FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Ashcraft, KA Peace, RM Betof, AS Dewhirst, MW Jones, LW AF Ashcraft, Kathleen A. Peace, Ralph M. Betof, Allison S. Dewhirst, Mark W. Jones, Lee W. TI Efficacy and Mechanisms of Aerobic Exercise on Cancer Initiation, Progression, and Metastasis: A Critical Systematic Review of In Vivo Preclinical Data SO CANCER RESEARCH LA English DT Review ID TUMOR-BEARING RATS; INDUCED MAMMARY CARCINOGENESIS; INDUCED COLON CARCINOGENESIS; RANDOMIZED CONTROLLED-TRIAL; HIGH-INTENSITY EXERCISE; HEALTHY FOOD CHOICES; MALE F344 RATS; BREAST-CANCER; PHYSICAL-ACTIVITY; VOLUNTARY EXERCISE AB A major objective of the emerging field of exercise-oncology research is to determine the efficacy of, and biological mechanisms by which, aerobic exercise affects cancer incidence, progression, and/or metastasis. There is a strong inverse association between self-reported exercise and the primary incidence of several forms of cancer; similarly, emerging data suggest that exercise exposure after a cancer diagnosis may improve outcomes for early-stage breast, colorectal, or prostate cancer. Arguably, critical next steps in the development of exercise as a candidate treatment in cancer control require preclinical studies to validate the biological efficacy of exercise, identify the optimal "dose", and pinpoint mechanisms of action. To evaluate the current evidence base, we conducted a critical systematic review of in vivo studies investigating the effects of exercise in cancer prevention and progression. Studies were evaluated on the basis of tumor outcomes (e.g., incidence, growth, latency, metastasis), dose-response, and mechanisms of action, when available. A total of 53 studies were identified and evaluated on tumor incidence (n = 24), tumor growth (n = 33), or metastasis (n = 10). We report that the current evidence base is plagued by considerable methodologic heterogeneity in all aspects of study design, endpoints, and efficacy. Such heterogeneity precludes meaningful comparisons and conclusions at present. To this end, we provide a framework of methodologic and data reporting standards to strengthen the field to guide the conduct of high-quality studies required to inform translational, mechanism-driven clinical trials. (C)2016 AACR. C1 [Ashcraft, Kathleen A.; Peace, Ralph M.; Dewhirst, Mark W.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [Betof, Allison S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jones, Lee W.] Mem Sloan Kettering Canc Ctr, New York, NY 10017 USA. RP Jones, LW (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 485 Lexington Ave, New York, NY 10017 USA.; Dewhirst, MW (reprint author), Duke Univ, Med Ctr, Dept Radiat Oncol, Box 3455,Med Sci Res Bldg 1,Room 201, Durham, NC 27710 USA. EM mark.dewhirst@duke.edu; jonesl3@mskcc.org FU NCI NIH HHS [P30 CA008748, R01 CA040355] NR 106 TC 1 Z9 1 U1 10 U2 12 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 JUL 15 PY 2016 VL 76 IS 14 BP 4032 EP 4050 DI 10.1158/0008-5472.CAN-16-0887 PG 19 WC Oncology SC Oncology GA DS9NY UT WOS:000381111400003 PM 27381680 ER PT J AU Weygant, N Ge, Y Qu, DF Kaddis, JS Berry, WL May, R Chandrakesan, P Bannerman-Menson, E Vega, KJ Tomasek, JJ Bronze, MS An, GY Houchen, CW AF Weygant, Nathaniel Ge, Yang Qu, Dongfeng Kaddis, John S. Berry, William L. May, Randal Chandrakesan, Parthasarathy Bannerman-Menson, Edwin Vega, Kenneth J. Tomasek, James J. Bronze, Michael S. An, Guangyu Houchen, Courtney W. TI Survival of Patients with Gastrointestinal Cancers Can Be Predicted by a Surrogate microRNA Signature for Cancer Stem-like Cells Marked by DCLK1 Kinase SO CANCER RESEARCH LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; GASTRIC-CANCER; COLORECTAL-CANCER; TUMOR-GROWTH; TUFT CELLS; DEPENDENT MECHANISM; RADIATION-INJURY; IDENTIFICATION; DOUBLECORTIN; EXPRESSION AB Doublecortin-like kinase 1 (DCLK1) is a gastrointestinal (GI) tuft cell kinase that has been investigated as a biomarker of cancer stem-like cells in colon and pancreatic cancers. However, its utility as a biomarker may be limited in principle by signal instability and dilution in heterogeneous tumors, where the proliferation of diverse tumor cell lineages obscures the direct measurement of DCLK1 activity. To address this issue, we explored the definition of a miRNA signature as a surrogate biomarker for DCLK1 in cancer stem-like cells. Utilizing RNA/miRNA-sequencing datasets from the Cancer Genome Atlas, we identified a surrogate 15-miRNA expression signature for DCLK1 activity across several GI cancers, including colon, pancreatic, and stomach cancers. Notably, Cox regression and Kaplan-Meier analysis demonstrated that this signature could predict the survival of patients with these cancers. Moreover, we identified patient subgroups that predicted the clinical utility of this DCLK1 surrogate biomarker. Our findings greatly strengthen the clinical significance for DCLK1 expression across GI cancers. Further, they provide an initial guidepost toward the development of improved prognostic biomarkers or companion biomarkers for DCLK1-targeted therapies to eradicate cancer stem-like cells in these malignancies. (C)2016 AACR. C1 [Weygant, Nathaniel; Qu, Dongfeng; May, Randal; Chandrakesan, Parthasarathy; Vega, Kenneth J.; Bronze, Michael S.; Houchen, Courtney W.] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. [Ge, Yang; An, Guangyu] Capital Med Univ, Beijing Chao Yang Hosp, Dept Oncol, Beijing, Peoples R China. [Qu, Dongfeng; May, Randal; Chandrakesan, Parthasarathy; Vega, Kenneth J.; Houchen, Courtney W.] US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. [Qu, Dongfeng; Chandrakesan, Parthasarathy; Houchen, Courtney W.] Peggy & Charles Stephenson Canc Ctr, Oklahoma City, OK USA. [Kaddis, John S.] City Hope Natl Med Ctr, 1500 E Duarte Rd, Duarte, CA 91010 USA. [Berry, William L.; Tomasek, James J.] Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, Oklahoma City, OK USA. [Bannerman-Menson, Edwin; Houchen, Courtney W.] COARE Biotechnol Inc, Oklahoma City, OK USA. RP Houchen, CW (reprint author), 920 Stanton L Young Blvd,WP 1345, Oklahoma City, OK 73104 USA.; An, GY (reprint author), 8 Gongren Tiyuchang Nanlu Rd, Beijing 100020, Peoples R China. EM anguangyu@hotmail.com; courtney-houchen@ouhsc.edu OI Berry, William/0000-0002-1661-5443 FU BLRD VA [I01 BX001952]; NCI NIH HHS [R01 CA182869, R21 CA186175] NR 40 TC 1 Z9 1 U1 4 U2 4 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 JUL 15 PY 2016 VL 76 IS 14 BP 4090 EP 4099 DI 10.1158/0008-5472.CAN-16-0029 PG 10 WC Oncology SC Oncology GA DS9NY UT WOS:000381111400008 PM 27287716 ER PT J AU Vo, KT Edwards, JV Epling, CL Sinclair, E Hawkins, DS Grier, HE Janeway, KA Barnette, P Mcllvaine, E Krailo, MD Barkauskas, DA Matthay, KK Womer, RB Gorlick, RG Lessnick, SL Mackall, CL DuBois, SG AF Vo, Kieuhoa T. Edwards, Jeremy V. Epling, C. Lorrie Sinclair, Elizabeth Hawkins, Douglas S. Grier, Holcombe E. Janeway, Katherine A. Barnette, Phillip Mcllvaine, Elizabeth Krailo, Mark D. Barkauskas, Donald A. Matthay, Katherine K. Womer, Richard B. Gorlick, Richard G. Lessnick, Stephen L. Mackall, Crystal L. DuBois, Steven G. TI Impact of Two Measures of Micrometastatic Disease on Clinical Outcomes in Patients with Newly Diagnosed Ewing Sarcoma: A Report from the Children's Oncology Group SO CLINICAL CANCER RESEARCH LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; CIRCULATING TUMOR-CELLS; BONE-MARROW; GROWTH-FACTOR; RT-PCR; RECEPTOR ANTIBODY; PERIPHERAL-BLOOD; FLOW-CYTOMETRY; PHASE-II; EXPRESSION AB Purpose: Flow cytometry and RT-PCR can detect occult Ewing sarcoma cells in the blood and bone marrow. These techniques were used to evaluate the prognostic significance of micrometastatic disease in Ewing sarcoma. Experimental Design: Newly diagnosed patients with Ewing sarcoma were enrolled on two prospective multicenter studies. In the flow cytometry cohort, patients were defined as "positive" for bone marrow micrometastatic disease if their CD99(+)/CD45(-) values were above the upper limit in 22 control patients. In the PCR cohort, RT-PCR on blood or bone marrow samples classified the patients as "positive" or "negative" for EWSR1/FLI1 translocations. The association between micrometastatic disease burden with clinical features and outcome was assessed. Coexpression of insulin-like growth factor-1 receptor (IGF-1R) on detected tumor cells was performed in a subset of flow cytometry samples. Results: The median total bone marrow CD99(+)CD45(-) percent was 0.0012%(range0%-1.10%) in the flow cytometry cohort, with 14 of 109 (12.8%) of Ewing sarcoma patients defined as "positive." In the PCR cohort, 19.6%(44/225) patients were "positive" for any EWSR1/FLI1 translocation in blood or bone marrow. There were no differences in baseline clinical features or event-free or overall survival between patients classified as "positive" versus "negative" by either method. CD99(+)CD45(-) cells had significantly higher IGF-1R expression compared with CD45(+) hematopoietic cells (mean geometric mean fluorescence intensity 982.7 vs. 190.9; P < 0.001). Conclusions: The detection of micrometastatic disease at initial diagnosis by flow cytometry or RT-PCR is not associated with outcome in newly diagnosed patients with Ewing sarcoma. Flow cytometry provides a tool to characterize occult micrometastatic tumor cells for proteins of interest. (C) 2016 AACR. C1 [Vo, Kieuhoa T.; Matthay, Katherine K.; DuBois, Steven G.] Univ Calif San Francisco, Sch Med, Dept Pediat, UCSF Benioff Childrens Hosp, San Francisco, CA 94143 USA. [Edwards, Jeremy V.] Walter Reed Army Med Ctr, Dept Pediat, Washington, DC 20307 USA. [Epling, C. Lorrie; Sinclair, Elizabeth] Univ Calif San Francisco, Sch Med, UCSF Benioff Childrens Hosp, Div Expt Med,Core Immunol Lab, San Francisco, CA USA. [Hawkins, Douglas S.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle Childrens Hosp, Div Hematol Oncol, Seattle, WA 98195 USA. [Grier, Holcombe E.; Janeway, Katherine A.] Harvard Med Sch, Dana Farber Boston Childrens Canc & Blood Disords, Boston, MA USA. [Barnette, Phillip] Univ Utah, Huntsman Canc Inst, Ctr Childrens Canc Res, Dept Pediat Hematol Oncol, Salt Lake City, UT USA. [Mcllvaine, Elizabeth; Krailo, Mark D.; Barkauskas, Donald A.] Univ Southern Calif, Keck Sch Med, Dept Preventat Med, Los Angeles, CA 90033 USA. [Womer, Richard B.] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Gorlick, Richard G.] Albert Einstein Coll Med, Childrens Hosp Montefiore, Div Pediat Hematol Oncol, Bronx, NY 10467 USA. [Lessnick, Stephen L.] Ohio State Univ, Ctr Childhood Canc & Blood Disorders, Nationwide Childrens Hosp, Columbus, OH 43210 USA. [Lessnick, Stephen L.] Ohio State Univ, Div Hematol Oncol & BMT, Columbus, OH 43210 USA. [Mackall, Crystal L.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP DuBois, SG (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 3, Boston, MA 02215 USA. EM steven_dubois@dfci.harvard.edu FU NIH [K23 CA154530, P30AI027763]; NIH Intramural Research Program; Alex's Lemonade Stand Foundation; Frank A. Campini Foundation; Hope Street Kids; Sarcoma Foundation of America; CureSearch for Children's Cancer; John M. Gilbertson Foundation; Daniel P. Sullivan Fund; WWWW (QuadW) Foundation; Children's Oncology Group grants [U10CA180886, U10CA180899, U10CA098543, U10CA098413] FX This work was supported in part by the NIH grant K23 CA154530 (to S.G. DuBois); NIH Intramural Research Program (to C.L. Mackall); NIH grant P30AI027763 to the UCSF-GIVI Center for AIDS Research (UCSF Flow Cytometry Core Laboratory); Alex's Lemonade Stand Foundation (to K.T. Vo, K.K. Matthay, and S.G. DuBois); Frank A. Campini Foundation (to K.K. Matthay and S.G. DuBois); Hope Street Kids (to S.G. DuBois); Sarcoma Foundation of America (to S.G. DuBois); CureSearch for Children's Cancer (to S.G. DuBois); John M. Gilbertson Foundation (to D.S. Hawkins); Daniel P. Sullivan Fund (to R.B. Womer); WWWW (QuadW) Foundation (to M.D. Krailo and D.A. Barkauskas); Children's Oncology Group grants (U10CA180886, U10CA180899, U10CA098543, and U10CA098413). NR 27 TC 0 Z9 0 U1 1 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 JUL 15 PY 2016 VL 22 IS 14 BP 3643 EP 3650 DI 10.1158/1078-0432.CCR-15-2516 PG 8 WC Oncology SC Oncology GA DS9ON UT WOS:000381113000023 PM 26861456 ER PT J AU Gao, S Ye, HH Gerrin, S Wang, HY Sharma, A Chen, S Patnaik, A Sowalsky, AG Voznesensky, O Han, WT Yu, ZY Mostaghel, EA Nelson, PS Taplin, ME Balk, SP Cai, CM AF Gao, Shuai Ye, Huihui Gerrin, Sean Wang, Hongyun Sharma, Ankur Chen, Sen Patnaik, Akash Sowalsky, Adam G. Voznesensky, Olga Han, Wanting Yu, Ziyang Mostaghel, Elahe A. Nelson, Peter S. Taplin, Mary-Ellen Balk, Steven P. Cai, Changmeng TI ErbB2 Signaling Increases Androgen Receptor Expression in Abiraterone-Resistant Prostate Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID PHASE-II TRIAL; HER-2/NEU EXPRESSION; TYROSINE KINASE; TUMOR-GROWTH; CELLS; INHIBITION; PHOSPHORYLATION; TRASTUZUMAB; PROGRESSION; INDUCTION AB Purpose: ErbB2 signaling appears to be increased and may enhance androgen receptor (AR) activity in a subset of patients with castration-resistant prostate cancer (CRPC), but agents targeting ErbB2 have not been effective. This study was undertaken to assess ErbB2 activity in abiraterone-resistant prostate cancer and to determine whether it may contribute to AR signaling in these tumors. Experimental Design: AR activity and ErbB2 signaling were examined in the radical prostatectomy specimens from a neoadjuvant clinical trial of leuprolide plus abiraterone and in the specimens from abiraterone-resistant CRPC xenograft models. The effect of ErbB2 signaling on AR activity was determined in two CRPC cell lines. Moreover, the effect of combination treatment with abiraterone and an ErbB2 inhibitor was assessed in a CRPC xenograft model. Results: We found that ErbB2 signaling was elevated in residual tumor following abiraterone treatment in a subset of patients and was associated with higher nuclear AR expression. In xenograft models, we similarly demonstrated that ErbB2 signaling was increased and associated with AR reactivation in abiraterone-resistant tumors. Mechanistically, we show that ErbB2 signaling and subsequent activation of the PI3K/AKT signaling stabilizes AR protein. Furthermore, concomitantly treating CRPC cells with abiraterone and an ErbB2 inhibitor, lapatinib, blocked AR reactivation and suppressed tumor progression. Conclusions: ErbB2 signaling is elevated in a subset of patients with abiraterone-resistant prostate cancer and stabilizes AR protein. Combination therapy with abiraterone and ErbB2 antagonists may be effective for treating the subset of CRPC with elevated ErbB2 activity. (C) 2016 AACR. C1 [Gao, Shuai; Han, Wanting; Cai, Changmeng] Univ Massachusetts, Ctr Personalized Canc Therapy, Boston, MA 02125 USA. [Gao, Shuai; Ye, Huihui; Gerrin, Sean; Wang, Hongyun; Sharma, Ankur; Chen, Sen; Patnaik, Akash; Sowalsky, Adam G.; Voznesensky, Olga; Yu, Ziyang; Balk, Steven P.; Cai, Changmeng] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA USA. [Patnaik, Akash] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Mostaghel, Elahe A.; Nelson, Peter S.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Taplin, Mary-Ellen] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. RP Cai, CM (reprint author), Univ Massachusetts, 100 Morrissey Blvd, Boston, MA 02125 USA.; Balk, SP (reprint author), Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. EM sbalk@bidmc.harvard.edu; changmeng.cai@umb.edu OI Sowalsky, Adam/0000-0003-2760-1853; Cai, Changmeng/0000-0002-8701-2586 FU NIH [R00CA166507, P01CA163227, P50CA090381-13, P50CA097186]; DOD [W81XWH-11-1-0295, W81XWH-13-1-0266]; DF/HCC Mazzone Impact Award; Prostate Cancer Foundation FX This work is supported by grants from NIH (R00CA166507, to C. Cai; P01CA163227, to S.P. Balk, P.S. Nelson, E.A. Mostaghel.; and SPORE in Prostate Cancer P50CA090381-13, to C. Cai, S.P. Balk; and P50CA097186, to P.S. Nelson and E.A. Mostaghel), and DOD (W81XWH-11-1-0295 and W81XWH-13-1-0266; to S.P. Balk), a DF/HCC Mazzone Impact Award, and by Awards from the Prostate Cancer Foundation. NR 51 TC 2 Z9 2 U1 1 U2 2 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 JUL 15 PY 2016 VL 22 IS 14 BP 3672 EP 3682 DI 10.1158/1078-0432.CCR-15-2309 PG 11 WC Oncology SC Oncology GA DS9ON UT WOS:000381113000026 PM 26936914 ER PT J AU Pell, VR Chouchani, ET Frezza, C Murphy, MP Krieg, T AF Pell, Victoria R. Chouchani, Edward T. Frezza, Christian Murphy, Michael P. Krieg, Thomas TI Succinate metabolism: a new therapeutic target for myocardial reperfusion injury SO CARDIOVASCULAR RESEARCH LA English DT Review DE Succinate; Reactive oxygen species; Mitochondria; Ischaemia; reperfusion ID MITOCHONDRIAL PERMEABILITY TRANSITION; SENSITIVE POTASSIUM CHANNELS; RANDOMIZED CONTROLLED-TRIAL; ELECTRON-TRANSPORT CHAIN; ISCHEMIA-REPERFUSION; COMPLEX-I; RAT-HEART; S-NITROSATION; CARDIAC MITOCHONDRIA; INHIBITOR MALONATE AB Myocardial ischaemia/reperfusion (IR) injury is a major cause of death worldwide and remains a disease for which current clinical therapies are strikingly deficient. While the production of mitochondrial reactive oxygen species (ROS) is a critical driver of tissue damage upon reperfusion, the precise mechanisms underlying ROS production have remained elusive. More recently, it has been demonstrated that a specific metabolic mechanism occurs during ischaemia that underlies elevated ROS at reperfusion, suggesting a unifying model as to why so many different compounds have been found to be cardioprotective against IR injury. This review will discuss the role of the citric acid cycle intermediate succinate in IR pathology focusing on the mechanism by which this metabolite accumulates during ischaemia and how it can drive ROS production at Complex I via reverse electron transport. We will then examine the potential for manipulating succinate accumulation and metabolism during IR injury in order to protect the heart against IR damage and discuss targets for novel therapeutics designed to reduce reperfusion injury in patients. C1 [Pell, Victoria R.; Krieg, Thomas] Univ Cambridge, Addenbrookes Hosp, Dept Med, Hills Rd, Cambridge CB2 0QQ, England. [Chouchani, Edward T.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Chouchani, Edward T.] Harvard Med Sch, Dept Cell Biol, Boston, MA USA. [Frezza, Christian] Univ Cambridge, Hutchison MRC Res Ctr, MRC Canc Unit, Box 197,Cambridge Biomed Campus, Cambridge CB2 0XZ, England. [Murphy, Michael P.] MRC Mitochondrial Biol Unit, Hills Rd, Cambridge CB2 0XY, England. RP Krieg, T (reprint author), Univ Cambridge, Addenbrookes Hosp, Dept Med, Hills Rd, Cambridge CB2 0QQ, England. EM tk382@medschl.cam.ac.uk FU Medical Research Council [MC_U105663142, MC_UU_12022/6] NR 83 TC 4 Z9 4 U1 13 U2 13 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 JUL 15 PY 2016 VL 111 IS 2 BP 134 EP 141 DI 10.1093/cvr/cvw100 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DT1TF UT WOS:000381264300006 PM 27194563 ER PT J AU Ebrahimi, R Uberoi, A Treadwell, M Rafie, AHS AF Ebrahimi, Ramin Uberoi, Abhimanyu Treadwell, Michelle Rafie, Amir H. Sadrzadeh TI Effect of Low-Frame Invasive Coronary Angiography on Radiation and Image Quality SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID IONIZING-RADIATION; CATARACT FORMATION; EXPOSURE; LENS; FLUOROSCOPY; COHORT AB Invasive coronary angiography (ICA) uses harmful x-ray energy. To date, there are no studies evaluating the effect of performing ICA at lower than the standard 15 frames per second (f/s) on radiation dose and image quality. In this study, we investigated the effect of performing IC As at 7.5 f/s as opposed to the standard 15 f/s on radiation exposure and image quality. Thirty-nine patients referred for ICA for clinical indications were assigned to have their ICA performed at 7.5 f/s or 15 f/s in a 2:1 ratio, respectively. All studies were performed by one experienced operator in the same laboratory. Magnification, table height, collimation, number of images, and specific angles for image acquisition were kept constant to account for these variables that also effect radiation. Studies performed at 7.5 f/s had significantly less radiation exposure than those performed at 15 f/s (252.2 mGy vs 433.7 mGy, p < 0.01). In addition, radiation per unit time was also significantly reduced in the 7.5 f/s versus the 15 f/s group (140.0 mGy/min vs 254.7 mGy/min, p < 0.01). Image quality was evaluated by an experienced operator blinded to the goals of the study; all studies were graded as good to excellent. In conclusion, performing ICA at 7.5 f/s versus 15 f/s significantly reduces x-ray exposure without compromising image quality. The results of this single-center study warrant a larger randomized clinical trial. Published by Elsevier Inc. C1 [Ebrahimi, Ramin; Treadwell, Michelle] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Div Cardiol, Los Angeles, CA USA. [Ebrahimi, Ramin] Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. [Uberoi, Abhimanyu] Cedars Sinai Med Ctr, Dept Med, Div Cardiol, Los Angeles, CA 90048 USA. [Rafie, Amir H. Sadrzadeh] Glendale Heart Inst Med Grp Inc, Dept Med, Div Cardiol, Glendale, CA USA. RP Ebrahimi, R (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Div Cardiol, Los Angeles, CA USA.; Ebrahimi, R (reprint author), Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90024 USA. EM ebrahimi@ucla.edu NR 13 TC 1 Z9 1 U1 1 U2 1 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 JUL 15 PY 2016 VL 118 IS 2 BP 195 EP 197 DI 10.1016/j.amjcard.2016.04.041 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DR8XA UT WOS:000380180500007 PM 27241835 ER PT J AU Barbash, IJ Kahn, JM Thompson, BT AF Barbash, Ian J. Kahn, Jeremy M. Thompson, B. Taylor TI OPENING THE DEBATE ON THE NEW SEPSIS DEFINITION Medicare's Sepsis Reporting Program: Two Steps Forward, One Step Back SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID INTERNATIONAL CONSENSUS DEFINITIONS; SEPTIC SHOCK SEPSIS-3; CLINICAL-CRITERIA; CARE; PERFORMANCE C1 [Barbash, Ian J.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15260 USA. [Barbash, Ian J.] Univ Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15260 USA. [Kahn, Jeremy M.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Dept Crit Care Med, Pittsburgh, PA USA. [Kahn, Jeremy M.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Thompson, B. Taylor] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA. RP Barbash, IJ (reprint author), Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15260 USA.; Barbash, IJ (reprint author), Univ Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15260 USA. FU NHLBI NIH HHS [F32 HL132461, T32 HL007563] NR 13 TC 0 Z9 0 U1 0 U2 0 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 JUL 15 PY 2016 VL 194 IS 2 BP 139 EP 141 PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DT7VY UT WOS:000381697500010 PM 27167169 ER PT J AU Prescott, HC Calfee, CS Thompson, BT Angus, DC Liu, VX AF Prescott, Hallie C. Calfee, Carolyn S. Thompson, B. Taylor Angus, Derek C. Liu, Vincent X. TI Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE sepsis; acute respiratory distress syndrome; endotype; prognostic enrichment; predictive enrichment ID COMMUNITY-ACQUIRED PNEUMONIA; CRITICALLY-ILL PATIENTS; PEDIATRIC SEPTIC SHOCK; ACUTE LUNG INJURY; INFLAMMATORY RESPONSE; PERSONALIZED MEDICINE; BERLIN DEFINITION; MORTALITY; CARE; CORTICOSTEROIDS AB Both quality improvement and clinical research efforts over the past fewdecades have focused on consensus definition of sepsis and acute respiratory distress syndrome (ARDS). Although clinical definitions based on readily available clinical data have advanced recognition and timely use of broad supportive treatments, they likely hinder the identification of more targeted therapies that manipulate select biological mechanisms underlying critical illness. Sepsis and ARDS are by definition heterogeneous, and patients vary in both their underlying biology and their severity of illness. We have long been able to identify subtypes of sepsis and ARDS that confer different prognoses. The key is that we are now on the verge of identifying subtypes that may confer different response to therapy. In this perspective, inspired by a 2015 American Thoracic Society International Conference Symposium entitled "Lumpers and Splitters: Phenotyping in Critical Illness," we highlight promising approaches to uncovering patient subtypes that may predict treatment responsiveness and not just differences in prognosis. We then discuss how this information can be leveraged to improve the success and translatability of clinical trials by using predictive enrichment and other design strategies. Last, we discuss the challenges and limitations to identifying biomarkers and endotypes and incorporating them into routine clinical practice. C1 [Prescott, Hallie C.] Univ Michigan, Dept Med, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA. [Prescott, Hallie C.] Vet Affairs Ctr Clin Management Res, Ann Arbor, MI USA. [Calfee, Carolyn S.] Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA USA. [Calfee, Carolyn S.] Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA 94143 USA. [Thompson, B. Taylor] Harvard Sch Med, Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Dept Med, Boston, MA USA. [Angus, Derek C.] Univ Pittsburgh, Sch Med, Clin Res Invest & Syst Modeling Acute Illness Ctr, Dept Crit Care Med, Pittsburgh, PA USA. [Liu, Vincent X.] Kaiser Permanente, Div Res, Oakland, CA USA. RP Prescott, HC (reprint author), NCRC Bldg 16,341E,2800 Plymouth Rd, Ann Arbor, MI 48109 USA. EM hprescot@med.umich.edu OI Prescott, Hallie/0000-0002-8442-6724 FU National Institutes of Health [K08 GM115859, HL131621, GM107650, K23 GM112018, U01 HL 123009-01] FX Supported by National Institutes of Health grants K08 GM115859 (H.C.P.), HL131621 (C.S.C.), GM107650 (D.C.A.), K23 GM112018 (V.X.L.), and U01 HL 123009-01 (D.C.A. and B.T.T.). NR 62 TC 6 Z9 6 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 15 PY 2016 VL 194 IS 2 BP 147 EP 155 DI 10.1164/rccm.201512-2544CP PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DT7VY UT WOS:000381697500012 PM 27244481 ER PT J AU Bhatt, SP Soler, X Wang, X Murray, S Anzueto, AR Beaty, TH Boriek, AM Casaburi, R Criner, GJ Diaz, AA Dransfield, MT Curran-Everett, D Galban, CJ Hoffman, EA Hogg, JC Kazerooni, EA Kim, V Kinney, GL Lagstein, A Lynch, DA Make, BJ Martinez, FJ Ramsdell, JW Reddy, R Ross, BD Rossiter, HB Steiner, RM Strand, MJ van Beek, EJR Wan, ES Washko, GR Wells, JM Wendt, CH Wise, RA Silverman, EK Crapo, JD Bowler, RP Han, MLK AF Bhatt, Surya P. Soler, Xavier Wang, Xin Murray, Susan Anzueto, Antonio R. Beaty, Terri H. Boriek, Aladin M. Casaburi, Richard Criner, Gerard J. Diaz, Alejandro A. Dransfield, Mark T. Curran-Everett, Douglas Galban, Craig J. Hoffman, Eric A. Hogg, James C. Kazerooni, Ella A. Kim, Victor Kinney, Gregory L. Lagstein, Amir Lynch, David A. Make, Barry J. Martinez, Fernando J. Ramsdell, Joe W. Reddy, Rishindra Ross, Brian D. Rossiter, Harry B. Steiner, Robert M. Strand, Matthew J. van Beek, Edwin J. R. Wan, Emily S. Washko, George R. Wells, J. Michael Wendt, Chris H. Wise, Robert A. Silverman, Edwin K. Crapo, James D. Bowler, Russell P. Han, MeiLan K. CA COPDGene Investigators TI Association between Functional Small Airway Disease and FEV1 Decline in Chronic Obstructive Pulmonary Disease SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE FEV1; lung function; parametric response mapping ID COPD; FLOW; EPIDEMIOLOGY; SPIROMETRY; SMOKERS; TIME; SITE AB Rationale: The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development. Objectives: We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV1 decline. Methods: We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRMemph) and functional small airways disease (PRMfSAD), a measure of nonemphysematous air trapping. Measurements and Main Results: Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRMfSAD but not PRMemph was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRMfSAD and PRMemph were associated with FEV1 decline (P, 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRMfSAD and PRMemph in GOLD 1/2 and 3/4, respectively. Conclusions: CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. C1 [Bhatt, Surya P.; Dransfield, Mark T.; Wells, J. Michael] Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Birmingham, AL USA. [Bhatt, Surya P.; Dransfield, Mark T.; Wells, J. Michael] Univ Alabama Birmingham, UAB Lung Hlth Ctr, Birmingham, AL USA. [Soler, Xavier; Ramsdell, Joe W.] Univ Calif San Diego, Div Pulm Crit Care & Sleep Med, San Diego, CA 92103 USA. [Wang, Xin; Murray, Susan] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Galban, Craig J.; Ross, Brian D.] Univ Michigan, Dept Radiol, Ctr Mol Imaging, Ann Arbor, MI 48109 USA. [Kazerooni, Ella A.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Lagstein, Amir] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Martinez, Fernando J.; Han, MeiLan K.] Univ Michigan, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA. [Reddy, Rishindra] Univ Michigan, Div Thorac Surg, Ann Arbor, MI 48109 USA. [Anzueto, Antonio R.] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm & Crit Care Med, San Antonio, TX 78229 USA. [Anzueto, Antonio R.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Beaty, Terri H.] Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Wise, Robert A.] Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD USA. [Boriek, Aladin M.] Baylor Coll Med, Pulm Crit Care & Sleep Med, Houston, TX 77030 USA. [Casaburi, Richard; Rossiter, Harry B.] Harbor UCLA Med Ctr, Div Pulm & Crit Care Physiol & Med, Torrance, CA 90509 USA. [Anzueto, Antonio R.] Harbor UCLA Med Ctr, Rehabil Clin Trials Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Criner, Gerard J.; Kim, Victor] Temple Univ Hosp & Med Sch, Pulm & Crit Care Med, Philadelphia, PA 19140 USA. [Steiner, Robert M.] Temple Univ Hosp & Med Sch, Dept Radiol, Philadelphia, PA 19140 USA. [Diaz, Alejandro A.; Washko, George R.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA. [Curran-Everett, Douglas; Strand, Matthew J.] Natl Jewish Hlth, Dept Biostat & Bioinformat, Denver, CO USA. [Lynch, David A.] Natl Jewish Hlth, Dept Radiol, Denver, CO USA. [Make, Barry J.; Crapo, James D.; Bowler, Russell P.] Natl Jewish Hlth, Div Pulm Crit Care & Sleep Med, Denver, CO USA. [Curran-Everett, Douglas; Strand, Matthew J.] Univ Colorado, Dept Biostat & Informat, Colorado Sch Publ Hlth, Denver, CO 80202 USA. [Kinney, Gregory L.] Univ Colorado, Dept Epidemiol, Colorado Sch Publ Hlth, Denver, CO 80202 USA. [Hoffman, Eric A.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Hoffman, Eric A.] Univ Iowa, Dept Med, Iowa City, IA 52242 USA. [Hoffman, Eric A.] Univ Iowa, Dept Biomed Engn, Iowa City, IA 52242 USA. [Hogg, James C.] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC, Canada. [Hogg, James C.] St Pauls Hosp, James Hogg Res Ctr, Vancouver, BC, Canada. [van Beek, Edwin J. R.] Univ Edinburgh, Clin Res Imaging Ctr, Edinburgh, Midlothian, Scotland. [Wan, Emily S.; Silverman, Edwin K.] Harvard Med Sch, Brigham & Womens Hosp, Channing Div Network Med, Boston, MA USA. [Wendt, Chris H.] Univ Minnesota, Pulm Allergy Crit Care & Sleep Med Sect, Minneapolis VAMC, Minneapolis, MN USA. RP Han, MLK (reprint author), Univ Michigan, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA. EM mrking@med.umich.edu FU NHLBI [R01 HL089897, R01 HL089856, R01 HL122438, R44 HL118837]; COPD Foundation FX Supported by Award R01 HL089897, R01 HL089856, R01 HL122438, and R44 HL118837 from the NHLBI. The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board composed of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Siemens, Sunovion, and GlaxoSmithKline. NR 22 TC 14 Z9 14 U1 2 U2 7 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 JUL 15 PY 2016 VL 194 IS 2 BP 178 EP 184 DI 10.1164/rccm.201511-2219OC PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA DT7VY UT WOS:000381697500015 PM 26808615 ER PT J AU Khanna, S Pardi, DS Kelly, CR Kraft, CS Dhere, T Henn, MR Lombardo, MJ Vulic, M Ohsumi, T Winkler, J Pindar, C McGovern, BH Pomerantz, RJ Aunins, JG Cook, DN Hohmann, EL AF Khanna, Sahil Pardi, Darrell S. Kelly, Colleen R. Kraft, Colleen S. Dhere, Tanvi Henn, Matthew R. Lombardo, Mary-Jane Vulic, Marin Ohsumi, Toshiro Winkler, Jonathan Pindar, Christina McGovern, Barbara H. Pomerantz, Roger J. Aunins, John G. Cook, David N. Hohmann, Elizabeth L. TI A Novel Microbiome Therapeutic Increases Gut Microbial Diversity and Prevents Recurrent Clostridium difficile Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Clostridium difficile infection; microbiome; dysbiosis; vancomycin-resistant Enterococcus; Clostridium difficile treatment ID RANDOMIZED CLINICAL-TRIAL; FECAL MICROBIOTA; SACCHAROMYCES-BOULARDII; TRANSPLANTATION; VANCOMYCIN; BURDEN; PATHOGENS; COLITIS; DISEASE AB Background. Patients with recurrent Clostridium difficile infection (CDI) have a = 60% risk of relapse, as conventional therapies do not address the underlying gastrointestinal dysbiosis. This exploratory study evaluated the safety and efficacy of bacterial spores for preventing recurrent CDI. Methods. Stool specimens from healthy donors were treated with ethanol to eliminate pathogens. The resulting spores were fractionated and encapsulated for oral delivery as SER-109. Following their response to standard-of-care antibiotics, patients in cohort 1 were treated with SER-109 on 2 consecutive days (geometric mean dose, 1.7 x 109 spores), and those in cohort 2 were treated on 1 day (geometric mean dose, 1.1 x 108 spores). The primary efficacy end point was absence of C. difficile-positive diarrhea during an 8-week follow-up period. Microbiome alterations were assessed. Results. Thirty patients (median age, 66.5 years; 67% female) were enrolled, and 26 (86.7%) met the primary efficacy end point. Three patients with early, self-limiting C. difficile-positive diarrhea did not require antibiotics and tested negative for C. difficile at 8 weeks; thus, 96.7% (29 of 30) achieved clinical resolution. In parallel, gut microbiota rapidly diversified, with durable engraftment of spores and no outgrowth of non-spore-forming bacteria found after SER-109 treatment. Adverse events included mild diarrhea, abdominal pain, and nausea. Conclusions. SER-109 successfully prevented CDI and had a favorable safety profile, supporting a novel microbiome-based intervention as a potential therapy for recurrent CDI. C1 [Khanna, Sahil; Pardi, Darrell S.] Mayo Clin, Rochester, MN USA. [Kelly, Colleen R.] Miriam Hosp, Womens Med Collaborat, Providence, RI 02906 USA. [Kraft, Colleen S.; Dhere, Tanvi] Emory Univ, Sch Med, Atlanta, GA USA. [Henn, Matthew R.; Lombardo, Mary-Jane; Vulic, Marin; Ohsumi, Toshiro; Winkler, Jonathan; McGovern, Barbara H.; Pomerantz, Roger J.; Aunins, John G.; Cook, David N.] Seres Therapeut, Cambridge, MA USA. [Pindar, Christina; Hohmann, Elizabeth L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP McGovern, BH (reprint author), Seres Therapeut, Needham, MA 02494 USA. EM bmcgovern@serestherapeutics.com FU Mayo Clinic Foundation, Rochester; Seres Therapeutics FX S. K., D. S. P., C. R. K., C. S. K., T. D., and E. L. H. were investigators in the SER-001 trial. D. S. P. is a consulting member of the clinical advisory board at Seres Therapeutics, and his fees in that capacity are paid to Mayo Clinic Foundation, Rochester, rather than to him. M. R. H., M.-J. L., M. V., T. O., J. W., B. H. M., R. J. P., J. G. A., and D. N. C. are employees of and hold equity positions in Seres Therapeutics, which funded the trial. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. NR 49 TC 29 Z9 30 U1 11 U2 23 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 15 PY 2016 VL 214 IS 2 BP 173 EP 181 DI 10.1093/infdis/jiv766 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DR3SM UT WOS:000379822900003 PM 26908752 ER PT J AU Williams, DR Mohammed, SA Shields, AE AF Williams, David R. Mohammed, Selina A. Shields, Alexandra E. TI Understanding and effectively addressing breast cancer in African American women: Unpacking the social context SO CANCER LA English DT Review DE African American women; breast cancer; race; socioeconomic status (SES); stress ID GLUCOCORTICOID-RECEPTOR GENE; US BLACK-WOMEN; SOCIOECONOMIC-STATUS; HEALTH DISPARITIES; ALLOSTATIC LOAD; EARLY-LIFE; RACIAL DISPARITIES; UNITED-STATES; INCREASES VULNERABILITY; CHILDHOOD MALTREATMENT AB Black women have a higher incidence of breast cancer before the age of 40 years, more severe disease at all ages, and an elevated mortality risk in comparison with white women. There is limited understanding of the contribution of social factors to these patterns. Elucidating the role of the social determinants of health in breast cancer disparities requires greater attention to how risk factors for breast cancer unfold over the lifecourse and to the complex ways in which socioeconomic status and racism shape exposure to psychosocial, physical, chemical, and other individual and community-level assaults that increase the risk of breast cancer. Research that takes seriously the social context in which black women live is also needed to maximize the opportunities to prevent breast cancer in this underserved group. Cancer 2016;122:2138-49. (c) 2016 American Cancer Society. Insufficient attention has been paid to how risk factors for breast cancer in African American women begin in childhood and are closely tied to the conditions in which they live and work. Future research needs to pay additional attention to how researchers, clinicians and the larger society can best understand and address the myriad factors linked to racial status that are associated with breast cancer risk among African American women. C1 [Williams, David R.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, 677 Huntington Ave,6th Floor, Boston, MA 02115 USA. [Williams, David R.] Harvard Univ, Dept African & African Amer Studies, Cambridge, MA 02138 USA. [Williams, David R.] Univ Cape Town, Dept Psychiat & Mental Hlth, Cape Town, South Africa. [Mohammed, Selina A.] Univ Washington Bothell, Sch Nursing & Hlth Studies, Bothell, WA USA. [Shields, Alexandra E.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Harvard MGH Ctr Genom Vulnerable Populat & Hlth D, Boston, MA 02114 USA. [Shields, Alexandra E.] Harvard Med Sch, Dept Med, Boston, MA USA. RP Williams, DR (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, 677 Huntington Ave,6th Floor, Boston, MA 02115 USA. EM dwilliam@hsph.harvard.edu FU National Cancer Institute [P50 CA 148596]; John Templeton Foundation [48424] FX The preparation of this article was supported by the National Cancer Institute (grant P50 CA 148596) and the John Templeton Foundation (grant 48424). NR 95 TC 3 Z9 3 U1 4 U2 8 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 JUL 15 PY 2016 VL 122 IS 14 BP 2138 EP 2149 DI 10.1002/cncr.29935 PG 12 WC Oncology SC Oncology GA DR4SY UT WOS:000379894000006 PM 26930024 ER PT J AU Font-Gonzalez, A Mulder, RL Loeffen, EAH Byrne, J van Dulmen-den Broeder, E van den Heuvel-Eibrink, MM Hudson, MM Kenney, LB Levine, JM Tissing, WJE van de Wetering, MD Kremer, LCM AF Font-Gonzalez, Anna Mulder, Renee L. Loeffen, Erik A. H. Byrne, Julianne van Dulmen-den Broeder, Eline van den Heuvel-Eibrink, Marry M. Hudson, Melissa M. Kenney, Lisa B. Levine, Jennifer M. Tissing, Wim J. E. van de Wetering, Marianne D. Kremer, Leontien C. M. CA PanCareLIFE Consortium TI Fertility preservation in children, adolescents, and young adults with cancer: Quality of clinical practice guidelines and variations in recommendations SO CANCER LA English DT Article DE childhood cancer; evidence-based medicine; fertility preservation; guidelines; pediatric oncology ID CHILDHOOD-CANCER; HARMONIZATION GROUP; FEMALE SURVIVORS; BREAST-CANCER; ONCOLOGY; ISSUES; SURVEILLANCE; MANAGEMENT; CONSENSUS; SOCIETY AB BACKGROUNDFertility preservation care for children, adolescents, and young adults (CAYAs) with cancer is not uniform among practitioners. To ensure high-quality care, evidence-based clinical practice guidelines (CPGs) are essential. The authors identified existing CPGs for fertility preservation in CAYAs with cancer, evaluated their quality, and explored differences in recommendations. METHODSA systematic search in PubMed (January 2000-October 2014); guideline databases; and Web sites of oncology, pediatric, and fertility organizations was performed. Two reviewers evaluated the quality of the identified CPGs using the Appraisal of Guidelines for Research and Evaluation II Instrument (AGREE II). From high-quality CPGs, the authors evaluated concordant and discordant areas among the recommendations. RESULTSA total of 25 CPGs regarding fertility preservation were identified. The average AGREE II domain scores (scale of 0%-100%) varied from 15% on applicability to 100% on clarity of presentation. The authors considered 8 CPGs (32%) to be of high quality, which was defined as scores 60% in any 4 domains. Large variations in the recommendations of the high-quality CPGs were observed, with 87.2% and 88.6%, respectively, of discordant guideline areas among the fertility preservation recommendations for female and male patients with cancer. CONCLUSIONSOnly approximately one-third of the identified CPGs were found to be of sufficient quality. Of these CPGs, the fertility preservation recommendations varied substantially, which can be a reflection of inadequate evidence for specific recommendations, thereby hindering the ability of providers to deliver high-quality care. CPGs including a transparent decision process for fertility preservation can help health care providers to deliver optimal and uniform care, thus improving the quality of life of CAYAs with cancer and cancer survivors. Cancer 2016;122:2216-23. (c) 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. Only approximately one-third of the identified clinical practice guidelines for fertility preservation in children, adolescents, and young adults with cancer were found to be of sufficient quality, and among these, the recommendations varied substantially. This finding supports the need for well-developed and transparent harmonized clinical practice guidelines for children and young adults diagnosed with cancer who are at risk of fertility impairment. C1 [Font-Gonzalez, Anna; Mulder, Renee L.; van de Wetering, Marianne D.; Kremer, Leontien C. M.] Emma Childrens Hosp, Dept Pediat Oncol, Acad Med Ctr, POB 22660, NL-1100 DD Amsterdam, Netherlands. [Loeffen, Erik A. H.; Tissing, Wim J. E.] Univ Groningen, Univ Med Ctr Groningen, Beatrix Childrens Hosp, Dept Pediat Oncol Hematol, Groningen, Netherlands. [Byrne, Julianne] Boyne Res Inst, Drogheda, Ireland. [van Dulmen-den Broeder, Eline] Vrije Univ Amsterdam, Dept Pediat Oncol Hematol, Med Ctr, Amsterdam, Netherlands. [van den Heuvel-Eibrink, Marry M.] Princess Maxima Ctr Pediat Oncol, Dept Pediat Oncol Hematol, Utrecht, Netherlands. [Hudson, Melissa M.] St Jude Childrens Res Hosp, Dept Pediat Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Kenney, Lisa B.] Harvard Med Sch, Childrens Hosp, Dept Pediat Oncol, Boston, MA USA. [Kenney, Lisa B.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Levine, Jennifer M.] Columbia Univ, Med Ctr, Div Pediat Hematol Oncol & Stem Cell Transplantat, New York, NY USA. RP Font-Gonzalez, A (reprint author), Emma Childrens Hosp, Dept Pediat Oncol, Acad Med Ctr, POB 22660, NL-1100 DD Amsterdam, Netherlands. EM a.fontgonzalez@amc.uva.nl FU European Union's Seventh Framework program [602030] FX This project received funding from the European Union's Seventh Framework program for research, technological development, and demonstration under grant agreement 602030. The funding source had no role in the study design; in the collection, analysis, and interpretation of the data; in the preparation of the article; or in the decision to submit the article for publication. NR 53 TC 2 Z9 2 U1 4 U2 4 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 JUL 15 PY 2016 VL 122 IS 14 BP 2216 EP 2223 DI 10.1002/cncr.30047 PG 8 WC Oncology SC Oncology GA DR4SY UT WOS:000379894000014 PM 27175973 ER PT J AU Sartelli, M Weber, DG Ruppe, E Bassetti, M Wright, BJ Ansaloni, L Catena, F Coccolini, F Abu-Zidan, FM Coimbra, R Moore, EE Moore, FA Maier, RV De Waele, JJ Kirkpatrick, AW Griffiths, EA Eckmann, C Brink, AJ Mazuski, JE May, AK Sawyer, RG Mertz, D Montravers, P Kumar, A Roberts, JA Vincent, JL Watkins, RR Lowman, W Spellberg, B Abbott, IJ Adesunkanmi, AK Al-Dahir, S Al-Hasan, MN Agresta, F Althani, AA Ansari, S Ansumana, R Augustin, G Bala, M Balogh, ZJ Baraket, O Bhangu, A Beltran, MA Bernhard, M Biffl, WL Boermeester, MA Brecher, SM Cherry-Bukowiec, JR Buyne, OR Cainzos, MA Cairns, KA Camacho-Ortiz, A Chandy, SJ Jusoh, AC Chichom-Mefire, A Colijn, C Corcione, F Cui, YF Curcio, D Delibegovic, S Demetrashvili, Z De Simone, B Dhingra, S Diaz, JJ Di Carlo, I Dillip, A Di Saverio, S Doyle, MP Dorj, G Dogjani, A Dupont, H Eachempati, SR Enani, MA Egiev, VN Elmangory, MM Ferrada, P Fitchett, JR Fraga, GP Guessennd, N Giamarellou, H Ghnnam, W Gkiokas, G Goldberg, SR Gomes, CA Gomi, H Guzman-Blanco, M Haque, M Hansen, S Hecker, A Heizmann, WR Herzog, T Hodonou, AM Hong, SK Kafka-Ritsch, R Kaplan, LJ Kapoor, G Karamarkovic, A Kees, MG Kenig, J Kiguba, R Kim, PK Kluger, Y Khokha, V Koike, K Kok, KYY Kong, V Knox, MC Inaba, K Isik, A Iskandar, K Ivatury, RR Labbate, M Labricciosa, FM Laterre, PF Latifi, R Lee, JG Lee, YR Leone, M Leppaniemi, A Li, YS Liang, SY Loho, T Maegele, M Malama, S Marei, HE Martin-Loeches, I Marwah, S Massele, A McFarlane, M Melo, RB Negoi, I Nicolau, DP Nord, CE Ofori-Asenso, R Omari, AH Ordonez, CA Ouadii, M Pereira, GA Piazza, D Pupelis, G Rawson, TM Rems, M Rizoli, S Rocha, C Sakakhushev, B Sanchez-Garcia, M Sato, N Lohse, HAS Sganga, G Siribumrungwong, B Shelat, VG Soreide, K Soto, R Talving, P Tilsed, JV Timsit, JF Trueba, G Trung, NT Ulrych, J van Goor, H Vereczkei, A Vohra, RS Wani, I Uhl, W Xiao, YH Yuan, KC Zachariah, SK Zahar, JR Zakrison, TL Corcione, A Melotti, RM Viscoli, C Viale, P AF Sartelli, Massimo Weber, Dieter G. Ruppe, Etienne Bassetti, Matteo Wright, Brian J. Ansaloni, Luca Catena, Fausto Coccolini, Federico Abu-Zidan, Fikri M. Coimbra, Raul Moore, Ernest E. Moore, Frederick A. Maier, Ronald V. De Waele, Jan J. Kirkpatrick, Andrew W. Griffiths, Ewen A. Eckmann, Christian Brink, Adrian J. Mazuski, John E. May, Addison K. Sawyer, Rob G. Mertz, Dominik Montravers, Philippe Kumar, Anand Roberts, Jason A. Vincent, Jean-Louis Watkins, Richard R. Lowman, Warren Spellberg, Brad Abbott, Iain J. Adesunkanmi, Abdulrashid Kayode Al-Dahir, Sara Al-Hasan, Majdi N. Agresta, Ferdinando Althani, Asma A. Ansari, Shamshul Ansumana, Rashid Augustin, Goran Bala, Miklosh Balogh, Zsolt J. Baraket, Oussama Bhangu, Aneel Beltran, Marcelo A. Bernhard, Michael Biffl, Walter L. Boermeester, Marja A. Brecher, Stephen M. Cherry-Bukowiec, Jill R. Buyne, Otmar R. Cainzos, Miguel A. Cairns, Kelly A. Camacho-Ortiz, Adrian Chandy, Sujith J. Jusoh, Asri Che Chichom-Mefire, Alain Colijn, Caroline Corcione, Francesco Cui, Yunfeng Curcio, Daniel Delibegovic, Samir Demetrashvili, Zaza De Simone, Belinda Dhingra, Sameer Diaz, Jose J. Di Carlo, Isidoro Dillip, Angel Di Saverio, Salomone Doyle, Michael P. Dorj, Gereltuya Dogjani, Agron Dupont, Herve Eachempati, Soumitra R. Enani, Mushira Abdulaziz Egiev, Valery N. Elmangory, Mutasim M. Ferrada, Paula Fitchett, Joseph R. Fraga, Gustavo P. Guessennd, Nathalie Giamarellou, Helen Ghnnam, Wagih Gkiokas, George Goldberg, Staphanie R. Gomes, Carlos Augusto Gomi, Harumi Guzman-Blanco, Manuel Haque, Mainul Hansen, Sonja Hecker, Andreas Heizmann, Wolfgang R. Herzog, Torsten Hodonou, Adrien Montcho Hong, Suk-Kyung Kafka-Ritsch, Reinhold Kaplan, Lewis J. Kapoor, Garima Karamarkovic, Aleksandar Kees, Martin G. Kenig, Jakub Kiguba, Ronald Kim, Peter K. Kluger, Yoram Khokha, Vladimir Koike, Kaoru Kok, Kenneth Y. Y. Kong, Victory Knox, Matthew C. Inaba, Kenji Isik, Arda Iskandar, Katia Ivatury, Rao R. Labbate, Maurizio Labricciosa, Francesco M. Laterre, Pierre-Francois Latifi, Rifat Lee, Jae Gil Lee, Young Ran Leone, Marc Leppaniemi, Ari Li, Yousheng Liang, Stephen Y. Loho, Tonny Maegele, Marc Malama, Sydney Marei, Hany E. Martin-Loeches, Ignacio Marwah, Sanjay Massele, Amos McFarlane, Michael Melo, Renato Bessa Negoi, Ionut Nicolau, David P. Nord, Carl Erik Ofori-Asenso, Richard Omari, AbdelKarim H. Ordonez, Carlos A. Ouadii, Mouaqit Pereira Junior, Gerson Alves Piazza, Diego Pupelis, Guntars Rawson, Timothy Miles Rems, Miran Rizoli, Sandro Rocha, Claudio Sakakhushev, Boris Sanchez-Garcia, Miguel Sato, Norio Lohse, Helmut A. Segovia Sganga, Gabriele Siribumrungwong, Boonying Shelat, Vishal G. Soreide, Kjetil Soto, Rodolfo Talving, Peep Tilsed, Jonathan V. Timsit, Jean-Francois Trueba, Gabriel Trung, Ngo Tat Ulrych, Jan van Goor, Harry Vereczkei, Andras Vohra, Ravinder S. Wani, Imtiaz Uhl, Waldemar Xiao, Yonghong Yuan, Kuo-Ching Zachariah, Sanoop K. Zahar, Jean-Ralph Zakrison, Tanya L. Corcione, Antonio Melotti, Rita M. Viscoli, Claudio Viale, Perluigi TI Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA) SO WORLD JOURNAL OF EMERGENCY SURGERY LA English DT Review ID INTENSIVE-CARE-UNIT; SPECTRUM-BETA-LACTAMASE; CRITICALLY-ILL PATIENTS; GRAM-NEGATIVE BACTERIA; VANCOMYCIN-RESISTANT ENTEROCOCCI; CLOSTRIDIUM-DIFFICILE INFECTION; VENTILATOR-ASSOCIATED PNEUMONIA; BLOOD-STREAM INFECTIONS; CARBAPENEMASE-PRODUCING ENTEROBACTERIACEAE; CLINICAL-PRACTICE GUIDELINES AB Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs. C1 [Sartelli, Massimo] Macerata Hosp, Dept Surg, Via Santa Lucia 2, I-62100 Macerata, Italy. [Weber, Dieter G.] Royal Perth Hosp, Dept Trauma Surg, Perth, WA, Australia. [Ruppe, Etienne] Univ Hosp Geneva, Genom Res Lab, Geneva, Switzerland. [Bassetti, Matteo] Santa Maria Misericordia Univ Hosp, Infect Dis Div, Udine, Italy. [Wright, Brian J.] SUNY Stony Brook, Sch Med, Dept Emergency Med & Surg, Stony Brook, NY USA. [Ansaloni, Luca] Papa Giovanni XXIII Hosp, Gen Surg Dept, Bergamo, Italy. [Catena, Fausto] Maggiore Hosp, Dept Gen, Parma, Italy. [Coccolini, Federico] Infermi Hosp, Dept Surg, Rimini, Italy. [Abu-Zidan, Fikri M.] UAE Univ, Coll Med & Hlth Sci, Dept Surg, Al Ain, U Arab Emirates. [Coimbra, Raul] UC San Diego Med Ctr, Dept Surg, San Diego, CA USA. [Moore, Ernest E.] Univ Colorado, Denver Hlth Med Ctr, Dept Surg, Denver, CO USA. [Moore, Frederick A.] Univ Florida, Coll Med, Dept Surg, Div Acute Care Surg, Gainesville, FL USA. [Moore, Frederick A.] Univ Florida, Coll Med, Ctr Sepsis & Crit Illness Res, Gainesville, FL USA. [Maier, Ronald V.] Univ Washington, Dept Surg, Seattle, WA USA. [De Waele, Jan J.] Ghent Univ Hosp, Dept Crit Care Med, Ghent, Belgium. [Kirkpatrick, Andrew W.] Foothills Med Ctr, Gen Acute Care & Trauma Surg, Calgary, AB, Canada. [Griffiths, Ewen A.] Queen Elizabeth Hosp, Gen & Upper GI Surg, Birmingham, W Midlands, England. [Eckmann, Christian] Hannover Med Sch, Acad Hosp, Klinikum Peine, Dept Gen Visceral & Thorac Surg, Peine, Germany. [Brink, Adrian J.] Milpark Hosp, Dept Clin Microbiol, Ampath Natl Lab Serv, Johannesburg, South Africa. 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[Kaplan, Lewis J.] Univ Penn, Perelman Sch Med, Philadelphia VA Med Ctr, Dept Surg, Philadelphia, PA USA. [Kapoor, Garima] Gandhi Med Coll, Dept Microbiol, Bhopal, India. [Karamarkovic, Aleksandar] Univ Belgrade, Fac Med, Clin Emergency Surg, Belgrade, Serbia. [Kees, Martin G.] Charite, Dept Anesthesiol & Intens Care, Campus Benjamin Franklin, Berlin, Germany. [Kenig, Jakub] Jagiellonian Univ, Coll Med, Dept Gen Surg 3, Krakow, Poland. [Kiguba, Ronald] Makerere Univ, Coll Hlth Sci, Dept Pharmacol & Therapeut, Kampala, Uganda. [Kim, Peter K.] Albert Einstein Coll Med, Dept Med, Bronx, NY USA. [Kim, Peter K.] Jacobi Med Ctr, Bronx, NY USA. [Kluger, Yoram] Rambam Hlth Care Campus, Dept Gen Surg, Div Surg, Haifa, Israel. [Khokha, Vladimir] City Hosp, Dept Emergency Surg, Mozyr, Byelarus. [Koike, Kaoru; Sato, Norio] Kyoto Univ, Grad Sch Med, Dept Primary Care & Emergency Med, Kyoto, Japan. [Kok, Kenneth Y. Y.] Brunei Canc Ctr, Dept Surg, Jerudong Pk, Brunei. 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[Leone, Marc] Aix Marseille Univ, Hop Nord, AP HP, Dept Anaesthesiol & Crit Care, Marseille, France. [Leppaniemi, Ari] Univ Hosp Meilahti, Abdominal Ctr, Helsinki, Finland. [Li, Yousheng] Nanjing Univ, Inling Hosp, Sch Med, Dept Surg, Nanjing, Jiangsu, Peoples R China. [Liang, Stephen Y.] Washington Univ, Sch Med, Div Emergency Med, Div Infect Dis, St Louis, MO USA. [Loho, Tonny] Univ Indonesia, Cipto Mangunkusumo Gen Hosp, Fac Med, Dept Clin Pathol,Div Infect Dis, Jakarta, Indonesia. [Maegele, Marc] UW H, CMMC, Dept Traumatol & Orthoped Surg, Cologne, Germany. [Malama, Sydney] Univ Zambia, Inst Econ & Social Res, Hlth Res Program, Lusaka, Zambia. [Martin-Loeches, Ignacio; Nicolau, David P.] St James Univ Hosp, Trinity Ctr Hlth Sci, MICRO, Dept Clin Med,Wellcome Trust HRB Clin Res, Dublin, Ireland. [Marwah, Sanjay] Postgrad Inst Med Sci, Dept Surg, Rohtak, Haryana, India. [Massele, Amos] Univ Botswana, Sch Med, Dept Clin Pharmacol, Gaborone, Botswana. [McFarlane, Michael] Radiol Univ Hosp West Indies Kingston, Dept Surg Radiol, Jamaica, NY USA. [Melo, Renato Bessa] Ctr Hosp Sao Joao, Dept Gen Surg, Oporto, Portugal. [Negoi, Ionut] Emergency Hosp Bucharest, Dept Surg, Bucharest, Romania. [Nicolau, David P.] Ctr Antiinfect Res & Dev, Hartford, CT USA. [Nord, Carl Erik] Karolinska Univ Hosp Huddinge, Dept Lab Med, Div Clin Microbiol, Stockholm, Sweden. [Ofori-Asenso, Richard] Hlth Policy Consult, Res Unit, Weija Accra, Ghana. [Omari, AbdelKarim H.] King Abdullah Univ Hosp, Dept Surg, Irbid, Jordan. [Ordonez, Carlos A.] Univ Valle, Fdn Valle Lili, Dept Surg & Crit Care, Cali, Colombia. [Ouadii, Mouaqit] Sidi Mohamed Benabdellah Univ, Hassan Univ Hosp 2, Med Sch Fez, Dept Surg, Fes, Morocco. [Pereira Junior, Gerson Alves] Ribeirao Preto Med Sch, Div Emergency & Trauma Surg, Ribeirao Preto, Brazil. [Piazza, Diego] Vittorio Emanuele Hosp, Div Surg, Catania, Italy. 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[Vohra, Ravinder S.] Univ Nottingham Hosp, Nottingham Oesophago Gastr Unit, Nottingham, England. [Wani, Imtiaz] Sheri Kashmir Inst Med Sci, Dept Surg, Srinagar, Jammu & Kashmir, India. [Xiao, Yonghong] Zhejiang Univ, Affiliated Hosp 1, State Key Lab Diag & Treatment Infect Dis, Hangzhou, Zhejiang, Peoples R China. [Yuan, Kuo-Ching] Chang Gung Mem Hosp, Trauma & Emergency Surg Dept, Taoyuan, Taiwan. [Zachariah, Sanoop K.] MOSC Med Coll Kolenchery, Dept Surg, Cochin, Kerala, India. [Zahar, Jean-Ralph] Univ Angers, CHU Angers, Infect Control Unit, Angers, France. [Zakrison, Tanya L.] Univ Miami, DeWitt Daughtry Family Dept Surgry, Div Trauma & Surg Crit Care, Miami, FL USA. [Corcione, Antonio] AORN Colli Vincenzo Monaldi Hosp, Anesthesia & Intens Care Unit, Naples, Italy. [Melotti, Rita M.] SantOrsola Univ Hosp, Anesthesiol & Intens Care Unit, Bologna, Italy. [Viscoli, Claudio] Univ Genoa DISSAL, Infect Dis Unit, Genoa, Italy. [Viscoli, Claudio] IRCCS San Martino IST, Genoa, Italy. [Viale, Perluigi] Univ Bologna, Sant Orsola Hosp, Dept Med & Surg Sci, Infect Dis Unit, Bologna, Italy. RP Sartelli, M (reprint author), Macerata Hosp, Dept Surg, Via Santa Lucia 2, I-62100 Macerata, Italy. EM massimosartelli@gmail.com RI Talving, Peep/G-8621-2015; RUPPE, ETIENNE/H-1073-2016; OI Talving, Peep/0000-0002-9741-2073; MELOTTI, RITA MARIA/0000-0001-6258-6607; Haque, Mainul/0000-0002-6124-7993; Marei, Hany/0000-0002-0069-4212; Kiguba, Ronald/0000-0002-2636-4115; Labbate, Maurizio/0000-0003-1428-3382; Trueba, Gabriel/0000-0003-2617-9021; Rawson, Timothy Miles/0000-0002-2630-9722; Ofori-Asenso, Richard/0000-0002-6643-3269 FU NIAID NIH HHS [R01 AI117211] NR 300 TC 2 Z9 2 U1 21 U2 28 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1749-7922 J9 WORLD J EMERG SURG JI World J. Emerg. Surg. PD JUL 15 PY 2016 VL 11 AR 33 DI 10.1186/s13017-016-0089-y PG 32 WC Emergency Medicine; Surgery SC Emergency Medicine; Surgery GA DR2IG UT WOS:000379727600001 PM 27429642 ER PT J AU Guo, SZ Lok, J Zhao, S Leung, W Som, AT Hayakawa, K Wang, QZ Xing, CH Wang, XY Ji, XM Zhou, YM Lo, EH AF Guo, Shuzhen Lok, Josephine Zhao, Song Leung, Wendy Som, Angel T. Hayakawa, Kazuhide Wang, Qingzhi Xing, Changhong Wang, Xiaoying Ji, Xunming Zhou, Yiming Lo, Eng H. TI Effects of Controlled Cortical Impact on the Mouse Brain Vasculome SO JOURNAL OF NEUROTRAUMA LA English DT Article DE extracellular matrix; inflammation; microvessels; neurovascular unit; traumatic brain injury ID ENDOTHELIAL GROWTH-FACTOR; FOCAL CEREBRAL-ISCHEMIA; LONG PENTRAXIN PTX3; GENE-EXPRESSION; XANTHINE-OXIDASE; ACTIVIN-A; EXTRACELLULAR-MATRIX; ALZHEIMERS-DISEASE; CELL PROLIFERATION; TUMOR ANGIOGENESIS AB Perturbations in blood vessels play a critical role in the pathophysiology of brain injury and neurodegeneration. Here, we use a systematic genome-wide transcriptome screening approach to investigate the vasculome after brain trauma in mice. Mice were subjected to controlled cortical impact and brains were extracted for analysis at 24 h post-injury. The core of the traumatic lesion was removed and then cortical microvesels were isolated from nondirectly damaged ipsilateral cortex. Compared to contralateral cortex and normal cortex from sham-operated mice, we identified a wide spectrum of responses in the vasculome after trauma. Up-regulated pathways included those involved in regulation of inflammation and extracellular matrix processes. Decreased pathways included those involved in regulation of metabolism, mitochondrial function, and transport systems. These findings suggest that microvascular perturbations can be widespread and not necessarily localized to core areas of direct injury per se and may further provide a broader gene network context for existing knowledge regarding inflammation, metabolism, and blood-brain barrier alterations after brain trauma. Further efforts are warranted to map the vasculome with higher spatial and temporal resolution from acute to delayed phase post-trauma. Investigating the widespread network responses in the vasculome may reveal potential mechanisms, therapeutic targets, and biomarkers for traumatic brain injury. C1 [Guo, Shuzhen; Lok, Josephine; Leung, Wendy; Som, Angel T.; Hayakawa, Kazuhide; Wang, Qingzhi; Xing, Changhong; Wang, Xiaoying; Zhou, Yiming; Lo, Eng H.] Harvard Med Sch, Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Radiol, Charlestown, MA USA. [Guo, Shuzhen; Lok, Josephine; Leung, Wendy; Som, Angel T.; Hayakawa, Kazuhide; Wang, Qingzhi; Xing, Changhong; Wang, Xiaoying; Zhou, Yiming; Lo, Eng H.] Harvard Med Sch, Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Neurol, Charlestown, MA USA. [Lok, Josephine] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pediat, Charlestown, MA USA. [Zhao, Song] Jilin Univ, Hosp 1, Dept Spine Surg, Changchun, Peoples R China. [Ji, Xunming] Capital Med Univ, Xuanwu Hosp, Cerebrovasc Res Ctr, Dept Neurosurg, Beijing, Peoples R China. RP Lo, EH (reprint author), Massachusetts Gen Hosp, Neuroprotect Res Lab, 149 13th St,Room 2401, Charlestown, MA 02129 USA. EM lo@helix.mgh.harvard.edu NR 148 TC 0 Z9 0 U1 6 U2 6 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 JUL 15 PY 2016 VL 33 IS 14 BP 1303 EP 1316 DI 10.1089/neu.2015.4101 PG 14 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DQ5CX UT WOS:000379223100003 PM 26528928 ER PT J AU Pagulayan, KF Temkin, NR Machamer, JE Dikmen, SS AF Pagulayan, Kathleen F. Temkin, Nancy R. Machamer, Joan E. Dikmen, Sureyya S. TI Patterns of Alcohol Use after Traumatic Brain Injury SO JOURNAL OF NEUROTRAUMA LA English DT Article DE alcohol; traumatic brain ID SPINAL-CORD-INJURY; SUBSTANCE-ABUSE; PSYCHIATRIC-DISORDERS; RANDOMIZED-TRIAL; HEAD-INJURY; FOLLOW-UP; DRUG-USE; AXIS-I; REHABILITATION; VALPROATE AB Alcohol misuse and traumatic brain injury (TBI) frequently co-occur. The negative consequences of this interaction are well documented, but the patterns of long-term post-injury alcohol consumption are less clear. This study examined patterns of alcohol use among 170 adults with a history of complicated mild to severe TBI. Participants were recruited from a Level 1 Trauma Center at the time of their injury and completed evaluations at 1 month, 6 months, 12 months, and 3-5 years post-injury. Pre-injury alcohol use was also assessed at the time of the 1-month assessment. A modified Quantity-Frequency Index of alcohol consumption was then calculated for each time point. The results revealed high levels of pre-injury alcohol consumption, followed by a reduction in consumption at 1-month post-injury. A significant increase in consumption was noted by 6 months post-injury, followed by more gradual increases in alcohol consumption at 1 year. Post-injury alcohol consumption was comparable to the general public at 6 months, 12 months, and 3-5 years post-injury. These results suggest that the first 6 months post-injury may be the critical window of opportunity for alcohol intervention. C1 [Pagulayan, Kathleen F.] VA Puget Sound Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. [Pagulayan, Kathleen F.; Dikmen, Sureyya S.] Univ Washington, Dept Psychiat & Behav Med, Seattle, WA 98195 USA. [Temkin, Nancy R.; Machamer, Joan E.; Dikmen, Sureyya S.] