY; ACTIVATION AB As near-infrared spectroscopy (NIRS) broadens its application area to different age and disease groups, motion artifacts in the NIRS signal due to subject movement is becoming an important challenge. Motion artifacts generally produce signal fluctuations that are larger than physiological NIRS signals, thus it is crucial to correct for them before obtaining an estimate of stimulus evoked hemodynamic responses. There are various methods for correction such as principle component analysis (PCA), wavelet-based filtering and spline interpolation. Here, we introduce a new approach to motion artifact correction, targeted principle component analysis (tPCA), which incorporates a PCA filter only on the segments of data identified as motion artifacts. It is expected that this will overcome the issues of filtering desired signals that plagues standard PCA filtering of entire data sets. We compared the new approach with the most effective motion artifact correction algorithms on a set of data acquired simultaneously with a collodion-fixed probe (low motion artifact content) and a standard Velcro probe (high motion artifact content). Our results show that tPCA gives statistically better results in recovering hemodynamic response function (HRF) as compared to wavelet-based filtering and spline interpolation for the Velcro probe. It results in a significant reduction in mean-squared error (MSE) and significant enhancement in Pearson's correlation coefficient to the true HRF. The collodion-fixed fiber probe with no motion correction performed better than the Velcro probe corrected for motion artifacts in terms of MSE and Pearson's correlation coefficient. Thus, if the experimental study permits, the use of a collodion-fixed fiber probe may be desirable. If the use of a collodion-fixed probe is not feasible, then we suggest the use of tPCA in the processing of motion artifact contaminated data. C1 [Yuecel, Meryem A.; Selb, Juliette; Boas, David A.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp,Dept Radiol, Charlestown, MA USA. [Cooper, Robert J.] UCL, Dept Med Phys & Bioengn, London, England. RP Yucel, MA (reprint author), Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp,Dept Radiol, Charlestown, MA USA. EM mayucel@nmr.mgh.harvard.edu OI Cooper, Robert/0000-0001-6696-8020 FU NIH [P41-RR14075] FX This work was supported by NIH grant P41-RR14075. NR 24 TC 8 Z9 8 U1 2 U2 11 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA 5 TOH TUCK LINK, SINGAPORE 596224, SINGAPORE SN 1793-5458 EI 1793-7205 J9 J INNOV OPT HEAL SCI JI J. Innov. Opt. Health Sci. PD MAR PY 2014 VL 7 IS 2 SI SI AR 1350066 DI 10.1142/S1793545813500661 PG 8 WC Optics; Radiology, Nuclear Medicine & Medical Imaging SC Optics; Radiology, Nuclear Medicine & Medical Imaging GA AF3HW UT WOS:000334603700011 ER PT J AU Mar, BG Bullinger, LB McLean, KM Grauman, PV Harris, MH Stevenson, K Neuberg, DS Sinha, AU Sallan, SE Silverman, LB Kung, AL Lo Nigro, L Ebert, BL Armstrong, SA AF Mar, Brenton G. Bullinger, Lars B. McLean, Kathleen M. Grauman, Peter V. Harris, Marian H. Stevenson, Kristen Neuberg, Donna S. Sinha, Amit U. Sallan, Stephen E. Silverman, Lewis B. Kung, Andrew L. Lo Nigro, Luca Ebert, Benjamin L. Armstrong, Scott A. TI Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia SO NATURE COMMUNICATIONS LA English DT Article ID DNA MISMATCH REPAIR; GENES; RESISTANCE; NT5C2; CELLS AB Relapsed paediatric acute lymphoblastic leukaemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here, we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signalling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance. C1 [Mar, Brenton G.; McLean, Kathleen M.; Sallan, Stephen E.; Silverman, Lewis B.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Mar, Brenton G.; Sallan, Stephen E.; Silverman, Lewis B.] Boston Childrens Hosp, Dept Hematol Oncol, Boston, MA 02115 USA. [Bullinger, Lars B.] Univ Ulm, Dept Internal Med 3, D-89081 Ulm, Germany. [Grauman, Peter V.; Ebert, Benjamin L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Hematol,Dept Med, Boston, MA 02115 USA. [Harris, Marian H.] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Stevenson, Kristen; Neuberg, Donna S.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Sinha, Amit U.; Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Sinha, Amit U.; Armstrong, Scott A.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10065 USA. [Kung, Andrew L.] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA. [Lo Nigro, Luca] Azienda Policlin OVE, I-95125 Catania, Italy. RP Armstrong, SA (reprint author), Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. EM armstros@mskcc.org OI Kung, Andrew/0000-0002-9091-488X; Mar, Brenton/0000-0002-3857-9324 FU National Institutes of Health [5T32CA136432-03, CA140575, CA068484]; Lady Tata Memorial Trust; William Lawrence and Blanche Hughes Foundation; Abraham Fellowship Fund; Friends of Dana Farber; Charles H. Hood Foundation; Leukemia and Lymphoma Society FX We are grateful to C. Lindsley, S. Jaiswal, A. Krivtsov, M. Correll, R. Rubio, F. Abderazzaq and Y. Wang for technical advice and valuable discussions. We would also like to thank S. Hunt, E. Swaim, J. Allen, H. Wang and A. Lack for assistance in obtaining clinical specimens. B. G. M. was supported by the National Institutes of Health (5T32CA136432-03), the Lady Tata Memorial Trust, the William Lawrence and Blanche Hughes Foundation, the Abraham Fellowship Fund and the Friends of Dana Farber. Additional research support was provided by the National Institutes of Health (CA140575 and CA068484), the Charles H. Hood Foundation and the Leukemia and Lymphoma Society. NR 17 TC 42 Z9 43 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2014 VL 5 AR 3469 DI 10.1038/ncomms4469 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE9CA UT WOS:000334300400052 PM 24662245 ER PT J AU Lehavot, K Stappenbeck, CA Luterek, JA Kaysen, D Simpson, TL AF Lehavot, Keren Stappenbeck, Cynthia A. Luterek, Jane A. Kaysen, Debra Simpson, Tracy L. TI Gender Differences in Relationships Among PTSD Severity, Drinking Motives, and Alcohol Use in a Comorbid Alcohol Dependence and PTSD Sample SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article DE alcohol dependence; posttraumatic stress disorder; dual diagnosis; drinking motives; gender differences ID POSTTRAUMATIC-STRESS-DISORDER; NATIONALLY REPRESENTATIVE SAMPLE; SEXUAL ASSAULT SURVIVORS; DSM-IV ALCOHOL; PSYCHIATRIC-DISORDERS; UNITED-STATES; SUBSTANCE USE; PSYCHOMETRIC PROPERTIES; VULNERABILITY MODEL; ANXIETY DISORDERS AB Alcohol dependence (AD) and posttraumatic stress disorder (PTSD) are highly prevalent and comorbid conditions associated with a significant level of impairment. Little systematic study has focused on gender differences specific to individuals with both AD and PTSD. The current study examined gender-specific associations between PTSD symptom severity, drinking to cope (i.e., reduce negative affect), drinking for enhancement (i.e., increase positive affect), and average alcohol use in a clinical sample of men (n = 46) and women (n = 46) with comorbid AD and PTSD. Results indicated that PTSD symptoms were highly associated with drinking-to-cope motives for both men and women, but with greater drinking for enhancement motives for men only. Enhancement motives were positively associated with average alcohol quantity for both men and women, but coping motives were significantly associated with average alcohol quantity for women only. These findings suggest that for individuals with comorbid AD and PTSD, interventions that focus on reducing PTSD symptoms are likely to lower coping motives for both genders, and targeting coping motives is likely to result in decreased drinking for women but not for men, whereas targeting enhancement motives is likely to lead to reduced drinking for both genders. C1 [Lehavot, Keren] VA Puget Sound Hlth Care Syst, Adv Fellowship Program Mental Illness Res & Treat, Seattle, WA USA. [Lehavot, Keren; Stappenbeck, Cynthia A.; Luterek, Jane A.; Kaysen, Debra; Simpson, Tracy L.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Luterek, Jane A.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Simpson, Tracy L.] VA Puget Sound Hlth Care Syst, Ctr Excellence Subs Abuse Treatment & Educ, Seattle, WA USA. RP Lehavot, K (reprint author), 1660 S Columbian Way, Seattle, WA 98108 USA. EM klehavot@uw.edu FU NIAAA NIH HHS [R21 AA017130] NR 78 TC 15 Z9 15 U1 5 U2 8 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X EI 1939-1501 J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD MAR PY 2014 VL 28 IS 1 BP 42 EP 52 DI 10.1037/a0032266 PG 11 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA AF4OR UT WOS:000334693600005 PM 23647151 ER PT J AU Kaysen, D Atkins, DC Simpson, TL Stappenbeck, CA Blayney, JA Lee, CM Larimer, ME AF Kaysen, Debra Atkins, David C. Simpson, Tracy L. Stappenbeck, Cynthia A. Blayney, Jessica A. Lee, Christine M. Larimer, Mary E. TI Proximal Relationships Between PTSD Symptoms and Drinking Among Female College Students: Results From a Daily Monitoring Study SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article DE posttraumatic stress disorder; PTSD; college students; victimization; alcohol use ID POSTTRAUMATIC-STRESS-DISORDER; ALCOHOL-USE DISORDERS; SEXUAL EXPERIENCES SURVEY; SUBSTANCE USE; SELF-MEDICATION; BINGE DRINKING; YOUNG-ADULTS; ATTENDING PEERS; NEGATIVE AFFECT; WITHIN-PERSON AB Self-medication has been theorized to explain comorbidity between posttraumatic stress disorder (PTSD) and drinking, whereupon problem drinking develops in order to modulate negative affect and ameliorate PTSD symptoms. Daily monitoring methodologies may help refine our understanding of proximal relations between PTSD, affect, and alcohol use. One hundred thirty-six female college drinkers with a past history of sexual victimization and 38 female college drinkers with no past trauma history completed electronic monitoring of PTSD symptoms, affect, alcohol use, and alcohol cravings, daily for 4 weeks. A two-part mixed hurdle model was used to examine likelihood of drinking and amount of alcohol consumed on drinking days. We found significant relationships between daily PTSD symptoms, affect, and drinking. On days women experienced more intrusive and behavioral avoidance symptoms of PTSD, they experienced stronger urges to drink and were more likely to drink on that day. On days in which women experienced more negative affect than their average, they experienced stronger urges to drink, whereas on days in which women experienced more of the dysphoric symptoms associated with PTSD than their average, they drank less. On days with higher positive affect, women reported stronger urges to drink and were more likely to drink. Results suggest the need to examine both aspects of affect and specific PTSD symptoms as they may differentially predict drinking behavior. Differences in the ways in which PTSD symptoms and affect influence drinking suggest that interventions more specifically address the function of drinking behaviors in reducing alcohol use among college women. C1 [Kaysen, Debra; Atkins, David C.; Stappenbeck, Cynthia A.; Blayney, Jessica A.; Lee, Christine M.; Larimer, Mary E.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Kaysen, Debra; Larimer, Mary E.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Kaysen, Debra] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Simpson, Tracy L.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Kaysen, D (reprint author), Dept Psychiat & Behav Sci, 1100 NE 45th St,Suite 300,UW Box 354944, Seattle, WA 98195 USA. EM dkaysen@u.washington.edu OI Atkins, David/0000-0002-5781-9880 FU NIAAA NIH HHS [R01 AA020252, R01AA020252, R21 AA016211, R21AA016211, T32 AA007455, T32AA007455] NR 89 TC 21 Z9 21 U1 5 U2 12 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X EI 1939-1501 J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD MAR PY 2014 VL 28 IS 1 BP 62 EP 73 DI 10.1037/a0033588 PG 12 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA AF4OR UT WOS:000334693600007 PM 23915369 ER PT J AU Tsai, AG Hosokawa, P Schoen, J Prochazka, AV AF Tsai, Adam G. Hosokawa, Patrick Schoen, Jonathan Prochazka, Allan V. TI Frequency of laboratory testing among gastric bypass patients SO SURGERY FOR OBESITY AND RELATED DISEASES LA English DT Article DE Bariatric surgery; Obesity surgery; Quality of care; Nutrition assessment; Clinical care ID NUTRITIONAL DEFICIENCIES; VITAMIN DEFICIENCY; BARIATRIC SURGERY AB Background: Long-term laboratory monitoring is recommended. after gastric bypass surgery to prevent the development of micronutrient deficiencies. The objective of this study was to characterize patterns of laboratory monitoring after surgery. Methods: We used a large insurance claims database to assess the frequency of laboratory testing after gastric bypass surgery. We assessed the tests recommended by an expert panel on bariatric surgery, including tests recommended routinely as well as second-line tests for specific clinical scenarios (e.g., tests for anemia when iron deficiency is not present). Results: With the exception of testing for diabetes, most gastric bypass patients did not undergo routine laboratory testing in the first year after their surgery, ranging from 54% (electrolytes) to 95% (zinc). However, for first-line tests, significantly more gastric bypass patients underwent testing in the first year,compared with gastric banding patients. Differences in testing frequency between gastric bypass and gastric banding patients were larger for tests of micronutrient deficiency than for common metabolic panels and complete blood counts. For second-line tests, much smaller percentages of both groups of patients underwent testing, either in the first year or after year 1. Conclusion: Patients undergoing gastric bypass do not routinely undergo recommended laboratory tests, although they are undergoing more monitoring than gastric banding patients. Efforts must be made by patients, surgeons, and primary care providers to ensure that routine testing is done to lower the risk of adverse health outcomes. (Surg Obes Relat Dis 2014;10:340-347.) (C) 2014 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved. C1 [Tsai, Adam G.; Prochazka, Allan V.] Univ Colorado, Div Gen Internal Med, Aurora, CO 80045 USA. [Tsai, Adam G.] Univ Colorado, Anschutz Ctr Hlth & Wellness, Aurora, CO 80045 USA. [Hosokawa, Patrick] Univ Colorado, Colorado Hlth Outcomes Program, Aurora, CO 80045 USA. [Schoen, Jonathan] Univ Colorado, Dept Surg, Aurora, CO 80045 USA. [Prochazka, Allan V.] Denver VA Med Ctr, Denver, CO USA. RP Tsai, AG (reprint author), Univ Colorado, Sch Med, Anschutz Hlth & Wellness Bldg, Aurora, CO 80045 USA. EM adam.tsai@ucdenver.edu NR 17 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1550-7289 EI 1878-7533 J9 SURG OBES RELAT DIS JI Surg. Obes. Relat. Dis. PD MAR-APR PY 2014 VL 10 IS 2 BP 340 EP 345 DI 10.1016/j.soard.2013.09.005 PG 6 WC Surgery SC Surgery GA AF3XW UT WOS:000334647000029 PM 24355327 ER PT J AU Gunel, C Feldman, RE Bleier, BS AF Gunel, Ceren Feldman, Rachel E. Bleier, Benjamin S. TI Osteitis is associated with P-glycoprotein overexpression in patients with chronic sinusitis without nasal polyps SO AMERICAN JOURNAL OF RHINOLOGY & ALLERGY LA English DT Article ID COMPUTED TOMOGRAPHIC FINDINGS; CHRONIC RHINOSINUSITIS; EOSINOPHILIA; INFLAMMATION; MARKER; EXPRESSION; SURGERY; ASTHMA; BONE AB Background: P-glycoprotein (P-gp) is a membrane-bound efflux pump that is up-regulated in eosinophilic chronic rhinosinusitis and participates in epithelial cytokine secretion. Osteitis is associated with eosinophilic inflammation and may represent a method to predict patients with P-gp overexpression. The purpose of this article was to determine whether P-gp overexpression and increased osteitis scores are associated in patients with chronic rhinosinusitis (CRS). Methods: An Institutional Review Board-approved study was performed using sinus tissue in 38 patients with CRS. P-gp expression was calculated using quantitative fluorescent immunohistochemistry to generate an epithelial-to-background staining ratio. Patients were stratified into low and high P-gp expression groups. Osteitis was scored radiologically using the Kennedy Osteitis Score (KOS) and Global Osteitis Score (GOS). Serum eosinophilia was assessed. KOS and GOS were compared using a Pearson's correlation coefficient. Osteitis scores and serum eosinophil concentrations between P-gp expression groups were compared using a nonparametric Mann-Whitney U test (two tailed). Results: Among the 38 patients, 7(18.42%) had high P-gp expression (mean +/- SD, 4.86 +/- 1.33) whereas 31(81.57%) had low expression ratios (1.93 +/- 0.45). No patients in the high P-gp expression group had undergone prior surgery. Median serum eosinophil values were significantly greater in the high versus low P-gp expression group (6.98 +/- 2.17 versus 2.36 +/- 1.38, p < 0.001). GOS and KOS values were significantly greater in the high versus low P-gp expression group (15.86 +/- 4.91 versus 6.29 +/- 1.25 and 4.55 +/- 4.33 verus 2.23 +/- 1.71; p < 0.001). KOS and GOS values were significantly correlated (r = 0.835; p < 0.001). Conclusion: Increased osteitis burden as measured by either the KOS or the GOS is associated with increased P-gp membranous expression in CRS. Radiographic quantification of osteitis may therefore be used to identify patients with P-gp overexpression thereby providing a novel potential therapeutic target. C1 [Gunel, Ceren] Adnan Menderes Univ, Med Sch Hosp, Dept Otolaryngol Head & Neck Surg, TR-09100 Aytepe Mevkii, Aydin, Turkey. [Feldman, Rachel E.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol, Boston, MA USA. [Bleier, Benjamin S.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol Head & Neck Surg, Boston, MA USA. RP Gunel, C (reprint author), Adnan Menderes Univ, Tip Fak, Hastanesi KBB AD, TR-09100 Aytepe Mevkii, Aydin, Turkey. EM drgunel@hotmail.com FU ARS FX B Bleier was the recipient of the ARS Investigator Grant. The remaining authors have no conflicts of interest pertaining to this article NR 17 TC 8 Z9 8 U1 0 U2 2 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1945-8924 EI 1945-8932 J9 AM J RHINOL ALLERGY JI Am. J. Rhinol. Allergy PD MAR-APR PY 2014 VL 28 IS 2 BP 99 EP 102 DI 10.2500/ajra.2014.28.4011 PG 4 WC Otorhinolaryngology SC Otorhinolaryngology GA AE5TL UT WOS:000334052100009 PM 24717943 ER PT J AU DeYoung, K Wentzel, JL Schlosser, RJ Nguyen, SA Soler, ZM AF DeYoung, Kristen Wentzel, Jennifer L. Schlosser, Rodney J. Nguyen, Shaun A. Soler, Zachary M. TI Systematic review of immunotherapy for chronic rhinosinusitis SO AMERICAN JOURNAL OF RHINOLOGY & ALLERGY LA English DT Review ID ALLERGIC FUNGAL SINUSITIS; GRASS-POLLEN IMMUNOTHERAPY; SUBCUTANEOUS IMMUNOTHERAPY; FOLLOW-UP; RHINITIS; DISEASE; ASTHMA AB Background: Immunotherapy (IT) has been well established as an effective treatment for allergic rhinitis (AR), but little is known about the benefits of IT on clinical outcomes of comorbid chronic rhinosinusitis (CRS). The goal of this publication is to systematically review the literature regarding outcomes of IT in patients with atopic CRS. Methods: A systematic review of the literature was conducted including studies that assessed the efficacy of IT on clinical outcome measures in CRS including without polyp, with polyp, and allergic fungal rhinosinusitis subgroups. Excluded articles were those only reporting outcomes specific to asthma or AR. Results: Seven studies met the inclusion and exclusion criteria for this review, none of which were randomized controlled trials. Generally, symptom scores improved in patients treated with IT when compared with baseline data and control patients. Objective endoscopic exam measures improved with IT treatment in short-term studies. Significant improvements were observed in radiographic assessments, and there was a decreased necessity for revision surgery, interventional office visits, and intranasal and oral steroid use. Conclusion: Conclusions are limited by the paucity of available data on the efficacy of IT for treating CRS-specific outcome measures. There is weak evidence to support the use of IT as an adjunctive treatment in CRS patients, particularly in the postoperative period. C1 [DeYoung, Kristen; Wentzel, Jennifer L.; Schlosser, Rodney J.; Nguyen, Shaun A.; Soler, Zachary M.] Med Univ S Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. [Schlosser, Rodney J.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Soler, ZM (reprint author), Med Univ S Carolina, Dept Otolaryngol Head & Neck Surg, 135 Rutledge Ave,MSC 550, Charleston, SC 29425 USA. EM solerz@musc.edu NR 24 TC 9 Z9 10 U1 1 U2 5 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1945-8924 EI 1945-8932 J9 AM J RHINOL ALLERGY JI Am. J. Rhinol. Allergy PD MAR-APR PY 2014 VL 28 IS 2 BP 145 EP 150 DI 10.2500/ajra.2014.28.4019 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA AE5TL UT WOS:000334052100017 PM 24717953 ER PT J AU Mainwaring, P Yu, EY Londhe, A Van Poppel, H Rathkopf, DE Smith, MR Souza, P Griffin, TW Ryan, CJ AF Mainwaring, P. Yu, E. Y. Londhe, A. Van Poppel, H. Rathkopf, D. E. Smith, M. R. Souza, P. Griffin, T. W. Ryan, C. J. CA Study COU-AA-302 Investigators TI Association of alkaline phosphatase with clinical outcomes in chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): results from COU-AA-302 SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the Urological-Society-of-Australia-and-New-Zealand CY MAR 16-19, 2014 CL Brisbane, AUSTRALIA SP Urol Soc Australia & New Zealand C1 [Mainwaring, P.] Hematol & Oncol Clin Australia, Brisbane, Qld, Australia. [Yu, E. Y.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Londhe, A.] Janssen Res & Dev LLC, Raritan, NJ USA. [Van Poppel, H.] Katholieke Univ Leuven Hosp, Louvain, Belgium. [Rathkopf, D. E.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Rathkopf, D. E.] Weill Cornell Med Coll, New York, NY USA. [Smith, M. R.] Harvard Univ, Sch Med, Boston, MA USA. [Smith, M. R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Souza, P.] Univ Western Sydney, Sch Med, Sydney, NSW, Australia. [Griffin, T. W.] Janssen Res & Dev, Los Angeles, CA USA. [Ryan, C. J.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD MAR PY 2014 VL 113 SU 4 MA 41 BP 21 EP 21 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA AB2DB UT WOS:000331602100042 ER PT J AU Pittman, K Smith, M Coleman, R Klotz, L Milecki, P Wei, R Balakumaran, A Fizazi, K AF Pittman, K. Smith, M. Coleman, R. Klotz, L. Milecki, P. Wei, R. Balakumaran, A. Fizazi, K. TI Denosumab for the prevention of symptomatic skeletal events in patients with castration-resistant advanced prostate cancer: a comparison with skeletal-related events SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the Urological-Society-of-Australia-and-New-Zealand CY MAR 16-19, 2014 CL Brisbane, AUSTRALIA SP Urol Soc Australia & New Zealand C1 [Pittman, K.] Queen Elizabeth Hosp, Woodville, SA 5011, Australia. [Smith, M.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Coleman, R.] Weston Pk Hosp, Acad Unit Clin Oncol, Sheffield, S Yorkshire, England. [Klotz, L.] Sunnybrook & Womens Coll, Hlth Sci Ctr, Toronto, ON, Canada. [Milecki, P.] Wielkopolskie Ctr Onkol, Poznan, Poland. [Wei, R.; Balakumaran, A.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Fizazi, K.] Univ Paris Sud, Inst Gustave Roussy, Paris, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD MAR PY 2014 VL 113 SU 4 MA 46 BP 23 EP 23 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA AB2DB UT WOS:000331602100047 ER PT J AU Marx, G Patrick, D Cleeland, C Fallowfield, L Smith, M Klotz, L Oudard, S Wei, R Ohrling, K Qian, Y AF Marx, G. Patrick, D. Cleeland, C. Fallowfield, L. Smith, M. Klotz, L. Oudard, S. Wei, R. Ohrling, K. Qian, Y. TI Denosumab or zoledronic acid therapy on pain interference and cancer-specific quality of life in patients with castrate-resistant prostate cancer and bone metastases SO BJU INTERNATIONAL LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the Urological-Society-of-Australia-and-New-Zealand CY MAR 16-19, 2014 CL Brisbane, AUSTRALIA SP Urol Soc Australia & New Zealand C1 [Marx, G.] Sydney Adventist Hosp, Integrated Canc Ctr, Wahroonga, Australia. [Patrick, D.] Univ Washington, Seattle, WA 98195 USA. [Cleeland, C.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Fallowfield, L.] Univ Sussex, Sussex Hlth Outcomes Res & Educ Canc SHORE C, Brighton, E Sussex, England. [Smith, M.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Klotz, L.] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Oudard, S.] European Georges Popidou Hosp, Paris, France. [Wei, R.; Ohrling, K.; Qian, Y.] Amgen Inc, Thousand Oaks, CA 91320 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD MAR PY 2014 VL 113 SU 4 MA 47 BP 24 EP 24 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA AB2DB UT WOS:000331602100048 ER PT J AU Wirth, LJ AF Wirth, Lori J. TI Chemoprevention of Squamous Cell Carcinoma of the Head and Neck: No Time to Lose Momentum SO CANCER PREVENTION RESEARCH LA English DT Article ID ORAL PREMALIGNANT LESIONS; PHASE IIB TRIAL; CYCLIN D1; HUMAN-PAPILLOMAVIRUS; RANDOMIZED-TRIAL; PRIMARY TUMORS; UNITED-STATES; HPV INFECTION; CANCER; LEUKOPLAKIA AB The prospects for chemoprevention to reduce the incidence of squamous cell carcinoma of the head and neck (SCCHN) are great. The tissue at risk for harboring disease is relatively accessible for examination and biopsy. Patients appropriate for study can be easily identified by their risk factors and the presence of premalignant lesions. Our understanding of the pathogenesis of SCCHN is ever increasing, and offers new opportunities to explore strategies for prevention therapies. In this issue of Cancer Prevention Research, Saba and colleagues report on a phase Ib trial of celecoxib plus erlotinib to prevent progression to higher-grade dysplasia or invasive carcinoma in patients with oral premalignant lesions. The overall response rate was 57%, though by the time of last analysis, 85% of patients relapsed. In this commentary, challenges to the success of chemoprevention clinical trials for SCCHN, such as pitfalls in using surrogate biomarkers and reversal of histologic premalignant changes as study endpoints, are discussed. In addition, strategies to help ensure further development in the field of head and neck cancer prevention are reviewed. These include focusing efforts on tobacco cessation and human papillomavirus vaccination, targeting key molecular drivers of head and neck carcinogenesis, and focusing on combination strategies that have the potential to eradicate premalignant clones, even if some toxicity is encountered. (C) 2014 AACR. C1 [Wirth, Lori J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Wirth, LJ (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. EM lwirth@partners.org NR 37 TC 2 Z9 2 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAR PY 2014 VL 7 IS 3 BP 279 EP 282 DI 10.1158/1940-6207.CAPR-13-0437 PG 4 WC Oncology SC Oncology GA AE5UW UT WOS:000334055800001 PM 24441671 ER PT J AU Choi, SE Perzan, KE Tramontano, AC Kong, CY Hur, C AF Choi, Sung Eun Perzan, Katherine E. Tramontano, Angela C. Kong, Chung Yin Hur, Chin TI Statins and Aspirin for Chemoprevention in Barrett's Esophagus: Results of a Cost-Effectiveness Analysis SO CANCER PREVENTION RESEARCH LA English DT Article ID HIGH-GRADE DYSPLASIA; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; EXTENDED TRANSTHORACIC RESECTION; GASTROESOPHAGEAL-REFLUX DISEASE; CORONARY-HEART-DISEASE; PRIMARY PREVENTION; RADIOFREQUENCY ABLATION; RANDOMIZED-TRIALS; CANCER-RISK; ADENOCARCINOMA AB Data suggest that aspirin, statins, or a combination of the two drugs may lower the progression of Barrett's esophagus to esophageal adenocarcinoma. However, aspirin is associated with potential complications such as gastrointestinal bleeding and hemorrhagic stroke, and statins are associated with myopathy. We developed a simulation disease model to study the effectiveness and cost effectiveness of aspirin and statin chemoprevention against esophageal adenocarcinoma. A decision analytic Markov model was constructed to compare four strategies for Barrett's esophagus management; all regimens included standard endoscopic surveillance regimens: (i) endoscopic surveillance alone, (ii) aspirin therapy, (iii) statin therapy, and (iv) combination therapy of aspirin and statin. Endpoints evaluated were life expectancy, quality-adjusted life years (QALY), costs, and incremental cost-effectiveness ratios (ICER). Sensitivity analysis was performed to determine the impact of model input uncertainty on results. Assuming an annual progression rate of 0.33% per year from Barrett's esophagus to esophageal adenocarcinoma, aspirin therapy was more effective and cost less than (dominated) endoscopic surveillance alone. When combination therapy was compared with aspirin therapy, the ICER was $ 158,000/QALY, which was above our willingness-to-pay threshold of $ 100,000/QALY. Statin therapy was dominated by combination therapy. When higher annual cancer progression rates were assumed in the model (0.5% per year), combination therapy was cost-effective compared with aspirin therapy, producing an ICER of $ 96,000/QALY. In conclusion, aspirin chemoprevention was both more effective and cost less than endoscopic surveillance alone. Combination therapy using both aspirin and statin is expensive but could be cost-effective in patients at higher risk of progression to esophageal adenocarcinoma. (C) 2013 AACR. C1 [Choi, Sung Eun; Perzan, Katherine E.; Tramontano, Angela C.; Kong, Chung Yin; Hur, Chin] Inst Technol Assessment, Boston, MA USA. [Perzan, Katherine E.; Hur, Chin] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Kong, Chung Yin; Hur, Chin] Harvard Univ, Sch Med, Boston, MA USA. RP Hur, C (reprint author), Massachusetts Gen Hosp, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM chur@partners.org OI Hur, Chin/0000-0002-2819-7576 FU NIH [R01-CA140574, U01-CA152926, K25-CA133141] FX This study was supported by NIH grants R01-CA140574 and U01-CA152926 (to C. Hur) and K25-CA133141 (to C.Y. Kong) NR 58 TC 8 Z9 8 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAR PY 2014 VL 7 IS 3 BP 341 EP 350 DI 10.1158/1940-6207.CAPR-13-0191-T PG 10 WC Oncology SC Oncology GA AE5UW UT WOS:000334055800008 PM 24380852 ER PT J AU Scaglia, N Tyekucheva, S Zadra, G Photopoulos, C Loda, M AF Scaglia, Natalia Tyekucheva, Svitlana Zadra, Giorgia Photopoulos, Cornelia Loda, Massimo TI De novo fatty acid synthesis at the mitotic exit is required to complete cellular division SO CELL CYCLE LA English DT Article DE de novo lipogenesis; phospholipid; fatty acid; cell cycle; cell cycle arrest; AMPK; metabolome; lysophospholipid; C75 ID CTP-PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE; ACETYL-COA CARBOXYLASE; CTPPHOSPHOCHOLINE CYTIDYLYLTRANSFERASE; PHOSPHOLIPID-METABOLISM; ENDOPLASMIC-RETICULUM; CYCLE REGULATION; CANCER-THERAPY; LIFE-CYCLE; MAST CELLS; S-PHASE AB Although the regulation of the cell cycle has been extensively studied, much less is known about its coordination with the cellular metabolism. Using mass spectrometry we found that lysophospholipid levels decreased drastically from G(2)/M to G(1) phase, while de novo phosphatidylcholine synthesis, the main phospholipid in mammalian cells, increased, suggesting that enhanced membrane production was concomitant to a decrease in its turnover. In addition, fatty acid synthesis and incorporation into membranes was increased upon cell division. The rate-limiting reaction for de novo fatty acid synthesis is catalyzed by acetyl-CoA carboxylase. As expected, its inhibiting phosphorylation decreased prior to cytokinesis initiation. Importantly, the inhibition of fatty acid synthesis arrested the cells at G(2)/M despite the presence of abundant fatty acids in the media. Our results suggest that de novo lipogenesis is essential for cell cycle completion. This "lipogenic checkpoint" at G(2)/M may be therapeutically exploited for hyperproliferative diseases such as cancer. C1 [Scaglia, Natalia; Zadra, Giorgia; Photopoulos, Cornelia; Loda, Massimo] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Tyekucheva, Svitlana] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Tyekucheva, Svitlana] Harvard Univ, Sch Med, Dept Biostat, Boston, MA 02115 USA. [Zadra, Giorgia; Loda, Massimo] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Loda, Massimo] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Loda, Massimo] Broad Inst, Cambridge, MA USA. [Loda, Massimo] Kings Coll London, Div Canc Studies, London WC2R 2LS, England. RP Loda, M (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM massimo_loda@dfci.harvard.edu FU Prostate Cancer Foundation; DF/HCC SPORE in Prostate Cancer [NIH/NCI P50 CA90381]; NIH [RO1CA131945]; Nuclea Biomarkers (Pittsfield, MA) FX We are in debt to Dr Lesley Wassef for critical review of the manuscript and Maria Elina Scaglia for her help with the figures. This work was supported by the Prostate Cancer Foundation, the DF/HCC SPORE in Prostate Cancer (NIH/NCI P50 CA90381), NIH grant RO1CA131945, and philanthropic funds from Nuclea Biomarkers (Pittsfield, MA) to M.L. NR 57 TC 12 Z9 12 U1 2 U2 11 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD MAR 1 PY 2014 VL 13 IS 5 BP 859 EP 868 DI 10.4161/cc.27767 PG 10 WC Cell Biology SC Cell Biology GA AE3UQ UT WOS:000333904200027 PM 24418822 ER PT J AU Oliva, E Young, R AF Oliva, Esther Young, Robert H. TI Endocrine Pathology of the Ovary SO ENDOCRINE PATHOLOGY LA English DT Article DE Ovary; Function; Endocrine; Pathology ID SERTOLI-LEYDIG-CELL; CORD-STROMAL TUMORS; ADULT-GRANULOSA-CELL; OF-THE-LITERATURE; ALPHA-FETOPROTEIN PRODUCTION; LUTEINIZED FOLLICLE CYST; MCCUNE-ALBRIGHT-SYNDROME; PEUTZ-JEGHERS SYNDROME; FEMALE GENITAL-TRACT; CLINICOPATHOLOGICAL ANALYSIS C1 [Oliva, Esther; Young, Robert H.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp,James Homer Wright Pathol, Boston, MA 02115 USA. [Oliva, Esther] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Oliva, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 219, Boston, MA 02114 USA. EM eoliva@partners.org NR 151 TC 1 Z9 1 U1 1 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1046-3976 EI 1559-0097 J9 ENDOCR PATHOL JI Endocr. Pathol. PD MAR PY 2014 VL 25 IS 1 BP 102 EP 119 DI 10.1007/s12022-013-9285-4 PG 18 WC Endocrinology & Metabolism; Pathology SC Endocrinology & Metabolism; Pathology GA AF0PH UT WOS:000334416000014 PM 24420639 ER PT J AU Haun, JN Lind, JD Shimada, SL Martin, TL Gosline, RM Antinori, N Stewart, M Simon, SR AF Haun, Jolie N. Lind, Jason D. Shimada, Stephanie L. Martin, Tracey L. Gosline, Robert M. Antinori, Nicole Stewart, Max Simon, Steven R. TI Evaluating User Experiences of the Secure Messaging Tool on the Veterans Affairs' Patient Portal System SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE veterans; secure messaging; patient-provider communication; Department of Veterans Affairs; usability testing; mixed methods; patient-centered care ID HEALTH-CARE; E-MAIL; COMMUNICATION; LITERACY; RECORDS; PERSPECTIVES; VALIDATION; PHYSICIANS; ATTITUDES; SETTINGS AB Background: The United States Department of Veterans Affairs has implemented an electronic asynchronous "Secure Messaging" tool within a Web-based patient portal (ie, My HealtheVet) to support patient-provider communication. This electronic resource promotes continuous and coordinated patient-centered care, but to date little research has evaluated patients' experiences and preferences for using Secure Messaging. Objective: The objectives of this mixed-methods study were to (1) characterize veterans' experiences using Secure Messaging in the My HealtheVet portal over a 3-month period, including system usability, (2) identify barriers to and facilitators of use, and (3) describe strategies to support veterans' use of Secure Messaging. Methods: We recruited 33 veterans who had access to and had previously used the portal's Secure Messaging tool. We used a combination of in-depth interviews, face-to-face user-testing, review of transmitted secure messages between veterans and staff, and telephone interviews three months following initial contact. We assessed participants' computer and health literacy during initial and follow-up interviews. We used a content-analysis approach to identify dominant themes in the qualitative data. We compared inferences from each of the data sources (interviews, user-testing, and message review) to identify convergent and divergent data trends. Results: The majority of veterans (27/33, 82%) reported being satisfied with Secure Messaging at initial interview; satisfaction ratings increased to 97% (31/32, 1 missing) during follow-up interviews. Veterans noted Secure Messaging to be useful for communicating with their primary care team to manage health care needs (eg, health-related questions, test requests and results, medication refills and questions, managing appointments). Four domains emerged from interviews: (1) perceived benefits of using Secure Messaging, (2) barriers to using Secure Messaging, (3) facilitators for using Secure Messaging, and (4) suggestions for improving Secure Messaging. Veterans identified and demonstrated impediments to successful system usage that can be addressed with education, skill building, and system modifications. Analysis of secure message content data provided insights to reasons for use that were not disclosed by participants during interviews, specifically sensitive health topics such as erectile dysfunction and sexually transmitted disease inquiries. Conclusions: Veterans perceive Secure Messaging in the My HealtheVet patient portal as a useful tool for communicating with health care teams. However, to maximize sustained utilization of Secure Messaging, marketing, education, skill building, and system modifications are needed. Data from this study can inform a large-scale quantitative assessment of Secure Messaging users' experiences in a representative sample to validate qualitative findings. C1 [Haun, Jolie N.; Lind, Jason D.; Antinori, Nicole] James A Haley VA Med Ctr, HSR&D RR&D Ctr Innovat Disabil & Rehabil Res, Dept Vet Affairs, Tampa, FL 33637 USA. [Haun, Jolie N.] Univ S Florida, Coll Publ Hlth, Dept Community & Family Med, Tampa, FL USA. [Lind, Jason D.] Univ S Florida, Dept Anthropol, Tampa, FL 33620 USA. [Shimada, Stephanie L.] Edith Nourse Rogers Mem VA Hosp, CHOIR, Dept Vet Affairs, Bedford, MA USA. [Shimada, Stephanie L.] Edith Nourse Rogers Mem VA Hosp, Natl Ehlth Qual Enhancement Res Initiat QUERI Coo, Bedford, MA USA. [Shimada, Stephanie L.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Shimada, Stephanie L.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Div Hlth Informat & Implementat Sci, Worcester, MA USA. [Martin, Tracey L.] VA New England Hlth Care Syst, Dept Vet Affairs, Bedford, MA USA. [Gosline, Robert M.] James A Haley VA Med Ctr, Dept Vet Affairs, Tampa, FL USA. [Stewart, Max; Simon, Steven R.] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Gen Internal Med Sect, Dept Vet Affairs, Boston, MA USA. RP Haun, JN (reprint author), James A Haley VA Med Ctr, HSR&D RR&D Ctr Innovat Disabil & Rehabil Res, Dept Vet Affairs, 8900 Grand Oak Cir 151R, Tampa, FL 33637 USA. EM Jolie.Haun@va.gov OI Lind, Jason/0000-0002-1610-0431 FU Department of Veterans Affairs; Veterans Health Administration; Office of Research and Development; Health Services Research and Development Service; National eHealth Quality Enhancement Research Initiative (QUERI) Coordinating Center [RRP 11-397]; Center of Innovation for Disability and Rehabilitation Research at the James A. Haley Veterans Hospital; Center for Healthcare Organization and Implementation Research (CHOIR) FX The development of this manuscript was supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development Service, and National eHealth Quality Enhancement Research Initiative (QUERI) Coordinating Center (RRP 11-397). This manuscript was also supported in part by the Center of Innovation for Disability and Rehabilitation Research at the James A. Haley Veterans Hospital, and the Center for Healthcare Organization and Implementation Research (CHOIR). NR 35 TC 16 Z9 16 U1 5 U2 16 PU JMIR PUBLICATIONS, INC PI TORONTO PA 59 WINNERS CIRCLE, TORONTO, ON M4L 3Y7, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD MAR PY 2014 VL 16 IS 3 BP 266 EP 281 AR e75 DI 10.2196/jmir.2976 PG 16 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA AE5IN UT WOS:000334021200022 PM 24610454 ER PT J AU Kaittanis, C Shaffer, TM Ogirala, A Santra, S Perez, JM Chiosis, G Li, YM Josephson, L Grimm, J AF Kaittanis, Charalambos Shaffer, Travis M. Ogirala, Anuja Santra, Santimukul Perez, J. Manuel Chiosis, Gabriela Li, Yueming Josephson, Lee Grimm, Jan TI Environment-responsive nanophores for therapy and treatment monitoring via molecular MRI quenching SO NATURE COMMUNICATIONS LA English DT Article ID DRUG-DELIVERY; MAGNETIC-RELAXATION; CANCER-THERAPY; PROSTATE-CANCER; NANOPARTICLES; NANOSENSORS; TELOMERASE; INHIBITOR; EFFICACY; TUMORS AB The effective delivery of therapeutics to disease sites significantly contributes to drug efficacy, toxicity and clearance. Here we demonstrate that clinically approved iron oxide nanoparticles (Ferumoxytol) can be utilized to carry one or multiple drugs. These so called 'nanophores' retain their cargo within their polymeric coating through weak electrostatic interactions and release it in slightly acidic conditions (pH 6.8 and below). The loading of drugs increases the nanophores' transverse T2 and longitudinal T1 nuclear magnetic resonance (NMR) proton relaxation times, which is proportional to amount of carried cargo. Chemotherapy with translational nanophores is more effective than the free drug in vitro and in vivo, without subjecting the drugs or the carrier nanoparticle to any chemical modification. Evaluation of cargo incorporation and payload levels in vitro and in vivo can be assessed via benchtop magnetic relaxometers, common NMR instruments or magnetic resonance imaging scanners. C1 [Kaittanis, Charalambos; Shaffer, Travis M.; Ogirala, Anuja; Chiosis, Gabriela; Li, Yueming; Grimm, Jan] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA. [Shaffer, Travis M.] CUNY Hunter Coll, Grad Ctr, Dept Chem, New York, NY 10065 USA. [Santra, Santimukul] Pittsburg State Univ, Dept Chem, Pittsburg, KS 66762 USA. [Perez, J. Manuel] Univ Cent Florida, NanoSci Technol Ctr, Orlando, FL 32826 USA. [Josephson, Lee] Massachusetts Gen Hosp, Ctr Adv Med Imaging Sci, Charlestown, MA 02129 USA. RP Grimm, J (reprint author), Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, 1275 York Ave, New York, NY 10065 USA. EM grimmj@mskcc.org RI Shaffer, Travis/I-6956-2015 FU Department of Defense Prostate Cancer Research Program of the Congressionally Directed Medical Research Programs [W81XWH-12-1-0509]; Louis V. Gerstner Young Investigator Award; Starr Cancer Consortium [I4-A427]; MSKCC Experimental Therapeutics Center; Alex's Lemonade Stand Foundation; NIH [P30 CA008748-44 S5]; National Science Foundation [IGERT 0965983] FX We thank Professor Lewis Cantley (Weill Cornell Medical College, Cornell University), Professor Charles Sawyers (MSKCC) and Dr Horst Kessler (Technische Universitat Munchen) for providing chemotherapeutics; Dr Jason S. Lewis for providing animals; Dr Naga Vara Kishore Pillarsetty, Dr Carl Le, Dr Simone Alidori, Dr Stefan Harmsen, Kuntalkumar Sevak, Dr Priyanka Shukla and Florian Rechenmacher for expert technical assistance. This study was supported by the Department of Defense Prostate Cancer Research Program of the Congressionally Directed Medical Research Programs under Award No. W81XWH-12-1-0509 to J.G. (opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the funding agency), Louis V. Gerstner Young Investigator Award (to J.G.), Starr Cancer Consortium (I4-A427 to J.G.), the MSKCC Experimental Therapeutics Center (to J.G.), Mr William H. and Mrs Alice Goodwin (to J.G.), the Alex's Lemonade Stand Foundation (to C. K.) and the NIH (P30 CA008748-44 S5). T. M. S. is funded by a National Science Foundation