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Temkin, Nancy R.; Dikmen, Sureyya S.] Univ Washington, Dept Neurol Surg, Seattle, WA 98195 USA. [Temkin, Nancy R.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Pagulayan, KF (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way S-116-MIRECC, Seattle, WA 98108 USA. EM farkat@u.washington.edu FU CSRD VA [IK2 CX000516] NR 41 TC 0 Z9 0 U1 8 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 JUL 15 PY 2016 VL 33 IS 14 BP 1390 EP 1396 DI 10.1089/neu.2015.4071 PG 7 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA DQ5CX UT WOS:000379223100011 PM 26530335 ER PT J AU Krystal, JH Abi-Dargham, A Akbarian, S Arnsten, AFT Barch, DM Bearden, CE Braff, DL Brown, ES Bullmore, ET Carlezon, WA Carter, CS Cook, EH Daskalakis, ZJ DiLeone, RJ Duman, RS Grace, AA Hariri, AR Harrison, PJ Hiroi, N Kenny, PJ Kleinman, JE Krystal, AD Lewis, DA Lipska, BK Marder, SR Mason, GF Mathalon, DH McClung, CA McDougle, CJ McIntosh, AM McMahon, FJ Mirnics, K Monteggia, LM Narendran, R Nestler, EJ Neumeister, A O'Donovan, MC Ongur, D Pariante, CM Paulus, MP Pearlson, G Phillips, ML Pine, DS Pizzagalli, DA Pletnikov, MV Ragland, JD Rapoport, JL Ressler, KJ Russo, SJ Sanacora, G Sawa, A Schatzberg, AF Shaham, Y Shamay-Tsoory, SG Sklar, P State, MW Stein, MB Strakowski, SM Taylor, SF Turecki, G Turetsky, BI Weissman, MM Zachariou, V Zarate, CA Zubieta, JK AF Krystal, John H. Abi-Dargham, Anissa Akbarian, Schahram Arnsten, Amy F. T. Barch, Deanna M. Bearden, Carrie E. Braff, David L. Brown, E. Sherwood Bullmore, Edward T. Carlezon, William A., Jr. Carter, Cameron S. Cook, Edwin H., Jr. Daskalakis, Zafiris Jeff DiLeone, Ralph J. Duman, Ronald S. Grace, Anthony A. Hariri, Ahmad R. Harrison, Paul J. Hiroi, Noboru Kenny, Paul J. Kleinman, Joel E. Krystal, Andrew D. Lewis, David A. Lipska, Barbara K. Marder, Stephen R. Mason, Graeme F. Mathalon, Daniel H. McClung, Colleen A. McDougle, Christopher J. McIntosh, Andrew M. McMahon, Francis J. Mirnics, Karoly Monteggia, Lisa M. Narendran, Rajesh Nestler, Eric J. Neumeister, Alexander O'Donovan, Michael C. Ongur, Dost Pariante, Carmine M. Paulus, Martin P. Pearlson, Godfrey Phillips, Mary L. Pine, Daniel S. Pizzagalli, Diego A. Pletnikov, Mikhail V. Ragland, J. Daniel Rapoport, Judith L. Ressler, Kerry J. Russo, Scott J. Sanacora, Gerard Sawa, Akira Schatzberg, Alan F. Shaham, Yavin Shamay-Tsoory, Simone G. Sklar, Pamela State, Matthew W. Stein, Murray B. Strakowski, Stephen M. Taylor, Stephan F. Turecki, Gustavo Turetsky, Bruce I. Weissman, Myrna M. Zachariou, Venetia Zarate, Carlos A., Jr. Zubieta, Jon-Kar TI Constance E. Lieber, Theodore R. Stanley, and the Enduring Impact of Philanthropy on Psychiatry Research SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material C1 [Krystal, John H.; Arnsten, Amy F. T.; Duman, Ronald S.] Yale Univ, Sch Med, Dept Psychiat & Neurosci, New Haven, CT 06511 USA. [Krystal, John H.] Yale New Haven Med Ctr, Behav Hlth Serv, 20 York St, New Haven, CT 06504 USA. [Krystal, John H.] VA Connecticut Healthcare Syst, Clin Neurosci Div, West Haven, CT USA. [Abi-Dargham, Anissa] Columbia Univ, Dept Psychiat, New York, NY USA. [Abi-Dargham, Anissa] Columbia Univ, Dept Radiol, New York, NY USA. [Abi-Dargham, Anissa] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Akbarian, Schahram] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Arnsten, Amy F. T.] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06511 USA. [Barch, Deanna M.] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Dept Psychiat, Los Angeles, CA 90024 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Dept Psychol, Los Angeles, CA 90024 USA. [Bearden, Carrie E.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Brain Res Inst, Los Angeles, CA 90024 USA. [Braff, David L.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Brown, E. Sherwood] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Bullmore, Edward T.] Univ Cambridge, Dept Psychiat & Behav, Cambridge, England. [Bullmore, Edward T.] Univ Cambridge, Neurosci Inst, Cambridge, England. [Bullmore, Edward T.] GlaxoSmithKline, ImmunoPsychiat, Cambridge, England. [Carlezon, William A., Jr.] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat & Neurosci, Belmont, MA 02178 USA. [Carter, Cameron S.] Univ Calif Davis, Dept Psychiat & Behav Sci, Imaging Res Ctr, Davis, CA 95616 USA. [Carter, Cameron S.] Univ Calif Davis, Ctr Neurosci, Davis, CA 95616 USA. [Cook, Edwin H., Jr.] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USA. [Daskalakis, Zafiris Jeff] Ctr Addict & Mental Hlth, Mood & Anxiety Div, Temerty Ctr Therapeut Brain Intervent, Toronto, ON, Canada. [Daskalakis, Zafiris Jeff] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [DiLeone, Ralph J.] Yale Univ, Dept Psychiat, New Haven, CT 06511 USA. [Grace, Anthony A.] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA USA. [Grace, Anthony A.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Grace, Anthony A.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Hariri, Ahmad R.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Harrison, Paul J.] Univ Oxford, Dept Psychiat, Oxford, England. [Hiroi, Noboru] Albert Einstein Coll Med, Dept Psychiat & Behav Sci, Bronx, NY 10467 USA. [Hiroi, Noboru] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10467 USA. [Hiroi, Noboru] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10467 USA. [Kenny, Paul J.] Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [Kleinman, Joel E.] Johns Hopkins Univ, Sch Med, Lieber Inst Brain Dev, Genet Neuropathol Sect, Baltimore, MD USA. [Kleinman, Joel E.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Krystal, Andrew D.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. [Lewis, David A.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Lipska, Barbara K.] NIMH, Human Brain Collect Core, Div Intramural Res Programs, NIH, Bethesda, MD 20892 USA. [Marder, Stephen R.] Univ Calif Los Angeles, Semel Inst Neurosci, Los Angeles, CA USA. [Marder, Stephen R.] VA Desert Pacific Mental Illness Res Educ & Clin, Los Angeles, CA USA. [Mason, Graeme F.] Yale Univ, Sch Med, Dept Radiol & Biomed Imaging, New Haven, CT 06511 USA. [Mason, Graeme F.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06511 USA. [Mathalon, Daniel H.; State, Matthew W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Mathalon, Daniel H.] San Francisco VA Med Ctr, Psychiat Serv, San Francisco, CA USA. [McClung, Colleen A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [McDougle, Christopher J.] Massachusetts Gen Hosp, Lexington, MA USA. [McDougle, Christopher J.] MassGen Hosp Children, Lurie Ctr Autism, Lexington, MA USA. [McDougle, Christopher J.; Pizzagalli, Diego A.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [McIntosh, Andrew M.] Univ Edinburgh, Div Psychiat, Edinburgh, Midlothian, Scotland. [McMahon, Francis J.] NIMH, Human Genet Branch, Intramural Res Program, Bethesda, MD 20892 USA. [McMahon, Francis J.] NIMH, Intramural Res Program, Genet Basis Mood & Anxiety Disorders Sect, Bethesda, MD 20892 USA. [Mirnics, Karoly] Vanderbilt Univ, Dept Psychiat, 221 Kirkland Hall, Nashville, TN 37235 USA. [Monteggia, Lisa M.] Univ Texas SW Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA. [Narendran, Rajesh] Univ Pittsburgh, Sch Med, Dept Radiol, Pittsburgh, PA USA. [Narendran, Rajesh] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Nestler, Eric J.; Russo, Scott J.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Nestler, Eric J.; Russo, Scott J.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Neumeister, Alexander] Mitsubishi Tanabe Pharma Dev Amer Inc, Jersey City, NJ USA. [O'Donovan, Michael C.] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales. [Ongur, Dost; Ressler, Kerry J.] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, Belmont, MA USA. [Pariante, Carmine M.] Kings Coll London, Inst Psychiat, Dept Psychol, London, England. [Pariante, Carmine M.] Kings Coll London, Inst Psychiat, Dept Neurosci, London, England. [Pariante, Carmine M.] Maurice Wohl Clin Neurosci Inst, Psychiat & Immunol Lab & Perinatal Psychiat, London, England. [Paulus, Martin P.] Laureate Inst Brain Res, Tulsa, OK USA. [Pearlson, Godfrey] Yale Univ, Dept Psychiat, Hartford, CT USA. [Pearlson, Godfrey] Yale Univ, Dept Neurobiol, Hartford, CT USA. [Pearlson, Godfrey] Olin Neuropsychiat Res Ctr, Hartford, CT USA. [Phillips, Mary L.] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA USA. [Pine, Daniel S.] NIMH, Intramural Res Program, Bethesda, MD 20892 USA. [Pizzagalli, Diego A.] McLean Hosp, McLean Imaging Ctr, 115 Mill St, Belmont, MA 02178 USA. [Pletnikov, Mikhail V.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Pletnikov, Mikhail V.] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21205 USA. [Ragland, J. Daniel] Univ Calif Davis, Imaging Res Ctr, Dept Psychiat & Behav Sci, Sacramento, CA 95817 USA. [Rapoport, Judith L.] NIMH, Child Psychiat Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA. [Sanacora, Gerard] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Sawa, Akira] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Schatzberg, Alan F.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA USA. [Shaham, Yavin] NIDA, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD USA. [Shamay-Tsoory, Simone G.] Univ Haifa, Dept Psychol, IL-31999 Haifa, Israel. [Sklar, Pamela] Icahn Sch Med Mt Sinai, Div Psychiat Genom, Dept Psychiat, New York, NY 10029 USA. [Stein, Murray B.] Univ Calif San Diego, Sch Med, Dept Psychiat, 9500 Gillman Dr, La Jolla, CA 92093 USA. [Stein, Murray B.] Univ Calif San Diego, Sch Med, Dept Family Med & Publ Hlth, La Jolla, CA USA. [Strakowski, Stephen M.] Univ Texas Austin, Dept Psychiat, Dell Med Sch, Austin, TX USA. [Taylor, Stephan F.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Turecki, Gustavo] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. [Turetsky, Bruce I.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weissman, Myrna M.] Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, New York, NY USA. [Weissman, Myrna M.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Zachariou, Venetia] Mt Sinai Sch Med, Fishberg Dept Neurosci, New York, NY USA. [Zarate, Carlos A., Jr.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. [Zubieta, Jon-Kar] Univ Utah, Hlth Sci Ctr, Dept Psychiat, Univ Neuropsychiat Inst, Salt Lake City, UT USA. RP Krystal, JH (reprint author), Yale Univ, Sch Med, Dept Psychiat, 300 George St,Suite 901, New Haven, CT 06511 USA. EM john.krystal@yale.edu RI Lipska, Barbara/E-4569-2017; OI McIntosh, Andrew/0000-0002-0198-4588 FU Medical Research Council [G1000183, MR/K026992/1] NR 2 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 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 2016 VL 80 IS 2 BP 84 EP 86 DI 10.1016/j.biopsych.2016.05.004 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DP5IT UT WOS:000378530200002 PM 27346079 ER PT J AU Hippolyte, L Maillard, AM Rodriguez-Herreros, B Pain, A Martin-Brevet, S Ferrari, C Conus, P Mace, A Hadjikhani, N Metspalu, A Reigo, A Kolk, A Mannik, K Barker, M Isidor, B Le Caignec, C Mignot, C Schneider, L Mottron, L Keren, B David, A Doco-Fenzy, M Gerard, M Bernier, R Goin-Kochel, RP Hanson, E Snyder, LG Ramus, F Beckmann, JS Draganski, B Reymond, A Jacquemont, S AF Hippolyte, Loyse Maillard, Anne M. Rodriguez-Herreros, Borja Pain, Aurelie Martin-Brevet, Sandra Ferrari, Carina Conus, Philippe Mace, Aurelien Hadjikhani, Nouchine Metspalu, Andres Reigo, Anu Kolk, Anneli Maennik, Katrin Barker, Mandy Isidor, Bertrand Le Caignec, Cedric Mignot, Cyril Schneider, Laurence Mottron, Laurent Keren, Boris David, Albert Doco-Fenzy, Martine Gerard, Marion Bernier, Raphael Goin-Kochel, Robin P. Hanson, Ellen Snyder, LeeAnne Green Ramus, Franck Beckmann, Jacques S. Draganski, Bogdan Reymond, Alexandre Jacquemont, Sebastien CA 16p11 2 European Consortium Simons Variation Individuals Proje TI The Number of Genomic Copies at the 16p11.2 Locus Modulates Language, Verbal Memory, and Inhibition SO BIOLOGICAL PSYCHIATRY LA English DT Article DE 16p11.2; ASD; Copy number variation; Inhibition; Language; Memory ID NEUROPSYCHIATRIC DISORDERS; DIAGNOSTIC INTERVIEW; SYNAPTIC PLASTICITY; CHROMOSOME 16P11.2; DELETION SYNDROME; AUTISM; SCHIZOPHRENIA; BRAIN; OBESITY; SPEECH AB BACKGROUND: Deletions and duplications of the 16p11.2 BP4-BP5 locus are prevalent copy number variations (CNVs), highly associated with autism spectrum disorder and schizophrenia. Beyond language and global cognition, neuropsychological assessments of these two CNVs have not yet been reported. METHODS: This study investigates the relationship between the number of genomic copies at the 16p11.2 locus and cognitive domains assessed in 62 deletion carriers, 44 duplication carriers, and 71 intrafamilial control subjects. RESULTS: IQ is decreased in deletion and duplication carriers, but we demonstrate contrasting cognitive profiles in these reciprocal CNVs. Deletion carriers present with severe impairments of phonology and of inhibition skills beyond what is expected for their IQ level. In contrast, for verbal memory and phonology, the data may suggest that duplication carriers outperform intrafamilial control subjects with the same IQ level. This finding is reminiscent of special isolated skills as well as contrasting language performance observed in autism spectrum disorder. Some domains, such as visuospatial and working memory, are unaffected by the 16p11.2 locus beyond the effect of decreased IQ. Neuroimaging analyses reveal that measures of inhibition covary with neuroanatomic structures previously identified as sensitive to 16p11.2 CNVs. CONCLUSIONS: The simultaneous study of reciprocal CNVs suggests that the 16p11.2 genomic locus modulates specific cognitive skills according to the number of genomic copies. Further research is warranted to replicate these findings and elucidate the molecular mechanisms modulating these cognitive performances. C1 [Hippolyte, Loyse; Rodriguez-Herreros, Borja; Pain, Aurelie; Martin-Brevet, Sandra; Beckmann, Jacques S.; Jacquemont, Sebastien] CHU Vaudois, Serv Genet Med, Lausanne, Switzerland. [Rodriguez-Herreros, Borja; Martin-Brevet, Sandra; Draganski, Bogdan] CHU Vaudois, Lab Res Neuroimaging, Dept Neurosci Clin, Lausanne, Switzerland. [Ferrari, Carina; Conus, Philippe] CHU Vaudois, Dept Psychiat, Lausanne, Switzerland. [Barker, Mandy] CHU Vaudois, CERY Hosp, Dept Child Psychiat, Lausanne, Switzerland. [Schneider, Laurence] CHU Vaudois, SUPEA, Lausanne, Switzerland. [Schneider, Laurence] CHU Vaudois, Serv Neuropsychol & Neurorehabil, Lausanne, Switzerland. Univ Lausanne, CH-1015 Lausanne, Switzerland. [Mace, Aurelien] Univ Lausanne, Dept Med Genet, CH-1015 Lausanne, Switzerland. [Mace, Aurelien; Beckmann, Jacques S.] Univ Lausanne, SIB Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Maennik, Katrin; Reymond, Alexandre] Univ Lausanne, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland. [Hadjikhani, Nouchine] Ecole Polytech Fed Lausanne, Sch Life Sci, Brain Mind Inst, Lausanne, Switzerland. [Metspalu, Andres; Reigo, Anu; Maennik, Katrin] Tartu Univ Hosp, Dept Neurol & Neurorehabil, Dept Genet, Tartu, Estonia. [Kolk, Anneli] Tartu Univ Hosp, Dept Neurol & Neurorehabil, United Labs, Tartu, Estonia. [Kolk, Anneli] Tartu Univ Hosp, Dept Neurol & Neurorehabil, Childrens Clin, Tartu, Estonia. [Isidor, Bertrand; Le Caignec, Cedric; David, Albert] CHU Nantes, Gen Med Serv, Nantes, France. [Le Caignec, Cedric] Fac Med, INSERM, UMR957, Nantes, France. [Mignot, Cyril; Keren, Boris; Gerard, Marion] Grp Hosp Pitie Salpetriere, AP HP, Unite Fonct Genet Clin, Dept Genet & Cytogenet, Paris, France. [Mignot, Cyril] UPMC, Ctr Reference Deficiences Intellectuelles Causes, Paris, France. [Mignot, Cyril] UPMC, Grp Rech Clin Deficience Intellectuelle & Autisme, Paris, France. [Mottron, Laurent] Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada. Hop Riviere Prairies, Montreal, PQ, Canada. [Doco-Fenzy, Martine] CHU, Serv Genet, Reims, France. [Gerard, Marion] Univ Paris VII Paris Diderot, Hop Robert Debre, Dept Genet, Paris, France. [Bernier, Raphael] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Goin-Kochel, Robin P.] Baylor Coll Med, Psychol Sect, Dept Pediat, Houston, TX 77030 USA. [Hanson, Ellen] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Psychiat, Boston, MA USA. [Snyder, LeeAnne Green] Clin Res Associates, New York, NY USA. [Ramus, Franck] PSL Res Univ, Dept Etud Cognit, CNRS, Ecole Normale Super,EHESS,Lab Sci Cognit & Psycho, Paris, France. [Draganski, Bogdan] Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany. [Hadjikhani, Nouchine] Univ Gothenburg, Sahlgrenska Acad, Gillberg Neuropsychiat Ctr, Gothenburg, Sweden. [Hadjikhani, Nouchine] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Charlestown, MA USA. [Jacquemont, Sebastien] Univ Montreal, Fac Med, Dept Pediat, Montreal, PQ H3C 3J7, Canada. RP Jacquemont, S (reprint author), Dept Pediat, Serv Genet, 3175 Ch Cote Sainte Catherine, Montreal, PQ H3T 1C4, Canada. EM sebastien.jacquemont@umontreal.ca RI Ramus, Franck/A-1755-2009; Centre d'imagerie Biomedicale, CIBM/B-5740-2012; Beckmann, Jacques S /A-9772-2008; OI Ramus, Franck/0000-0002-1122-5913; Beckmann, Jacques S /0000-0002-9741-1900; Hadjikhani, Nouchine/0000-0003-4075-3106; Draganski, Bogdan/0000-0002-5159-5919 FU Leenaards Foundation Prize; Swiss National Science Foundation (SNSF) Sinergia Grant [CRIS FN CRSII33-133044]; National Center of Competence in Research Synapsy Project Grant [320030_135679]; Special Program University Medicin [33CM30_140332/1]; Simons Foundation Autism Research Initiative (SFARI) Grant [SFARI274424]; Foundation Parkinson Switzerland; Foundation Synapsis; Human Brain Project, a European Union initiative; SNSF Grant [PP00P3_144902/2]; Canada Research Chair; Jeanne and Jean Louis Levesque Foundation; Center of Excellence in Genomics (Estonian Genome Center, the University of Tartu [EGCUT]); University of Tartu [SP1GVARENG]; Estonian Research Council [IUT20-60]; Swiss Scientific Exchange New Member States Program; doctoral school of the Faculty of Biology and Medicine, University of Lausanne; Roger de Spoelberg Foundation; Partridge Foundation; Agence Nationale [ANR-10-LABX-0087 IEC, ANR-10-IDEX-0001-02 PSL] FX This work was supported by the Leenaards Foundation Prize (SJ, ARey, NH), Swiss National Science Foundation (SNSF) Sinergia Grant No. CRIS FN CRSII33-133044 (ARey, SJ), National Center of Competence in Research Synapsy Project Grant Nos. 320030_135679 and Special Program University Medicin 33CM30_140332/1 (BD), Simons Foundation Autism Research Initiative (SFARI) Grant No. SFARI274424 (ARey), Foundation Parkinson Switzerland (BD), Foundation Synapsis (BD), Human Brain Project, a European Union initiative (BD), SNSF Grant No. PP00P3_144902/2 (SJ), a Canada Research Chair (SJ), Jeanne and Jean Louis Levesque Foundation (SJ), Center of Excellence in Genomics (Estonian Genome Center, the University of Tartu [EGCUT] [AMe, ARei, AK, KM]), University of Tartu Grant No. SP1GVARENG (EGCUT [AMe, ARei, AK, KM]), Estonian Research Council Grant No. IUT20-60 (EGCUT [AMe, ARei, AK, KM]), Swiss Scientific Exchange New Member States Program (KM), and a fellowship from the doctoral school of the Faculty of Biology and Medicine, University of Lausanne (MZ). Laboratory for Research in Neuroimaging is supported by the Roger de Spoelberg and Partridge Foundations. FR received funding from Agence Nationale (contracts ANR-10-LABX-0087 IEC and ANR-10-IDEX-0001-02 PSL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 2 Z9 2 U1 7 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 15 PY 2016 VL 80 IS 2 BP 129 EP 139 DI 10.1016/j.biopsych.2015.10.021 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DP5IT UT WOS:000378530200010 PM 26742926 ER PT J AU Zietman, AL Smith, J Klein, E Droller, M Dasgupta, P Catto, J AF Zietman, Anthony L. Smith, Joseph Klein, Eric Droller, Michael Dasgupta, Prokar Catto, James TI Editorial Statement on Gleason Scoring for Prostate Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material C1 [Zietman, Anthony L.] Massachusetts Gen Hosp, 100 Blossom St, Boston, MA 02114 USA. RP Zietman, AL (reprint author), Massachusetts Gen Hosp, 100 Blossom St, Boston, MA 02114 USA. EM azietman@partners.org OI catto, james/0000-0003-2787-8828 NR 1 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2016 VL 95 IS 4 BP 1092 EP 1092 DI 10.1016/j.ijrobp.2016.02.055 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DP0VC UT WOS:000378207000002 PM 27354124 ER PT J AU Verma, V Shah, C Lautenschlaeger, T Lin, C Beriwal, S Zhen, WN Mehta, MP Zietman, AL AF Verma, Vivek Shah, Chirag Lautenschlaeger, Tim Lin, Chi Beriwal, Sushil Zhen, Weining Mehta, Minesh P. Zietman, Anthony L. TI International Medical Graduates in Radiation Oncology: Historical Trends and Comparison With Other Medical Specialties SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID RESIDENCY; WORKFORCE AB Purpose: This is the first National Resident Matching Program analysis evaluating historical patterns of international medical graduates (IMGs) in radiation oncology (RO) and providing comparison with American (MD) medical graduates (AMGs), osteopathic students (DOs), unfilled positions, and other specialties. Methods and Materials: National Resident Matching Program data for IMGs were available from 2003 to 2015, with limited data for other specialty matches. The following RO-specific figures were obtained per year: total positions available; total matched positions; number of unfilled positions; and number of IMG, AMG, and DO matches. In addition, the number of IMG matches and total matched positions were obtained for 19 other specialties. Fisher exact tests and chi(2) tests were considered significant at alpha < .05. Results: From 2010 to 2015, 0.8% of RO matches were IMGs, a decline from 2.4% in 2003 to 2009 ( P=. 006). Proportions of DO matches during these intervals increased by 40% (from 1.0% to 1.4%), significantly lower than IMGs for 2003 to 2009 (P =. 03) but not 2010 to 2015 (P =. 26). From 2003 to 2015, the percentage of IMG matches, at 1.5%, was significantly lower than the percentage of unfilled seats, at 3.5% (P <. 001). In comparison with other specialties (2003-2015), RO had the fewest IMG matches (1.5%), followed by otolaryngology (1.9%) and orthopedics (2.2%); specialties with the highest IMG proportions were internal medicine (37.1%), family medicine (35.7%), and neurology (31.1%). Conclusions: Presently, IMGs represent < 1% of RO matches, the lowest among major specialties. There are several speculative factors associated with this low proportion. There are significantly more unfilled positions than those filled by IMGs; programs at risk of not matching could weigh the advantages and disadvantages of interviewing IMGs. (C) 2016 Elsevier Inc. All rights reserved. C1 [Verma, Vivek; Lin, Chi; Zhen, Weining] Univ Nebraska Med Ctr, Dept Radiat Oncol, 987521 Nebraska Med Ctr, Omaha, NE 68198 USA. [Shah, Chirag] Cleveland Clin, Dept Radiat Oncol, Taussig Canc Inst, Cleveland, OH 44106 USA. [Lautenschlaeger, Tim] Indiana Univ Sch Med, Dept Radiat Oncol, Indianapolis, IN 46202 USA. [Beriwal, Sushil] Univ Pittsburgh, Dept Radiat Oncol, Med Ctr, Pittsburgh, PA USA. [Mehta, Minesh P.] Miami Canc Inst, Dept Radiat Oncol, Coral Gables, FL USA. [Zietman, Anthony L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Verma, V (reprint author), Univ Nebraska Med Ctr, Dept Radiat Oncol, 987521 Nebraska Med Ctr, Omaha, NE 68198 USA. EM vivek333@gmail.com OI mehta, minesh/0000-0002-4812-5713 NR 11 TC 2 Z9 2 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 JUL 15 PY 2016 VL 95 IS 4 BP 1102 EP 1106 DI 10.1016/j.ijrobp.2016.03.008 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DP0VC UT WOS:000378207000004 PM 27209507 ER PT J AU Huynh, MA Chen, MH Wu, J Braccioforte, MH Moran, BJ D'Amico, AV AF Mai Anh Huynh Chen, Ming-Hui Wu, Jing Braccioforte, Michelle H. Moran, Brian J. D'Amico, Anthony V. TI Influence of Comorbidity on the Risk of Mortality in Men With Unfavorable-Risk Prostate Cancer Undergoing High-Dose Radiation Therapy Alone SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID RANDOMIZED-TRIAL; ANDROGEN SUPPRESSION; DISEASE; ASSOCIATION; DEPRIVATION; SURVIVAL; FAILURE; UPDATE; DEATH; AGE AB Purpose: To explore whether a subgroup of men with unfavorable-risk prostate cancer (PC) exists in whom high-dose radiation therapy (RT) alone is sufficient to avoid excess PC death due to competing risk from cardiometabolic comorbidity. Methods and Materials: This was a cohort study of 7399 men in whom comorbidity (including congestive heart failure, diabetes mellitus, or myocardial infarction) was assessed and recorded with T1-3NxM0 PC treated with brachytherapy with or without neoadjuvant RT, October 1997 to May 2013 at a single providing institution. Cox and competing risks regression analyses were used to assess whether men with unfavorable-intermediate/high-risk versus favorable-intermediate/low-risk PC were at increased risk of PC-specific, all-cause, or other-cause mortality (PCSM, ACM, OCM), adjusting for number of comorbidities, age at and year of brachytherapy, RT use, and an RT treatment propensity score. Results: After a median follow-up of 7.7 years, 935 men died: 80 of PC and 855 of other causes. Among men with no comorbidity, PCSM risk (adjusted hazard ratio [AHR] 2.74 [95% confidence interval (CI) 1.49-5.06], P = .001) and ACM risk (AHR 1.30 [95% CI 1.07-1.58], P = .007) were significantly increased in men with unfavorable-intermediate/high-risk PC versus favorable-intermediate/low-risk PC, with no difference in OCM (P = .07). Although PCSM risk was increased in men with 1 comorbidity (AHR 2.87 [95% CI 1.11-7.40], P = .029), ACM risk was not (AHR 1.03 [95% CI 0.78-1.36], P = .84). Neither PCSM risk (AHR 4.39 [95% CI 0.37-51.98], P = .24) or ACM risk (AHR 1.43 [95% CI 0.83-2.45], P = .20) was increased in men with 2 comorbidities. Conclusions: To minimize death from PC, high-dose RT alone may be sufficient treatment in men with 2 or more cardiometabolic comorbidities and unfavorablee intermediate- and high-risk PC. (C) 2016 Elsevier Inc. All rights reserved. C1 [Mai Anh Huynh] Brigham & Womens Hosp, Harvard Radiat Oncol Program, 75 Francis St, Boston, MA 02115 USA. [Chen, Ming-Hui; Wu, Jing] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Braccioforte, Michelle H.; Moran, Brian J.] Prostate Canc Fdn Chicago, Westmont, IL USA. [D'Amico, Anthony V.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. RP Huynh, MA (reprint author), Brigham & Womens Hosp, Harvard Radiat Oncol Program, 75 Francis St, Boston, MA 02115 USA. EM mahuynh@lroc.harvard.edu NR 28 TC 0 Z9 0 U1 4 U2 4 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 JUL 15 PY 2016 VL 95 IS 4 BP 1158 EP 1167 DI 10.1016/j.ijrobp.2016.03.004 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DP0VC UT WOS:000378207000011 PM 27209511 ER PT J AU Gaffney, DK King, B Viswanathan, AN Barkati, M Beriwal, S Eifel, P Erickson, B Fyles, A Goulart, J Harkenrider, M Jhingran, A Klopp, A Koh, WJ Lim, K Petersen, I Portelance, L Small, W Stewart, A Wiebe, E Wolfson, A Yashar, C Bosch, W AF Gaffney, David K. King, Bronwyn Viswanathan, Akila N. Barkati, Maroie Beriwal, Sushil Eifel, Patricia Erickson, Beth Fyles, Anthony Goulart, Jennifer Harkenrider, Matthew Jhingran, Anuja Klopp, Ann Koh, Wui-Jin Lim, Karen Petersen, Ivy Portelance, Lorraine Small, William, Jr. Stewart, Alexandra Wiebe, Ericka Wolfson, Aaron Yashar, Catheryn Bosch, Walter TI Consensus Recommendations for Radiation Therapy Contouring and Treatment of Vulvar Carcinoma SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID INTENSITY-MODULATED RADIOTHERAPY; SQUAMOUS-CELL CARCINOMA; GYNECOLOGIC-ONCOLOGY-GROUP; PELVIC NODE RESECTION; LYMPH-NODES; PHASE-II; CANCER; CHEMOTHERAPY; DELINEATION; RECURRENCE AB Purpose: The purpose of this study was to develop a radiation therapy (RT) contouring atlas and recommendations for women with postoperative and locally advanced vulvar carcinoma. Methods and Materials: An international committee of 35 expert gynecologic radiation oncologists completed a survey of the treatment of vulvar carcinoma. An initial set of recommendations for contouring was discussed and generated by consensus. Two cases, 1 locally advanced and 1 postoperative, were contoured by 14 physicians. Contours were compared and analyzed using an expectation-maximization algorithm for simultaneous truth and performance level estimation (STAPLE), and a 95% confidence interval contour was developed. The level of agreement among contours was assessed using a kappa statistic. STAPLE contours underwent full committee editing to generate the final atlas consensus contours. Results: Analysis of the 14 contours showed substantial agreement, with kappa statistics of 0.69 and 0.64 for cases 1 and 2, respectively. There was high specificity for both cases (>= 99%) and only moderate sensitivity of 71.3% and 64.9% for cases 1 and 2, respectively. Expert review and discussion generated consensus recommendations for contouring target volumes and treatment for postoperative and locally advanced vulvar cancer. Conclusions: These consensus recommendations for contouring and treatment of vulvar cancer identified areas of complexity and controversy. Given the lack of clinical research evidence in vulvar cancer radiation therapy, the committee advocates a conservative and consistent approach using standardized recommendations. (C) 2016 Elsevier Inc. All rights reserved. C1 [Gaffney, David K.] Huntsman Canc Hosp, Dept Radiat Oncol, Salt Lake City, UT 84112 USA. [King, Bronwyn] Peter MacCallum Canc Ctr & Epworth Radiat Oncol, Dept Radiat Oncol & Canc Imaging, Melbourne, Vic, Australia. [Viswanathan, Akila N.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, Boston, MA USA. [Barkati, Maroie] Univ Montreal, Ctr Hosp, Dept Radiat Oncol, Montreal, PQ, Canada. [Beriwal, Sushil] Univ Pittsburgh, Inst Canc, Dept Radiat Oncol, Pittsburgh, PA USA. [Eifel, Patricia; Jhingran, Anuja; Klopp, Ann] Univ Texas Houston, MD Anderson Canc Ctr, Dept Radiat Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA. [Erickson, Beth] Proedtert & Med Coll Clin Canc Ctr, Dept Radiat Oncol, Milwaukee, WI USA. [Fyles, Anthony] Princess Margaret Canc Ctr, Dept Radiat Oncol, Toronto, ON, Canada. [Goulart, Jennifer] British Columbia Canc Agcy, Dept Radiat Oncol, Victoria, BC, Canada. [Harkenrider, Matthew; Small, William, Jr.] Loyola Univ, Stritch Sch Med, Dept Radiat Oncol, 2160 S 1st Ave, Maywood, IL 60153 USA. [Koh, Wui-Jin] Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA. [Lim, Karen] Liverpool Canc Therapy Ctr, Radiat Oncol Unit, Sydney, NSW, Australia. [Petersen, Ivy] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA. [Portelance, Lorraine; Wolfson, Aaron] Univ Miami, Miller Sch Med, Dept Radiat Oncol, Miami, FL 33136 USA. [Stewart, Alexandra] Royal Surrey Country Hosp, St Lukes Canc Ctr, Surrey, England. [Wiebe, Ericka] Cross Canc Inst, Dept Radiat Oncol, Edmonton, AB T6G 1Z2, Canada. [Yashar, Catheryn] Univ Calif San Diego, Radiat Med & Appl Sci, San Diego, CA 92103 USA. [Bosch, Walter] Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO USA. RP Gaffney, DK (reprint author), Huntsman Canc Hosp, Dept Radiat Oncol, Salt Lake City, UT 84112 USA. EM david.gaffney@hci.utah.edu OI Fyles, Anthony/0000-0002-3633-2483 FU NCI NIH HHS [U10 CA180818, U10 CA180868, U24 CA180803] NR 25 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2016 VL 95 IS 4 BP 1191 EP 1200 DI 10.1016/j.ijrobp.2016.02.043 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA DP0VC UT WOS:000378207000015 PM 27130794 ER PT J AU Mirzaalian, H Ning, L Savadjiev, P Pasternak, O Bouix, S Michailovich, O Grant, G Marx, CE Morey, RA Flashman, LA George, MS McAllister, TW Andaluz, N Shutter, L Coimbra, R Zafonte, RD Coleman, MJ Kubicki, M Westin, CF Stein, MB Shenton, ME Rathi, Y AF Mirzaalian, H. Ning, L. Savadjiev, P. Pasternak, O. Bouix, S. Michailovich, O. Grant, G. Marx, C. E. Morey, R. A. Flashman, L. A. George, M. S. McAllister, T. W. Andaluz, N. Shutter, L. Coimbra, R. Zafonte, R. D. Coleman, M. J. Kubicki, M. Westin, C. F. Stein, M. B. Shenton, M. E. Rathi, Y. TI Inter-site and inter-scanner diffusion MRI data harmonization SO NEUROIMAGE LA English DT Article DE Diffusion MRI; Harmonization; Multi-site; Inter-scanner; Intra-site ID MAGNETIC-RESONANCE IMAGES; SPATIAL STATISTICS; RELIABILITY; MULTISITE; MULTICENTER; VARIABILITY AB We propose a novel method to harmonize diffusion MRI data acquired from multiple sites and scanners, which is imperative for joint analysis of the data to significantly increase sample size and statistical power of neuroimaging studies. Our method incorporates the following main novelties: i) we take into account the scanner-dependent spatial variability of the diffusion signal in different parts of the brain; ii) our method is independent of compartmental modeling of diffusion (e.g., tensor, and intra/extra cellular compartments) and the acquired signal itself is corrected for scanner related differences; and iii) inter-subject variability as measured by the coefficient of variation is maintained at each site. We represent the signal in a basis of spherical harmonics and compute several rotation invariant spherical harmonic features to estimate a region and tissue specific linear mapping between the signal from different sites (and scanners). We validate our method on diffusion data acquired from seven different sites (including two GE, three Philips, and two Siemens scanners) on a group of age-matched healthy subjects. Since the extracted rotation invariant spherical harmonic features depend on the accuracy of the brain parcellation provided by Freesurfer, we propose a feature based refinement of the original parcellation such that it better characterizes the anatomy and provides robust linear mappings to harmonize the dMRI data. We demonstrate the efficacy of our method by statistically comparing diffusion measures such as fractional anisotropy, mean diffusivity and generalized fractional anisotropy across multiple sites before and after data harmonization. We also show results using tract-based spatial statistics before and after harmonization for independent validation of the proposed methodology. Our experimental results demonstrate that, for nearly identical acquisition protocol across sites, scanner-specific differences can be accurately removed using the proposed method. (C) 2016 Published by Elsevier Inc. C1 [Mirzaalian, H.; Ning, L.; Savadjiev, P.; Pasternak, O.; Bouix, S.; Zafonte, R. D.; Coleman, M. J.; Kubicki, M.; Westin, C. F.; Shenton, M. E.; Rathi, Y.] Harvard Univ, Sch Med, Boston, MA USA. [Mirzaalian, H.; Ning, L.; Savadjiev, P.; Pasternak, O.; Bouix, S.; Coleman, M. J.; Kubicki, M.; Westin, C. F.; Shenton, M. E.; Rathi, Y.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Michailovich, O.] Univ Waterloo, Waterloo, ON N2L 3G1, Canada. [Grant, G.] Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. [Grant, G.; Shutter, L.] Duke Univ, Durham, NC 27706 USA. [Marx, C. E.; Morey, R. A.] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Marx, C. E.; Morey, R. A.] VA Midatlantic MIRECC, Durham, NC USA. [Flashman, L. A.] Dartmouth Coll, Hanover, NH USA. [Flashman, L. A.; McAllister, T. W.] Geisel Sch Med Dartmouth, Hanover, NH USA. [George, M. S.] Med Univ S Carolina, Charleston, SC 29425 USA. [George, M. S.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [McAllister, T. W.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Andaluz, N.] Univ Cincinnati, Coll Med, Dept Neurosurg, Cincinnati, OH 45267 USA. [Andaluz, N.] UC Neurosci Inst, Neurotrauma Ctr, Cincinnati, OH USA. [Andaluz, N.] Mayfield Clin, Cincinnati, OH USA. [Shutter, L.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Coimbra, R.] Univ Calif San Diego, Dept Surg, San Diego, CA 92103 USA. [Zafonte, R. D.] Spaulding Rehabil Hosp, Boston, MA USA. [Stein, M. B.] Univ Calif San Diego, San Diego, CA 92103 USA. [Shenton, M. E.] VA Boston Healthcare Syst, Boston, MA USA. RP Mirzaalian, H (reprint author), Psychiat Neuroimaging Lab, 1249 Boylston St, Boston, MA 02215 USA. EM hengameh.mirzaalian@gmail.com OI Shutter, Lori/0000-0002-1390-0628 FU Swedish Research Council (VR) [2012-3682]; Swedish Foundation for Strategic Research (SSF) [AM13-0090]; VA Merit (PI: Shenton); [W81XWH-08-2-0159]; [R01MH099797]; [R01MH074794]; [P41EB015902] FX The authors would like to acknowledge the following grants which supported this work: W81XWH-08-2-0159 (Imaging Core PI: Shenton, Contact PI: Stein, Site PIs: George, Grant, Marx, McCallister, Zafonte; Other: Bouix, Coleman, Bouix, Kubicki, Mirzaalian, Pasternak, Savadjiev, Rathi), R01MH099797 (PI: Rathi), R01MH074794 (PI: Westin), P41EB015902 (PI: Kikinis), Swedish Research Council (VR) grant 2012-3682, Swedish Foundation for Strategic Research (SSF) grant AM13-0090, and VA Merit (PI: Shenton). NR 34 TC 2 Z9 2 U1 3 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2016 VL 135 BP 311 EP 323 DI 10.1016/j.neuroimage.2016.04.041 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA DO8QF UT WOS:000378047600028 PM 27138209 ER PT J AU Sharma, A Sharma, SK Vallakati, A Garg, A Lavie, CJ Mukherjee, D Marmur, JD AF Sharma, Abhishek Sharma, Samin K. Vallakati, Ajay Garg, Akash Lavie, Carl J. Mukherjee, Debabrata Marmur, Jonathan D. TI Duration of dual antiplatelet therapy after various drug-eluting stent implantation SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Dual anti-platelet therapy; Drug-eluting stents ID PERCUTANEOUS CORONARY INTERVENTION; RANDOMIZED CONTROLLED-TRIALS; NETWORK METAANALYSIS; THROMBOSIS; TERM; ENDOTHELIALIZATION; MULTICENTER; GUIDELINES; MORTALITY; PAIRWISE AB Objective: To evaluate efficacy and safety of long duration dual anti-platelet therapy i.e., >12 months (L-DAPT) and short duration DAPT i.e., <= 12 months (S-DAPT) after various drug-eluting stent (DES) implantation. Methods: We searched Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials (RCTs) assessing the effect of L-DAPT versus S-DAPT after sirolimus-eluting (Cypher (R)); paclitaxel-eluting stents (Taxus (R)); zotarolimus-eluting (Endeavor (R)) and everolimus-eluting stents (Xience V (R)) implantation. Odds ratio (OR) and 95% confidence intervals (CI) were calculated using random-effects models. Subgroup analyses were performed comparing two second generation DES and for RCTs comparing S-DAPT and L-DAPT. Results: We included six RCTs that randomized 19,012 patients to S-DAPT versus L-DAPT (4638 in first generation DES; 14,374 in second generation DES; 8099 EES; 4876 in ZES). Compared with L-DAPT, S-DAPT was associated with a higher rate of myocardial infarction (MI) and stent thrombosis (ST) after first [2.65 (1.88, 3.73) and 3.85 (2.14-6.93) respectively] and a higher rate of MI after second generation DES [1.33 (1.06, 1.67)]. There were no significant differences in the rates of all cause mortality, cardiovascular (CV) mortality and stroke with L-DAPT and S-DAPT after implantation of first [0.97 (0.52, 1.81); 1.19 (0.52-2.70); and 1.12 (0.36-3.52) respectively] and second generation DES [0.93 (0.69, 1.25); 0.93 (0.63, 1.36); and 0.58 (0.19, 1.75), respectively]. On further analysis of type of second generation DES, S-DAPT continues to show a higher rate of MI and ST after EES implantation [1.54 (1.11, 2.13) and 2.68 (1.20-5.94) respectively]; however there was no significant difference in the rate of MI and ST with S-DAPT and L-DAPT after ZES implantation [1.07 (0.44, 2.61) and 1.11(0.39, 3.13), respectively]. Conclusion: 1) Compared with L-DAPT, S-DAPT was associated with a higher rate of MI without any significant difference in the rate of all cause mortality, CV mortality and stroke after first and second generation DES. 2) Rate of ST was also higher with S-DAPT compared to L-DAPT after first generation DES implantation; however, it was not significantly different after second generation DES. 3) On further subgroup analysis of second generation stent there was no significant difference in the rate of all cause mortality, CV mortality, MI, ST and stroke with S-DAPT and L-DAPT after ZES implantation. S-DAPT may be optimal for newer generation stents particularly ZES. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Sharma, Abhishek; Marmur, Jonathan D.] Suny Downstate Med Ctr, Div Cardiovasc Med, New York, NY USA. [Sharma, Samin K.] Mt Sinai Med Ctr, Icahn Sch Med Mt Sinai, Inst Heart & Vasc, Dept Cardiovasc Med, New York, NY 10029 USA. [Vallakati, Ajay] Case Western Reserve Univ, Metrohlth Med Ctr, Div Cardiol, Cleveland, OH USA. [Garg, Akash] James J Peters VA Med Ctr, Mt Sinai Sch Med, Dept Med, New York, NY USA. [Lavie, Carl J.] Univ Queensland, John Ochsner Heart & Vasc Inst, Ochsner Clin Sch, Dept Cardiovasc Dis,Sch Med, New Orleans, LA USA. [Mukherjee, Debabrata] Texas Tech Univ, Div Cardiol, El Paso, TX USA. RP Sharma, A (reprint author), Suny Downstate Med Ctr, Div Cardiovasc Med, 450 Clarkson Ave, Brooklyn, NY 11203 USA. EM abhisheksharma4mamc@gmail.com RI Lavie, Carl/A-6014-2011 NR 31 TC 0 Z9 0 U1 0 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 15 PY 2016 VL 215 BP 157 EP 166 DI 10.1016/j.ijcard.2016.04.118 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM4DX UT WOS:000376297100040 PM 27116326 ER PT J AU Kalra, A Pokharel, Y Glusenkamp, N Wei, J Kerkar, PG Oetgen, WJ Virani, SS AF Kalra, Ankur Pokharel, Yashashwi Glusenkamp, Nathan Wei, Jessica Kerkar, Prafulla G. Oetgen, William J. Virani, Salim S. CA PINNACLE India Quality Improvement TI Gender disparities in cardiovascular care access and delivery in India: Insights from the American College of Cardiology's PINNACLE India Quality Improvement Program (PIQIP) SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Gender disparity; Cardiovascular care; India; Quality improvement; American College of Cardiology ID HEART-DISEASE; DOUBLE BURDEN; WOMEN; MORTALITY; HEALTH; MEN AB Background: Limited data are available to assess whether access to and quality of cardiovascular disease (CVD) care are comparable among men and women in India. We analyzed data from the American College of Cardiology's PINNACLE (Practice Innovation and Clinical Excellence) India Quality Improvement Program (PIQIP) to evaluate gender disparities in CVD care delivery. Methods and results: Between 2011 and 2015, we collected data on performance measures for patients with coronary artery disease (CAD) (n = 14,010), heart failure (HF) (n = 11,965) and atrial fibrillation (AF) (n = 496) in PIQIP, among 17 participating practices. The total number of women was 31,796 (32.0%). Women had fewer total encounters compared to men during the study interval (mean number of encounters = 2.59 vs. 2.82 for women and men, respectively, p <= 0.001). Women were significantly younger (48.9 years vs. 51.5 years, p <= 0.01), but had a higher co-morbidity burden compared to men - hypertension (62.0% vs. 45.6%, p <= 0.01), diabetes (39.4% vs. 35%, p <= 0.01), and hyperlipidemia (3.7% vs. 3.1%, p = 0.19). On the contrary, the guideline-directed medication prescriptions were strikingly lower in women with CAD compared to men - aspirin (38% vs. 50.4%, p <= 0.001), aspirin or thienopyridine combination (46.9% vs. 57.2%, p <= 0.001), and beta-blockers (36.8% vs. 47.8%, p <= 0.001). Similarly, among women with ejection fraction <= 40%, the use of guideline-directed medical therapy was significantly lower compared to men for beta-blockers (30.8% vs. 37.0%, p <= 0.001), angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin receptor blockers (ARBs) (29.3% vs. 34.9%, p <= 0.001), and beta-blockers/ACE-i or ARBs (24.6% vs. 31.0%, p <= 0.001). Among patients with atrial fibrillation and CHADS2 score >= 2, more women were on oral anticoagulation (19.6% vs. 14.6%, p = 0.34), although this was not significantly different, and the overall number of patients with atrial fibrillation was low. Conclusions: Despite a significantly higher co-morbidity burden in women, we found fewer women receiving guideline-directed medical therapy for CVD compared with men. If such disparities are confirmed in the larger Indian population, it is important to find potential causes for, and seek solutions to narrow this gap. Published by Elsevier Ireland Ltd. C1 [Kalra, Ankur] Kalra Hosp SRCNC Sri Ram Cardiothorac & Neurosci, Dept Med, Div Cardiol, New Delhi, India. [Kalra, Ankur] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Intervent Cardiol, Boston, MA 02215 USA. [Kalra, Ankur] Harvard Univ, Sch Med, Safety Qual Informat & Leadership Program, Boston, MA USA. [Pokharel, Yashashwi] Univ Missouri, Dept Cardiovasc Res, St Lukes Mid Amer Heart Inst, Kansas City, MO 64110 USA. [Glusenkamp, Nathan; Wei, Jessica; Oetgen, William J.] Amer Coll Cardiol Fdn, Washington, DC USA. [Kerkar, Prafulla G.] King Edward VII Mem Hosp & Seth GS Med Coll, Bombay, Maharashtra, India. [Virani, Salim S.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Hlth Policy Qual & Informat Program, Hlth Serv Res & Dev Ctr Innovat, Houston, TX 77030 USA. [Virani, Salim S.] Baylor Coll Med, Dept Med, Sect Cardiovasc Res, Houston, TX 77030 USA. RP Virani, SS (reprint author), Michael E DeBakey VA Med Ctr, Hlth Serv Res & Dev 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM virani@bcm.edu OI Virani, Salim/0000-0001-9541-6954 FU American College of Cardiology Foundation, Washington, DC; Bristol Myers-Squibb; Pfizer, Inc. FX This work was supported by the American College of Cardiology Foundation, Washington, DC. Bristol Myers-Squibb and Pfizer, Inc. are Founding Sponsors of PIQIP. NR 10 TC 0 Z9 0 U1 2 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 15 PY 2016 VL 215 BP 248 EP 251 DI 10.1016/j.ijcard.2016.04.058 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM4DX UT WOS:000376297100057 PM 27128540 ER PT J AU Krishnaswami, A Go, AS Forman, DE Leong, TK Lee, H Maurer, MS McCulloch, CE AF Krishnaswami, Ashok Go, Alan S. Forman, Daniel E. Leong, Thomas K. Lee, Hon Maurer, Mathew S. McCulloch, Charles E. TI Multimorbidity is strongly associated with long-term but not short-term mortality after cardiac valve replacement SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Multiple chronic conditions; Multimorbidity; Valvular heart disease; Cardiac valve replacement; Mortality; Proportional hazards models ID HEART-FAILURE; DIALYSIS PATIENTS; OLDER-ADULTS; RISK; DISEASE; SURGERY; COMORBIDITY; SURVIVAL; HEALTH; CARE AB Background: The presence of multimorbidity is known to be related to adverse clinical outcomes. However, its association with mortality in patients undergoing cardiac valve replacement is not known. Methods: Multimorbidity (as a continuous variable) was characterized in adults receiving cardiac valve replacement surgery between 2008 and 2012 within Kaiser Permanente Northern California based on information from health plan electronic health records. Our primary outcome was 3-year all-causemortality after surgery. We used Cox proportional hazards regression to evaluate the independent association of each additional comorbidity with mortality. Results: Among 3686 eligible patients, mean age was 67.9 +/- 13.5 years and median comorbidity burden was 3 (IQR: 2). The presence of most individual comorbidities except hypertension and hyperlipidemia did not occur in isolation. The unadjusted annual incidence (per 100 person-years) of death increased with higher comorbidity burden: <= 1: 4.61 (95% CI: 3.29-6.45), 2-3: 13.7 (95% CI: 11.9-15.8), 4-5: 23.6 (95% CI: 20.6-26.9), and >= 6: 43.4(95% CI: 34.654.4). Advancing age, diabetes mellitus, cerebrovascular accident, heart failure, lung disease, urgent status and use of aldosterone-receptor antagonists were independently associated with an increased risk of mortality. Inmultivariable analyses, each additional comorbidity was significantly associated with an increased risk of long-term (adjusted hazard ratio (HR) 1.30, 95% CI: 1.22-1.39) but not short-term mortality (HR 0.92, 95% CI: 0.80-1.07). Conclusions: Our study demonstrated that multimorbidity in patients undergoing cardiac valve replacement is significantly associated with long-term but not short-term mortality. (C) 2016 Elsevier Ireland Ltd. All rights reserved. C1 [Krishnaswami, Ashok] Kaiser Permanente San Jose Med Ctr, Div Cardiol, San Jose, CA USA. [Go, Alan S.; Leong, Thomas K.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Go, Alan S.; McCulloch, Charles E.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Go, Alan S.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Go, Alan S.] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Forman, Daniel E.] Univ Pittsburgh, Div Geriatr Cardiol, Pittsburgh, PA USA. [Forman, Daniel E.] VA Pittsburgh Healthcare Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. [Lee, Hon] Kaiser Permanente Santa Clara Med Ctr, Dept Cardiovasc Surg, Santa Clara, CA USA. [Maurer, Mathew S.] Columbia Univ, Med Ctr, Div Cardiol, New York, NY USA. RP Krishnaswami, A (reprint author), Kaiser Permanente San Jose Med Ctr, 270 Int Circle,2nd Floor, San Jose, CA 95119 USA. EM ashok.krishnaswami@kp.org FU Kaiser Permanente Northern California Community Benefit grant [KR021350]; NIA grant [P30 AG024827]; VA Office of Rehabilitation Research and Development grant [F0834-R]; Mid-Career Mentoring Award in Geriatric Cardiology from NIA [K24-AG036778-06] FX Dr. Krishnaswami was supported by a Kaiser Permanente Northern California Community Benefit grant (KR021350). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of themanuscript; and the decision to submit themanuscript for publication. No other disclosures are present.; Dr. Forman is supported in part by NIA grant P30 AG024827 and VA Office of Rehabilitation Research and Development grant F0834-R.; Dr. Maurer is supported by a Mid-Career Mentoring Award in Geriatric Cardiology from NIA (K24-AG036778-06). NR 37 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 15 PY 2016 VL 215 BP 417 EP 421 DI 10.1016/j.ijcard.2016.04.110 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM4DX UT WOS:000376297100091 PM 27131261 ER PT J AU Poulsen, CB Al-Mashhadi, AL von Wachenfeldt, K Bentzon, JF Nielsen, LB Al-Mashhadi, RH Thygesen, J Tolbod, L Larsen, JR Frokiaer, J Tawakol, A Vucic, E Fredrickson, J Baruch, A Frendeus, B Robertson, AKL Moestrup, SK Drouet, L Falk, E AF Poulsen, Christian Bo Al-Mashhadi, Ahmed Ludvigsen von Wachenfeldt, Karin Bentzon, Jacob Fog Nielsen, Lars Bo Al-Mashhadi, Rozh H. Thygesen, Jesper Tolbod, Lars Larsen, Jens Rolighed Frokiaer, Jorgen Tawakol, Ahmed Vucic, Esad Fredrickson, Jill Baruch, Amos Frendeus, Bjorn Robertson, Anna-Karin L. Moestrup, Soren Kragh Drouet, Ludovic Falk, Erling TI Treatment with a human recombinant monoclonal IgG antibody against oxidized LDL in atherosclerosis-prone pigs reduces cathepsin S in coronary lesions SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Atherosclerosis; Cholesterol; Antibody ID LOW-DENSITY-LIPOPROTEIN; POSITRON-EMISSION-TOMOGRAPHY; INHIBIT ATHEROSCLEROSIS; INSULIN SENSITIVITY; VULNERABLE PLAQUE; ARTERY-DISEASE; /-MICE; INFLAMMATION; MACROPHAGES; MECHANISMS AB Background: Immunization with oxidized LDL (oxLDL) reduces atherosclerosis in rodents. We tested the hypothesis that treatment with a human recombinant monoclonal antibody against oxLDL will reduce the burden or composition of atherosclerotic lesions in hypercholesterolemic minipigs. Methods and results: Thirty-eight hypercholesterolemic minipigs with defective LDL receptors were injected with an oxLDL antibody or placebo weekly for 12 weeks. An 18F-fluorodeoxyglucose positron emission tomography (FDG PET) scan (n = 9) was performed before inclusion and after 3 months of treatment. Blood samples were obtained prior to each injection. Following the last injection all animals were sacrificed, and the heart, aorta, and iliac arteries were removed. The left anterior descending coronary artery was sectioned at 5 mm intervals for quantitative and qualitative assessments of atherosclerosis, including immunohistochemical phenotyping of macrophages using a pan-macrophage marker (CD68) and markers for putative pro-atherogenic (cathepsin S) and atheroprotective (CD163) macrophages. Aorta, right coronary artery, and left iliac artery were stained en face with Sudan IV and the amount of atherosclerosis quantified. There was no effect of treatment on plasma lipid profile, vascular FDG-PET signal or the amount of atherosclerosis in any of the examined arteries. However, immunostaining of coronary lesions revealed reduced cathepsin S positivity in the treated group compared with placebo (4.8% versus 8.2% of intima area, p = 0.03) with no difference in CD68 or CD163 positivity. Conclusions: In hypercholesterolemic minipigs, treatment with a human recombinant monoclonal antibody against oxLDL reduced cathepsin S in coronary lesions without any effect on the burden of atherosclerosis or aortic FDG-PET signal. (C) 2016 Published by Elsevier Ireland Ltd. C1 [Poulsen, Christian Bo; Al-Mashhadi, Ahmed Ludvigsen; Bentzon, Jacob Fog; Al-Mashhadi, Rozh H.; Falk, Erling] Aarhus Univ, Dept Clin Med, Aarhus Univ Hosp, Dept Cardiol, Aarhus, Denmark. [von Wachenfeldt, Karin] Truly Translat, Lund, Sweden. [Nielsen, Lars Bo] Univ Copenhagen, Rigshosp, Dept Clin Biochem, DK-2100 Copenhagen, Denmark. [Thygesen, Jesper] Aarhus Univ Hosp, Dept Clin Engn, DK-8000 Aarhus, Denmark. [Tolbod, Lars; Frokiaer, Jorgen] Aarhus Univ Hosp, Dept Nucl Med, DK-8000 Aarhus, Denmark. [Tolbod, Lars; Frokiaer, Jorgen] Aarhus Univ Hosp, PET Ctr, DK-8000 Aarhus, Denmark. [Larsen, Jens Rolighed] Aarhus Univ Hosp, Dept Cardiothorac & Vasc Surg, DK-8000 Aarhus, Denmark. [Tawakol, Ahmed; Vucic, Esad] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Tawakol, Ahmed; Vucic, Esad] Harvard Univ, Sch Med, Boston, MA USA. [Fredrickson, Jill; Baruch, Amos] Genentech Inc, 460 Point San Bruno Blvd, San Francisco, CA 94080 USA. [Frendeus, Bjorn; Robertson, Anna-Karin L.] BioInvent Int AB, Lund, Sweden. [Moestrup, Soren Kragh] Univ Southern Denmark, Dept Mol Med, Odense, Denmark. [Drouet, Ludovic] Hosp Lariboisiere, Dept Angiohematol, Paris, France. RP Poulsen, CB (reprint author), Aarhus Univ Hosp, Dept Cardiol, Palle Juul Jensens Blvd 99, DK-8000 Aarhus, Denmark. EM cbpoulsen@clin.au.dk RI Poulsen Tolbod, Lars/A-7768-2008; Bentzon, Jacob/B-5302-2016; OI Poulsen Tolbod, Lars/0000-0002-8105-7046; Bentzon, Jacob/0000-0002-3020-5002; Al-Mashhadi, Rozh/0000-0001-9721-8054; Frokiaer, Jorgen/0000-0002-6206-8065 FU BioInvent International (Lund, Sweden); Faculty of Health, Aarhus University [904606]; [MLDL1278A] FX The study was funded by BioInvent International (Lund, Sweden), which also provided the drug (MLDL1278A), and the Faculty of Health, Aarhus University (904606). NR 53 TC 3 Z9 3 U1 3 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD JUL 15 PY 2016 VL 215 BP 506 EP 515 DI 10.1016/j.ijcard.2016.03.222 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DM4DX UT WOS:000376297100111 PM 27135822 ER PT J AU Ng, EX Miller, MA Jing, TY Chen, CH AF Ng, Ee Xien Miller, Miles A. Jing, Tengyang Chen, Chia-Hung TI Single cell multiplexed assay for proteolytic activity using droplet microfluidics SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Single cell assay; Proteolytic activity matrix analysis; Droplet microfluidics; FRET-sensors ID EPITHELIAL-MESENCHYMAL TRANSITION; MATRIX METALLOPROTEINASES; BREAST-CANCER; PROTEASE; CLEAVAGE; SYSTEM; HETEROGENEITY; TECHNOLOGIES; EXPRESSION; BIOLOGY AB Cellular enzymes interact in a post-translationally regulated fashion to govern individual cell behaviors, yet current platform technologies are limited in their ability to measure multiple enzyme activities simultaneously in single cells. Here, we developed multi-color Forster resonance energy transfer (FRET) based enzymatic substrates and use them in a microfluidics platform to simultaneously measure multiple specific protease activities from water-in-oil droplets that contain single cells. By integrating the microfluidic platform with a computational analytical method, Proteolytic Activity Matrix Analysis (PrAMA), we are able to infer six different protease activity signals from individual cells in a high throughput manner (similar to 100 cells/experimental run). We characterized protease activity profiles at single cell resolution for several cancer cell lines including breast cancer cell MDA-MB-231, lung cancer cell line PC-9, and leukemia cell line K-562 using both live-cell and in-situ cell lysis assay formats, with special focus on metalloproteinases important in metastasis. The ability to measure multiple proteases secreted from or expressed in individual cells allows us to characterize cell heterogeneity and has potential applications including systems biology, pharmacology, cancer diagnosis and stem cell biology. (C) 2016 Elsevier B.V. All rights reserved. C1 [Ng, Ee Xien; Jing, Tengyang; Chen, Chia-Hung] Natl Univ Singapore, Dept Biomed Engn, Block E4,04-08,4 Engn Dr 3, Singapore 117583, Singapore. [Miller, Miles A.