Integrative Graduate Education and Research Traineeship (MAD, IGERT 0965983). NR 43 TC 20 Z9 20 U1 7 U2 88 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2014 VL 5 AR 3384 DI 10.1038/ncomms4384 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE9BB UT WOS:000334297600001 PM 24594970 ER PT J AU Lamoureux, F Baud'huin, M Calleja, LR Jacques, C Berreur, M Redini, F Lecanda, F Bradner, JE Heymann, D Ory, B AF Lamoureux, Francois Baud'huin, Marc Calleja, Lidia Rodriguez Jacques, Camille Berreur, Martine Redini, Francoise Lecanda, Fernando Bradner, James E. Heymann, Dominique Ory, Benjamin TI Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle SO NATURE COMMUNICATIONS LA English DT Article ID TRANSCRIPTION FACTOR RUNX2; OSTEOSARCOMA CELL-LINES; C-MYC; SUPER-ENHANCERS; NUCLEAR-FACTOR; ONCOSTATIN-M; IN-VIVO; PROTEIN; CANCER; EXPRESSION AB The vicious cycle established between bone-associated tumours and bone resorption is the central problem with therapeutic strategies against primary bone tumours and bone metastasis. Here we report data to support inhibition of BET bromodomain proteins as a promising therapeutic strategy that target simultaneously the three partners of the vicious cycle. Treatment with JQ1, a BET bromodomain inhibitor, reduces cell viability of osteosarcoma cells and inhibits osteoblastic differentiation both in vitro and in vivo. These effects are associated with transcriptional silencing of MYC and RUNX2, resulting from the depletion of BRD4 from their respective loci. Moreover, JQ1 also inhibits osteoclast differentiation by interfering with BRD4-dependent RANKL activation of NFATC1 transcription. Collectively, our data indicate that JQ1 is a potent inhibitor of osteoblast and osteoclast differentiation as well as bone tumour development. C1 [Lamoureux, Francois; Baud'huin, Marc; Calleja, Lidia Rodriguez; Jacques, Camille; Berreur, Martine; Redini, Francoise; Heymann, Dominique; Ory, Benjamin] INSERM, UMR 957, Equipe Labellise Ligue 2012, F-44035 Nantes, France. [Lamoureux, Francois; Baud'huin, Marc; Calleja, Lidia Rodriguez; Jacques, Camille; Berreur, Martine; Redini, Francoise; Heymann, Dominique; Ory, Benjamin] Univ Nantes, Nantes Atlantique Univ, F-44035 Nantes, France. [Baud'huin, Marc] Nantes Univ Hosp, F-44035 Nantes, France. [Lecanda, Fernando] Univ Navarra, Ctr Appl Med Res CIMA, Div Oncol, Adhes & Metastasis Lab, Navarra 31008, Spain. [Bradner, James E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bradner, James E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Ory, B (reprint author), INSERM, UMR 957, Equipe Labellise Ligue 2012, 1 Rue Gaston Veil, F-44035 Nantes, France. EM Benjamin.ory@univ-nantes.fr RI Lamoureux, Francois/K-8021-2015; REDINI, Francoise/K-7981-2015; ory, benjamin/K-8231-2015; Baud'huin, Marc/K-8519-2015 FU Seventh Framework Programme [264817-BONE-NET]; INSERM; Region Pays de la loire; Fondation ARC FX This paper was written as a part of research project that received funding from the Seventh Framework Programme ([FP7/2007-2013]) under Grant agreement number 264817-BONE-NET. C.J. is funded by INSERM and Region Pays de la loire. F. La. is funded by INSERM and Fondation ARC. We thank Douangsone Vadysirisack for critical review of the manuscript. NR 44 TC 44 Z9 44 U1 4 U2 29 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD MAR PY 2014 VL 5 AR 3511 DI 10.1038/ncomms4511 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AE9CQ UT WOS:000334302200002 PM 24646477 ER PT J AU Estevez, AO Morgan, KL Szewczyk, NJ Gems, D Estevez, M AF Estevez, Annette O. Morgan, Kathleen L. Szewczyk, Nathaniel J. Gems, David Estevez, Miguel TI The neurodegenerative effects of selenium are inhibited by FOX() and PINK1/PTEN regulation of insulin/insulin-like growth factor signaling in Caenorhabditis elegans SO NEUROTOXICOLOGY LA English DT Article DE Selenium; Neurodegeneration; Insulin/insulin-like signaling; PTEN; PINKI; Amyotrophic lateral sclerosis ID AMYOTROPHIC-LATERAL-SCLEROSIS; COLORECTAL-CANCER CELLS; AGE-1 PI3 KINASE; SUPEROXIDE-DISMUTASE; C-ELEGANS; LIFE-SPAN; OXIDATIVE STRESS; SODIUM SELENITE; TRANSCRIPTION FACTOR; INSULIN-RESISTANCE AB Exposures to high levels of environmental selenium have been associated with motor neuron disease in both animals and humans and high levels of selenite have been identified in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). We have shown previously that exposures to high levels of sodium selenite in the environment of Caenorhabditis elegans adult animals can induce neurodegeneration and cell loss resulting in motor deficits and death and that this is at least partially caused by a reduction in cholinergic signaling across the neuromuscular junction. Here we provide evidence that reduction in insulin/insulin-like (IIS) signaling alters response to high dose levels of environmental selenium which in turn can regulate the IIS pathway. Most specifically we show that nuclear localization and thus activation of the OAF-16/forkhead box transcription factor occurs in response to selenium exposure although this was not observed in motor neurons of the ventral cord. Yet, tissue specific expression and generalized overexpression of DAF-16 can partially rescue the neurodegenerative and behavioral deficits observed with high dose selenium exposures in not only the cholinergic, but also the GABAergic motor neurons. In addition, two modifiers of IIS signaling, PTEN (phosphatase and tensin homolog, deleted on chromosome 10) and PINK1 (PTEN-induced putative kinase I) are required for the cellular antioxidant reduced glutathione to mitigate the selenium-induced movement deficits. Studies have suggested that environmental exposures can lead to ALS or other neurological diseases and this model of selenium-induced neurodegeneration developed in a genetically tractable organism provides a tool for examining the combined roles of genetics and environment in the neuro-pathologic disease process. (C) 2014 The Authors. Published by Elsevier Inc. All rights reserved. C1 [Estevez, Annette O.; Estevez, Miguel] Univ Arizona, Coll Med, Dept Neurol, Tucson, AZ 85724 USA. [Morgan, Kathleen L.; Estevez, Miguel] Vet Affairs Pittsburgh Healthcare Syst, Res & Dev, Pittsburgh, PA 15240 USA. [Szewczyk, Nathaniel J.] Univ Pittsburgh, Dept Biol Sci, Pittsburgh, PA 15260 USA. [Gems, David] UCL, Inst Hlth Ageing, London WC1E 6BT, England. [Gems, David] UCL, Dept Genet Evolut & Environm, London WC1E 6BT, England. RP Estevez, AO (reprint author), Neurometrica, 1900 Millrace Dr,Suite 113N, Eugene, OR 97403 USA. EM neurometrica@gmail.com; kathleen@immunetrics.com; mbzns3@exmail.nottingham.ac.uk; david.gems@ucl.ac.uk; m_estevez@yahoo.com OI Estevez, Annette/0000-0001-8840-1340 FU Jim Himelic Foundation; Southern Arizona Foundation; Keatings Institute; National Institutes of Environmental Health Sciences [R21-ES012305]; Career Development Award [ME] provided through the Office of Research and Development, Department of Veterans Affairs; NIH National Center for Research Resources (NCRR); International C. elegans Gene Knockout Consortium FX This research was supported by grants from the Jim Himelic Foundation (ME), Southern Arizona Foundation (ME), Keatings Institute (ME), National Institutes of Environmental Health Sciences [R21-ES012305 to AE and ME], and a Career Development Award [ME] provided through the Office of Research and Development, Department of Veterans Affairs. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR) and the International C. elegans Gene Knockout Consortium. NR 114 TC 8 Z9 8 U1 3 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X EI 1872-9711 J9 NEUROTOXICOLOGY JI Neurotoxicology PD MAR PY 2014 VL 41 BP 28 EP 43 DI 10.1016/j.neuro.2013.12.012 PG 16 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA AE6HW UT WOS:000334092200004 PM 24406377 ER PT J AU Miodovnik, A Edwards, A Bellinger, DC Hauser, R AF Miodovnik, Amir Edwards, Andrea Bellinger, David C. Hauser, Russ TI Developmental neurotoxicity of ortho-phthalate diesters: Review of human and experimental evidence SO NEUROTOXICOLOGY LA English DT Review DE Endocrine disruptors; Epidemiology; Neurodevelopment; Phthalates; Prenatal ID ENDOCRINE DISRUPTING CHEMICALS; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; THYROID-HORMONE BINDING; SCHOOL-AGE-CHILDREN; LACTATIONAL EXPOSURE; URINARY PHTHALATE; IN-UTERO; DI(2-ETHYLHEXYL) PHTHALATE; PERINATAL EXPOSURE; DIBUTYL PHTHALATE AB Ortho-phthalate diesters, or phthalates, are widely used synthetic chemicals found primarily in consumer products and polyvinyl chloride plastics. Experimental evidence suggests that several phthalates possess antiandrogenic properties and may disrupt endocrine pathways resulting in abnormal reproductive outcomes. Low-level exposure to phthalates has been well documented in humans, with higher levels found in children and women of childbearing age. Recent epidemiologic studies postulate that prenatal exposure to measurable urine phthalate concentrations may be associated with altered genital and pubertal development in infants and children. This review addresses the emerging evidence that some phthalates may have an adverse impact on the developing brain. The supporting animal studies and proposed mechanisms underlying the deleterious properties of phthalates in relation to neurodevelopmental outcomes are also discussed. While the observed associations are based on limited studies with a broad range of endpoints, the implications of such outcomes are of concern from a public health standpoint and merit further investigation given the widespread nature of the exposure. (C) 2014 Elsevier Inc. All rights reserved. C1 [Miodovnik, Amir; Bellinger, David C.] Boston Childrens Hosp, Boston, MA 02115 USA. [Miodovnik, Amir; Bellinger, David C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Edwards, Andrea] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, Russ] Massachusetts Gen Hosp, Boston, MA 02215 USA. [Hauser, Russ] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Miodovnik, A (reprint author), Boston Childrens Hosp, Dev Med Ctr, Boston, MA 02215 USA. EM amir.miodovnik@childrens.harvard.edu NR 81 TC 25 Z9 26 U1 7 U2 49 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X EI 1872-9711 J9 NEUROTOXICOLOGY JI Neurotoxicology PD MAR PY 2014 VL 41 BP 112 EP 122 DI 10.1016/j.neuro.2014.01.007 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA AE6HW UT WOS:000334092200012 PM 24486776 ER PT J AU Swirski, FK Hilgendorf, I Robbins, CS AF Swirski, Filip K. Hilgendorf, Ingo Robbins, Clinton S. TI From proliferation to proliferation: monocyte lineage comes full circle SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE Monocyte; Hematopoiesis; Macrophage; Proliferation; Atherosclerosis ID HEMATOPOIETIC STEM-CELLS; LOW-DENSITY-LIPOPROTEIN; ATHEROSCLEROTIC LESION DEVELOPMENT; MACROPHAGE-SPECIFIC EXPRESSION; TISSUE-RESIDENT MACROPHAGES; ACUTE MYOCARDIAL-INFARCTION; MARROW PROGENITOR CELLS; RECEPTOR KNOCKOUT MICE; A SCAVENGER RECEPTORS; BONE-MARROW AB Monocytes are mononuclear circulating phagocytes that originate in the bone marrow and give rise to macrophages in peripheral tissue. For decades, our understanding of monocyte lineage was bound to a stepwise model that favored an inverse relationship between cellular proliferation and differentiation. Sophisticated molecular and surgical cell tracking tools have transformed our thinking about monocyte topo-ontogeny and function. Here, we discuss how recent studies focusing on progenitor proliferation and differentiation, monocyte mobilization and recruitment, and macrophage differentiation and proliferation are reshaping knowledge of monocyte lineage in steady state and disease. C1 [Swirski, Filip K.; Hilgendorf, Ingo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. [Robbins, Clinton S.] Univ Toronto, Toronto Gen Res Inst, Heart & Stroke Richard Lewar Ctr Excellence Cardi, Toronto, ON M5G 1L7, Canada. RP Swirski, FK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. EM fswirski@mgh.harvard.edu FU NHLBI NIH HHS [R01 HL095612] NR 152 TC 9 Z9 9 U1 2 U2 11 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 EI 1863-2300 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD MAR PY 2014 VL 36 IS 2 BP 137 EP 148 DI 10.1007/s00281-013-0409-1 PG 12 WC Immunology; Pathology SC Immunology; Pathology GA AF1UK UT WOS:000334499200002 PM 24435095 ER PT J AU Nierenberg, A AF Nierenberg, A. TI Comparative effectiveness designs for bipolar disorder: signal or noise? SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-for-Bipolar-Disorders CY MAR 18-21, 2014 CL Seoul, SOUTH KOREA SP Int Soc Bipolar Disorders C1 [Nierenberg, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 SU 1 SI SI BP 34 EP 34 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0FE UT WOS:000332169400048 ER PT J AU Nierenberg, A Hansen, N Peters, A Sylvia, LG Magalhaes, PV Berk, M Otto, M Miklowitz, D Frank, E Deckersbach, T AF Nierenberg, A. Hansen, N. Peters, A. Sylvia, L. G. Magalhaes, P. V. Berk, M. Otto, M. Miklowitz, D. Frank, E. Deckersbach, T. TI Co-morbid anxiety moderates psychosocial treatment outcome for bipolar depression SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-for-Bipolar-Disorders CY MAR 18-21, 2014 CL Seoul, SOUTH KOREA SP Int Soc Bipolar Disorders C1 [Nierenberg, A.; Hansen, N.; Sylvia, L. G.; Deckersbach, T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Peters, A.] Univ Illinois, Chicago, IL USA. [Magalhaes, P. V.] Hosp Clin Porto Alegre, Natl Inst Translat Med, Porto Alegre, RS, Brazil. [Berk, M.] Deakin Univ, Geelong, Vic 3217, Australia. [Otto, M.] Boston Univ, Boston, MA 02215 USA. [Miklowitz, D.] Univ Calif Los Angeles, Los Angeles, CA USA. [Frank, E.] Univ Pittsburgh, Pittsburgh, PA USA. RI Magalhaes, Pedro/A-8519-2008 OI Magalhaes, Pedro/0000-0002-5644-6357 NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 SU 1 SI SI BP 43 EP 44 PG 2 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0FE UT WOS:000332169400073 ER PT J AU Miklowitz, D Stange, J Sylvia, LG Magalhaes, PV Otto, M Frank, E Peters, A Berkh, M Nierenberg, A Deckersbach, T AF Miklowitz, D. Stange, J. Sylvia, L. G. Magalhaes, P. V. Otto, M. Frank, E. Peters, A. Berkh, M. Nierenberg, A. Deckersbach, T. TI Extreme attributions predict the course of bipolar disorder following psychotherapy treatment for depression SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-for-Bipolar-Disorders CY MAR 18-21, 2014 CL Seoul, SOUTH KOREA SP Int Soc Bipolar Disorders C1 [Miklowitz, D.] Univ Calif Los Angeles, Los Angeles, CA USA. [Stange, J.] Temple Univ, Philadelphia, PA 19122 USA. [Sylvia, L. G.; Nierenberg, A.; Deckersbach, T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Magalhaes, P. V.] Hosp Clin Porto Alegre, Natl Inst Translat Med, Porto Alegre, RS, Brazil. [Otto, M.] Boston Univ, Boston, MA 02215 USA. [Frank, E.] Univ Pittsburgh, Pittsburgh, PA USA. [Peters, A.] Univ Illinois, Chicago, IL USA. [Berkh, M.] Deakin Univ, Geelong, Vic 3217, Australia. RI Magalhaes, Pedro/A-8519-2008 OI Magalhaes, Pedro/0000-0002-5644-6357 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 SU 1 SI SI BP 44 EP 44 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0FE UT WOS:000332169400075 ER PT J AU Peters, A Sylvia, LG Magalhaes, PV Miklowitz, D Frank, E Otto, M Berk, M Nierenberg, A Deckersbach, T AF Peters, A. Sylvia, L. G. Magalhaes, P. V. Miklowitz, D. Frank, E. Otto, M. Berk, M. Nierenberg, A. Deckersbach, T. TI Age of onset, course of illness, and response to psychotherapy for bipolar depression SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-for-Bipolar-Disorders CY MAR 18-21, 2014 CL Seoul, SOUTH KOREA SP Int Soc Bipolar Disorders C1 [Peters, A.] Univ Illinois, Chicago, IL USA. [Sylvia, L. G.; Nierenberg, A.; Deckersbach, T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Magalhaes, P. V.] Hosp Clin Porto Alegre, Natl Inst Translat Med, Porto Alegre, RS, Brazil. [Miklowitz, D.] Univ Calif Los Angeles, Los Angeles, CA USA. [Frank, E.] Univ Pittsburgh, Pittsburgh, PA USA. [Otto, M.] Boston Univ, Boston, MA 02215 USA. [Berk, M.] Deakin Univ, Geelong, Vic 3217, Australia. RI Magalhaes, Pedro/A-8519-2008 OI Magalhaes, Pedro/0000-0002-5644-6357 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 SU 1 SI SI BP 44 EP 44 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0FE UT WOS:000332169400074 ER PT J AU Yu, X Ma, Y Si, T Jing, L Liu, Z Gang, W Jing, S Yiru, F Yang, H Zhang, Y Wang, X Gary, S AF Yu, X. Ma, Y. Si, T. Jing Li Liu, Z. Gang Wang Jing Sun Yiru Fang Yang, H. Zhang, Y. Wang, X. Gary, S. TI Bipolarity index as an assessment instrument in the diagnosis and one year outcome of bipolar disorders SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-for-Bipolar-Disorders CY MAR 18-21, 2014 CL Seoul, SOUTH KOREA SP Int Soc Bipolar Disorders C1 [Yu, X.; Ma, Y.; Si, T.] Peking Univ, Inst Mental Hlth, Beijing 100871, Peoples R China. [Jing Li] Sichuan Univ, Hua Xi Psychol Ctr, Chengdu 610064, Peoples R China. [Liu, Z.] Xiang Ya 2nd Hosp, Changsha, Hunan, Peoples R China. [Gang Wang] Beijing Anding Hosp, Beijing, Peoples R China. [Jing Sun] Nanjing Brain Hosp, Nanjing, Jiangsu, Peoples R China. [Yiru Fang] Shanghai Mental Hlth Ctr, Shanghai, Peoples R China. [Yang, H.] Shenzhen Kangning Hosp, Shenzhen, Peoples R China. [Zhang, Y.] Hangzhou 7th Hosp, Hangzhou, Zhejiang, Peoples R China. [Wang, X.] Hebei Med Univ, Hosp 1, Shijiazhuang, Hebei, Peoples R China. [Gary, S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 SU 1 SI SI BP 48 EP 48 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0FE UT WOS:000332169400086 ER PT J AU Baek, JH Bernstein, EE Nierenberg, AA AF Baek, J. H. Bernstein, E. E. Nierenberg, A. A. TI One carbon metabolism and bipolar disorder SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-for-Bipolar-Disorders CY MAR 18-21, 2014 CL Seoul, SOUTH KOREA SP Int Soc Bipolar Disorders C1 [Baek, J. H.; Bernstein, E. E.; Nierenberg, A. A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 SU 1 SI SI BP 51 EP 51 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0FE UT WOS:000332169400096 ER PT J AU Peters, A Sylvia, LG Nierenberg, AA Hansen, N Stange, JP Peckham, AD Deckersbach, T AF Peters, A. Sylvia, L. G. Nierenberg, A. A. Hansen, N. Stange, J. P. Peckham, A. D. Deckersbach, T. TI Cognitive remediation and mindfulness- based cognitive therapy for bipolar disorder SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-for-Bipolar-Disorders CY MAR 18-21, 2014 CL Seoul, SOUTH KOREA SP Int Soc Bipolar Disorders C1 [Peters, A.] Univ Illinois, Chicago, IL USA. [Sylvia, L. G.; Nierenberg, A. A.; Hansen, N.; Deckersbach, T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Stange, J. P.] Temple Univ, Philadelphia, PA 19122 USA. [Peckham, A. D.] Univ Calif Berkeley, Berkeley, CA 94720 USA. NR 0 TC 0 Z9 0 U1 4 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 SU 1 SI SI BP 57 EP 57 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0FE UT WOS:000332169400111 ER PT J AU Sellgren, C Kegel, ME Bergen, SE Ekman, CJ Olsson, S Larsson, M Sullivan, PF Sklar, P Purcell, S Smoller, JW Magnusson, PKE Hultman, CM Walther-Jallow, L Svensson, CI Lichtenstein, P Engberg, G Erhardt, S Landen, M AF Sellgren, C. Kegel, M. E. Bergen, S. E. Ekman, C. J. Olsson, S. Larsson, M. Sullivan, P. F. Sklar, P. Purcell, S. Smoller, J. W. Magnusson, P. K. E. Hultman, C. M. Walther-Jallow, L. Svensson, C. I. Lichtenstein, P. Engberg, G. Erhardt, S. Landen, M. TI An inflammatory pathway linked to psychosis in bipolar disorder SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-for-Bipolar-Disorders CY MAR 18-21, 2014 CL Seoul, SOUTH KOREA SP Int Soc Bipolar Disorders C1 [Sellgren, C.; Bergen, S. E.; Magnusson, P. K. E.; Hultman, C. M.; Lichtenstein, P.; Landen, M.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Kegel, M. E.; Olsson, S.; Larsson, M.; Svensson, C. I.; Engberg, G.; Erhardt, S.] Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. [Ekman, C. J.] Karolinska Inst, Dept Clin Neurosci, Sect Psychiat, Stockholm, Sweden. [Sullivan, P. F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Sullivan, P. F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Sklar, P.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Purcell, S.; Smoller, J. W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Walther-Jallow, L.] Karolinska Inst, Dept Med, Ctr Infect Med, Stockholm, Sweden. RI Magnusson, Patrik/C-4458-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 SU 1 SI SI BP 65 EP 65 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0FE UT WOS:000332169400128 ER PT J AU Ma, Y Yu, X Si, T Li, J Liu, Z Wang, G Sun, J Fang, Y Yang, H Zhang, Y Wang, X Sachs, G AF Ma, Y. Yu, Xin Si, T. Li, Jing Liu, Z. Wang, Gang Sun, Jing Fang, Y. Yang, H. Zhang, Y. Wang, X. Sachs, G. TI Bipolarity index as an assessment instrument in the diagnosis and one year outcome of bipolar disorders SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-for-Bipolar-Disorders CY MAR 18-21, 2014 CL Seoul, SOUTH KOREA SP Int Soc Bipolar Disorders C1 [Ma, Y.; Yu, Xin; Si, T.] Peking Univ, Inst Mental Hlth, Beijing 100871, Peoples R China. [Li, Jing] Sichuan Univ, Huaxi Psychol Ctr, Chengdu 610064, Peoples R China. [Liu, Z.] Xiang Ya 2nd Hosp, Changsha, Hunan, Peoples R China. [Wang, Gang] Beijing Anding Hosp, Beijing, Peoples R China. [Sun, Jing] Nanjing Brain Hosp, Nanjing, Jiangsu, Peoples R China. [Fang, Y.] Shanghai Mental Hlth Ctr, Shanghai, Peoples R China. [Yang, H.] Shenzhen Kangning Hosp, Shenzhen, Peoples R China. [Zhang, Y.] Hangzhou 7th Hosp, Hangzhou, Zhejiang, Peoples R China. [Wang, X.] Hebei Med Univ, Hosp 1, Shijiazhuang, Hebei, Peoples R China. [Sachs, G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 SU 1 SI SI BP 68 EP 68 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0FE UT WOS:000332169400136 ER PT J AU Peters, A West, A Eisner, L Deckersbach, T AF Peters, A. West, A. Eisner, L. Deckersbach, T. TI The burden of recurrent mood episodes in bipolar I disorder: results from the national epidemiological survey on alcohol and related conditions (NESARC) SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-for-Bipolar-Disorders CY MAR 18-21, 2014 CL Seoul, SOUTH KOREA SP Int Soc Bipolar Disorders C1 [Peters, A.; West, A.] Univ Illinois, Chicago, IL USA. [Eisner, L.; Deckersbach, T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 SU 1 SI SI BP 117 EP 118 PG 2 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0FE UT WOS:000332169400286 ER PT J AU Loebel, A Cucchiaro, J Silva, R Sarma, K Kroger, H Calabrese, J Sachs, G Grossman, F Pikalov, A AF Loebel, A. Cucchiaro, J. Silva, R. Sarma, K. Kroger, H. Calabrese, J. Sachs, G. Grossman, F. Pikalov, A. TI Efficacy and safety of lurasidone in bipolar depression: results from two, double blind, placebo-controlled studies SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 16th Annual Conference of the International-Society-for-Bipolar-Disorders CY MAR 18-21, 2014 CL Seoul, SOUTH KOREA SP Int Soc Bipolar Disorders C1 [Loebel, A.; Cucchiaro, J.; Silva, R.; Sarma, K.; Kroger, H.; Grossman, F.; Pikalov, A.] Sunov Pharmaceut Inc, Clin Dev, Ft Lee, NJ USA. [Calabrese, J.] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Sachs, G.] Massachusetts Gen Hosp, Bipolar Clin, Boston, MA 02114 USA. [Sachs, G.] Massachusetts Gen Hosp, Res Program, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 SU 1 SI SI BP 131 EP 132 PG 2 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0FE UT WOS:000332169400332 ER PT J AU Ostergaard, SD Straszek, S Petrides, G Skadhede, S Jensen, SOW Munk-Jorgensen, P Nielsen, J AF Ostergaard, Soren Dinesen Straszek, Sune Petrides, Georgios Skadhede, Soren Jensen, Signe Olrik Wallenstein Munk-Jorgensen, Povl Nielsen, Jimmi TI Risk factors for conversion from unipolar psychotic depression to bipolar disorder SO BIPOLAR DISORDERS LA English DT Article DE epidemiology; bipolar disorder; population register; psychotic mood disorders ID POPULATION-BASED COHORT; DELUSIONAL DEPRESSION; MAJOR DEPRESSION; OLDER-ADULTS; DOUBLE-BLIND; NONPSYCHOTIC DEPRESSION; SCHOOL PERFORMANCE; CONTROLLED-TRIAL; NATIONAL COHORT; I DISORDER AB Objectives Patients with unipolar psychotic depression (PD) are at high risk of developing bipolar disorder (BD). This conversion has important implications for the choice of treatment. This study, therefore, aimed to identify risk factors associated with diagnostic conversion from PD to BD. Methods We conducted a population-based, historical prospective cohort study by merging data from Danish registers. Patients assigned an ICD-10 diagnosis of PD between 1 January 1995 and 31 December 2007 were identified in the Danish Central Psychiatric Research Register and were followed until the development of BD, death, loss to follow-up, or 31 December 2007. Potential risk factors for conversion to BD, also defined through various Danish registers, were tested in multiple logistic regression analyses with risk expressed as adjusted odds ratios (AOR). Results We identified 8,588 patients with PD, of whom 609 (7.1%) developed BD during follow-up. The following characteristics were significantly associated with diagnostic conversion from PD to BD: early onset of PD [AOR=0.99 (per year of increasing age), p=0.044], recurrent depression [AOR=1.02 (per episode), p=0.036], living alone (AOR=1.29, p=0.007), receiving a disability pension (AOR=1.55, p<0.001), and the highest educational level being a technical education (AOR=1.55, p<0.001), short-cycle higher education (AOR=2.65, p<0.001), or medium-cycle higher education (AOR=1.75, p<0.001). Conclusions Diagnostic conversion to BD was prevalent among patients with PD. The following characteristics were significantly associated with this conversion: early onset of PD, recurrent depression, living alone, receiving a disability pension, and the highest educational level being a technical education, short-cycle higher education, or medium-cycle higher education. C1 [Ostergaard, Soren Dinesen; Jensen, Signe Olrik Wallenstein] Aalborg Univ Hosp, Aalborg Psychiat Hosp, Psychiat Res Unit, DK-9000 Aalborg, Denmark. [Ostergaard, Soren Dinesen] Aarhus Univ Hosp, Inst Clin Med, DK-8000 Aarhus, Denmark. [Ostergaard, Soren Dinesen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. [Straszek, Sune] Aarhus Univ Hosp, Dept Q, Risskov, Denmark. [Petrides, Georgios] Northshore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Glen Oaks, NY USA. [Skadhede, Soren; Munk-Jorgensen, Povl] Aarhus Univ Hosp, Dept M, Risskov, Denmark. [Nielsen, Jimmi] Aalborg Univ Hosp, Aalborg Psychiat Hosp, Ctr Schizophrenia, DK-9000 Aalborg, Denmark. RP Ostergaard, SD (reprint author), Aalborg Univ Hosp, Aalborg Psychiat Hosp, Psychiat Res Unit, Molleparkvej 10, DK-9000 Aalborg, Denmark. EM sdo@rn.dk OI Ostergaard, Soren Dinesen/0000-0002-8032-6208 FU Janssen-Cilag; Bristol-Myers Squibb; AstraZeneca; National Institute of Mental Health (NIMH); Novartis; Proteus; Corcept Pharmaceuticals; Sunovion; Servier; Lundbeck; Pfizer; Chempaq; Hemocue FX SDO received speaking fees, consultant honoraria, and travel support from Janssen-Cilag until April 2011; and he received travel support, on one occasion in 2010, from Bristol-Myers Squibb. S. Straszek has received speaking fees from Bristol-Myers Squibb and AstraZeneca; and has served as a consultant to Pfizer. GP has received research support from the National Institute of Mental Health (NIMH), Novartis, Proteus, Corcept Pharmaceuticals, and Sunovion. PM-J has received non-conditional educational grants and/or minor honoraria from AstraZeneca, Janssen-Cilag, Servier, and Bristol-Myers Squibb. JN has received research grants from Lundbeck, Pfizer, and Chempaq for clinical trials; and speaker fees from Bristol-Myers Squibb, AstraZeneca, Janssen-Cilag, Lundbeck, and Hemocue. S. Skadhede and SOWJ have no conflicts of interest to report. NR 83 TC 14 Z9 14 U1 1 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 IS 2 BP 180 EP 189 DI 10.1111/bdi.12152 PG 10 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0TR UT WOS:000332208700011 PM 24215495 ER PT J AU Ostacher, MJ Iosifescu, DV Hay, A Blumenthal, SR Sklar, P Perlis, RH AF Ostacher, Michael J. Iosifescu, Dan V. Hay, Aleena Blumenthal, Sarah R. Sklar, Pamela Perlis, Roy H. TI Pilot investigation of isradipine in the treatment of bipolar depression motivated by genome-wide association SO BIPOLAR DISORDERS LA English DT Article DE proof-of-concept; calcium channel antagonist; depression; dihydropyridine; L-type calcium channel; genome-wide; isradipine; bipolar disorder ID PSYCHIATRIC-DISORDERS; RELIABILITY; VALIDITY; CACNA1C; SCALE AB Objectives Motivated by genetic association data implicating L-type calcium channels in bipolar disorder liability, we sought to estimate the tolerability, safety, and efficacy of isradipine in the adjunctive treatment of bipolar depression. Methods A total of 12 patients with bipolar I or II depression entered this pilot, proof-of-concept eight-week investigation and 10 returned for at least one post-baseline visit. They were initiated on isradipine at 2.5mg and titrated up to 10mg daily, with blinded assessments of depression using the Montgomery-angstrom sberg Depression Rating Scale (MADRS) as well as adverse effects. Results Among the 10 patients, three had bipolar II disorder; all but two reported current episode duration longer than six months. In all, four of 10 completed the study; no significant adverse events were observed, although one subject discontinued treatment per protocol because of possible hypomanic symptoms which had resolved prior to study visit. In a mixed-effects model, mean improvement in depression severity, assessed by MADRS, was 2.1 (standard error=0.36) points/week (p<0.001). Two of the 10 subjects remitted and four of the 10 subjects experienced 50% or greater symptomatic improvement with treatment. Conclusions Isradipine merits further investigation for the treatment of bipolar depression. This preliminary trial illustrates the potential utility of genetic investigation in identifying psychiatric treatment targets. C1 [Ostacher, Michael J.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Iosifescu, Dan V.; Sklar, Pamela] Icahn Sch Med Mt Sinai, Dept Psychiat, Mood & Anxiety Disorders Program, New York, NY USA. [Hay, Aleena] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Blumenthal, Sarah R.; Perlis, Roy H.] Massachusetts Gen Hosp, Ctr Expt Drugs & Diagnost, Dept Psychiat, Boston, MA 02114 USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Ctr Expt Drugs & Diagnost, Dept Psychiat, Simches Res Bldg,185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM rperlis@chgr.mgh.harvard.edu OI Ostacher, Michael/0000-0003-0353-7535 FU Stanley Center for Psychiatric Research at the Broad Institute, Cambridge, MA, USA FX This study was supported by the Stanley Center for Psychiatric Research at the Broad Institute, Cambridge, MA, USA. NR 19 TC 12 Z9 12 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2014 VL 16 IS 2 BP 199 EP 203 DI 10.1111/bdi.12143 PG 5 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AC0TR UT WOS:000332208700013 PM 24372835 ER PT J AU Cho, HJ Herzka, T Zheng, W Qi, J Wilkinson, JE Bradner, JE Robinson, BD Castillo-Martin, M Cordon-Cardo, C Trotman, LC AF Cho, Hyejin Herzka, Tali Zheng, Wu Qi, Jun Wilkinson, John E. Bradner, James E. Robinson, Brian D. Castillo-Martin, Mireia Cordon-Cardo, Carlos Trotman, Lloyd C. TI RapidCaP, a Novel GEM Model for Metastatic Prostate Cancer Analysis and Therapy, Reveals Myc as a Driver of Pten-Mutant Metastasis SO CANCER DISCOVERY LA English DT Article ID ENGINEERED MOUSE MODELS; TUMOR SUPPRESSION; ACTIVATION; MUTATIONS; CELLS; MICE; AKT; IDENTIFICATION; INACTIVATION; INHIBITION AB Genetically engineered mouse (GEM) models are a pillar of functional cancer research. Here, we developed RapidCaP, a GEM modeling system that uses surgical injection for viral gene delivery to the prostate. We show that in Pten deficiency, loss of p53 suffices to trigger metastasis to distant sites at greater than 50% penetrance by four months, consistent with results from human prostate cancer genome analysis. Live bioluminescence tracking showed that endogenous primary and metastatic disease responds to castration before developing lethal castration resistance. To our surprise, the resulting lesions showed no activation of Akt but activation of the Myc oncogene. Using RapidCaP, we find that Myc drives local prostate metastasis and is critical for maintenance of metastasis, as shown by using the Brd4 inhibitor JQ1. Taken together, our data suggest that a "MYC-switch" away from AKT forms a critical and druggable event in PTEN-mutant prostate cancer metastasis and castration resistance. SIGNIFICANCE: The RapidCaP system introduces fast and flexible genetics for functional analysis and therapy for endogenous metastatic prostate cancer. The approach introduces targeting of MYC as a critical strategy against PTEN-deficient lethal prostate cancer. (C) 2014 AACR. C1 [Cho, Hyejin; Herzka, Tali; Zheng, Wu; Trotman, Lloyd C.] Cold Spring Harbor Lab, Ctr Canc, Cold Spring Harbor, NY 11724 USA. [Robinson, Brian D.] Weill Cornell Med Coll, New York Presbyterian Hosp, Dept Pathol & Lab Med, New York, NY USA. [Castillo-Martin, Mireia; Cordon-Cardo, Carlos] Mt Sinai Sch Med, New York, NY USA. [Qi, Jun] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Wilkinson, John E.] Univ Michigan, Sch Med, Unit Lab Anim Med, Ann Arbor, MI USA. RP Trotman, LC (reprint author), Cold Spring Harbor Lab, Ctr Canc, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA. EM trotman@cshl.edu RI Castillo-Martin, Mireia/H-6152-2013 FU NIH [CA137050]; Department of the Army [W81XWH-09-1-0557]; STARR foundation; Robertson Research Fund of CSHL; CSHL CTD2 Cancer Target Discovery and Development Network [U01CA168409] FX This work was supported by grants to L.C. Trotman from the NIH (CA137050), the Department of the Army (W81XWH-09-1-0557), the STARR foundation, the Robertson Research Fund of CSHL, and by support from the CSHL CTD2 Cancer Target Discovery and Development Network Grant (U01CA168409, to S. Powers, Principal Investigator). NR 44 TC 21 Z9 22 U1 0 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD MAR PY 2014 VL 4 IS 3 BP 318 EP 333 DI 10.1158/2159-8290.CD-13-0346 PG 16 WC Oncology SC Oncology GA AE2YC UT WOS:000333838600024 PM 24444712 ER PT J AU Pan, RQ Hogdal, LJ Benito, JM Bucci, D Han, L Borthakur, G Cortes, J DeAngelo, DJ Debose, L Mu, H Dohner, H Gaidzik, VI Galinsky, I Golfman, LS Haferlach, T Harutyunyan, KG Hu, JH Leverson, JD Marcucci, G Muschen, M Newman, R Park, E Ruvolo, PP Ruvolo, V Ryan, J Schindela, S Zweidler-McKay, P Stone, RM Kantarjian, H Andreeff, M Konopleva, M Letai, AG AF Pan, Rongqing Hogdal, Leah J. Benito, Juliana M. Bucci, Donna Han, Lina Borthakur, Gautam Cortes, Jorge DeAngelo, Daniel J. Debose, LaKeisha Mu, Hong Doehner, Hartmut Gaidzik, Verena I. Galinsky, Ilene Golfman, Leonard S. Haferlach, Torsten Harutyunyan, Karine G. Hu, Jianhua Leverson, Joel D. Marcucci, Guido Mueschen, Markus Newman, Rachel Park, Eugene Ruvolo, Peter P. Ruvolo, Vivian Ryan, Jeremy Schindela, Sonja Zweidler-McKay, Patrick Stone, Richard M. Kantarjian, Hagop Andreeff, Michael Konopleva, Marina Letai, Anthony G. TI Selective BCL-2 Inhibition by ABT-199 Causes On-Target Cell Death in Acute Myeloid Leukemia SO CANCER DISCOVERY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ANTI-APOPTOTIC MCL-1; MITOCHONDRIAL APOPTOSIS; STEM-CELLS; ABT-737; SENSITIVITY; BAX; MICROENVIRONMENT; RESISTANCE; PLATELETS AB B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profiling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML. SIGNIFICANCE: Although targeting BCL-2 has largely been investigated in lymphoid cancers, we present preclinical results of targeting BCL-2 in AML. These results support clinical testing of the small-molecule BCL-2 antagonist ABT-199 in AML, accompanied by testing of predictive biomarkers used in this study. C1 [Pan, Rongqing; Benito, Juliana M.; Han, Lina; Borthakur, Gautam; Cortes, Jorge; Debose, LaKeisha; Mu, Hong; Harutyunyan, Karine G.; Ruvolo, Peter P.; Ruvolo, Vivian; Kantarjian, Hagop; Andreeff, Michael; Konopleva, Marina] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Golfman, Leonard S.; Zweidler-McKay, Patrick] Univ Texas MD Anderson Canc Ctr, Dept Pediat, Houston, TX 77030 USA. [Hu, Jianhua; Newman, Rachel] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Hogdal, Leah J.; Letai, Anthony G.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Hogdal, Leah J.; DeAngelo, Daniel J.; Galinsky, Ilene; Ryan, Jeremy; Stone, Richard M.; Letai, Anthony G.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bucci, Donna; Marcucci, Guido] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Leverson, Joel D.] AbbVie Inc, N Chicago, IL USA. [Mueschen, Markus; Park, Eugene] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Doehner, Hartmut; Gaidzik, Verena I.] Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany. [Haferlach, Torsten; Schindela, Sonja] MLL Munich Leukemia Lab, Munich, Germany. RP Letai, AG (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM mkonople@mdanderson.org; Anthony_Letai@dfci.harvard.edu RI Han, Lina/J-5119-2015; OI Han, Lina/0000-0003-1538-1734; Zweidler-McKay, Patrick/0000-0001-6621-523X; Pan, Rongqing/0000-0002-9494-412X FU Leukemia and Lymphoma Society [6387-13, LS2012-36558, AML-P01 5 P01 CA055164-19] FX This work was supported by funds from the Leukemia and Lymphoma Society Translational Research Award 6387-13 (to A. Letai) and LS2012-36558 and AML-P01 5 P01 CA055164-19 (to M. Konopleva and M. Andreeff). NR 31 TC 87 Z9 87 U1 4 U2 32 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD MAR PY 2014 VL 4 IS 3 BP 362 EP 375 DI 10.1158/2159-8290.CD-13-0609 PG 14 WC Oncology SC Oncology GA AE2YC UT WOS:000333838600027 PM 24346116 ER PT J AU Giri, J Yeh, RW Kennedy, KF Hawkins, BM Weinberg, I Weinberg, MD Parikh, SA Garasic, J Jaff, MR White, CJ Rosenfield, K AF Giri, Jay Yeh, Robert W. Kennedy, Kevin F. Hawkins, Beau M. Weinberg, Ido Weinberg, Mitchell D. Parikh, Sahil A. Garasic, Joseph Jaff, Michael R. White, Christopher J. Rosenfield, Kenneth TI Unprotected Carotid Artery Stenting in Modern Practice SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article ID CEREBRAL PROTECTION DEVICES; RANDOMIZED-TRIAL; ACUTE STROKE; ANGIOPLASTY; OUTCOMES; PREDICTORS; REGISTRY; RISK C1 [Giri, Jay] Hosp Univ Penn, Cardiovasc Med Div, Philadelphia, PA 19104 USA. [Yeh, Robert W.; Hawkins, Beau M.; Weinberg, Ido; Weinberg, Mitchell D.; Garasic, Joseph; Jaff, Michael R.; Rosenfield, Kenneth] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Kennedy, Kevin F.] Univ Missouri, St Lukes Midamer Heart Inst, Kansas City, MO 64110 USA. [Parikh, Sahil A.] Univ Hosp Harrington Heart & Vasc Inst, Cleveland, OH USA. [Parikh, Sahil A.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [White, Christopher J.] Ochsner Med Ctr, John Ochsner Heart & Vasc Inst, New Orleans, LA USA. RP Giri, J (reprint author), Hosp Univ Penn, Cardiovasc Med Div, Gates Pavill,9th Floor,3400 Spruce St, Philadelphia, PA 19104 USA. EM giri.jay@gmail.com RI White, Christopher/J-6686-2012 OI White, Christopher/0000-0001-8618-7539 FU Abbott Vascular; Bard Peripheral Vascular; Medtronic/Invatec; Atrium; Boston Scientific Corp; Complete Conference Management; Harvard Clinical Research Institute; Contego; Micell; Becker Ventures; Becker Venture Services; Bluegrass Vascular Therapies; Hansen Biomedical; Trivascular; Vortex Medical; Medtronic; CR Bard FX Dr. Yeh is an investigator at the Harvard Clinical Research Institute and has served as a consultant for the Kaiser Permanente Division of Research. Dr. White is an investigator for the Carotid Stenting Boston Scientific Surveillance Program (CABANA) trial from Boston Scientific Corp. Dr. Rosenfield reports receiving research grants from Abbott Vascular, Bard Peripheral Vascular, Medtronic/Invatec, and Atrium; receiving consulting/advisory board fees from Abbott Vascular, Boston Scientific Corp, Complete Conference Management, Harvard Clinical Research Institute, Contego, Micell, and Becker Ventures; having equity in Lumen Biomedical, Medical Stimulation Corp, Angioguard (Cordis), and Micell; and serving on the board of directors for VIVA Physicians (501C3). Dr. Jaff reports that he is a noncompensated advisor to Abbott Vascular, Cordis Corporation, Covidien Vascular, Medtronic Vascular; received advisory board fees from Becker Venture Services, Bluegrass Vascular Therapies, Hansen Biomedical, Trivascular, and Vortex Medical; has equity interests in Access Closure, Embolitech, Hotspur, Icon Interventional, I. C. Sciences, Janacare, Northwind Medical, PQ Bypass, Primacea, Sadra Medical, Trireme, Vascular Therapies; and is a member of the board of directors of VIVA Physicians, a 501(c) 3 education and research not-for-profit organization. Dr. Parikh receives research grants from Medtronic and CR Bard and is a consultant to Medtronic and Boston Scientific. Dr. Giri, Dr. Hawkins, Mr. Kennedy, Dr. I. Weinberg, and Dr. M. Weinberg have no relevant disclosures. NR 22 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1522-1946 EI 1522-726X J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD MAR 1 PY 2014 VL 83 IS 4 BP 595 EP 602 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AA9WR UT WOS:000331444200016 PM 23804411 ER PT J AU Weinberg, I Keyes, MJ Giri, J Rogers, KR Olin, JW White, CJ Jaff, MR AF Weinberg, Ido Keyes, Michelle J. Giri, Jay Rogers, Kevin R. Olin, Jeffrey W. White, Christopher J. Jaff, Michael R. TI Blood Pressure Response to Renal Artery Stenting in 901 Patients From Five Prospective Multicenter FDA-Approved Trials SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article ID ATHEROSCLEROTIC RENOVASCULAR DISEASE; FRACTIONAL FLOW RESERVE; 4-YEAR FOLLOW-UP; HYPERTENSIVE PATIENTS; BALLOON ANGIOPLASTY; RANDOMIZED-TRIAL; PERCUTANEOUS REVASCULARIZATION; MEDICAL THERAPY; CLINICAL-TRIALS; STENOSIS C1 [Weinberg, Ido; Keyes, Michelle J.; Jaff, Michael R.] Massachusetts Gen Hosp, Inst Heart Vasc & Stroke Care, Boston, MA 02114 USA. [Giri, Jay] Univ Penn, Cardiovasc Med Div, Philadelphia, PA 19104 USA. [Rogers, Kevin R.] Univ Colorado, Div Cardiol, Denver, CO 80202 USA. [Olin, Jeffrey W.] Icahn Sch Med, Zena & Michael A Wiener Cardiovasc Inst, New York, NY USA. [Olin, Jeffrey W.] Icahn Sch Med, Marie Josee & Henry R Kravis Ctr Cardiovasc Hlth, New York, NY USA. [White, Christopher J.] Univ Queensland, Ochsner Clin Sch, John Ochsner Heart & Vasc Inst, New Orleans, LA USA. [White, Christopher J.] Ochsner Hlth Syst, New Orleans, LA USA. RP Jaff, MR (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Warren 905, Boston, MA 02114 USA. EM mjaff@partners.org RI White, Christopher/J-6686-2012 OI White, Christopher/0000-0001-8618-7539 FU Neovasc, Vancouver, BC, Canada; St. Jude Medical, Saint Paul, MN FX Conflict of interest: Michael R. Jaff: Board member, VIVA Physicians, a 501 c 3 not-for-profit education and research organization. Christopher J. White: Research grant recipient with Neovasc, Vancouver, BC, Canada and St. Jude Medical, Saint Paul, MN. NR 35 TC 13 Z9 13 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1522-1946 EI 1522-726X J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD MAR 1 PY 2014 VL 83 IS 4 BP 603 EP 609 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AA9WR UT WOS:000331444200017 PM 24307609 ER PT J AU del Conde, I Galin, ID Trost, B Kang, J Lookstein, R Woodward, M Gustavson, S Cambria, RP Jaff, MR Olin, JW AF del Conde, Ian Galin, Ira D. Trost, Biana Kang, Jeanwan Lookstein, Robert Woodward, Mark Gustavson, Susan Cambria, Richard P. Jaff, Michael R. Olin, Jeffrey W. TI Renal Artery Duplex Ultrasound Criteria for the Detection of Significant In-Stent Restenosis SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article ID MULTIDETECTOR CT ANGIOGRAPHY; FOLLOW-UP; VELOCITY CRITERIA; CAROTID-ARTERY; DOPPLER ULTRASOUND; STENOSIS; ULTRASONOGRAPHY; DIAGNOSIS; DISEASE; INTERVENTIONS C1 [del Conde, Ian; Galin, Ira D.; Trost, Biana; Gustavson, Susan; Olin, Jeffrey W.] Icahn Sch Med Mt Sinai, Zena & Michael A Wiener Cardiovasc Inst, New York, NY