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Jing, Tengyang] Singapore MIT Alliance Res & Technol SMART Ctr, Singapore 1385602, Singapore. [Chen, Chia-Hung] Singapore Inst Neurotechnol, 28 Med Dr 05 COR, Singapore 117456, Singapore. RP Chen, CH (reprint author), Natl Univ Singapore, Dept Biomed Engn, Block E4,04-08,4 Engn Dr 3, Singapore 117583, Singapore. EM biecch@nus.edu.sg FU NUS Tier-1 Grant, Ministry of Health (MOH) IAF [R-397-000-213-112, R-397-000-153-112, Cat-1 R-397-000-230-511]; Singapore-MIT Alliance for Research and Technology (SMART) research Grant [R-397-000-146-592] FX We would like to thank Dr. Marcia L. Moss for her kind assist in substrate FRET pair selection. We gratefully acknowledge the funding provided by the NUS Tier-1 Grants R-397-000-213-112, R-397-000-153-112, Ministry of Health (MOH) IAF Cat-1 R-397-000-230-511, the Singapore-MIT Alliance for Research and Technology (SMART) research Grant R-397-000-146-592, and the facilities provided by Singapore Institute for Neurotechnology (SINAPSE). NR 34 TC 6 Z9 6 U1 18 U2 71 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 EI 1873-4235 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD JUL 15 PY 2016 VL 81 BP 408 EP 414 DI 10.1016/j.bios.2016.03.002 PG 7 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA DK3JB UT WOS:000374811800056 PM 26995287 ER PT J AU Ryan, KA Assari, S Pester, BD Hinrichs, K Angers, K Baker, A Marshall, DF Stringer, D Saunders, EFH Kamali, M McInnis, MG Langenecker, SA AF Ryan, Kelly A. Assari, Shervin Pester, Bethany D. Hinrichs, Kristin Angers, Kaley Baker, Amanda Marshall, David F. Stringer, Deborah Saunders, Erika F. H. Kamali, Masoud McInnis, Melvin G. Langenecker, Scott A. TI Similar Trajectory of Executive Functioning Performance over 5 years among individuals with Bipolar Disorder and Unaffected Controls using Latent Growth Modeling SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article DE Bipolar disorder; Neurodegenerative; Cognition; Affective disorders ID FOLLOW-UP; COGNITIVE IMPAIRMENT; OLDER-ADULTS; I DISORDER; 1ST-DEGREE RELATIVES; UNIPOLAR DEPRESSION; EUTHYMIC PATIENTS; LITHIUM; METAANALYSIS; SYMPTOMS AB Objective: Executive Functioning (EF) deficits in bipolar disorder (BD) are commonly present regardless of mood state and therefore are considered core features of the illness. However, very little is known about the temporal stability of these deficits. We examined the natural course of EF over a five year period in BD and healthy control (HC) samples. Method: Using a 5-year longitudinal cohort, 91 individuals with BD and 17 HC were administered a battery of neuropsychological tests that captured four main areas of EF: Processing Speed with Interference Resolution, Verbal Fluency with Processing Speed, Inhibitory Control, and Conceptual Reasoning and Set Shifting. Evaluations occurred at study entry, one, and five years later. Results: Latent Growth Curve Modeling demonstrated that the BD group performed significantly worse in all EF areas than the HC group. Changes in EF from baseline to 5-year follow-up were similar across both diagnostic groups. Older age at baseline, above and beyond education and diagnosis, was associated with worse initial performance in EF. Being of older age was associated with greater decline in Processing Speed with Interference Resolution, and Verbal Fluency with Processing Speed. Higher education was marginally associated with a smaller declining slope for Processing Speed with Interference Resolution. Conclusions: Executive functioning deficits in BD persist over time, and in the context of normative age related decline, may place individuals at greater risk for cognitive disability as the disease progresses. Age and having a BD diagnosis together, however, do not accelerate executive functioning decline over time. (C) 2016 Elsevier B.V. All rights reserved. C1 [Ryan, Kelly A.; Assari, Shervin; Pester, Bethany D.; Hinrichs, Kristin; Angers, Kaley; Baker, Amanda; Marshall, David F.; Stringer, Deborah; Kamali, Masoud; McInnis, Melvin G.] Univ Michigan, Dept Psychiat, 2101 Commonwealth Blvd,Suite C, Ann Arbor, MI 48109 USA. [Langenecker, Scott A.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Saunders, Erika F. H.] Penn State Coll Med, Dept Psychiat, Hershey, PA USA. [Kamali, Masoud] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Ryan, KA (reprint author), Univ Michigan, Dept Psychiat, 2101 Commonwealth Blvd,Suite C, Ann Arbor, MI 48109 USA. EM karyan@umich.edu FU Heinz C. Prechter Bipolar Research Fund at the University of Michigan Depression Center; Richard Tam Foundation; National Center for Advancing Translational Sciences of the National Institutes of Health [2KL2TR000434] FX This research was supported by the Heinz C. Prechter Bipolar Research Fund at the University of Michigan Depression Center and the Richard Tam Foundation (KR, SA, BP, KH, DM, AB, KA, DS, MK, MM), and grant support from the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number 2KL2TR000434 (KR). We would like to express appreciation to our research participants in the Prechter Longitudinal Study of Bipolar Disorder. We would also like to acknowledge and thank our research team consisting of Holli Bertram, Christine Brucksch, Brent Doil, Valerie Foster, Laura Gabriel, Nicole Greer, Lauren Grove, Brennan Haase, Gloria Harrington, Alexander Hayek, Michelle Kassel, Marisa Kelly, Katie Lavin, Kortni Meyers, Jennifer Montgomery, Lisa O'Donnell, Philip Presnell, Anne Weldon, and the rest of the staff of the Prechter Bipolar Research Team for their contributions to this project. NR 63 TC 0 Z9 0 U1 3 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 EI 1573-2517 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD JUL 15 PY 2016 VL 199 BP 87 EP 94 DI 10.1016/j.jad.2016.04.016 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA DL1OL UT WOS:000375401500012 PM 27093492 ER PT J AU Lampson, BL Kasar, SN Matos, TR Morgan, EA Rassenti, L Davids, MS Fisher, DC Freedman, AS Jacobson, CA Armand, P Abramson, JS Arnason, JE Kipps, TJ Fein, J Fernandes, S Hanna, J Ritz, J Kim, HT Brown, JR AF Lampson, Benjamin L. Kasar, Siddha N. Matos, Tiago R. Morgan, Elizabeth A. Rassenti, Laura Davids, Matthew S. Fisher, David C. Freedman, Arnold S. Jacobson, Caron A. Armand, Philippe Abramson, Jeremy S. Arnason, Jon E. Kipps, Thomas J. Fein, Joshua Fernandes, Stacey Hanna, John Ritz, Jerome Kim, Haesook T. Brown, Jennifer R. TI Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity SO BLOOD LA English DT Article ID REGULATORY T-CELLS; B-CELL; PHOSPHATIDYLINOSITOL 3-KINASE; MUTATION STATUS; LIVER-INJURY; P110-DELTA; DISEASE; ZAP-70; CANCER; IMGT AB Idelalisib is a small-molecule inhibitor of PI3Kd with demonstrated efficacy for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as front-line therapy, we enrolled 24 subjects in a phase 2 study consisting of 2 months of idelalisib monotherapy followed by 6 months of combination therapy with idelalisib and the anti-CD20 antibody ofatumumab. After a median follow-up period of 14.7 months, hepatotoxicity was found to be a frequent and often severe adverse event. A total of 19 subjects (79%) experienced either grade >= 1 ALT or AST elevation during the study, and 13 subjects (54%) experienced grade >= 3 transaminitis. The median time to development of transaminitis was 28 days, occurring before ofatumumab introduction. Younger age and mutated immunoglobulin heavy chain status were significant risk factors for the development of hepatotoxicity. Multiple lines of evidence suggest that this hepatotoxicity was immune mediated. A lymphocytic infiltrate was seen on liver biopsy specimens taken from 2 subjects with transaminitis, and levels of the proinflammatory cytokines CCL-3 and CCL-4 were higher in subjects experiencing hepatotoxicity. All cases of transaminitis resolved either by holding the drug, initiating immunosuppressants, or both, and rates of recurrent toxicity were lower in patients taking steroids when idelalisib was reinitiated. A decrease in peripheral blood regulatory T cells was seen in patients experiencing toxicity on therapy, which is consistent with an immune-mediated mechanism. These results suggest that caution should be taken as drugs within this class are developed for CLL, particularly in younger patients who have not received prior disease-specific therapy. This study was registered at www.clinicaltrials.gov as #NCT02135133. C1 [Lampson, Benjamin L.; Kasar, Siddha N.; Matos, Tiago R.; Davids, Matthew S.; Fisher, David C.; Freedman, Arnold S.; Jacobson, Caron A.; Armand, Philippe; Fein, Joshua; Fernandes, Stacey; Hanna, John; Ritz, Jerome; Brown, Jennifer R.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Lampson, Benjamin L.; Kasar, Siddha N.; Matos, Tiago R.; Davids, Matthew S.; Fisher, David C.; Freedman, Arnold S.; Jacobson, Caron A.; Armand, Philippe; Fein, Joshua; Fernandes, Stacey; Hanna, John; Ritz, Jerome; Brown, Jennifer R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Morgan, Elizabeth A.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Rassenti, Laura; Kipps, Thomas J.] Univ Calif San Diego, Dept Med, Div Hematol Oncol, La Jolla, CA 92093 USA. [Rassenti, Laura; Davids, Matthew S.; Kipps, Thomas J.; Fernandes, Stacey; Brown, Jennifer R.] Moores UCSD Canc Ctr, CLL Res Consortium, La Jolla, CA USA. [Abramson, Jeremy S.] Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, Boston, MA USA. [Arnason, Jon E.] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Matos, Tiago R.] Univ Lisbon, Fac Med, Inst Mol Med, Lisbon, Portugal. [Fein, Joshua] Tel Aviv Univ, Sackler Sch Med, Tel Aviv, Israel. RP Brown, JR (reprint author), Dana Farber Canc Inst, Mayer Bldg,Room 226,450 Brookline Ave, Boston, MA 02215 USA. EM jennifer_brown@dfci.harvard.edu OI Matos, Tiago R./0000-0003-2864-8207; Morgan, Elizabeth/0000-0001-5880-9337 FU Gilead; Novartis; Dana-Farber Cancer Institute Medical Oncology Grant program; Melton Family Fund for CLL Research; Susan and Gary Rosenbach Fund for Lymphoma Research; National Institutes of Health, National Cancer Institute of the CLL Research Consortium [P01-CA81534] FX This study is an investigator-initiated trial run by J.R.B. and funded by Gilead and Novartis; both companies provided their study drug at no cost. Correlative studies were funded by the Dana-Farber Cancer Institute Medical Oncology Grant program 2015, as well as the Melton Family Fund for CLL Research and the Susan and Gary Rosenbach Fund for Lymphoma Research. This work was supported in part by a grant from the National Institutes of Health, National Cancer Institute (P01-CA81534) of the CLL Research Consortium (L.R. and T.J.K.). NR 37 TC 21 Z9 20 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 JUL 14 PY 2016 VL 128 IS 2 BP 195 EP 203 DI 10.1182/blood-2016-03-707133 PG 9 WC Hematology SC Hematology GA DW7KQ UT WOS:000383830000011 PM 27247136 ER PT J AU Kim, PG Canver, MC Rhee, C Ross, SJ Harriss, JV Tu, HC Orkin, SH Tucker, HO Daley, GQ AF Kim, Peter Geon Canver, Matthew C. Rhee, Catherine Ross, Samantha J. Harriss, June V. Tu, Ho-Chou Orkin, Stuart H. Tucker, Haley O. Daley, George Q. TI Interferon-alpha signaling promotes embryonic HSC maturation SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; DEFINITIVE HEMATOPOIESIS; AORTIC ENDOTHELIUM; IN-VIVO; DEPENDENCE DISTINGUISHES; PROGENITOR CELLS; BINDING PROTEIN; FETAL LIVER; MOUSE; EXPRESSION AB In the developing mouse embryo, the first hematopoietic stem cells (HSCs) arise in the aorta-gonad-mesonephros (AGM) and mature as they transit through the fetal liver (FL). Compared with FL and adult HSCs, AGM HSCs have reduced repopulation potential in irradiated adult transplant recipients but mechanisms underlying this deficiency in AGM HSCs are poorly understood. By co-expression gene network analysis, we deduced that AGM HSCs show lower levels of interferon-alpha (IFN-alpha)/Jak-Stat1-associated gene expression than FL HSCs. Treatment of AGM HSCs with IFN-alpha enhanced long-term hematopoietic engraftment and donor chimerism. Conversely, IFN-alpha receptor-deficient AGMs (Ifnar1(-/-)), had significantly reduced donor chimerism. We identify adenine-thymine-rich interactive domain-3a (Arid3a), a factor essential for FL and B lymphopoiesis, as a key transcriptional co-regulator of IFN-alpha/Stat1 signaling. Arid3a occupies the genomic loci of Stat1 as well as several IFN-alpha effector genes, acting to regulate their expression. Accordingly, Arid3a(-/-) AGM HSCs had significantly reduced transplant potential, which was rescued by IFN-alpha treatment. Our results implicate the inflammatory IFN-alpha/Jak-Stat pathway in the developmental maturation of embryonic HSCs, whose manipulation may lead to increased potency of reprogrammed HSCs for transplantation. C1 [Kim, Peter Geon; Canver, Matthew C.; Ross, Samantha J.; Tu, Ho-Chou; Orkin, Stuart H.; Daley, George Q.] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA USA. [Kim, Peter Geon; Canver, Matthew C.; Ross, Samantha J.; Tu, Ho-Chou; Orkin, Stuart H.; Daley, George Q.] Harvard Med Sch, Harvard Stem Cell Inst, Howard Hughes Med Inst, Dana Farber Canc Inst, Boston, MA USA. [Kim, Peter Geon; Ross, Samantha J.; Tu, Ho-Chou; Daley, George Q.] Boston Childrens Hosp, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA USA. [Kim, Peter Geon; Ross, Samantha J.; Tu, Ho-Chou; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kim, Peter Geon; Ross, Samantha J.; Tu, Ho-Chou; Daley, George Q.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. [Rhee, Catherine; Harriss, June V.; Tucker, Haley O.] Univ Texas Austin, Inst Cellular & Mol Biol, Dept Mol Biosci, Austin, TX 78712 USA. RP Daley, GQ (reprint author), Boston Childrens Hosp, Howard Hughes Med Inst, Karp Family Res Bldg,7th Floor,300 Longwood Ave, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu FU National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [R24-DK092760]; National Heart, Lung, and Blood Institute Progenitor Cell Biology Consortium [UO1-HL100001]; Doris Duke Medical Foundation; National Institutes of Health National Cancer Institute [RO1CA31534]; Cancer Prevention and Research Institute of Texas [RP120459]; Marie Betzner Morrow Centennial Endowment; Center of Excellence in Molecular Hematology [P01HL032262, P30DK049216] FX G.Q.D. is supported by grants from the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (R24-DK092760), the National Heart, Lung, and Blood Institute Progenitor Cell Biology Consortium (UO1-HL100001), and the Doris Duke Medical Foundation. G.Q.D. is an associate member of the Broad Institute, and an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. H.O.T. is supported by grants from the National Institutes of Health National Cancer Institute (RO1CA31534), the Cancer Prevention and Research Institute of Texas (RP120459), and the Marie Betzner Morrow Centennial Endowment. S.H.O. is supported by the Center of Excellence in Molecular Hematology (P01HL032262 and P30DK049216). NR 66 TC 4 Z9 4 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 JUL 14 PY 2016 VL 128 IS 2 BP 204 EP 216 DI 10.1182/blood-2016-01-689281 PG 13 WC Hematology SC Hematology GA DW7KQ UT WOS:000383830000012 PM 27095787 ER PT J AU Matthews, JM Bhatt, S Patricelli, MP Nomanbhoy, TK Jiang, XY Natkunam, Y Gentles, AJ Martinez, E Zhu, DX Chapman, JR Cortizas, E Shyam, R Chinichian, S Advani, R Tan, L Zhang, JM Choi, HG Tibshirani, R Buhrlage, SJ Gratzinger, D Verdun, R Gray, NS Lossos, IS AF Matthews, Julie Marie Bhatt, Shruti Patricelli, Matthew P. Nomanbhoy, Tyzoon K. Jiang, Xiaoyu Natkunam, Yasodha Gentles, Andrew J. Martinez, Ezequiel Zhu, Daxing Chapman, Jennifer Rose Cortizas, Elena Shyam, Ragini Chinichian, Shideh Advani, Ranjana Tan, Li Zhang, Jianming Choi, Hwan Geun Tibshirani, Robert Buhrlage, Sara J. Gratzinger, Dita Verdun, Ramiro Gray, Nathanael S. Lossos, Izidore S. TI Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma SO BLOOD LA English DT Article ID ACTIVATION; EXPRESSION; RECEPTOR; SURVIVAL; CHEMOTHERAPY; INHIBITOR; PATHWAYS; CHOP; PATHOGENESIS; MUTATIONS AB Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, yet 40% to 50% of patients will eventually succumb to their disease, demonstrating a pressing need for novel therapeutic options. Gene expression profiling has identified messenger RNAs that lead to transformation, but critical events transforming cells are normally executed by kinases. Therefore, we hypothesized that previously unrecognized kinases may contribute to DLBCL pathogenesis. We performed the first comprehensive analysis of global kinase activity in DLBCL, to identify novel therapeutic targets, and discovered that germinal center kinase (GCK) was extensively activated. GCK RNA interference and small molecule inhibition induced cell-cycle arrest and apoptosis in DLBCL cell lines and primary tumors in vitro and decreased the tumor growth rate in vivo, resulting in a significantly extended lifespan of mice bearing DLBCL xenografts. GCK expression was also linked to adverse clinical outcome in a cohort of 151 primary DLBCL patients. These studies demonstrate, for the first time, that GCK is a molecular therapeutic target in DLBCL tumors and that inhibiting GCK may significantly extend DLBCL patient survival. Because the majority of DLBCL tumors (similar to 80%) exhibit activation of GCK, this therapy may be applicable to most patients. C1 [Matthews, Julie Marie; Jiang, Xiaoyu; Zhu, Daxing; Lossos, Izidore S.] Univ Miami, Dept Med, Sylvester Comprehens Canc Ctr, Div Hematol Oncol, Miami, FL USA. [Matthews, Julie Marie; Bhatt, Shruti; Lossos, Izidore S.] Univ Miami, Dept Mol & Cellular Pharmacol, Miami, FL USA. [Patricelli, Matthew P.; Nomanbhoy, Tyzoon K.] ActivX Biosci Inc, La Jolla, CA USA. [Natkunam, Yasodha; Gratzinger, Dita] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Gentles, Andrew J.] Stanford Univ, Sch Med, Ctr Canc Syst Biol, Stanford, CA 94305 USA. [Gentles, Andrew J.] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA. [Martinez, Ezequiel; Lossos, Izidore S.] Univ Miami, Dept Canc Biol, Miami, FL USA. [Chapman, Jennifer Rose] Univ Miami, Sylvester Comprehens Canc Ctr, Dept Pathol, Miami, FL USA. [Cortizas, Elena] Univ Miami, Dept Med, Sylvester Comprehens Canc Ctr, Div Gerontol & Geriatr Med, Miami, FL USA. [Shyam, Ragini; Chinichian, Shideh; Advani, Ranjana] Stanford Univ, Sch Med, Div Oncol, Stanford, CA 94305 USA. [Tan, Li; Zhang, Jianming; Gray, Nathanael S.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. [Tan, Li; Zhang, Jianming; Choi, Hwan Geun; Buhrlage, Sara J.; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Tibshirani, Robert] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Tibshirani, Robert] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. RP Lossos, IS (reprint author), Univ Miami, Sylvester Comprehens Canc Ctr, Div Hematol & Oncol, 1475 NW 12th Ave D8-4, Miami, FL 33136 USA. EM ilossos@med.miami.edu OI Gratzinger, Dita/0000-0002-9182-8123 FU Dwoskin Family Foundation; Recio Family Foundation; Anthony Rizzo Family Foundation; Greg Olsen Foundation; National Institutes of Health National Cancer Institute [CA173469-01]; Linde Family chemical biology funds; Lymphoma Research Foundation FX I.S.L. is supported by the Dwoskin Family, Recio Family, Anthony Rizzo Family, and Greg Olsen Foundations. N.S.G., S.B., and L.T. were supported by National Institutes of Health National Cancer Institute grant CA173469-01 and the Linde Family chemical biology funds.; This work was funded by Lymphoma Research Foundation (I.S.L. and N.S.G.). NR 42 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 JUL 14 PY 2016 VL 128 IS 2 BP 239 EP 248 DI 10.1182/blood-2016-02-696856 PG 10 WC Hematology SC Hematology GA DW7KQ UT WOS:000383830000015 PM 27151888 ER PT J AU Lin, JH Zhang, WH Zhao, JJ Kwart, AH Yang, C Ma, DD Ren, XB Tai, YT Anderson, KC Handin, RI Munshi, NC AF Lin, Jianhong Zhang, Weihong Zhao, Jian-Jun Kwart, Ariel H. Yang, Chun Ma, Dongdong Ren, Xiubao Tai, Yu-Tzu Anderson, Kenneth C. Handin, Robert I. Munshi, Nikhil C. TI A clinically relevant in vivo zebrafish model of human multiple myeloma to study preclinical therapeutic efficacy SO BLOOD LA English DT Article ID IMMUNE-SYSTEM; MOUSE MODEL; MATURATION; INHIBITOR AB Patient-derived multiple myeloma (MM) cells are difficult to establish in culture or propagate in vivo in murine model. Here, we describe a zebrafish xenograft model that permits rapid, reliable growth of human MM cells injected into the perivitelline space of albino zebrafish (Casper) embryos 48 hours postfertilization. MM1S and MM1R MM cell lines and primary CD138(+) MM cells were stained with CM-Dil red fluorescent dye and suspended in Matrigel prior to their injection. The cells grew at the site of injection and disseminated throughout the developing embryos and larvae. Tumor size was quantified by fluorescent microscopy, and cell fate was followed for 4 days. All of the cell line xenografts showed responses similar to those previously observed with in vitro assays. CD138(+) plasma cell xenografts derived from MM patients also grew and were inhibited by the same drugs patients had responded to clinically. Using this technique, we can assess drug sensitivity or resistance with a small number of MM cells in a short period. This raises the possibility that one might be able to assess drug sensitivity in real time with readily obtainable clinical samples. C1 [Lin, Jianhong; Zhang, Weihong; Zhao, Jian-Jun; Kwart, Ariel H.; Yang, Chun; Tai, Yu-Tzu; Anderson, Kenneth C.; Munshi, Nikhil C.] Harvard Med Sch, Dana Farber Canc Inst, Med Oncol, Boston, MA USA. [Lin, Jianhong; Zhang, Weihong; Kwart, Ariel H.; Yang, Chun; Tai, Yu-Tzu; Anderson, Kenneth C.; Munshi, Nikhil C.] Harvard Med Sch, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Boston, MA USA. [Lin, Jianhong; Zhang, Weihong; Kwart, Ariel H.; Yang, Chun; Tai, Yu-Tzu; Anderson, Kenneth C.; Munshi, Nikhil C.] Harvard Med Sch, Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma Res, Boston, MA USA. [Zhang, Weihong; Ren, Xiubao] Tianjin Med Univ, Canc Inst & Hosp, Natl Clin Res Ctr Canc, Biotherapy Ctr,Key Lab Canc Immunol & Biotherapy, Tianjin, Peoples R China. [Yang, Chun] Haerbin Med Univ, Hosp 4, Dept Clin Lab, Harbin, Heilongjiang, Peoples R China. [Ma, Dongdong; Handin, Robert I.] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. [Munshi, Nikhil C.] VA Boston Healthcare Syst, Boston, MA USA. RP Munshi, NC (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA.; Handin, RI (reprint author), Brigham & Womens Hosp, Div Hematol, Karp Family Res Bldg,Room 6210, Boston, MA 02115 USA. EM rhandin@partners.org; nikhil_munshi@dfci.harvard.edu FU Veterans Administration [I01-BX001584]; National Institutes of Health, National Cancer Institute [R01-124929, P50-100007, P01-78378, P01-155258, R01-50947]; Leukemia Society of America; Dana-Farber/Harvard Cancer Center Specialized Programs of Research Excellence in Multiple Myeloma Career Development Award FX This work was supported in part by grants from the Veterans Administration (I01-BX001584), National Institutes of Health, National Cancer Institute (R01-124929; P50-100007, P01-78378, and P01-155258 [N.C.M. and K.C.A.]; and R01-50947 [K.C.A.]), and Leukemia Society of America (N.C.M.); and by a Dana-Farber/Harvard Cancer Center Specialized Programs of Research Excellence in Multiple Myeloma Career Development Award (J.L.). K.C.A. is an American Cancer Society Clinical Research Professor. NR 13 TC 0 Z9 0 U1 2 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 JUL 14 PY 2016 VL 128 IS 2 BP 249 EP 252 DI 10.1182/blood-2016-03-704460 PG 4 WC Hematology SC Hematology GA DW7KQ UT WOS:000383830000016 PM 27207793 ER PT J AU Hoggatt, J AF Hoggatt, Jonathan TI Gene Therapy for "Bubble Boy" Disease SO CELL LA English DT Editorial Material C1 [Hoggatt, Jonathan] Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02129 USA. [Hoggatt, Jonathan] Massachusetts Gen Hosp, Ctr Transplantat Sci, Boston, MA 02129 USA. RP Hoggatt, J (reprint author), Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02129 USA.; Hoggatt, J (reprint author), Massachusetts Gen Hosp, Ctr Transplantat Sci, Boston, MA 02129 USA. EM hoggatt.jonathan@mgh.harvard.edu NR 0 TC 1 Z9 1 U1 0 U2 0 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 JUL 14 PY 2016 VL 166 IS 2 BP 263 EP 263 DI 10.1016/j.cell.2016.06.049 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DR9ZR UT WOS:000380255400002 PM 27419862 ER PT J AU Long, JZ Svensson, KJ Bateman, LA Lin, H Kamenecka, T Lokurkar, IA Lou, J Rao, RR Chang, MR Jedrychowski, MP Paulo, JA Gygi, SP Griffin, PR Nomura, DK Spiegelman, BM AF Long, Jonathan Z. Svensson, Katrin J. Bateman, Leslie A. Lin, Hua Kamenecka, Theodore Lokurkar, Isha A. Lou, Jesse Rao, Rajesh R. Chang, Mi Ra Jedrychowski, Mark P. Paulo, Joao A. Gygi, Steven P. Griffin, Patrick R. Nomura, Daniel K. Spiegelman, Bruce M. TI The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria SO CELL LA English DT Article ID BROWN ADIPOSE-TISSUE; BEIGE FAT; THERMOGENESIS; MICE; ABLATION; IDENTIFICATION; DIPEPTIDASE; PROTEINS; OBESITY; PRDM16 AB Brown and beige adipocytes are specialized cells that express uncoupling protein 1 ( UCP1) and dissipate chemical energy as heat. These cells likely possess alternative UCP1-independent thermogenic mechanisms. Here, we identify a secreted enzyme, peptidase M20 domain containing 1 ( PM20D1), that is enriched in UCP1(+) versus UCP1(-) adipocytes. We demonstrate that PM20D1 is a bidirectional enzyme in vitro, catalyzing both the condensation of fatty acids and amino acids to generate N-acyl amino acids and also the reverse hydrolytic reaction. N-acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. Mice with increased circulating PM20D1 have augmented respiration and increased N-acyl amino acids in blood. Lastly, administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure. These data identify an enzymatic node and a family of metabolites that regulate energy homeostasis. This pathway might be useful for treating obesity and associated disorders. C1 [Long, Jonathan Z.; Svensson, Katrin J.; Lokurkar, Isha A.; Lou, Jesse; Rao, Rajesh R.; Jedrychowski, Mark P.; Spiegelman, Bruce M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Long, Jonathan Z.; Svensson, Katrin J.; Rao, Rajesh R.; Jedrychowski, Mark P.; Paulo, Joao A.; Gygi, Steven P.; Spiegelman, Bruce M.] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Bateman, Leslie A.; Nomura, Daniel K.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. [Bateman, Leslie A.; Nomura, Daniel K.] Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. [Bateman, Leslie A.; Nomura, Daniel K.] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Lin, Hua; Kamenecka, Theodore; Chang, Mi Ra; Griffin, Patrick R.] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA. [Rao, Rajesh R.] Novartis Res Fdn GNF, Genom Inst, San Diego, CA 92121 USA. RP Spiegelman, BM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.; Spiegelman, BM (reprint author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.; Nomura, DK (reprint author), Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA.; Nomura, DK (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA.; Nomura, DK (reprint author), Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. EM dnomura@berkeley.edu; bruce_spiegelman@dfci.harvard.edu FU NIH [DK105203, DK098285, R01CA172667, DK5447, DK31405]; Swedish Research Council [PE2013/613]; American Cancer Society [RSG14-242-01-TBE]; JPB Foundation FX We thank Marc Kirschner for many critical discussions as well as members of the B.M.S., D.K.N., and P.R.G. labs for helpful comments. We are grateful to Julie J. Johnson and Arbansjit Sandhu at the University of Pennsylvania Vector Core for AAV production. This work was supported by grants to J.Z.L. (NIH DK105203), K.J.S. (Swedish Research Council Postdoctoral Fellowship PE2013/613), J.A.P. (NIH DK098285), D.K.N. (American Cancer Society Research Scholar Award RSG14-242-01-TBE and NIH R01CA172667), and B.M.S. (NIH DK5447, DK31405 and the JPB Foundation). B.M.S. is a consultant for Calico Life Sciences, LLC. NR 30 TC 7 Z9 7 U1 8 U2 16 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 JUL 14 PY 2016 VL 166 IS 2 BP 424 EP 435 DI 10.1016/j.cell.2016.05.071 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DR9ZR UT WOS:000380255400019 PM 27374330 ER PT J AU Vidadala, RSR Rivas, KL Ojo, KK HuIverson, MA Zambriski, JA Bruzual, I Schultz, TL Huang, WL Zhang, ZS Scheele, S DeRocher, AE Choi, R Barrett, LK Siddaramaiah, LK Hol, WGJ Fan, EK Merritt, EA Parsons, M Freiberg, G Marsh, K Kempf, DJ Carruthers, VB Isoherranen, N Doggett, JS Van Voorhis, WC Maly, DJ AF Vidadala, Rama Subba Rao Rivas, Kasey L. Ojo, Kayode K. HuIverson, Matthew A. Zambriski, Jennifer A. Bruzual, Igor Schultz, Tracey L. Huang, Wenlin Zhang, Zhongsheng Scheele, Suzanne DeRocher, Amy E. Choi, Ryan Barrett, Lynn K. Siddaramaiah, Latha Kallur Hol, Wim G. J. Fan, Erkang Merritt, Ethan A. Parsons, Marilyn Freiberg, Gail Marsh, Kennan Kempf, Dale J. Carruthers, Vern B. Isoherranen, Nina Doggett, J. Stone Van Voorhis, Wesley C. Maly, Dustin J. TI Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SELECTIVE INHIBITORS; C. PARVUM; T. GONDII; IN-VITRO; POTENT; INFECTION; CDPK1; DRUG; TRANSMISSION; DISCOVERY AB New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy. C1 [Huang, Wenlin; Zhang, Zhongsheng; Siddaramaiah, Latha Kallur; Hol, Wim G. J.; Fan, Erkang; Merritt, Ethan A.; Maly, Dustin J.] Univ Washington, Dept Biochem, Seattle, WA 98195 USA. [Rivas, Kasey L.; Ojo, Kayode K.; HuIverson, Matthew A.; Choi, Ryan; Barrett, Lynn K.; Van Voorhis, Wesley C.] Univ Washington, Dept Med, Div Allergy & Infect Dis, Seattle, WA 98109 USA. [Rivas, Kasey L.; Ojo, Kayode K.; HuIverson, Matthew A.; Choi, Ryan; Barrett, Lynn K.; Van Voorhis, Wesley C.] Univ Washington, Ctr Emerging & Re Emerging Infect Dis CERID, Seattle, WA 98109 USA. [Vidadala, Rama Subba Rao; Parsons, Marilyn; Maly, Dustin J.] Univ Washington, Dept Chem, Seattle, WA 98195 USA. [Scheele, Suzanne; DeRocher, Amy E.; Parsons, Marilyn] Seattle Biomed Res Inst, Ctr Infect Dis Res, 4 Nickerson St, Seattle, WA 98109 USA. [Parsons, Marilyn; Van Voorhis, Wesley C.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Bruzual, Igor; Doggett, J. Stone] Portland VA Med Ctr, Portland, OR 97239 USA. [Zambriski, Jennifer A.] Washington State Univ, Paul G Allen Sch Global Anim Hlth, Coll Vet Med, Pullman, WA 99164 USA. [Schultz, Tracey L.; Carruthers, Vern B.] Univ Michigan, Dept Microbiol & Immunol, Sch Med, Ann Arbor, MI 48109 USA. [Isoherranen, Nina] Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA. [Freiberg, Gail; Marsh, Kennan; Kempf, Dale J.] AbbVie, N Chicago, IL 60064 USA. RP Maly, DJ (reprint author), Univ Washington, Dept Biochem, Seattle, WA 98195 USA.; Van Voorhis, WC (reprint author), Univ Washington, Dept Med, Div Allergy & Infect Dis, Seattle, WA 98109 USA.; Van Voorhis, WC (reprint author), Univ Washington, Ctr Emerging & Re Emerging Infect Dis CERID, Seattle, WA 98109 USA.; Maly, DJ (reprint author), Univ Washington, Dept Chem, Seattle, WA 98195 USA.; Van Voorhis, WC (reprint author), Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. EM wesley@uw.edu; maly@chem.washington.edu OI Parsons, Marilyn/0000-0003-3994-8096 FU National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Human Development of the National Institutes of Health [R01GM086858, R01AI089441, R01AI111341, R01HD080670]; United States Department of Agriculture [2014-06183]; United States Department of Veterans Affairs Biomedical Laboratory Research and Development [BX002440]; Stanley Medical Research Institute [07R1857]; U.S. Department of Energy Office of Basic Energy Sciences [DE-AC02-76SF00515]; National Institutes of Health [P41GM103393] FX We thank DeAnne Stolarik (AbbVie) and Lance Heinle (AbbVie) for assistance with the dog and monkey PK studies. Research reported in this publication was supported by the National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, and National Institute of Child Health and Human Development of the National Institutes of Health under Awards R01GM086858, R01AI089441, R01AI111341, and R01HD080670. This work was also supported in part by Award 2014-06183 from the United States Department of Agriculture, by Career Development Award BX002440 from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development, and by Award 07R1857 from the Stanley Medical Research Institute. Crystallography performed in support of the work benefitted from remote access to resources at the Stanford Synchrotron Radiation Lightsource supported by the U.S. Department of Energy Office of Basic Energy Sciences under Contract DE-AC02-76SF00515 and by the National Institutes of Health (Grant P41GM103393). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 36 TC 7 Z9 7 U1 7 U2 12 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 JUL 14 PY 2016 VL 59 IS 13 BP 6531 EP 6546 DI 10.1021/acs.jmedchem.6b00760 PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA DR6CN UT WOS:000379989800040 PM 27309760 ER PT J AU Powers, JT Tsanov, KM Pearson, DS Roels, F Spina, CS Ebright, R Seligson, M de Soysa, Y Cahan, P Theissen, J Tu, HC Han, A Kurek, KC LaPier, GS Osborne, JK Ross, SJ Cesana, M Collins, JJ Berthold, F Daley, GQ AF Powers, John T. Tsanov, Kaloyan M. Pearson, Daniel S. Roels, Frederik Spina, Catherine S. Ebright, Richard Seligson, Marc de Soysa, Yvanka Cahan, Patrick Theissen, Jessica Tu, Ho-Chou Han, Areum Kurek, Kyle C. LaPier, Grace S. Osborne, Jihan K. Ross, Samantha J. Cesana, Marcella Collins, James J. Berthold, Frank Daley, George Q. TI Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma SO NATURE LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; COMPETITIVE ENDOGENOUS RNA; GENE-EXPRESSION; N-MYC; CANCER; TUMOR; LIN28B; CELLS; MIRNA; AMPLIFICATION AB Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis. C1 [Powers, John T.; Tsanov, Kaloyan M.; Pearson, Daniel S.; Ebright, Richard; Seligson, Marc; de Soysa, Yvanka; Cahan, Patrick; Tu, Ho-Chou; Han, Areum; LaPier, Grace S.; Osborne, Jihan K.; Ross, Samantha J.; Cesana, Marcella; Daley, George Q.] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Roels, Frederik; Theissen, Jessica; Berthold, Frank] Univ Hosp Koln, Dept Pediat Oncol, D-50937 Cologne, Germany. [Spina, Catherine S.; Collins, James J.] Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Kurek, Kyle C.] Boston Childrens Hosp, Dept Pathol, Boston, MA 02215 USA. [Collins, James J.] Broad Inst MIT & Harvard, MIT, Dept Biol Engn, Cambridge, MA 02142 USA. [Daley, George Q.] Dana Farber Canc Inst, Stem Cell Transplantat Program, Boston, MA 02115 USA. [Daley, George Q.] Boston Childrens Hosp, Boston, MA 02115 USA. [Daley, George Q.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Daley, George Q.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Daley, GQ (reprint author), Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA.; Daley, GQ (reprint author), Dana Farber Canc Inst, Stem Cell Transplantat Program, Boston, MA 02115 USA.; Daley, GQ (reprint author), Boston Childrens Hosp, Boston, MA 02115 USA.; Daley, GQ (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA.; Daley, GQ (reprint author), Harvard Stem Cell Inst, Cambridge, MA 02138 USA. EM george.daley@childrens.harvard.edu FU National Institutes of Health [R01GM107536]; Alex's Lemonade Stand Foundation; Ellison Medical Foundation; National Institute of General Medical Sciences [T32GM007753] FX G.Q.D. is supported by National Institutes of Health grant R01GM107536, Alex's Lemonade Stand Foundation, and the Ellison Medical Foundation. G.Q.D. is an affiliate member of the Broad Institute, and an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. J.T.P. was supported by Alex's Lemonade Stand Foundation. K.M.T. was supported as a Howard Hughes Medical Institute International Student Research Fellow and as a Herchel Smith Graduate Fellow. D.S.P. and R.E. were supported by award number T32GM007753 from the National Institute of General Medical Sciences. NR 58 TC 7 Z9 8 U1 16 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUL 14 PY 2016 VL 535 IS 7611 BP 246 EP U112 DI 10.1038/nature18632 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR4ZN UT WOS:000379912600049 PM 27383785 ER PT J AU Debruyne, DN Bhatnagar, N Sharma, B Luther, W Moore, NF Cheung, K Gray, NS George, RE AF Debruyne, D. N. Bhatnagar, N. Sharma, B. Luther, W. Moore, N. F. Cheung, K. Gray, N. S. George, R. E. TI ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT SO ONCOGENE LA English DT Article ID RECEPTOR TYROSINE KINASE; GENE-EXPRESSION SIGNATURE; CANCER-CELLS; LUNG-CANCER; BREAST-CANCER; THERAPEUTIC TARGET; PROLONGS SURVIVAL; MUTATIONS; GROWTH; EGFR AB The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALK(F1174L). Here we demonstrate acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation conferred TAE684 resistance to NB cells through upregulated extracellular signal-regulated kinase (ERK) signaling. Inhibition of AXL partly rescued TAE684 resistance, resensitizing these cells to this compound. AXL activation in resistant cells was mediated through increased expression of the active form of its ligand, GAS6, that also served to stabilize the AXL protein. Although ectopic expression of AXL and TWIST2 individually in TAE684-sensitive parental cells led to the elevated expression of mesenchymal markers and invasive capacity, only AXL overexpression induced resistance to TAE684 as well. TAE684-resistant cells showed greater sensitivity to HSP90 inhibition than did their parental counterparts, with downregulation of AXL and AXL-mediated ERK signaling. Our studies indicate that aberrant AXL signaling and development of an EMT phenotype underlie resistance of ALK(F1174L)-driven NB cells to TAE684 and its derivatives. We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay the emergence of such resistance. C1 [Debruyne, D. N.; Bhatnagar, N.; Sharma, B.; Luther, W.; Moore, N. F.; George, R. E.] Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. [Debruyne, D. N.; Bhatnagar, N.; Sharma, B.; Luther, W.; Moore, N. F.; George, R. E.] Boston Childrens Hosp, Boston, MA USA. [Cheung, K.] Mem Sloan Kettering Canc Ctr, Dept Pediat Oncol, 1275 York Ave, New York, NY 10021 USA. [Gray, N. S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Gray, N. S.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. [George, R. E.] Harvard Med Sch, Dept Pediat, Boston, MA USA. RP George, RE (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Dana 640E,450 Brookline Ave, Boston, MA 02215 USA. EM rani_george@dfci.harvard.edu FU NIH/NCI [R01 CA148688]; Friends for Life Neuroblastoma Fellowship; Ruth L Kirschstein NRSA [F32CA183566] FX This study was supported by NIH/NCI R01 CA148688 (to REG), Friends for Life Neuroblastoma Fellowship (to DND) and a Ruth L Kirschstein NRSA F32CA183566 (to NFM). NR 47 TC 7 Z9 7 U1 1 U2 1 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 JUL 14 PY 2016 VL 35 IS 28 BP 3681 EP 3691 DI 10.1038/onc.2015.434 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DR0UQ UT WOS:000379622800007 PM 26616860 ER PT J AU Kussman, BD Aasted, CM Yucel, MA Steele, SC Alexander, ME Boas, DA Borsook, D Becerra, L AF Kussman, Barry D. Aasted, Christopher M. Yucel, Meryem A. Steele, Sarah C. Alexander, Mark E. Boas, David A. Borsook, David Becerra, Lino TI Capturing Pain in the Cortex during General Anesthesia: Near Infrared Spectroscopy Measures in Patients Undergoing Catheter Ablation of Arrhythmias SO PLOS ONE LA English DT Article ID MEDIAL PREFRONTAL CORTEX; CEREBRAL-BLOOD-FLOW; POSTTRAUMATIC-STRESS-DISORDER; POSITRON-EMISSION-TOMOGRAPHY; DIFFUSE OPTICAL TOMOGRAPHY; PULMONARY VEIN ISOLATION; FRONTAL-CORTEX; RADIOFREQUENCY ABLATION; BRAIN ACTIVATION; CENTRAL SENSITIZATION AB The predictability of pain makes surgery an ideal model for the study of pain and the development of strategies for analgesia and reduction of perioperative pain. As functional near-infrared spectroscopy reproduces the known functional magnetic resonance imaging activations in response to a painful stimulus, we evaluated the feasibility of functional near-infrared spectroscopy to measure cortical responses to noxious stimulation during general anesthesia. A multichannel continuous wave near-infrared imager was used to measure somatosensory and frontal cortical activation in patients undergoing catheter ablation of arrhythmias under general anesthesia. Anesthetic technique was standardized and intra-operative NIRS signals recorded continuously with markers placed in the data set for the timing and duration of each cardiac ablation event. Frontal cortical signals only were suitable for analysis in five of eight patients studied (mean age 14 +/- 1 years, weight 66.7 +/- 17.6 kg, 2 males). Thirty ablative lesions were recorded for the five patients. Radiofrequency or cryoablation was temporally associated with a hemodynamic response function in the frontal cortex characterized by a significant decrease in oxyhemoglobin concentration (paired t-test, p<0.05) with the nadir occurring in the period 4 to 6 seconds after application of the ablative lesion. Cortical signals produced by catheter ablation of arrhythmias in patients under general anesthesia mirrored those seen with noxious stimulation in awake, healthy volunteers, during sedation for colonoscopy, and functional Magnetic Resonance Imaging activations in response to pain. This study demonstrates the feasibility and potential utility of functional near-infrared spectroscopy as an objective measure of cortical activation under general anesthesia. C1 [Kussman, Barry D.; Aasted, Christopher M.; Steele, Sarah C.; Borsook, David; Becerra, Lino] Harvard Med Sch, Ctr Pain & Brain, Boston, MA 02115 USA. [Kussman, Barry D.; Aasted, Christopher M.; Steele, Sarah C.; Borsook, David; Becerra, Lino] Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Kussman, Barry D.; Aasted, Christopher M.; Yucel, Meryem A.; Steele, Sarah C.; Alexander, Mark E.; Boas, David A.; Borsook, David; Becerra, Lino] Harvard Med Sch, Boston, MA 02115 USA. [Aasted, Christopher M.; Yucel, Meryem A.; Steele, Sarah C.; Boas, David A.; Borsook, David; Becerra, Lino] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, 32 Fruit St, Boston, MA 02114 USA. [Alexander, Mark E.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. RP Becerra, L (reprint author), Harvard Med Sch, Ctr Pain & Brain, Boston, MA 02115 USA.; Becerra, L (reprint author), Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA.; Becerra, L (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Becerra, L (reprint author), Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, 32 Fruit St, Boston, MA 02114 USA. EM Lino.Becerra@childrens.harvard.edu FU Mayday Foundation; Anesthesia Research Distinguished Trailblazer Award; National Institute of General Medical Science of the National Institutes of Health [R01GM104986] FX Research reported in this article was supported by the Mayday Foundation, the Anesthesia Research Distinguished Trailblazer Award, and the National Institute of General Medical Science of the National Institutes of Health under award number R01GM104986. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 66 TC 1 Z9 1 U1 5 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 JUL 14 PY 2016 VL 11 IS 7 AR e0158975 DI 10.1371/journal.pone.0158975 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR0DZ UT WOS:000379579500056 PM 27415436 ER PT J AU Lin, MV Sise, ME Pavlakis, M Amundsen, BM Chute, D Rutherford, AE Chung, RT Curry, MP Hanifi, JM Gabardi, S Chandraker, A Heher, EC Elias, N Riella, LV AF Lin, Ming V. Sise, Meghan E. Pavlakis, Martha Amundsen, Beth M. Chute, Donald Rutherford, Anna E. Chung, Raymond T. Curry, Michael P. Hanifi, Jasmine M. Gabardi, Steve Chandraker, Anil Heher, Eliot C. Elias, Nahel Riella, Leonardo V. TI Efficacy and Safety of Direct Acting Antivirals in Kidney Transplant Recipients with Chronic Hepatitis C Virus Infection SO PLOS ONE LA English DT Article ID RENAL-REPLACEMENT THERAPY; LIVER-TRANSPLANT; GENOTYPE 1; DISEASE; IMPACT; METAANALYSIS; SOFOSBUVIR; SURVIVAL; SIMEPREVIR; EXPERIENCE AB The prevalence of Hepatitis C Virus (HCV) infection is significantly higher in patients with end-stage renal disease compared to the general population and poses important clinical challenges in patients who undergo kidney transplantation. Historically, interferon-based treatment options have been limited by low rates of efficacy and significant side effects, including risk of precipitating rejection. Limited data exist on the use of all-oral, interferon-free direct-acting antiviral (DAA) therapies in kidney transplant recipients. In this study, we performed a retrospective chart review with prospective clinical follow-up of post-kidney transplant patients treated with DAA therapies at three major hospitals in Boston, MA. A total of 24 kidney recipients with HCV infection received all-oral DAA therapy post-transplant. Patients were predominantly male (79%) with a median age of 60 years (range 34-70 years), median creatinine of 1.2 mg/dL (0.66-1.76), and 42% had advanced fibrosis or cirrhosis. The majority had HCV genotype 1a infection (58%). All patients received full-dose sofosbuvir; it was paired with simeprevir (9 patients without and 3 patients with ribavirin), ledipasvir (7 patients without and 1 patient with ribavirin) or ribavirin alone (4 patients). The overall sustained virologic response (SVR12) was 91% (21 out of 23 patients). One patient achieved SVR4 but demised prior to SVR12 check point due to treatment unrelated cause. Two treatment failures were successfully retreated with alternative DAA regimens and achieved SVR. Both initials failures occurred in patients with advanced fibrosis or cirrhosis, with genotype 1a infection, and prior HCV treatment failure. Adverse events were reported in 11 patients (46%) and were managed clinically without discontinuation of therapy. Calcineurin inhibitor trough levels did not significantly change during therapy. In this multi-center series of patients, all-oral DAA therapy appears to be safe and effective in post-kidney transplant patients with chronic HCV infection. C1 [Lin, Ming V.; Rutherford, Anna E.] Harvard Med Sch, Brigham & Womens Hosp, Div Gastroenterol Hepatol & Endoscopy, Boston, MA 02115 USA. [Sise, Meghan E.; Heher, Eliot C.] Harvard Med Sch, Massachusetts Gen Hosp, Div Nephrol, Boston, MA USA. [Pavlakis, Martha] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA USA. [Amundsen, Beth M.; Heher, Eliot C.; Elias, Nahel] Harvard Med Sch, Massachusetts Gen Hosp, Div Transplant Surg, Boston, MA USA. [Chute, Donald; Chung, Raymond T.] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Liver, Div Gastroenterol, Boston, MA USA. [Curry, Michael P.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Gastroenterol & Hepatol, Boston, MA USA. [Hanifi, Jasmine M.] Harvard Med Sch, Brigham & Womens Hosp, Dept Internal Med, Boston, MA USA. [Gabardi, Steve; Chandraker, Anil; Riella, Leonardo V.] Harvard Med Sch, Brigham & Womens Hosp, Div Renal, Transplantat Res Ctr, Boston, MA USA. RP Lin, MV (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Gastroenterol Hepatol & Endoscopy, Boston, MA 02115 USA.; Riella, LV (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Div Renal, Transplantat Res Ctr, Boston, MA USA. EM mvlin@partners.org; lriella@bwh.harvard.edu OI Gabardi, Steven/0000-0001-8022-2751 NR 33 TC 6 Z9 7 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 14 PY 2016 VL 11 IS 7 AR e0158431 DI 10.1371/journal.pone.0158431 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR0DZ UT WOS:000379579500021 PM 27415632 ER PT J AU Davids, MS Kim, HT Bachireddy, P Costello, C Liguori, R Savell, A Lukez, AP Avigan, D Chen, YB McSweeney, P LeBoeuf, NR Rooney, MS Bowden, M Zhou, CSW Granter, SR Hornick, JL Rodig, SJ Hirakawa, M Severgnini, M Hodi, FS Wu, CJ Ho, VT Cutler, C Koreth, J Alyea, EP Antin, JH Armand, P Streicher, H Ball, ED Ritz, J Bashey, A Soiffer, RJ AF Davids, Matthew S. Kim, Haesook T. Bachireddy, Pavan Costello, Caitlin Liguori, Rebecca Savell, Alexandra Lukez, Alexander P. Avigan, David Chen, Yi-Bin McSweeney, Peter LeBoeuf, Nicole R. Rooney, Michael S. Bowden, Michaela Zhou, Chensheng W. Granter, Scott R. Hornick, Jason L. Rodig, Scott J. Hirakawa, Masahiro Severgnini, Mariano Hodi, F. Stephen Wu, Catherine J. Ho, Vincent T. Cutler, Corey Koreth, John Alyea, Edwin P. Antin, Joseph H. Armand, Philippe Streicher, Howard Ball, Edward D. Ritz, Jerome Bashey, Asad Soiffer, Robert J. CA Leukemia Lymphoma Soc Blood Canc R TI Ipilimumab for Patients with Relapse after Allogeneic Transplantation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID STEM-CELL TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; VERSUS-HOST-DISEASE; HEMATOLOGIC MALIGNANCIES; T-CELLS; BLOCKADE; CTLA-4; PATTERN; HLA AB BACKGROUND Loss of donor-mediated immune antitumor activity after allogeneic hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic cancers. We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte-associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect. METHODS We conducted a phase 1/1b multicenter, investigator-initiated study to determine the safety and efficacy of ipilimumab in patients with relapsed hematologic cancer after allogeneic HSCT. Patients received induction therapy with ipilimumab at a dose of 3 or 10 mg per kilogram of body weight every 3 weeks for a total of 4 doses, with additional doses every 12 weeks for up to 60 weeks in patients who had a clinical benefit. RESULTS A total of 28 patients were enrolled. Immune-related adverse events, including one death, were observed in 6 patients (21%), and graft-versus-host disease (GVHD) that precluded further administration of ipilimumab was observed in 4 patients (14%). No responses that met formal response criteria occurred in patients who received a dose of 3 mg per kilogram. Among 22 patients who received a dose of 10 mg per kilogram, 5 (23%) had a complete response, 2 (9%) had a partial response, and 6 (27%) had decreased tumor burden. Complete responses occurred in 4 patients with extramedullary acute myeloid leukemia and 1 patient with the myelodysplastic syndrome developing into acute myeloid leukemia. Four patients had a durable response for more than 1 year. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells in the blood. CONCLUSIONS Our early-phase data showed that administration of ipilimumab was feasible in patients with recurrent hematologic cancers after allogeneic HSCT, although immune-mediated toxic effects and GVHD occurred. Durable responses were observed in association with several histologic subtypes of these cancers, including extramedullary acute myeloid leukemia. C1 [Davids, Matthew S.; Kim, Haesook T.; Bachireddy, Pavan; Liguori, Rebecca; Savell, Alexandra; Lukez, Alexander P.; Hirakawa, Masahiro; Severgnini, Mariano; Hodi, F. Stephen; Wu, Catherine J.; Ho, Vincent T.; Cutler, Corey; Koreth, John; Alyea, Edwin P.; Antin, Joseph H.; Armand, Philippe; Ritz, Jerome; Soiffer, Robert J.] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. [Davids, Matthew S.; Kim, Haesook T.; Bachireddy, Pavan; Liguori, Rebecca; Savell, Alexandra; Lukez, Alexander P.; Avigan, David; Chen, Yi-Bin; Hirakawa, Masahiro; Severgnini, Mariano; Hodi, F. Stephen; Wu, Catherine J.; Ho, Vincent T.; Cutler, Corey; Koreth, John; Alyea, Edwin P.; Antin, Joseph H.; Armand, Philippe; Ritz, Jerome; Soiffer, Robert J.] Harvard Med Sch, Boston, MA USA. [Avigan, David] Beth Israel Deaconess Med Ctr, Bone Marrow Transplant Program, Boston, MA 02215 USA. [Chen, Yi-Bin] Massachusetts Gen Hosp, Ctr Canc, Bone Marrow Transplant Program, Boston, MA USA. [LeBoeuf, Nicole R.] Dana Farber & Brigham & Womens Canc Ctr, Dept Dermatol, Boston, MA USA. [Granter, Scott R.; Hornick, Jason L.; Rodig, Scott J.] Dana Farber & Brigham & Womens Canc Ctr, Dept Pathol, Boston, MA USA. [Bowden, Michaela; Zhou, Chensheng W.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Bachireddy, Pavan; Wu, Catherine J.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA. [Rooney, Michael S.] Neon Therapeut, Cambridge, MA USA. [Costello, Caitlin; Ball, Edward D.] Univ Calif San Diego, Blood & Marrow Transplant Program, Moores Canc Ctr, La Jolla, CA 92093 USA. [McSweeney, Peter] Colorado Blood Canc Inst, Denver, CO USA. [Streicher, Howard] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Bashey, Asad] Northside Hosp, Blood & Marrow Transplant Grp Georgia, Atlanta, GA USA. RP Davids, MS (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM matthew_davids@dfci.harvard.edu FU National Institutes of Health FX Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01822509. NR 22 TC 17 Z9 17 U1 3 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 JUL 14 PY 2016 VL 375 IS 2 BP 143 EP 153 DI 10.1056/NEJMoa1601202 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA DQ9KY UT WOS:000379530000007 PM 27410923 ER PT J AU Fenves, AZ Schaefer, PW Luther, J Pierce, VM AF Fenves, Andrew Z. Schaefer, Pamela W. Luther, Jay Pierce, Virginia M. TI Case 21-2016: A 32-Year-Old Man in an Unresponsive State SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HEPATITIS-B-VIRUS; ACUTE-LIVER-FAILURE; ACETAMINOPHEN; PREVALENCE; INFECTION; OUTCOMES; DISEASE; TESTS C1 [Fenves, Andrew Z.; Luther, Jay] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Schaefer, Pamela W.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. [Pierce, Virginia M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Fenves, Andrew Z.; Luther, Jay] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Schaefer, Pamela W.] Harvard Med Sch, Dept Radiol, Boston, MA USA. [Pierce, Virginia M.] Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Fenves, AZ (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA.; Fenves, AZ (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. NR 27 TC 0 Z9 0 U1 3 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 14 PY 2016 VL 375 IS 2 BP 163 EP 171 DI 10.1056/NEJMcpc1600838 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DQ9KY UT WOS:000379530000011 PM 27410926 ER PT J AU Birrer, MJ AF Birrer, Michael J. TI Premedicate with the Standard Regimen (Aprepitant, Ondansetron, and Dexamethasone) SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Birrer, Michael J.] Massachusetts Gen Hosp, Gynecol Oncol Res Program, Boston, MA 02114 USA. RP Birrer, MJ (reprint author), Massachusetts Gen Hosp, Gynecol Oncol Res Program, 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 JUL 14 PY 2016 VL 375 IS 2 BP 177 EP 178 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DQ9KY UT WOS:000379530000015 ER PT J AU Sepulcre, J Schultz, AP Sabuncu, M Gomez-Isla, T Chhatwal, J Becker, A Sperling, R Johnson, KA AF Sepulcre, Jorge Schultz, Aaron P. Sabuncu, Mert Gomez-Isla, Teresa Chhatwal, Jasmeer Becker, Alex Sperling, Reisa Johnson, Keith A. TI In Vivo Tau, Amyloid, and Gray Matter Profiles in the Aging Brain SO JOURNAL OF NEUROSCIENCE LA English DT Article DE aging; Alzheimer's disease; amyloid; gray matter; Tau ID EARLY ALZHEIMERS-DISEASE; POSITRON-EMISSION-TOMOGRAPHY; PITTSBURGH COMPOUND-B; MILD AD DEMENTIA; NEURODEGENERATIVE DISEASES; NEUROPATHOLOGIC ASSESSMENT; NEUROFIBRILLARY CHANGES; CORTICAL SIGNATURE; CEREBRAL-CORTEX; BETA AB We provide a comparative in vivo examination of the brain network-based distribution of two hallmarks of Alzheimer's disease (AD) pathology in cognitively normal individuals: (1) Tau, detected with a novel positron emission tomography (PET) tracer known as F-18-AV-1451; and (2) amyloid-beta, quantified with C-11-PiB PET. We used a high-resolution graph-based approach to investigate local-to-local and local-to-distributed cortical associations between the maps of Tau, amyloid-beta, and gray matter intensity. Our study shows that Tau and amyloid-beta deposits are associated with distinctive spatial patterns of brain tissue loss. Moreover, Tau and amyloid-beta accumulations have strong network interdigitations in heteromodal and associative areas of the cortical mantle, particularly the inferior-lateral temporal lobe. These findings contribute significantly to our understanding of how these two main hallmarks of AD pathology propagate across the elderly human brain. C1 [Sepulcre, Jorge; Becker, Alex; Johnson, Keith A.] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Gomez-Isla, Teresa; Sperling, Reisa; Johnson, Keith A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Gomez-Isla, Teresa; Sperling, Reisa; Johnson, Keith A.] Harvard Med Sch, Boston, MA 02114 USA. [Sepulcre, Jorge; Schultz, Aaron P.; Sabuncu, Mert; Chhatwal, Jasmeer; Sperling, Reisa] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Sperling, Reisa; Johnson, Keith A.] Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, Boston, MA 02115 USA. [Sperling, Reisa; Johnson, Keith A.] Harvard Med Sch, Boston, MA 02115 USA. RP Sepulcre, J (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, 149 13th St,Suite 5-209, Charlestown, MA 02129 USA. EM sepulcre@nmr.mgh.harvard.edu FU National Institutes of Health [K23-EB019023, R01-AG046396, R01-AG027435-S1, P50-AG00513421, P01-AG036694, K25-EB013649, K23-AG049087]; Massachusetts Alzheimer's Disease Research Center, Alzheimer's Association [NIRG-11-205690, IIRG-06-32444, ZEN-10-174210]; Bright-Focus Foundation/American Health Assistance Foundation [A2012333, A2013003]; American Brain Foundation/American Academy of Neurology FX This research was supported by National Institutes of Health Grants K23-EB019023 (J.S.), R01-AG046396 (K.A.J.), R01-AG027435-S1 (R.A.S. and K.A.J.), P50-AG00513421 (K.A.J. and R.A.S.), P01-AG036694 (R.A.S. and K.A.J.), K25-EB013649 (M.R.S.), and K23-AG049087 (J.P.C.), Massachusetts Alzheimer's Disease Research Center, Alzheimer's Association Grants NIRG-11-205690 (J.S.), IIRG-06-32444 (R.A.S. and K.A.J.), and ZEN-10-174210 (K.A.J.), Bright-Focus Foundation/American Health Assistance Foundation Grants A2012333 (M.R.S.) and A2013003 (J.P.C.), and the American Brain Foundation/American Academy of Neurology (J.P.C.). We thank the investigators and staff of the Harvard Aging Brain Study and the Massachusetts Alzheimer's Disease Research Center, the individual research participants, and their families and caregivers. We also thank the PET Core of Massachusetts General Hospital, and the Athinoula A. Martinos Center for imaging support. NR 65 TC 7 Z9 8 U1 2 U2 7 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 JUL 13 PY 2016 VL 36 IS 28 BP 7364 EP 7374 DI 10.1523/JNEUROSCI.0639-16.2016 PG 11 WC Neurosciences SC Neurosciences & Neurology GA DS1ST UT WOS:000380380500005 PM 27413148 ER PT J AU Shaw, KA Bertha, M Hofmekler, T Chopra, P Vatanen, T Srivatsa, A Prince, J Kumar, A Sauer, C Zwick, ME Satten, GA Kostic, AD Mulle, JG Xavier, RJ Kugathasan, S AF Shaw, Kelly A. Bertha, Madeline Hofmekler, Tatyana Chopra, Pankaj Vatanen, Tommi Srivatsa, Abhiram Prince, Jarod Kumar, Archana Sauer, Cary Zwick, Michael E. Satten, Glen A. Kostic, Aleksandar D. Mulle, Jennifer G. Xavier, Ramnik J. Kugathasan, Subra TI Dysbiosis, inflammation, and response to treatment: a longitudinal study of pediatric subjects with newly diagnosed inflammatory bowel disease SO GENOME MEDICINE LA English DT Article DE Inflammatory bowel disease; Microbiome; Crohn's disease; Dysbiosis ID CROHNS-DISEASE; ULCERATIVE-COLITIS; ACTIVITY INDEX; FUSOBACTERIUM-NECROPHORUM; BACTERIAL DIVERSITY; GUT MICROBIOTA; HOST GENETICS; VALIDATION; INFECTIONS; PREVALENCE AB Background: Gut microbiome dysbiosis has been demonstrated in subjects with newly diagnosed and chronic inflammatory bowel disease (IBD). In this study we sought to explore longitudinal changes in dysbiosis and ascertain associations between dysbiosis and markers of disease activity and treatment outcome. Methods: We performed a prospective cohort study of 19 treatment-naive pediatric IBD subjects and 10 healthy controls, measuring fecal calprotectin and assessing the gut microbiome via repeated stool samples. Associations between clinical characteristics and the microbiome were tested using generalized estimating equations. Random forest classification was used to predict ultimate treatment response (presence of mucosal healing at follow-up colonoscopy) or non-response using patients' pretreatment samples. Results: Patients with Crohn's disease had increased markers of inflammation and dysbiosis compared to controls. Patients with ulcerative colitis had even higher inflammation and dysbiosis compared to those with Crohn's disease. For all cases, the gut microbial dysbiosis index associated significantly with clinical and biological measures of disease severity, but did not associate with treatment response. We found differences in specific gut microbiome genera between cases/controls and responders/non-responders including Akkermansia, Coprococcus, Fusobacterium, Veillonella, Faecalibacterium, and Adlercreutzia. Using pretreatment microbiome data in a weighted random forest classifier, we were able to obtain 76.5 % accuracy for prediction of responder status. Conclusions: Patient dysbiosis improved over time but persisted even among those who responded to treatment and achieved mucosal healing. Although dysbiosis index was not significantly different between responders and non-responders, we found specific genus-level differences. We found that pretreatment microbiome signatures are a promising avenue for prediction of remission and response to treatment. C1 [Shaw, Kelly A.] Emory Univ, Grad Div Biol & Biomed Sci, Grad Program Genet & Mol Biol, Atlanta, GA 30322 USA. [Bertha, Madeline; Hofmekler, Tatyana; Chopra, Pankaj; Srivatsa, Abhiram; Prince, Jarod; Kumar, Archana; Sauer, Cary; Kugathasan, Subra] Emory Univ, Dept Pediat, Sch Med, 2015 Uppergate Dr,Room 248, Atlanta, GA 30322 USA. [Bertha, Madeline; Hofmekler, Tatyana; Chopra, Pankaj; Srivatsa, Abhiram; Prince, Jarod; Kumar, Archana; Sauer, Cary; Kugathasan, Subra] Childrens Healthcare Atlanta, 2015 Uppergate Dr,Room 248, Atlanta, GA 30322 USA. [Vatanen, Tommi; Kostic, Aleksandar D.; Xavier, Ramnik J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Vatanen, Tommi] Aalto Univ, Dept Comp Sci, Sch Sci, Espoo 02150, Finland. [Zwick, Michael E.; Mulle, Jennifer G.; Kugathasan, Subra] Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. [Satten, Glen A.] Ctr Dis Control & Prevent, Atlanta, GA 30341 USA. [Kostic, Aleksandar D.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Kostic, Aleksandar D.; Xavier, Ramnik J.] Harvard Med Sch, Boston, MA 02114 USA. [Mulle, Jennifer G.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. RP Kugathasan, S (reprint author), Emory Univ, Dept Pediat, Sch Med, 2015 Uppergate Dr,Room 248, Atlanta, GA 30322 USA.; Kugathasan, S (reprint author), Childrens Healthcare Atlanta, 2015 Uppergate Dr,Room 248, Atlanta, GA 30322 USA.; Kugathasan, S (reprint author), Emory Univ, Dept Human Genet, Atlanta, GA 30322 USA. EM skugath@emory.edu FU Marcus Foundation [DK087694, DK098231]; BWF [1008188]; NIH [NRSA F31DK107229] FX The Marcus Foundation (to SK) primarily supported this work, with further support from DK087694 (SK) and DK098231 (SK). KAS received support from BWF training grant ID 1008188 and NIH NRSA F31DK107229. NR 50 TC 6 Z9 6 U1 3 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD JUL 13 PY 2016 VL 8 AR 75 DI 10.1186/s13073-016-0331-y PG 13 WC Genetics & Heredity SC Genetics & Heredity GA DR9IB UT WOS:000380209200001 PM 27412252 ER PT J AU Cleary, JM Mamon, HJ Szymonifka, J Bueno, R Choi, N Donahue, DM Fidias, PM Gaissert, HA Jaklitsch, MT Kulke, MH Lynch, TP Mentzer, SJ Meyerhardt, JA Swanson, RS Wain, J Fuchs, CS Enzinger, PC AF Cleary, James M. Mamon, Harvey J. Szymonifka, Jackie Bueno, Raphael Choi, Noah Donahue, Dean M. Fidias, Panos M. Gaissert, Henning A. Jaklitsch, Michael T. Kulke, Matthew H. Lynch, Thomas P. Mentzer, Steven J. Meyerhardt, Jeffrey A. Swanson, Richard S. Wain, John Fuchs, Charles S. Enzinger, Peter C. TI Neoadjuvant irinotecan, cisplatin, and concurrent radiation therapy with celecoxib for patients with locally advanced esophageal cancer SO BMC CANCER LA English DT Article DE Esophageal cancer; Neoadjuvant therapy; Chemoradiation; Cyclooxygenase 2 inhibition ID SQUAMOUS-CELL CARCINOMA; PLUS CISPLATIN; CYCLOOXYGENASE-2 EXPRESSION; COLORECTAL ADENOMAS; SURVIVAL; CHEMORADIOTHERAPY; ADENOCARCINOMA; METAANALYSIS; TRIAL; RADIOTHERAPY AB Background: Patients with locally advanced esophageal cancer who are treated with trimodality therapy have a high recurrence rate. Preclinical evidence suggests that inhibition of cyclooxygenase 2 (COX2) increases the effectiveness of chemoradiation, and observational studies in humans suggest that COX-2 inhibition may reduce esophageal cancer risk. This trial tested the safety and efficacy of combining a COX2 inhibitor, celecoxib, with neoadjuvant irinotecan/cisplatin chemoradiation. Methods: This single arm phase 2 trial combined irinotecan, cisplatin, and celecoxib with concurrent radiation therapy. Patients with stage IIA-IVA esophageal cancer received weekly cisplatin 30 mg/m(2) plus irinotecan 65 mg/m(2) on weeks 1, 2, 4, and 5 concurrently with 5040 cGy of radiation therapy. Celecoxib 400 mg was taken orally twice daily during chemoradiation, up to 1 week before surgery, and for 6 months following surgery. Results: Forty patients were enrolled with stage IIa (30 %), stage IIb (20 %), stage III (22.5 %), and stage IVA (27.5 %) esophageal or gastroesophageal junction cancer (AJCC, 5th Edition). During chemoradiation, grade 3-4 treatment-related toxicity included dysphagia (20 %), anorexia (17.5 %), dehydration (17.5 %), nausea (15 %), neutropenia (12.5 %), diarrhea (10 %), fatigue (7.5 %), and febrile neutropenia (7.5 %). The pathological complete response rate was 32.5 %. The median progression free survival was 15.7 months and the median overall survival was 34.7 months. 15 % (n = 6) of patients treated on this study developed brain metastases. Conclusions: The addition of celecoxib to neoadjuvant cisplatin-irinotecan chemoradiation was tolerable; however, overall survival appeared comparable to prior studies using neoadjuvant cisplatin-irinotecan chemoradiation alone. Further studies adding celecoxib to neoadjuvant chemoradiation in esophageal cancer are not warranted. C1 [Cleary, James M.; Mamon, Harvey J.; Szymonifka, Jackie; Bueno, Raphael; Jaklitsch, Michael T.; Kulke, Matthew H.; Mentzer, Steven J.; Meyerhardt, Jeffrey A.; Swanson, Richard S.; Fuchs, Charles S.; Enzinger, Peter C.] Dana Farber Canc Inst, Dana Farber Brigham & Womens Canc Ctr, Ctr Esophageal & Gastr Canc, 450 Brookline Ave, Boston, MA 02215 USA. [Cleary, James M.; Mamon, Harvey J.; Szymonifka, Jackie; Bueno, Raphael; Jaklitsch, Michael T.; Kulke, Matthew H.; Mentzer, Steven J.; Meyerhardt, Jeffrey A.; Swanson, Richard S.; Fuchs, Charles S.; Enzinger, Peter C.] Dana Farber Canc Inst, Gastrointestinal Canc Ctr, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. [Cleary, James M.; Mamon, Harvey J.; Szymonifka, Jackie; Bueno, Raphael; Jaklitsch, Michael T.; Kulke, Matthew H.; Mentzer, Steven J.; Meyerhardt, Jeffrey A.; Swanson, Richard S.; Fuchs, Charles S.; Enzinger, Peter C.] Harvard Med Sch, 450 Brookline Ave, Boston, MA 02215 USA. [Choi, Noah; Donahue, Dean M.; Fidias, Panos M.; Gaissert, Henning A.; Lynch, Thomas P.; Wain, John] Harvard Med Sch, Ctr Canc, Massachusetts Gen Hosp, Boston, MA USA. [Fidias, Panos M.] Univ Arizona, Ctr Canc, St Josephs Hosp & Med Ctr, Phoenix, AZ USA. RP Enzinger, PC (reprint author), Dana Farber Canc Inst, Dana Farber Brigham & Womens Canc Ctr, Ctr Esophageal & Gastr Canc, 450 Brookline Ave, Boston, MA 02215 USA.; Enzinger, PC (reprint author), Dana Farber Canc Inst, Gastrointestinal Canc Ctr, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA.; Enzinger, PC (reprint author), Harvard Med Sch, 450 Brookline Ave, Boston, MA 02215 USA. EM peter_enzinger@dfci.harvard.edu FU National Institute of Health [P50CA127003]; Pharmacia Oncology FX This work was supported by a grant from the National Institute of Health (P50CA127003). Pharmacia Oncology supported the trial by providing the Celecoxib to each of the participants. NR 47 TC 0 Z9 0 U1 3 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUL 13 PY 2016 VL 16 AR 468 DI 10.1186/s12885-016-2485-9 PG 9 WC Oncology SC Oncology GA DR8ZN UT WOS:000380187000001 PM 27412386 ER PT J AU Burberry, A Suzuki, N Wang, JY Moccia, R Mordes, DA Stewart, MH Suzuki-Uematsu, S Ghosh, S Singh, A Merkle, FT Koszka, K Li, QZ Zon, L Rossi, DJ Trowbridge, JJ Notarangelo, LD Eggan, K AF Burberry, Aaron Suzuki, Naoki Wang, Jin-Yuan Moccia, Rob Mordes, Daniel A. Stewart, Morag H. Suzuki-Uematsu, Satomi Ghosh, Sulagna Singh, Ajay Merkle, Florian T. Koszka, Kathryn Li, Quan-Zhen Zon, Leonard Rossi, Derrick J. Trowbridge, Jennifer J. Notarangelo, Luigi D. Eggan, Kevin TI Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; SPINAL-CORD; ALS; REPEAT; MECHANISMS; EXPANSION; CELLS; TBK1; MICE AB C9ORF72 mutations are found in a significant fraction of patients suffering from amyotrophic lateral sclerosis and frontotemporal dementia, yet the function of the C9ORF72 gene product remains poorly understood. We show that mice harboring loss-of-function mutations in the ortholog of C9ORF72 develop splenomegaly, neutrophilia, thrombocytopenia, increased expression of inflammatory cytokines, and severe autoimmunity, ultimately leading to a high mortality rate. Transplantation of mutant mouse bone marrow into wild-type recipients was sufficient to recapitulate the phenotypes observed in the mutant animals, including autoimmunity and premature mortality. Reciprocally, transplantation of wild-type mouse bone marrow into mutant mice improved their phenotype. We conclude that C9ORF72 serves an important function within the hematopoietic system to restrict inflammation and the development of autoimmunity. C1 [Burberry, Aaron; Suzuki, Naoki; Wang, Jin-Yuan; Moccia, Rob; Mordes, Daniel A.; Stewart, Morag H.; Suzuki-Uematsu, Satomi; Ghosh, Sulagna; Singh, Ajay; Merkle, Florian T.; Koszka, Kathryn; Zon, Leonard; Rossi, Derrick J.; Eggan, Kevin] Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Burberry, Aaron; Suzuki, Naoki; Wang, Jin-Yuan; Moccia, Rob; Mordes, Daniel A.; Suzuki-Uematsu, Satomi; Ghosh, Sulagna; Singh, Ajay; Merkle, Florian T.; Koszka, Kathryn; Eggan, Kevin] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Mordes, Daniel A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Stewart, Morag H.; Rossi, Derrick J.] Boston Childrens Hosp, Div Hematol Oncol, Program Cellular & Mol Med, Boston, MA 02115 USA. [Li, Quan-Zhen] Univ Texas Southwestern Med Ctr, Dept Immunol, Dallas, TX 75390 USA. [Li, Quan-Zhen] Univ Texas Southwestern Med Ctr, Dept Internal Med, Dallas, TX 75390 USA. [Zon, Leonard; Rossi, Derrick J.; Notarangelo, Luigi D.] Harvard Med Sch, Boston, MA 02115 USA. [Trowbridge, Jennifer J.] Jackson Lab Mammalian Genet, Bar Harbor, ME 04609 USA. [Notarangelo, Luigi D.] Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. RP Eggan, K (reprint author), Harvard Univ, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA.; Eggan, K (reprint author), Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. EM eggan@mcb.harvard.edu FU Howard Hughes Medical Institute; p2ALS; Target ALS; NIH [5K99NS083713]; Wellcome Trust; Academy of Medical Sciences; Medical Research Council [MR/P501967/1]; [NIH5R01NS089742] FX K.E. was supported by the Howard Hughes Medical Institute, p2ALS, Target ALS, and NIH5R01NS089742. F.T.M. was supported by the NIH (5K99NS083713), the Wellcome Trust, the Academy of Medical Sciences, and the Medical Research Council (MR/P501967/1). NR 45 TC 7 Z9 7 U1 2 U2 23 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 JUL 13 PY 2016 VL 8 IS 347 AR 347ra93 DI 10.1126/scitranslmed.aaf6038 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA DR6RW UT WOS:000380030000002 PM 27412785 ER PT J AU Loscertales, M Nicolaou, F Jeanne, M Longoni, M Gould, DB Sun, YW Maalouf, FI Nagy, N Donahoe, PK AF Loscertales, Maria Nicolaou, Fotini Jeanne, Marion Longoni, Mauro Gould, Douglas B. Sun, Yunwei Maalouf, Faouzi I. Nagy, Nandor Donahoe, Patricia K. TI Type IV collagen drives alveolar epithelial-endothelial association and the morphogenetic movements of septation SO BMC BIOLOGY LA English DT Article DE Type IV collagen; Basement membrane; Blood-gas barrier; Alveolar development; Lung epithelium; Lung vasculature; Alveolar myofibroblast migration and differentiation ID CHRONIC LUNG-DISEASE; GROWTH-FACTOR; BASEMENT-MEMBRANE; COL4A2 MUTATIONS; GENE-EXPRESSION; MOUSE-LUNG; BRONCHOPULMONARY DYSPLASIA; PERINATAL LETHALITY; HEMORRHAGIC STROKE; DEFICIENT MICE AB Background: Type IV collagen is the main component of the basement membrane that gives strength to the blood-gas barrier (BGB). In mammals, the formation of a mature BGB occurs primarily after birth during alveologenesis and requires the formation of septa from the walls of the saccule. In contrast, in avians, the formation of the BGB occurs rapidly and prior to hatching. Mutation in basement membrane components results in an abnormal alveolar phenotype; however, the specific role of type IV collagen in regulating alveologenesis remains unknown. Results: We have performed a microarray expression analysis in late chick lung development and found that COL4A1 and COL4A2 were among the most significantly upregulated genes during the formation of the avian BGB. Using mouse models, we discovered that mutations in murine Col4a1 and Col4a2 genes affected the balance between lung epithelial progenitors and differentiated cells. Mutations in Col4a1 derived from the vascular component were sufficient to cause defects in vascular development and the BGB. We also show that Col4a1 and Col4a2 mutants displayed disrupted myofibroblast proliferation, differentiation and migration. Lastly, we revealed that addition of type IV collagen protein induced myofibroblast proliferation and migration in monolayer culture and increased the formation of mesenchymal-epithelial septal-like structures in co-culture. Conclusions: Our study showed that type IV collagen and, therefore the basement membrane, play fundamental roles in coordinating alveolar morphogenesis. In addition to its role in the formation of epithelium and vasculature, type IV collagen appears to be key for alveolar myofibroblast development by inducing their proliferation, differentiation and migration throughout the developing septum. C1 [Loscertales, Maria; Nicolaou, Fotini; Longoni, Mauro; Sun, Yunwei; Maalouf, Faouzi I.; Nagy, Nandor; Donahoe, Patricia K.] Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. [Loscertales, Maria; Longoni, Mauro; Nagy, Nandor; Donahoe, Patricia K.] Harvard Med Sch, Dept Surg, Boston, MA 02115 USA. [Jeanne, Marion; Gould, Douglas B.] Univ Calif San Francisco, Sch Med, Inst Human Genet, Dept Ophthalmol, San Francisco, CA 94143 USA. [Jeanne, Marion; Gould, Douglas B.] Univ Calif San Francisco, Sch Med, Inst Human Genet, Dept Anat, San Francisco, CA 94143 USA. [Nagy, Nandor] Semmelweis Univ, Dept Human Anat Histol & Embryol, Fac Med, H-1094 Budapest, Hungary. [Donahoe, Patricia K.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Loscertales, M (reprint author), Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA.; Loscertales, M (reprint author), Harvard Med Sch, Dept Surg, Boston, MA 02115 USA. EM MLOSCERTALES@mgh.harvard.edu FU NICHD [P01HD068250]; NINDS [R01NS083830] FX We thank Adam Tracy, Regis Hila and Pooja Bhayani for technical assistance, and Drucilla J Roberts, M.D., Allan Goldstein, M.D., and Casey Kelleher, M.D., for advice, discussions and careful revision of the manuscript. Funding was provided by NICHD P01HD068250 (to PKD) and NINDS R01NS083830 (to DBG). NR 74 TC 3 Z9 3 U1 3 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD JUL 13 PY 2016 VL 14 AR 59 DI 10.1186/s12915-016-0281-2 PG 21 WC Biology SC Life Sciences & Biomedicine - Other Topics GA DR3BJ UT WOS:000379777300001 PM 27412481 ER PT J AU Huang, F Dong, JX Kong, J Wang, HC Meng, H Spaeth, RB Camhi, S Liao, X Li, X Zhai, X Li, SY Zhu, B Rong, PJ AF Huang, Feng Dong, Jianxun Kong, Jian Wang, Hongcai Meng, Hong Spaeth, Rosa B. Camhi, Stephanie Liao, Xing Li, Xia Zhai, Xu Li, Shaoyuan Zhu, Bing Rong, Peijing TI Effect of transcutaneous auricular vagus nerve stimulation on impaired glucose tolerance: a pilot randomized study (vol 14, 203, 2016) SO BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE LA English DT Correction C1 [Huang, Feng; Wang, Hongcai; Meng, Hong; Zhai, Xu; Li, Shaoyuan; Zhu, Bing; Rong, Peijing] China Acad Chinese Med Sci, Inst Acu Mox, 16 Nanxiao St, Beijing 100700, Peoples R China. [Huang, Feng; Li, Xia] Beijing Univ Chinese Med, Beijing 100029, Peoples R China. [Dong, Jianxun] Capital Univ Med Sci, Beijing Hosp TCM, Beijing 100010, Peoples R China. [Kong, Jian; Spaeth, Rosa B.; Camhi, Stephanie] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Camhi, Stephanie] Endicott Coll, Dept Psychol, Beverly, MA USA. [Liao, Xing] China Acad Chinese Med Sci, Inst Basic Res Clin Med, Beijing 100700, Peoples R China. RP Rong, PJ (reprint author), China Acad Chinese Med Sci, Inst Acu Mox, 16 Nanxiao St, Beijing 100700, Peoples R China. EM drrongpj@163.com NR 1 TC 0 Z9 0 U1 2 U2 7 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 JUL 13 PY 2016 VL 16 AR 218 DI 10.1186/s12906-016-1190-1 PG 4 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA DR3RG UT WOS:000379819700007 ER PT J AU Cox, AR Barrandon, O Cai, EP Rios, JS Chavez, J Bonnyman, CW Lam, CJ Yi, P Melton, DA Kushner, JA AF Cox, Aaron R. Barrandon, Ornella Cai, Erica P. Rios, Jacqueline S. Chavez, Julia Bonnyman, Claire W. Lam, Carol J. Yi, Peng Melton, Douglas A. Kushner, Jake A. TI Resolving Discrepant Findings on ANGPTL8 in beta-Cell Proliferation: A Collaborative Approach to Resolving the Betatrophin Controversy SO PLOS ONE LA English DT Article ID MALTOSE-BINDING-PROTEIN; METABOLISM; GENE; MICE AB The beta-cell mitogenic effects of ANGPTL8 have been subjected to substantial debate. The original findings suggested that ANGPTL8 overexpression in mice induced a 17-fold increase in beta-cell proliferation. Subsequent studies in mice contested this claim, but a more recent report in rats supported the original observations. These conflicting results might be explained by variable ANGPTL8 expression and differing methods of beta-cell quantification. To resolve the controversy, three independent labs collaborated on a blinded study to test the effects of ANGPTL8 upon beta-cell proliferation. Recombinant human betatrophin (hBT) fused to maltose binding protein (MBP) was delivered to mice by intravenous injection. The results demonstrate that ANGPTL8 does not stimulate significant beta-cell proliferation. Each lab employed different methods for beta-cell identification, resulting in variable quantification of beta-cell proliferation and suggests a need for standardizing practices for beta-cell quantification. We also observed a new action of ANGPTL8 in stimulating CD45(+) hematopoietic-derived cell proliferation which may explain, in part, published discrepancies. Overall, the hypothesis that ANGPTL8 induces dramatic and specific beta-cell proliferation can no longer be supported. However, while ANGPTL8 does not stimulate robust beta-cell proliferation, the original experimental model using drug-induced (S961) insulin resistance was validated in subsequent studies, and thus still represents a robust system for studying signals that are either necessary or sufficient for beta-cell expansion. As an added note, we would like to commend collaborative group efforts, with repetition of results and procedures in multiple laboratories, as an effective method to resolve discrepancies in the literature. C1 [Cox, Aaron R.; Rios, Jacqueline S.; Chavez, Julia; Bonnyman, Claire W.; Lam, Carol J.; Kushner, Jake A.] Texas Childrens Hosp, Baylor Coll Med, McNair Med Inst, Pediat Diabet & Endocrinol, Houston, TX 77030 USA. [Barrandon, Ornella; Cai, Erica P.; Yi, Peng; Melton, Douglas A.] Harvard Univ, Harvard Stem Cell Inst, Stem Cell & Regenerat Biol, Cambridge, MA USA. [Cai, Erica P.; Yi, Peng] Harvard Med Sch, Joslin Diabet Ctr, Boston, MA USA. RP Kushner, JA (reprint author), Texas Childrens Hosp, Baylor Coll Med, McNair Med Inst, Pediat Diabet & Endocrinol, Houston, TX 77030 USA. EM kushner@bcm.edu FU National Institutes of Health (NIH NIA) [1R01AG04101]; Howard Hughes Medical Institute (HHMI); Harvard Stem Cell Institute; Robert and Janice McNair Foundation; Diabetes Research Center at Baylor College of Medicine FX This work was supported by the National Institutes of Health (NIH NIA - 1R01AG04101) (www.nia.nih.gov), the Howard Hughes Medical Institute (HHMI) (www.hhmi.org), the Harvard Stem Cell Institute (hsci.harvard.edu), the Robert and Janice McNair Foundation (www.mcnairfoundation.org) and the Diabetes Research Center at Baylor College of Medicine (www.bcm.edu/research/centers/diabetesresearch/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 14 TC 1 Z9 1 U1 5 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 JUL 13 PY 2016 VL 11 IS 7 AR e0159276 DI 10.1371/journal.pone.0159276 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ9CP UT WOS:000379508300076 PM 27410263 ER PT J AU Iandiorio, MJ Fair, JM Chatzipanagiotou, S Ioannidis, A Trikka-Graphakos, E Charalampaki, N Sereti, C Tegos, GP Hoogesteijn, AL Rivas, AL AF Iandiorio, Michelle J. Fair, Jeanne M. Chatzipanagiotou, Stylianos Ioannidis, Anastasios Trikka-Graphakos, Eleftheria Charalampaki, Nikoletta Sereti, Christina Tegos, George P. Hoogesteijn, Almira L. Rivas, Ariel L. TI Preventing Data Ambiguity in Infectious Diseases with Four-Dimensional and Personalized Evaluations SO PLOS ONE LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; SYSTEMS BIOLOGY; IN-VITRO; EMERGENCE; CHALLENGES; IMMUNITY; MODELS; HETEROGENEITY; HOMEOSTASIS; UNFOLDOMICS AB Background Diagnostic errors can occur, in infectious diseases, when anti-microbial immune responses involve several temporal scales. When responses span from nanosecond to week and larger temporal scales, any pre-selected temporal scale is likely to miss some (faster or slower) responses. Hoping to prevent diagnostic errors, a pilot study was conducted to evaluate a four-dimensional (4D) method that captures the complexity and dynamics of infectious diseases. Methods Leukocyte-microbial-temporal data were explored in canine and human (bacterial and/or viral) infections, with: (i) a non-structured approach, which measures leukocytes or microbes in isolation; and (ii) a structured method that assesses numerous combinations of interacting variables. Four alternatives of the structured method were tested: (i) a noise-reduction oriented version, which generates a single (one data point-wide) line of observations; (ii) a version that measures complex, three-dimensional (3D) data interactions; (iii) a non-numerical version that displays temporal data directionality (arrows that connect pairs of consecutive observations); and (iv) a full 4D (single line-, complexity-, directionality-based) version. Results In all studies, the non-structured approach revealed non-interpretable ( ambiguous) data: observations numerically similar expressed different biological conditions, such as recovery and lack of recovery from infections. Ambiguity was also found when the data were structured as single lines. In contrast, two or more data subsets were distinguished and ambiguity was avoided when the data were structured as complex, 3D, single lines and, in addition, temporal data directionality was determined. The 4D method detected, even within one day, changes in immune profiles that occurred after antibiotics were prescribed. Conclusions Infectious disease data may be ambiguous. Four-dimensional methods may prevent ambiguity, providing earlier, in vivo, dynamic, complex, and personalized information that facilitates both diagnostics and selection or evaluation of anti-microbial therapies. C1 [Iandiorio, Michelle J.; Rivas, Ariel L.] Univ New Mexico, Sch Med, Dept Internal Med, Albuquerque, NM 87131 USA. [Fair, Jeanne M.] Los Alamos Natl Lab, Global Secur, Mailstop M888, Los Alamos, NM 87545 USA. [Chatzipanagiotou, Stylianos] Univ Athens, Sch Med, Aeginition Hosp, Dept Biopathol & Clin Microbiol, Athens, Greece. [Ioannidis, Anastasios] Univ Peloponnese, Fac Human Movement & Qual Life Sci, Dept Nursing, Sparta, Greece. [Trikka-Graphakos, Eleftheria; Charalampaki, Nikoletta; Sereti, Christina] Thriasio Gen Hosp, Dept Clin Microbiol, Magoula, Greece. [Tegos, George P.] Torrey Pines Inst Mol Studies, Port St Lucie, FL USA. [Tegos, George P.] Harvard Med Sch, Dept Dermatol, Boston, MA USA. [Tegos, George P.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hoogesteijn, Almira L.] Ctr Invest Avanzadas, Dept Human Ecol, Merida, Mexico. [Rivas, Ariel L.] Univ New Mexico, Sch Med, Ctr Global Hlth, Div Infect Dis, Albuquerque, NM 87131 USA. RP Rivas, AL (reprint author), Univ New Mexico, Sch Med, Dept Internal Med, Albuquerque, NM 87131 USA.; Rivas, AL (reprint author), Univ New Mexico, Sch Med, Ctr Global Hlth, Div Infect Dis, Albuquerque, NM 87131 USA. EM alrivas@unm.edu NR 58 TC 0 Z9 0 U1 4 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 JUL 13 PY 2016 VL 11 IS 7 AR e0159001 DI 10.1371/journal.pone.0159001 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ9CP UT WOS:000379508300047 PM 27411058 ER PT J AU Gao, L Hong, XF Guo, XP Cao, DF Gao, XH DeLaney, TF Gong, XQ Chen, RR Ni, JJ Yao, Y Wang, RZ Chen, X Tian, PZH Xing, B AF Gao, Lu Hong, Xiafei Guo, Xiaopeng Cao, Dengfeng Gao, Xiaohuan DeLaney, Thomas F. Gong, Xinqi Chen, Rongrong Ni, Jianjiao Yao, Yong Wang, Renzhi Chen, Xi Tian, Pangzehuan Xing, Bing TI Targeted next-generation sequencing of dedifferentiated chondrosarcoma in the skull base reveals combined TP53 and PTEN mutations with increased proliferation index, an implication for pathogenesis SO ONCOTARGET LA English DT Article DE dedifferentiated; chondrosarcoma; TP53; PTEN; proliferation ID DE-DIFFERENTIATED CHONDROSARCOMA; PROGNOSTIC-FACTORS; CANCER GENOMICS; P53 EXPRESSION; REARRANGEMENTS; OSTEOSARCOMA; DISTINCTION; COMPONENT; LYMPHOMA; PATTERNS AB Dedifferentiated chondrosarcoma (DDCS) is a rare disease with a dismal prognosis. DDCS consists of two morphologically distinct components: the cartilaginous and noncartilaginous components. Whether the two components originate from the same progenitor cells has been controversial. Recurrent DDCS commonly displays increased proliferation compared with the primary tumor. However, there is no conclusive explanation for this mechanism. In this paper, we present two DDCSs in the sellar region. Patient 1 exclusively exhibited a noncartilaginous component with a TP53 frameshift mutation in the pathological specimens from the first surgery. The tumor recurred after radiation therapy with an exceedingly increased proliferation index. Targeted next-generation sequencing (NGS) revealed the presence of both a TP53 mutation and a PTEN deletion in the cartilaginous and the noncartilaginous components of the recurrent tumor. Fluorescence in situ hybridization and immunostaining confirmed reduced DNA copy number and protein levels of the PTEN gene as a result of the PTEN deletion. Patient 2 exhibited both cartilaginous and noncartilaginous components in the surgical specimens. Targeted NGS of cells from both components showed neither TP53 nor PTEN mutations, making Patient 2 a naive TP53 and PTEN control for comparison. In conclusion, additional PTEN loss in the background of the TP53 mutation could be the cause of increased proliferation capacity in the recurrent tumor. C1 [Gao, Lu; Guo, Xiaopeng; Yao, Yong; Wang, Renzhi; Xing, Bing] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Neurosurg, Beijing, Peoples R China. [Gao, Lu; Hong, Xiafei; Guo, Xiaopeng; Chen, Rongrong; Ni, Jianjiao; Yao, Yong; Wang, Renzhi; Xing, Bing] Peking Union Med Coll, Beijing, Peoples R China. [Hong, Xiafei] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Gen Surg, Beijing, Peoples R China. [Cao, Dengfeng] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Gao, Xiaohuan; Chen, Xi; Tian, Pangzehuan] BGI Tianjin, Binhai Genom Inst, Tianjin, Peoples R China. [Gao, Xiaohuan; Chen, Xi; Tian, Pangzehuan] BGI Tianjin, Tianjin Translat Genom Ctr, Tianjin, Peoples R China. [DeLaney, Thomas F.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. [Gong, Xinqi] Renmin Univ China, Inst Math Sci, Beijing, Peoples R China. [Chen, Rongrong] Chinese Acad Med Sci, Peking Union Med Coll, Inst Basic Med Sci, Beijing, Peoples R China. [Chen, Rongrong] Chinese Acad Med Sci, Peking Union Med Coll, Sch Basic Med, Beijing, Peoples R China. [Ni, Jianjiao] Chinese Acad Med Sci, Peking Union Med Coll, Dept Med Oncol, Beijing, Peoples R China. [Gao, Xiaohuan] Jingke Biotech, Dept Canc Res, Guangzhou, Guangdong, Peoples R China. RP Xing, B (reprint author), Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Neurosurg, Beijing, Peoples R China.; Xing, B (reprint author), Peking Union Med Coll, Beijing, Peoples R China. EM xingbingemail@aliyun.com NR 43 TC 0 Z9 0 U1 3 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 12 PY 2016 VL 7 IS 28 BP 43557 EP 43569 DI 10.18632/oncotarget.9618 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8QU UT WOS:000385395700054 PM 27248819 ER PT J AU Loffler, H Pfarr, N Kriegsmann, M Endris, V Hielscher, T Lohneis, P Folprecht, G Stenzinger, A Dietel, M Weichert, W Kramer, A AF Loeffler, Harald Pfarr, Nicole Kriegsmann, Mark Endris, Volker Hielscher, Thomas Lohneis, Philipp Folprecht, Gunnar Stenzinger, Albrecht Dietel, Manfred Weichert, Wilko Kraemer, Alwin TI Molecular driver alterations and their clinical relevance in cancer of unknown primary site SO ONCOTARGET LA English DT Article DE CUP; carcinoma of unknown primary; massive parallel sequencing; driver mutations; p53 ID LUNG-CANCER; PERSONALIZED MEDICINE; BREAST-CANCER; TP53 MUTATION; PRIMARY TUMOR; P53 GENE; CARCINOMA; DIAGNOSIS; SURVIVAL; THERAPY AB Cancer of unknown primary (CUP) is defined as metastatic solid malignancy where no primary tumor is detected despite appropriate staging. About 90% of CUP represent adenocarcinoma or undifferentiated carcinoma. Since therapy regimens are only modestly effective, identification of the molecular landscape of these neoplasms might be a promising approach to direct CUP therapy and aid in tumor classification. We screened a cohort of 128 patients with adenocarcinoma or undifferentiated carcinoma meeting the definition of CUP. Massive parallel multigene sequencing of 50 genes, which had been selected due to their relevance as oncogenic drivers or druggable molecular targets could ultimately be performed on samples from 55 patients for whom complete clinical datasets were also available. Overall, 60 tumor-specific mutations and 29 amplifications/deletions, as revealed by coverage analysis, were detected in 46 cases (84%). The most frequently mutated genes were TP53 (30 cases, 55%), KRAS (9 cases, 16%), CDKN2A (5 cases, 9%), and SMAD4 (5 cases, 9%). The most frequently deleted gene was CDKN2A (8 cases, 15%). KRAS and CDKN2A mutations significantly correlated with poor progression-free survival (PFS) and, in case of KRAS, overall survival (OS). WIldtype TP53 and female sex defined a relatively favorable category, with favorable PFS and OS. 8 cases (15%) harbored mutations that may be targetable by currently approved drugs. Taken together, Mutations of relevant driver genes are present in the vast majority of CUP tumors. Some of them impact on prognosis and a subset is putatively druggable. C1 [Loeffler, Harald; Kraemer, Alwin] Heidelberg Univ, Clin Cooperat Unit Mol Hematol Oncol, German Canc Res Ctr DKFZ, Heidelberg, Germany. [Loeffler, Harald; Kraemer, Alwin] Heidelberg Univ, Dept Med 5, Heidelberg, Germany. [Pfarr, Nicole; Kriegsmann, Mark; Endris, Volker; Stenzinger, Albrecht; Weichert, Wilko] Heidelberg Univ, Inst Pathol, Heidelberg, Germany. [Pfarr, Nicole; Weichert, Wilko] Tech Univ Munich, Inst Pathol, Munich, Germany. [Hielscher, Thomas] German Canc Res Ctr, Div Biostat, Heidelberg, Germany. [Lohneis, Philipp; Dietel, Manfred] Charite, Inst Pathol, Berlin, Germany. [Folprecht, Gunnar] Univ Hosp Carl Gustav Carus, Dept Med 1, Dresden, Germany. [Stenzinger, Albrecht] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Integrated Diagnost, Dept Pathol, Boston, MA USA. [Weichert, Wilko] Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Weichert, Wilko; Kraemer, Alwin] German Canc Consortium DKTK, Heidelberg, Germany. RP Kramer, A (reprint author), Heidelberg Univ, Clin Cooperat Unit Mol Hematol Oncol, German Canc Res Ctr DKFZ, Heidelberg, Germany.; Kramer, A (reprint author), Heidelberg Univ, Dept Med 5, Heidelberg, Germany.; Weichert, W (reprint author), Heidelberg Univ, Inst Pathol, Heidelberg, Germany.; Weichert, W (reprint author), Tech Univ Munich, Inst Pathol, Munich, Germany.; Weichert, W (reprint author), Natl Ctr Tumor Dis NCT, Heidelberg, Germany.; Weichert, W; Kramer, A (reprint author), German Canc Consortium DKTK, Heidelberg, Germany. EM wilko.weichert@tum.de; a.kraemer@dkfz.de RI Folprecht, Gunnar/F-8638-2011 OI Folprecht, Gunnar/0000-0002-9321-9911 FU Arbeitsgemeinschaft Internistische Onkologie; Deutsche Krebsgesellschaft (German Cancer Society); German Cancer Consortium (DKTK) FX This work was supported by the Arbeitsgemeinschaft Internistische Onkologie, Deutsche Krebsgesellschaft (German Cancer Society) and the German Cancer Consortium (DKTK). Further, we acknowledge excellent technical assistance by Kathrin Ridinger, Katja Lorenz and Jennifer Gruber. NR 38 TC 0 Z9 0 U1 1 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 12 PY 2016 VL 7 IS 28 BP 44322 EP 44329 DI 10.18632/oncotarget.10035 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8QU UT WOS:000385395700109 PM 27322425 ER PT J AU Han, SW Ma, XM Zhao, YX Zhao, HY Batista, A Zhou, S Zhou, XN Yang, Y Wang, TT Bi, JT Xia, Z Bai, ZG Garkavtsev, I Zhang, ZT AF Han, Shiwei Ma, Xuemei Zhao, Yanxia Zhao, Hongying Batista, Ana Zhou, Sheng Zhou, Xiaona Yang, Yao Wang, Tingting Bi, Jingtao Xia, Zheng Bai, Zhigang Garkavtsev, Igor Zhang, Zhongtao TI Identification of Glypican-3 as a potential metastasis suppressor gene in gastric cancer SO ONCOTARGET LA English DT Article DE gastric cancer; Glypican-3; metastasis; FoxM1; Erk1/2 ID GOLABI-BEHMEL-SYNDROME; FOXM1; OVERGROWTH; EXPRESSION; PATHWAYS; THERAPY; KINASE; TARGET; TUMORS; CELLS AB Gastric cancer is a prevalent tumor that is usually detected at an advanced metastatic stage. Currently, standard therapies are mostly ineffective. Here, we report that Glypican-3 (GPC3) is absent in invasive tumors and metastatic lymph nodes, in particular in aggressive and highly disseminated signet ring cell carcinomas. We demonstrate that loss of GPC3 correlates with poor overall survival in patients. Moreover, we show that absence of GPC3 causes up-regulation of MAPK/FoxM1 signaling and that blockade of this pathway alters cellular invasion. An inverse correlation between GPC3 and FoxM1 is also shown in patient samples. These data identify GPC3 as a potential metastasis suppressor gene and suggest its value as a prognostic marker in gastric cancer. Development of therapies targeting signaling downstream of GPC3 are warranted. C1 [Han, Shiwei; Ma, Xuemei; Zhou, Xiaona; Yang, Yao; Wang, Tingting; Bai, Zhigang; Zhang, Zhongtao] Capital Med Univ, Beijing Friendship Hosp, Dept Gen Surg, Beijing, Peoples R China. [Han, Shiwei; Batista, Ana; Garkavtsev, Igor] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Han, Shiwei; Ma, Xuemei; Zhou, Xiaona; Yang, Yao; Wang, Tingting; Bai, Zhigang; Zhang, Zhongtao] Beijing Key Lab Canc Invas & Metastasis Res, Beijing, Peoples R China. [Han, Shiwei; Ma, Xuemei; Zhou, Xiaona; Yang, Yao; Wang, Tingting; Bai, Zhigang; Zhang, Zhongtao] Natl Clin Res Ctr Digest Dis, Beijing, Peoples R China. [Zhao, Yanxia] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Ctr Canc, Wuhan, Peoples R China. [Zhao, Hongying] Capital Med Univ, Beijing Chaoyang Hosp, Dept Pathol, Beijing, Peoples R China. [Zhou, Sheng] Huazhong Univ Sci & Technol, Inst Pathol, Union Hosp, Tongji Med Coll, Wuhan, Peoples R China. [Bi, Jingtao] Peking Univ, Dept Gen Surg, Beijing Jishuitan Hosp, Med Coll 4, Beijing, Peoples R China. [Xia, Zheng] Cent S Univ, Dept Surg, Xiangya Hosp, Changsha, Hunan, Peoples R China. RP Han, SW; Zhang, ZT (reprint author), Capital Med Univ, Beijing Friendship Hosp, Dept Gen Surg, Beijing, Peoples R China.; Han, SW (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.; Han, SW; Zhang, ZT (reprint author), Beijing Key Lab Canc Invas & Metastasis Res, Beijing, Peoples R China.; Han, SW; Zhang, ZT (reprint author), Natl Clin Res Ctr Digest Dis, Beijing, Peoples R China. EM shiwei@steele.mgh.harvard.edu; zhangzht@medmail.com.cn FU National Natural Science Foundation of China [30972887, 81402197, 81172317]; Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding [ZYLX201504]; Capital Medical University FX We would like to thank Dr. Susan Hagen (Beth Israel Deaconess Medical Center, Harvard Medical School) for providing the human MKN28 cell line; Drs. Mitchell Ho (NIH), Genevieve Boland, Jelena Grahovac, Julien Daubriac, Mei Ng, Thomas Reiberger (Massachusetts General Hospital, Harvard Medicial School) for critically reviewing the manuscript; and Victoria Xiao (Massachusetts General Hospital) for editing the manuscript. This research was supported by grants from the National Natural Science Foundation of China (no. 30972887 to ZZ), the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding (no. ZYLX201504 to ZZ), the National Natural Science Foundation of China (no. 81402197 to YZ) and the National Natural Science Foundation of China (no. 81172317 to ZB). S.H. received a doctoral joint training fellowship from Capital Medical University. NR 30 TC 0 Z9 0 U1 2 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 12 PY 2016 VL 7 IS 28 BP 44406 EP 44416 DI 10.18632/oncotarget.9763 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8QU UT WOS:000385395700116 PM 27259271 ER PT J AU Zhang, W Yu, XQ Kwak, M Xu, L Zhang, LJ Yu, Q Jin, JO AF Zhang, Wei Yu, Xiaoqian Kwak, Minseok Xu, Li Zhang, Lijun Yu, Qing Jin, Jun-O TI Maturation of dendritic cells by pullulan promotes anti-cancer effect SO ONCOTARGET LA English DT Article DE pullulan; adjuvant; dendritic cell; immunotherapy; anti-cancer ID IMMUNE-RESPONSES; CANCER-IMMUNOTHERAPY; T-CELLS; ADJUVANT; VACCINES; SURVIVAL; NANOGEL; SUBSET; SYSTEM; BLOOD AB Previous studies have demonstrated that pullulan, a polysaccharide purified from Aureobasidium pullulans, has immune-stimulatory effects on T and B cells. Moreover, pullulan has been used as a carrier in the delivery of the antigen (Ag) peptide to lymphoid tissues. However, the in vivo effect of pullulan on dendritic cells (DC) has not been well characterized. In this study, we assessed the effect of pullulan on DC activation and anti-cancer immunity. The results showed that the pullulan treatment up-regulated co-stimulatory molecule expression and enhanced pro-inflammatory cytokine production in bone marrow-derived DCs (BMDC) in vitro and in spleen DCs in vivo. Moreover, the combination of ovalbumin (OVA) and pullulan induced OVA antigen-specific T cell activations in vivo. In tumor-bearing mice, pullulan induced the maturation of DCs in spleen and tumor draining lymph node (drLN), and promoted the OVA-specific T cell activation and migration of the T cells into the tumor. In addition, the combination of OVA and pullulan inhibited B16-OVA tumor growth and liver metastasis. The combination of tyrosinase-related protein 2 (TRP2) peptide and pullulan treatment also suppressed B16 melanoma growth. Thus, the results demonstrated that pullulan enhanced DC maturation and function, and it acted as an adjuvant in promoting Ag-specific immune responses in mice. Thus, pullulan could be a new and useful adjuvant for use in therapeutic cancer vaccines. C1 [Zhang, Wei; Xu, Li; Zhang, Lijun; Jin, Jun-O] Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, Shanghai, Peoples R China. [Yu, Xiaoqian] Peking Univ, Periodontal Dept, Sch & Hosp Stomatol, Beijing, Peoples R China. [Kwak, Minseok] Pukyong Natl Univ, Dept Chem, Busan, South Korea. [Yu, Qing] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. [Yu, Qing] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA USA. RP Jin, JO (reprint author), Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, Shanghai, Peoples R China. EM Junojin1@gmail.com OI Kwak, Minseok/0000-0002-0480-1804 FU National Natural Science Foundation of China [81550110507, 81271834, 81470740]; National 863 Project of China [2014AA021403]; National Research Foundation of Korea Grant; Korean Government [NRF-2014R1A1A2059063] FX We thank the Shanghai Public Health Clinical Center animal facility for maintaining the animals in this study. This study was supported by Research Fund for International Young Scientists from National Natural Science Foundation of China (81550110507). LiJun Zhang was supported by the National Natural Science Foundation of China (81271834) and the National 863 Project of China (2014AA021403). Xiaoqian Yu was supported by the National Nature Science Foundation of China (81470740). Minseok Kwak was supported by the National Research Foundation of Korea Grant, which is funded by the Korean Government (NRF-2014R1A1A2059063). NR 35 TC 1 Z9 1 U1 4 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 12 PY 2016 VL 7 IS 28 BP 44644 EP 44659 DI 10.18632/oncotarget.10183 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DY8QU UT WOS:000385395700135 PM 27341129 ER PT J AU Patel, KR Ramsey, LE Metcalf, NV Shulman, GL Corbetta, M AF Patel, Kevin R. Ramsey, Lenny E. Metcalf, Nicholas V. Shulman, Gordon L. Corbetta, Maurizio TI Early diffusion evidence of retrograde transsynaptic degeneration in the human visual system SO NEUROLOGY LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; RETINAL GANGLION-CELLS; HOMONYMOUS HEMIANOPIA; AXONAL DEGENERATION; AUTOMATED PERIMETRY; TRACT DEGENERATION; MULTIPLE-SCLEROSIS; FIELD DEFECTS; INFARCTION; RECOVERY AB Objective: We investigated whether diffusion tensor imaging (DTI) indices of white matter integrity would offer early markers of retrograde transsynaptic degeneration (RTD) in the visual system after stroke. Methods: We performed a prospective longitudinal analysis of the sensitivity of DTI markers of optic tract health in 12 patients with postsynaptic visual pathway stroke, 12 stroke controls, and 28 healthy controls. We examined group differences in (1) optic tract fractional anisotropy (FA-asymmetry), (2) perimetric measures of visual impairment, and (3) the relationship between FA-asymmetry and perimetric assessment. Results: FA-asymmetry was higher in patients with visual pathway lesions than in control groups. These differences were evident 3 months from the time of injury and did not change significantly at 12 months. Perimetric measures showed evidence of impairment in participants with visual pathway stroke but not in control groups. A significant association was observed between FA-asymmetry and perimetric measures at 3 months, which persisted at 12 months. Conclusions: DTI markers of RTD are apparent 3 months from the time of injury. This represents the earliest noninvasive evidence of RTD in any species. Furthermore, these measures associate with measures of visual impairment. DTI measures offer a reproducible, noninvasive, and sensitive method of investigating RTD and its role in visual impairment. C1 [Patel, Kevin R.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Ramsey, Lenny E.; Metcalf, Nicholas V.; Shulman, Gordon L.; Corbetta, Maurizio] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Corbetta, Maurizio] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Corbetta, Maurizio] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Corbetta, Maurizio] Univ Padua, Dept Neurosci, I-35100 Padua, Italy. RP Patel, KR (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. EM kpatel40@mgh.harvard.edu FU National Institute of Mental Health [RO1 NS095741, 5R01HD061117-07]; Rehabilitation Institute of St. Louis FX This study was supported by the National Institute of Mental Health (RO1 NS095741 to M.C.) and the Rehabilitation Institute of St. Louis. The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: This study was supported by the National Institute of Mental Health (5R01HD061117-07 to M.C.) and the Rehabilitation Institute of St. Louis. NR 34 TC 1 Z9 1 U1 3 U2 3 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 JUL 12 PY 2016 VL 87 IS 2 BP 198 EP 205 DI 10.1212/WNL.0000000000002841 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DT4SI UT WOS:000381470700040 PM 27306632 ER PT J AU Sridharan, V Margalit, DN Lynch, SA Severgnini, M Zhou, J Chau, NG Rabinowits, G Lorch, JH Hammerman, PS Hodi, FS Haddad, RI Tishler, RB Schoenfeld, JD AF Sridharan, Vishwajith Margalit, Danielle N. Lynch, Stephanie A. Severgnini, Mariano Zhou, Jun Chau, Nicole G. Rabinowits, Guilherme Lorch, Jochen H. Hammerman, Peter S. Hodi, F. Stephen Haddad, Robert I. Tishler, Roy B. Schoenfeld, Jonathan D. TI Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE immune checkpoint; cytokines; radiation; head and neck cancer; PD-1; tumour antigens; anti-tumour immunity; abscopal ID CELL LUNG-CANCER; TUMOR-INFILTRATING LYMPHOCYTES; DEATH LIGAND 1; T-CELLS; ANTITUMOR IMMUNITY; CHEMOKINE CXCL16; OROPHARYNGEAL CANCER; HUMAN-PAPILLOMAVIRUS; METASTATIC MELANOMA; COLORECTAL-CANCER AB Background: Preclinical and clinical studies suggest potential synergy between high dose per fraction focal radiation and immunotherapy. However, conventionally fractionated radiation regimens in combination with concurrent chemotherapy are more commonly administered to patients as definitive treatment and may have both immune-stimulating and -suppressive effects. Methods: We prospectively collected longitudinal samples from head and neck squamous cell carcinoma patients receiving definitive radiation therapy. We quantified changes in populations of circulating immune cells and chemokines CXCL9, 10, and 16. Analyses of humoral and cellular immune responses were conducted in select patients via proteomic analysis and T-cell receptor sequencing. Results: Treatment not only increased circulating CD-8+ T-effector cells, but also myeloid-derived suppressor cells, regulatory T cells, and checkpoint receptor-expressing T cells, particularly PD-1+ T cells. Significant decreases in CXCL10 and increases in CXLC16 were noted. Treatment also increased the percentage of unique and dominant TCR clones, and increased humoral responses as measured by proteomic array. Conclusions: Our results suggest that fractionated chemoradiation leads to quantifiable effects in circulating immune mediators, including a balance of stimulatory and suppressive mechanisms. These results suggest future combinations with immune checkpoint blockade. C1 [Sridharan, Vishwajith; Margalit, Danielle N.; Lynch, Stephanie A.; Tishler, Roy B.; Schoenfeld, Jonathan D.] Brigham & Womens Hosp, Dana Farber Canc Ctr, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. [Sridharan, Vishwajith] Harvard Med Sch, Harvard Mit Div Hlth Sci & Technol, Boston, MA USA. [Severgnini, Mariano; Zhou, Jun; Hodi, F. Stephen] Dana Farber Canc Inst, Ctr Immunooncol, Boston, MA 02115 USA. [Chau, Nicole G.; Rabinowits, Guilherme; Lorch, Jochen H.; Hammerman, Peter S.; Hodi, F. Stephen; Haddad, Robert I.] Brigham & Womens Hosp, Dept Med Oncol, Dana Farber Canc Ctr, 75 Francis St, Boston, MA 02115 USA. RP Schoenfeld, JD (reprint author), Brigham & Womens Hosp, Dana Farber Canc Ctr, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM jdschoenfeld@partners.org FU Claudia Adams Barr Program for Innovative Cancer Research; Joint Center for Radiation Therapy; Harvard Catalyst; Harvard Clinical and Translational Science Center (National Center for Research Resources); Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102]; Harvard University and its affiliated academic health-care centres FX JDS is supported by the Claudia Adams Barr Program for Innovative Cancer Research and the Joint Center for Radiation Therapy. We acknowledge assistance provided by the Center for Immuno-Oncology at the Dana-Farber Cancer Institute. 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, National Institutes of Health Award UL1 TR001102), and financial contributions from Harvard University and its affiliated academic health-care centres. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University, and its affiliated academic health-care centres, or the National Institutes of Health. NR 58 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 12 PY 2016 VL 115 IS 2 BP 252 EP 260 DI 10.1038/bjc.2016.166 PG 9 WC Oncology SC Oncology GA DS1SR UT WOS:000380380300014 PM 27380136 ER PT J AU Jarvis, D Mitchell, JS Law, PJ Palin, K Tuupanen, S Gylfe, A Hanninen, UA Cajuso, T Tanskanen, T Kondelin, J Kaasinen, E Sarin, AP Kaprio, J Eriksson, JG Rissanen, H Knekt, P Pukkala, E Jousilahti, P Salomaa, V Ripatti, S Palotie, A Jarvinen, H Renkonen-Sinisalo, L Lepisto, A Bohm, J Mecklin, JP Al-Tassan, NA Palles, C Martin, L Barclay, E Farrington, SM Timofeeva, MN Meyer, BF Wakil, SM Campbell, H Smith, CG Idziaszczyk, S Maughan, TS Kaplan, R Kerr, R Kerr, D Buchanan, DD Win, AK Hopper, JL Jenkins, MA Lindor, NM Newcomb, PA Gallinger, S Conti, D Schumacher, F Casey, G Taipale, J Aaltonen, LA Cheadle, JP Dunlop, MG Tomlinson, IP Houlston, RS AF Jarvis, David Mitchell, Jonathan S. Law, Philip J. Palin, Kimmo Tuupanen, Sari Gylfe, Alexandra Hanninen, Ulrika A. Cajuso, Tatiana Tanskanen, Tomas Kondelin, Johanna Kaasinen, Eevi Sarin, Antti-Pekka Kaprio, Jaakko Eriksson, Johan G. Rissanen, Harri Knekt, Paul Pukkala, Eero Jousilahti, Pekka Salomaa, Veikko Ripatti, Samuli Palotie, Aarno Jarvinen, Heikki Renkonen-Sinisalo, Laura Lepisto, Anna Bohm, Jan Mecklin, Jukka-Pekka Al-Tassan, Nada A. Palles, Claire Martin, Lynn Barclay, Ella Farrington, Susan M. Timofeeva, Maria N. Meyer, Brian F. Wakil, Salma M. Campbell, Harry Smith, Christopher G. Idziaszczyk, Shelley Maughan, Timothy S. Kaplan, Richard Kerr, Rachel Kerr, David Buchanan, Daniel D. Win, Aung K. Hopper, John L. Jenkins, Mark A. Lindor, Noralane M. Newcomb, Polly A. Gallinger, Steve Conti, David Schumacher, Fred Casey, Graham Taipale, Jussi Aaltonen, Lauri A. Cheadle, Jeremy P. Dunlop, Malcolm G. Tomlinson, Ian P. Houlston, Richard S. TI Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE Mendelian randomisation; adiposity; colorectal cancer ID BODY-MASS INDEX; OBESITY; METAANALYSIS; EPIDEMIOLOGY; INSTRUMENTS; WEIGHT; COMMON AB Background: Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC. Methods: We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls. Results: In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P = 0.033), 1.59 (95% CI: 1.08-2.34, P = 0.019) and 1.07 (95% CI: 1.03-1.13, P = 0.018), respectively. There was no evidence for association between birth weight and CRC (OR = 1.22, 95% CI: 0.89-1.67, P = 0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P = 7.7 x 10(-4)) and 1.40 (95% CI: 1.14-1.72, P = 1.2 x 10(-3)), respectively. Conclusions: These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity. C1 [Gylfe, Alexandra] Human Longev Inc, La Jolla, CA 92121 USA. [Jarvis, David; Mitchell, Jonathan S.; Law, Philip J.; Houlston, Richard S.] Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England. [Palin, Kimmo; Tuupanen, Sari; Gylfe, Alexandra; Hanninen, Ulrika A.; Cajuso, Tatiana; Tanskanen, Tomas; Kondelin, Johanna; Kaasinen, Eevi; Taipale, Jussi; Aaltonen, Lauri A.] Univ Helsinki, Res Programs Unit, Genome Scale Biol Res Program, FIN-00014 Helsinki, Finland. [Palin, Kimmo; Tuupanen, Sari; Gylfe, Alexandra; Hanninen, Ulrika A.; Cajuso, Tatiana; Tanskanen, Tomas; Kondelin, Johanna; Kaasinen, Eevi; Taipale, Jussi; Aaltonen, Lauri A.] Univ Helsinki, Med, Dept Med & Clin Genet, FIN-00014 Helsinki, Finland. [Sarin, Antti-Pekka; Kaprio, Jaakko; Ripatti, Samuli; Palotie, Aarno] Univ Helsinki, Inst Mol Med Finland, FIN-00014 Helsinki, Finland. [Kaprio, Jaakko; Eriksson, Johan G.; Rissanen, Harri; Knekt, Paul; Jousilahti, Pekka; Salomaa, Veikko] Natl Inst Hlth & Welf, Helsinki 00271, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki 00250, Finland. [Eriksson, Johan G.] Univ Helsinki, Helsinki Univ Hosp, Unit Gen Practice & Primary Hlth Care, FIN-00014 Helsinki, Finland. [Pukkala, Eero] Finnish Canc Registry, Inst Stat & Epidemiol Canc Res, Helsinki 00130, Finland. [Pukkala, Eero] Univ Tampere, Sch Hlth Sci, Tampere 33014, Finland. [Palotie, Aarno] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Dept Med, Boston, MA 02114 USA. [Palotie, Aarno] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Palotie, Aarno] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Jarvinen, Heikki] Univ Helsinki, Cent Hosp, Hosp Dist Helsinki & Uusimaa, Dept Surg, Helsinki 00029, Finland. [Renkonen-Sinisalo, Laura; Lepisto, Anna] Helsinki Univ Hosp Helsinki, Abdominal Ctr, Dept Surg, Helsinki 00029, Finland. [Bohm, Jan] Cent Finland Cent Hosp, Dept Pathol, Jyvaskyla 40620, Finland. [Mecklin, Jukka-Pekka] Univ Eastern Finland, Dept Surg, Jyvaskyla Cent Hosp, Jyvaskyla 40620, Finland. [Al-Tassan, Nada A.; Meyer, Brian F.; Wakil, Salma M.] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 12713, Saudi Arabia. [Palles, Claire; Martin, Lynn; Barclay, Ella; Tomlinson, Ian P.] Wellcome Trust Ctr Human Genet, NIHR Comprehens Biomed Res Ctr, Oxford OX3 7BN, England. [Farrington, Susan M.; Timofeeva, Maria N.; Dunlop, Malcolm G.] Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, Colon Canc Genet Grp, Edinburgh EH4 2XU, Midlothian, Scotland. [Farrington, Susan M.] Univ Edinburgh, Roslin Inst, Roslin EH25 9RG, Midlothian, Scotland. [Campbell, Harry] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Smith, Christopher G.; Idziaszczyk, Shelley; Cheadle, Jeremy P.] Cardiff Univ, Sch Med, Inst Canc & Genet, Cardiff CF14 4XN, S Glam, Wales. [Maughan, Timothy S.] Univ Oxford, CRUK MRC Oxford Inst Radiat Oncol, Oxford OX3 7DQ, England. [Kaplan, Richard] MRC Clin Trials Unit, Aviat House, London WC2B 6NH, England. [Kerr, Rachel] Univ Oxford, Churchill Hosp, Oxford Canc Ctr, Dept Oncol, Oxford OX3 7LE, England. [Kerr, David] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Lab Sci, Oxford OX3 9DU, England. [Buchanan, Daniel D.] Univ Melbourne, Colorectal Oncogenom Grp, Genet Epidemiol Lab, Dept Pathol, Melbourne, Vic 3010, Australia. [Buchanan, Daniel D.; Win, Aung K.; Hopper, John L.; Jenkins, Mark A.] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne, Vic 3010, Australia. [Lindor, Noralane M.] Mayo Clin, Dept Hlth Sci Res, Scottsdale, AZ 85259 USA. [Newcomb, Polly A.