USA. [del Conde, Ian; Galin, Ira D.; Trost, Biana; Gustavson, Susan; Olin, Jeffrey W.] Icahn Sch Med Mt Sinai, Marie Josee & Henry R Kravis Ctr Cardiovasc Hlth, New York, NY USA. [Kang, Jeanwan; Cambria, Richard P.; Jaff, Michael R.] Massachusetts Gen Hosp, Vasc Ctr, Boston, MA 02114 USA. [Lookstein, Robert] Icahn Sch Med Mt Sinai, Dept Radiol, Div Vasc & Intervent Radiol, New York, NY USA. [Woodward, Mark] Univ Sydney, George Inst Global Hlth, Sydney, NSW 2006, Australia. RP Olin, JW (reprint author), Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, One Gustave L Levy Pl,Box 1033, New York, NY 10029 USA. EM jeffrey.olin@mountsinai.org RI Woodward, Mark/D-8492-2015 NR 37 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1522-1946 EI 1522-726X J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD MAR 1 PY 2014 VL 83 IS 4 BP 612 EP 618 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AA9WR UT WOS:000331444200019 PM 24155154 ER PT J AU Filbin, MR Arias, SA Camargo, CA Barche, A Pallin, DJ AF Filbin, Michael R. Arias, Sarah A. Camargo, Carlos A., Jr. Barche, Apurv Pallin, Daniel J. TI Sepsis Visits and Antibiotic Utilization in U.S. Emergency Departments SO CRITICAL CARE MEDICINE LA English DT Article DE antibacterial agents; emergency treatment; epidemiology; mortality; sepsis ID RESISTANT STAPHYLOCOCCUS-AUREUS; GOAL-DIRECTED THERAPY; UNITED-STATES; SEPTIC SHOCK; ANTIMICROBIAL THERAPY; EPIDEMIOLOGY; POPULATION; INFECTIONS; MORTALITY; SURVIVAL AB Objectives: To monitor the frequency of sepsis visits in U.S. emergency departments and assess the appropriateness of antibiotic utilization. Design: We analyzed data from the National Hospital Ambulatory Medical Care Survey, defining sepsis as an explicit diagnosis of sepsis via International Classification of Diseases, 9th Revision, Clinical Modification codes 038, 995.91, 995.92, or 785.52. We also monitored trends using cases inferred by infection plus organ dysfunction without explicit diagnosis of sepsis, which we refer to as implicit sepsis cases. We assess changes in visit frequency and ascertain emergency department antibiotic administration rates. Setting: Four-stage probability sample of visits to U.S. emergency departments, excluding Federal/military. Patients: Adult emergency department visits, United States, 1994-2009. Measurements and Main Results: Sepsis was diagnosed explicitly at 260,000 visits per year in U.S. emergency departments (95% CI, 251,000-270,000) or 1.23 visits per 1,000 U.S. population. The visit rate remained stable from 1994 to 2009 (p for trend 0.42). By contrast, the rate of visits with an implicit diagnosis of sepsis increased by 0.07 every 2 years (95% CI, 0.04-0.10; p for trend 0.002). Antibiotics were prescribed in the emergency department during 61% (95% CI, 57-65) of explicit sepsis visits. This increased from 52% in 1994-1997 to 69% in 2006-2009 (difference, 17%; 95% CI, 16.8-17.2). Of antibiotic regimens, 18% covered methicillin-resistant Staphylococcus aureus, 27% Pseudomonas, and 10% extended-spectrum beta-lactamase-producing bacteria, without evidence of targeting according to known risk factors. Of explicit sepsis cases, 31% were admitted to the ICU with 40% mortality (95% CI, 30-51). Overall hospital mortality was 17% (95% CI, 11-22). Conclusions: Explicitly diagnosed sepsis visits did not become more common during 1994-2009. Our data suggest that many emergency department patients with sepsis do not receive antibiotics until they arrive on the inpatient unit. When antibiotics are used among septic emergency department patients, drug-resistant bacteria are covered infrequently. These methods provide a simple approach to tracking the frequency with which sepsis is diagnosed among emergency department patients and to monitoring antibiotic therapy. C1 [Filbin, Michael R.; Arias, Sarah A.; Camargo, Carlos A., Jr.; Barche, Apurv] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Pallin, Daniel J.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Pallin, Daniel J.] Cambridge Hlth Alliance, Dept Emergency Med, Cambridge, MA USA. RP Filbin, MR (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. EM mfilbin@partners.org RI Pallin, Daniel/H-6382-2013; OI Pallin, Daniel/0000-0002-8517-9702; Arias, Sarah/0000-0003-1832-8824 FU Department of Emergency Medicine at Massachusetts General Hospital FX Dr. Filbin is employed by the Massachusetts General Hospital, provided expert testimony for Padberg & Corrigan Law Firm, and receives royalties from Wolters Kluwer/Lippincott Williams & Wilkins. Dr. Arias' institution received support for review activities from Emergency Medicine Network (EMNet-a seed grant from the Department of Emergency Medicine at Massachusetts General Hospital was used to pay for Dr. Arias' time on this project). The remaining authors have disclosed that they do not have any potential conflicts of interest. NR 27 TC 16 Z9 16 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD MAR PY 2014 VL 42 IS 3 BP 528 EP 535 DI 10.1097/CCM.0000000000000037 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA AA9AX UT WOS:000331387200033 PM 24201179 ER PT J AU Shaikh, H Laghi, F AF Shaikh, Hameeda Laghi, Franco TI Eating on Noninvasive Ventilation SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE chronic obstructive pulmonary disease; noninvasive ventilation; nutrition; respiratory failure; swallowing ID OBSTRUCTIVE PULMONARY-DISEASE; COORDINATION; VOLUME; RESPIRATION; TUBE C1 [Shaikh, Hameeda] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Pulm & Crit Care Sect, Hines, IL 60141 USA. [Laghi, Franco] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Div Pulm & Crit Care Med, Hines, IL 60141 USA. [Laghi, Franco] Loyola Univ, Div Pulm & Crit Care, Dept Med, Maywood, IL 60153 USA. RP Shaikh, H (reprint author), US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Pulm & Crit Care Sect, Roosevelt Rd & 5th Ave, Hines, IL 60141 USA. NR 15 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD MAR PY 2014 VL 42 IS 3 BP 737 EP 738 DI 10.1097/CCM.0000000000000002 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA AA9AX UT WOS:000331387200062 PM 24534964 ER PT J AU Saddawi-Konefka, D Berg, SM Nejad, SH Bittner, EA AF Saddawi-Konefka, Daniel Berg, Sheri M. Nejad, Shamim H. Bittner, Edward A. TI Catatonia in the ICU: An Important and Underdiagnosed Cause of Altered Mental Status. A Case Series and Review of the Literature SO CRITICAL CARE MEDICINE LA English DT Letter DE antipsychotic agents; benzodiazepines; catatonia; critical care; delirium; dopamine antagonists; encephalopathy; neuroleptic malignant syndrome; psychiatry ID NEUROLEPTIC MALIGNANT SYNDROME; BENZODIAZEPINE WITHDRAWAL; ELECTROCONVULSIVE-THERAPY; LETHAL CATATONIA; RISK-FACTOR; ECT; LORAZEPAM AB Objective: Catatonia is a neuropsychiatric syndrome with motor and behavioral symptoms occurring in patients with or without a history of psychiatric illness. Although it is associated with significant morbidity and mortality, the prevalence of catatonia in the ICU setting is unknown. The diagnosis and management of catatonia in the critically ill patient raises unique challenges. Furthermore, the diagnosis and management are not included in most critical care curricula. The objective of this retrospective study is to increase the awareness of this clinically important condition among critical care providers. Design: Retrospective case series study. Setting: Multiple critical care units at a university-affiliated tertiary care hospital. Patients: Five critically ill patients with catatonia, aged 17 to 78. Interventions: None. Measurements and Main Results: All notes, laboratory data, imaging results, other diagnostic studies, therapeutic interventions, and responses to treatment were reviewed for five critically ill patients with catatonia. No unifying cause of catatonia or predisposing conditions were identified for these patients. Currently available diagnostic criteria for catatonia were found to be nonspecific in the ICU setting. New diagnostic criteria for catatonia specific to the critically ill patient are proposed. Conclusions: Catatonia can occur in a wide variety of critical care settings, with or without precedent psychiatric illness, and it may be exacerbated or induced by common intensive care practices. Psychomotor findings are imperative in examination of critically ill patients with altered mental status in order to diagnose catatonia. C1 [Saddawi-Konefka, Daniel; Berg, Sheri M.; Bittner, Edward A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Nejad, Shamim H.] Massachusetts Gen Hosp, Div Psychiat & Med, Dept Psychiat, Psychiat Consultat Serv, Boston, MA 02114 USA. RP Saddawi-Konefka, D (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,WHT 437, Boston, MA 02114 USA. EM dsaddawi@gmail.com NR 33 TC 10 Z9 10 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD MAR PY 2014 VL 42 IS 3 BP E234 EP E241 DI 10.1097/CCM.0000000000000053 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA AA9AX UT WOS:000331387200007 PM 24275514 ER PT J AU Zulauf, CA Sprich, SE Safren, SA Wilens, TE AF Zulauf, Courtney A. Sprich, Susan E. Safren, Steven A. Wilens, Timothy E. TI The Complicated Relationship Between Attention Deficit/Hyperactivity Disorder and Substance Use Disorders SO CURRENT PSYCHIATRY REPORTS LA English DT Article DE Adolescence; Substance use disorders; Attention deficit/hyperactivity disorder; Stimulants comorbidity; Cognitive-behavioral therapy ID DEFICIT-HYPERACTIVITY DISORDER; RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIORAL THERAPY; MEDICATION-TREATED ADULTS; PLACEBO-CONTROLLED TRIAL; OSMOTIC-RELEASE METHYLPHENIDATE; ALCOHOL-USE DISORDERS; SUPPLEMENT NCS-A; FOLLOW-UP; DRUG-USE AB Adolescents and young adults with substance use disorders (SUD) and attention deficit/hyperactivity disorder (ADHD) are increasingly presenting in clinical practice. The overlap and role of treatment for these co-occurring disorders remains unclear. A review of the literature was conducted to highlight and update recent evidence on the overlap of ADHD and SUD, the role of ADHD medication on later SUD, and the treatment of ADHD and SUD in adolescents and young adults. Recent work continues to highlight the high risk for comorbid ADHD in patients with SUD; and conversely, the high risk for SUD developing in ADHD across the lifespan, particularly in the context of comorbid conduct disorder. Although the data remains discordant, it appears that ADHD pharmacotherapy does not increase the risk for SUD. Medication treatment alone does not appear to be particularly effective in treating SUD in currently active substance abusing individuals with ADHD. Structured therapies may be effective in treating adolescents and young adults with ADHD and SUD. Further controlled trials evaluating the sequence and effect of structured psychotherapies and/or ADHD pharmacotherapy on SUD relapse in these groups are warranted. C1 [Zulauf, Courtney A.; Wilens, Timothy E.] Massachusetts Gen Hosp, Clin Program Pediat Psychopharmacol & Adult ADHD, Boston, MA 02114 USA. [Zulauf, Courtney A.; Wilens, Timothy E.] Massachusetts Gen Hosp, Res Program Pediat Psychopharmacol & Adult ADHD, Boston, MA 02114 USA. [Sprich, Susan E.] Massachusetts Gen Hosp, Cognit Behav Therapy Program, Boston, MA 02114 USA. [Safren, Steven A.] Massachusetts Gen Hosp, Dept Behav Med, Boston, MA 02114 USA. [Wilens, Timothy E.] Massachusetts Gen Hosp, Ctr Addict Med, Boston, MA 02114 USA. [Wilens, Timothy E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wilens, TE (reprint author), Massachusetts Gen Hosp, YAW 6A,55 Fruit St, Boston, MA 02114 USA. EM twilens@partners.org FU NIH(NIDA); Shire FX Dr. Timothy Wilens receives or has received grant support from the following sources: NIH(NIDA) and Shire. Dr. Wilens is or has been a consultant for: Euthymics, NIH (NIDA), Shire, Tris and Theravance. Dr. Wilens has a published book with Guilford Press. Straight Talk About Psychiatric Medications for Kids. Dr. Wilens is a consultant to the US National Football League (ERM Associates), U.S. Minor/Major League Baseball and Bay Cove Human Services (Clinical Services). NR 92 TC 13 Z9 13 U1 2 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 EI 1535-1645 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD MAR PY 2014 VL 16 IS 3 AR 436 DI 10.1007/s11920-013-0436-6 PG 11 WC Psychiatry SC Psychiatry GA AE5VP UT WOS:000334057700003 PM 24526271 ER PT J AU Guenova, E Watanabe, R Gehad, A Teague, JE Adams, N Dorosario, AA Glinert, R Walsch, D Tawa, M Carter, JB Chaney, KA Fisher, DE Cutler, CS Kupper, TS Clark, RA AF Guenova, E. Watanabe, R. Gehad, A. Teague, J. E. Adams, N. Dorosario, A. A. Glinert, R. Walsch, D. Tawa, M. Carter, J. B. Chaney, K. A. Fisher, D. E. Cutler, C. S. Kupper, T. S. Clark, R. A. TI Reversible suppression of normal thymic output in patients with leukemic cutaneous T cell lymphoma SO EXPERIMENTAL DERMATOLOGY LA English DT Meeting Abstract CT 41st Annual Meeting of the Arbeitsgemeinschaft-Dermatologische-Forschung (ADF) CY MAR 13-15, 2014 CL Cologne, GERMANY SP Arbeitsgemeinschaft Dermatologische Forsch C1 Harvard Univ, Skin Dis Res Ctr, Boston, MA 02446 USA. Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02446 USA. RI Guenova, Emmanuella/A-4656-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0906-6705 EI 1600-0625 J9 EXP DERMATOL JI Exp. Dermatol. PD MAR PY 2014 VL 23 IS 3 BP E35 EP E35 PG 1 WC Dermatology SC Dermatology GA AC2MP UT WOS:000332335500228 ER PT J AU Tosto, MG Petrill, SA Halberda, J Trzaskowski, M Tikhomirova, TN Bogdanova, OY Ly, R Wilmer, JB Naiman, DQ Germine, L Plomin, R Kovas, Y AF Tosto, M. G. Petrill, S. A. Halberda, J. Trzaskowski, M. Tikhomirova, T. N. Bogdanova, O. Y. Ly, R. Wilmer, J. B. Naiman, D. Q. Germine, L. Plomin, R. Kovas, Y. TI Why do we differ in number sense? Evidence from a genetically sensitive investigation SO INTELLIGENCE LA English DT Article DE Number sense; Mathematical ability; Behaviour genetics; Heritability Directional selection ID MATHEMATICAL LEARNING-DISABILITY; EARLY LITERACY DEVELOPMENT; GENOME-WIDE ASSOCIATION; COMMON SNPS EXPLAIN; INDIVIDUAL-DIFFERENCES; ENVIRONMENTAL ETIOLOGY; NUMERICAL CAPACITIES; CONTINUOUS QUANTITY; GENDER-DIFFERENCES; LONGITUDINAL TWIN AB Basic intellectual abilities of quantity and numerosity estimation have been detected across animal species. Such abilities are referred to as 'number sense'. For human species, individual differences in number sense are detectable early in life, persist in later development, and relate to general intelligence. The origins of these individual differences are unknown. To address this question, we conducted the first large-scale genetically sensitive investigation of number sense, assessing numerosity discrimination abilities in 837 pairs of monozygotic and 1422 pairs of dizygotic 16-year-old twin pairs. Univariate genetic analysis of the twin data revealed that number sense is modestly heritable (32%), with individual differences being largely explained by non-shared environmental influences (68%) and no contribution from shared environmental factors. Sex-Limitation model fitting revealed no differences between males and females in the etiology of individual differences in number sense abilities. We also carried out Genome-wide Complex Trait Analysis (GCTA) that estimates the population variance explained by additive effects of DNA differences among unrelated individuals. For 1118 unrelated individuals in our sample with genotyping information on 1.7 million DNA markers, GCTA estimated zero heritability for number sense, unlike other cognitive abilities in the same twin study where the GCTA heritability estimates were about 25%. The low heritability of number sense, observed in this study, is consistent with the directional selection explanation whereby additive genetic variance for evolutionary important traits is reduced. (C) 2014 The Authors. Published by Elsevier Inc. All rights reserved. C1 [Tosto, M. G.] Univ York, Dept Psychol, York YO10 5DD, N Yorkshire, England. [Tosto, M. G.; Tikhomirova, T. N.; Bogdanova, O. Y.; Kovas, Y.] Tomsk State Univ, Dept Psychol, Tomsk 634050, Russia. [Petrill, S. A.] Ohio State Univ, Columbus, OH 43210 USA. [Halberda, J.; Ly, R.; Naiman, D. Q.] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD 21218 USA. [Trzaskowski, M.; Plomin, R.; Kovas, Y.] Kings Coll London, MRC Social Genet & Dev Psychiat Ctr, Inst Psychiat, London SE5 8AF, England. [Wilmer, J. B.] Wellesley Coll, Dept Psychol, Wellesley, MA 02481 USA. [Germine, L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Kovas, Y.] Univ London, London SE14 6NW, England. RP Tosto, MG (reprint author), Univ York, Dept Psychol, York YO10 5DD, N Yorkshire, England. EM maria.tosto@york.ac.uk RI Bogdanova, Olga/N-3018-2014; Tikhomirova, Tatiana/N-3016-2014; OI Ly, Ryan/0000-0001-9238-0642; Plomin, Robert/0000-0002-0756-3629; Germine, Laura/0000-0001-8690-8412; Trzaskowski, Maciej/0000-0001-8559-6525 FU European Research Council [295366]; Medical Research Council [G0500079, G0500079(73692), G0901245, G9817803B]; NICHD NIH HHS [R01 HD044454, R01 HD046167, R01 HD059215, R01 HD068728] NR 87 TC 4 Z9 5 U1 4 U2 26 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0160-2896 EI 1873-7935 J9 INTELLIGENCE JI Intelligence PD MAR-APR PY 2014 VL 43 BP 35 EP 46 DI 10.1016/j.intell.2013.12.007 PG 12 WC Psychology, Multidisciplinary SC Psychology GA AE5DG UT WOS:000334007400005 PM 24696527 ER PT J AU Mueller, EL Park, ER Davis, MM AF Mueller, Emily L. Park, Elyse R. Davis, Matthew M. TI What the Affordable Care Act Means for Survivors of Pediatric Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID HEALTH-INSURANCE COVERAGE; CHILDHOOD-CANCER; ADULT SURVIVORS C1 [Mueller, Emily L.; Davis, Matthew M.] Univ Michigan, Ann Arbor, MI 48109 USA. [Park, Elyse R.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Davis, Matthew M.] Inst Healthcare Policy & Innovat, Ann Arbor, MI USA. RP Mueller, EL (reprint author), Univ Michigan, Ann Arbor, MI 48109 USA. FU NICHD NIH HHS [T32 HD007534, T32 HD07534] NR 14 TC 9 Z9 9 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2014 VL 32 IS 7 BP 615 EP + DI 10.1200/JCO.2013.52.6467 PG 4 WC Oncology SC Oncology GA AC4HY UT WOS:000332483100005 PM 24395862 ER PT J AU Schwartz, MD Valdimarsdottir, HB Peshkin, BN Mandelblatt, J Nusbaum, R Huang, AT Chang, YJ Graves, K Isaacs, C Wood, M McKinnon, W Garber, J McCormick, S Kinney, AY Luta, G Kelleher, S Leventhal, KG Vegella, P Tong, A King, L AF Schwartz, Marc D. Valdimarsdottir, Heiddis B. Peshkin, Beth N. Mandelblatt, Jeanne Nusbaum, Rachel Huang, An-Tsun Chang, Yaojen Graves, Kristi Isaacs, Claudine Wood, Marie McKinnon, Wendy Garber, Judy McCormick, Shelley Kinney, Anita Y. Luta, George Kelleher, Sarah Leventhal, Kara-Grace Vegella, Patti Tong, Angie King, Lesley TI Randomized Noninferiority Trial of Telephone Versus In-Person Genetic Counseling for Hereditary Breast and Ovarian Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID POLICY STATEMENT UPDATE; COST-EFFECTIVENESS; MUTATION CARRIERS; AMERICAN-SOCIETY; RISK; SUSCEPTIBILITY; COMMUNICATION; BRCA1; WOMEN; VALIDATION AB Purpose Although guidelines recommend in-person counseling before BRCA1/BRCA2 gene testing, genetic counseling is increasingly offered by telephone. As genomic testing becomes more common, evaluating alternative delivery approaches becomes increasingly salient. We tested whether telephone delivery of BRCA1/2 genetic counseling was noninferior to in-person delivery. Patients and Methods Participants (women age 21 to 85 years who did not have newly diagnosed or metastatic cancer and lived within a study site catchment area) were randomly assigned to usual care (UC; n = 334) or telephone counseling (TC; n = 335). UC participants received in-person pre- and post-test counseling; TC participants completed all counseling by telephone. Primary outcomes were knowledge, satisfaction, decision conflict, distress, and quality of life; secondary outcomes were equivalence of BRCA1/2 test uptake and costs of delivering TC versus UC. Results TC was noninferior to UC on all primary outcomes. At 2 weeks after pretest counseling, knowledge (d = 0.03; lower bound of 97.5% CI, -0.61), perceived stress (d = -0.12; upper bound of 97.5% CI, 0.21), and satisfaction (d = -0.16; lower bound of 97.5% CI, -0.70) had group differences and confidence intervals that did not cross their 1-point noninferiority limits. Decision conflict (d = 1.1; upper bound of 97.5% CI, 3.3) and cancer distress (d = -1.6; upper bound of 97.5% CI, 0.27) did not cross their 4-point noninferiority limit. Results were comparable at 3 months. TC was not equivalent to UC on BRCA1/2 test uptake (UC, 90.1%; TC, 84.2%). TC yielded cost savings of $114 per patient. Conclusion Genetic counseling can be effectively and efficiently delivered via telephone to increase access and decrease costs. C1 [Schwartz, Marc D.; Peshkin, Beth N.; Mandelblatt, Jeanne; Nusbaum, Rachel; Huang, An-Tsun; Chang, Yaojen; Graves, Kristi; Isaacs, Claudine; Luta, George; Kelleher, Sarah; Leventhal, Kara-Grace; Vegella, Patti; Tong, Angie; King, Lesley] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Valdimarsdottir, Heiddis B.] Mt Sinai Sch Med, New York, NY USA. [Wood, Marie; McKinnon, Wendy] Univ Vermont, Coll Med, Vermont Canc Ctr, Familial Canc Program, Burlington, VT USA. [Garber, Judy; McCormick, Shelley] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Kinney, Anita Y.