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98109 USA. [Gallinger, Steve] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Conti, David; Schumacher, Fred; Casey, Graham] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90033 USA. [Taipale, Jussi] Karolinska Inst, SciLife Ctr, Dept Biosci & Nutr, SE-14183 Solna, Sweden. RP Houlston, RS (reprint author), Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England. EM richard.houlston@icr.ac.uk RI Jenkins, Mark/P-7803-2015; Gallinger, Steven/E-4575-2013; Dunlop, Malcolm/F-1973-2011; OI Jenkins, Mark/0000-0002-8964-6160; Dunlop, Malcolm/0000-0002-3033-5851; Kaprio, Jaakko/0000-0002-3716-2455; Win, Aung Ko/0000-0002-2794-5261; Houlston, Richard/0000-0002-5268-0242 FU Cancer Research UK (Bobby Moore Fund for Cancer Research UK) [C1298/A8362]; National Cancer Research Network; BBRSC; Programme Grant funding from Cancer Research UK [C348/A12076]; Oxford Comprehensive Biomedical Research Centre; EU FP7 CHIBCHA grant; European Union [258236]; FP7 collaborative project SYSCOL; COST Action in the UK [BM1206]; Medical Research Council; National Institute of Health Research Cancer Research Network; Bobby Moore Fund from Cancer Research UK; Tenovus; Kidani Trust; Cancer Research Wales; National Institute for Social Care and Health Research Cancer Genetics Biomedical Research Unit; KFSHRC; Academy of Finland (Finnish Center of Excellence Program) [250345]; Jane and Aatos Erkko Foundation; Finnish Cancer Society; European Research Council (ERC) [268648]; Sigrid Juselius Foundation; SYSCOL; Nordic Information for Action eScience Center (NIASC); Nordic Center of Excellence - NordForsk [62721]; State Research Funding of Kuopio University Hospital [B1401]; Academy of Finland [271642, 263164, 100499, 205585, 265240, 263278]; Ministry of Education and Culture, Finland; Finnish Academy [139635]; National Institute of Alcohol Abuse and Alcoholism [AA-12502, AA-00145, K02AA018755]; Wellcome Trust Sanger Institute; ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4 [201413]; National Cancer Institute [UM1 CA167551]; National Institutes of Health; CCFR centre: Australasian Colorectal Cancer Family Registry [U01 CA074778, U01/U24 CA097735]; CCFR centre: USC Consortium Colorectal Cancer Family Registry [U01/U24 CA074799]; CCFR centre: Mayo Clinic Cooperative Familial Registry for Colon Cancer Studies [U01/U24 CA074800]; CCFR centre: Ontario Familial Colorectal Cancer Registry [U01/U24 CA074783]; CCFR centre: Seattle Colorectal Cancer Family Registry [U01/U24 CA074794]; CCFR centre: University of Hawaii Colorectal Cancer Family Registry [U01/U24 CA074806]; National Cancer Institute, National Institutes of Health [U01 CA122839, R01 CA143237]; Cancer Surveillance System of the Fred Hutchinson Cancer Research Center-Control [N01-CN-67009, N01-PC-35142]; Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute [HHSN2612013000121]; Fred Hutchinson Cancer Research Center; Hawaii Department of Health as part of the statewide cancer reporting program; National Cancer Institute's Surveillance, Epidemiology and End Results Program (SEER) [N01-PC-67001, N01-PC-35137, HHSN26120100037C, HHSN261201300009I]; California Department of Public Health as part of the statewide cancer reporting program; National Cancer Institute's Surveillance, Epidemiology and End Results Program [HHSN261201000035C, HHSN261201000034C]; Centers for Disease Control and Prevention's National Program of Cancer Registries [U58DP003862-01]; [090532/Z/09/Z] FX We are grateful to all individuals who participated in the various studies. This study made use of genotyping data from the 1958 Birth Cohort, kindly made available by the Wellcome Trust Case Control Consortium 2. A full list of the investigators who contributed to the generation of the data is available at http://www.wtccc.org.uk/. At the Institute of Cancer Research, this work was supported by Cancer Research UK (C1298/A8362-Bobby Moore Fund for Cancer Research UK). Additional support was provided by the National Cancer Research Network. DJ was supported by a summer student grant from the BBRSC. In Edinburgh, the work was supported by Programme Grant funding from Cancer Research UK (C348/A12076). In Oxford, additional funding was provided by the Oxford Comprehensive Biomedical Research Centre and the EU FP7 CHIBCHA grant. Core infrastructure support to the Wellcome Trust Centre for Human Genetics, Oxford was provided by grant (090532/Z/09/Z). We are grateful to many colleagues within UK Clinical Genetics Departments (for CORGI) and to many collaborators who participated in the VICTOR and QUASAR2 trials. We also thank colleagues from the UK National Cancer Research Network (for NSCCG). Support from the European Union (FP7/207-2013, grant 258236) and FP7 collaborative project SYSCOL and COST Action in the UK is also acknowledged (BM1206). The COIN and COIN-B trials were funded by Cancer Research UK and the Medical Research Council and were conducted with the support of the National Institute of Health Research Cancer Research Network. COIN and COIN-B translational studies were supported by the Bobby Moore Fund from Cancer Research UK, Tenovus, the Kidani Trust, Cancer Research Wales and the National Institute for Social Care and Health Research Cancer Genetics Biomedical Research Unit (2011-2014). NAA, RPM and SMW were funded and supported by KFSHRC. In Finland, this work was supported by grants from the Academy of Finland (Finnish Center of Excellence Program 2012-2017, 250345), the Jane and Aatos Erkko Foundation, the Finnish Cancer Society (to KP), the European Research Council (ERC; 268648), the Sigrid Juselius Foundation, SYSCOL, the Nordic Information for Action eScience Center (NIASC), the Nordic Center of Excellence financed by NordForsk (project 62721, to KP) and State Research Funding of Kuopio University Hospital (B1401). We acknowledge the computational resources provided by the ELIXIR node, hosted at the CSC-IT Center for Science, Finland, and funded by the Academy of Finland (grants 271642 and 263164), the Ministry of Education and Culture, Finland. VS was supported by the Finnish Academy (grant number 139635). Sample collection and genotyping in the Finnish Twin Cohort has been supported by the Wellcome Trust Sanger Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007 (201413), the National Institute of Alcohol Abuse and Alcoholism (grants AA-12502 and AA-00145 to Richard J Rose, and K02AA018755 to Danielle M Dick) and the Academy of Finland (100499, 205585, 265240 and 263278 to Jaakko Ka.prio (JK)).; The work of the Colon Cancer Family Registry (CCFR) was supported by the National Cancer Institute (UM1 CA167551), National Institutes of Health and through cooperative agreements with the following CCFR centres: Australasian Colorectal Cancer Family Registry (U01 CA074778, U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (U01/U24 CA074799), Mayo Clinic Cooperative Familial Registry for Colon Cancer Studies (U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (U01/U24 CA074794) and University of Hawaii Colorectal Cancer Family Registry (U01/U24 CA074806). The CCFR Illumina GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (U01 CA122839 and R01 CA143237 to GC). Seattle CCFR research was also supported by the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center-Control Nos. N01-CN-67009 (1996-2003), N01-PC-35142 (2003-2010) and the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute (Contract No. HHSN2612013000121, 2010-2017) with additional support from the Fred Hutchinson Cancer Research Center. The collection of cancer incidence data for the State of Hawaii used in this study was supported by the Hawaii Department of Health as part of the statewide cancer reporting program mandated by Hawai`i Revised Statutes; the National Cancer Institute's Surveillance, Epidemiology and End Results Program (SEER) awarded to the University of Hawaii (Control Nos. N01-PC-67001 1996-2003, N01-PC-35137 2003-10, Contract Nos. HHSN26120100037C 2010-13, HHSN261201300009I 2010-). The collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology and End Results Program contract HHSN261201000035C-awarded to the University of Southern California, and contract HHSN261201000034C-awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement-U58DP003862-01-awarded to the California Department of Public Health. NR 25 TC 1 Z9 1 U1 5 U2 9 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 JUL 12 PY 2016 VL 115 IS 2 BP 266 EP 272 DI 10.1038/bjc.2016.188 PG 7 WC Oncology SC Oncology GA DS1SR UT WOS:000380380300016 PM 27336604 ER PT J AU Ron-Harel, N Santos, D Ghergurovich, JM Sage, PT Reddy, A Lovitch, SB Dephoure, N Satterstrom, FK Sheffer, M Spinelli, JB Gygi, S Rabinowitz, JD Sharpe, AH Haigis, MC AF Ron-Harel, Noga Santos, Daniel Ghergurovich, Jonathan M. Sage, Peter T. Reddy, Anita Lovitch, Scott B. Dephoure, Noah Satterstrom, F. Kyle Sheffer, Michal Spinelli, Jessica B. Gygi, Steven Rabinowitz, Joshua D. Sharpe, Arlene H. Haigis, Marcia C. TI Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation SO Cell Metabolism LA English DT Article ID CALORIE RESTRICTION; LYMPHOCYTE ACTIVATION; SKELETAL-MUSCLE; REGULATORY T; FOLATE; CANCER; SERINE; PATHWAY; PROLIFERATION; BIOSYNTHESIS AB Naive T cell stimulation activates anabolic metabolism to fuel the transition from quiescence to growth and proliferation. Here we show that naive CD4(+) T cell activation induces a unique program of mitochondrial biogenesis and remodeling. Using mass spectrometry, we quantified protein dynamics during T cell activation. We identified substantial remodeling of the mitochondrial proteome over the first 24 hr of T cell activation to generate mitochondria with a distinct metabolic signature, with one-carbon metabolism as the most induced pathway. Salvage pathways and mitochondrial one-carbon metabolism, fed by serine, contribute to purine and thymidine synthesis to enable T cell proliferation and survival. Genetic inhibition of the mitochondrial serine catabolic enzyme SHMT2 impaired T cell survival in culture and antigen-specific T cell abundance in vivo. Thus, during T cell activation, mitochondrial proteome remodeling generates specialized mitochondria with enhanced one-carbon metabolism that is critical for T cell activation and survival. C1 [Ron-Harel, Noga; Santos, Daniel; Reddy, Anita; Dephoure, Noah; Satterstrom, F. Kyle; Spinelli, Jessica B.; Gygi, Steven; Haigis, Marcia C.] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. [Santos, Daniel] Univ Coimbra, CNC Ctr Neurosci & Cell Biol, P-3004504 Coimbra, Portugal. [Ghergurovich, Jonathan M.; Rabinowitz, Joshua D.] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Ghergurovich, Jonathan M.] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. [Sage, Peter T.; Lovitch, Scott B.; Sharpe, Arlene H.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Sage, Peter T.; Lovitch, Scott B.; Sharpe, Arlene H.] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Sheffer, Michal] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Rabinowitz, Joshua D.] Princeton Univ, Dept Chem, Princeton, NJ 08544 USA. RP Haigis, MC (reprint author), Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA. EM marcia_haigis@hms.harvard.edu FU NIH/NIAID [HHSN272201100018C]; F. Hoffmann-La Roche Ltd.; Glenn Foundation for Medical Research; Ludwig center at Harvard; European Molecular Biology Organization; Portuguese Foundation for Science and Technology (FCT-MCTES) FX The authors thank the Electron Microscopy Core at BIDMC. This study was supported in part by grants from NIH/NIAID HHSN272201100018C (to M.C.H. and A.H.S.), F. Hoffmann-La Roche Ltd. (to A.H.S. and M.C.H.), the Glenn Foundation for Medical Research (to M.C.H.), and the Ludwig center at Harvard (to M.C.H.). N.R.-H. was supported by The European Molecular Biology Organization long-term postdoctoral fellowship. D.S. was supported by a PhD Fellowship from Portuguese Foundation for Science and Technology (FCT-MCTES). NR 40 TC 10 Z9 10 U1 4 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD JUL 12 PY 2016 VL 24 IS 1 BP 104 EP 117 DI 10.1016/j.cmet.2016.06.007 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA DS5AR UT WOS:000380793400015 PM 27411012 ER PT J AU Fontana, L Cummings, NE Apelo, SIA Neuman, JC Kasza, I Schmidt, BA Cava, E Spelta, F Tosti, V Syed, FA Baar, EL Veronese, N Cottrell, SE Fenske, RJ Bertozzi, B Brar, HK Pietka, T Bullock, AD Figenshau, RS Andriole, GL Merrins, MJ Alexander, CM Kimple, ME Lamming, DW AF Fontana, Luigi Cummings, Nicole E. Apelo, Sebastian I. Arriola Neuman, Joshua C. Kasza, Ildiko Schmidt, Brian A. Cava, Edda Spelta, Francesco Tosti, Valeria Syed, Faizan A. Baar, Emma L. Veronese, Nicola Cottrell, Sara E. Fenske, Rachel J. Bertozzi, Beatrice Brar, Harpreet K. Pietka, Terri Bullock, Arnold D. Figenshau, Robert S. Andriole, Gerald L. Merrins, Matthew J. Alexander, Caroline M. Kimple, Michelle E. Lamming, Dudley W. TI Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health SO CELL REPORTS LA English DT Article ID ISLET BETA-CELLS; CALORIC RESTRICTION; INSULIN-RESISTANCE; DIETARY-PROTEIN; LIFE-SPAN; METHIONINE RESTRICTION; GLUCOSE-METABOLISM; ADIPOSE-TISSUE; VISCERAL FAT; MICE AB Protein-restricted (PR), high-carbohydrate diets improve metabolic health in rodents, yet the precise dietary components that are responsible for these effects have not been identified. Furthermore, the applicability of these studies to humans is unclear. Here, we demonstrate in a randomized controlled trial that a moderate PR diet also improves markers of metabolic health in humans. Intriguingly, we find that feeding mice a diet specifically reduced in branched-chain amino acids (BCAAs) is sufficient to improve glucose tolerance and body composition equivalently to a PR diet via metabolically distinct pathways. Our results highlight a critical role for dietary quality at the level of amino acids in the maintenance of metabolic health and suggest that diets specifically reduced in BCAAs, or pharmacological interventions in this pathway, may offer a translatable way to achieve many of the metabolic benefits of a PR diet. C1 [Fontana, Luigi; Cava, Edda; Spelta, Francesco; Tosti, Valeria; Veronese, Nicola; Bertozzi, Beatrice; Pietka, Terri] Washington Univ, Div Geriatr & Nutr Sci, St Louis, MO 63130 USA. [Fontana, Luigi] Univ Brescia, Sch Med, Dept Clin & Expt Sci, I-25121 Brescia, Italy. [Fontana, Luigi] CEINGE Biotecnol Avanzate, I-80145 Naples, Italy. [Cummings, Nicole E.; Apelo, Sebastian I. Arriola; Neuman, Joshua C.; Schmidt, Brian A.; Syed, Faizan A.; Baar, Emma L.; Cottrell, Sara E.; Fenske, Rachel J.; Brar, Harpreet K.; Merrins, Matthew J.; Kimple, Michelle E.; Lamming, Dudley W.] Univ Wisconsin, Dept Med, Madison, WI 53705 USA. [Cummings, Nicole E.; Apelo, Sebastian I. Arriola; Neuman, Joshua C.; Schmidt, Brian A.; Syed, Faizan A.; Baar, Emma L.; Cottrell, Sara E.; Fenske, Rachel J.; Brar, Harpreet K.; Merrins, Matthew J.; Kimple, Michelle E.; Lamming, Dudley W.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. [Cummings, Nicole E.; Kimple, Michelle E.; Lamming, Dudley W.] Univ Wisconsin, Endocrinol & Reprod Physiol Grad Training Program, Madison, WI 53706 USA. [Neuman, Joshua C.; Fenske, Rachel J.; Kimple, Michelle E.; Lamming, Dudley W.] Univ Wisconsin, Interdisciplinary Grad Program Nutr Sci, Madison, WI 53706 USA. [Kasza, Ildiko; Alexander, Caroline M.] Univ Wisconsin, McArdle Lab Canc Res, Madison, WI 53705 USA. [Cava, Edda] Sapienza Univ Rome, Dept Expt Med, I-00185 Rome, Italy. [Spelta, Francesco; Tosti, Valeria] Univ Verona, Dept Med, I-37129 Verona, Italy. [Veronese, Nicola] Univ Padua, Dept Med, Div Geriatr, I-35122 Padua, Italy. [Cottrell, Sara E.; Lamming, Dudley W.] Univ Wisconsin, Rural & Urban Scholars Community Hlth Program, Madison, WI 53706 USA. [Bullock, Arnold D.; Figenshau, Robert S.; Andriole, Gerald L.] Washington Univ, Sch Med St Louis, Div Urol, St Louis, MO 63110 USA. [Merrins, Matthew J.] Univ Wisconsin, Dept Biomol Chem, Madison, WI 53706 USA. [Kimple, Michelle E.] Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53705 USA. RP Fontana, L (reprint author), Washington Univ, Div Geriatr & Nutr Sci, St Louis, MO 63130 USA.; Fontana, L (reprint author), Univ Brescia, Sch Med, Dept Clin & Expt Sci, I-25121 Brescia, Italy.; Fontana, L (reprint author), CEINGE Biotecnol Avanzate, I-80145 Naples, Italy.; Lamming, DW (reprint author), Univ Wisconsin, Dept Med, Madison, WI 53705 USA.; Lamming, DW (reprint author), William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA.; Lamming, DW (reprint author), Univ Wisconsin, Endocrinol & Reprod Physiol Grad Training Program, Madison, WI 53706 USA.; Lamming, DW (reprint author), Univ Wisconsin, Interdisciplinary Grad Program Nutr Sci, Madison, WI 53706 USA.; Lamming, DW (reprint author), Univ Wisconsin, Rural & Urban Scholars Community Hlth Program, Madison, WI 53706 USA. EM lfontana@dom.wustl.edu; dlamming@medicine.wisc.edu OI Lamming, Dudley/0000-0002-0079-4467 FU NIH/National Institute on Aging [K99/R00, AG041765]; Wisconsin Partnership Program; Glenn Foundation Award for Research in the Biological Mechanisms of Aging; UW-Madison School of Medicine and Public Health; UW-Madison Department of Medicine; American Federation for Aging Research; Bakewell Foundation; Longer Life Foundation (an RGA/Washington University Partnership); National Center for Research Resources [UL1 RR024992]; American Diabetes Association [1-14-BS-115, 1-16-IBS-212, 1-16-PMF-001]; NIH/NIDDK [R01 DK102598, K01 DK101683]; UW Institute on Aging (NIA) [T32 AG000213]; McArdle Departmental Funds; Rural and Urban Scholars in Community Health Program FX We would like to thank all the members of the D.W.L., L.F., C.M.A., M.E.K., and M.J.M. labs for their assistance and insight, and the Davis lab for their continual support. We would like to thank Dena Cohen for advice and consultation, Tina Herfel (Envigo) for assistance with the formulation of the amino-acid-defined diets, and the reviewers of this manuscript, who greatly aided us with their suggestions. We thank Kathleen Obert, MS, RD, LD for the photograph of a sample dinner used in the slider image accompanying this manuscript and Clint Thayer for assistance with preparation of the slider image. The D.W.L. lab is supported by a K99/R00 Pathway to Independence Award to D.W.L. from the NIH/National Institute on Aging (AG041765), a New Investigator Program Award from the Wisconsin Partnership Program, and a Glenn Foundation Award for Research in the Biological Mechanisms of Aging, as well as startup funds from the UW-Madison School of Medicine and Public Health and the UW-Madison Department of Medicine. This research was conducted while D.W.L. was an AFAR Research Grant recipient from the American Federation for Aging Research. The L.F. lab is supported by grants from the Bakewell Foundation, the Longer Life Foundation (an RGA/Washington University Partnership), and the National Center for Research Resources (UL1 RR024992). This work was also supported by grants from the American Diabetes Association (1-14-BS-115) and the NIH/NIDDK (R01 DK102598) to M.E.K. The M.J.M. lab is supported in part by a Research Scientist Development Award from the NIH/NIDDK (K01 DK101683) and an Innovative Basic Science Award from the American Diabetes Association (1-16-IBS-212) to M.J.M. S.I.A.A. is supported in part by a fellowship from the American Diabetes Association (1-16-PMF-001). J.C.N. is supported in part by a training grant from the UW Institute on Aging (NIA T32 AG000213). I.K. is supported in part by McArdle Departmental Funds. S.E.C. was supported by the Rural and Urban Scholars in Community Health Program. This work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. This work does not represent the views of the Department of Veterans Affairs or the United States Government. NR 47 TC 2 Z9 2 U1 10 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUL 12 PY 2016 VL 16 IS 2 BP 520 EP 530 DI 10.1016/j.celrep.2016.05.092 PG 11 WC Cell Biology SC Cell Biology GA DS0CG UT WOS:000380262300022 PM 27346343 ER PT J AU Li, H Kuwajima, T Oakley, D Nikulina, E Hou, JW Yang, WS Lowry, ER Lamas, NJ Amoroso, MW Croft, GF Hosur, R Wichterle, H Sebti, S Filbin, MT Stockwell, B Henderson, CE AF Li, Hai Kuwajima, Takaaki Oakley, Derek Nikulina, Elena Hou, Jianwei Yang, Wan Seok Lowry, Emily Rhodes Lamas, Nuno Jorge Amoroso, Mackenzie Weygandt Croft, Gist F. Hosur, Raghavendra Wichterle, Hynek Sebti, Said Filbin, Marie T. Stockwell, Brent Henderson, Christopher E. TI Protein Prenylation Constitutes an Endogenous Brake on Axonal Growth SO CELL REPORTS LA English DT Article ID CHONDROITIN SULFATE PROTEOGLYCANS; AMYOTROPHIC-LATERAL-SCLEROSIS; CENTRAL-NERVOUS-SYSTEM; NEURITE OUTGROWTH; STEM-CELLS; NEURONAL PROTECTION; CHEMICAL SCREEN; MOTOR-NEURONS; CYCLIC-AMP; STATIN USE AB Suboptimal axonal regeneration contributes to the consequences of nervous system trauma and neurodegenerative disease, but the intrinsic mechanisms that regulate axon growth remain unclear. We screened 50,400 small molecules for their ability to promote axon outgrowth on inhibitory substrata. The most potent hits were the statins, which stimulated growth of all mouse- and human-patient-derived neurons tested, both in vitro and in vivo, as did combined inhibition of the protein prenylation enzymes farnesyltransferase (PFT) and geranylgeranyl transferase I (PGGT-1). Compensatory sprouting of motor axons may delay clinical onset of amyotrophic lateral sclerosis (ALS). Accordingly, elevated levels of PGGT1B, which would be predicted to reduce sprouting, were found in motor neurons of early-versus late-onset ALS patients postmortem. The mevalonate-prenylation pathway therefore constitutes an endogenous brake on axonal growth, and its inhibition provides a potential therapeutic approach to accelerate neuronal regeneration in humans. C1 [Li, Hai; Kuwajima, Takaaki; Yang, Wan Seok; Wichterle, Hynek; Stockwell, Brent; Henderson, Christopher E.] Columbia Univ, Ctr Motor Neuron Biol & Dis Columbia Stem Cell In, New York, NY 10032 USA. [Henderson, Christopher E.] Columbia Univ, Coll Phys & Surg, Dept Rehabil & Regenerat Med, New York, NY 10032 USA. [Li, Hai; Kuwajima, Takaaki; Lamas, Nuno Jorge; Wichterle, Hynek; Henderson, Christopher E.] Columbia Univ, Coll Phys & Surg, Dept Pathol & Cell Biol Neurol & Neurosci, New York, NY 10032 USA. [Nikulina, Elena; Hou, Jianwei; Filbin, Marie T.] CUNY, Hunter Coll, Dept Biol Sci, New York, NY 10065 USA. [Yang, Wan Seok; Stockwell, Brent] Columbia Univ, Howard Hughes Med Inst, New York, NY 10027 USA. [Yang, Wan Seok; Stockwell, Brent] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Yang, Wan Seok; Stockwell, Brent] Columbia Univ, Dept Chem, New York, NY 10027 USA. [Oakley, Derek; Lowry, Emily Rhodes; Lamas, Nuno Jorge; Amoroso, Mackenzie Weygandt; Croft, Gist F.; Wichterle, Hynek; Henderson, Christopher E.] Project ALS Jenifer Estess Lab Stem Cell Res, New York, NY 10032 USA. [Lamas, Nuno Jorge] Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst, P-4710057 Braga, Minho, Portugal. [Sebti, Said] Univ S Florida, Moffitt Canc Ctr, Tampa, FL 33612 USA. [Sebti, Said] Univ S Florida, Res Inst, Tampa, FL 33612 USA. [Hosur, Raghavendra] Biogen Inc, Computat Biol, Cambridge, MA 02142 USA. [Henderson, Christopher E.] Target ALS Fdn, New York, NY 10032 USA. [Oakley, Derek] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Yang, Wan Seok] St Johns Univ, Dept Biol Sci, Jamaica, NY 11439 USA. [Amoroso, Mackenzie Weygandt] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Croft, Gist F.] Rockefeller Univ, Lab Stem Cell Biol & Mol Embryol, New York, NY 10066 USA. [Henderson, Christopher E.] Biogen Inc, Neurol Res, Cambridge, MA 02142 USA. RP Henderson, CE (reprint author), Columbia Univ, Ctr Motor Neuron Biol & Dis Columbia Stem Cell In, New York, NY 10032 USA.; Henderson, CE (reprint author), Columbia Univ, Coll Phys & Surg, Dept Rehabil & Regenerat Med, New York, NY 10032 USA.; Henderson, CE (reprint author), Columbia Univ, Coll Phys & Surg, Dept Pathol & Cell Biol Neurol & Neurosci, New York, NY 10032 USA.; Henderson, CE (reprint author), Project ALS Jenifer Estess Lab Stem Cell Res, New York, NY 10032 USA.; Henderson, CE (reprint author), Target ALS Fdn, New York, NY 10032 USA.; Henderson, CE (reprint author), Biogen Inc, Neurol Res, Cambridge, MA 02142 USA. EM chris.henderson@biogen.com FU New York State Spinal Cord Injury Research Board (NYS-SCIRB) [C020923]; P2ALS; Target ALS; Tow Foundation; SMA Foundation; Project A.L.S.; NYSTEM [C026715]; Helmsley Charitable Trust; NINDS [R01-NS056422, NS072428]; Columbia MD-PhD program; NIH [5R01CA097061, R01CA161061]; New York State Stem Cell Science [C026715] FX We thank Samaher Fageiry and Cyndel Vollmer for help with the culture model, Kevin Eggan and collaborators for kindly providing Hb9::GFP human ESC reporter lines, and Chuck Karan and members of the High-Throughput Screening and Chemistry Shared Facility for support and technical guidance. We thank the He lab (Harvard) for training in optic nerve crush. We are grateful to members of the Project A.L.S., Henderson, Wichterle, and Stockwell laboratories at Columbia University for much help and continuous critical discussion. We thank our Biogen colleagues Alex McCampbell, Sha Mi, and Richard Ransohoff for critical reading of the manuscript. This work received invaluable support from the New York State Spinal Cord Injury Research Board (NYS-SCIRB C020923), P2ALS, Target ALS, the Tow Foundation, the SMA Foundation, Project A.L.S., NYSTEM (C026715), The Helmsley Charitable Trust, NINDS R01-NS056422 and NS072428, and the Columbia MD-PhD program. Brent R. Stockwell is an Early Career Scientist of the Howard Hughes Medical Institute, and this research was additionally funded by the NIH (5R01CA097061 and R01CA161061, to B.S.) and New York State Stem Cell Science (C026715). NR 58 TC 1 Z9 1 U1 3 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD JUL 12 PY 2016 VL 16 IS 2 BP 545 EP 558 DI 10.1016/j.celrep.2016.06.013 PG 14 WC Cell Biology SC Cell Biology GA DS0CG UT WOS:000380262300024 PM 27373155 ER PT J AU Gordon, LB Kleinman, ME Massaro, J D'Agostino, RB Shappell, H Gerhard-Herman, M Smoot, LB Gordon, CM Cleveland, RH Nazarian, A Snyder, BD Ullrich, NJ Silvera, VM Liang, MG Quinn, N Miller, DT Huh, SY Dowton, AA Littlefield, K Greer, MM Kieran, MW AF Gordon, Leslie B. Kleinman, Monica E. Massaro, Joe D'Agostino, Ralph B. Shappell, Heather Gerhard-Herman, Marie Smoot, Leslie B. Gordon, Catherine M. Cleveland, Robert H. Nazarian, Ara Snyder, Brian D. Ullrich, Nicole J. Silvera, V. Michelle Liang, Marilyn G. Quinn, Nicolle Miller, David T. Huh, Susanna Y. Dowton, Anne A. Littlefield, Kelly Greer, Maya M. Kieran, Mark W. TI Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome SO CIRCULATION LA English DT Article DE aging; atherosclerosis; progeria ID MUTANT LAMIN-A; FARNESYLTRANSFERASE INHIBITOR; MOUSE MODEL; VASCULAR MEDICINE; SYNDROME MUTATION; AMERICAN SOCIETY; DISEASE; ECHOCARDIOGRAPHY; PROGRESSION; MORTALITY AB Background: Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein progerin. Without progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation. Methods: Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial. Results: No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (P < 0.0001). Key cardiovascular and skeletal secondary variables were predefined. Secondary improvements included increased areal (P = 0.001) and volumetric (P < 0.001-0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (P< 0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%; P = 0.001) and femoral (0% to 12%; P = 0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P = 0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial. Conclusions: Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid. C1 [Gordon, Leslie B.] Hasbro Childrens Hosp, Dept Pediat, 593 Eddy St, Providence, RI 02903 USA. [Gordon, Leslie B.; Kleinman, Monica E.; Dowton, Anne A.; Littlefield, Kelly; Greer, Maya M.] Boston Childrens Hosp, Dept Anesthesia, Boston, MA USA. [Smoot, Leslie B.] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA. [Cleveland, Robert H.; Silvera, V. Michelle] Boston Childrens Hosp, Dept Radiol, Boston, MA USA. [Snyder, Brian D.] Boston Childrens Hosp, Dept Orthoped, Boston, MA USA. [Ullrich, Nicole J.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA. [Liang, Marilyn G.] Boston Childrens Hosp, Dept Dermatol, Boston, MA USA. [Miller, David T.] Boston Childrens Hosp, Dept Genet & Genom, Boston, MA USA. [Huh, Susanna Y.] Boston Childrens Hosp, Dept Gastroenterol & Nutr, Boston, MA USA. [Kieran, Mark W.] Boston Childrens Hosp, Dept Hematol Oncol, Boston, MA USA. [Quinn, Nicolle] Boston Childrens Hosp, Clin Translat Study Unit, Boston, MA USA. [Gerhard-Herman, Marie; Nazarian, Ara] Harvard Med Sch, Boston, MA USA. [Gordon, Leslie B.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Massaro, Joe; D'Agostino, Ralph B.; Shappell, Heather] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Massaro, Joe; D'Agostino, Ralph B.; Shappell, Heather] Harvard Clin Res Inst, Boston, MA USA. [Gerhard-Herman, Marie] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Gordon, Catherine M.] Univ Cincinnati, Med Ctr, Cincinnati Childrens Hosp, Coll Med,Dept Pediat, Cincinnati, OH 45267 USA. [Nazarian, Ara] Beth Israel Deaconess Med Ctr, Dept Orthoped Surg, Ctr Adv Orthopaed Studies, Boston, MA 02215 USA. [Kieran, Mark W.] Harvard Med Sch, Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA USA. RP Gordon, LB (reprint author), Hasbro Childrens Hosp, Dept Pediat, 593 Eddy St, Providence, RI 02903 USA.; Kieran, MW (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM Leslie_Gordon@brown.edu; Mark_Kieran@dfci.harvard.edu FU Progeria Research Foundation [PRFCLIN2007-02, PRFCLIN2009-03]; National Institutes of Health National Heart, Lung, and Blood Institute [1RC2HL101631-0]; Harvard Clinical and Translational Science Center (National Center for Research Resources); Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health) [UL1 TR001102] FX Funding was received from The Progeria Research Foundation (PRFCLIN2007-02 and PRFCLIN2009-03), National Institutes of Health National Heart, Lung, and Blood Institute grant 1RC2HL101631-0, and the Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102). NR 38 TC 3 Z9 3 U1 18 U2 21 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 JUL 12 PY 2016 VL 134 IS 2 BP 114 EP + DI 10.1161/CIRCULATIONAHA.116.022188 PG 26 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DR8EA UT WOS:000380130000009 PM 27400896 ER PT J AU Piccini, JP Hellkamp, AS Washam, JB Becker, RC Breithardt, G Berkowitz, SD Halperin, JL Hankey, GJ Hacke, W Mahaffey, KW Nessel, CC Singer, DE Fox, KAA Patel, MR AF Piccini, Jonathan P. Hellkamp, Anne S. Washam, Jeffrey B. Becker, Richard C. Breithardt, Guenter Berkowitz, Scott D. Halperin, Jonathan L. Hankey, Graeme J. Hacke, Werner Mahaffey, Kenneth W. Nessel, Christopher C. Singer, Daniel E. Fox, Keith A. A. Patel, Manesh R. TI Response by Piccini et al to Letters Regarding Article, "Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation" SO CIRCULATION LA English DT Letter C1 [Piccini, Jonathan P.; Hellkamp, Anne S.; Patel, Manesh R.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Piccini, Jonathan P.; Washam, Jeffrey B.; Patel, Manesh R.] Duke Univ, Med Ctr, Duke Heart Ctr, Durham, NC 27710 USA. [Becker, Richard C.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Breithardt, Guenter] Hosp Univ Munster, Munster, Germany. [Berkowitz, Scott D.] Bayer HealthCare Pharmaceut, Parsippany, NJ USA. [Halperin, Jonathan L.] Mt Sinai Med Ctr, Zena & Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. [Hankey, Graeme J.] Univ Western Australia, Sch Med & Pharmacol, Crawley, Australia. [Hacke, Werner] Heidelberg Univ, Heidelberg, Germany. [Mahaffey, Kenneth W.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Nessel, Christopher C.] Janssen Pharmaceut Res & Dev, Raritan, NJ USA. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Med Sch, Boston, MA USA. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. RP Piccini, JP (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA.; Piccini, JP (reprint author), Duke Univ, Med Ctr, Duke Heart Ctr, Durham, NC 27710 USA. RI Hankey, Graeme /H-4968-2014 OI Hankey, Graeme /0000-0002-6044-7328 NR 3 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD JUL 12 PY 2016 VL 134 IS 2 BP E7 EP E8 DI 10.1161/CIRCULATIONAHA.116.022737 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DR8EA UT WOS:000380130000003 PM 27400902 ER PT J AU Joseph, TT Mincer, JS AF Joseph, Thomas T. Mincer, Joshua S. TI Common Internal Allosteric Network Links Anesthetic Binding Sites in a Pentameric Ligand-Gated Ion Channel SO PLOS ONE LA English DT Article ID GENERAL-ANESTHETICS; TRANSMEMBRANE DOMAIN; DYNAMICS; ACETYLCHOLINE; PROPOFOL; KETAMINE; RECEPTOR; MODULATION; MECHANISMS; SIMULATION AB General anesthetics bind reversibly to ion channels, modifying their global conformational distributions, but the underlying atomic mechanisms are not completely known. We examine this issue by way of the model protein Gloeobacter violaceous ligand-gated ion channel (GLIC) using computational molecular dynamics, with a coarse-grained model to enhance sampling. We find that in flooding simulations, both propofol and a generic particle localize to the crystallographic transmembrane anesthetic binding region, and that propofol also localizes to an extracellular region shared with the crystallographic ketamine binding site. Subsequent simulations to probe these binding modes in greater detail demonstrate that ligand binding induces structural asymmetry in GLIC. Consequently, we employ residue interaction correlation analysis to describe the internal allosteric network underlying the coupling of ligand and distant effector sites necessary for conformational change. Overall, the results suggest that the same allosteric network may underlie the actions of various anesthetics, regardless of binding site. C1 [Joseph, Thomas T.; Mincer, Joshua S.] Icahn Sch Med Mt Sinai, Dept Anesthesiol, New York, NY 10029 USA. [Mincer, Joshua S.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. RP Mincer, JS (reprint author), Icahn Sch Med Mt Sinai, Dept Anesthesiol, New York, NY 10029 USA.; Mincer, JS (reprint author), James J Peters Vet Affairs Med Ctr, Bronx, NY USA. EM joshua.mincer@mountsinai.org RI Mincer, Joshua/B-4785-2008 OI Mincer, Joshua/0000-0002-2482-3154 FU Eliasberg Clinical Scientist Training Program of the Department of Anesthesiology at Icahn School of Medicine at Mount Sinai; National Science Foundation's XSEDE program [TG-MCB140093]; Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai FX Support to T.T.J. is acknowledged from the Eliasberg Clinical Scientist Training Program of the Department of Anesthesiology at Icahn School of Medicine at Mount Sinai. Computational resources on the Stampede computer cluster at the Texas Advanced Computing Center, University of Texas, were supplied through the National Science Foundation's XSEDE program (allocation TG-MCB140093). This work was supported in part through the computational resources and staff expertise provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 0 Z9 0 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 JUL 12 PY 2016 VL 11 IS 7 AR e0158795 DI 10.1371/journal.pone.0158795 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ9CO UT WOS:000379508200015 PM 27403526 ER PT J AU Liu, YL Gunda, V Zhu, X Xu, XD Wu, J Askhatova, D Farokhzad, OC Parangi, S Shi, JJ AF Liu, Yanlan Gunda, Viswanath Zhu, Xi Xu, Xiaoding Wu, Jun Askhatova, Diana Farokhzad, Omid C. Parangi, Sareh Shi, Jinjun TI Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE theranostic; nanoparticle; NIR imaging; siRNA delivery; anaplastic thyroid cancer ID DRUG-DELIVERY; IN-VIVO; NANOPARTICLES; THERAPEUTICS; ACTIVATION; MECHANISMS; CARCINOMA; TOXICITY; THERAPY; TUMORS AB Anaplastic thyroid cancer (ATC), one of the most aggressive solid tumors, is characterized by rapid tumor growth and severe metastasis to other organs. Owing to the lack of effective treatment options, ATC has a mortality rate of similar to 100% and median survival of less than 5 months. RNAi nanotechnology represents a promising strategy for cancer therapy through nanoparticle (NP)-mediated delivery of RNAi agents (e.g., siRNA) to solid tumors for specific silencing of target genes driving growth and/or metastasis. Nevertheless, the clinical success of RNAi cancer nanotherapies remains elusive in large part because of the suboptimal systemic siRNA NP delivery to tumors and the fact that tumor heterogeneity produces variable NP accumulation and thus, therapeutic response. To address these challenges, we here present an innovative theranostic NP platform composed of a near-infrared (NIR) fluorescent polymer for effective in vivo siRNA delivery to ATC tumors and simultaneous tracking of the tumor accumulation by noninvasive NIR imaging. The NIR polymeric NPs are small (similar to 50 nm), show long blood circulation and high tumor accumulation, and facilitate tumor imaging. Systemic siRNA delivery using these NPs efficiently silences the expression of V-Raf murine sarcoma viral oncogene homolog B (BRAF) in tumor tissues and significantly suppresses tumor growth and metastasis in an orthotopic mouse model of ATC. These results suggest that this theranostic NP system could become an effective tool for NIR imaging-guided siRNA delivery for personalized treatment of advanced malignancies. C1 [Liu, Yanlan; Zhu, Xi; Xu, Xiaoding; Wu, Jun; Askhatova, Diana; Farokhzad, Omid C.; Shi, Jinjun] Harvard Med Sch, Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA. [Gunda, Viswanath; Parangi, Sareh] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02214 USA. RP Farokhzad, OC; Shi, JJ (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA.; Parangi, S (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02214 USA. EM ofarokhzad@bwh.harvard.edu; sparangi@partners.org; jshi@bwh.harvard.edu FU NIH [R00CA160350, CA200900, CA149738, EB015419, U54-CA151884]; Department of Defense Prostate Cancer Research Program Synergistic Idea Development Award; Movember-Prostate Cancer Foundation (PCF) Challenge Award; PCF Young Investigator Award; Koch PCF Program in Nanotherapeutics; National Research Foundation of Korea [K1A1A2048701] FX This work was supported by NIH Grants R00CA160350 (to J.S.), CA200900 (to J.S.), CA149738 (to S.P.), EB015419 (to O.C.F.), and U54-CA151884 (to O.C.F.); the Department of Defense Prostate Cancer Research Program Synergistic Idea Development Award (to O.C.F. and J.S.); the Movember-Prostate Cancer Foundation (PCF) Challenge Award (to O.C.F. and J.S.); the PCF Young Investigator Award (to J.S.); the Koch PCF Program in Nanotherapeutics (O.C.F.); and National Research Foundation of Korea Grant K1A1A2048701 (to O.C.F.). NR 29 TC 2 Z9 2 U1 25 U2 40 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 JUL 12 PY 2016 VL 113 IS 28 BP 7750 EP 7755 DI 10.1073/pnas.1605841113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR1VX UT WOS:000379694100035 PM 27342857 ER PT J AU Lin, SG Ba, ZQ Du, Z Zhang, Y Hu, JZ Alt, FW AF Lin, Sherry G. Ba, Zhaoqing Du, Zhou Zhang, Yu Hu, Jiazhi Alt, Frederick W. TI Highly sensitive and unbiased approach for elucidating antibody repertoires SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antibody repertoires; HTGTS-Rep-seq; V(D)J recombination ID DOUBLE-STRANDED BREAKS; B-CELL DEVELOPMENT; HEAVY-CHAIN LOCUS; V(D)J RECOMBINATION; ALLELIC EXCLUSION; VARIABLE-REGION; GENOMIC INSTABILITY; GENE SEGMENTS; EXPRESSION; IGH AB Developing B lymphocytes undergo V(D)J recombination to assemble germ-line V, D, and J gene segments into exons that encode the antigen-binding variable region of Ig heavy (H) and light (L) chains. IgH and IgL chains associate to form the B-cell receptor (BCR), which, upon antigen binding, activates B cells to secrete BCR as an antibody. Each of the huge number of clonally independent B cells expresses a unique set of IgH and IgL variable regions. The ability of V(D)J recombination to generate vast primary B-cell repertoires results from a combinatorial assortment of large numbers of different V, D, and J segments, coupled with diversification of the junctions between them to generate the complementary determining region 3 (CDR3) for antigen contact. Approaches to evaluate in depth the content of primary antibody repertoires and, ultimately, to study how they are further molded by secondary mutation and affinity maturation processes are of great importance to the B-cell development, vaccine, and antibody fields. We now describe an unbiased, sensitive, and readily accessible assay, referred to as high-throughput genome-wide translocation sequencing-adapted repertoire sequencing (HTGTS-Rep-seq), to quantify antibody repertoires. HTGTS-Rep-seq quantitatively identifies the vast majority of IgH and IgL V(D)J exons, including their unique CDR3 sequences, from progenitor and mature mouse B lineage cells via the use of specific J primers. HTGTS-Rep-seq also accurately quantifies DJ(H) intermediates and V(D)J exons in either productive or nonproductive configurations. HTGTS-Rep-seq should be useful for studies of human samples, including clonal B-cell expansions, and also for following antibody affinity maturation processes. C1 [Lin, Sherry G.; Ba, Zhaoqing; Zhang, Yu; Hu, Jiazhi; Alt, Frederick W.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Lin, Sherry G.; Ba, Zhaoqing; Du, Zhou; Zhang, Yu; Hu, Jiazhi; Alt, Frederick W.] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA. [Du, Zhou; Alt, Frederick W.] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Hu, JZ; Alt, FW (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Hu, JZ; Alt, FW (reprint author), Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.; Alt, FW (reprint author), Harvard Med Sch, Howard Hughes Med Inst, Boston, MA 02115 USA. EM jiazhi.hu@childrens.harvard.edu; alt@enders.tch.harvard.edu FU National Institutes of Health [R01AI020047, F31-AI117920]; Cancer Research Institute; Robertson Foundation/Cancer Research Institute; Leukemia and Lymphoma Society FX We thank members of the F.W.A. laboratory for stimulating discussions and Dr. Richard Frock for experimental advice. This work is supported by National Institutes of Health Grant R01AI020047 (to F.W.A.) and Grant F31-AI117920 (to S.G.L.). Z.B. is supported by a Cancer Research Institute Irvington Fellowship; J.H. by a Robertson Foundation/Cancer Research Institute Irvington Fellowship; and Y.Z. by a career development fellowship from the Leukemia and Lymphoma Society. F.W.A. is an investigator of the Howard Hughes Medical Institute. NR 38 TC 1 Z9 1 U1 5 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 JUL 12 PY 2016 VL 113 IS 28 BP 7846 EP 7851 DI 10.1073/pnas.1608649113 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR1VX UT WOS:000379694100051 PM 27354528 ER PT J AU Gunthard, HF Saag, MS Benson, CA del Rio, C Eron, JJ Gallant, JE Hoy, JF Mugavero, MJ Sax, PE Thompson, MA Gandhi, RT Landovitz, RJ Smith, DM Jacobsen, DM Volberding, PA AF Gunthard, Huldrych F. Saag, Michael S. Benson, Constance A. del Rio, Carlos Eron, Joseph J. Gallant, Joel E. Hoy, Jennifer F. Mugavero, Michael J. Sax, Paul E. Thompson, Melanie A. Gandhi, Rajesh T. Landovitz, Raphael J. Smith, Davey M. Jacobsen, Donna M. Volberding, Paul A. TI Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults 2016 Recommendations of the International Antiviral Society-USA Panel SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID NON-INFERIORITY TRIAL; TENOFOVIR DISOPROXIL FUMARATE; RANDOMIZED CONTROLLED-TRIAL; VIROLOGICALLY SUPPRESSED ADULTS; RITONAVIR PLUS LAMIVUDINE; ONCE-DAILY DOLUTEGRAVIR; MYCOBACTERIUM-TUBERCULOSIS INFECTION; REVERSE-TRANSCRIPTASE INHIBITORS; COGNITIVE-BEHAVIORAL THERAPY; BOOSTED PROTEASE INHIBITOR AB IMPORTANCE New data and therapeutic options warrant updated recommendations for the use of antiretroviral drugs (ARVs) to treat or to prevent HIV infection in adults. OBJECTIVE To provide updated recommendations for the use of antiretroviral therapy in adults (aged >= 18 years) with established HIV infection, including when to start treatment, initial regimens, and changing regimens, along with recommendations for using ARVs for preventing HIV among those at risk, including preexposure and postexposure prophylaxis. EVIDENCE REVIEW A panel of experts in HIV research and patient care convened by the International Antiviral Society-USA reviewed data published in peer-reviewed journals, presented by regulatory agencies, or presented as conference abstracts at peer-reviewed scientific conferences since the 2014 report, for new data or evidence that would change previous recommendations or their ratings. Comprehensive literature searches were conducted in the PubMed and EMBASE databases through April 2016. Recommendations were by consensus, and each recommendation was rated by strength and quality of the evidence. FINDINGS Newer data support the widely accepted recommendation that antiretroviral therapy should be started in all individuals with HIV infection with detectable viremia regardless of CD4 cell count. Recommended optimal initial regimens for most patients are 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI). Other effective regimens include nonnucleoside reverse transcriptase inhibitors or boosted protease inhibitors with 2 NRTIs. Recommendations for special populations and in the settings of opportunistic infections and concomitant conditions are provided. Reasons for switching therapy include convenience, tolerability, simplification, anticipation of potential new drug interactions, pregnancy or plans for pregnancy, elimination of food restrictions, virologic failure, or drug toxicities. Laboratory assessments are recommended before treatment, and monitoring during treatment is recommended to assess response, adverse effects, and adherence. Approaches are recommended to improve linkage to and retention in care are provided. Daily tenofovir disoproxil fumarate/emtricitabine is recommended for use as preexposure prophylaxis to prevent HIV infection in persons at high risk. When indicated, postexposure prophylaxis should be started as soon as possible after exposure. CONCLUSIONS AND RELEVANCE Antiretroviral agents remain the cornerstone of HIV treatment and prevention. All HIV-infected individuals with detectable plasma virus should receive treatment with recommended initial regimens consisting of an InSTI plus 2 NRTIs. Preexposure prophylaxis should be considered as part of an HIV prevention strategy for at-risk individuals. When used effectively, currently available ARVs can sustain HIV suppression and can prevent new HIV infection. With these treatment regimens, survival rates among HIV-infected adults who are retained in care can approach those of uninfected adults. C1 [Gunthard, Huldrych F.] Univ Zurich, Univ Zurich Hosp, Zurich, Switzerland. [Gunthard, Huldrych F.] Univ Zurich, Inst Med Virol, Zurich, Switzerland. [Saag, Michael S.; Mugavero, Michael J.] Univ Alabama Birmingham, Birmingham, AL USA. [Benson, Constance A.] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. [del Rio, Carlos] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [del Rio, Carlos] Emory Univ, Sch Med, Atlanta, GA USA. [Eron, Joseph J.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Gallant, Joel E.] Southwest CARE Ctr, Santa Fe, NM USA. [Hoy, Jennifer F.] Alfred Hosp, Melbourne, Vic, Australia. [Hoy, Jennifer F.] Monash Univ, Melbourne, Vic, Australia. [Sax, Paul E.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Sax, Paul E.; Gandhi, Rajesh T.] Harvard Med Sch, Boston, MA USA. [Thompson, Melanie A.] AIDS Res Consortium Atlanta, Atlanta, GA USA. [Gandhi, Rajesh T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Landovitz, Raphael J.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Smith, Davey M.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Jacobsen, Donna M.] Int Antiviral Soc USA, San Francisco, CA USA. [Volberding, Paul A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Gunthard, HF (reprint author), Univ Zurich Hosp, Div Infect Dis & Hosp Epidemiol, Ramistr 100, CH-8091 Zurich, Switzerland. EM huldrych.guenthard@usz.ch RI del Rio, Carlos/B-3763-2012; Infektiologie, USZ/A-6921-2011; gunthard, huldrych/F-1724-2011 OI del Rio, Carlos/0000-0002-0153-3517; gunthard, huldrych/0000-0002-1142-6723 FU International Antiviral Society-USA (IAS-USA); AbbVie; Bristol-Myers Squibb; Gilead Sciences; GlaxoSmithKline; Janssen Therapeutics; Merck; Mylan; Pfizer; Salix Pharmaceuticals; ViiV Healthcare FX The work is sponsored and funded by the International Antiviral Society-USA (IAS-USA), a mission-based, nonmembership, 501(c)(3) not-for-profit organization. In the last 5 years, the IAS-USA has received grants for selected CME activities that are pooled (ie, no single company supports any single effort) from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen Therapeutics, Merck, Mylan, Pfizer, Salix Pharmaceuticals, and ViiV Healthcare. NR 206 TC 28 Z9 28 U1 18 U2 23 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 12 PY 2016 VL 316 IS 2 BP 191 EP 210 DI 10.1001/jama.2016.8900 PG 20 WC Medicine, General & Internal SC General & Internal Medicine GA DQ9CW UT WOS:000379509000015 PM 27404187 ER PT J AU Lee, JS Giesler, DL Fine, MJ AF Lee, Jonathan S. Giesler, Daniel L. Fine, Michael J. TI Management of Community-Acquired Pneumonia Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Lee, Jonathan S.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Giesler, Daniel L.] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Pittsburgh, PA USA. [Fine, Michael J.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Univ Dr 151C,Bldg 30, Pittsburgh, PA 15240 USA. RP Fine, MJ (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Univ Dr 151C,Bldg 30, Pittsburgh, PA 15240 USA. EM michael.fine@va.gov NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 12 PY 2016 VL 316 IS 2 BP 222 EP 223 DI 10.1001/jama.2016.5028 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DQ9CW UT WOS:000379509000023 PM 27404195 ER PT J AU Semigran, MJ AF Semigran, Marc J. TI Transthyretin Amyloidosis A "Zebra" of Many Stripes SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE amyloid; heart failure; transthyretin ID POLYNEUROPATHY; DIFLUNISAL; DEPOSITION; TAFAMIDIS; TRIAL C1 [Semigran, Marc J.] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Semigran, Marc J.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. RP Semigran, MJ (reprint author), Massachusetts Gen Hosp, Div Cardiol, Fruit St,Bigelow 800, Boston, MA 02114 USA. EM msemigran@partners.org NR 13 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 JUL 12 PY 2016 VL 68 IS 2 BP 173 EP 175 DI 10.1016/j.jacc.2016.05.020 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DQ3SV UT WOS:000379123800006 PM 27386770 ER PT J AU Kadian-Dodov, D Gornik, HL Gu, XK Froehlich, J Bacharach, JM Chi, YW Gray, BH Jaff, MR Kim, ESH Mace, P Sharma, A Kline-Rogers, E White, C Olin, JW AF Kadian-Dodov, Daniella Gornik, Heather L. Gu, Xiaokui Froehlich, James Bacharach, J. Michael Chi, Yung-Wei Gray, Bruce H. Jaff, Michael R. Kim, Esther S. H. Mace, Pamela Sharma, Aditya Kline-Rogers, Eva White, Christopher Olin, Jeffrey W. TI Dissection and Aneurysm in Patients With Fibromuscular Dysplasia Findings From the US Registry for FMD SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE angiography; beading; stenosis; tortuosity ID CORONARY-ARTERY DISSECTION; UNRUPTURED INTRACRANIAL ANEURYSMS; UNITED-STATES REGISTRY; CONNECTIVE-TISSUE DISORDERS; AMERICAN-HEART-ASSOCIATION; VASCULAR ABNORMALITIES; CLINICAL-FEATURES; NATURAL-HISTORY; PREVALENCE; MANAGEMENT AB BACKGROUND Fibromuscular dysplasia (FMD) is a noninflammatory arterial disease that predominantly affects women. The arterial manifestations may include beading, stenosis, aneurysm, dissection, or tortuosity. OBJECTIVES This study compared the frequency, location, and outcomes of FMD patients with aneurysm and/or dissection to those of patients without. METHODS The U.S. Registry for FMD involves 12 clinical centers. This analysis included clinical history, diagnostic, and therapeutic procedure results for 921 FMD patients enrolled in the registry as of October 17, 2014. RESULTS Aneurysm occurred in 200 patients (21.7%) and dissection in 237 patients (25.7%); in total, 384 patients (41.7%) had an aneurysm and/or a dissection by the time of FMD diagnosis. The extracranial carotid, renal, and intracranial arteries were the most common sites of aneurysm; dissection most often occurred in the extracranial carotid, vertebral, renal, and coronary arteries. FMD patients with dissection were younger at presentation (48.4 vs. 53.5 years of age, respectively; p < 0.0001) and experienced more neurological symptoms and other end-organ ischemic events than those without dissection. One-third of aneurysm patients (63 of 200) underwent therapeutic intervention for aneurysm repair. CONCLUSIONS Patients with FMD have a high prevalence of aneurysm and/or dissection prior to or at the time of FMD diagnosis. Patients with dissection were more likely to experience ischemic events, and a significant number of patients with dissection or aneurysm underwent therapeutic procedures for these vascular events. Because of the high prevalence and associated morbidity in patients with FMD who have an aneurysm and/ or dissection, it is recommended that every patient with FMD undergo one-time cross-sectional imaging from head to pelvis with computed tomographic angiography or magnetic resonance angiography. (C) 2016 by the American College of Cardiology Foundation. C1 [Kadian-Dodov, Daniella; Olin, Jeffrey W.] Icahn Sch Med Mt Sinai, Zena & Michael Wiener Cardiovasc Inst, 1 Gustave L Levy Pl,Box 1033, New York, NY 10029 USA. [Kadian-Dodov, Daniella; Olin, Jeffrey W.] Icahn Sch Med Mt Sinai, Marie Josee & Henry R Kravis Ctr Cardiovasc Hlth, 1 Gustave L Levy Pl,Box 1033, New York, NY 10029 USA. [Gornik, Heather L.; Kim, Esther S. H.; Kline-Rogers, Eva] Cleveland Clin Heart & Vasc Inst, Dept Cardiovasc Med, Vasc Med Sect, Cleveland, OH USA. [Gu, Xiaokui; Froehlich, James] Univ Michigan, Cardiovasc Ctr, Ann Arbor, MI 48109 USA. [Bacharach, J. Michael] Avera Heart Hosp South Dakota, Dept Cardiol, Sioux Falls, SD USA. [Chi, Yung-Wei] Univ Calif Davis, Med Ctr, Div Cardiovasc Med, Sacramento, CA USA. [Gray, Bruce H.] Vasc Hlth Alliance, Greenville, SC USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Fireman Vasc Ctr, Boston, MA 02114 USA. [Mace, Pamela] Fibromuscular Dysplasia Soc Amer, Rocky River, OH USA. [Sharma, Aditya] Univ Virginia, Div Cardiovasc Med, Charlottesville, VA USA. [White, Christopher] Univ Queensland, Ochsner Clin Sch, Ochsner Med Ctr, Dept Cardiovasc Dis,John Ochsner Heart & Vasc Ins, New Orleans, LA USA. RP Olin, JW (reprint author), Icahn Sch Med Mt Sinai, Zena & Michael Wiener Cardiovasc Inst, 1 Gustave L Levy Pl,Box 1033, New York, NY 10029 USA.; Olin, JW (reprint author), Icahn Sch Med Mt Sinai, Marie Josee & Henry R Kravis Ctr Cardiovasc Hlth, 1 Gustave L Levy Pl,Box 1033, New York, NY 10029 USA. EM jeffrey.olin@mountsinai.org FU FMD Society of America (FMDSA) FX From the aZena and Michael A. Wiener Cardiovascular Institute and Marie-Josee and Henry R. Kravis Center for Cardiovascular Health, Icahn School of Medicine at Mount Sinai, New York, New York; bVascular Medicine Section, Department of Cardiovascular Medicine, Cleveland Clinic Heart and Vascular Institute, Cleveland, Ohio; cCardiovascular Center, University of Michigan, Ann Arbor, Michigan; dDepartment of Cardiology, Avera Heart Hospital of South Dakota, Sioux Falls, South Dakota; eDivision of Cardiovascular Medicine, University of California Davis Medical Center, Sacremento, California; fVascular Health Alliance, Greenville, South Carolina; gFireman Vascular Center, Massachusetts General Hospital, Boston, Massachusetts; hFibromuscular Dysplasia Society of America, Rocky River, Ohio; iDivision of Cardiovascular Medicine, University of Virginia, Charlottesville, Virginia; and the jDepartment of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Medical Center, University of Queensland Ochsner Clinical School, New Orleans, Louisiana. The U.S. Registry for Fibromuscular Dysplasia (FMD) is supported by the FMD Society of America (FMDSA). Dr. Gornik is an FMDSA Medical Advisory Board member. Dr. Froehlich is a consultant for Pfizer, Merck, Novartis, Janssen, and Boehringer-Ingelheim. Ms. Mace is FMDSA Executive Board Director. Dr. Olin is FMDSA Medical Advisory Board Chair. Dr. Jaff is a VIVA Physicians and Society for Cardiovascular Angiography and Intervention board member. Dr. Kim is consultant for Philips Ultrasound. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Mark Creager, MD, served as Guest Editor for this paper. NR 54 TC 2 Z9 2 U1 2 U2 4 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 JUL 12 PY 2016 VL 68 IS 2 BP 176 EP 185 DI 10.1016/j.jacc.2016.04.044 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DQ3SV UT WOS:000379123800007 PM 27386771 ER PT J AU Gyuricza, MR Manheimer, KB Apte, V Krishnan, B Joyce, EF Mckee, BD McKim, KS AF Gyuricza, Mercedes R. Manheimer, Kathryn B. Apte, Vandana Krishnan, Badri Joyce, Eric F. Mckee, Bruce D. McKim, Kim S. TI Dynamic and Stable Cohesins Regulate Synaptonemal Complex Assembly and Chromosome Segregation SO CURRENT BIOLOGY LA English DT Article ID SISTER-CHROMATID COHESION; DROSOPHILA OOCYTES; MEIOTIC PROPHASE; AXIAL ELEMENT; CROSSING-OVER; PROTEIN ORD; NIPPED-B; SYNAPSIS; MEIOSIS; MELANOGASTER AB Assembly of the synaptonemal complex (SC) in Drosophila depends on two independent pathways defined by the chromosome axis proteins C(2) M and ORD. Because C(2) M encodes a Kleisin-like protein and ORD is required for sister-chromatid cohesion, we tested the hypothesis that these two SC assembly pathways depend on two cohesin complexes. Through single-and double-mutant analysis to study the mitotic cohesion proteins Stromalin (SA) and Nipped-B (SCC2) in meiosis, we provide evidence that there are at least two meiosis-specific cohesin complexes. One complex depends on C(2) M, SA, and Nipped-B. Despite the presence of mitotic cohesins SA and Nipped-B, this pathway has only a minor role in meiotic sister-centromere cohesion and is primarily required for homolog interactions. C(2) M is continuously incorporated into pachytene chromosomes even though SC assembly is complete. In contrast, the second complex, which depends on meiosis-specific proteins SOLO, SUNN, and ORD is required for sister-chromatid cohesion, localizes to the centromeres and is not incorporated during prophase. Our results show that the two cohesin complexes have unique functions and are regulated differently. Multiple cohesin complexes may provide the diversity of activities required by the meiotic cell. For example, a dynamic complex may allow the chromosomes to regulate meiotic recombination, and a stable complex may be required for sister- chromatid cohesion. C1 [Gyuricza, Mercedes R.; Manheimer, Kathryn B.; Apte, Vandana; Joyce, Eric F.; McKim, Kim S.] Rutgers State Univ, Waksman Inst, POB 759, Piscataway, NJ 08854 USA. [Gyuricza, Mercedes R.; Manheimer, Kathryn B.; Apte, Vandana; Joyce, Eric F.; McKim, Kim S.] Rutgers State Univ, Dept Genet, Piscataway, NJ 08854 USA. [Krishnan, Badri; Mckee, Bruce D.] Univ Tennessee, Dept Biochem & Cellular & Mol Biol, Knoxville, TN 37996 USA. [Manheimer, Kathryn B.] Grad Sch Biomed Sci Mt Sinai, New York, NY 10029 USA. [Krishnan, Badri] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Krishnan, Badri] Harvard Med Sch, Boston, MA 02114 USA. [Joyce, Eric F.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA. RP McKim, KS (reprint author), Rutgers State Univ, Waksman Inst, POB 759, Piscataway, NJ 08854 USA.; McKim, KS (reprint author), Rutgers State Univ, Dept Genet, Piscataway, NJ 08854 USA. EM mckim@rci.rutgers.edu FU Busch Predoctoral Fellowship; Aresty Foundation Summer Research Fellowship; NIH [GM101955, GM040489] FX We thank Li Nguyen for technical assistance; Scott Hawley, Gary Karpen, Christian Lehner, and Claudio Sunkel for providing antibodies; Oren Schuldiner for an SMC1 clone; and Sarah Radford for helpful comments on the manuscript. We thank the TRiP at Harvard Medical School for providing transgenic RNAi fly stocks used in this study. Fly stocks obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) were also used in this study. M.R.G. was funded by a Busch Predoctoral Fellowship, and V.A. was funded by an Aresty Foundation Summer Research Fellowship. This work was supported by NIH grant GM101955 to K.S.M. and GM040489 to B.D.M. NR 50 TC 2 Z9 2 U1 6 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 EI 1879-0445 J9 CURR BIOL JI Curr. Biol. PD JUL 11 PY 2016 VL 26 IS 13 BP 1688 EP 1698 DI 10.1016/j.cub.2016.05.006 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA DY0PU UT WOS:000384799500034 PM 27291057 ER PT J AU Fassbender, P Herbstreit, F Eikermann, M Teschler, H Peters, J AF Fassbender, Philipp Herbstreit, Frank Eikermann, Matthias Teschler, Helmut Peters, Juergen TI Obstructive Sleep Apnea-Perioperative Risk Factor SO DEUTSCHES ARZTEBLATT INTERNATIONAL LA English DT Review ID RESIDUAL NEUROMUSCULAR BLOCKADE; NEGATIVE PHARYNGEAL PRESSURE; GENIOGLOSSUS MUSCLE-ACTIVITY; NATIONWIDE INPATIENT SAMPLE; UPPER-AIRWAY COLLAPSIBILITY; OF-THE-LITERATURE; STOP-BANG SCORE; POSTOPERATIVE COMPLICATIONS; BERLIN QUESTIONNAIRE; GENERAL-POPULATION AB Background: Obstructive sleep apnea (OSA) is a common disorder of breathing but is probably underappreciated as a perioperative risk factor. Methods: This review is based on pertinent articles, published up to 15 August 2015, that were retrieved by a selective search in PubMed based on the terms "sleep apnea AND anesthesia" OR "sleep apnea AND pathophysiology." The guidelines of multiple specialty societies were considered as well. Results: OSA is characterized by phases of upper airway obstruction accompanied by apnea/hypoventilation, with hypoxemia, hypercapnia, and recurrent overactivation of the sympathetic nervous system. It has been reported that 22% to 82% of all adults who are about to undergo surgery have OSA. The causes of OSA are multifactorial and include, among others, an anatomical predisposition and / or a reduced inspiratory activation of the bronchodilator muscles, particularly when the patient is sleeping or has taken a sedative drug, anesthetic agent, or muscle relaxant. OSA is associated with arterial hypertension, coronary heart disease, and congestive heart failure. It can be assessed before the planned intervention with polysomnography and structured questionnaires (STOP/STOP-BANG), with sensitivities of 62% and 88%. The utility of miniaturized screening devices is debated. Patients with OSA are at risk for perioperative problems including difficult or ineffective mask ventilation and/or intubation, postoperative airway obstruction, and complications arising from other comorbid conditions. They should be appropriately monitored postoperatively depending on the type of intervention they have undergone, and depending on individually varying, patient-related factors; postoperative management in an intensive care unit may be indicated, although no validated data on this topic are yet available. Conclusion: OSA patients need care by specialists from multiple disciplines, including anesthesiologists with experience in recognizing OSA, securing the airway of OSA patients, and managing them postoperatively. No randomized trials have yet compared the modalities of general anesthesia for OSA patients with respect to postoperative complications or phases of apnea or hypopnea. C1 [Fassbender, Philipp; Herbstreit, Frank; Peters, Juergen] Clin Anesthesiol & Intens Care, Essen, Germany. [Fassbender, Philipp; Herbstreit, Frank; Peters, Juergen] Essen Univ Hosp, Essen, Germany. [Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Eikermann, Matthias] Harvard Med Sch, Boston, MA USA. [Eikermann, Matthias] Univ Duisburg Essen, Essen, Germany. [Teschler, Helmut] Univ Hosp Essen, Ruhrlandklin, Dept Intervent Pneumol, Essen, Germany. RP Fassbender, P (reprint author), Univ Klinikum Essen, Klin Anasthesiol & Intens Med, Hufelandstr 55, D-45122 Essen, Germany. EM philipp.fassbender@uk-essen.de FU Merck; ResMed company FX Prof. Eikermann owns stock in Calabash Bioscience Incorporated as well as patents for the use of acyclic curcurbiturile (also known as calabadione) to reverse pharmacological muscle relaxation. He has received third-party research funding from Merck.; Prof. Teschler has served as a paid consultant for the ResMed company, from which he has also received lecture honoraria, third-party research funding, and reimbursement of meeting participation fees and travel expenses. NR 90 TC 0 Z9 0 U1 2 U2 2 PU DEUTSCHER AERZTE-VERLAG GMBH PI COLOGNE PA DIESELSTRABE 2, POSTFACH 400265, D-50859 COLOGNE, GERMANY SN 1866-0452 J9 DTSCH ARZTEBL INT JI Dtsch. Arztebl. Int. PD JUL 11 PY 2016 VL 113 IS 27-28 BP 463 EP + DI 10.3238/arztebl.2016.0463 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA DS5VY UT WOS:000380852300001 PM 27476705 ER PT J AU Singhal, S Bhojnagarwala, PS O'Brien, S Moon, EK Garfall, AL Rao, AS Quatromoni, JG Stephen, TL Litzky, L Deshpande, C Feldman, MD Hancock, WW Conejo-Garcia, JR Albelda, SM Eruslanov, EB AF Singhal, Sunil Bhojnagarwala, Pratik S. O'Brien, Shaun Moon, Edmund K. Garfall, Alfred L. Rao, Abhishek S. Quatromoni, Jon G. Stephen, Tom Li Litzky, Leslie Deshpande, Charuhas Feldman, Michael D. Hancock, Wayne W. Conejo-Garcia, Jose R. Albelda, Steven M. Eruslanov, Evgeniy B. TI Origin and Role of a Subset of Tumor-Associated Neutrophils with Antigen-Presenting Cell Features in Early-Stage Human Lung Cancer SO CANCER CELL LA English DT Article ID POLYMORPHONUCLEAR NEUTROPHILS; CLASS-II; T-CELLS; INDUCTION; GROWTH; TRANSDIFFERENTIATION; DIFFERENTIATION; PROLIFERATION; ACTIVATION; NY-ESO-1 AB Based on studies in mouse tumor models, granulocytes appear to play a tumor-promoting role. However, there are limited data about the phenotype and function of tumor-associated neutrophils (TANs) in humans. Here, we identify a subset of TANs that exhibited characteristics of both neutrophils and antigen-presenting cells (APCs) in early-stage human lung cancer. These APC-like "hybrid neutrophils," which originate from CD11b(+)CD15(hi)CD10(-)CD16(low) immature progenitors, are able to cross-present antigens, as well as trigger and augment anti-tumor T cell responses. Interferon-g and granulocyte-macrophage colony-stimulating factor are requisite factors in the tumor that, working through the Ikaros transcription factor, synergistically exert their APC-promoting effects on the progenitors. Overall, these data demonstrate the existence of a specialized TAN subset with anti-tumor capabilities in human cancer. C1 [Singhal, Sunil; Bhojnagarwala, Pratik S.; Rao, Abhishek S.; Quatromoni, Jon G.; Eruslanov, Evgeniy B.] Univ Penn, Perelman Sch Med, Dept Surg, Div Thorac Surg, Philadelphia, PA 19104 USA. [O'Brien, Shaun; Moon, Edmund K.; Albelda, Steven M.] Univ Penn, Perelman Sch Med, Div Pulm Allergy & Crit Care, Dept Med, Philadelphia, PA 19104 USA. [Garfall, Alfred L.] Univ Penn, Perelman Sch Med, Div Hematol Oncol, Dept Med, Philadelphia, PA 19104 USA. [Litzky, Leslie; Deshpande, Charuhas; Feldman, Michael D.; Hancock, Wayne W.] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Singhal, Sunil] Philadelphia VA Med Ctr, Div Thorac Surg, Dept Surg, Philadelphia, PA 19104 USA. [Stephen, Tom Li; Conejo-Garcia, Jose R.] Wistar Inst Anat & Biol, Tumor Microenvironm & Metastasis Program, 3601 Spruce St, Philadelphia, PA 19104 USA. [Hancock, Wayne W.] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Eruslanov, EB (reprint author), Univ Penn, Perelman Sch Med, Dept Surg, Div Thorac Surg, Philadelphia, PA 19104 USA. EM evgeniy.eruslanov@uphs.upenn.edu FU Department of Defense [LC140199]; NIH [RO1 CA187392-01A1, R01 CA193556, K12CA076931]; Lung Cancer Translation Center of Excellence of the Abramson Cancer Center at the University of Pennsylvania FX This work was supported by the Department of Defense (LC140199 to E.E.), NIH (RO1 CA187392-01A1 to E.E.), NIH (R01 CA193556 to S.S.), NIH (K12CA076931 to A.G.), and the Lung Cancer Translation Center of Excellence of the Abramson Cancer Center at the University of Pennsylvania. NR 38 TC 10 Z9 11 U1 9 U2 12 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 JUL 11 PY 2016 VL 30 IS 1 BP 120 EP 135 DI 10.1016/j.ccell.2016.06.001 PG 16 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DR7JY UT WOS:000380077100016 PM 27374224 ER PT J AU Okello, S Churchill, C Owori, R Nasasira, B Tumuhimbise, C Abonga, CL Mutiibwa, D Christiani, DC Corey, KE AF Okello, Samson Churchill, Cristina Owori, Rogers Nasasira, Benson Tumuhimbise, Christine Abonga, Charles Lagoro Mutiibwa, David Christiani, David C. Corey, Kathleen E. TI Population attributable fraction of Esophageal squamous cell carcinoma due to smoking and alcohol in Uganda SO BMC CANCER LA English DT Article DE Population attributable fraction; Esophageal squamous cell carcinoma; Alcohol; Smoking; Africa ID RISK-FACTORS; HUMAN-PAPILLOMAVIRUS; GASTRIC CANCERS; LINXIAN; TOBACCO; METHYLATION; DRINKING; COHORT; CHINA; TRIAL AB Background: Despite the high rates and regional variation of esophageal squamous cell carcinoma (ESCC) in East Africa, the contributions of smoking and alcohol to the ESCC burden in the general population are unknown. Methods: We conducted a case-control study of patients presenting for upper gastrointestinal endoscopic examination at Mbarara Regional Referral Hospital, Uganda. Sociodemographic data including smoking and alcohol intake were collected prior to endoscopy. Cases were those with histological diagnosis of ESCC and controls were participants with normal endoscopic examination and gastritis/duodentitis or normal histology. We used odds ratios associated with ESCC risk to determine the population attributable fractions for smoking, alcohol use, and a combination of smoking and alcohol use among adults aged 30 years or greater who underwent upper gastrointestinal endoscopy. Results: Our study consisted of 67 cases and 142 controls. Median age was 51 years (IQR 40-64); and participants were predominantly male (59 %). Dysphagia and/or odynophagia as indications for endoscopy were significantly more in cases compared to controls (72 % vs 6 %, p < 0.0001). Male gender and increasing age were statistically associated with ESCC. In the unadjusted models, the population attributable fraction of ESCC due to male gender was 55 %, female gender - 49 %, smoking 20 %, alcohol 9 % and a combination of alcohol & smoking 15 %. After adjusting for gender and age, the population attributable fraction of ESCC due to smoking, alcohol intake and a combination of alcohol & smoking were 16, 10, and 13 % respectively. Conclusion: In this population, 13 % of esophageal squamous cell carcinoma cases would be avoided if smoking and alcohol use were discontinued. These results suggest that other important risk factors for ESCC in southwestern Uganda remain unknown. C1 [Okello, Samson; Nasasira, Benson; Tumuhimbise, Christine; Abonga, Charles Lagoro] Mbarara Univ Sci & Technol, Dept Internal Med, POB 1410, Mbarara, Uganda. [Okello, Samson] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Churchill, Cristina] Univ Virginia, Dept Med, Charlottesville, VA USA. [Owori, Rogers] Gwatiiro Hosp, Wakiso, Uganda. [Mutiibwa, David] Mbarara Univ Sci & Technol, Dept Surg, Mbarara, Uganda. [Christiani, David C.] Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Christiani, David C.; Corey, Kathleen E.] Massachusetts Gen Hosp, Harvard Med Sch, Boston, MA USA. [Corey, Kathleen E.] Massachusetts Gen Hosp, Dept Med, Boston, MA USA. RP Okello, S (reprint author), Mbarara Univ Sci & Technol, Dept Internal Med, POB 1410, Mbarara, Uganda.; Okello, S (reprint author), Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. EM okello.samson@must.ac.ug OI Okello, Samson/0000-0001-7377-6094 NR 34 TC 0 Z9 0 U1 3 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD JUL 11 PY 2016 VL 16 AR 446 DI 10.1186/s12885-016-2492-x PG 6 WC Oncology SC Oncology GA DR6LZ UT WOS:000380014700001 PM 27400987 ER PT J AU Shin, M Suzuki, M Guan, XM Smith, CE Bartlett, JD AF Shin, Masashi Suzuki, Maiko Guan, Xiaomu Smith, Charles E. Bartlett, John D. TI Murine matrix metalloproteinase-20 overexpression stimulates cell invasion into the enamel layer via enhanced Wnt signaling SO SCIENTIFIC REPORTS LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; GENE-EXPRESSION; MOUSE INCISOR; BETA-CATENIN; E-CADHERIN; ELECTRON-MICROSCOPY; ENDOTHELIAL-CELLS; DENTAL ENAMEL; TOOTH; AMELOBLASTS AB Matrix metalloproteinase-20 (MMP20) is expressed by ameloblasts in developing teeth and MMP20 mutations cause enamel malformation. We established a stably transfected Tet-Off Mmp20-inducible ameloblast-lineage cell line and found that MMP20 expression promoted cell invasion. Previously, we engineered transgenic mice (Tg) that drive Mmp20 expression and showed that Mmp20(+/+) Tg mice had soft enamel. Here we asked if Mmp20 overexpression disrupts ameloblast function. Incisors from Mmp20(+/+) mice expressing the Mmp20 Tg had a striking cell infiltrate which nearly replaced the entire enamel layer. A thin layer of enamel-like material remained over the dentin and at the outer tooth surface, but between these regions were invading fibroblasts and epithelial cells that surrounded ectopic bone-like calcifications. Mmp20(+/+) Tg mice had decreased enamel organ cadherin levels compared to the Mmp20 ablated and WT mice and, instead of predominantly locating adjacent to the ameloblast cell membrane, beta-catenin was predominantly present within the nuclei of invading cells. Our data suggest that increased cadherin cleavage by transgenic MMP20 in the WT background releases excess beta-catenin, which translocates to ameloblast nuclei to promote cell migration/invasion. Therefore, we conclude that MMP20 plays a role in normal ameloblast migration through tightly controlled Wnt signaling and that MMP20 overexpression disrupts this process. C1 [Shin, Masashi; Suzuki, Maiko; Bartlett, John D.] Ohio State Univ, Coll Dent, Div Biosci, Columbus, OH 43210 USA. [Guan, Xiaomu] Dept Mineralized Tissue Biol, Cambridge, MA 02142 USA. [Guan, Xiaomu] Harvard Sch Dent Med, Forsyth Inst, Cambridge, MA 02142 USA. [Smith, Charles E.] McGill Univ, Facil Electron Microscopy Res, Dept Anat & Cell Biol, Montreal, PQ H3A 0C7, Canada. RP Bartlett, JD (reprint author), Ohio State Univ, Coll Dent, Div Biosci, Columbus, OH 43210 USA. EM bartlett.196@osu.edu FU National Institute of Dental and Craniofacial Research of the National Institutes of Health [R01DE016276] FX The authors thank Dr. Toshihiro Sugiyama for his generous gift of ALC cells and Justine Dobeck for providing mouse incisor sections. Research reported in this publication was supported by National Institute of Dental and Craniofacial Research of the National Institutes of Health under award number R01DE016276 (JDB). NR 61 TC 0 Z9 0 U1 4 U2 6 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 JUL 11 PY 2016 VL 6 AR 29492 DI 10.1038/srep29492 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ9LF UT WOS:000379530700001 PM 27403713 ER PT J AU Stifter, K Schuster, C Schlosser, M Boehm, BO Schirmbeck, R AF Stifter, Katja Schuster, Cornelia Schlosser, Michael Boehm, Bernhard Otto Schirmbeck, Reinhold TI Exploring the induction of preproinsulin-specific Foxp3(+) CD4(+) Treg cells that inhibit CD8(+) T cell-mediated autoimmune diabetes by DNA vaccination SO SCIENTIFIC REPORTS LA English DT Article ID PD-1 PATHWAY; CD8+T CELLS; NOD MICE; TGF-BETA; TYPE-1; INSULIN; EXPRESSION; ANTIGEN; TOLERANCE; RESPONSES AB DNA vaccination is a promising strategy to induce effector T cells but also regulatory Foxp3(+) CD25(+) CD4(+) Treg cells and inhibit autoimmune disorders such as type 1 diabetes. Little is known about the antigen requirements that facilitate priming of Treg cells but not autoreactive effector CD8(+) T cells. We have shown that the injection of preproinsulin (ppins)-expressing pCI/ppins vector into PD-1- or PD-L1-deficient mice induced K-b/A12-21-monospecific CD8(+) T cells and autoimmune diabetes. A pCI/ppins Delta A12-21 vector (lacking the critical K-b/A12-21 epitope) did not induce autoimmune diabetes but elicited a systemic Foxp3(+) CD25(+) Treg cell immunity that suppressed diabetes induction by a subsequent injection of the diabetogenic pCI/ppins. TGF-beta expression was significantly enhanced in the Foxp3(+) CD25(+) Treg cell population of vaccinated/ppins-primed mice. Ablation of Treg cells in vaccinated/ppins-primed mice by anti-CD25 antibody treatment abolished the protective effect of the vaccine and enabled diabetes induction by pCI/ppins. Adoptive transfer of Treg cells from vaccinated/ppins-primed mice into PD-L1(-/-) hosts efficiently suppressed diabetes induction by pCI/ppins. We narrowed down the Treg-stimulating domain to a 15-residue ppins76-90 peptide. Vaccine-induced Treg cells thus play a crucial role in the control of de novo primed autoreactive effector CD8(+) T cells in this diabetes model. C1 [Stifter, Katja; Schuster, Cornelia; Schirmbeck, Reinhold] Univ Ulm, Dept Internal Med 1, Med Ctr, Ulm, Germany. [Schlosser, Michael] Univ Med Ctr Greifswald, Dept Med Biochem & Mol Biol, Res Grp Predict Diagnost, Karlsburg, Germany. [Boehm, Bernhard Otto] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore 636921, Singapore. [Boehm, Bernhard Otto] Imperial Coll London, London, England. [Schuster, Cornelia] Harvard Med Sch, Joslin Diabet Ctr, Boston, MA USA. RP Schirmbeck, R (reprint author), Univ Ulm, Dept Internal Med 1, Med Ctr, Ulm, Germany. EM reinhold.schirmbeck@uni-ulm.de FU Deutsche Forschungsgemeinschaft [GRK-1789, DFG SCHI-505/4-1] FX We thank Ellen Allmendinger and Andrea Wissmann for outstanding technical assistance. We thank Dr. T. Honjo (Department of Immunology and Genomic Medicine, Kyoto University, Kyoto, Japan) for PD-1-/- mice and Dr. Lieping Chen (Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA) for PD-L1 (B7-H1)-/- mice. We thank Dr. Erik Lindblad (Brenntag Biosector, Frederikssund, Denmark) for providing Alhydrogel. This work was supported by grants from the Deutsche Forschungsgemeinschaft: GRK-1789 'CEMMA' and DFG SCHI-505/4-1 to R.S. NR 52 TC 0 Z9 0 U1 5 U2 5 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 JUL 11 PY 2016 VL 6 AR 29419 DI 10.1038/srep29419 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ8FT UT WOS:000379445200001 PM 27406624 ER PT J AU Zietman, AL AF Zietman, Anthony L. TI Making Radiation Therapy for Prostate Cancer More Economical and More Convenient SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID RANDOMIZED-TRIAL; BREAST-CANCER; RADIOTHERAPY; FRACTIONATION; SCHEDULES; LONG C1 [Zietman, Anthony L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Zietman, AL (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 10 TC 1 Z9 1 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 JUL 10 PY 2016 VL 34 IS 20 BP 2323 EP U30 DI 10.1200/JCO.2016.67.3764 PG 3 WC Oncology SC Oncology GA DQ3TW UT WOS:000379127400001 PM 27091711 ER PT J AU Lee, WR Dignam, JJ Amin, MB Bruner, DW Low, D Swanson, GP Shah, AB D'Souza, DP Michalski, JM Dayes, IS Seaward, SA Hall, WA Nguyen, PL Pisansky, TM Faria, SL Chen, Y Koontz, BF Paulus, R Sandler, HM AF Lee, W. Robert Dignam, James J. Amin, Mahul B. Bruner, Deborah W. Low, Daniel Swanson, Gregory P. Shah, Amit B. D'Souza, David P. Michalski, Jeff M. Dayes, Ian S. Seaward, Samantha A. Hall, William A. Nguyen, Paul L. Pisansky, Thomas M. Faria, Sergio L. Chen, Yuhchyau Koontz, Bridget F. Paulus, Rebecca Sandler, Howard M. TI Randomized Phase III Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INTENSITY-MODULATED RADIOTHERAPY; RADIATION-THERAPY; CONTROLLED-TRIAL; HYPOFRACTIONATION; FAILURE; MEN; TOXICITY AB Purpose Conventional radiotherapy (C-RT) treatment schedules for patients with prostate cancer typically require 40 to 45 treatments that take place from. 8 to 9 weeks. Preclinical and clinical research suggest that hypofractionation-fewer treatments but at a higher dose per treatment-may produce similar outcomes. This trial was designed to assess whether the efficacy of a hypofractionated radiotherapy (H-RT) treatment schedule is no worse than a C-RT schedule in men with low-risk prostate cancer. Patients and Methods A total of 1,115 men with low-risk prostate cancer were randomly assigned 1: 1 to C-RT (73.8 Gy in 41 fractions over 8.2 weeks) or to H-RT (70 Gy in 28 fractions over 5.6 weeks). This trial was designed to establish (with 90% power and an alpha of .05) that treatment with H-RT results in 5-year disease-free survival (DFS) that is not worse than C-RT by more than 7.65% (H-RT/C-RT hazard ratio [HR] < 1.52). Results A total of 1,092 men were protocol eligible and had follow-up information; 542 patients were assigned to C-RT and 550 to H-RT. Median follow-up was 5.8 years. Baseline characteristics were not different according to treatment assignment. The estimated 5-year DFS was 85.3% (95% CI, 81.9 to 88.1) in the C-RT arm and 86.3% (95% CI, 83.1 to 89.0) in the H-RT arm. The DFS HR was 0.85 (95% CI, 0.64 to 1.14), and the predefined noninferiority criterion that required that DFS outcomes be consistent with HR < 1.52 was met (P<.001). Late grade 2 and 3 GI and genitourinary adverse events were increased (HR, 1.31 to 1.59) in patients who were treated with H-RT. Conclusion In men with low-risk prostate cancer, the efficacy of 70 Gy in 28 fractions over 5.6 weeks is not inferior to 73.8 Gy in 41 fractions over 8.2 weeks, although an increase in late GI/genitourinary adverse events was observed in patients treated with H-RT. (C) 2016 by American Society of Clinical Oncology C1 [Lee, W. Robert; Koontz, Bridget F.] Duke Univ, Med Ctr, Durham, NC USA. [Dignam, James J.] Univ Chicago, Chicago, IL USA. [Amin, Mahul B.; Sandler, Howard M.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Low, Daniel] Univ Calif Los Angeles, Los Angeles, CA USA. [Seaward, Samantha A.] Kaiser Permanente No Calif, Santa Clara, CA USA. [Bruner, Deborah W.] Emory Univ, Atlanta, GA 30322 USA. [Swanson, Gregory P.] Baylor Scott & White Healthcare Temple Clin, Temple, TX USA. [Shah, Amit B.] York Canc Ctr, York, N Yorkshire, England. [Dignam, James J.; Paulus, Rebecca] NRG Oncol Stat & Data Management Ctr, Philadelphia, PA USA. [D'Souza, David P.] London Reg Canc Program, London, ON, Canada. [Dayes, Ian S.] McMaster Univ, Hamilton, ON, Canada. [Faria, Sergio L.] McGill Univ, Ctr Hlth, Montreal, PQ, Canada. [Michalski, Jeff M.] Washington Univ, Sch Med, St Louis, MO USA. [Hall, William A.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Nguyen, Paul L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Nguyen, Paul L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Pisansky, Thomas M.] Mayo Clin, Rochester, MN USA. [Chen, Yuhchyau] Univ Rochester, Rochester, NY USA. RP Lee, WR (reprint author), Duke Univ, Med Ctr, Dept Radiat Oncol, Box 3085, Durham, NC 27710 USA. EM w.robert.lee@duke.edu FU National Cancer Institute [U10CA21661, U10CA37422, CA81647, U10CA180868, U10CA180822] FX Supported by National Cancer Institute Grants No. U10CA21661 (Radiation Therapy Oncology Group Statistical Operations), U10CA37422 (Community Clinical Oncology Program), CA81647 (Advanced Technology Quality Assurance Center), U10CA180868 (NRG Oncology Operations), and U10CA180822 (NRG Oncology Data Monitoring Committee). NR 29 TC 20 Z9 20 U1 1 U2 2 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 JUL 10 PY 2016 VL 34 IS 20 BP 2325 EP U39 DI 10.1200/JCO.2016.67.0448 PG 9 WC Oncology SC Oncology GA DQ3TW UT WOS:000379127400002 PM 27044935 ER PT J AU Denduluri, N Somerfield, MR Eisen, A Holloway, JN Hurria, A King, TA Lyman, GH Partridge, AH Telli, ML Trudeau, ME Wolff, AC AF Denduluri, Neelima Somerfield, Mark R. Eisen, Andrea Holloway, Jamie N. Hurria, Arti King, Tari A. Lyman, Gary H. Partridge, Ann H. Telli, Melinda L. Trudeau, Maureen E. Wolff, Antonio C. TI Selection of Optimal Adjuvant Chemotherapy Regimens for Human Epidermal Growth Factor Receptor 2 (HER2) -Negative and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COMPLETE RESPONSE RATES; RANDOMIZED-TRIALS; SYSTEMIC THERAPY; PLUS TRASTUZUMAB; OLDER-ADULTS; CYCLOPHOSPHAMIDE; WOMEN; DOXORUBICIN; PACLITAXEL; DOCETAXEL AB Purpose A Cancer Care Ontario (CCO) guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer including adjuvant targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancers was identified for adaptation. Methods The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for adapting clinical practice guidelines developed by other organizations. The CCO guideline was reviewed for developmental rigor and content applicability. Results On the basis of the content review of the CCO guideline, the ASCO Panel agreed that, in general, the recommendations were clear and thorough and were based on the most relevant scientific evidence, and they presented options that will be acceptable to patients. However, for some topics addressed in the CCO guideline, the ASCO Panel formulated a set of adapted recommendations on the basis of local context and practice beliefs of the Panel members. Recommendations Decisions regarding adjuvant chemotherapy regimens should take into account baseline recurrence risk, toxicities, likelihood of benefit, and host factors such as comorbidities. In high-risk HER2-negative populations with excellent performance status, anthracycline-and taxane-containing regimens are the standard of care. Docetaxel and cyclophosphamide for four cycles is an acceptable non-anthracycline regimen. In high-risk HER2-positive disease, sequential anthracycline and taxanes administered concurrently with trastuzumab or docetaxel, carboplatin, and trastuzumab for six cycles are recommended. An alternative regimen in a lower-risk, node-negative, HER2-positive population is paclitaxel and trastuzumab once per week for 12 cycles. Trastuzumab should be given for 1 year. Platinum salts should not be routinely administered in the adjuvant triple-negative population until survival efficacy data become available. (C) 2016 by American Society of Clinical Oncology C1 [Denduluri, Neelima] US Oncol Network, Virginia Canc Specialists, Arlington, VA USA. [Somerfield, Mark R.] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. [Eisen, Andrea; Trudeau, Maureen E.] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Eisen, Andrea; Trudeau, Maureen E.] Canc Care Ontario, Toronto, ON, Canada. [Hurria, Arti] City Hope Natl Med Ctr, Duarte, CA USA. [Telli, Melinda L.] Stanford Univ, Palo Alto, CA 94304 USA. [King, Tari A.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Partridge, Ann H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lyman, Gary H.] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. [Wolff, Antonio C.] Johns Hopkins Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Denduluri, N (reprint author), Amer Soc Clin Oncol, Alexandria, VA 22314 USA. EM guidelines@asco.org NR 32 TC 13 Z9 13 U1 3 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 JUL 10 PY 2016 VL 34 IS 20 BP 2416 EP U186 DI 10.1200/JCO.2016.67.0182 PG 14 WC Oncology SC Oncology GA DQ3TW UT WOS:000379127400013 PM 27091714 ER PT J AU Kimball, AB Javorsky, E Ron, ES Crowley, W Langer, R AF Kimball, A. B. Javorsky, E. Ron, E. S. Crowley, W., Jr. Langer, R. TI A novel approach to administration of peptides in women: Systemic absorption of a GnRH agonist via transvaginal ring delivery system SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Intravaginal Ring; EVA; GnRH Agonist; Peptide; Phase 1; Transepithelial ID GONADOTROPIN-RELEASING-HORMONE; IDIOPATHIC PRECOCIOUS PUBERTY; DRUG-DELIVERY; LHRH AGONIST; CONTRACEPTION; POLYMERS; ANALOG; ROUTE AB trans-Epithelial delivery of medication across the vagina has proven successful for administration of small, lipophilic molecules such as sex steroids. However, little information is available regarding the vaginal delivery of larger and more polar molecules that currently require parenteral administration because the vaginal epithelium is perceived as a barrier to absorption of larger molecular weight (MW) molecules. Six healthy women underwent administration of 18 or 36 mg of leuprolide, a GnRH agonist and a larger MW peptide, via a novel ethylene vinyl acetate (EVA) ring transvaginal drug delivery system (TVDS). Serum levels rose within 8 h following insertion: low dose at 310 pg/ml and high dose at 1220 pg/ml, i.e. levels typically following parenteral injections of leuprolide. GnRHa biological activity was validated by secretion of gonadotropins and sex steroids. These results demonstrate that the non-keratinized vaginal epithelium permits a rapid absorption of a biologically active peptide and that there is significant potential for a novel TVDS to deliver peptides and possibly other macromolecules therapeutically. Significance statement: Current routes of administration of medications can include oral, subcutaneous, intravenous, intramuscular, transcutaneous, etc. Many of these approaches have limitations, including pain, poor tolerability, lack of adherence, and inadequate delivery. Peptides, in particular, cannot typically be given orally because they are broken down in the intestinal tract before they are absorbed. While the skin is an attractive way to deliver medications, its superb intrinsic barrier function often makes this route untenable at times. The vaginal epithelium, in contrast, is not keratinized and can allow absorption of other molecules. In this study, we demonstrate that a novel transvaginal drug delivery system(TVDS) is capable of delivering peptide therapeutics to women in a non-parenteral fashion as demonstrated by both blood levels and biologic effects of its delivery. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. C1 [Kimball, A. B.; Javorsky, E.; Crowley, W., Jr.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Ron, E. S.] Madash LLC, Lexington, MA USA. [Langer, R.] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Kimball, AB (reprint author), Massachusetts Gen Hosp, 50 Staniford St 240, Boston, MA 02114 USA. EM harvardskinstudies@partners.org FU Swensrud Foundation and Combinent Biomedical Systems; Juniper Pharmaceuticals FX Funding for this study was supplied in part by The Swensrud Foundation and Combinent Biomedical Systems. An exclusive worldwide license to the novel vaginal ring delivery system was acquired by Juniper Pharmaceuticals, Inc., in April 2015. Final editing of the manuscript and the submission thereof was funded by Juniper Pharmaceuticals. NR 22 TC 2 Z9 2 U1 10 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD JUL 10 PY 2016 VL 233 BP 19 EP 28 DI 10.1016/j.jconrel.2016.04.035 PG 10 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA DO8TJ UT WOS:000378056400003 PM 27130696 ER PT J AU Das, F Dey, N Bera, A Kasinath, BS Ghosh-Choudhury, N Choudhury, GG AF Das, Falguni Dey, Nirmalya Bera, Amit Kasinath, Balakuntalam S. Ghosh-Choudhury, Nandini Choudhury, Goutam Ghosh TI MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Akt PKB; cancer; cell signaling; microRNA (miRNA); mTOR complex (mTORC) ID PHASE-III TRIAL; MAMMALIAN TARGET; CLEAR-CELL; MESSENGER-RNA; TRANSLATION INITIATION; TUMOR PROGRESSION; PROMOTER ACTIVITY; MESANGIAL CELLS; CANCER; RAPAMYCIN AB Elevated IGF-1/insulin-like growth factor-1 receptor (IGF-1R) autocrine/paracrine signaling in patients with renal cell carcinoma is associated with poor prognosis of the disease independent of their von Hippel-Lindau (VHL) status. Increased expression of IGF-1R in renal cancer cells correlates with their potency of tumor development and progression. The mechanism by which expression of IGF-1R is increased in renal carcinoma is not known. We report that VHL-deficient and VHL-positive renal cancer cells possess significantly decreased levels of mature, pre-, and pri-miR-214 than normal proximal tubular epithelial cells. We identified an miR-214 recognition element in the 3UTR of IGF-1R mRNA and confirmed its responsiveness to miR-214. Overexpression of miR-214 decreased the IGF-1R protein levels, resulting in the inhibition of Akt kinase activity in both types of renal cancer cells. IGF-1 provoked phosphorylation and inactivation of PRAS40 in an Akt-dependent manner, leading to the activation of mTORC1 signal transduction to increase phosphorylation of S6 kinase and 4EBP-1. Phosphorylation-deficient mutants of PRAS40 and 4EBP-1 significantly inhibited IGF-1R-driven proliferation of renal cancer cells. Expression of miR-214 suppressed IGF-1R-induced phosphorylation of PRAS40, S6 kinase, and 4EBP-1, indicating inhibition of mTORC1 activity. Finally, miR-214 significantly blocked IGF-1R-forced renal cancer cell proliferation, which was reversed by expression of 3UTR-less IGF-1R and constitutively active mTORC1. Together, our results identify a reciprocal regulation of IGF-1R levels and miR-214 expression in renal cancer cells independent of VHL status. Our data provide evidence for a novel mechanism for IGF-1R-driven renal cancer cell proliferation involving miR-214 and mTORC1. C1 [Kasinath, Balakuntalam S.; Ghosh-Choudhury, Nandini; Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, Vet Affairs Res & Geriatr Res, San Antonio, TX 78229 USA. [Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, Educ & Clin Ctr, San Antonio, TX 78229 USA. [Das, Falguni; Dey, Nirmalya; Bera, Amit; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Ghosh-Choudhury, Nandini] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. RP Choudhury, GG (reprint author), South Texas Vet Hlth Care Syst, Vet Affairs Res & Geriatr Res, San Antonio, TX 78229 USA.; Choudhury, GG (reprint author), South Texas Vet Hlth Care Syst, Educ & Clin Ctr, San Antonio, TX 78229 USA.; Choudhury, GG (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. EM choudhuryg@uthscsa.edu FU Veterans Affairs Research Service Merit Review Grant [2 I01 BX000926]; National Institutes of Health [RO1 DK50190]; Veterans Affairs Merit Review Grant [5I01BX001340, 5I01BX000150]; Veterans Affairs Senior Research Career Scientist Award FX This work was supported in part by the Veterans Affairs Research Service Merit Review Grant 2 I01 BX000926 and National Institutes of Health Grant RO1 DK50190 (to G. G. C.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.; Supported by Veterans Affairs Merit Review Grant 5I01BX001340.; Supported by Veterans Affairs Merit Review Grant 5I01BX000150.; Recipient of a Veterans Affairs Senior Research Career Scientist Award. To whom correspondence should be addressed. E-mail: choudhuryg@uthscsa.edu. NR 91 TC 2 Z9 2 U1 3 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 8 PY 2016 VL 291 IS 28 BP 14662 EP 14676 DI 10.1074/jbc.M115.694331 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA DS1OV UT WOS:000380366700021 PM 27226530 ER PT J AU Valm, AM Oldenbourg, R Borisy, GG AF Valm, Alex M. Oldenbourg, Rudolf Borisy, Gary G. TI Multiplexed Spectral Imaging of 120 Different Fluorescent Labels SO PLOS ONE LA English DT Article ID ARCHITECTURE; MICROSCOPY; PROTEINS AB The number of fluorescent labels that can unambiguously be distinguished in a single image when acquired through band pass filters is severely limited by the spectral overlap of available fluorophores. The recent development of spectral microscopy and the application of linear unmixing algorithms to spectrally recorded image data have allowed simultaneous imaging of fluorophores with highly overlapping spectra. However, the number of distinguishable fluorophores is still limited by the unavoidable decrease in signal to noise ratio when fluorescence signals are fractionated over multiple wavelength bins. Here we present a spectral image analysis algorithm to greatly expand the number of distinguishable objects labeled with binary combinations of fluorophores. Our algorithm utilizes a priori knowledge about labeled specimens and imposes a binary label constraint on the unmixing solution. We have applied our labeling and analysis strategy to identify microbes labeled by fluorescence in situ hybridization and here demonstrate the ability to distinguish 120 differently labeled microbes in a single image. C1 [Valm, Alex M.; Oldenbourg, Rudolf] Marine Biol Lab, Woods Hole, MA 02543 USA. [Valm, Alex M.; Oldenbourg, Rudolf] Brown Univ, Providence, RI 02912 USA. [Borisy, Gary G.] Forsyth Inst, Cambridge, MA USA. [Valm, Alex M.] NICHHD, NIH, NIH NICHD, Bethesda, MD 20892 USA. RP Valm, AM (reprint author), Marine Biol Lab, Woods Hole, MA 02543 USA.; Valm, AM (reprint author), Brown Univ, Providence, RI 02912 USA.; Valm, AM (reprint author), NICHHD, NIH, NIH NICHD, Bethesda, MD 20892 USA. EM Alex.Valm@nih.gov FU Alfred P. Sloan Foundation [2007-3-13]; National Institutes of Health from the National Institute of Dental and Craniofacial Research (NIDCR) [1RC1-DE020630]; National Institutes of Health from NIDCR [1F31-DE019576] FX This work was supported by Grant 2007-3-13 from the Alfred P. Sloan Foundation (to GGB), National Institutes of Health Grant 1RC1-DE020630 from the National Institute of Dental and Craniofacial Research (NIDCR) (to GGB) and by National Institutes of Health Fellowship 1F31-DE019576 from NIDCR (to AMV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 0 Z9 0 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 JUL 8 PY 2016 VL 11 IS 7 AR e0158495 DI 10.1371/journal.pone.0158495 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR6IK UT WOS:000380005400069 PM 27391327 ER PT J AU Mpondo, BCT Neilson, E Ernest, A AF Mpondo, Bonaventura C. T. Neilson, Eric Ernest, Alex TI Prevalence of chronic kidney disease in diabetic adult out-patients in Tanzania SO BMC NEPHROLOGY LA English DT Editorial Material DE Diabetes mellitus; Schistosomiasis; Microalbuminuria; Proteinuria; Chronic kidney disease ID SCHISTOSOMIASIS; EPIDEMIOLOGY; ALBUMINURIA AB Despite the increasing number of patients with Diabetes Mellitus in sub-Saharan Africa, the magnitude of chronic kidney disease among diabetics has not been well established. A study done by Janmohamed et al. found chronic kidney disease in 83.7 % of diabetics which is relatively higher than the prevalence reported elsewhere. However this study was conducted in schistosoma endemic area along the shores of Lake Victoria. Schistosomiasis has been reported to cause a range of renal diseases. Interpretation of these findings should therefore take into account the possibility of schistosomiasis as a possible confounder. C1 [Mpondo, Bonaventura C. T.] Univ Dodoma, Coll Hlth & Allied Sci, Sch Med & Dent, Dept Internal Med, Dodoma, Tanzania. [Neilson, Eric] Massachusetts Gen Hosp Ctr Global Hlth, Peace Corps SEED Global Hlth Serv Partnership, Boston, MA USA. [Ernest, Alex] Univ Dodoma, Coll Hlth & Allied Sci, Sch Med & Dent, Dept Surg & Maternal Hlth, Dodoma, Tanzania. RP Mpondo, BCT (reprint author), Univ Dodoma, Coll Hlth & Allied Sci, Sch Med & Dent, Dept Internal Med, Dodoma, Tanzania. EM boniempondo@gmail.com NR 14 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JUL 8 PY 2016 VL 17 AR 71 DI 10.1186/s12882-016-0276-9 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA DR3QZ UT WOS:000379819000004 PM 27391318 ER PT J AU Morris, A Paulson, JN Talukder, H Tipton, L Kling, H Cui, LJ Fitch, A Pop, M Norris, KA Ghedin, E AF Morris, Alison Paulson, Joseph N. Talukder, Hisham Tipton, Laura Kling, Heather Cui, Lijia Fitch, Adam Pop, Mihai Norris, Karen A. Ghedin, Elodie TI Longitudinal analysis of the lung microbiota of cynomolgous macaques during long-term SHIV infection SO MICROBIOME LA English DT Article DE SHIV; Microbiota; 16S rRNA; Time series ID OBSTRUCTIVE PULMONARY-DISEASE; PREVOTELLA-INTERMEDIA; PRIMATE MODEL; HIV-INFECTION; COLONIZATION AB Background: Longitudinal studies of the lung microbiome are challenging due to the invasive nature of sample collection. In addition, studies of the lung microbiome in human disease are usually performed after disease onset, limiting the ability to determine early events in the lung. We used a non-human primate model to assess lung microbiome alterations over time in response to an HIV-like immunosuppression and determined impact of the lung microbiome on development of obstructive lung disease. Cynomolgous macaques were infected with the SIV-HIV chimeric virus SHIV89.6P. Bronchoalveolar lavage fluid samples were collected pre-infection and every 4 weeks for 53 weeks post-infection. The microbiota was characterized at each time point by 16S ribosomal RNA (rRNA) sequencing. Results: We observed individual variation in the composition of the lung microbiota with a proportion of the macaques having Tropheryma whipplei as the dominant organism in their lungs. Bacterial communities varied over time both within and between animals, but there did not appear to be a systematic alteration due to SHIV infection. Development of obstructive lung disease in the SHIV-infected animals was characterized by a relative increase in abundance of oral anaerobes. Network analysis further identified a difference in community composition that accompanied the development of obstructive disease with negative correlations between members of the obstructed and non-obstructed groups. This emphasizes how species shifts can impact multiple other species, potentially resulting in disease. Conclusions: This study is the first to investigate the dynamics of the lung microbiota over time and in response to immunosuppression in a non-human primate model. The persistence of oral bacteria in the lung and their association with obstruction suggest a potential role in pathogenesis. The lung microbiome in the non-human primate is a valuable tool for examining the impact of the lung microbiome in human health and disease. C1 [Morris, Alison; Fitch, Adam] Univ Pittsburgh, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA. [Morris, Alison; Kling, Heather; Norris, Karen A.] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA USA. [Paulson, Joseph N.; Talukder, Hisham; Pop, Mihai] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. [Tipton, Laura; Ghedin, Elodie] New York Univ, Dept Biol, Ctr Genom & Syst Biol, 12 Waverly Pl, New York, NY 10003 USA. [Tipton, Laura; Ghedin, Elodie] New York Univ, Coll Global Publ Hlth, 12 Waverly Pl, New York, NY 10003 USA. [Tipton, Laura; Ghedin, Elodie] Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA. [Cui, Lijia] Tsinghua Univ, Sch Med, Beijing, Peoples R China. [Paulson, Joseph N.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Paulson, Joseph N.] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Ghedin, E (reprint author), New York Univ, Dept Biol, Ctr Genom & Syst Biol, 12 Waverly Pl, New York, NY 10003 USA.; Ghedin, E (reprint author), New York Univ, Coll Global Publ Hlth, 12 Waverly Pl, New York, NY 10003 USA.; Ghedin, E (reprint author), Univ Pittsburgh, Sch Med, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA. EM elodie.ghedin@nyu.edu FU US National Science Foundation [DGE0750616]; NIH/NHLBI [U01 HL098962, K24 HL123342, R01 HL077095, R01 HL083462]; NIH/NIAID [R01 AI100947]; China Scholarship Council; [T32 AI49820] FX JNP was supported by a US National Science Foundation Graduate Research Fellowship (DGE0750616). EG, AM, MP, and LT were supported by NIH/NHLBI U01 HL098962. AM was also supported by NIH/NHLBI K24 HL123342. KAN was supported by NIH/NHLBI R01 HL077095 and R01 HL083462. MP was supported by NIH/NIAID R01 AI100947. HK was supported by T32 AI49820. LC was a visiting scholar from Tsinghua University and supported in part by the China Scholarship Council. NR 29 TC 1 Z9 1 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2049-2618 J9 MICROBIOME JI Microbiome PD JUL 8 PY 2016 VL 4 AR 38 DI 10.1186/s40168-016-0183-0 PG 11 WC Microbiology SC Microbiology GA DR4UI UT WOS:000379898200001 PM 27391224 ER PT J AU Weiniger, CF Lyell, DJ Tsen, LC Butwick, AJ Shachar, B Callaghan, WM Creanga, AA Bateman, BT AF Weiniger, Carolyn F. Lyell, Deirdre J. Tsen, Lawrence C. Butwick, Alexander J. Shachar, BatZion Callaghan, William M. Creanga, Andreea A. Bateman, Brian T. TI Maternal outcomes of term breech presentation delivery: impact of successful external cephalic version in a nationwide sample of delivery admissions in the United States SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article DE Breech; Cesarean delivery; External cephalic version; Maternal morbidity ID PRIMARY CESAREAN DELIVERY; VAGINAL BIRTH; RISK; MORBIDITY; RATES; ASSOCIATION; PREDICTORS; MORTALITY; SECTION; WOMEN AB Background: We aimed to define the frequency and predictors of successful external cephalic version in a nationally-representative cohort of women with breech presentations and to compare maternal outcomes associated with successful external cephalic version versus persistent breech presentation. Methods: Using the Nationwide Inpatient Sample, a United States healthcare utilization database, we identified delivery admissions between 1998 and 2011 for women who had successful external cephalic version or persistent breech presentation (including unsuccessful or no external cephalic version attempt) at term. Multivariable logistic regression identified patient and hospital-level factors associated with successful external cephalic version. Maternal outcomes were compared between women who had successful external cephalic version versus persistent breech. Results: Our study cohort comprised 1,079,576 delivery admissions with breech presentation; 56,409 (5.2 %) women underwent successful external cephalic version and 1,023,167 (94.8 %) women had persistent breech presentation at the time of delivery. The rate of cesarean delivery was lower among women who had successful external cephalic version compared to those with persistent breech (20.2 % vs. 94.9 %; p < 0.001). Compared to women with persistent breech at the time of delivery, women with successful external cephalic version were also less likely to experience several measures of significant maternal morbidity including endometritis (adjusted Odds Ratio (aOR) = 0.36, 95 % Confidence Interval (CI) 0.24-0.52), sepsis (aOR = 0.35, 95 % CI 0.24-0.51) and length of stay > 7 days (aOR = 0.53, 95 % CI 0.40-0.70), but had a higher risk of chorioamnionitis (aOR = 1.83, 95 % CI 1.54-2.17). Conclusions: Overall a low proportion of women with breech presentation undergo successful external cephalic version, and it is associated with significant reduction in the frequency of cesarean delivery and a number of measures of maternal morbidity. Increased external cephalic version use may be an important approach to mitigate the high rate of cesarean delivery observed in the United States. C1 [Weiniger, Carolyn F.] Hadassah Hebrew Univ, Med Ctr, Dept Anesthesiol & Crit Care Med, POB 12000, Jerusalem, Israel. [Lyell, Deirdre J.] Stanford Univ, Sch Med, Dept Obstet & Gynecol, Stanford, CA 94305 USA. [Tsen, Lawrence C.] Harvard Med Sch, Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA USA. [Butwick, Alexander J.] Stanford Univ, Dept Anesthesiol Perioperat & Pain Med, Sch Med, Stanford, CA 94305 USA. [Shachar, BatZion] Stanford Univ, Sch Med, Sheba Met & March Dimes Prematur Res Ctr, Maternal Fetal Med Unit,Dept Obstet & Gynecol, Stanford, CA 94305 USA. [Callaghan, William M.] Ctr Dis Control & Prevent, Div Reprod Hlth, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Creanga, Andreea A.] Johns Hopkins Bloomberg Sch Publ Hlth, Int Ctr Maternal & Newborn Hlth, Dept Int Hlth, 615 N Wolfe St, Baltimore, MD USA. [Bateman, Brian T.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. [Bateman, Brian T.] Harvard Med Sch, Boston, MA USA. [Bateman, Brian T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, Boston, MA USA. RP Weiniger, CF (reprint author), Hadassah Hebrew Univ, Med Ctr, Dept Anesthesiol & Crit Care Med, POB 12000, Jerusalem, Israel. EM carolynfweiniger@gmail.com OI Butwick, Alexander/0000-0002-2048-0879 NR 34 TC 0 Z9 0 U1 1 U2 2 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 JUL 8 PY 2016 VL 16 AR 150 DI 10.1186/s12884-016-0941-9 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA DR0NX UT WOS:000379605300001 PM 27392035 ER PT J AU Ortiz-Teran, L Ortiz, T Perez, DL Aragon, JI Diez, I Pascual-Leone, A Sepulcre, J AF Ortiz-Teran, Laura Ortiz, Tomas Perez, David L. Ignacio Aragon, Jose Diez, Ibai Pascual-Leone, Alvaro Sepulcre, Jorge TI Brain Plasticity in Blind Subjects Centralizes Beyond the Modal Cortices SO FRONTIERS IN SYSTEMS NEUROSCIENCE LA English DT Article DE congenital blind; fMRI; functional connectivity; late-onset blind; multimodal integration network ID INTRINSIC FUNCTIONAL CONNECTIVITY; HUMAN CEREBRAL-CORTEX; PRIMARY VISUAL-CORTEX; OCCIPITAL CORTEX; MULTISENSORY INTEGRATION; NEUROCOGNITIVE NETWORKS; ORGANIZATION; HUMANS; EXPERIENCE; LANGUAGE AB It is well established that the human brain reorganizes following sensory deprivations. In blind individuals, visual processing regions including the lateral occipital cortex (LOC) are activated by auditory and tactile stimuli as demonstrated by neurophysiological and neuroimaging investigations. The mechanisms for such plasticity remain unclear, but shifts in connectivity across existing neural networks appear to play a critical role. The majority of research efforts to date have focused on neuroplastic changes within visual unimodal regions, however we hypothesized that neuroplastic alterations may also occur in brain networks beyond the visual cortices including involvement of multimodal integration regions and heteromodal cortices. In this study, two recently developed graph-theory based functional connectivity analyses, interconnector analyses and local and distant connectivity, were applied to investigate functional reorganization in regional and distributed neural-systems in late-onset blind (LB) and congenitally blind (CB) cohorts each compared to their own group of sighted controls. While functional network alterations as measured by the degree of differential links (DDL) occurred in sensory cortices, neuroplastic changes were most prominent within multimodal and association cortices. Subjects with LB showed enhanced multimodal integration connections in the parieto-opercular, temporoparietal junction (TPJ) and ventral premotor (vPM) regions, while CB individuals exhibited increased superior parietal cortex (SPC) connections. This study reveals the critical role of recipient multi-sensory integration areas in network reorganization and cross-modal plasticity in blind individuals. These findings suggest that aspects of cross-modal neuroplasticity and adaptive sensory-motor and auditory functions may potentially occur through reorganization in multimodal integration regions. C1 [Ortiz-Teran, Laura; Pascual-Leone, Alvaro] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Dept Neurol,Div Cognit Neurol, Boston, MA USA. [Ortiz-Teran, Laura; Diez, Ibai; Sepulcre, Jorge] Harvard Med Sch, Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Dept Radiol, Boston, MA USA. [Ortiz-Teran, Laura; Diez, Ibai; Sepulcre, Jorge] Massachusetts Gen Hosp, Gordon Ctr Med Imaging, Boston, MA 02114 USA. [Ortiz, Tomas] Univ Complutense Madrid, Fac Med, Dept Psiquiatria, Madrid, Spain. [Perez, David L.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Perez, David L.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Perez, David L.; Sepulcre, Jorge] Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed imaging, Boston, MA USA. [Ignacio Aragon, Jose] Hosp Univ Puerta Hierro Majadahonda, Dept Radiodiagnost, Madrid, Spain. [Diez, Ibai] Cruces Univ Hosp, BioCruces Hlth Res Inst, Baracaldo, Spain. RP Sepulcre, J (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Dept Radiol, Boston, MA USA.; Sepulcre, J (reprint author), Massachusetts Gen Hosp, Gordon Ctr Med Imaging, Boston, MA 02114 USA.; Sepulcre, J (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed imaging, Boston, MA USA. EM sepulcre@nmr.mgh.harvard.edu FU NIBIB NIH HHS [T32 EB013180] NR 60 TC 0 Z9 0 U1 6 U2 6 PU FRONTIERS MEDIA SA PI LAUSANNE PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015, SWITZERLAND SN 1662-5137 J9 FRONT SYST NEUROSCI JI Front. Syst. Neurosci. PD JUL 8 PY 2016 VL 10 AR 61 DI 10.3389/fnsys.2016.00061 PG 13 WC Neurosciences SC Neurosciences & Neurology GA DQ6JV UT WOS:000379311700001 PM 27458350 ER PT J AU Weng, LD Ziaei, S Elliott, GD AF Weng, Lindong Ziaei, Shima Elliott, Gloria D. TI Effects of Water on Structure and Dynamics of Trehalose Glasses at Low Water Contents and its Relationship to Preservation Outcomes SO SCIENTIFIC REPORTS LA English DT Article ID MOLECULAR-DYNAMICS; INTRACELLULAR GLASSES; MAMMALIAN-CELLS; TEMPERATURE; CRYOPRESERVATION; VITRIFICATION; SIMULATION; GLYCEROL; SYSTEMS; STATE AB Dry preservation of biologics in sugar glasses is regarded as a promising alternative to conventional cryopreservation. Evidence from various studies has suggested that there is a critical range of water content beyond which the viability of preserved biologics can be greatly compromised. In this study the viability of T-cells was determined as a function of end water content after microwave-assisted drying in trehalose solutions. Hydrogen-bonding and clustering phenomena in trehalose solutions of the same moisture content were also evaluated using molecular dynamics simulation. Post-rehydration viability decreased dramatically within the range of 0.1-1 gH(2)O/gdw. Molecular modeling revealed that as the water content approached 0.1 gH(2)O/gdw the matrix formed a large interconnected trehalose skeleton with a minimal number of bound water molecules scattered in the bulk. The diffusion coefficients of trehalose oxygen atoms most distant from the glycosidic linkage fluctuated around 7.5 x 10(-14) m(2)/s within the range of 0.02-0.1 gH(2)O/gdw and increased again to similar to 1.13 x 10(-13) m(2)/s at 0.01 gH(2)O/gdw and below due to the loss of water in the free volume between trehalose molecules. These insights can guide the optimal selection of final moisture contents to advance dry preservation methods. C1 [Weng, Lindong; Ziaei, Shima; Elliott, Gloria D.] Univ N Carolina, Dept Mech Engn & Engn Sci, Charlotte, NC 28223 USA. [Weng, Lindong] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02129 USA. RP Elliott, GD (reprint author), Univ N Carolina, Dept Mech Engn & Engn Sci, Charlotte, NC 28223 USA. EM gdelliot@uncc.edu RI Weng, Lindong/A-6041-2017 OI Weng, Lindong/0000-0003-4811-6531 FU National Institutes of Health [5R01GM101796] FX This study was supported by grant # 5R01GM101796 from the National Institutes of Health. The MD simulations were performed on the University Research Computing (URC) High Performance Computing (HPC) clusters at UNC Charlotte. NR 33 TC 0 Z9 1 U1 18 U2 25 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 JUL 8 PY 2016 VL 6 AR 28795 DI 10.1038/srep28795 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ5HL UT WOS:000379235700001 PM 27387435 ER PT J AU Harrington, D Parmigiani, G AF Harrington, David Parmigiani, Giovanni TI I-SPY 2-A Glimpse of the Future of Phase 2 Drug Development? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID CLINICAL-TRIALS C1 [Harrington, David] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Harrington, D (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. NR 5 TC 3 Z9 3 U1 1 U2 1 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 JUL 7 PY 2016 VL 375 IS 1 BP 7 EP 9 DI 10.1056/NEJMp1602256 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA EL8VA UT WOS:000394897200003 PM 27406345 ER PT J AU Hotta, K Aoyama, A Oura, T Yamada, Y Tonsho, M Huh, KH Kawai, K Schoenfeld, D Allan, JS Madsen, JC Benichou, G Smith, RN Colvin, RB Sachs, DH Cosimi, AB Kawai, T AF Hotta, Kiyohiko Aoyama, Akihiro Oura, Tetsu Yamada, Yohei Tonsho, Makoto Huh, Kyu Ha Kawai, Kento Schoenfeld, David Allan, James S. Madsen, Joren C. Benichou, Gilles Smith, Rex-Neal Colvin, Robert B. Sachs, David H. Cosimi, A. Benedict Kawai, Tatsuo TI Induced regulatory T cells in allograft tolerance via transient mixed chimerism SO JCI INSIGHT LA English DT Article ID BONE-MARROW-TRANSPLANTATION; MHC CLASS-II; MISMATCHED RENAL-TRANSPLANTATION; NONHUMAN-PRIMATES; MAINTENANCE IMMUNOSUPPRESSION; HEMATOPOIETIC CHIMERISM; PERIPHERAL TOLERANCE; CYNOMOLGUS MACAQUES; ENDOTHELIAL-CELLS; DONOR ANTIGEN AB Successful induction of allograft tolerance has been achieved in nonhuman primates (NHPs) and humans via induction of transient hematopoietic chimerism. Since allograft tolerance was achieved in these recipients without durable chimerism, peripheral mechanisms are postulated to play a major role. Here, we report our studies of T cell immunity in NHP recipients that achieved long-term tolerance versus those that rejected the allograft (AR). All kidney, heart, and lung transplant recipients underwent simultaneous or delayed donor bone marrow transplantation (DBMT) following conditioning with a nonmyeloablative regimen. After DBMT, mixed lymphocyte culture with CFSE consistently revealed donor-specific loss of CD8(+) T cell responses in tolerant (TOL) recipients, while marked CD4(+) T cell proliferation in response to donor antigens was found to persist. Interestingly, a significant proportion of the proliferated CD4(+) cells were FOXP3(+) in TOL recipients, but not in AR or naive NHPs. In TOL recipients, CD4(+) FOXP3(+) cell proliferation against donor antigens was greater than that observed against third-party antigens. Finally, the expanded Tregs appeared to be induced Tregs (iTregs) that were converted from non-Tregs. These data provide support for the hypothesis that specific induction of iTregs by donor antigens is key to long-term allograft tolerance induced by transient mixed chimerism. C1 [Hotta, Kiyohiko; Aoyama, Akihiro; Oura, Tetsu; Yamada, Yohei; Tonsho, Makoto; Huh, Kyu Ha; Kawai, Kento; Allan, James S.; Madsen, Joren C.; Benichou, Gilles; Sachs, David H.; Cosimi, A. Benedict; Kawai, Tatsuo] Massachusetts Gen Hosp, Ctr Transplantat Sci, Dept Surg, Boston, MA 02114 USA. [Hotta, Kiyohiko; Aoyama, Akihiro; Oura, Tetsu; Yamada, Yohei; Tonsho, Makoto; Huh, Kyu Ha; Kawai, Kento; Allan, James S.; Madsen, Joren C.; Benichou, Gilles; Smith, Rex-Neal; Colvin, Robert B.; Sachs, David H.; Cosimi, A. Benedict; Kawai, Tatsuo] Harvard Med Sch, Boston, MA USA. [Schoenfeld, David] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Smith, Rex-Neal; Colvin, Robert B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Kawai, T (reprint author), Harvard Med Sch, Ctr Transplantat Sci, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02114 USA. EM TKAWAI@mgh.harvard.edu NR 43 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JUL 7 PY 2016 VL 1 IS 10 AR e86419 DI 10.1172/jci.insight.86419 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1LL UT WOS:000387113300008 ER PT J AU Iwanicki, MP Chen, HY Iavarone, C Zervantonakis, IK Muranen, T Novak, M Ince, TA Drapkin, R Brugge, JS AF Iwanicki, Marcin P. Chen, Hsing-Yu Iavarone, Claudia Zervantonakis, Ioannis K. Muranen, Taru Novak, Marian Ince, Tan A. Drapkin, Ronny Brugge, Joan S. TI Mutant p53 regulates ovarian cancer transformed phenotypes through autocrine matrix deposition SO JCI INSIGHT LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; GRADE SEROUS CARCINOMA; TUBAL INTRAEPITHELIAL CARCINOMA; DISTAL FALLOPIAN-TUBE; ANOIKIS RESISTANCE; MESOTHELIAL CELLS; GENE-EXPRESSION; UP-REGULATION; TUMOR-CELLS; MOUSE MODEL AB High-grade serous ovarian carcinoma (HGS-OvCa) harbors p53 mutations and can originate from the epithelial cell compartment of the fallopian tube fimbriae. From this site, neoplastic cells detach, survive in the peritoneal cavity, and form cellular clusters that intercalate into the mesothelium to form ovarian and peritoneal masses. To examine the contribution of mutant p53 to phenotypic alterations associated with HGS-OvCA, we developed live-cell microscopy assays that recapitulate these early events in cultured fallopian tube nonciliated epithelial (FNE) cells. Expression of stabilizing mutant variants of p53, but not depletion of endogenous wild-type p53, in FNE cells promoted survival and cell-cell aggregation under conditions of cell detachment, leading to the formation of cell clusters with mesothelium-intercalation capacity. Mutant p53(R175H)-induced phenotypes were dependent on fibronectin production, alpha 5 beta 1 fibronectin receptor engagement, and TWIST1 expression. These results indicate that FNE cells expressing stabilizing p53 mutants acquire anchorage independence and subsequent mesothelial intercalation capacity through a mechanism involving mesenchymal transition and matrix production. These findings provide important new insights into activities of mutant p53 in the cells of origin of HGS-OvCa. C1 [Iwanicki, Marcin P.; Chen, Hsing-Yu; Iavarone, Claudia; Zervantonakis, Ioannis K.; Muranen, Taru; Brugge, Joan S.] Harvard Med Sch, Dept Cell Biol, Boston, MA USA. [Novak, Marian; Drapkin, Ronny] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Dept Med Oncol, Boston, MA 02115 USA. [Ince, Tan A.] Univ Miami, Miller Sch Med, Stem Cell Inst, Miami, FL 33136 USA. [Drapkin, Ronny] Univ Penn, Perelman Sch Med, Basser Ctr BRCA, Penn Ovarian Canc Res Ctr, 421 Curie Blvd, Philadelphia, PA 19104 USA. RP Drapkin, R (reprint author), Univ Penn, Perelman Sch Med, Basser Ctr BRCA, Penn Ovarian Canc Res Ctr, 421 Curie Blvd, Philadelphia, PA 19104 USA.; Brugge, JS (reprint author), Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA. EM rdrapkin@mail.med.upenn.edu; Joan_Brugge@hms.harvard.edu NR 82 TC 4 Z9 4 U1 1 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 2379-3708 J9 JCI INSIGHT JI JCI Insight PD JUL 7 PY 2016 VL 1 IS 10 AR e86829 DI 10.1172/jci.insight.86829 PG 20 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA EB1LL UT WOS:000387113300011 ER PT J AU Liu, CT Raghavan, S Maruthur, N Kabagambe, EK Hong, J Ng, MCY Hivert, MF Lu, YC An, P Bentley, AR Drolet, AM Gaulton, KJ Guo, XQ Armstrong, LL Irvin, MR Li, M Lipovich, L Rybin, DV Taylor, KD Agyemang, C Palmer, ND Cade, BE Chen, WM Dauriz, M Delaney, JAC Edwards, TL Evans, DS Evans, MK Lange, LA Leong, A Liu, JM Liu, YM Nayak, U Patel, SR Porneala, BC Rasmussen-Torvik, LJ Snijder, MB Stallings, SC Tanaka, T Yanek, LR Zhao, W Becker, DM Bielak, LF Biggs, ML Bottinger, EP Bowden, DW Chen, GJ Correa, A Couper, DJ Crawford, DC Cushman, M Eicher, JD Fornage, M Franceschini, N Fu, YP Goodarzi, MO Gottesman, O Hara, K Harris, TB Jensen, RA Johnson, AD Jhun, MA Karter, AJ Keller, MF Kho, AN Kizer, JR Krauss, RM Langefeld, CD Li, XH Liang, JL Liu, SM Lowe, WL Mosley, TH North, KE Pacheco, JA Peyser, PA Patrick, AL Rice, KM Selvin, E Sims, M Smith, JA Tajuddin, SM Vaidya, D Wren, MP Yao, J Zhu, XF Ziegler, JT Zmuda, JM Zonderman, AB Zwinderman, AH Adeyemo, A Boerwinkle, E Ferrucci, L Hayes, MG Kardia, SLR Miljkovic, I Pankow, JS Rotimi, CN Sale, MM Wagenknecht, LE Arnett, DK Chen, YDI Nalls, MA Province, MA Kao, WHL Siscovick, DS Psaty, BM Wilson, JG Loos, RJF Dupuis, J Rich, SS Florez, JC Rotter, JI Morris, AP Meigs, JB AF Liu, Ching-Ti Raghavan, Sridharan Maruthur, Nisa Kabagambe, Edmond Kato Hong, Jaeyoung Ng, Maggie C. Y. Hivert, Marie-France Lu, Yingchang An, Ping Bentley, Amy R. Drolet, Anne M. Gaulton, Kyle J. Guo, Xiuqing Armstrong, Loren L. Irvin, Marguerite R. Li, Man Lipovich, Leonard Rybin, Denis V. Taylor, Kent D. Agyemang, Charles Palmer, Nicholette D. Cade, Brian E. Chen, Wei-Min Dauriz, Marco Delaney, Joseph A. C. Edwards, Todd L. Evans, Daniel S. Evans, Michele K. Lange, Leslie A. Leong, Aaron Liu, Jingmin Liu, Yongmei Nayak, Uma Patel, Sanjay R. Porneala, Bianca C. Rasmussen-Torvik, Laura J. Snijder, Marieke B. Stallings, Sarah C. Tanaka, Toshiko Yanek, Lisa R. Zhao, Wei Becker, Diane M. Bielak, Lawrence F. Biggs, Mary L. Bottinger, Erwin P. Bowden, Donald W. Chen, Guanjie Correa, Adolfo Couper, David J. Crawford, Dana C. Cushman, Mary Eicher, John D. Fornage, Myriam Franceschini, Nora Fu, Yi-Ping Goodarzi, Mark O. Gottesman, Omri Hara, Kazuo Harris, Tamara B. Jensen, Richard A. Johnson, Andrew D. Jhun, Min A. Karter, Andrew J. Keller, Margaux F. Kho, Abel N. Kizer, Jorge R. Krauss, Ronald M. Langefeld, Carl D. Li, Xiaohui Liang, Jingling Liu, Simin Lowe, William L., Jr. Mosley, Thomas H. North, Kari E. Pacheco, Jennifer A. Peyser, Patricia A. Patrick, Alan L. Rice, Kenneth M. Selvin, Elizabeth Sims, Mario Smith, Jennifer A. Tajuddin, Salman M. Vaidya, Dhananjay Wren, Mary P. Yao, Jie Zhu, Xiaofeng Ziegler, Julie T. Zmuda, Joseph M. Zonderman, Alan B. Zwinderman, Aeilko H. Adeyemo, Adebowale Boerwinkle, Eric Ferrucci, Luigi Hayes, M. Geoffrey Kardia, Sharon L. R. Miljkovic, Iva Pankow, James S. Rotimi, Charles N. Sale, Michele M. Wagenknecht, Lynne E. Arnett, Donna K. Chen, Yii-Der Ida Nalls, Michael A. Province, Michael A. Kao, W. H. Linda Siscovick, David S. Psaty, Bruce M. Wilson, James G. Loos, Ruth J. F. Dupuis, Josee Rich, Stephen S. Florez, Jose C. Rotter, Jerome I. Morris, Andrew P. Meigs, James B. CA AAAG Consortium CARe Consortium COGENT-BP Consortium eMERGE Consortium MEDIA Consortium MAGIC Consortium TI Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; TYPE-2 DIABETES RISK; GLUCOKINASE REGULATORY PROTEIN; BETA-CELL FUNCTION; BODY-MASS INDEX; TRIGLYCERIDE LEVELS; PLASMA-GLUCOSE; TRANSETHNIC METAANALYSIS; AFRICAN-ANCESTRY; GLYCEMIC TRAITS AB Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci. C1 [Liu, Ching-Ti; Hong, Jaeyoung; Rybin, Denis V.; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Raghavan, Sridharan; Leong, Aaron; Porneala, Bianca C.; Meigs, James B.] Harvard Med Sch, Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. [Raghavan, Sridharan] Eastern Colorado Hlth Care Syst, Dept Vet Affairs Med Ctr, Denver, CO 80220 USA. [Raghavan, Sridharan] Univ Colorado, Sch Med, Dept Med, Div Gen Internal Med, Denver, CO 80220 USA. [Maruthur, Nisa] Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD 21287 USA. [Maruthur, Nisa; Selvin, Elizabeth] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21287 USA. [Maruthur, Nisa; Li, Man; Selvin, Elizabeth; Vaidya, Dhananjay; Kao, W. H. Linda] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21287 USA. [Kabagambe, Edmond Kato; Edwards, Todd L.] Vanderbilt Univ, Med Ctr, Sch Med, Div Epidemiol,Dept Med, Nashville, TN 37203 USA. [Ng, Maggie C. Y.; Palmer, Nicholette D.; Bowden, Donald W.] Wake Forest Univ, Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC 27157 USA. [Ng, Maggie C. Y.; Bowden, Donald W.] Wake Forest Univ, Bowman Gray Sch Med, Ctr Diabet Res, Winston Salem, NC 27157 USA. [Hivert, Marie-France] Harvard Med Sch, Harvard Pilgrim Hlth Care Inst, Dept Populat Med, Boston, MA 02215 USA. [Hivert, Marie-France; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Hivert, Marie-France] Univ Sherbrooke, Dept Med, Sherbrooke, PQ J1G 0A2, Canada. [Lu, Yingchang; Bottinger, Erwin P.; Gottesman, Omri; Hara, Kazuo; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [An, Ping; Province, Michael A.