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Kinney, Anita Y.] Huntsman Canc Inst, Salt Lake City, UT USA. RP Schwartz, MD (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. EM schwartm@georgetown.edu RI Kelly, Scott/D-3195-2013; OI Kelly, Scott/0000-0002-0375-1040; Luta, George/0000-0001-9013-2207; Luta, George/0000-0002-4035-7632 FU National Cancer Institute [R01 CA108933, U01 CA152958, P30 CA051008]; Lombardi Comprehensive Cancer Center Biostatistics and Bioinformatics Shared Resource; Jess and Mildred Fisher Center for Familial Cancer Research FX Supported by Grants No. R01 CA108933, U01 CA152958, and P30 CA051008 from the National Cancer Institute; by the Lombardi Comprehensive Cancer Center Biostatistics and Bioinformatics Shared Resource; and by the Jess and Mildred Fisher Center for Familial Cancer Research. NR 54 TC 42 Z9 42 U1 2 U2 10 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2014 VL 32 IS 7 BP 618 EP + DI 10.1200/JCO.2013.51.3226 PG 10 WC Oncology SC Oncology GA AC4HY UT WOS:000332483100006 PM 24449235 ER PT J AU Siddiqui, JD Loeffler, JS Murphy, MA AF Siddiqui, Jamal D. Loeffler, Jay S. Murphy, Marjorie A. TI Response SO JOURNAL OF NEURO-OPHTHALMOLOGY LA English DT Letter C1 [Siddiqui, Jamal D.] Rhode Isl Hosp, Dept Ophthalmol, Providence, RI 02903 USA. [Loeffler, Jay S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Murphy, Marjorie A.] Providence Vet Affairs Med Ctr, Dept Ophthalmol, Providence, RI USA. RP Siddiqui, JD (reprint author), Rhode Isl Hosp, Dept Ophthalmol, Providence, RI 02903 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 1070-8022 EI 1536-5166 J9 J NEURO-OPHTHALMOL JI J. Neuro-Ophthal. PD MAR PY 2014 VL 34 IS 1 BP 102 EP 102 DI 10.1097/01.wno.0000444665.80302.c7 PG 1 WC Clinical Neurology; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA AB5AV UT WOS:000331802200033 PM 24531321 ER PT J AU Hansen, L Leo, MC Chang, MF Zucker, BL Sasaki, A AF Hansen, Lissi Leo, Michael C. Chang, Michael F. Zucker, Betsy L. Sasaki, Anna TI Pain and Self-Care Behaviours in Adult Patients with End-Stage Liver Disease: A longitudinal description SO JOURNAL OF PALLIATIVE CARE LA English DT Article DE palliative care; survival time; simple prognostic scores ID QUALITY-OF-LIFE; INTEGRATING PALLIATIVE CARE; CANCER PAIN; PSYCHOLOGICAL DISTRESS; TRANSPLANT CANDIDATES; MODEL; ACUPUNCTURE; MEDICATIONS; CIRRHOSIS; SEVERITY AB This prospective descriptive study investigated pain characteristics in 20 outpatients with end-stage liver disease (ESLD) who were approaching the end of life, described variability in pain between and within patients, and described the pharmacological and nonpharmacological pain management strategies used. The instruments we utilized were the Brief Pain Inventory (BPI) and the self-care behaviour (SCB) log for pain. Data were collected once a month over a six-month period. BPI severity of, and interference from pain mean scores ranged from 5.52 to 6.03 and 5.36 to 6.64, respectively. The top three pain-relieving behaviours reported by patients were "taking pain medication," "taking a nap," and "asking for help." Pain medication intake differed between patients who were pursuing a liver transplant and those who were not eligible for one. If we are to effectively improve care for ESLD patients, it is essential that we understand the ways in which these patients experience pain and the pain management strategies they employ. C1 [Hansen, Lissi] Oregon Hlth & Sci Univ, Sch Nursing, SN ORD, Portland, OR 97239 USA. [Leo, Michael C.] Kaiser Permanente, Ctr Hlth Res, Portland, OR USA. [Chang, Michael F.; Zucker, Betsy L.; Sasaki, Anna] Portland VA Med Ctr, Portland, OR USA. [Sasaki, Anna] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. RP Hansen, L (reprint author), Oregon Hlth & Sci Univ, Sch Nursing, SN ORD, 3455 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM hansenli@ohsu.edu FU National Institute of Nursing Research, National Institutes of Health (NIH) [R03 NR010614] FX Special thanks go to the patients who participated in the study and to Dr. Christine A. Miaskowski at the University of California, San Francisco, for giving us permission to use the SCB log for pain. This study was supported by research grant R03 NR010614 from the National Institute of Nursing Research, National Institutes of Health (NIH). NR 44 TC 0 Z9 0 U1 0 U2 11 PU CENTRE RECHERCHE INSTITUT UNIV GERIATRIE MONTREAL PI MONTREAL PA 4565 CHEMIN QUEEN MARY, MONTREAL, QUEBEC H3W 1W5, CANADA SN 0825-8597 J9 J PALLIAT CARE JI J. Palliative Care PD SPR PY 2014 VL 30 IS 1 BP 32 EP 40 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AE2HW UT WOS:000333794900005 PM 24826441 ER PT J AU Greene, M Steinman, MA McNicholl, IR Valcour, V AF Greene, Meredith Steinman, Michael A. McNicholl, Ian R. Valcour, Victor TI Polypharmacy, Drug Drug Interactions, and Potentially Inappropriate Medications in Older Adults with Human Immunodeficiency Virus Infection SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE polypharmacy; HIV infection; drug interactions; inappropriate prescribing ID HIV-INFECTION; ANTIRETROVIRAL THERAPY; UNITED-STATES; INDIVIDUALS; COHORT; RISK; MEN; PREVALENCE AB ObjectivesTo describe the frequency of medication-related problems in older adults with human immunodeficiency virus (HIV) infection. DesignRetrospective chart review. SettingCommunity. ParticipantsHIV-positive individuals aged 60 and older and age- and sex-matched HIV-negative individuals. MeasurementsTotal number of medications, potentially inappropriate medications (PIMs) according to the modified Beers Criteria, anticholinergic drug burden according to the Anticholinergic Risk Scale (ARS), and drug-drug interactions using the Lexi-Interact online drug interactions database. ResultsOf 89 HIV-positive participants, most were Caucasian (91%) and male (94%), with a median age of 64 (range 60-82). Common comorbidities included hyperlipidemia, hypertension, and depression. Participants were taking a median of 13 medications (range 2-38), of which only a median of four were antiretrovirals. At least one PIM was prescribed in 46 participants (52%). Sixty-two (70%) participants had at least one Category D (consider therapy modification) drug-drug interaction, and 10 (11%) had a Category X (avoid combination) interaction. One-third of these interactions were between two nonantiretroviral medications. Fifteen participants (17%) had an ARS score of 3 or greater. In contrast, HIV-negative participants were taking a median of six medications, 29% had at least one PIM, and 4% had an ARS score of 3 or greater (P<.05 for each comparison, except P=.07 for anticholinergic burden). ConclusionHIV-positive older adults have a high frequency of medication-related problems, of which a large portion is due to medications used to treat comorbid diseases. These medication issues were substantially higher than HIV-negative participants. Attention to the principles of geriatric prescribing is needed as this population ages in order to minimize complications from multiple medication use. C1 [Greene, Meredith; Steinman, Michael A.; Valcour, Victor] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA USA. [Greene, Meredith; Steinman, Michael A.] San Francisco VA Med Ctr, San Francisco, CA USA. [McNicholl, Ian R.] Univ Calif San Francisco, San Francisco Gen Hosp, Posit Hlth Program, San Francisco, CA USA. [McNicholl, Ian R.] Univ Calif San Francisco, Sch Pharm, San Francisco, CA 94143 USA. [Valcour, Victor] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USA. RP Greene, M (reprint author), San Francisco VA Med Ctr, 4150 Clement St,UCSF Box VA-181G, San Francisco, CA 94121 USA. EM meredith.greene@ucsf.edu FU ADRC [K23-AG-032872, P50 AG023501]; UCSF CFAR [P30-AI027763]; UCSF GCRC [UL1 RR024131]; Larry L. Hillblom Foundation; AIDS Research Institute at UCSF; National institutes of Health (NTH) [NIA T32-AG00212]; S.D. Bechtel, Jr. Foundation, Program for the Aging Century; National Institute on Aging; American Federation for Aging Research [1K23-AG030999]; NIH [AG032872]; NIH, University of California at San Francisco-Gladstone Institute of Virology and Immunology Center for AIDS Research [P30-AI027763] FX This work was funded by K23-AG-032872, P50 AG023501 (ADRC, PI: Bruce Miller), P30-AI027763 (UCSF CFAR), UL1 RR024131 (UCSF GCRC), the Larry L. Hillblom Foundation, and the AIDS Research Institute at UCSF. Dr. Greene receives salary support through National institutes of Health (NTH) research training grant NIA T32-AG00212 and has received research funding from the S.D. Bechtel, Jr. Foundation, Program for the Aging Century. Dr. Steinman receives funding from the National Institute on Aging and the American Federation for Aging Research (1K23-AG030999). Dr. Valcour receives research support from NIH, including salary support for work related to HIV and aging (AG032872). Drs. Greene and Valcour receive research funding from the NIH, University of California at San Francisco-Gladstone Institute of Virology and Immunology Center for AIDS Research (P30-AI027763). NR 35 TC 16 Z9 16 U1 5 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2014 VL 62 IS 3 BP 447 EP 453 DI 10.1111/jgs.12695 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AC8HJ UT WOS:000332773800005 PM 24576251 ER PT J AU Feng, WG Chumley, P Allon, M George, J Scott, DW Patel, RP Litovsky, S Jaimes, EA AF Feng, Wenguang Chumley, Phillip Allon, Michael George, James Scott, David W. Patel, Rakesh P. Litovsky, Silvio Jaimes, Edgar A. TI The Transcription Factor E26 Transformation-Specific Sequence-1 Mediates Neointima Formation in Arteriovenous Fistula SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID VASCULAR ACCESS; ANGIOTENSIN-II; FACTOR ETS-1; HEMODIALYSIS-PATIENTS; INTIMAL HYPERPLASIA; GENE-EXPRESSION; MESANGIAL CELLS; INCREASED RISK; DNA-BINDING; MORTALITY AB Hemodialysis vascular access dysfunction contributes to increased morbidity and mortality in hemodialysis patients. Arteriovenous fistula (AVF) is the preferred type of vascular access for hemodialysis but has high rates of dysfunction, in part because of excessive neointima formation. The transcription factor E26 transformation-specific sequence-1 (ETS-1) is a mediator of proinflammatory responses in hypertension and endovascular injury. We examined the role of ETS-1 in the formation of neointima in AVF. Right carotid artery to internal jugular vein fistulas were created in C57BL/6 mice and assigned to treatment with an ETS-1-dominant negative peptide (ETS-DN), an inactive mutant peptide (ETS-MU), or vehicle (n=6 per group). After 7 and 21 days, AVFs or contralateral internal jugular veins were processed for PCR, immunofluorescence, immunohistochemistry, and morphometry. In AVFs, ETS-1 mRNA increased 2.5-fold at 7 days and 4-fold at 21 days. By immunofluorescence, we confirmed increased expression of ETS-1 predominantly in the neointima and overlying endothelium. Similarly, ETS-1 expression increased in human AVFs compared with normal veins. In mice, ETS-DN, but not ETS-MU, reduced neointima formation at days 7 and 21 and reduced the expression of nitric oxide synthase 2, NADPH oxidase (NOX) 2, NOX4, E-selectin, and monocyte chemotactic protein-1. Shear stress increased ETS-1 phosphorylation in human umbilical vein cells in a NOX-dependent manner, demonstrating a role for reactive oxygen species in ETS-1 activation. These results unveil the role of ETS-1 as a mediator of neointima formation in AVF and may result in the development of novel strategies for the treatment of AVF dysfunction. C1 [Feng, Wenguang; Chumley, Phillip; Allon, Michael; George, James; Jaimes, Edgar A.] Univ Alabama Birmingham, Div Nephrol, Birmingham, AL 35294 USA. [George, James] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA. [Scott, David W.; Patel, Rakesh P.; Litovsky, Silvio] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Jaimes, Edgar A.] Birmingham Vet Affairs Med Ctr, Res Serv, Birmingham, AL USA. RP Jaimes, EA (reprint author), Univ Alabama Birmingham, Ziegler Res Bldg,637 1720 2nd Ave South, Birmingham, AL 35294 USA. EM ejaimes@uab.edu OI Patel, Rakesh/0000-0002-1526-4303 FU Veterans Affairs Administration [I01BX001073-03]; National Institutes of Health Research [DK085027-03]; UAB-UCSD O'Brien Core Center for Kidney Research [P30DK079337-05] FX These studies were funded by a Merit Review Award (I01BX001073-03) and a Program Project Award from the Veterans Affairs Administration (IP1BX001595-01A1) to E.A.J., a National Institutes of Health Research Grant (DK085027-03) to M.A., and the UAB-UCSD O'Brien Core Center for Kidney Research Grant (P30DK079337-05). NR 41 TC 5 Z9 5 U1 0 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD MAR PY 2014 VL 25 IS 3 BP 475 EP 487 DI 10.1681/ASN.2013040424 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA AB9YB UT WOS:000332150500009 PM 24203999 ER PT J AU Iaquinto, JM Tsai, R Haynor, DR Fassbind, MJ Sangeorzan, BJ Ledoux, WR AF Iaquinto, Joseph M. Tsai, Richard Haynor, David R. Fassbind, Michael J. Sangeorzan, Bruce J. Ledoux, William R. TI Marker-based validation of a biplane fluoroscopy system for quantifying foot kinematics SO MEDICAL ENGINEERING & PHYSICS LA English DT Article DE Biplane fluoroscopy; X-ray; Foot; Biomechanics ID MODEL AB Introduction: Radiostereometric analysis has demonstrated its capacity to track precise motion of the bones within a subject during motion. Existing devices for imaging the body in two planes are often custom built systems: we present here the design and marker-based validation of a system that has been optimized to image the foot during gait. Methods: Mechanical modifications were made to paired BV Pulsera C-arms (Philips Medical Systems) to allow unfettered gait through the imaging area. Image quality improvements were obtained with high speed cameras and the correction of image distorting artifacts. To assess the system's accuracy, we placed beads at known locations throughout the imaging field, and used post processing software to calculate their apparent locations. Results: Distortion correction reduced overall RMS error from 6.56 mm to 0.17 mm. When tracking beads in static images a translational accuracy of 0.094 +/- 0.081 mm and rotational accuracy of 0.083 +/- 0.068 degrees was determined. In dynamic trials simulating speeds seen during walking, accuracy was 0.126 +/- 0.122 mm. Discussion: The accuracies and precisions found are within the reported ranges from other such systems. With the completion of marker-based validation, we look to model-based validation of the foot during gait. Published by Elsevier Ltd on behalf of IPEM. C1 [Iaquinto, Joseph M.; Tsai, Richard; Fassbind, Michael J.; Sangeorzan, Bruce J.; Ledoux, William R.] VA Puget Sound Hlth Care Syst, Dept Vet Affairs, RR&D Ctr Excellence Limb Loss Prevent & Prosthet, Seattle, WA USA. [Iaquinto, Joseph M.; Ledoux, William R.] Univ Washington, Dept Mech Engn, Seattle, WA 98195 USA. [Haynor, David R.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Sangeorzan, Bruce J.; Ledoux, William R.] Univ Washington, Dept Orthopaed & Sports Med, Seattle, WA 98195 USA. RP Ledoux, WR (reprint author), VA Puget Sound, Ms 151,1660 S Columbian Way, Seattle, WA 98108 USA. EM wrledoux@u.washington.edu RI Ledoux, William/K-6815-2015 OI Ledoux, William/0000-0003-4982-7714 FU Department of Veterans Affairs Rehabilitation Research and Development [A4843C, F7468R]; Magnuson Award FX This research was funded in part by the Department of Veterans Affairs Rehabilitation Research and Development grants A4843C, F7468R and the Magnuson Award. The study sponsor has no role in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. NR 12 TC 5 Z9 5 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1350-4533 EI 1873-4030 J9 MED ENG PHYS JI Med. Eng. Phys. PD MAR PY 2014 VL 36 IS 3 BP 391 EP 396 DI 10.1016/j.medengphy.2013.08.013 PG 6 WC Engineering, Biomedical SC Engineering GA AE5DT UT WOS:000334008700015 PM 24075068 ER PT J AU Yao, M Gu, C Doyle, FJ Zhu, H Redmond, RW Kochevar, IE AF Yao, Min Gu, Chuan Doyle, Francis J., Jr. Zhu, Hong Redmond, Robert W. Kochevar, Irene E. TI Why is Rose Bengal More Phototoxic to Fibroblasts In Vitro Than In Vivo? SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID PHOTODYNAMIC THERAPY; SINGLET OXYGEN; FLUENCE RATE; INDUCED APOPTOSIS; CELL-SURVIVAL; TUMOR; LIGHT; TISSUE; MODEL; SKIN AB Photosensitized protein cross-linking has been recently developed to seal wounds and strengthen tissue. Although the photosensitizing dye, Rose Bengal (RB), is phototoxic to cultured cells, cytotoxicity does not accompany RB-photosensitized tissue repair in vivo. We investigated whether the environment surrounding cells in tissue or the high irradiances used for photo-cross-linking inhibited RB phototoxicity. Fibroblasts (FB) grown within collagen gels to mimic a tissue environment and monolayer cultured FB were treated with RB (0.01-1mm) and the high 532nm laser irradiances used in vivo for tissue repair (0.10-0.50Wcm(-2)). Monolayer FB were substantially more sensitive to RB photosensitization: the LD50 was >200-fold lower than that in collagen gels. Collagen gel protection was associated with increased Akt phosphorylation, a prosurvival pathway. RB phototoxicity in collagen gels was 25-fold greater at low (0.030Wcm(-2)) that at high (0.50Wcm(-2)) irradiances. Oxygen depletion at high irradiance only partially accounted for the irradiance dependence of phototoxicity as replacing air with nitrogen only increased the LD50 by four-fold in monolayers. These results indicate that the lack of RB phototoxicity during in vivo tissue repair results from upregulation of prosurvival pathways in tissue cells, oxygen depletion and irradiance-dependent RB photochemistry. C1 [Yao, Min; Gu, Chuan; Doyle, Francis J., Jr.; Zhu, Hong; Redmond, Robert W.; Kochevar, Irene E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02115 USA. RP Kochevar, IE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02115 USA. EM kochevar@helix.mgh.harvard.edu NR 45 TC 5 Z9 5 U1 2 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0031-8655 EI 1751-1097 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD MAR PY 2014 VL 90 IS 2 BP 297 EP 305 DI 10.1111/php.12215 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AC8HP UT WOS:000332774400007 PM 24266530 ER PT J AU Cuijpers, P Turner, EH Mohr, DC Hofmann, SG Andersson, G Berking, M Coyne, J AF Cuijpers, P. Turner, E. H. Mohr, D. C. Hofmann, S. G. Andersson, G. Berking, M. Coyne, J. TI Comparison of psychotherapies for adult depression to pill placebo control groups: a meta-analysis SO PSYCHOLOGICAL MEDICINE LA English DT Review DE placebo; psychotherapy; Depression; meta-analysis ID RANDOMIZED CONTROLLED-TRIAL; PRIMARY-CARE PATIENTS; COGNITIVE THERAPY; MAJOR DEPRESSION; ANTIDEPRESSANT MEDICATION; PSYCHOLOGICAL TREATMENTS; BEHAVIORAL ACTIVATION; MINOR DEPRESSION; PUBLICATION BIAS; FOLLOW-UP AB Background The effects of antidepressants for treating depressive disorders have been overestimated because of selective publication of positive trials. Reanalyses that include unpublished trials have yielded reduced effect sizes. This in turn has led to claims that antidepressants have clinically insignificant advantages over placebo and that psychotherapy is therefore a better alternative. To test this, we conducted a meta-analysis of studies comparing psychotherapy with pill placebo. Method Ten 10 studies comparing psychotherapies with pill placebo were identified. In total, 1240 patients were included in these studies. For each study, Hedges' g was calculated. Characteristics of the studies were extracted for subgroup and meta-regression analyses. Results The effect of psychotherapy compared to pill placebo at post-test was g=0.25 [95% confidence interval (CI) 0.14-0.36, I (2)=0%, 95% CI 0-58]. This effect size corresponds to a number needed to treat (NNT) of 7.14 (95% CI 5.00-12.82). The psychotherapy conditions scored 2.66 points lower on the Hamilton Depression Rating Scale (HAMD) than the placebo conditions, and 3.20 points lower on the Beck Depression Inventory (BDI). Some indications for publication bias were found (two missing studies). We found no significant differences between subgroups of the studies and in meta-regression analyses we found no significant association between baseline severity and effect size. Conclusions Although there are differences between the role of placebo in psychotherapy and pharmacotherapy research, psychotherapy has an effect size that is comparable to that of antidepressant medications. Whether these effects should be deemed clinically relevant remains open to debate. C1 [Cuijpers, P.] Vrije Univ Amsterdam, Dept Clin Psychol, NL-1081 BT Amsterdam, Netherlands. [Cuijpers, P.] EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Turner, E. H.] Portland VA Med Ctr, Behav Hlth & Neurosci Div, Portland, OR USA. [Turner, E. H.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Turner, E. H.] Oregon Hlth & Sci Univ, Dept Pharmacol, Portland, OR 97201 USA. [Mohr, D. C.] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Hofmann, S. G.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Andersson, G.] Linkoping Univ, Swedish Inst Disabil Res, Dept Behav Sci & Learning, S-58183 Linkoping, Sweden. [Andersson, G.] Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, Stockholm, Sweden. [Berking, M.] Univ Marburg, Dept Clin Psychol, D-35032 Marburg, Germany. [Coyne, J.] Univ Groningen, Univ Med Ctr Groningen, Dept Hlth Sci, Hlth Psychol Sect, Groningen, Netherlands. RP Cuijpers, P (reprint author), Vrije Univ Amsterdam, Dept Clin Psychol, Van der Boechorststr 1, NL-1081 BT Amsterdam, Netherlands. EM p.cuijpers@vu.nl RI Andersson, Gerhard/J-8529-2012; Hofmann, Stefan/B-8769-2014; OI Andersson, Gerhard/0000-0003-4753-6745; Hofmann, Stefan/0000-0002-3548-9681; Cuijpers, Pim/0000-0001-5497-2743 NR 46 TC 22 Z9 22 U1 4 U2 30 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 EI 1469-8978 J9 PSYCHOL MED JI Psychol. Med. PD MAR PY 2014 VL 44 IS 4 BP 685 EP 695 DI 10.1017/S0033291713000457 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA AD0WJ UT WOS:000332954700003 PM 23552610 ER PT J AU Bird, GH Gavathiotis, E LaBelle, JL Katz, SG Walensky, LD AF Bird, Greg H. Gavathiotis, Evripidis LaBelle, James L. Katz, Samuel G. Walensky, Loren D. TI Distinct BimBH3 (BimSAHB) Stapled Peptides for Structural and Cellular Studies SO ACS CHEMICAL BIOLOGY LA English DT Letter ID STABILIZED ALPHA-HELICES; BH3 HELIX; PROAPOPTOTIC BAX; BCL-2 DOMAINS; ACTIVATION; APOPTOSIS AB Hydrocarbon stapling is a chemical approach to restoring and fortifying the natural a-helical structure of peptides that otherwise unfold when taken out of context from the host protein. By iterating the peptide sequence, staple type, and sites of insertion, discrete compositions can be generated to suit a diversity of biochemical, structural, proteomic, cellular, and drug development applications. Here, we reinforce key design considerations to avoid pitfalls and maximize progress when applying stapled peptides in chemistry and biology research. C1 [Bird, Greg H.; Walensky, Loren D.