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA. [Bentley, Amy R.; Chen, Guanjie; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Drolet, Anne M.; Lipovich, Leonard] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Gaulton, Kyle J.; Morris, Andrew P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Guo, Xiuqing; Taylor, Kent D.; Li, Xiaohui; Yao, Jie; Chen, Yii-Der Ida; Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA. [Armstrong, Loren L.; Kho, Abel N.; Lowe, William L., Jr.; Pacheco, Jennifer A.; Hayes, M. Geoffrey] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Irvin, Marguerite R.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Lipovich, Leonard] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA. [Agyemang, Charles; Snijder, Marieke B.; Zwinderman, Aeilko H.] Acad Med Ctr Amsterdam, Dept Publ Hlth, Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands. [Palmer, Nicholette D.; Bowden, Donald W.; Wren, Mary P.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27157 USA. [Cade, Brian E.] Harvard Med Sch, Brigham & Womens Hosp, Div Sleep & Circadian Disorders, Boston, MA 02115 USA. [Chen, Wei-Min; Nayak, Uma; Sale, Michele M.; Rich, Stephen S.] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Dauriz, Marco] Univ Verona, Dept Med, Div Endocrinol Diabet & Metab, I-37126 Verona, Italy. [Delaney, Joseph A. C.; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Evans, Daniel S.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94107 USA. [Evans, Michele K.; Tajuddin, Salman M.] NIA, Hlth Dispar Res Sect, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27607 USA. [Liu, Jingmin] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA. [Patel, Sanjay R.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. [Rasmussen-Torvik, Laura J.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Harbor Hosp, Baltimore, MD 21225 USA. [Yanek, Lisa R.; Becker, Diane M.; Vaidya, Dhananjay] Johns Hopkins Univ, Dept Med, Div Gen Internal Med, GeneSTAR Res Program, Baltimore, MD 21287 USA. [Zhao, Wei; Bielak, Lawrence F.; Jhun, Min A.; Peyser, Patricia A.; Smith, Jennifer A.; Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Becker, Diane M.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21287 USA. [Biggs, Mary L.; Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Biggs, Mary L.; Jensen, Richard A.; Siscovick, David S.; Psaty, Bruce M.] Univ Washington, Sch Med, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Correa, Adolfo; Sims, Mario] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Couper, David J.] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC 27514 USA. [Crawford, Dana C.] Case Western Reserve Univ, Inst Computat Biol, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Cushman, Mary] Univ Vermont, Coll Med, Dept Pathol & Med, Burlington, VT 05405 USA. [Eicher, John D.; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Eicher, John D.; Johnson, Andrew D.] NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Framingham, MA 01702 USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Fu, Yi-Ping] NHLBI, Cardiovasc Epidemiol & Human Genom Branch, NIH, Framingham, MA 01702 USA. [Goodarzi, Mark O.] Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA. [Hara, Kazuo] Univ Tokyo, Grad Sch Med, Dept Diabet & Metab Dis, Tokyo 1138655, Japan. [Hara, Kazuo] Tokyo Med Univ, Dept Diabet Endocrinol & Metab, Tokyo 1630023, Japan. [Harris, Tamara B.] NIH, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA. [Karter, Andrew J.] Kaiser Permanente, Div Res, Oakland, CA 94612 USA. [Keller, Margaux F.] Merck Res Labs, Dept Genet & Pharmacogen, 33 Ave Louis Pasteur, Boston, MA 02115 USA. [Kizer, Jorge R.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. [Kizer, Jorge R.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Krauss, Ronald M.] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. [Langefeld, Carl D.; Ziegler, Julie T.] Wake Forest Univ, Bowman Gray Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27157 USA. [Langefeld, Carl D.; Ziegler, Julie T.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Liang, Jingling; Zhu, Xiaofeng] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Liu, Simin] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Liu, Simin] Brown Univ, Dept Med, Providence, RI 02903 USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr Gerontol, Jackson, MS 39216 USA. [Patrick, Alan L.] Tobago Hlth Studies Off, Scarborough, Trinid & Tobago. [Zmuda, Joseph M.; Miljkovic, Iva] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Zonderman, Alan B.] NIA, Behav Epidemiol Sect, Lab Epidemiol & Populat Sci, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Pankow, James S.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Wagenknecht, Lynne E.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Arnett, Donna K.] Univ Kentucky, Coll Publ Hlth, Lexington, KY 40563 USA. [Nalls, Michael A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Siscovick, David S.] New York Acad Med, New York, NY 10029 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Program Metab, Cambridge, MA 02142 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Florez, Jose C.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Inst Translat Med, Liverpool L69 3BX, Merseyside, England. [Stallings, Sarah C.] Vanderbilt Univ, Med Ctr, Vanderbilt Inst Clin & Translat Res, Nashville, TN 37203 USA. RP Liu, CT (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.; Meigs, JB (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA. EM ctliu@bu.edu; jmeigs@partners.org RI Johnson, Andrew/G-6520-2013; Dauriz, Marco/S-5843-2016; OI Dauriz, Marco/0000-0002-5542-5941; Tajuddin, Salman M./0000-0002-7919-8528; Patel, Sanjay/0000-0002-9142-5172; Zonderman, Alan B/0000-0002-6523-4778; Vaidya, Dhananjay/0000-0002-7164-1601; Smith, Jennifer/0000-0002-3575-5468; Pankow, James/0000-0001-7076-483X FU Johnson Johnson FX B.M.P. serves on the DSMB of a clinical trial for the device manufacturer Zoll LifeCor and on the Steering Committee for the Yale Open Data Access Project funded by Johnson & Johnson. D.V. is a consultant for Consumable Science, Inc. J.R.K. holds stock in Pfizer, Inc., and Gilead Sciences, Inc. NR 61 TC 1 Z9 1 U1 1 U2 2 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 JUL 7 PY 2016 VL 99 IS 1 BP 56 EP 75 DI 10.1016/j.ajhg.2016.05.006 PG 20 WC Genetics & Heredity SC Genetics & Heredity GA DT6TI UT WOS:000381616600005 PM 27321945 ER PT J AU Zhang, J Ratanasirintrawoot, S Chandrasekaran, S Wu, ZT Ficarro, SB Yu, CX Ross, CA Cacchiarelli, D Xia, Q Seligson, M Shinoda, G Xie, W Cahan, P Wang, LF Ng, SC Tintara, S Trapnell, C Onder, T Loh, YH Mikkelsen, T Sliz, P Teitell, MA Asara, JM Marto, JA Li, H Collins, JJ Daley, GQ AF Zhang, Jin Ratanasirintrawoot, Sutheera Chandrasekaran, Sriram Wu, Zhaoting Ficarro, Scott B. Yu, Chunxiao Ross, Christian A. Cacchiarelli, Davide Xia, Qing Seligson, Marc Shinoda, Gen Xie, Wen Cahan, Patrick Wang, Longfei Ng, Shyh-Chang Tintara, Supisara Trapnell, Cole Onder, Tamer Loh, Yuin-Han Mikkelsen, Tarjei Sliz, Piotr Teitell, Michael A. Asara, John M. Marto, Jarrod A. Li, Hu Collins, James J. Daley, George Q. TI LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency SO CELL STEM CELL LA English DT Article ID GROUND-STATE PLURIPOTENCY; HUMAN SOMATIC-CELLS; MICRORNA BIOGENESIS; SELF-RENEWAL; GLUCOSE-METABOLISM; DEFINED FACTORS; MESSENGER-RNAS; LET-7; CANCER; PROLIFERATION AB The RNA-binding proteins LIN28A and LIN28B play critical roles in embryonic development, tumorigenesis, and pluripotency, but their exact functions are poorly understood. Here, we show that, like LIN28A, LIN28B can function effectively with NANOG, OCT4, and SOX2 in reprogramming to pluripotency and that reactivation of both endogenous LIN28A and LIN28B loci are required for maximal reprogramming efficiency. In human fibroblasts, LIN28B is activated early during reprogramming, while LIN28A is activated later during the transition to bona fide induced pluripotent stem cells (iPSCs). In murine cells, LIN28A and LIN28B facilitate conversion from naive to primed pluripotency. Proteomic and metabolomic analysis highlighted roles for LIN28 in maintaining the low mitochondrial function associated with primed pluripotency and in regulating one-carbon metabolism, nucleotide metabolism, and histone methylation. LIN28 binds to mRNAs of proteins important for oxidative phosphorylation and modulates protein abundance. Thus, LIN28A and LIN28B play cooperative roles in regulating reprogramming, naive/primed pluripotency, and stem cell metabolism. C1 [Zhang, Jin; Ratanasirintrawoot, Sutheera; Wu, Zhaoting; Xia, Qing; Seligson, Marc; Shinoda, Gen; Xie, Wen; Cahan, Patrick; Ng, Shyh-Chang; Tintara, Supisara; Onder, Tamer; Loh, Yuin-Han; Daley, George Q.] Boston Childrens Hosp, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. [Zhang, Jin; Ratanasirintrawoot, Sutheera; Wu, Zhaoting; Ficarro, Scott B.; Yu, Chunxiao; Xia, Qing; Seligson, Marc; Shinoda, Gen; Xie, Wen; Cahan, Patrick; Wang, Longfei; Ng, Shyh-Chang; Tintara, Supisara; Onder, Tamer; Loh, Yuin-Han; Sliz, Piotr; Marto, Jarrod A.; Daley, George Q.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Chandrasekaran, Sriram; Collins, James J.] MIT, Dept Biol Engn, Inst Med Engn & Sci, Cambridge, MA 02142 USA. [Chandrasekaran, Sriram; Collins, James J.] MIT, Synthet Biol Ctr, Cambridge, MA 02142 USA. [Chandrasekaran, Sriram; Cacchiarelli, Davide; Trapnell, Cole; Mikkelsen, Tarjei; Collins, James J.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Chandrasekaran, Sriram; Collins, James J.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Ficarro, Scott B.; Marto, Jarrod A.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02115 USA. [Yu, Chunxiao; Sliz, Piotr] Harvard Med Sch, Boston Childrens Hosp, Mol Med Lab, Boston, MA 02115 USA. [Ross, Christian A.; Li, Hu] Mayo Clin, Ctr Individualized Med, Rochester, MN 55905 USA. [Ross, Christian A.; Li, Hu] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA. [Cacchiarelli, Davide; Trapnell, Cole; Mikkelsen, Tarjei] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Xia, Qing] Peking Univ, Sch Pharmaceut Sci, Dept Biol Chem, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China. [Loh, Yuin-Han] A STAR Inst Mol & Cell Biol, Epigenet & Cell Fates Lab, Singapore 138673, Singapore. [Loh, Yuin-Han] Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore. [Teitell, Michael A.] Univ Calif Los Angeles, Dept Pathol & Lab Med, Broad Stem Cell Res Ctr, Los Angeles, CA 90095 USA. [Teitell, Michael A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Asara, John M.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA. [Asara, John M.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Ratanasirintrawoot, Sutheera] Chulalongkorn Univ, Fac Med, Bangkok 10330, Thailand. RP Daley, GQ (reprint author), Boston Childrens Hosp, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA.; Daley, GQ (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu FU Howard Hughes Medical Institute; SysCODE (Systems-based Consortium for Organ Design Engineering); NIH [RL1DE019021, CA196631-01A1, 1U54GM114838-01, R01GM107536, P50GM099117, U01 HL100001, P01CA120964, S10RR032861, P30CA006516]; Mayo Clinic Foundation; Mayo Clinic Center for Individualized Medicine; Ellison Medical Foundation FX J.J.C. and H.L. were supported by the Howard Hughes Medical Institute, SysCODE (Systems-based Consortium for Organ Design & Engineering), and NIH grant RL1DE019021. H.L. was supported by NIH (grants CA196631-01A1 and 1U54GM114838-01), the Mayo Clinic Foundation, and the Mayo Clinic Center for Individualized Medicine. G.Q.D. was supported by grants from the NIH (R01GM107536, P50GM099117, and U01 HL100001) and by the Ellison Medical Foundation and is an investigator of the Howard Hughes Medical Institute. J.M.A. is supported by NIH grants P01CA120964, S10RR032861, and P30CA006516. We thank Min Yuan and Susanne Breit-kopf for help with mass spectrometry experiments; the Marcia Haigis laboratory for Seahorse Analyzer facility; Lewis Cantley and Matthew Vander Heiden for discussion; Michael Chen and the Brigham and Women's Hospital Transgenic Core Facility for help with embryo analysis; The Boston Children's Hospital Molecular Genetics Core Facility for microarray experiments; and Thorsten Schlaeger and the Boston Children's Hospital hESC Core Facility for support with stem cells. NR 50 TC 11 Z9 11 U1 6 U2 8 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 JUL 7 PY 2016 VL 19 IS 1 BP 66 EP 80 PG 15 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA DT6UT UT WOS:000381620500012 PM 27320042 ER PT J AU Chami, N Chen, MH Slater, AJ Eicher, JD Evangelou, E Tajuddin, SM Love-Gregory, L Kacprowski, T Schick, UM Nomura, A Giri, A Lessard, S Brody, JA Schurmann, C Pankratz, N Yanek, LR Manichaikul, A Pazoki, R Mihailov, E Hill, WD Raffield, LM Burt, A Bartz, TM Becker, DM Becker, LC Boerwinkle, E Bork-Jensen, J Bottinger, EP O'Donoghue, ML Crosslin, DR de Denus, S Dube, MP Elliott, P Engstrom, G Evans, MK Floyd, JS Fornage, M Gao, H Greinacher, A Gudnason, V Hansen, T Harris, TB Hayward, C Hernesniemi, J Highland, HM Hirschhorn, JN Hofman, A Irvin, MR Kahonen, M Lange, E Launer, LJ Lehtimaki, T Li, J Liewald, DCM Linneberg, A Liu, YM Lu, YC Lyytikainen, LP Magi, R Mathias, RA Melander, O Metspalu, A Mononen, N Nalls, MA Nickerson, DA Nikus, K O'Donnell, CJ Orho-Melander, M Pedersen, O Petersmann, A Polfus, L Psaty, BM Raitakari, OT Raitoharju, E Richard, M Rice, KM Rivadeneira, F Rotter, JI Schmidt, F Smith, AV Starr, JM Taylor, KD Teumer, A Thuesen, BH Torstenson, ES Tracy, RP Tzoulaki, I Zakai, NA Vacchi-Suzzi, C van Duijn, CM van Rooij, FJA Cushman, M Deary, IJ Edwards, DRV Vergnaud, AC Wallentin, L Waterworth, DM White, HD Wilson, JG Zonderman, AB Kathiresan, S Grarup, N Esko, T Loos, RJF Lange, LA Faraday, N Abumrad, NA Edwards, TL Ganesh, SK Auer, PL Johnson, AD Reiner, AP Lettre, G AF Chami, Nathalie Chen, Ming-Huei Slater, Andrew J. Eicher, John D. Evangelou, Evangelos Tajuddin, Salman M. Love-Gregory, Latisha Kacprowski, Tim Schick, Ursula M. Nomura, Akihiro Giri, Ayush Lessard, Samuel Brody, Jennifer A. Schurmann, Claudia Pankratz, Nathan Yanek, Lisa R. Manichaikul, Ani Pazoki, Raha Mihailov, Evelin Hill, W. David Raffield, Laura M. Burt, Amber Bartz, Traci M. Becker, Diane M. Becker, Lewis C. Boerwinkle, Eric Bork-Jensen, Jette Bottinger, Erwin P. O'Donoghue, Michelle L. Crosslin, David R. de Denus, Simon Dube, Marie-Pierre Elliott, Paul Engstrom, Gunnar Evans, Michele K. Floyd, James S. Fornage, Myriam Gao, He Greinacher, Andreas Gudnason, Vilmundur Hansen, Torben Harris, Tamara B. Hayward, Caroline Hernesniemi, Jussi Highland, Heather M. Hirschhorn, Joel N. Hofman, Albert Irvin, Marguerite R. Kahonen, Mika Lange, Ethan Launer, Lenore J. Lehtimaki, Terho Li, Jin Liewald, David C. M. Linneberg, Allan Liu, Yongmei Lu, Yingchang Lyytikainen, Leo-Pekka Magi, Reedik Mathias, Rasika A. Melander, Olle Metspalu, Andres Mononen, Nina Nalls, Mike A. Nickerson, Deborah A. Nikus, Kjell O'Donnell, Chris J. Orho-Melander, Marju Pedersen, Oluf Petersmann, Astrid Polfus, Linda Psaty, Bruce M. Raitakari, Olli T. Raitoharju, Emma Richard, Melissa Rice, Kenneth M. Rivadeneira, Fernando Rotter, Jerome I. Schmidt, Frank Smith, Albert Vernon Starr, John M. Taylor, Kent D. Teumer, Alexander Thuesen, Betina H. Torstenson, Eric S. Tracy, Russell P. Tzoulaki, Ioanna Zakai, Neil A. Vacchi-Suzzi, Caterina van Duijn, Cornelia M. van Rooij, Frank J. A. Cushman, Mary Deary, Ian J. Edwards, Digna R. Velez Vergnaud, Anne-Claire Wallentin, Lars Waterworth, Dawn M. White, Harvey D. Wilson, James G. Zonderman, Alan B. Kathiresan, Sekar Grarup, Niels Esko, Tonu Loos, Ruth J. F. Lange, Leslie A. Faraday, Nauder Abumrad, Nada A. Edwards, Todd L. Ganesh, Santhi K. Auer, Paul L. Johnson, Andrew D. Reiner, Alexander P. Lettre, Guillaume TI Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-HEART-DISEASE; AFRICAN-AMERICANS; DILATED CARDIOMYOPATHY; NATURAL-SELECTION; SEQUENCE VARIANTS; PYRUVATE-KINASE; LOW-FREQUENCY; LOCI; GENE AB Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 x 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 x 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 x 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 x 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 x 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated. C1 [Chami, Nathalie; Lessard, Samuel; Dube, Marie-Pierre; Lettre, Guillaume] Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada. [Chami, Nathalie; Lessard, Samuel; de Denus, Simon; Dube, Marie-Pierre; Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1CB, Canada. [Chen, Ming-Huei; Eicher, John D.; O'Donnell, Chris J.; Johnson, Andrew D.] NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA. [Slater, Andrew J.] GlaxoSmithKline, Genet Target Sci, Res Triangle Pk, Res Triangle Pk, NC 27709 USA. [Slater, Andrew J.] OmicSoft Corp, Cary, NC 27513 USA. [Evangelou, Evangelos; Elliott, Paul; Gao, He; Tzoulaki, Ioanna; Vergnaud, Anne-Claire] Imperial Coll London, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, London W2 1PG, England. [Evangelou, Evangelos; Tzoulaki, Ioanna] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Ioannina 45110, Greece. [Tajuddin, Salman M.; Evans, Michele K.; Zonderman, Alan B.] NIA, Lab Epidemiol & Populat Sci, Baltimore, MD 21224 USA. [Love-Gregory, Latisha; Abumrad, Nada A.] Washington Univ, Sch Med, Dept Med, Ctr Human Nutr, St Louis, MO 63110 USA. [Kacprowski, Tim; Schmidt, Frank] Ernst Moritz Arndt Univ Greifswald, Dept Funct Gen, Interfaculty Inst Genet & Funct Gen, Univ Med, D-17475 Greifswald, Germany. [Kacprowski, Tim] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany. [Schick, Ursula M.; Schurmann, Claudia; Bottinger, Erwin P.; Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10069 USA. [Nomura, Akihiro; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Nomura, Akihiro; Hirschhorn, Joel N.; Kathiresan, Sekar; Esko, Tonu] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Nomura, Akihiro; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Nomura, Akihiro; Kathiresan, Sekar] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Nomura, Akihiro] Kanazawa Univ, Grad Sch Med Sci, Div Cardiovasc Med, Kanazawa, Ishikawa 9200942, Japan. [Giri, Ayush; Torstenson, Eric S.; Edwards, Todd L.] Vanderbilt Univ, Inst Med & Publ Hlth, Vanderbilt Genet Inst, Div Epidemiol, Nashville, TN 37235 USA. [Brody, Jennifer A.; Floyd, James S.] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Schurmann, Claudia; Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10069 USA. [Pankratz, Nathan] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55454 USA. [Yanek, Lisa R.; Becker, Diane M.] Johns Hopkins Univ, Sch Med, Dept Med Div Gen Internal Med icine, Div Gen Internal Med, Baltimore, MD 21205 USA. [Manichaikul, Ani] Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA 22908 USA. [Pazoki, Raha; Hofman, Albert; Rivadeneira, Fernando; van Duijn, Cornelia M.; van Rooij, Frank J. A.] Erasmus, Dept Epidemiol, NL-3000 Mcrotterdam, Netherlands. [Mihailov, Evelin; Magi, Reedik; Metspalu, Andres; Esko, Tonu] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Hill, W. David; Liewald, David C. M.; Starr, John M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Hill, W. David; Liewald, David C. M.; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Raffield, Laura M.; Lange, Leslie A.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA. [Burt, Amber] Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98195 USA. [Bartz, Traci M.; Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Becker, Lewis C.] Johns Hopkins Univ Sch Med, Dept Med, Div Cardiol & Gen Internal Med, Baltimore, MD 21205 USA. [Boerwinkle, Eric; Highland, Heather M.; Polfus, Linda] Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Bork-Jensen, Jette; Hansen, Torben; Pedersen, Oluf; Grarup, Niels] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metabol Res, DK-2100 Copenhagen, Denmark. [O'Donoghue, Michelle L.] Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp, Boston, MA 02115 USA. [Crosslin, David R.] Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98195 USA. [de Denus, Simon] Univ Montreal, Fac Pharm, Montreal, PQ H3T 1J4, Canada. [Engstrom, Gunnar; Melander, Olle; Orho-Melander, Marju] Lund Univ, Dept Clin Sci, S-22100 Malmo, Sweden. [Engstrom, Gunnar; Melander, Olle; Orho-Melander, Marju] Skane Univ Hosp, S-22241 Malmo, Sweden. [Fornage, Myriam; Richard, Melissa] Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX 77030 USA. [Greinacher, Andreas] Univ Med Greifswald, Inst Immunol & Transfus Med, D-17475 Greifswald, Germany. [Gudnason, Vilmundur; Smith, Albert Vernon] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Gudnason, Vilmundur; Smith, Albert Vernon] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Intramural Res Program, NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Hayward, Caroline] Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Hernesniemi, Jussi; Lehtimaki, Terho; Lyytikainen, Leo-Pekka; Mononen, Nina; Raitoharju, Emma] Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland. [Hernesniemi, Jussi; Lehtimaki, Terho; Lyytikainen, Leo-Pekka; Mononen, Nina; Raitoharju, Emma] Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland. [Hernesniemi, Jussi; Nikus, Kjell] Univ Tampere, Sch Med, Tampere 33014, Finland. [Highland, Heather M.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Hirschhorn, Joel N.] Boston Childrens Hosp, Dept Endocrinol, Boston, MA 02115 USA. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Irvin, Marguerite R.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland. [Kahonen, Mika] Univ Tampere, Dept Clin Physiol, Sch Med, Tampere 33014, Finland. [Lange, Ethan] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Lange, Ethan] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. [Li, Jin] Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Palo Alto, CA 94305 USA. 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[Waterworth, Dawn M.] Genet Target Sci, GlaxoSmithKline, King Of Prussia, PA 19406 USA. [White, Harvey D.] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland 1142, New Zealand. [White, Harvey D.] Univ Auckland, Auckland 1142, New Zealand. [Wilson, James G.] Univ Mississippi Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10069 USA. [Faraday, Nauder] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Ganesh, Santhi K.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48108 USA. [Ganesh, Santhi K.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48108 USA. [Auer, Paul L.] Univ Wisconsin, Zilber Sch Publ Hlth, Milwaukee, WI 53205 USA. [Reiner, Alexander P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Reiner, Alexander P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. RP Lettre, G (reprint author), Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada.; Lettre, G (reprint author), Montreal Heart Inst, Montreal, PQ H1T 1CB, Canada.; Reiner, AP (reprint author), Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.; Reiner, AP (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. EM apreiner@u.washington.edu; guillaume.lettre@umontreal.ca RI Schurmann, Claudia/L-1204-2016; Floyd, James/G-7563-2015; Johnson, Andrew/G-6520-2013; Kacprowski, Tim/K-8650-2013; Dube, Marie-Pierre/B-9364-2008; Grarup, Niels/K-2807-2015; OI Schurmann, Claudia/0000-0003-4158-9192; Evangelou, Evangelos/0000-0002-5488-2999; Linneberg, Allan/0000-0002-0994-0184; Kacprowski, Tim/0000-0002-5393-2413; Dube, Marie-Pierre/0000-0001-8442-4393; Grarup, Niels/0000-0001-5526-1070; Manichaikul, Ani/0000-0002-5998-795X; Tajuddin, Salman M./0000-0002-7919-8528; Zonderman, Alan B/0000-0002-6523-4778 FU Fonds de Recherche du Queebec-Santee (FRQS); Canadian Institute of Health Research (Banting-CIHR); Canadian Institute of Health Research (operating grant MOP) [123382]; Canada Research Chair program; NHLBI [R21 HL121422-02]; NIH [DK060022]; Yoshida Scholarship Foundation; Research Scholar award from the Massachusetts General Hospital (MGH); Howard Goodman Fellowship from MGH; Donovan Family Foundation [R01HL107816]; Fondation Leducq FX We thank all participants, staff, and study coordinating centers. We also thank Raymond Doty and Jan Abkowitz for discussion of the ALAS2 finding. We would like to thank Liling Warren for contributions to the genetic analysis of the SOLID-TIMI-52 and STABILITY datasets. Young Finns Study (YFS) acknowledges the expert technical assistance in the statistical analyses by Ville Aalto and Irina Lisinen. Estonian Genome Center, University of Tartu (EGCUT) thanks co-workers at the Estonian Biobank, especially Mr. V. Soo, Mr. S. Smith, and Dr. L. Milani. Airwave thanks Louisa Cavaliero who assisted in data collection and management as well as Peter McFarlane and the Glasgow CARE, Patricia Munroe at Queen Mary University of London, and Joanna Sarnecka and Ania Zawodniak at Northwick Park for their contributions to the study. This work was supported by the Fonds de Recherche du Queebec-Santee (FRQS, scholarship to N.C.), the Canadian Institute of Health Research (Banting-CIHR, scholarship to S.L. and operating grant MOP#123382 to G.L.), and the Canada Research Chair program (to G.L.). P.L.A. was supported by NHLBI R21 HL121422-02. N.A.A. is funded by NIH DK060022. A.N. was supported by the Yoshida Scholarship Foundation. S.K. was supported by a Research Scholar award from the Massachusetts General Hospital (MGH), the Howard Goodman Fellowship from MGH, the Donovan Family Foundation, R01HL107816, and a grant from Fondation Leducq. Additional acknowledgments and funding information is provided in the Supplemental Data. NR 65 TC 3 Z9 3 U1 5 U2 6 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 JUL 7 PY 2016 VL 99 IS 1 BP 8 EP 21 DI 10.1016/j.ajhg.2016.05.007 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA DT6TI UT WOS:000381616600002 PM 27346685 ER PT J AU Tajuddin, SM Schick, UM Eicher, JD Chami, N Giri, A Brody, JA Hill, WD Kacprowski, T Li, J Lyytikainen, LP Manichaikul, A Mihailov, E O'Donoghue, ML Pankratz, N Pazoki, R Polfus, LM Smith, AV Schurmann, C Vacchi-Suzzi, C Waterworth, DM Evangelou, E Yanek, LR Burt, A Chen, MH van Rooij, FJA Floyd, JS Greinacher, A Harris, TB Highland, HM Lange, LA Liu, Y Magi, R Nalls, MA Mathias, RA Nickerson, DA Nikus, K Starr, JM Tardif, JC Tzoulaki, I Edwards, DRV Wallentin, L Bartz, TM Becker, LC Denny, JC Raffield, LM Rioux, JD Friedrich, N Fornage, M Gao, H Hirschhorn, JN Liewald, DCM Rich, SS Uitterlinden, A Bastarache, L Becker, DM Boerwinkle, E de Denus, S Bottinger, EP Hayward, C Hofman, A Homuth, G Lange, E Launer, LJ Lehtimaki, T Lu, YC Metspalu, A O'Donnell, CJ Quarells, RC Richard, M Torstenson, ES Taylor, KD Vergnaud, AC Zonderman, AB Crosslin, DR Deary, IJ Dorr, M Elliott, P Evans, MK Gudnason, V Kahonen, M Psaty, BM Rotter, JI Slater, AJ Dehghan, A White, HD Ganesh, SK Loos, RJF Esko, T Faraday, N Wilson, JG Cushman, M Johnson, AD Edwards, TL Zakai, NA Lettre, G Reiner, AP Auer, PL AF Tajuddin, Salman M. Schick, Ursula M. Eicher, John D. Chami, Nathalie Giri, Ayush Brody, Jennifer A. Hill, W. David Kacprowski, Tim Li, Jin Lyytikainen, Leo-Pekka Manichaikul, Ani Mihailov, Evelin O'Donoghue, Michelle L. Pankratz, Nathan Pazoki, Raha Polfus, Linda M. Smith, Albert Vernon Schurmann, Claudia Vacchi-Suzzi, Caterina Waterworth, Dawn M. Evangelou, Evangelos Yanek, Lisa R. Burt, Amber Chen, Ming-Huei van Rooij, Frank J. A. Floyd, James S. Greinacher, Andreas Harris, Tamara B. Highland, Heather M. Lange, Leslie A. Liu, Yongmei Magi, Reedik Nalls, Mike A. Mathias, Rasika A. Nickerson, Deborah A. Nikus, Kjell Starr, John M. Tardif, Jean-Claude Tzoulaki, Ioanna Edwards, Digna R. Velez Wallentin, Lars Bartz, Traci M. Becker, Lewis C. Denny, Joshua C. Raffield, Laura M. Rioux, John D. Friedrich, Nele Fornage, Myriam Gao, He Hirschhorn, Joel N. Liewald, David C. M. Rich, Stephen S. Uitterlinden, Andre Bastarache, Lisa Becker, Diane M. Boerwinkle, Eric de Denus, Simon Bottinger, Erwin P. Hayward, Caroline Hofman, Albert Homuth, Georg Lange, Ethan Launer, Lenore J. Lehtimaki, Terho Lu, Yingchang Metspalu, Andres O'Donnell, Chris J. Quarells, Rakale C. Richard, Melissa Torstenson, Eric S. Taylor, Kent D. Vergnaud, Anne-Claire Zonderman, Alan B. Crosslin, David R. Deary, Ian J. Dorr, Marcus Elliott, Paul Evans, Michele K. Gudnason, Vilmundur Kahonen, Mika Psaty, Bruce M. Rotter, Jerome I. Slater, Andrew J. Dehghan, Abbas White, Harvey D. Ganesh, Santhi K. Loos, Ruth J. F. Esko, Tonu Faraday, Nauder Wilson, James G. Cushman, Mary Johnson, Andrew D. Edwards, Todd L. Zakai, Neil A. Lettre, Guillaume Reiner, Alex P. Auer, Paul L. TI Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ACUTE MYELOID-LEUKEMIA; UROKINASE RECEPTOR; GENETIC-VARIANTS; LYMPHOBLASTIC-LEUKEMIA; TRANSCRIPTION FACTORS; SUSCEPTIBILITY LOCI; LYMPHOID ORGANS; EMERGE NETWORK; RISK LOCI; EXPRESSION AB White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of similar to 157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3 ' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases. C1 [Tajuddin, Salman M.; Zonderman, Alan B.; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Schick, Ursula M.; Schurmann, Claudia; Bottinger, Erwin P.; Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Schick, Ursula M.; Schurmann, Claudia; Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Eicher, John D.; Chen, Ming-Huei; Johnson, Andrew D.] NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA. [Chami, Nathalie; Tardif, Jean-Claude; Rioux, John D.; Lettre, Guillaume] Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada. [Chami, Nathalie; Tardif, Jean-Claude; Rioux, John D.; de Denus, Simon; Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Giri, Ayush; Torstenson, Eric S.] Vanderbilt Univ, Div Epidemiol, Inst Med & Publ Hlth, Nashville, TN 37235 USA. [Brody, Jennifer A.; Floyd, James S.] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Hill, W. David; Starr, John M.; Liewald, David C. M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Hill, W. David; Liewald, David C. M.; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Kacprowski, Tim; Homuth, Georg] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, D-17475 Greifswald, Germany. [Kacprowski, Tim; Homuth, Georg] Ernst Moritz Arndt Univ Greifswald, D-17475 Greifswald, Germany. [Kacprowski, Tim; Friedrich, Nele; Dorr, Marcus] DZHK German Ctr Cardiovasc Res, Greifswald, Germany. [Li, Jin] Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Palo Alto, CA 94305 USA. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Sch Med, Dept Clin Chem, Tampere 33014, Finland. [Manichaikul, Ani; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. [Mihailov, Evelin; Magi, Reedik; Metspalu, Andres; Esko, Tonu] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [O'Donoghue, Michelle L.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Pankratz, Nathan] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55454 USA. [Pazoki, Raha; van Rooij, Frank J. A.; Uitterlinden, Andre; Hofman, Albert; Dehghan, Abbas] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 DR Rotterdam, Netherlands. [Polfus, Linda M.; Highland, Heather M.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Vacchi-Suzzi, Caterina] SUNY Stony Brook, Dept Family Populat & Prevent Med, Stony Brook, NY 11794 USA. [Waterworth, Dawn M.] GlaxoSmithKline, Target Sci, Genet, King Of Prussia, PA 19406 USA. [Evangelou, Evangelos; Tzoulaki, Ioanna; Gao, He; Vergnaud, Anne-Claire; Elliott, Paul] Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, London W2 1PG, England. [Evangelou, Evangelos; Tzoulaki, Ioanna] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Yanek, Lisa R.; Becker, Diane M.] Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. [Burt, Amber] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Greinacher, Andreas] Univ Med Greifswald, Inst Immunol & Transfus Med, D-17475 Greifswald, Germany. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Highland, Heather M.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Lange, Leslie A.; Raffield, Laura M.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA. [Nalls, Mike A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Mathias, Rasika A.] Johns Hopkins Univ, Sch Med, Dept Med, Div Allergy & Clin Immunol, Baltimore, MD 21205 USA. [Mathias, Rasika A.; Becker, Lewis C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. [Nickerson, Deborah A.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98105 USA. [Nikus, Kjell] Tampere Univ Hosp, Dept Cardiol, Ctr Heart, Tampere 33521, Finland. [Nikus, Kjell] Univ Tampere, Sch Med, Tampere 33014, Finland. [Starr, John M.] Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Edwards, Digna R. Velez] Vanderbilt Univ, Vanderbilt Genet Inst, Inst Med & Publ Hlth, Vanderbilt Epidemiol Ctr,Dept Obstet & Gynecol, Nashville, TN 37203 USA. [Wallentin, Lars] Uppsala Univ, Cardiol, Dept Med Sci, S-75185 Uppsala, Sweden. [Wallentin, Lars] Uppsala Univ, Uppsala Clin Res Ctr, S-75185 Uppsala, Sweden. [Bartz, Traci M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Becker, Lewis C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Denny, Joshua C.; Bastarache, Lisa] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37203 USA. [Friedrich, Nele] Univ Med Greifswald, Inst Clin Chem & Lab Med, D-13347 Greifswald, Germany. [Fornage, Myriam; Richard, Melissa] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Hirschhorn, Joel N.; Esko, Tonu] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Hirschhorn, Joel N.] Boston Childrens Hosp, Dept Endocrinol, Boston, MA 02115 USA. [Uitterlinden, Andre] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 DR Rotterdam, Netherlands. [Uitterlinden, Andre] NCHA, NL-3015 GD Rotterdam, Netherlands. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [de Denus, Simon] Univ Montreal, Fac Pharm, Montreal, PQ H3T 1J4, Canada. [Hayward, Caroline] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Hofman, Albert] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lange, Ethan] Univ N Carolina, Dept Genet & Biostat, Chapel Hill, NC 27599 USA. [O'Donnell, Chris J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [O'Donnell, Chris J.] Boston Vet Adm Healthcare, Cardiol Sect, Boston, MA 02118 USA. [O'Donnell, Chris J.] Boston Vet Adm Healthcare, Ctr Populat Genom, Boston, MA 02118 USA. [Quarells, Rakale C.] Morehouse Sch Med, Social Epidemiol Res Ctr, Cardiovasc Res Inst, Atlanta, GA 30310 USA. [Taylor, Kent D.; Rotter, Jerome I.] Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA. [Taylor, Kent D.; Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA. [Crosslin, David R.] Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98195 USA. [Dorr, Marcus] Univ Med Greifswald, Dept Cardiol, D-17475 Greifswald, Germany. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland. [Kahonen, Mika] Univ Tampere, Sch Med, Dept Clin Physiol, Tampere 33014, Finland. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Epidemiol, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Hlth Serv, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Slater, Andrew J.] OmicSoft Corp, Cary, NC 27513 USA. [Slater, Andrew J.] GlaxoSmithKline, Genet Target Sci, Res Triangle Pk, NC 27709 USA. [White, Harvey D.] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland 1142, New Zealand. [White, Harvey D.] Univ Auckland, Auckland 1142, New Zealand. [Ganesh, Santhi K.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48108 USA. [Ganesh, Santhi K.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48108 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Faraday, Nauder] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Cushman, Mary; Zakai, Neil A.] Univ Vermont, Dept Med, Div Hematol Oncol, Colchester, VT 05446 USA. [Edwards, Todd L.] Vanderbilt Univ, Vanderbilt Genet Inst, Inst Med & Publ Hlth, Div Epidemiol,Dept Med, Nashville, TN 37203 USA. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Auer, Paul L.] Univ Wisconsin Milwaukee, Zilber Sch Publ Hlth, Milwaukee, WI 53205 USA. RP Reiner, AP (reprint author), Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.; Reiner, AP (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA.; Auer, PL (reprint author), Univ Wisconsin Milwaukee, Zilber Sch Publ Hlth, Milwaukee, WI 53205 USA. EM apreiner@u.washington.edu; pauer@uwm.edu RI Schurmann, Claudia/L-1204-2016; Floyd, James/G-7563-2015; Rioux, John/A-9599-2015; Johnson, Andrew/G-6520-2013; Kacprowski, Tim/K-8650-2013; OI Schurmann, Claudia/0000-0003-4158-9192; Rioux, John/0000-0001-7560-8326; Kacprowski, Tim/0000-0002-5393-2413; Manichaikul, Ani/0000-0002-5998-795X; Tajuddin, Salman M./0000-0002-7919-8528; Zonderman, Alan B/0000-0002-6523-4778; Evangelou, Evangelos/0000-0002-5488-2999; Dehghan, Abbas/0000-0001-6403-016X FU NHLBI [R21 HL121422-02, R01 HL086694]; Canada Research Chair program; Canadian Institute of Health Research MOP [123382]; National Institute on Aging, NIH Intramural Research Program; a component of the NIH Roadmap for Medical Research [UL1RR025005] FX We thank all participants and study coordinating centers of the participating studies and cohorts. P.L.A. was supported by NHLBI R21 HL121422-02. G.L. was supported by the Canada Research Chair program and the Canadian Institute of Health Research MOP#123382. This work was supported in part by the National Institute on Aging, NIH Intramural Research Program. Data analyses utilized the computational resources of the NIH HPC Biowulf cluster at the NIH. The Framingham Heart Study (FHS) acknowledges the Shared Computing Cluster at Boston University. Infrastructure and data analysis for the ARIC study was partly supported by Grant Number UL1RR025005, a component of the NIH Roadmap for Medical Research, and grant R01 HL086694 from the NHLBI. Airwave study thanks Louisa Cavaliero who assisted in data collection and management, Peter McFarlane and the Glasgow CARE, Patricia Munroe at Queen Mary University of London, and Joanna Sarnecka and Ania Zawodniak at Northwick Park for their contributions to the study. SOLID-TIMI-52 and STABILITY thank Liling Warren for contributions to the genetic analysis of the study datasets. Estonian Genome Center, University of Tartu (EGCUT) thanks Mr. V. Soo, Mr. S. Smith, and Dr. L. Milani for their contribution. The Rotterdam Study (RS) thanks Ms. Mila Jhamai, Ms. Sarah Higgins, and Mr. Marijn Verkerk for their help in creating the Exomechip database, and Ms. Carolina MedinaGomez, Mr. Lennard Karsten, and Dr. Linda Broer. Additional acknowledgments and funding information are provided in the Supplemental Data. NR 96 TC 3 Z9 3 U1 7 U2 8 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 JUL 7 PY 2016 VL 99 IS 1 BP 22 EP 39 DI 10.1016/j.ajhg.2016.05.003 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA DT6TI UT WOS:000381616600003 PM 27346689 ER PT J AU Eicher, JD Chami, N Kacprowski, T Nomura, A Chen, MH Yanek, LR Tajuddin, SM Schick, UM Slater, AJ Pankratz, N Polfus, L Schurmann, C Giri, A Brody, JA Lange, LA Manichaikul, A Hill, WD Pazoki, R Elliot, P Evangelou, E Tzoulaki, I Gao, H Vergnaud, AC Mathias, RA Becker, DM Becker, LC Burt, A Crosslin, DR Lyytikainen, LP Nikus, K Hernesniemi, J Kahonen, M Raitoharju, E Mononen, N Raitakari, OT Lehtimaki, T Cushman, M Zakai, NA Nickerson, DA Raffield, LM Quarells, R Willer, CJ Peloso, GM Abecasis, GR Liu, DJJ Deloukas, P Samani, NJ Schunkert, H Erdmann, J Fornage, M Richard, M Tardif, JC Rioux, JD Dube, MP de Denus, S Lu, YC Bottinger, EP Loos, RJF Smith, AV Harris, TB Launer, LJ Gudnason, V Edwards, DRV Torstenson, ES Liu, YM Tracy, RP Rotter, JI Rich, SS Highland, HM Boerwinkle, E Li, J Lange, E Wilson, JG Mihailov, E Magi, R Hirschhorn, J Metspalu, A Esko, T Vacchi-Suzzi, C Nalls, MA Zonderman, AB Evans, MK Engstrom, G Orho-Melander, M Melander, O O'Donoghue, ML Waterworth, DM Wallentin, L White, HD Floyd, JS Bartz, TM Rice, KM Psaty, BM Starr, JM Liewald, DCM Hayward, C Deary, IJ Greinacher, A Volker, U Thiele, T Volzke, H van Rooij, FJA Uitterlinden, AG Franco, OH Dehghan, A Edwards, TL Ganesh, SK Kathiresan, S Faraday, N Auer, PL Reiner, AP Lettre, G Johnson, AD AF Eicher, John D. Chami, Nathalie Kacprowski, Tim Nomura, Akihiro Chen, Ming-Huei Yanek, Lisa R. Tajuddin, Salman M. Schick, Ursula M. Slater, Andrew J. Pankratz, Nathan Polfus, Linda Schurmann, Claudia Giri, Ayush Brody, Jennifer A. Lange, Leslie A. Manichaikul, Ani Hill, W. David Pazoki, Raha Elliot, Paul Evangelou, Evangelos Tzoulaki, Ioanna Gao, He Vergnaud, Anne-Claire Mathias, Rasika A. Becker, Diane M. Becker, Lewis C. Burt, Amber Crosslin, David R. Lyytikainen, Leo-Pekka Nikus, Kjell Hernesniemi, Jussi Kahonen, Mika Raitoharju, Emma Mononen, Nina Raitakari, Olli T. Lehtimaki, Terho Cushman, Mary Zakai, Neil A. Nickerson, Deborah A. Raffield, Laura M. Quarells, Rakale Willer, Cristen J. Peloso, Gina M. Abecasis, Goncalo R. Liu, Dajiang J. Deloukas, Panos Samani, Nilesh J. Schunkert, Heribert Erdmann, Jeanette Fornage, Myriam Richard, Melissa Tardif, Jean-Claude Rioux, John D. Dube, Marie-Pierre de Denus, Simon Lu, Yingchang Bottinger, Erwin P. Loos, Ruth J. F. Smith, Albert Vernon Harris, Tamara B. Launer, Lenore J. Gudnason, Vilmundur Edwards, Digna R. Velez Torstenson, Eric S. Liu, Yongmei Tracy, Russell P. Rotter, Jerome I. Rich, Stephen S. Highland, Heather M. Boerwinkle, Eric Li, Jin Lange, Ethan Wilson, James G. Mihailov, Evelin Magi, Reedik Hirschhorn, Joel Metspalu, Andres Esko, Tonu Vacchi-Suzzi, Caterina Nalls, Mike A. Zonderman, Alan B. Evans, Michele K. Engstrom, Gunnar Orho-Melander, Marju Melander, Olle O'Donoghue, Michelle L. Waterworth, Dawn M. Wallentin, Lars White, Harvey D. Floyd, James S. Bartz, Traci M. Rice, Kenneth M. Psaty, Bruce M. Starr, J. M. Liewald, David C. M. Hayward, Caroline Deary, Ian J. Greinacher, Andreas Volker, Uwe Thiele, Thomas Volzke, Henry van Rooij, Frank J. A. Uitterlinden, Andre G. Franco, Oscar H. Dehghan, Abbas Edwards, Todd L. Ganesh, Santhi K. Kathiresan, Sekar Faraday, Nauder Auer, Paul L. Reiner, Alex P. Lettre, Guillaume Johnson, Andrew D. CA Global Lipids Genetics Consortium CARDIoGRAM Exome Consortium Myocardial Infarction Genetics TI Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; EPSILON-RI-ALPHA; PIAS-LIKE PROTEIN; IMMUNE THROMBOCYTOPENIA; MYOCARDIAL-INFARCTION; AFRICAN-AMERICANS; SEQUENCE VARIANTS; BLOOD-PRESSURE; BINDING-SITE; IGE BINDING AB Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common(ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV(PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors. C1 [Eicher, John D.; Chen, Ming-Huei; Johnson, Andrew D.] NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA. [Chami, Nathalie; Tardif, Jean-Claude; Rioux, John D.; Dube, Marie-Pierre; Lettre, Guillaume] Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada. [Chami, Nathalie; Tardif, Jean-Claude; Rioux, John D.; Dube, Marie-Pierre; de Denus, Simon; Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Kacprowski, Tim; Volker, Uwe] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, D-17475 Greifswald, Germany. [Kacprowski, Tim; Volker, Uwe] Ernst Mortiz Arndt Univ Greifswald, D-17475 Greifswald, Germany. [Kacprowski, Tim; Volker, Uwe; Volzke, Henry] DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany. [Nomura, Akihiro; Peloso, Gina M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Nomura, Akihiro; Peloso, Gina M.; Hirschhorn, Joel; Esko, Tonu; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Nomura, Akihiro; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Nomura, Akihiro; Kathiresan, Sekar] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. [Nomura, Akihiro] Kanazawa Univ, Div Cardiovasc Med, Grad Sch Med Sci, Kanazawa, Ishikawa 9200942, Japan. [Yanek, Lisa R.; Mathias, Rasika A.; Becker, Diane M.; Becker, Lewis C.] Johns Hopkins Univ, Div Gen Internal Med, Dept Med, Sch Med, Baltimore, MD 21205 USA. [Tajuddin, Salman M.; Zonderman, Alan B.; Evans, Michele K.] NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA. [Schick, Ursula M.; Schurmann, Claudia; Lu, Yingchang; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Schick, Ursula M.; Schurmann, Claudia] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Slater, Andrew J.] GlaxoSmithKline, Genet, Target Sci, Res Triangle Pk, NC 27709 USA. [Slater, Andrew J.] OmicSoft Corp, Cary, NC 27513 USA. [Pankratz, Nathan] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55454 USA. [Polfus, Linda; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA. [Giri, Ayush; Torstenson, Eric S.; Edwards, Todd L.] Vanderbilt Univ, Inst Med & Publ Hlth, Div Epidemiol, Nashville, TN 37235 USA. [Brody, Jennifer A.; Floyd, James S.] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Lange, Leslie A.; Raffield, Laura M.; Lange, Ethan] Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA. [Manichaikul, Ani; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA 22908 USA. [Hill, W. David; Starr, J. M.; Liewald, David C. M.; Deary, Ian J.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Hill, W. David; Liewald, David C. M.; Deary, Ian J.] Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Pazoki, Raha; van Rooij, Frank J. A.; Uitterlinden, Andre G.; Franco, Oscar H.; Dehghan, Abbas] Erasmus MC, Dept Epidemiol, NL-3000 Rotterdam, Netherlands. [Elliot, Paul; Evangelou, Evangelos; Tzoulaki, Ioanna; Gao, He; Vergnaud, Anne-Claire] Univ London Imperial Coll Sci Technol & Med, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, Sch Publ Hlth, London W2 1PG, England. [Evangelou, Evangelos; Tzoulaki, Ioanna] Univ Ioannina, Dept Hyg & Epidemiol, Sch Med, Ioannina 45110, Greece. [Mathias, Rasika A.] Johns Hopkins Univ, Sch Med, Dept Med, Div Allergy, Baltimore, MD 21205 USA. [Mathias, Rasika A.] Johns Hopkins Univ, Sch Med, Dept Med, Div Immunol, Baltimore, MD 21205 USA. [Becker, Lewis C.] Johns Hopkins Univ, Div Cardiol, Dept Med, Sch Med, Baltimore, MD 21205 USA. [Burt, Amber] Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98195 USA. [Crosslin, David R.] Univ Washington, Dept Biomed Informat & Med Educ, Seattle, WA 98105 USA. [Lyytikainen, Leo-Pekka; Hernesniemi, Jussi; Raitoharju, Emma; Mononen, Nina; Lehtimaki, Terho] Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland. [Lyytikainen, Leo-Pekka; Hernesniemi, Jussi; Raitoharju, Emma; Mononen, Nina; Lehtimaki, Terho] Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33514, Finland. [Nikus, Kjell; Hernesniemi, Jussi] Tampere Univ Hosp, Dept Cardiol, Ctr Heart, Tampere 33521, Finland. [Nikus, Kjell] Univ Tampere, Sch Med, Tampere 33514, Finland. [Kahonen, Mika] Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland. [Kahonen, Mika] Univ Tampere, Dept Clin Physiol, Tampere 33514, Finland. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland. [Cushman, Mary; Zakai, Neil A.] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Cushman, Mary; Zakai, Neil A.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98105 USA. [Quarells, Rakale] Morehouse Sch Med, Social Epidemiol Res Ctr, Cardiovasc Res Inst, Atlanta, GA 30310 USA. [Willer, Cristen J.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48108 USA. [Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Dept Human Genet, Ann Arbor, MI 48108 USA. [Willer, Cristen J.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48108 USA. [Peloso, Gina M.] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02118 USA. [Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48108 USA. [Liu, Dajiang J.] Penn State Univ Hosp, Dept Publ Hlth Sci, Coll Med, Hershey, PA 17033 USA. [Deloukas, Panos] Queen Mary Univ London, William Harvey Res Inst, London E1 4NS, England. [Deloukas, Panos] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21589, Saudi Arabia. [Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester LE1 7RH, Leics, England. [Samani, Nilesh J.] Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England. [Schunkert, Heribert] DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, D-80333 Munich, Germany. [Schunkert, Heribert] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80333 Munich, Germany. [Erdmann, Jeanette] Univ Lubeck, Inst Integrat & Expt Genom, D-23562 Lubeck, Germany. [Erdmann, Jeanette] DZHK German Res Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, D-23562 Lubeck, Germany. [Fornage, Myriam; Richard, Melissa] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [de Denus, Simon] Univ Montreal, Fac Pharm, Montreal H3T 1J4, PQ, Canada. [Smith, Albert Vernon; Gudnason, Vilmundur] Icelandic Heart Assoc, IS-201 Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Edwards, Digna R. Velez] Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Dept Obstet & Gynecol, Inst Med & Publ Hlth,Vanderbilt Genet Inst, Nashville, TN 37203 USA. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Ctr Human Genet, Winston Salem, NC 27157 USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol & Lab Med, Colchester, VT 05446 USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Biochem, Colchester, VT 05446 USA. [Rotter, Jerome I.] Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA. [Highland, Heather M.] Univ Texas Hlth Sci Ctr Houston, Univ Texas Grad Sch Biomed Sci Houston, Univ Texas Sch Publ Hlth, Houston, TX 77030 USA. [Highland, Heather M.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Boerwinkle, Eric] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Li, Jin] Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Palo Alto, CA 94305 USA. [Lange, Ethan] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27514 USA. [Wilson, James G.] Univ Mississippi, Dept Physiol & Biophys, Med Ctr, Jackson, MS 39216 USA. [Mihailov, Evelin; Magi, Reedik; Metspalu, Andres; Esko, Tonu] Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia. [Hirschhorn, Joel] Boston Childrens Hosp, Dept Endocrinol, Boston, MA 02115 USA. [Vacchi-Suzzi, Caterina] SUNY Stony Brook, Dept Family Populat & Prevent Med, Stony Brook, NY 11794 USA. [Nalls, Mike A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 21224 USA. [Engstrom, Gunnar; Orho-Melander, Marju; Melander, Olle] Lund Univ, Dept Clin Sci Malmo, S-22100 Malmo, Sweden. [Engstrom, Gunnar; Orho-Melander, Marju; Melander, Olle] Skane Univ Hosp, S-22241 Malmo, Sweden. [O'Donoghue, Michelle L.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. [Waterworth, Dawn M.] GlaxoSmithKline, Target Sci, Genet, King Of Prussia, PA 19406 USA. [Wallentin, Lars] Uppsala Univ, Dept Med Sci, Cardiol, S-75185 Uppsala, Sweden. [Wallentin, Lars] Uppsala Univ, Dept Med Sci, Uppsala Clin Res Ctr, S-75185 Uppsala, Sweden. [White, Harvey D.] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland 1142, New Zealand. [White, Harvey D.] Univ Auckland, Auckland 1142, New Zealand. [Bartz, Traci M.; Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA. [Starr, J. M.] Alzheimer Scotland Res Ctr, Edinburgh EH8 9JZ, Midlothian, Scotland. [Hayward, Caroline] Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland. [Greinacher, Andreas; Thiele, Thomas] Univ Med Greifswald, Inst Immunol & Transfus Med, D-17475 Greifswald, Germany. [Volzke, Henry] Univ Med Greifswald, Inst Community Med, D-13347 Greifswald, Germany. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 Rotterdam, Netherlands. [Uitterlinden, Andre G.] Netherlands Consortium Hlth Ageing, NL-3015 Rotterdam, Netherlands. [Ganesh, Santhi K.] Univ Michigan, Dept Internal & Human Genet, Ann Arbor, MI 48108 USA. [Faraday, Nauder] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Auer, Paul L.] Univ Wisconsin, Zilber Sch Publ Hlth, Milwaukee, WI 53205 USA. [Reiner, Alex P.] Univ Washington, Dept Epidemiol, Seattle, WA 98105 USA. [Eicher, John D.; Chami, Nathalie; Kacprowski, Tim; Nomura, Akihiro; Faraday, Nauder; Auer, Paul L.; Reiner, Alex P.; Lettre, Guillaume; Johnson, Andrew D.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. RP Johnson, AD (reprint author), NHLBI, Populat Sci Branch, Framingham Heart Study, Framingham, MA 01702 USA.; Johnson, AD (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. EM johnsonad2@nhlbi.nih.gov RI Schurmann, Claudia/L-1204-2016; Floyd, James/G-7563-2015; Rioux, John/A-9599-2015; Johnson, Andrew/G-6520-2013; Kacprowski, Tim/K-8650-2013; Deloukas, Panos/B-2922-2013; Dube, Marie-Pierre/B-9364-2008; OI Evangelou, Evangelos/0000-0002-5488-2999; Dehghan, Abbas/0000-0001-6403-016X; Schurmann, Claudia/0000-0003-4158-9192; Rioux, John/0000-0001-7560-8326; Kacprowski, Tim/0000-0002-5393-2413; Deloukas, Panos/0000-0001-9251-070X; Dube, Marie-Pierre/0000-0001-8442-4393; Manichaikul, Ani/0000-0002-5998-795X; Tajuddin, Salman M./0000-0002-7919-8528; Zonderman, Alan B/0000-0002-6523-4778 FU British Heart Foundation [RG/14/5/30893]; Medical Research Council [MC_PC_U127561128, MR/K026992/1]; NCATS NIH HHS [UL1 TR000124, UL1 TR000445]; NHGRI NIH HHS [U01 HG004402, U01 HG004603]; NHLBI NIH HHS [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HHSN268201100037C, HHSN268201300026C, HHSN268201300028C, N01 HC025195, N01 HC095159, N01 HC095160, R01 HL059367, R01 HL086694, R01 HL087641, R01 HL087698, R01 HL112064, R01 HL122684, R01 HL127564, RC2 HL102419, U01 HL072518]; NICHD NIH HHS [R01 HD074711]; NIDDK NIH HHS [P30 DK063491] NR 77 TC 4 Z9 4 U1 3 U2 6 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 JUL 7 PY 2016 VL 99 IS 1 BP 40 EP 55 DI 10.1016/j.ajhg.2016.05.005 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA DT6TI UT WOS:000381616600004 PM 27346686 ER PT J AU Kasenda, B Loeffler, J Illerhaus, G Ferreri, AJM Rubenstein, J Batchelor, TT AF Kasenda, Benjamin Loeffler, Jay Illerhaus, Gerald Ferreri, Andres J. M. Rubenstein, James Batchelor, Tracy T. TI The role of whole brain radiation in primary CNS lymphoma SO BLOOD LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; STEM-CELL TRANSPLANTATION; HIGH-DOSE CHEMOTHERAPY; NON-HODGKINS-LYMPHOMA; TERM-FOLLOW-UP; IMMUNOCOMPETENT PATIENTS; 1ST-LINE TREATMENT; ELDERLY-PATIENTS; X-IRRADIATION; PHASE-II C1 [Kasenda, Benjamin; Illerhaus, Gerald] Klinikum Stuttgart, Dept Hematol Oncol & Palliat Care, Stuttgart, Germany. [Loeffler, Jay] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Ferreri, Andres J. M.] Ist Sci San Raffaele, Ist Ricovero & Cura Carattere Sci, Dept Oncohematol, Unit Lymphoid Malignancies, Milan, Italy. [Rubenstein, James] Univ Calif San Francisco, San Francisco Helen Diller Family Comprehens Canc, Div Hematol Oncol, San Francisco, CA 94143 USA. [Batchelor, Tracy T.] Harvard Med Sch, Partners Neurol Residency Program, Boston, MA USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Stephen E & Catherine Pappas Ctr Neurooncol, Boston, MA 02114 USA. RP Batchelor, TT (reprint author), Massachusetts Gen Hosp, Stephen E & Catherine Pappas Ctr Neurooncol, Boston, MA 02114 USA. EM tbatchelor@mgh.harvard.edu FU Genentech; Pfizer FX J.R. receives research funding from Genentech; T.T.B. receives consulting honoraria from Accerta, Cavion, Champions Biotechnology, Merck, OXiGENE, Proximagen, Roche, UpToDate, and research funding from Pfizer. The remaining authors declare no competing financial interests. NR 37 TC 0 Z9 0 U1 4 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 JUL 7 PY 2016 VL 128 IS 1 BP 32 EP 36 DI 10.1182/blood-2016-01-650101 PG 5 WC Hematology SC Hematology GA DQ5MN UT WOS:000379249600010 PM 27207798 ER PT J AU Usmani, SZ Weiss, BM Plesner, T Bahlis, NJ Belch, A Lonial, S Lokhorst, HM Voorhees, PM Richardson, PG Chari, A Sasser, AK Axel, A Feng, HB Uhlar, CM Wang, JP Khan, I Ahmadi, T Nahi, H AF Usmani, Saad Z. Weiss, Brendan M. Plesner, Torben Bahlis, Nizar J. Belch, Andrew Lonial, Sagar Lokhorst, Henk M. Voorhees, Peter M. Richardson, Paul G. Chari, Ajai Sasser, A. Kate Axel, Amy Feng, Huaibao Uhlar, Clarissa M. Wang, Jianping Khan, Imran Ahmadi, Tahamtan Nahi, Hareth TI Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma SO BLOOD LA English DT Article ID SINGLE-AGENT; IMPROVED SURVIVAL; OPEN-LABEL; ANTIBODY; PHASE-2; CANCER; SAFETY; BLOOD; INTERFERENCE; TRIAL AB The efficacy and favorable safety profile of daratumumab monotherapy in multiple myeloma (MM) was previously reported. Here, we present an updated pooled analysis of 148 patients treated with daratumumab 16 mg/kg. Data were combined from part 2 of a first-in-human phase 1/2 study of patients who relapsed after or were refractory to >= 2 prior therapies and a phase 2 study of patients previously treated with >= 3 prior lines of therapy (including a proteasome inhibitor [PI] and an immunomodulatory drug [IMiD]) or were double refractory. Among the pooled population, patients received a median of 5 prior lines of therapy (range, 2 to 14 prior lines of therapy), and 86.5% were double refractory to a PI and an IMiD. Overall response rate was 31.1%, including 13 very good partial responses, 4 complete responses, and 3 stringent complete responses. The median duration of response was 7.6 months (95% confidence interval [CI], 5.6 to not evaluable [NE]). The median progression-free survival (PFS) and overall survival (OS) were 4.0 months (95% CI, 2.8-5.6 months) and 20.1 months (95% CI, 16.6 months to NE), respectively. When stratified by responders vs stable disease/minimal response vs progressive disease/NE, median PFS was 15.0 months (95% CI, 7.4 months to NE) vs 3.0 months(95% CI, 2.8-3.7months) vs 0.9 months (95% CI, 0.9-1.0 months), respectively, and median OS was NE(95% CI, NE to NE) vs 18.5 months (95% CI, 15.1-22.4 months) vs 3.7 months (95% CI, 1.7-7.6 months), respectively. No new safety signals were identified. In this pooled data set, daratumumab 16 mg/kg monotherapy demonstrated rapid, deep, and durable responses, with a clinical benefit that extended to patients with stable disease or better. C1 [Usmani, Saad Z.] Carolinas HealthCare Syst, Levine Canc Inst, Charlotte, NC USA. [Weiss, Brendan M.] Univ Penn, Abramson Canc Ctr, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Weiss, Brendan M.