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Gavathiotis, Evripidis] Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10461 USA. [LaBelle, James L.] Univ Chicago, Comer Childrens Hosp, Dept Pediat Hematol Oncol Stem Cell Transplantat, Chicago, IL 60637 USA. [Katz, Samuel G.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. RP Walensky, LD (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM Loren_Walensky@dfci.harvard.edu FU NCI NIH HHS [5R01CA050239, K08 CA151450, R01 CA050239, R01 CA178394]; NIGMS NIH HHS [5R01GM090299, R01 GM090299] NR 22 TC 38 Z9 38 U1 1 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 EI 1554-8937 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD MAR PY 2014 VL 9 IS 3 BP 831 EP 837 DI 10.1021/cb4003305 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AD7WI UT WOS:000333477300031 PM 24358963 ER PT J AU Lee, S Koo, H Na, JH Han, SJ Min, HS Lee, SJ Kim, SH Yun, SH Jeong, SY Kwon, IC Choi, K Kim, K AF Lee, Sangmin Koo, Heebeom Na, Jin Hee Han, Seung Jin Min, Hyun Su Lee, So Jin Kim, Sun Hwa Yun, Seok Hyun Jeong, Seo Young Kwon, Ick Chan Choi, Kuiwon Kim, Kwangmeyung TI Chemical Tumor-Targeting of Nanoparticles Based on Metabolic Glycoengineering and Click Chemistry SO ACS NANO LA English DT Article DE nanoparticle; click chemistry; metabolic glycoengineering; tumor-targeting; drug delivery ID GLYCOL CHITOSAN NANOPARTICLES; IN-VIVO; MULTIFUNCTIONAL NANOPARTICLES; DRUG-DELIVERY; BIOORTHOGONAL CHEMISTRY; CANCER-THERAPY; COPPER-FREE; REAL-TIME; EFFICACY; GLYCANS AB Tumor-targeting strategies for nanoparticles have been predominantly based on optimization of physical properties or conjugation with biological ligands. However, their tumor-targeting abilities remain limited and insufficient. Furthermore, traditional biological binding molecules have intrinsic limitations originating from the limited amount of cellular receptors and the heterogeneity of tumor cells. Our two-step in vivo tumor-targeting strategy for nanoparticles is based on metabolic glycoengineering and click chemistry. First, an intravenous injection of precursor-loaded glycol chitosan nanoparticles generates azide groups on tumor tissue specifically by the enhanced permeation and retention (EPR) effect followed by metabolic glycoengineering. These 'receptor-like' chemical groups then enhance the tumor-targeting ability of drug-containing nanoparticles by copper-free click chemistry in vivo during a second intravenous injection. The advantage of this protocol over traditional binding molecules is that there are significantly more binding molecules on the surface of most tumor cells regardless of cell type. The subsequent enhanced tumor-targeting ability can significantly enhance the cancer therapeutic efficacy in animal studies. C1 [Lee, Sangmin; Koo, Heebeom; Na, Jin Hee; Han, Seung Jin; Min, Hyun Su; Lee, So Jin; Kim, Sun Hwa; Kwon, Ick Chan; Choi, Kuiwon; Kim, Kwangmeyung] Korea Inst Sci & Technol, Ctr Theragnosis, Biomed Res Inst, Seoul 136791, South Korea. [Lee, Sangmin; Na, Jin Hee; Han, Seung Jin; Jeong, Seo Young] Kyung Hee Univ, Dept Life & Nanopharmaceut Sci, Seoul 130701, South Korea. [Koo, Heebeom; Yun, Seok Hyun] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Cambridge, MA 02139 USA. [Kwon, Ick Chan] Korea Univ, KU KIST Sch, Seoul 136701, South Korea. RP Choi, K (reprint author), Korea Inst Sci & Technol, Ctr Theragnosis, Biomed Res Inst, 39-1 Hawolgok Dong, Seoul 136791, South Korea. EM choi@kist.re.kr; kim@kist.re.kr FU Global Research Laboratory Project [NRF-2013K1A1A2032346, NRF-2013K1A1A2A02050115]; Fusion Technology Project [2009-0081876]; Intramural Research Program (Theragnosis) of KIST FX This study was funded by the Global Research Laboratory Project (NRF-2013K1A1A2032346 & NRF-2013K1A1A2A02050115), the Fusion Technology Project (2009-0081876), and the Intramural Research Program (Theragnosis) of KIST. NR 49 TC 24 Z9 24 U1 7 U2 78 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 EI 1936-086X J9 ACS NANO JI ACS Nano PD MAR PY 2014 VL 8 IS 3 BP 2048 EP 2063 DI 10.1021/nn406584y PG 16 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA AD8TU UT WOS:000333539400020 PM 24499346 ER PT J AU Olsen, RW Li, GD Wallner, M Trudell, JR Bertaccini, EJ Lindahl, E Miller, KW Alkana, RL Davies, DL AF Olsen, Richard W. Li, Guo-Dong Wallner, Martin Trudell, James R. Bertaccini, Edward J. Lindahl, Erik Miller, Keith W. Alkana, Ronald L. Davies, Daryl L. TI Structural Models of Ligand-Gated Ion Channels: Sites of Action for Anesthetics and Ethanol SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE GABA(A) Receptors; GluCl Pentameric Ion Channels; ELIC; GLIC; Loop 2; Ethanol Sites of Action ID NICOTINIC ACETYLCHOLINE-RECEPTOR; GABA(A) RECEPTOR; GLYCINE RECEPTORS; GENERAL-ANESTHETICS; BINDING-SITES; A RECEPTORS; DELTA-SUBUNIT; ALCOHOL; ETOMIDATE; AGONIST AB The molecular mechanism(s) of action of anesthetic, and especially, intoxicating doses of alcohol (ethanol [EtOH]) have been of interest even before the advent of the Research Society on Alcoholism. Recent physiological, genetic, and biochemical studies have pin-pointed molecular targets for anesthetics and EtOH in the brain as ligand-gated ion channel (LGIC) membrane proteins, especially the pentameric (5 subunit) Cys-loop superfamily of neurotransmitter receptors including nicotinic acetylcholine (nAChRs), GABA(A) (GABA(A)Rs), and glycine receptors (GlyRs). The ability to demonstrate molecular and structural elements of these proteins critical for the behavioral effects of these drugs on animals and humans provides convincing evidence for their role in the drugs' actions. Amino acid residues necessary for pharmacologically relevant allosteric modulation of LGIC function by anesthetics and EtOH have been identified in these channel proteins. Site-directed mutagenesis revealed potential allosteric modulatory sites in both the trans-membrane domain (TMD) and extracellular domain (ECD). Potential sites of action and binding have been deduced from homology modeling of other LGICs with structures known from crystallography and cryo-electron microscopy studies. Direct information about ligand binding in the TMD has been obtained by photoaffinity labeling, especially in GABA(A)Rs. Recent structural information from crystallized procaryotic (ELIC and GLIC) and eukaryotic (GluCl) LGICs allows refinement of the structural models including evaluation of possible sites of EtOH action. C1 [Olsen, Richard W.; Li, Guo-Dong; Wallner, Martin] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Olsen, Richard W.; Li, Guo-Dong] Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol, Los Angeles, CA 90095 USA. [Trudell, James R.; Bertaccini, Edward J.] Stanford Univ, Sch Med, Dept Anesthesia, Stanford, CA 94305 USA. [Lindahl, Erik] KTH Royal Inst Technol, Stockholm, Sweden. [Miller, Keith W.] Harvard Univ, Sch Med, Dept Anesthesia & Crit Care, Massachusetts Gen Hosp, Boston, MA USA. [Alkana, Ronald L.; Davies, Daryl L.] Univ So Calif, Sch Pharm, Los Angeles, CA USA. RP Olsen, RW (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Room CHS 23-120,650 Young Dr South, Los Angeles, CA 90095 USA. EM rolsen@mednet.ucla.edu RI Wallner, Martin/B-8322-2009; Davies, Daryl/P-1137-2016 OI Wallner, Martin/0000-0003-4134-8946; Davies, Daryl/0000-0003-2940-7739 FU NIAAA [AA007680, AA013378]; NIGMS [GM 58448]; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital; USC School of Pharmacy FX This work was supported, in whole or in part, by NIAAA grants AA007680 to RWO and AA013378 to JRT; NIGMS (GM 58448) and the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital to KWM; and USC School of Pharmacy to RLA and DLD. NR 53 TC 18 Z9 18 U1 0 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAR PY 2014 VL 38 IS 3 BP 595 EP 603 DI 10.1111/acer.12283 PG 9 WC Substance Abuse SC Substance Abuse GA AC8BO UT WOS:000332758200001 PM 24164436 ER PT J AU Tartaglione, EV Derleth, M Yu, L Ioannou, GN AF Tartaglione, Erica V. Derleth, Mark Yu, Lei Ioannou, George N. TI Can Computerized Brain Training Games be Used to Identify Early Cognitive Impairment in Cirrhosis? SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID MINIMAL HEPATIC-ENCEPHALOPATHY; INHIBITORY CONTROL TEST; LIVER-TRANSPLANTATION; TESTS; DIAGNOSIS; TASK AB OBJECTIVES: We evaluated whether commercially available, computerized "brain-training" games can be used to identify subtle cognitive impairments in patients with cirrhosis. METHODS: We compared patients with cirrhosis who did not have overt encephalopathy (n = 31), patients with pre-cirrhotic chronic liver disease (n = 28), and normal controls without liver disease (n = 16) with respect to their scores on the number connection test-A (NCT-A), the Inhibitory Control Test (ICT), and five, short (similar to 2.5 min), brain-training games that were administered on an Apple iPad and tested different cognitive domains. RESULTS: Patients with cirrhosis had similar scores to patients with pre-cirrhotic liver disease and slightly worse scores than normal controls in the NCT-A and the ICT, although these differences were not statistically significant. In contrast, patients with cirrhosis had significantly worse scores than patients with pre-cirrhotic liver disease and even more so than normal controls in all five of the brain-training games. After adjustment for age and educational attainment, these differences remained significant for two of the tests, "Color Match" which is a version of the Stroop test and measures selective attention, and "Memory Matrix", which measures visuospatial memory. The area under the receiver operating characteristic curve discriminating cirrhosis from pre-cirrhotic liver disease was 0.56 (95% confidence interval (CI) 0.41-0.72) for the ICT and 0.58 (95% CI 0.43-0.73) for the NCT-A, indicating no discrimination, while it was 0.75 (95% CI 0.63-0.87) for "Color Match" and 0.77 (95% CI 0.64-0.90) for "Memory Matrix", indicating good discrimination. CONCLUSIONS: Short, brain-training games administered on an iPad can be used as psychometric tests to detect subtle cognitive impairments in patients with cirrhosis without overt encephalopathy that could not be detected by the NCT-A or the ICT. C1 [Tartaglione, Erica V.; Ioannou, George N.] Vet Affairs Puget Sound Hlth Care Syst, Res & Dev, Seattle, WA 98108 USA. [Derleth, Mark; Ioannou, George N.] Vet Affairs Puget Sound Hlth Care Syst, Div Gastroenterol, Dept Med, Seattle, WA 98108 USA. [Derleth, Mark; Yu, Lei; Ioannou, George N.] Univ Washington, Dept Med, Div Gastroenterol, Seattle, WA USA. RP Ioannou, GN (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Gastroenterol, S-111 Gastro,1660 S Columbian Way, Seattle, WA 98108 USA. EM georgei@medicine.washington.edu FU Research Enhancement Award Program (REAP) by the Veterans Affairs Office of Research and Development FX This study was supported by a Research Enhancement Award Program (REAP) by the Veterans Affairs Office of Research and Development (awarded to G.N.I.). NR 31 TC 1 Z9 1 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD MAR PY 2014 VL 109 IS 3 BP 316 EP 323 DI 10.1038/ajg.2013.306 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AD4RX UT WOS:000333239300002 PM 24594947 ER PT J AU Ananthakrishnan, AN Huang, HL Nguyen, DD Sauk, J Yajnik, V Xavier, RJ AF Ananthakrishnan, Ashwin N. Huang, Hailiang Nguyen, Deanna D. Sauk, Jenny Yajnik, Vijay Xavier, Ramnik J. TI Differential Effect of Genetic Burden on Disease Phenotypes in Crohn's Disease and Ulcerative Colitis: Analysis of a North American Cohort SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; IBD; PREVALENCE; MECHANISMS; VARIANTS; GENOTYPE; THERAPY; SAFETY; NOD2; RISK AB OBJECTIVES: Crohn' s disease (CD) and ulcerative colitis (UC) are chronic immunologically mediated diseases with a progressive relapsing remitting course. There is considerable heterogeneity in disease course and accurate prediction of natural history has been challenging. The phenotypic implication of increasing genetic predisposition to CD or UC is unknown. METHODS: The data source for our study was a prospective cohort of CD and UC patients recruited from a tertiary referral center. All patients underwent genotyping on the Illumina Immunochip. A genetic risk score (GRS) incorporating strength of association (log odds ratio) and allele dose for each of the 163 infl ammatory bowel disease (IBD) risk loci was calculated and phenotypic associations examined across GRS quartiles. RESULTS: Our study cohort included 1,105 patients (697 CD, 408 UC). Increasing genetic burden was associated with earlier age of diagnosis of CD (P-trend = 0.008). Patients in the highest GRS quartile were likely to develop disease 5 years earlier than those in the lowest quartile. Increasing genetic burden was also associated with ileal involvement in CD (P-trend < 0.0001). The effect of genetic burden was independent of the NOD2 locus and was stronger among those with no NOD2 variants, and in never smokers. UC patients with an involved first-degree relative had a higher genetic burden, but GRS was not associated with disease phenotype in UC. CONCLUSIONS: Increasing genetic burden is associated with early age of diagnosis in CD, but not UC. The expanded panel of IBD risk loci explains only a fraction of variance of disease phenotype, suggesting limited clinical utility of genetics in predicting natural history. C1 [Ananthakrishnan, Ashwin N.; Nguyen, Deanna D.; Sauk, Jenny; Yajnik, Vijay; Xavier, Ramnik J.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Ananthakrishnan, Ashwin N.; Nguyen, Deanna D.; Sauk, Jenny; Yajnik, Vijay; Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA USA. [Huang, Hailiang] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Huang, Hailiang; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, Div Gastroenterol, 165 Cambridge St ,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@partners.org OI Huang, Hailiang/0000-0003-1461-5762 FU National Institutes of Health (NIH) [P30 DK043351, K23 DK097142, U01 DK062432, R01 DK064869] FX This work is supported by the National Institutes of Health (NIH) (P30 DK043351) to the Center for Study of Inflammatory Bowel Diseases. A.N. Ananthakrishnan is supported in part by a grant from the National Institutes of Health (K23 DK097142). R.J. Xavier is supported by grants U01 DK062432 and R01 DK064869 from the NIH. NR 25 TC 26 Z9 26 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD MAR PY 2014 VL 109 IS 3 BP 395 EP 400 DI 10.1038/ajg.2013.464 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AD4RX UT WOS:000333239300012 PM 24419484 ER PT J AU Brawman-Mintzer, O Durkalski, V Wu, Q Romagnuolo, J Fogel, E Tarnasky, P Aliperti, G Freeman, M Kozarek, R Jamidar, P Wilcox, M Elta, G Orrell, K Wood, A Mauldin, P Serrano, J Drossman, D Robuck, P Cotton, P AF Brawman-Mintzer, Olga Durkalski, Valerie Wu, Qi Romagnuolo, Joseph Fogel, Evan Tarnasky, Paul Aliperti, Giuseppe Freeman, Martin Kozarek, Richard Jamidar, Priya Wilcox, Mel Elta, Grace Orrell, Kyle Wood, April Mauldin, Patrick Serrano, Jose Drossman, Douglas Robuck, Patricia Cotton, Peter TI Psychosocial Characteristics and Pain Burden of Patients With Suspected Sphincter of Oddi Dysfunction in the EPISOD Multicenter Trial SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; IRRITABLE-BOWEL-SYNDROME; FUNCTIONAL GASTROINTESTINAL DISORDERS; NATIONAL-COMORBIDITY-SURVEY; SELF-REPORTED ABUSE; FINDINGS TYPE-I; ABDOMINAL-PAIN; PHYSICAL ABUSE; HEALTH-STATUS; DSM-IV AB OBJECTIVES: Patients with several painful functional gastrointestinal disorders (FGIDs) are reported to have a high prevalence of psychosocial disturbance. These aspects have not been studied extensively in patients with suspected Sphincter of Oddi dysfunction (SOD). METHODS: A total of 214 patients with post-cholecystectomy pain and suspected SOD were enrolled in seven US centers in a multicenter-randomized trial (Evaluating Predictors and Interventions in Sphincter of Oddi Dysfunction). Baseline assessments included pain descriptors and burden, structured psychosocial assessments of anxiety/depression, coping, trauma, and health-related quality of life. Patients with high levels of depression, suicidal ideation, or psychosis were excluded. RESULTS: The study population (92% female, mean age 38) reported anxiety (9%), depression (8%), past sexual trauma (18%), and physical abuse (10%). Of the total screened population (n = 1460), 3.9% of the patients were excluded because of the presence of defined severe psychological problems. The mean medical outcomes study short-form-36 (SF-36) physical and mental composite scores were 38.70 (s.d. = 7.89) and 48.74 (s.d. = 9.60), respectively. Most subjects reported symptoms of other FGIDs. There were no correlations between the extent of the pain burden in the 3 months before enrollment and the baseline anxiety scores or victimization history. However, those with greater pain burden were significantly more depressed. There were no meaningful differences in the psychosocial parameters in subjects with or without irritable bowel, and those who had cholecystectomy for stones or functional gallbladder disease. Those declining randomization were comparable to those randomized. CONCLUSIONS: Psychosocial comorbidity in SOD is high. However, it does not appear to differ significantly from that reported in surveys of age-and gender-matched general populations, and may be lower than reported with other FGIDs. C1 [Brawman-Mintzer, Olga; Durkalski, Valerie; Wu, Qi; Romagnuolo, Joseph; Orrell, Kyle; Wood, April; Mauldin, Patrick; Cotton, Peter] Med Univ S Carolina, Ctr Digest Dis, Charleston, SC 29425 USA. [Brawman-Mintzer, Olga] Ralph H Johnson VAMC, Charleston, SC USA. [Fogel, Evan] Indiana Univ, Indianapolis, IN 46204 USA. [Tarnasky, Paul] Methodist Dallas Med Ctr, Dallas, TX USA. [Aliperti, Giuseppe] Midwest Therapeut Endoscopy Consultants, St Louis, MO USA. [Freeman, Martin] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Kozarek, Richard] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Jamidar, Priya] Yale Univ, Newhaven, CT USA. [Wilcox, Mel] Univ Alabama Birmingham, Birmingham, AL USA. [Elta, Grace] Univ Michigan, Ann Arbor, MI 48109 USA. [Serrano, Jose; Robuck, Patricia] NIDDK, Bethesda, MD 20892 USA. [Drossman, Douglas] Univ N Carolina, Chapel Hill, NC USA. [Drossman, Douglas] Drossman Gastroenterol PLLC, Chapel Hill, NC USA. RP Cotton, P (reprint author), Med Univ S Carolina, Ctr Digest Dis, 25 Courtney Dr,ART 7100A,MSC 290, Charleston, SC 29425 USA. EM cottonp@musc.edu FU NIDDK [U01 DK074739] FX This work was funded by NIDDK, study number U01 DK074739. NR 39 TC 10 Z9 10 U1 4 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD MAR PY 2014 VL 109 IS 3 BP 436 EP 442 DI 10.1038/ajg.2013.467 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AD4RX UT WOS:000333239300017 PM 24445573 ER PT J AU Eikermann, M Melo, MFV AF Eikermann, Matthias Melo, Marcos F. Vidal TI Therapeutic Range of Spontaneous Breathing during Mechanical Ventilation SO ANESTHESIOLOGY LA English DT Editorial Material ID ACUTE LUNG INJURY; MUSCLE PARALYSIS; DIAPHRAGM; DYSFUNCTION; WEAKNESS; SUPPORT; UNIT C1 [Eikermann, Matthias; Melo, Marcos F. Vidal] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesiol Crit Care & Pain Med, Boston, MA 02115 USA. [Eikermann, Matthias] Dusiburg Essen Univ, Univ Klinikum Essen, Klin Anaesthesiol & Intens Med, Essen, Germany. RP Eikermann, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesiol Crit Care & Pain Med, Boston, MA 02115 USA. EM meikermann@partners.org FU NHLBI NIH HHS [R01 HL086827, R01 HL121228] NR 21 TC 3 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2014 VL 120 IS 3 BP 536 EP 539 DI 10.1097/ALN.0000000000000126 PG 4 WC Anesthesiology SC Anesthesiology GA AC9FR UT WOS:000332840300007 PM 24424072 ER PT J AU Musch, G Winkler, T Harris, RS Melo, MFV Wellman, TJ de Prost, N Kradin, RL Venegas, JG AF Musch, Guido Winkler, Tilo Harris, R. Scott Melo, Marcos F. Vidal Wellman, Tyler J. de Prost, Nicolas Kradin, Richard L. Venegas, Jose G. TI Lung [ F-18] fluorodeoxyglucose Uptake and Ventilation-Perfusion Mismatch in the Early Stage of Experimental Acute Smoke Inhalation SO ANESTHESIOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; PEROXYNITRITE DECOMPOSITION CATALYST; BRONCHIAL ARTERY; OVINE MODEL; MECHANICAL VENTILATION; REGIONAL VENTILATION; GLUCOSE-UTILIZATION; METABOLIC-ACTIVITY; PULMONARY-FUNCTION; COMBINED BURN AB Background: Acute lung injury occurs in a third of patients with smoke inhalation injury. Its clinical manifestations usually do not appear until 48-72 h after inhalation. Identifying inflammatory changes that occur in pulmonary parenchyma earlier than that could provide insight into the pathogenesis of smoke-induced acute lung injury. Furthermore, noninvasive measurement of such changes might lead to earlier diagnosis and treatment. Because glucose is the main source of energy for pulmonary inflammatory cells, the authors hypothesized that its pulmonary metabolism is increased shortly after smoke inhalation, when classic manifestations of acute lung injury are not yet expected. Methods: In five sheep, the authors induced unilateral injury with 48 breaths of cotton smoke while the contralateral lung served as control. The authors used positron emission tomography with: (1) [F-18]fluorodeoxyglucose to measure metabolic activity of pulmonary inflammatory cells; and (2) [N-13]nitrogen in saline to measure shunt and ventilation-perfusion distributions separately in the smoke-exposed and control lungs. Results: The pulmonary [F-18]fluorodeoxyglucose uptake rate was increased at 4 h after smoke inhalation (mean SD: 0.0031 +/- 0.0013 vs. 0.0026 +/- 0.0010 min(-1); P < 0.05) mainly as a result of increased glucose phosphorylation. At this stage, there was no worsening in lung aeration or shunt. However, there was a shift of perfusion toward units with lower ventilation-to-perfusion ratio (mean ratio +/- SD: 0.82 +/- 0.10 vs. 1.12 +/- 0.02; P < 0.05) and increased heterogeneity of the ventilation-perfusion distribution (mean +/- SD: 0.21 +/- 0.07 vs. 0.13 +/- 0.01; P < 0 .05). Conclusion: Using noninvasive imaging, the authors demonstrated that increased pulmonary [F-18]fluorodeoxyglucose uptake and ventilation-perfusion mismatch occur early after smoke inhalation. C1 [Musch, Guido; Winkler, Tilo; Melo, Marcos F. Vidal; Wellman, Tyler J.; de Prost, Nicolas; Venegas, Jose G.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Harris, R. Scott] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Kradin, Richard L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kradin, Richard L.] Harvard Univ, Sch Med, Boston, MA USA. RP Musch, G (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, GRJ-4-418,55 Fruit St, Boston, MA 02114 USA. EM gmusch@partners.org RI Winkler, Tilo/B-5337-2009; OI Winkler, Tilo/0000-0002-7276-5550; de Prost, Nicolas/0000-0002-4833-4320 FU Shriners Hospitals for Children, Boston, Massachusetts [8895]; National Institutes of Health Grant, Bethesda, Maryland [R01HL094639] FX Supported by a Research Grant 8895, from Shriners Hospitals for Children, Boston, Massachusetts, and by National Institutes of Health Grant R01HL094639, Bethesda, Maryland. NR 58 TC 5 Z9 5 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2014 VL 120 IS 3 BP 683 EP 693 DI 10.1097/01.anes.0000435742.04859.e8 PG 11 WC Anesthesiology SC Anesthesiology GA AC9FR UT WOS:000332840300021 PM 24051392 ER PT J AU Gardner, RC Yaffe, K AF Gardner, Raquel C. Yaffe, Kristine TI Traumatic brain injury may increase risk of young onset dementia SO ANNALS OF NEUROLOGY LA English DT Editorial Material ID ALZHEIMERS-DISEASE; HEAD-INJURY; PROPAGATION; POPULATION; CONCUSSION; PROTEINS; FIBRILS; TAU C1 [Gardner, Raquel C.; Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Gardner, Raquel C.] San Francisco Vet Adm Med Ctr, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Gardner, RC (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. FU NIA NIH HHS [K24 AG031155, P01 AG019724, P50 AG023501, R01 AG026720, R01 AG05401]; NIDDK NIH HHS [R01 DK069406]; NIMH NIH HHS [R01 MH086498] NR 30 TC 8 Z9 9 U1 2 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD MAR PY 2014 VL 75 IS 3 BP 339 EP 341 DI 10.1002/ana.24121 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AD8WS UT WOS:000333547000004 PM 24550062 ER PT J AU Titulaer, MJ Hoftberger, R Iizuka, T Leypoldt, F McCracken, L Cellucci, T Benson, LA Shu, H Irioka, T Hirano, M Singh, G Calvo, AC Kaida, K Morales, PS Wirtz, PW Yamamoto, T Reindl, M Rosenfeld, MR Graus, F Saiz, A Dalmau, J AF Titulaer, Maarten J. Hoeftberger, Romana Iizuka, Takahiro Leypoldt, Frank McCracken, Lindsey Cellucci, Tania Benson, Leslie A. Shu, Huidy Irioka, Takashi Hirano, Makito Singh, Gagandeep Cobo Calvo, Alvaro Kaida, Kenichi Morales, Pamela S. Wirtz, Paul W. Yamamoto, Tomotaka Reindl, Markus Rosenfeld, Myrna R. Graus, Francesc Saiz, Albert Dalmau, Josep TI Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis SO ANNALS OF NEUROLOGY LA English DT Article ID MYELIN-OLIGODENDROCYTE GLYCOPROTEIN; ACUTE DISSEMINATED ENCEPHALOMYELITIS; NEUROMYELITIS-OPTICA; NMDAR ENCEPHALITIS; ANTIBODIES; COMPLEMENT; SPECTRUM; DISORDERS; DIAGNOSIS; MOG AB Objective To report the clinical, radiological, and immunological association of demyelinating disorders with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Methods Clinical and radiological analysis was done of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4), and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays. Results Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent magnetic resonance imaging (MRI) and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of neuromyelitis optica (NMO) spectrum disorder (5 cases, 4 anti-AQP4 positive) or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4 positive, 2 MOG positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis; NMDAR antibodies were detected only in the 50 anti-NMDAR patients, MOG antibodies in 3 of 50 anti-NMDAR and 1 of 56 NMO patients, and AQP4 antibodies in 48 of 56 NMO and 1 of 50 anti-NMDAR patients (p < 0.0001 for all comparisons with Groups 1 and 2). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1 of 23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18 of 50 anti-NMDAR controls (p = 0.011). Interpretation Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (eg, dyskinesias, psychosis) may have anti-NMDAR encephalitis. Ann Neurol 2014;75:411-428 C1 [Titulaer, Maarten J.; Hoeftberger, Romana; Leypoldt, Frank; Rosenfeld, Myrna R.; Graus, Francesc; Saiz, Albert; Dalmau, Josep] Univ Barcelona, Hosp Clin Barcelona, Dept Neurol, E-08036 Barcelona, Spain. [Titulaer, Maarten J.; Hoeftberger, Romana; Leypoldt, Frank; Rosenfeld, Myrna R.; Graus, Francesc; Saiz, Albert; Dalmau, Josep] August Pi i Sunyer Inst Biomed Res IDIBAPS, Barcelona, Spain. [Titulaer, Maarten J.] Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [Hoeftberger, Romana] Med Univ Vienna, Inst Neurol, Vienna, Austria. [Iizuka, Takahiro] Kitasato Univ, Sch Med, Dept Neurol, Tokyo, Kanagawa, Japan. [Leypoldt, Frank] Univ Med Ctr Hamburg Eppendorf, Dept Neurol, Hamburg, Germany. [McCracken, Lindsey; Dalmau, Josep] Univ Penn, Perelman Sch Med, Hosp Univ Penn, Dept Neurol & Neurosci, Philadelphia, PA 19104 USA. [Cellucci, Tania] McMaster Univ, Dept Pediat, McMaster Childrens Hosp, Hamilton, ON, Canada. [Benson, Leslie A.] Massachusetts Gen Hosp, Dept Child Neurol, Partners Pediat Multiple Sclerosis Ctr, Boston, MA 02114 USA. [Benson, Leslie A.] Boston Childrens Hosp, Pediat Multiple Sclerosis & Related Disorders Cli, Boston, MA USA. [Shu, Huidy] Pali Momi Med Ctr, Dept Neurol, Aiea, HI USA. [Irioka, Takashi] Yokosuka Kyosai Hosp, Dept Neurol, Yokosuka, Kanagawa, Japan. [Hirano, Makito] Kinki Univ, Fac Med, Sakai Hosp, Dept Neurol, Sakai, Osaka, Japan. [Singh, Gagandeep] Dayanand Med Coll, Dept Neurol, Ludhiana, Punjab, India. [Singh, Gagandeep] UCL, Dept Clin & Expt Epilepsy, London, England. [Cobo Calvo, Alvaro] Univ Hosp Bellvitge, Dept Neurol, Barcelona, Spain. [Kaida, Kenichi] Natl Def Med Coll, Dept Neurol, Tokorozawa, Saitama 359, Japan. [Morales, Pamela S.] Pontificia Univ Catolica Chile, Dept Pediat, Santiago, Chile. [Wirtz, Paul W.] Haga Hosp, Dept Neurol, The Hague, Netherlands. [Yamamoto, Tomotaka] Tokyo Univ Hosp, Med Safety Management Ctr, Tokyo 113, Japan. [Reindl, Markus] Med Univ Innsbruck, Dept Clin Neurol, A-6020 Innsbruck, Austria. [Dalmau, Josep] Catalan Inst Res & Adv Studies ICREA, Barcelona, Spain. RP Dalmau, J (reprint author), Univ Barcelona, IDIBAPS Hosp Clin, Serv Neurol, 143 Floor 5,Lab 503,Dept 2, E-08036 Barcelona, Spain. EM Josep.dalmau@uphs.upenn.edu RI Saiz, Albert/K-8236-2014; OI Saiz, Albert/0000-0002-5793-8791; Reindl, Markus/0000-0003-2817-1402; Rosenfeld, Myrna/0000-0001-5095-2534; Dalmau, Josep/0000-0001-5856-2813 FU Dutch Cancer Society; ErasmusMC fellowship; Fonds zur Forderung der wissenschaftlichen Forschung, Austria [J3230, W1206, I916]; Forschungsforderungsfonds Hamburg Eppendorf Exzellenzjahr; NIH National Institute of Neurologic Disorders and Stroke [RO1NS077851]; McKnight Neuroscience of Brain Disorders award; Fundacio la Marato TV3 [101530, 101610]; Fondo de Investigaciones Sanitarias de la Seguridad Social, Spain [PI11/01780]; A National MS Society; Ministry of Education, Culture, Sports, Science, and Technology of Japan [25461297]; Kinki University FX This study was supported by a Dutch Cancer Society fellowship (M.J.T.); an ErasmusMC fellowship (M.J.T.); the Fonds zur Forderung der wissenschaftlichen Forschung, Austria (Project J3230, R.H.; Projects W1206 and I916 [ERA-Net ERare project Eden], M.R.); the Forschungsforderungsfonds Hamburg Eppendorf Exzellenzjahr (F.L.); the NIH National Institute of Neurologic Disorders and Stroke (RO1NS077851, J.D.); a McKnight Neuroscience of Brain Disorders award (J.D.); Fundacio la Marato TV3 (101530, J.D.; 101610, A.S.); Fondo de Investigaciones Sanitarias de la Seguridad Social, Spain (PI11/01780, J.D.); A National MS Society Clinical Care Fellowship (L.A.B); Grants-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (25461297, M.H.); and a University Research Grant from Kinki University (M.H.). The funding sources had no role in the design, collection, analysis, or interpretation of the study, nor in the writing of the article or decision to submit. NR 32 TC 70 Z9 76 U1 1 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD MAR PY 2014 VL 75 IS 3 BP 411 EP 428 DI 10.1002/ana.24117 PG 18 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AD8WS UT WOS:000333547000011 PM 24700511 ER PT J AU Shih, YYI Yash, TV Rogers, B Duong, TQ AF Shih, Yen-Yu Ian Yash, Tiwari V. Rogers, Bill Duong, Timothy Q. TI fMRI of Deep Brain Stimulation at the Rat Ventral Posteromedial Thalamus SO BRAIN STIMULATION LA English DT Article DE Striatum; Deep brain stimulation; fMRI; Thalamus; Rat; Isoflurane ID BLOOD-FLOW; RESPONSES; BOLD; ACTIVATION; MRI; PLASTICITY AB Background: Functional magnetic resonance imaging (fMRI) of deep brain stimulation (DBS) has potentials to reveal neuroanatomical connectivity of a specific brain region in vivo. Objective: This study aimed to demonstrate frequency and amplitude tunings of the thalamocortical tract using DBS fMRI at the rat ventral posteromedial thalamus. Methods: Blood oxygenation level dependent (BOLD) fMRI data were acquired in a total of twelve rats at a high-field 11.7 T MRI scanner with modulation of nine stimulus frequencies (1-40 Hz) and seven stimulus amplitudes (0.2-3.6 mA). Results: BOLD response in the barrel cortex peaked at 25 Hz. The response increased with stimulus amplitude and reached a plateau at 1 mA. Cortical spreading depolarization (CSD) was observed occasionally after DBS that carries >10% BOLD waves spanning the entire ipsilateral cortex. Conclusion: fMRI is sensitive to the frequency effect of DBS and has potential to investigate the function of a particular neuroanatomical pathway. (C) 2014 Elsevier Inc. All rights reserved. C1 [Shih, Yen-Yu Ian; Yash, Tiwari V.; Rogers, Bill; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Shih, Yen-Yu Ian] Univ N Carolina, Dept Neurol, Chapel Hill, NC 27599 USA. [Shih, Yen-Yu Ian] Univ N Carolina, Biomed Res Imaging Ctr, Chapel Hill, NC 27599 USA. [Shih, Yen-Yu Ian] Univ N Carolina, Dept Biomed Engn, Chapel Hill, NC 27599 USA. [Yash, Tiwari V.] Univ Texas San Antonio, Dept Biomed Engn, San Antonio, TX 78249 USA. [Duong, Timothy Q.] South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX USA. RP Shih, YYI (reprint author), Univ N Carolina, Dept Neurol, Expt Neuroimaging Lab, 130 Mason Farm Rd,CB 7513, Chapel Hill, NC 27599 USA. EM shihy@unc.edu; duongt@uthscsa.edu OI Shih, Yen-Yu Ian/0000-0001-6529-911X FU American Heart Association [10POST4290091]; Clinical Translational Science Awards (CTSA) [UL1RR025767]; San Antonio Area Foundation; NIH/NINDS [R01 NS45879]; VA MERIT FX This work was supported in part by the American Heart Association (10POST4290091), Clinical Translational Science Awards (CTSA, parent grant UL1RR025767), and San Antonio Area Foundation to Dr. Yen-Yu Ian Shih and the NIH/NINDS R01 NS45879 and VA MERIT to Dr. Timothy Q. Duong. NR 19 TC 8 Z9 8 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1935-861X EI 1876-4754 J9 BRAIN STIMUL JI Brain Stimul. PD MAR-APR PY 2014 VL 7 IS 2 BP 190 EP 193 DI 10.1016/j.brs.2013.11.001 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AD7KH UT WOS:000333442200006 PM 24309153 ER PT J AU Suemoto, CK Apolinario, D Nakamura-Palacios, EM Lopes, L Leite, REP Sales, MC Nitrini, R Brucki, SM Morillo, LS Magaldi, RM Fregni, F AF Suemoto, Claudia Kimie Apolinario, Daniel Nakamura-Palacios, Ester Miyuki Lopes, Leonardo Paraizo Leite, Renata Elaine Sales, Manuela Castro Nitrini, Ricardo Brucki, Sonia Maria Morillo, Lilian Shafirovitz Magaldi, Regina Miksian Fregni, Felipe TI Effects of a Non-focal Plasticity Protocol on Apathy in Moderate Alzheimer's Disease: A Randomized, Double-blind, Sham-controlled Trial SO BRAIN STIMULATION LA English DT Article DE Apathy; Dementia; Alzheimer's disease; Cognition; Depression; Transcranial direct current stimulation ID DIRECT-CURRENT STIMULATION; PARKINSONS-DISEASE; DEMENTIA; METHYLPHENIDATE; DEPRESSION; MEMORY; DIAGNOSIS; EFFICACY; BRAIN; MODEL AB Background: Apathy is the most common neuropsychiatric symptom in Alzheimer's disease (AD) and it is associated with changes in prefrontal neural circuits involved with generation of voluntary actions. To date no effective treatment for apathy has been demonstrated. Objective: We aimed to investigate the effects and safety of repetitive transcranial direct current stimulation (tDCS) on apathy in moderate AD patients. Methods: Forty patients were randomized to receive either active or sham-tDCS over the left dorsolateral prefrontal cortex (DLPFC). Patients received six sessions of intervention during 2 weeks and were evaluated at baseline, at week 1 and 2, and after 1 week without intervention. Clinical raters, patients, and caregivers were blinded. The primary outcome was apathy. Global cognition and neuropsychiatric symptoms were examined as secondary outcomes. Results: The mean MMSE score at baseline was 15.2 +/- 2.9 and the mean Apathy Scale score was 27.7 +/- 6.7. Changes on apathy scores over time were not different between active and sham tDCS (P = 0.552 for repeated measures). Further analyses confirm that changes from baseline did not differ between groups after the sixth session (active tDCS -1.95 (95%CI -3.49, -0.41); sham-tDCS -2.05 (95% Cl -3.68, 0.42); P = 0.9891. Similarly, tDCS had no effect on secondary outcomes (P > 0.40). tDCS was well tolerated and not associated with significant adverse effects. Conclusion: In this adequately powered study for minimal clinically significant difference, our findings show that using the parameters we chose for this study, repeated anodal tDCS over the left DLPFC had no effect on apathy in elderly patients with moderate AD. (C) 2014 Elsevier Inc. All rights reserved. C1 [Suemoto, Claudia Kimie; Apolinario, Daniel; Lopes, Leonardo; Sales, Manuela Castro; Morillo, Lilian Shafirovitz; Magaldi, Regina Miksian] Univ Sao Paulo, Sch Med, Dept Internal Med, Discipline Geriatr, Sao Paulo, Brazil. [Nakamura-Palacios, Ester Miyuki] Univ Fed Espirito Santo, Dept Physiol Sci, Vitoria, Espirito Santo, Brazil. [Paraizo Leite, Renata Elaine] Univ Sao Paulo, Sch Med, LIM 22, Dept Pathol, Sao Paulo, Brazil. [Nitrini, Ricardo; Brucki, Sonia Maria] Univ Sao Paulo, Sch Med, Dept Neurol, Sao Paulo, Brazil. [Fregni, Felipe] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [Fregni, Felipe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Suemoto, CK (reprint author), Univ Sao Paulo, Dept Internal Med, Discipline Geriatr, Ave Doutor Arnaldo 455,Room 1353, Sao Paulo, Brazil. EM cksuemoto@usp.br RI Apolinario, Daniel/D-2816-2014; Suemoto, Claudia/C-7218-2012 OI Apolinario, Daniel/0000-0002-0261-129X; Suemoto, Claudia/0000-0002-5942-4778 FU Scala Institute FX Scala Institute. NR 30 TC 15 Z9 16 U1 4 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1935-861X EI 1876-4754 J9 BRAIN STIMUL JI Brain Stimul. PD MAR-APR PY 2014 VL 7 IS 2 BP 308 EP 313 DI 10.1016/j.brs.2013.10.003 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AD7KH UT WOS:000333442200023 PM 24262299 ER PT J AU Gunda, V Bucur, O Varnau, J Vanden Borre, P Bernasconi, MJ Khosravi-Far, R Parangi, S AF Gunda, V. Bucur, O. Varnau, J. Vanden Borre, P. Bernasconi, M. J. Khosravi-Far, R. Parangi, S. TI Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways SO CELL DEATH & DISEASE LA English DT Article DE apoptosis; thyroid cancer; BRAF(V600E) inhibitor; orthotropic; TRAIL ID TRAIL-INDUCED APOPTOSIS; DOWN-REGULATION; LEUKEMIA-CELLS; BRAF(V600E) MUTATION; DEPENDENT MANNER; CARCINOMA-CELLS; MELANOMA-CELLS; SOLID TUMORS; PHASE-I; B-RAF AB Current treatment for recurrent and aggressive/anaplastic thyroid cancers is ineffective. Novel targeted therapies aimed at the inhibition of the mutated oncoprotein BRAF(V600E) have shown promise in vivo and in vitro but do not result in cellular apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner by activating the extrinsic apoptotic pathway. Here, we show that a TRAIL-R2 agonist antibody, lexatumumab, induces apoptosis effectively in some thyroid cancer cell lines (HTh-7, TPC-1 and BCPAP), while more aggressive anaplastic cell lines (8505c and SW1736) show resistance. Treatment of the most resistant cell line, 8505c, using lexatumumab in combination with the BRAF(V600E) inhibitor, PLX4720, and the PI3K inhibitor, LY294002, (triple-drug combination) sensitizes the cells by triggering both the extrinsic and intrinsic apoptotic pathways in vitro as well as 8505c orthotopic thyroid tumors in vivo. A decrease in anti-apoptotic proteins, pAkt, Bcl-xL, Mcl-1 and c-FLIP, coupled with an increase in the activator proteins, Bax and Bim, results in an increase in the Bax to Bcl-xL ratio that appears to be critical for sensitization and subsequent apoptosis of these resistant cells. Our results suggest that targeting the death receptor pathway in thyroid cancer can be a promising strategy for inducing apoptosis in thyroid cancer cells, although combination with other kinase inhibitors may be needed in some of the more aggressive tumors initially resistant to apoptosis. C1 [Gunda, V.; Vanden Borre, P.; Bernasconi, M. J.; Parangi, S.] Harvard Univ, Sch Med, Endocrine Unit, Surg Unit,Massachusetts Gen Hosp,Thyroid Canc Res, Boston, MA 02115 USA. [Bucur, O.; Khosravi-Far, R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Bucur, O.; Khosravi-Far, R.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Bucur, O.] Acad Romana, Inst Biochem, Dept Mol Cell Biol, Bucharest, Romania. [Varnau, J.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Parangi, S (reprint author), Harvard Univ, Sch Med, Endocrine Unit, Surg Unit,Massachusetts Gen Hosp,Thyroid Canc Res, Wang ACC 460,15 Parkman St, Boston, MA 02115 USA. EM sparangi@partners.org RI Bucur, Octavian/G-2823-2010 OI Bucur, Octavian/0000-0002-8501-588X FU National Institutes of Health [NIH-NCI R01 1R01CA149738-01A1] FX We thank Gideon Bollag, Paul Lin at Plexxikon/Roche for providing us with PLX4720; and Matthew Nehs and Andrew Scott Liss for technical assistance. This work was supported by The National Institutes of Health grant to Dr. Sareh Parangi (NIH-NCI R01 1R01CA149738-01A1). NR 50 TC 15 Z9 17 U1 0 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD MAR PY 2014 VL 5 AR e1104 DI 10.1038/cddis.2014.78 PG 13 WC Cell Biology SC Cell Biology GA AE1TW UT WOS:000333754100008 PM 24603332 ER PT J AU Munoz, JL Rodriguez-Cruz, V Greco, SJ Ramkissoon, SH Ligon, KL Rameshwar, P AF Munoz, J. L. Rodriguez-Cruz, V. Greco, S. J. Ramkissoon, S. H. Ligon, K. L. Rameshwar, P. TI Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43 SO CELL DEATH & DISEASE LA English DT Article DE connexin 43; glioblastoma; resistance; temozolomide EGF receptor; stem cell; immune therapy ID MESENCHYMAL STEM-CELLS; CENTRAL-NERVOUS-SYSTEM; HUMAN GLIOMA-CELLS; GAP-JUNCTIONS; INTERCELLULAR COMMUNICATION; MOLECULAR-MECHANISMS; SIGNALING PATHWAY; PROTEIN; HEMICHANNELS; EXPRESSION AB Glioblastoma Multiforme (GBM) is an aggressive adult primary brain tumor with poor prognosis. GBM patients develop resistance to the frontline chemotherapy, temozolomide (TMZ). As the connexins (Cx) have been shown to have a complex role in GBM, we investigated the role of Cx43 in TMZ resistance. Cx43 was increased in the TMZ-resistant low passage and cell lines. This correlated with the data in The Cancer Genome Atlas. Cx43 knockdown, reporter gene assays, chromatin immunoprecipitation assay, real-time PCR and western blots verified a role for Cx43 in TMZ resistance. This occurred by TMZ-resistant GBM cells being able to activate epidermal growth factor receptor (EGFR). In turn, EGFR activated the JNK-ERK1/2-AP-1 axis to induce Cx43. The increased Cx43 was functional as indicated by gap junctional intercellular communication among the resistant GBM cells. Cell therapy could be a potential method to deliver drugs, such as anti-EGF to tumor cells. Similar strategies could be used to reverse the expression of Cx43 to sensitize GBM cells to TMZ. The studies showed the potential for targeting EGF in immune therapy. These agents can be used in conjunction with stem cell therapy to treat GBM. C1 [Munoz, J. L.] Rutgers Grad Sch Biomed Sci, Newark, NJ USA. [Munoz, J. L.; Rodriguez-Cruz, V.; Greco, S. J.; Rameshwar, P.] Rutgers Sch Biomed Hlth Sci, New Jersey Med Sch, Dept Med, Newark, NJ 07103 USA. [Ramkissoon, S. H.; Ligon, K. L.] Boston Childrens Hosp, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. [Ramkissoon, S. H.; Ligon, K. L.] Harvard Univ, Sch Med, Boston, MA USA. [Ramkissoon, S. H.; Ligon, K. L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Rameshwar, P (reprint author), Rutgers Sch Biomed Hlth Sci, New Jersey Med Sch, Dept Med, 185 South Orange Ave,MSB E-585, Newark, NJ 07103 USA. EM rameshwa@njms.rutgers.edu FU F M Kirby Foundation; Research Initiative for Science Enhancement Program at the University of Puerto Rico in Cayey [R25 GM59429] FX This work was supported by the F M Kirby Foundation and this work is in partial fulfillment of JLM's PhD thesis. VR-C was supported by the Research Initiative for Science Enhancement Program at the University of Puerto Rico in Cayey (R25 GM59429). We would also like to thank Sukhwinder Singh, PhD and the Flow Cytometry and Immunology Core Laboratory at New Jersey Medical School. NR 36 TC 23 Z9 23 U1 3 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-4889 J9 CELL DEATH DIS JI Cell Death Dis. PD MAR PY 2014 VL 5 AR e1145 DI 10.1038/cddis.2014.111 PG 10 WC Cell Biology SC Cell Biology GA AE1TW UT WOS:000333754100049 PM 24675463 ER EF