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Plesner, Torben] Vejle Hosp, Vejle, Denmark. [Plesner, Torben] Univ Southern Denmark, Vejle, Denmark. [Bahlis, Nizar J.] Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. [Belch, Andrew] Cross Canc Inst, Edmonton, AB, Canada. [Lonial, Sagar] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Lokhorst, Henk M.] Vrije Univ Amsterdam Med Ctr, Dept Hematol, Amsterdam, Netherlands. [Voorhees, Peter M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Div Hematol Oncol, Chapel Hill, NC USA. [Richardson, Paul G.] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA USA. [Chari, Ajai] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Sasser, A. Kate; Axel, Amy; Uhlar, Clarissa M.; Wang, Jianping; Ahmadi, Tahamtan] Janssen Res & Dev LLC, Spring House, PA USA. [Feng, Huaibao; Khan, Imran] Janssen Res & Dev LLC, Raritan, NJ USA. [Nahi, Hareth] Karolinska Univ Hosp Huddinge, Dept Med, Karolinska Inst, Div Hematol, Stockholm, Sweden. RP Usmani, SZ (reprint author), Levine Canc Inst, 1021 Morehead Med Dr, Charlotte, NC 28204 USA. EM saad.usmani@carolinashealthcare.org RI Voorhees, Peter /B-6700-2009; OI nahi, hareth/0000-0003-4711-5094 FU Janssen Research & Development, LLC.; Janssen Global Services, LLC. FX This study was sponsored by Janssen Research & Development, LLC. Medical writing and editorial support were provided by Erica Chevalier-Larsen of MedErgy and were funded by Janssen Global Services, LLC. NR 26 TC 12 Z9 12 U1 2 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 JUL 7 PY 2016 VL 128 IS 1 BP 37 EP 44 DI 10.1182/blood-2016-03-705210 PG 8 WC Hematology SC Hematology GA DQ5MN UT WOS:000379249600011 PM 27216216 ER PT J AU Lu, YZ Hanada, T Fujiwara, Y Nwankwo, JO Wieschhaus, AJ Hartwig, J Huang, S Han, J Chishti, AH AF Lu, Yunzhe Hanada, Toshihiko Fujiwara, Yuko Nwankwo, Jennifer O. Wieschhaus, Adam J. Hartwig, John Huang, Sha Han, Jongyoon Chishti, Athar H. TI Gene disruption of dematin causes precipitous loss of erythrocyte membrane stability and severe hemolytic anemia SO BLOOD LA English DT Article ID RED-BLOOD-CELLS; HEADPIECE DOMAIN; TARGETED DISRUPTION; PROTEIN-KINASE; GLYCOPHORIN-C; IN-VITRO; SKELETON; MICE; SPECTRIN; ADDUCIN AB Dematin is a relatively low abundance actin binding and bundling protein associated with the spectrin-actin junctions of mature erythrocytes. Primary structure of dematin includes a loosely folded core domain and a compact headpiece domain that was originally identified in villin. Dematin's actin binding properties are regulated by phosphorylation of its headpiece domain by cyclic adenosine monophosphate-dependent protein kinase. Here, we used a novel gene disruption strategy to generate the whole body dematin gene knockout mouse model (FLKO). FLKO mice, while born at a normal Mendelian ratio, developed severe anemia and exhibited profound aberrations of erythrocyte morphology and membrane stability. Having no apparent effect on primitive erythropoiesis, FLKO mice show significant enhancement of erythroblast enucleation during definitive erythropoiesis. Using membrane protein analysis, domain mapping, electron microscopy, and dynamic deformability measurements, we investigated the mechanism of membrane instability in FLKO erythrocytes. Although many membrane and cytoskeletal proteins remained at their normal levels, the major peripheral membrane proteins spectrin, adducin, and actin were greatly reduced in FLKO erythrocytes. Our results demonstrate that dematin plays a critical role in maintaining the fundamental properties of the membrane cytoskeleton complex. C1 [Lu, Yunzhe; Hanada, Toshihiko; Nwankwo, Jennifer O.; Wieschhaus, Adam J.; Chishti, Athar H.] Tufts Univ, Sch Med, Dept Dev Mol & Chem Biol, Jaharis Bldg,Room 714,150 Harrison Ave, Boston, MA 02111 USA. [Fujiwara, Yuko] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. [Fujiwara, Yuko] Harvard Med Sch, Harvard Stem Cell Inst, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Nwankwo, Jennifer O.; Chishti, Athar H.] Tufts Univ, Sch Med, Pharmacol & Expt Therapeut, Jaharis Bldg,Room 714,150 Harrison Ave, Boston, MA 02111 USA. [Hartwig, John] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA USA. [Huang, Sha; Han, Jongyoon] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA USA. [Han, Jongyoon] MIT, Dept Biol Engn, Cambridge, MA USA. [Chishti, Athar H.] Tufts Univ, Sch Med, Sackler Sch Grad Biomed Sci, Programs Cellular & Mol Physiol, Jaharis Bldg,Room 714,150 Harrison Ave, Boston, MA 02111 USA. [Chishti, Athar H.] Tufts Univ, Sch Med, Dept Mol Microbiol, Jaharis Bldg,Room 714,150 Harrison Ave, Boston, MA 02111 USA. RP Chishti, AH (reprint author), Tufts Univ, Sch Med, Sackler Sch Grad Biomed Sci, Program Cellular & Mol Physiol,Program Pharmacol, Jaharis Bldg,Room 714,150 Harrison Ave, Boston, MA 02111 USA. EM athar.chishti@tufts.edu FU National Institutes of Health, National Human Genome Research Institute [U01HG004085]; CSD Consortium [U01HG004080]; National Heart, Lung, and Blood Institute [HL095050, HL051445]; American Society of Hematology Bridge grant award; Howard Hughes Medical Institute International Student Research Fellowship; American Heart Association FX National Institutes of Health, National Human Genome Research Institute grants to Velocigene at Regeneron (U01HG004085) and the CSD Consortium (U01HG004080) funded the generation of gene-targeted ES cells for 8500 genes in the KOMP Program and archived and distributed by the KOMP Repository at University of California, Davis and Children's Hospital Oakland Research Institute (U42RR024244). This work was supported in part by National Heart, Lung, and Blood Institute grants HL095050 and HL051445, an American Society of Hematology Bridge grant award, a Howard Hughes Medical Institute International Student Research Fellowship (J.O.N.), and a Grant-in-Aid from the American Heart Association. NR 44 TC 1 Z9 1 U1 4 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUL 7 PY 2016 VL 128 IS 1 BP 93 EP 103 DI 10.1182/blood-2016-01-692251 PG 11 WC Hematology SC Hematology GA DQ5MN UT WOS:000379249600017 PM 27073223 ER PT J AU Koreth, J Kim, HT Jones, KT Lange, PB Reynolds, CG Chammas, MJ Dusenbury, K Whangbo, J Nikiforow, S Alyea, EP Armand, P Cutler, CS Ho, VT Chen, YB Avigan, D Blazar, BR Antin, JH Ritz, J Soiffer, RJ AF Koreth, John Kim, Haesook T. Jones, Kyle T. Lange, Paulina B. Reynolds, Carol G. Chammas, Marie J. Dusenbury, Katherine Whangbo, Jennifer Nikiforow, Sarah Alyea, Edwin P., III Armand, Philippe Cutler, Corey S. Ho, Vincent T. Chen, Yi-Bin Avigan, David Blazar, Bruce R. Antin, Joseph H. Ritz, Jerome Soiffer, Robert J. TI Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease SO BLOOD LA English DT Article ID REGULATORY T-CELLS; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; BONE-MARROW-TRANSPLANTATION; CLINICAL-TRIALS; CHRONIC GVHD; CRITERIA; TOLERANCE; IL-2; VALIDATION AB Chronic graft-versus-host disease (cGVHD) is associated with inadequate reconstitution of tolerogenic CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs). Previous phase 1 studies identified a low daily dose of interleukin-2 (IL-2) that was well tolerated, did not exacerbate alloimmunity, augmented Treg in vivo, and was associated with improvement of active cGVHD. In the current phase 2 study, 35 adults with steroid-refractory cGVHD received daily IL-2(1 x 10(6) IU/m(2)) for 12 weeks. Median time from transplantation and cGVHD onset was 616 days (range, 270-2145 days) and 317 days (range, 28-1880 days), respectively. Two patients withdrew and 5 required IL-2 dose reductions due to side effects. Twenty of 33 evaluable patients (61%) had clinical responses at multiple cGVHD sites (liver, skin, gastrointestinal tract, lung, joint/muscle/fascia). Three patients (9%) had progressive cGVHD. Compared with pretreatment levels, Treg and natural killer cell counts rose > fivefold (P < .001) and > fourfold (P < .001), respectively, without significant change in conventional CD4 T cells (Tcons) or CD8 T cells. The Treg: Tcon ratio rose > fivefold (P < .001). Clinical responders initiated IL-2 earlier (508 vs 917 days after transplantation, P = .005; 249 vs 461 days after cGVHD onset; P = .03). Treg: Tcon ratios >= 0.07 at baseline and >= 0.2 at week 1 also predicted clinical response (P = .003; P = .0003, respectively). After a 4-week treatment hiatus, clinical responders were eligible to continue IL-2 therapy indefinitely. During 2 years of extended IL-2 therapy, clinical and Treg immune responses persisted, while Tcon count and Treg: Tcon ratio gradually normalized. Low-dose IL-2 provides durable clinical improvement in active cGVHD and extended therapy is well-tolerated. C1 [Koreth, John; Jones, Kyle T.; Lange, Paulina B.; Reynolds, Carol G.; Chammas, Marie J.; Dusenbury, Katherine; Whangbo, Jennifer; Nikiforow, Sarah; Alyea, Edwin P., III; Armand, Philippe; Cutler, Corey S.; Ho, Vincent T.; Antin, Joseph H.; Ritz, Jerome; Soiffer, Robert J.] Dana Farber Canc Inst, Div Hematol Malignancies, D2029,450 Brookline Ave, Boston, MA 02115 USA. [Koreth, John; Kim, Haesook T.; Jones, Kyle T.; Lange, Paulina B.; Reynolds, Carol G.; Chammas, Marie J.; Dusenbury, Katherine; Whangbo, Jennifer; Nikiforow, Sarah; Alyea, Edwin P., III; Armand, Philippe; Cutler, Corey S.; Ho, Vincent T.; Chen, Yi-Bin; Avigan, David; Antin, Joseph H.; Ritz, Jerome; Soiffer, Robert J.] Harvard Med Sch, Boston, MA USA. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Chen, Yi-Bin] Massachusetts Gen Hosp, Hematol Oncol Div, Boston, MA 02114 USA. [Avigan, David] Beth Israel Deaconess Med Ctr, Hematol Oncol, Boston, MA 02215 USA. [Blazar, Bruce R.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Blazar, Bruce R.] Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN USA. RP Koreth, J (reprint author), Dana Farber Canc Inst, D2029,450 Brookline Ave, Boston, MA 02215 USA. EM john_koreth@dfci.harvard.edu FU National Institutes of Health National Cancer Institute [RO1CA183559, RO1CA183560, PO1CA142106]; Leukemia & Lymphoma Society [6005-12]; Prometheus Laboratories Inc; Ted and Eileen Pasquarello Research Fund FX This work was supported by National Institutes of Health National Cancer Institute grants RO1CA183559, RO1CA183560, and PO1CA142106; Leukemia & Lymphoma Society grant 6005-12; Prometheus Laboratories Inc; and the Ted and Eileen Pasquarello Research Fund. NR 41 TC 15 Z9 15 U1 2 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 JUL 7 PY 2016 VL 128 IS 1 BP 130 EP 137 DI 10.1182/blood-2016-02-702852 PG 8 WC Hematology SC Hematology GA DQ5MN UT WOS:000379249600021 PM 27073224 ER PT J AU Kotani, H Ebi, H Kitai, H Nanjo, S Kita, K Huynh, TG Ooi, A Faber, AC Mino-Kenudson, M Yano, S AF Kotani, H. Ebi, H. Kitai, H. Nanjo, S. Kita, K. Huynh, T. G. Ooi, A. Faber, A. C. Mino-Kenudson, M. Yano, S. TI Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression SO ONCOGENE LA English DT Article ID IN-SITU HYBRIDIZATION; ACQUIRED-RESISTANCE; GENE AMPLIFICATION; TARGETED THERAPIES; BREAST-CANCER; GROWTH; SENSITIVITY; ACTIVATION; GENOMICS; AZD4547 AB Targeted therapies are effective in subsets of lung cancers with EGFR mutations and anaplastic lymphoma kinase (ALK) translocations. Large-scale genomics have recently expanded the lung cancer landscape with FGFR1 amplification found in 10-20% of squamous cell carcinomas (SCCs). However, the response rates have been low for biomarker-directed fibroblast growth factor receptor (FGFR) inhibitor therapy in SCC, which contrasts to the relatively high rates of response seen in EGFR mutant and ALK-translocated lung cancers treated with epidermal growth factor receptor (EGFR) inhibitors and ALK inhibitors, respectively. In order to better understand the low response rates of FGFR1-amplified lung cancers to FGFR inhibitors, relationships between gene copy number, mRNA expression and protein expression of FGFR1 were assessed in cell lines, tumor specimens and data from The Cancer Genome Atlas. The importance of these factors for the sensitivity to FGFR inhibitors was determined by analyzing drug screen data and conducting in vitro and in vivo experiments. We report that there was a discrepancy between FGFR1 amplification level and FGFR1 protein expression in a number of these cell lines, and the cancers with unexpectedly low FGFR1 expression were uniformly resistant to the different FGFR inhibitors. Further interrogation of the receptor tyrosine kinase activity in these discordant cell lines revealed co-activation of HER2 and platelet-derived growth factor receptor-a (PDGFRa) caused by gene amplification or ligand overexpression maintained phosphoinositide 3-kinase (PI3K) and MEK/ERK signaling even in the presence of FGFR inhibitor. Accordingly, co-inhibition of FGFR1 and HER2 or PDGFRa led to enhanced drug responses. In contrast, FGFR1-amplified high FGFR1 protein-expressing lung cancers are sensitive to FGFR inhibitor monotherapy by downregulating ERK signaling. Addition of a PI3K inhibitor to these high FGFR1 protein-expressing cancers further sensitized them to FGFR inhibitor. These data reveal that biomarker-directed trials for FGFR1-amplified SCC require assessment of FGFR1 protein expression and uncover novel therapeutic strategies for FGFR1-amplified SCC with low FGFR1 protein expression. C1 [Kotani, H.; Ebi, H.; Kitai, H.; Nanjo, S.; Kita, K.; Yano, S.] Kanazawa Univ, Canc Res Inst, Div Med Oncol, 13-1 Takaramachi, Kanazawa, Ishikawa 9200934, Japan. [Huynh, T. G.; Mino-Kenudson, M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ooi, A.] Kanazawa Univ, Grad Sch Med Sci, Dept Mol & Cellular Pathol, Kanazawa, Ishikawa, Japan. [Faber, A. C.] Virginia Commonwealth Univ, Sch Dent, VCU Philips Inst Oral Hlth Res, Richmond, VA USA. [Faber, A. C.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. RP Ebi, H; Yano, S (reprint author), Kanazawa Univ, Canc Res Inst, Div Med Oncol, 13-1 Takaramachi, Kanazawa, Ishikawa 9200934, Japan. EM hebi@staff.kanazawa-u.ac.jp; syano@staff.kanazawa-u.ac.jp OI Ebi, Hiromichi/0000-0003-3155-7576 FU Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [26830105, 22112010A01] FX We thank Dr Shuta Tomida at Okayama University for his assistance with the statistics. This work was supported by Grants-in-Aid for Scientific Research (H Ebi, 26830105 and S Yano, 21390256), Scientific Research on Innovative Areas 'Integrative Research on Cancer Microenvironment Network' (H Ebi and S Yano, 22112010A01) and Grant-in-Aid for Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. NR 49 TC 5 Z9 5 U1 3 U2 7 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 JUL 7 PY 2016 VL 35 IS 27 BP 3587 EP 3597 DI 10.1038/onc.2015.426 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DR0UD UT WOS:000379621500011 PM 26549034 ER PT J AU Wang, Q Liu, P Spangle, JM Von, T Roberts, TM Lin, NU Krop, IE Winer, EP Zhao, JJ AF Wang, Q. Liu, P. Spangle, J. M. Von, T. Roberts, T. M. Lin, N. U. Krop, I. E. Winer, E. P. Zhao, J. J. TI PI3K-p110 alpha mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers SO ONCOGENE LA English DT Article ID P110-ALPHA ISOFORM; PI3K; PIK3CA; TUMORIGENESIS; TRASTUZUMAB; INHIBITION; RECEPTORS; P110-BETA; TUMORS; METASTASIS AB Human epidermal growth factor receptor-2 (HER2) amplification/overexpression (HER2+) frequently co-occurs with PI3K pathway activation in breast tumors. PI3K signaling is most often activated by PIK3CA mutation or PTEN loss, which frequently results in sensitivity to p110 alpha or p110 beta inhibitors, respectively. To examine the p110 isoform dependence in HER2+, PTEN-deficient tumors, we generated genetic mouse models of breast tumors driven by concurrent Her2 activation and Pten loss coupled with deletion of p110 alpha or p110 beta. Ablation of p110 alpha, but not p110 beta, significantly impaired the development of Her2+/Pten-null tumors in mice. We further show that p110 alpha primarily mediates oncogenic signaling in HER2+/PTEN-deficient human cancers while p110 beta conditionally mediates PI3K/AKT signaling only upon HER2 inhibition. Combined HER2 and p110 alpha inhibition effectively reduced PI3K/AKT signaling and growth of cancer cells both in vitro and in vivo. Addition of the p110 beta inhibitor to dual HER2 and p110 alpha inhibition induced tumor regression in a xenograft model of HER2+/PTEN-deficient human cancers. Together, our data suggest that combined inhibition of HER2 and p110 alpha/beta may serve as a potent and durable therapeutic regimen for the treatment of HER2+, PTEN-deficient breast tumors. C1 [Wang, Q.; Liu, P.; Spangle, J. M.; Von, T.; Roberts, T. M.; Zhao, J. J.] Dana Farber Canc Inst, Dept Canc Biol, 450 Brookline Ave,Smith 936B, Boston, MA 02115 USA. [Wang, Q.; Spangle, J. M.; Von, T.; Roberts, T. M.; Zhao, J. J.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. [Liu, P.] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Ctr Canc, Wuhan, Peoples R China. [Lin, N. U.; Krop, I. E.; Winer, E. P.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wang, Q.] Med Univ South Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. RP Zhao, JJ (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 450 Brookline Ave,Smith 936B, Boston, MA 02115 USA. EM jean_zhao@dfci.harvard.edu FU Department of Pathology and Laboratory Medicine, Medical University of South Carolina; Susan G. Komen Breast Cancer Foundation [CCR 12225834]; Breast Cancer Research Foundation; NIH grants [CA187918, CA172461-01, 1P50CA168504] FX We thank Dr Roderick Bronson and the Dana-Farber/Harvard Cancer Center Rodent Histopathology Core for histopathological analyses. MMTV-NIC mice were provided by W Muller (McGill University). Floxed Pten mice were provided by H Wu (UCLA). This work was supported by start-up fund from Department of Pathology and Laboratory Medicine, Medical University of South Carolina (QW), the Susan G. Komen Breast Cancer Foundation CCR 12225834 (IEK), the Breast Cancer Research Foundation (NUL, EPW, JJZ), NIH grants CA187918 (TMR and JJZ), CA172461-01 (JJZ) and 1P50CA168504 (TMR, IEK, EPW, NUL and JJZ). NR 27 TC 1 Z9 1 U1 3 U2 4 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 JUL 7 PY 2016 VL 35 IS 27 BP 3607 EP 3612 DI 10.1038/onc.2015.406 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA DR0UD UT WOS:000379621500013 PM 26500061 ER PT J AU Atwoli, L Platt, JM Basu, A Williams, DR Stein, DJ Koenen, KC AF Atwoli, Lukoye Platt, Jonathan M. Basu, Archana Williams, David R. Stein, Dan J. Koenen, Karestan C. TI Associations between lifetime potentially traumatic events and chronic physical conditions in the South African Stress and Health Survey: a cross-sectional study SO BMC PSYCHIATRY LA English DT Article DE Trauma; Physical health; South Africa; Posttraumatic stress disorder ID ADVERSE CHILDHOOD EXPERIENCES; NATIONAL EPIDEMIOLOGIC SURVEY; INTIMATE PARTNER VIOLENCE; CORONARY-HEART-DISEASE; MEDICAL CONDITIONS; PRIMARY-CARE; PSYCHOLOGICAL TRAUMA; MENTAL-DISORDERS; INFORMED CARE; PTSD SYMPTOMS AB Background: This study examined the association between the type, and cumulative number of lifetime potentially traumatic events (PTEs), and chronic physical conditions, in a South African sample. PTE exposures have been associated with an increased risk for a wide range of chronic physical conditions, but it is unclear whether psychiatric disorders mediate this association. Given the established differences in trauma occurrence, and the epidemiology of posttraumatic stress disorder (PTSD) in South Africa relative to other countries, examining associations between PTEs and chronic physical conditions, particularly while accounting for psychiatric comorbidity is important. Methods: Data were drawn from the South African Stress and Health Study, a cross-sectional population-representative study of psychological and physical health of South African adults. Twenty-seven PTEs, based on the World Health Organization Composite International Diagnostic Interview Version 3.0, DSM-IV PTSD module were grouped into seven PTE types (war events, physical violence, sexual violence, accidents, unexpected death of a loved one, network events, and witnessing PTEs). Five clusters of physical conditions (cardiovascular, arthritis, respiratory, chronic pain, and other health conditions) were examined. Logistic regressions assessed the odds of reporting a physical condition in relation to type and cumulative number of PTEs. Cochran-Armitage test for trend was used to examine dose-response effect of cumulative PTEs on physical conditions. Results: After adjusting for sociodemographic variables and psychiatric disorders, respondents with any PTE had increased odds of all assessed physical conditions, ranging between 1.48 (95 % CI: 1.06-2.07) for arthritis and 2.07 (95 % CI: 1.57-2.73) for respiratory conditions, compared to those without PTE exposure. Sexual violence, physical violence, unexpected death of a loved one, and network PTEs significantly increased the odds of all or nearly all the physical conditions assessed. There was a dose-response relationship between number of PTEs and increased odds of all physical conditions. Conclusions: Results from this study, the first in an African general population, are consistent with other population-based studies; PTEs confer a broad-spectrum risk for chronic physical conditions, independent of psychiatric disorders. These risks increase with each cumulative PTE exposure. Clinically, comprehensive evaluations for risk of mental and physical health morbidities should be considered among PTE survivors. C1 [Atwoli, Lukoye] Moi Univ, Sch Med, Dept Mental Hlth, POB 1493, Eldoret 30100, Kenya. [Atwoli, Lukoye; Stein, Dan J.] Univ Cape Town, Dept Psychiat & Mental Hlth, MRC, Unit Anxiety & Stress Disorders, Cape Town, South Africa. [Platt, Jonathan M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Basu, Archana; Koenen, Karestan C.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Williams, David R.] Harvard TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Koenen, Karestan C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. RP Atwoli, L (reprint author), Moi Univ, Sch Med, Dept Mental Hlth, POB 1493, Eldoret 30100, Kenya.; Atwoli, L (reprint author), Univ Cape Town, Dept Psychiat & Mental Hlth, MRC, Unit Anxiety & Stress Disorders, Cape Town, South Africa. EM Lukoye.atwoli@mu.ac.ke RI Stein, Dan/A-1752-2008; OI Stein, Dan/0000-0001-7218-7810; Atwoli, Lukoye/0000-0001-7710-9723 FU Medical Research Council of South Africa; National Institute of Mental Health [5-T32-MH-13043-43]; [T32-MH 017119]; [R01-MH101269]; [R01-MH101227]; [R21-MH102570]; [R21TW009795]; [R01MH093612]; [U01OH010407]; [P51RR000165] FX Dan J. Stein is supported by the Medical Research Council of South Africa. Jonathan Platt is supported by the National Institute of Mental Health [5-T32-MH-13043-43]. Archana Basu is supported by T32-MH 017119. Karestan C. Koenen is supported by R01-MH101269, R01-MH101227, R21-MH102570, R21TW009795, R01MH093612, U01OH010407 and P51RR000165. NR 64 TC 0 Z9 0 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-244X J9 BMC PSYCHIATRY JI BMC Psychiatry PD JUL 7 PY 2016 VL 16 AR 214 DI 10.1186/s12888-016-0929-z PG 10 WC Psychiatry SC Psychiatry GA DQ5DS UT WOS:000379225400005 PM 27389090 ER PT J AU Liu, X Zhang, ZB Ruan, JB Pan, YD Magupalli, VG Wu, H Lieberman, J AF Liu, Xing Zhang, Zhibin Ruan, Jianbin Pan, Youdong Magupalli, Venkat Giri Wu, Hao Lieberman, Judy TI Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores SO NATURE LA English DT Article ID MIXED LINEAGE KINASE; LISTERIA-MONOCYTOGENES; INTRACELLULAR BACTERIA; CASPASE-1 ACTIVATION; NLRP3 INFLAMMASOME; CELL-DEATH; INTERLEUKIN-1-BETA; GRANULYSIN; GRANZYMES; PERFORIN AB Inflammatory caspases (caspases 1, 4, 5 and 11) are activated in response to microbial infection and danger signals. When activated, they cleave mouse and human gasdermin D (GSDMD) after Asp276 and Asp275, respectively, to generate an N-terminal cleavage product (GSDMD-NT) that triggers inflammatory death (pyroptosis) and release of inflammatory cytokines such as interleukin-1 beta(1,2). Cleavage removes the C-terminal fragment (GSDMD-CT), which is thought to fold back on GSDMD-NT to inhibit its activation. However, how GSDMD-NT causes cell death is unknown. Here we show that GSDMD-NT oligomerizes in membranes to form pores that are visible by electron microscopy. GSDMD-NT binds to phosphatidylinositol phosphates and phosphatidylserine (restricted to the cell membrane inner leaflet) and cardiolipin (present in the inner and outer leaflets of bacterial membranes). Mutation of four evolutionarily conserved basic residues blocks GSDMD-NT oligomerization, membrane binding, pore formation and pyroptosis. Because of its lipid-binding preferences, GSDMD-NT kills from within the cell, but does not harm neighbouring mammalian cells when it is released during pyroptosis. GSDMD-NT also kills cell-free bacteria in vitro and may have a direct bactericidal effect within the cytosol of host cells, but the importance of direct bacterial killing in controlling in vivo infection remains to be determined. C1 [Liu, Xing; Zhang, Zhibin; Ruan, Jianbin; Magupalli, Venkat Giri; Wu, Hao; Lieberman, Judy] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Liu, Xing; Zhang, Zhibin; Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Ruan, Jianbin; Magupalli, Venkat Giri; Wu, Hao] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Pan, Youdong] Brigham & Womens Hosp, Dept Dermatol, 75 Francis St, Boston, MA 02115 USA. [Pan, Youdong] Brigham & Womens Hosp, Harvard Skin Dis Res Ctr, 75 Francis St, Boston, MA 02115 USA. RP Wu, H; Lieberman, J (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Lieberman, J (reprint author), Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA.; Wu, H (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM wu@crystal.harvard.edu; judy.lieberman@childrens.harvard.edu FU US NIH [R01AI123265] FX This work was supported by US NIH grant R01AI123265 (J.L.). NR 29 TC 35 Z9 35 U1 14 U2 26 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 JUL 7 PY 2016 VL 535 IS 7610 BP 153 EP + DI 10.1038/nature18629 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2EU UT WOS:000379015600043 PM 27383986 ER PT J AU Kellnberger, S Assmann, W Lehrack, S Reinhardt, S Thirolf, P Queiros, D Sergiadis, G Dollinger, G Parodi, K Ntziachristos, V AF Kellnberger, Stephan Assmann, Walter Lehrack, Sebastian Reinhardt, Sabine Thirolf, Peter Queiros, Daniel Sergiadis, George Dollinger, Guenther Parodi, Katia Ntziachristos, Vasilis TI Ionoacoustic tomography of the proton Bragg peak in combination with ultrasound and optoacoustic imaging SO SCIENTIFIC REPORTS LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; COMPUTED-TOMOGRAPHY; IN-VIVO; PHOTOACOUSTIC MICROSCOPY; PLASMA ACCELERATORS; RANGE UNCERTAINTIES; THERAPY; BEAM; SIMULATION; VERIFICATION AB Ions provide a more advantageous dose distribution than photons for external beam radiotherapy, due to their so-called inverse depth dose deposition and, in particular a characteristic dose maximum at their end-of-range (Bragg peak). The favorable physical interaction properties enable selective treatment of tumors while sparing surrounding healthy tissue, but optimal clinical use requires accurate monitoring of Bragg peak positioning inside tissue. We introduce ionoacoustic tomography based on detection of ion induced ultrasound waves as a technique to provide feedback on the ion beam profile. We demonstrate for 20 MeV protons that ion range imaging is possible with submillimeter accuracy and can be combined with clinical ultrasound and optoacoustic tomography of similar precision. Our results indicate a simple and direct possibility to correlate, in-vivo and in real-time, the conventional ultrasound echo of the tumor region with ionoacoustic tomography. Combined with optoacoustic tomography it offers a well suited pre-clinical imaging system. C1 [Kellnberger, Stephan; Queiros, Daniel; Ntziachristos, Vasilis] Tech Univ Munich, Inst Biol & Med Imaging, D-85764 Neuherberg, Germany. [Kellnberger, Stephan; Queiros, Daniel; Ntziachristos, Vasilis] Helmholtz Zentrum Munchen, D-85764 Neuherberg, Germany. [Kellnberger, Stephan] Harvard Med Sch, Massachusetts Gen Hosp, Div Cardiol, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Assmann, Walter; Lehrack, Sebastian; Reinhardt, Sabine; Thirolf, Peter; Parodi, Katia] Univ Munich, Dept Med Phys, D-85748 Garching, Germany. [Sergiadis, George] Aristotle Univ Thessaloniki, Dept Elect & Comp Engn, Thessaloniki 54124, Greece. [Dollinger, Guenther] Univ Bundeswehr, Inst Appl Phys & Measurement Technol, D-85577 Neubiberg, Germany. RP Ntziachristos, V (reprint author), Tech Univ Munich, Inst Biol & Med Imaging, D-85764 Neuherberg, Germany.; Ntziachristos, V (reprint author), Helmholtz Zentrum Munchen, D-85764 Neuherberg, Germany. EM v.ntziachristos@tum.de FU Alexander von Humboldt-Stiftung; DFG Cluster of Excellence Munich Centre for Advanced Photonics (MAP); DFG Reinhart Koselleck award 'High resolution near-field thermoacoustic sensing and imaging' [NT 3/9-1] FX We thank Murad Omar, Juan Sebastian Osorio Valencia, Christoph Gabisch, Thomas Hellerer, and Marcus Moser for their experimental support, George Dedes for his help in simulations. S. K. acknowledges financial support from the Alexander von Humboldt-Stiftung though a Feodor Lynen Research Fellowship. This work was funded by the DFG Cluster of Excellence Munich Centre for Advanced Photonics (MAP) and the DFG Reinhart Koselleck award 'High resolution near-field thermoacoustic sensing and imaging' (NT 3/9-1). NR 39 TC 0 Z9 0 U1 2 U2 6 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 JUL 7 PY 2016 VL 6 AR 29305 DI 10.1038/srep29305 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ4AP UT WOS:000379145700001 PM 27384505 ER PT J AU Carey, LA Winer, EP AF Carey, Lisa A. Winer, Eric P. TI I-SPY 2-Toward More Rapid Progress in Breast Cancer Treatment SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID TRASTUZUMAB; TRIAL; CARBOPLATIN C1 [Carey, Lisa A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Div Hematol Oncol, Chapel Hill, NC 27599 USA. [Winer, Eric P.] Dana Farber Canc Inst, Breast Oncol Program, Boston, MA 02115 USA. RP Carey, LA (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Div Hematol Oncol, Chapel Hill, NC 27599 USA. NR 9 TC 5 Z9 5 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 7 PY 2016 VL 375 IS 1 BP 83 EP 84 DI 10.1056/NEJMe1603691 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DQ1ZP UT WOS:000379000200010 PM 27406352 ER PT J AU Bearnot, B Schmitt, W Nejad, S AF Bearnot, Benjamin Schmitt, William Nejad, Shamim TI Mitigation Strategies for Opioid Abuse SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Bearnot, Benjamin; Schmitt, William; Nejad, Shamim] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bearnot, B (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM bbearnot@partners.org NR 2 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 JUL 7 PY 2016 VL 375 IS 1 BP 95 EP 95 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DQ1ZP UT WOS:000379000200025 PM 27406368 ER PT J AU Yip, SSF Aerts, HJWL AF Yip, Stephen S. F. Aerts, Hugo J. W. L. TI Applications and limitations of radiomics SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Review DE PET; quantitative imaging; radiomics ID CELL LUNG-CANCER; TUMOR TEXTURE ANALYSIS; TRACER UPTAKE HETEROGENEITY; STANDARDIZED UPTAKE VALUES; F-18-FDG PET/CT IMAGES; CONTRAST-ENHANCED MRI; ESOPHAGEAL CANCER; FDG UPTAKE; PATHOLOGICAL RESPONSE; PULMONARY NODULES AB Radiomics is an emerging field in quantitative imaging that uses advanced imaging features to objectively and quantitatively describe tumour phenotypes. Radiomic features have recently drawn considerable interest due to its potential predictive power for treatment outcomes and cancer genetics, which may have important applications in personalized medicine. In this technical review, we describe applications and challenges of the radiomic field. We will review radiomic application areas and technical issues, as well as proper practices for the designs of radiomic studies. C1 [Yip, Stephen S. F.; Aerts, Hugo J. W. L.] Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. [Yip, Stephen S. F.; Aerts, Hugo J. W. L.] Harvard Univ, Sch Med, Boston, MA USA. [Aerts, Hugo J. W. L.] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. RP Aerts, HJWL (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA.; Aerts, HJWL (reprint author), Harvard Univ, Sch Med, Boston, MA USA.; Aerts, HJWL (reprint author), Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. EM Hugo_Aerts@dfci.harvard.edu RI Aerts, Hugo/P-6350-2015 OI Aerts, Hugo/0000-0002-2122-2003 FU National Institute of Health [U01CA190234, U24CA194354]; American Association of Physicists in Medicine FX The authors would like to acknowledge the support from National Institute of Health (Award Number U01CA190234 and U24CA194354) and research seed funding grant from the American Association of Physicists in Medicine. The authors would also like to thank Dr Elizabeth Huynh for editorial assistance. NR 119 TC 7 Z9 7 U1 16 U2 38 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 JUL 7 PY 2016 VL 61 IS 13 BP R150 EP R166 DI 10.1088/0031-9155/61/13/R150 PG 17 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA DO9GS UT WOS:000378094000002 PM 27269645 ER PT J AU Lee, S Shang, YL Redmond, SA Urisman, A Tang, AA Li, KH Burlingame, AL Pak, RA Jovicic, A Gitler, AD Wang, JH Gray, NS Seeley, WW Siddique, T Bigio, EH Lee, VMY Trojanowski, JQ Chan, JR Huang, EJ AF Lee, Sebum Shang, Yulei Redmond, Stephanie A. Urisman, Anatoly Tang, Amy A. Li, Kathy H. Burlingame, Alma L. Pak, Ryan A. Jovicic, Ana Gitler, Aaron D. Wang, Jinhua Gray, Nathanael S. Seeley, William W. Siddique, Teepu Bigio, Eileen H. Lee, Virginia M. -Y. Trojanowski, John Q. Chan, Jonah R. Huang, Eric J. TI Activation of HIPK2 Promotes ER Stress-Mediated Neurodegeneration in Amyotrophic Lateral Sclerosis SO NEURON LA English DT Article ID UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; FRONTOTEMPORAL LOBAR DEGENERATION; C9ORF72 REPEAT EXPANSION; MUTANT SOD1; MOTOR-NEURONS; WILD-TYPE; NUCLEOCYTOPLASMIC TRANSPORT; KINASE ACTIVATION; TDP-43 PATHOLOGY AB Persistent accumulation of misfolded proteins causes endoplasmic reticulum (ER) stress, a prominent feature in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here we report the identification of homeodomain interacting protein kinase 2 (HIPK2) as the essential link that promotes ER-stress-induced cell death via the IRE1 alpha-ASK1-JNK pathway. ER stress, induced by tunicamycin or SOD1(G93A), activates HIPK2 by phosphorylating highly conserved serine and threonine residues (S359/T360) within the activation loop of the HIPK2 kinase domain. In SOD1 G93A mice, loss of HIPK2 delays disease onset, reduces cell death in spinal motor neurons, mitigates glial pathology, and improves survival. Remarkably, HIPK2 activation positively correlates with TDP-43 proteinopathy in NEFH-tTA/tetO-hTDP-43DNLS mice, sporadic ALS and C9ORF72 ALS, and blocking HIPK2 kinase activity protects motor neurons from TDP-43 cytotoxicity. These results reveal a previously unrecognized role of HIPK2 activation in ER-stress-mediated neurodegeneration and its potential role as a biomarker and therapeutic target for ALS. C1 [Lee, Sebum; Shang, Yulei; Urisman, Anatoly; Tang, Amy A.; Pak, Ryan A.; Seeley, William W.; Huang, Eric J.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94158 USA. [Redmond, Stephanie A.; Seeley, William W.; Chan, Jonah R.; Huang, Eric J.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA. [Redmond, Stephanie A.; Chan, Jonah R.; Huang, Eric J.] Univ Calif San Francisco, Neurosci Grad Program, San Francisco, CA 94158 USA. [Li, Kathy H.; Burlingame, Alma L.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. [Jovicic, Ana; Gitler, Aaron D.] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA. [Wang, Jinhua; Gray, Nathanael S.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Wang, Jinhua; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Siddique, Teepu] Northwestern Univ, Feinberg Sch Med, Div Neuromuscular Med, Chicago, IL 60611 USA. [Siddique, Teepu] Northwestern Univ, Feinberg Sch Med, Davee Dept Neurol, Chicago, IL 60611 USA. [Bigio, Eileen H.] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. [Lee, Virginia M. -Y.; Trojanowski, John Q.] Univ Penn, Perelman Sch Med, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Huang, Eric J.] VA Med Ctr, Pathol Serv 113B, San Francisco, CA 94121 USA. RP Huang, EJ (reprint author), Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94158 USA.; Huang, EJ (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA.; Huang, EJ (reprint author), Univ Calif San Francisco, Neurosci Grad Program, San Francisco, CA 94158 USA.; Huang, EJ (reprint author), VA Med Ctr, Pathol Serv 113B, San Francisco, CA 94121 USA. EM eric.huang2@ucsf.edu FU NIH [F31 NS081905-02, U54 HG006097-02, 8P41GM103481, 1S10OD016229-01, P50 AG023501, P01 AG019724, OD010927, OD011915, AG017586, AG013854, NS062796]; Les Turner ALS Foundation; Department of Veterans Affairs Merit Review Awards [I01-BX001108, I01-RX002133] FX We thank Linda Kwong, John Robinson, and Theresa Schuck from the Center for Neurodegenerative Disease Research at the University of Pennsylvania for their assistance with NEFH-tTA/tetO-hTDP-43 Delta NLS and human samples; Dr. Kevan Shokat for advice on HIPK2 kinase characterization; and members of the Huang lab for discussions. This work was supported by NIH F31 NS081905-02 (S.A.R.), U54 HG006097-02 (N.S.G.), 8P41GM103481 and 1S10OD016229-01 (A.L.B.), P50 AG023501 and P01 AG019724 (W.W.S.), OD010927 and OD011915 (E.J.H.), AG017586 (V.M.-Y.L.), AG013854 (E.H.B.), NS062796 (J.R.C.), Les Turner ALS Foundation (T.S.), and the Department of Veterans Affairs Merit Review Awards I01-BX001108 and I01-RX002133 (E.J.H.). NR 48 TC 2 Z9 2 U1 0 U2 0 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 JUL 6 PY 2016 VL 91 IS 1 BP 41 EP 55 DI 10.1016/j.neuron.2016.05.021 PG 15 WC Neurosciences SC Neurosciences & Neurology GA DU7KY UT WOS:000382394300010 PM 27321923 ER PT J AU Cheng, CY Cheng, T Xiao, H Krzyaniak, MD Wang, YP McGonigal, PR Frasconi, M Barnes, JC Fahrenbach, AC Wasielewski, MR Goddard, WA Stoddart, JF AF Cheng, Chuyang Cheng, Tao Xiao, Hai Krzyaniak, Matthew D. Wang, Yuping McGonigal, Paul R. Frasconi, Marco Barnes, Jonathan C. Fahrenbach, Albert C. Wasielewski, Michael R. Goddard, William A., III Stoddart, J. Fraser TI Influence of Constitution and Charge on Radical Pairing Interactions in Tris-radical Tricationic Complexes SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MECHANICALLY INTERLOCKED MOLECULES; FUNCTIONAL SUPRAMOLECULAR POLYMERS; CONTINUUM DIELECTRIC THEORY; ELECTRON-TRANSFER REACTIONS; GAUSSIAN-BASIS SETS; PI-PI INTERACTIONS; DONOR-ACCEPTOR; BIOMEDICAL APPLICATIONS; DIMERIZATION EQUILIBRIUM; NONCOVALENT INTERACTIONS AB The results of a systematic investigation of trisradical tricationic complexes formed between cyclobis(paraquat-p-phenylene) bisradical dicationic (CBPQT(2(center dot+))) rings and a series of 18 dumbbells, containing centrally located 4,4'-bipyridinium radical cationic (BIPY center dot+) units within oligomethylene chains terminated for the most part by charged 3,5-dimethylpyridinium (PY+) and/or neutral 3,5-dimethylphenyl (PH) groups, are reported. The complexes were obtained by treating equimolar amounts of the CBPQT(4+) ring and the dumbbells containing BIPY2+ units with zinc dust in acetonitrile solutions. Whereas UV-Vis-NIR spectra revealed absorption bands centered on ca. 1100 nm with quite different intensities for the 1:1 complexes depending on the constitutions and charges on the dumbbells, titration experiments showed that the association constants (K-a) for complex formation vary over a wide range, from 800 M-1 for the weakest to 180 000 M-1 for the strongest. While Coulombic repulsions emanating from PY+ groups located at the ends of some of the dumbbells undoubtedly contribute to the destabilization of the trisradical tricationic complexes, solid-state superstructures support the contention that those dumbbells with neutral PH groups at the ends of flexible and appropriately constituted links to the BIPY center dot+ units stand to gain some additional stabilization from C-H center dot center dot center dot pi interactions between the CBPQT(2(center dot+)) rings and the PH termini on the dumbbells. The findings reported in this Article demonstrate how structural changes implemented remotely from the BIPY center dot+ units influence their non-covalent bonding interactions with CBPQT(2(center dot+)) rings. Different secondary effects (Coulombic repulsions versus C-H center dot center dot center dot pi interactions) are uncovered, and their contributions to both binding strengths associated with trisradical interactions and the kinetics of associations and dissociations are discussed at some length, supported by extensive DFT calculations at the M06-D3 level. A fundamental understanding of molecular recognition in radical complexes has relevance when it comes to the design and synthesis of non-equilibrium systems. C1 [Cheng, Chuyang; Krzyaniak, Matthew D.; Wang, Yuping; McGonigal, Paul R.; Frasconi, Marco; Barnes, Jonathan C.; Fahrenbach, Albert C.; Wasielewski, Michael R.; Stoddart, J. Fraser] Northwestern Univ, Dept Chem, 2145 Sheridan Rd, Evanston, IL 60208 USA. [Cheng, Tao; Xiao, Hai; Goddard, William A., III] CALTECH, Mat & Proc Simulat Ctr MC 139 74, Pasadena, CA 91125 USA. [Krzyaniak, Matthew D.; Wasielewski, Michael R.] Northwestern Univ, Argonne Northwestern Solar Energy Res ANSER Ctr, 2145 Sheridan Rd, Evanston, IL 60208 USA. [McGonigal, Paul R.] Univ Durham, Dept Chem, South Rd, Durham DH1 3LE, England. [Frasconi, Marco] Univ Padua, Dept Chem Sci, Via Marzolo 1, I-35131 Padua, Italy. [Barnes, Jonathan C.] MIT, Dept Chem, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Fahrenbach, Albert C.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Dept Mol Biol, 185 Cambridge St, Boston, MA 02114 USA. [Fahrenbach, Albert C.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Ctr Computat & Integrat Biol, 185 Cambridge St, Boston, MA 02114 USA. [Fahrenbach, Albert C.] Tokyo Inst Technol, Earth Life Sci Inst, Meguro Ku, 2-12-1-IE-1 Ookayama, Tokyo 1528550, Japan. RP Stoddart, JF (reprint author), Northwestern Univ, Dept Chem, 2145 Sheridan Rd, Evanston, IL 60208 USA. EM stoddart@northwestern.edu RI Wasielewski, Michael/K-5888-2016; McGonigal, Paul/J-8291-2012; Cheng, Tao/B-3491-2016; Frasconi, Marco/C-4767-2014; Cheng, Chuyang/B-6608-2014; OI McGonigal, Paul/0000-0002-8538-7579; Cheng, Tao/0000-0003-4830-177X; Frasconi, Marco/0000-0003-2010-175X; Cheng, Chuyang/0000-0002-3834-0479; Xiao, Hai/0000-0001-9399-1584 FU National Science Foundation (NSF) [CHE-1308107]; Office of Science of the U.S. Department of Energy [DE-SC0004993]; NSF [CHE-1565925]; Chinese Scholarship Council; Foresight Institute; Earth-Life Science Institute; Howard Hughes Medical Institute through the Life Sciences Research Foundation FX This research is supported by National Science Foundation (NSF) under grant no. CHE-1308107. T.C., H.X., and W.A.G. thank the Joint Center for Artificial Photosynthesis, a DOE Energy Innovation Hub, supported through the Office of Science of the U.S. Department of Energy under Award DE-SC0004993. This work was also supported by the NSF under grant no. CHE-1565925 (M.R.W.). The authors acknowledge the Integrated Molecular Structure Education and Research Center (IMSERC) at Northwestern University for NMR and HRMS characterizations. We thank Dr. Amy Sarjeant and Charlotte C. Stern for solving the single-crystal X-ray structures. C.C. thanks the Chinese Scholarship Council for the Award for Outstanding Self-Financed Students Abroad and Foresight Institute for the Distinguished Student Award. A.C.F. acknowledges support from the Earth-Life Science Institute. J.C.B. acknowledges postdoctoral support from the Howard Hughes Medical Institute through the Life Sciences Research Foundation. NR 159 TC 2 Z9 2 U1 45 U2 75 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 6 PY 2016 VL 138 IS 26 BP 8288 EP 8300 DI 10.1021/jacs.6b04343 PG 13 WC Chemistry, Multidisciplinary SC Chemistry GA DQ8JA UT WOS:000379455600036 PM 27264680 ER PT J AU Zheng, DF Wang, R Ye, T Yu, S Hu, HC Shen, XX Li, Y Ji, HB Sun, YH Chen, HQ AF Zheng, Difan Wang, Rui Ye, Ting Yu, Su Hu, Haichuan Shen, Xuxia Li, Yuan Ji, Hongbin Sun, Yihua Chen, Haiquan TI MET exon 14 skipping defines a unique molecular class of non-small cell lung cancer SO ONCOTARGET LA English DT Article DE MET; non-small cell lung cancer; surgery; targeted therapy ID DRIVER MUTATIONS; ADENOCARCINOMA; CRIZOTINIB; AMPLIFICATION; GEFITINIB; RESPONSIVENESS; RESISTANCE; SURVIVAL; SMOKERS; GROWTH AB Purpose: Recurrent MET exon 14 splicing has been revealed in lung cancers and is a promising therapeutic target. Because we have limited knowledge about the natural history of MET mutant tumors, the current study was aiming to determine the clinical and pathological characteristics in non-small cell lung cancers (NSCLC). Results: Twenty-three patients (1.3%) were positive for MET exon 14 skipping. Patients with MET exon 14 skipping displayed unique characteristics: female, nonsmokers, earlier pathology stage and older age. MET exon 14 skipping indicated an early event as other drivers in lung cancer, while MET copy number gain was more likely a late event in lung cancer. Overall survival (OS) of patients harboring MET exon 14 skipping was longer than patients with KRAS mutation. Almost four-fifths of the lung tumors with MET exon 14 skipping had EGFR and/or HER2 gene copy number gains. EGFR inhibitor showed moderate antitumor activity in treatment of a patient harboring MET exon 14 skipping. Patients and Methods: From October 2007 to June 2013, we screened 1770 patients with NSCLC and correlated MET status with clinical pathologic characteristics and mutations in EGFR, KRAS, BRAF, HER2, and ALK. Quantitative Real-Time PCR was used to detect MET gene copy number gain. Immunohistochemistry (IHC) was also performed to screen MET exon 14 skipping. Clinicopathological characteristics and survival information were analyzed. Conclusions: MET exon 14 skipping was detected in 1.3% (23/ 1770) of the Chinese patients with NSCLC. MET exon 14 skipping defined a new molecular subset of NSCLC with identifiable clinical characteristics. The therapeutic EGFR inhibitors might be an alternative treatment for patients with MET mutant NSCLC. C1 [Zheng, Difan; Wang, Rui; Ye, Ting; Yu, Su; Hu, Haichuan; Sun, Yihua; Chen, Haiquan] Fudan Univ, Dept Thorac Surg, Shanghai Canc Ctr, Shanghai, Peoples R China. [Zheng, Difan; Wang, Rui; Ye, Ting; Yu, Su; Hu, Haichuan; Shen, Xuxia; Li, Yuan; Sun, Yihua; Chen, Haiquan] Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China. [Shen, Xuxia; Li, Yuan] Fudan Univ, Dept Pathol, Shanghai Canc Ctr, Shanghai, Peoples R China. [Chen, Haiquan] Fudan Univ, Inst Biomed Sci, Shanghai, Peoples R China. [Yu, Su] Fudan Univ, Canc Res Lab, Shanghai Canc Ctr, Shanghai, Peoples R China. [Ji, Hongbin] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Innovat Ctr Cell Signaling Network, Shanghai, Peoples R China. [Hu, Haichuan] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Sun, YH; Chen, HQ (reprint author), Fudan Univ, Dept Thorac Surg, Shanghai Canc Ctr, Shanghai, Peoples R China.; Sun, YH; Chen, HQ (reprint author), Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China.; Chen, HQ (reprint author), Fudan Univ, Inst Biomed Sci, Shanghai, Peoples R China. EM Sun_yihua76@hotmail.com; hqchen1@yahoo.com FU National Natural Science Foundation of China [81330056, 81401886, 81401891, 81422029, 81472173, 81372525]; Science and Technology Commission of Shanghai Municipality [JGGG1302]; Wu Jieping Medical Foundation [320.6750.14317]; Shen-Kang Center Project [SKMB1201]; Shanghai rising star program [16QA1403500] FX This work was supported by the National Natural Science Foundation of China (81330056, 81401886, 81401891, 81422029, 81472173 and 81372525), the Key Project of Science and Technology Commission of Shanghai Municipality (JGGG1302), Wu Jieping Medical Foundation (320.6750.14317) and Shen-Kang Center Project (SKMB1201), Shanghai rising star program (16QA1403500). NR 23 TC 1 Z9 1 U1 8 U2 8 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD JUL 5 PY 2016 VL 7 IS 27 BP 41691 EP 41702 DI 10.18632/oncotarget.9541 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA DS7DI UT WOS:000380942600058 PM 27223439 ER PT J AU Kim, S Lee, JH Kang, I Hyun, S Yu, J Shin, C AF Kim, Soyoung Lee, Jung Hyun Kang, Igojo Hyun, Soonsil Yu, Jaehoon Shin, Chanseok TI An Amphiphilic Peptide Induces Apoptosis Through the miR29b-p53 Pathway in Cancer Cells SO MOLECULAR THERAPY-NUCLEIC ACIDS LA English DT Article DE apoptosis; cancer therapy; Dicer processing; miR29b-p53 pathway; synthesized amphiphilic peptide ID ANTICANCER ACTIVITY; P53; MICRORNA; RNA; TARGETS; MIRNAS; DRUGS; DICER; OLIGONUCLEOTIDES; EXPRESSION AB Peptides have been in the limelight, as therapeutic agents for cancer treatment through various applications due to their high target selectivity and exceptional ability to penetrate the cell membrane. Recent studies have revealed that synthesized peptides bind to hairpin structures of RNA that affect their activities such as changing the efficacy of microRNA maturation. MicroRNA-mediated p53 activation by the microRNA-29 (miR29) family is one of the most important regulatory pathways in cancer therapeutics. By targeting the suppressors of p53, a tumor suppressor protein, miR29 induces apoptosis of cancer cells through p53 stabilization. Here, we identify a novel synthesized amphiphilic peptide, LK-L1C/K6W/L8C, which enhances expression of miR29b and promotes p53 activity. In the presence of LK-L1C/K6W/L8C, pre-miR29b preferentially forms a complex with the Dicer protein through interaction of LK-L1C/K6W/L8C with the terminal loop region of pre-miR29b, leading to an increase in Dicer processing. Furthermore, LK-L1C/K6W/L8C stimulates apoptosis by improving p53 stability in miR29-inducible HeLa and MCF7 cells. Collectively, our study shows that a peptide can directly influence the miR29b-mediated p53 activation pathway in cancer cells. Therefore, our findings provide the basis for a new, potentially promising peptide-based drug for cancer therapy. C1 [Kim, Soyoung; Kang, Igojo; Shin, Chanseok] Seoul Natl Univ, Dept Agr Biotechnol, Seoul, South Korea. [Lee, Jung Hyun] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Lee, Jung Hyun] Harvard Med Sch, Charlestown, MA USA. [Hyun, Soonsil; Yu, Jaehoon] Seoul Natl Univ, Dept Chem & Educ, Seoul, South Korea. [Shin, Chanseok] Seoul Natl Univ, Res Inst Agr & Life Sci, Seoul, South Korea. [Shin, Chanseok] Seoul Natl Univ, Plant Genom & Breeding Inst, 1 Gwanak Ro, Seoul 08826, South Korea. RP Shin, C (reprint author), Seoul Natl Univ, Plant Genom & Breeding Inst, 1 Gwanak Ro, Seoul 08826, South Korea.; Shin, C (reprint author), Seoul Natl Univ, Dept Agr Biotechnol, Res Inst Agr & Life Sci, 1 Gwanak Ro, Seoul 08826, South Korea. EM cshin@snu.ac.kr FU Next-Generation BioGreen 21 Program [PJ01115601]; Rural Development Administration, Republic of Korea; Seoul National University Research Grant (Brain Fusion Program) [500-20120248] FX We are grateful for helpful discussion with members of the Shin laboratory. We also thank V. Narry Kim for providing pG 13-luciferase plasmid and miR29-inducible HeLa cells. This work was supported by the Next-Generation BioGreen 21 Program (No. PJ01115601), Rural Development Administration, Republic of Korea and the Seoul National University Research Grant (Brain Fusion Program: 500-20120248). The authors declare that there are no conflicts of interest. NR 49 TC 1 Z9 1 U1 4 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2162-2531 J9 MOL THER-NUCL ACIDS JI Mol. Ther.-Nucl. Acids PD JUL 5 PY 2016 VL 5 AR e330 DI 10.1038/mtna.2016.45 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DU3PL UT WOS:000382124300001 PM 27377134 ER PT J AU Pasnoor, M He, JH Herbelin, L Burns, TM Nations, S Bril, V Wang, AK Elsheikh, BH Kissel, JT Saperstein, D Shaibani, JA Jackson, C Swenson, A Howard, JF Goyal, N David, W Wicklund, M Pulley, M Becker, M Mozaffar, T Benatar, M Pazcuzzi, R Simpson, E Rosenfeld, J Dimachkie, MM Statland, JM Barohn, RJ AF Pasnoor, Mamatha He, Jianghua Herbelin, Laura Burns, Ted M. Nations, Sharon Bril, Vera Wang, Annabel K. Elsheikh, Bakri H. Kissel, John T. Saperstein, David Shaibani, J. Aziz Jackson, Carlayne Swenson, Andrea Howard, James F., Jr. Goyal, Namita David, William Wicklund, Matthew Pulley, Michael Becker, Mara Mozaffar, Tahseen Benatar, Michael Pazcuzzi, Robert Simpson, Ericka Rosenfeld, Jeffrey Dimachkie, Mazen M. Statland, Jeffrey M. Barohn, Richard J. CA Methotrexate MG Investigators Musc TI A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis SO NEUROLOGY LA English DT Article ID DAILY LIVING PROFILE; MYCOPHENOLATE-MOFETIL; DOUBLE-BLIND; RECOMMENDATIONS; AZATHIOPRINE; CYCLOSPORINE; PREDNISONE; SCORE AB Objective:To determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG).Methods:We performed a 12-month multicenter, randomized, double-blind, placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody-positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living.Results:Fifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4-12 prednisone AUDTC when compared to placebo (difference MTX - placebo: -488.0 mg, 95% confidence interval -2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%).Conclusions:We found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials.Classification of evidence:This study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy. C1 [He, Jianghua] Univ Kansas, Med Ctr, Dept Biostat, Kansas City, KS USA. [Pasnoor, Mamatha; He, Jianghua; Herbelin, Laura; Dimachkie, Mazen M.; Statland, Jeffrey M.; Barohn, Richard J.] Univ Kansas, Med Ctr, Kansas City, KS 66160 USA. [Burns, Ted M.] Univ Virginia, Charlottesville, VA USA. [Nations, Sharon] Univ Texas Southwestern, Dallas, TX USA. [Bril, Vera] Univ Toronto, Toronto, ON M5S 1A1, Canada. [Wang, Annabel K.; Mozaffar, Tahseen] Univ Calif Irvine, Orange, CA 92668 USA. [Elsheikh, Bakri H.; Kissel, John T.] Ohio State Univ, Columbus, OH 43210 USA. [Saperstein, David] Phoenix Neurol Associates, Phoenix, AZ USA. [Shaibani, J. Aziz] Nerve & Muscle Ctr Texas, Houston, TX USA. [Jackson, Carlayne] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Swenson, Andrea] Univ Iowa, Iowa City, IA USA. [Howard, James F., Jr.] Univ N Carolina, Chapel Hill, NC USA. [Goyal, Namita; David, William] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wicklund, Matthew] Penn State Hershey Med Ctr, Hershey, PA USA. Univ Florida Jacksonville, Jacksonville, FL USA. [Becker, Mara] Childrens Mercy Hosp & Clin, Kansas City, MO USA. [Benatar, Michael] Univ Miami, Coral Gables, FL 33124 USA. [Pazcuzzi, Robert] Indiana Univ, Indianapolis, IN 46204 USA. [Simpson, Ericka] Methodist Hosp Syst, Houston, TX USA. [Rosenfeld, Jeffrey] Univ San Francisco, San Francisco, CA 94117 USA. RP Pasnoor, M (reprint author), Univ Kansas, Med Ctr, Kansas City, KS 66160 USA. EM mpasnoor@kumc.edu OI Howard, James/0000-0002-7136-8617 FU Food and Drug Administration Orphan Products Division [RO1 FD 003538]; University of Kansas Medical Center Clinical and Translational Science Awards (CTSA) [UL1 RR 033179, UL1 TR 000001]; NCATS grant [KL2TR000119] FX This study was funded by Food and Drug Administration Orphan Products Division RO1 FD 003538 (M.P.). Additional funding was provided in part by grants UL1 RR 033179 (which is now UL1 TR 000001) from the University of Kansas Medical Center Clinical and Translational Science Awards (CTSA). Dr. Statland's work on this project was supported by a NCATS grant awarded to the University of Kansas Medical Center for Frontiers: The Heartland Institute for Clinical and Translational Research #KL2TR000119. NR 25 TC 8 Z9 9 U1 6 U2 8 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 JUL 5 PY 2016 VL 87 IS 1 BP 57 EP 64 DI 10.1212/WNL.0000000000002795 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA DR7VH UT WOS:000380107300015 PM 27306628 ER PT J AU Du, MM Jiao, S Bien, SA Gala, M Abecasis, G Bezieau, S Brenner, H Butterbach, K Caan, BJ Carlson, CS Casey, G Chang-Claude, J Conti, DV Curtis, KR Duggan, D Gallinger, S Haile, RW Harrison, TA Hayes, RB Hoffmeister, M Hopper, JL Hudson, TJ Jenkins, MA Kury, S Le Marchand, L Leal, SM Newcomb, PA Nickerson, DA Potter, JD Schoen, RE Schumacher, FR Seminara, D Slattery, ML Hsu, L Chan, AT White, E Berndt, SI Peters, U AF Du, Mengmeng Jiao, Shuo Bien, Stephanie A. Gala, Manish Abecasis, Goncalo Bezieau, Stephane Brenner, Hermann Butterbach, Katja Caan, Bette J. Carlson, Christopher S. Casey, Graham Chang-Claude, Jenny Conti, David V. Curtis, Keith R. Duggan, David Gallinger, Steven Haile, Robert W. Harrison, Tabitha A. Hayes, Richard B. Hoffmeister, Michael Hopper, John L. Hudson, Thomas J. Jenkins, Mark A. Kury, Sebastien Le Marchand, Loic Leal, Suzanne M. Newcomb, Polly A. Nickerson, Deborah A. Potter, John D. Schoen, Robert E. Schumacher, Fredrick R. Seminara, Daniela Slattery, Martha L. Hsu, Li Chan, Andrew T. White, Emily Berndt, Sonja I. Peters, Ulrike TI Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; CANCER SUSCEPTIBILITY LOCI; PROSTATE-CANCER; GENOTYPE IMPUTATION; CHROMOSOME 8Q24; COMPLEX TRAITS; SNP RS6983267; TARGET GENES; METAANALYSIS; EXPRESSION AB Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). C1 [Du, Mengmeng] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Du, Mengmeng; Jiao, Shuo; Bien, Stephanie A.; Carlson, Christopher S.; Curtis, Keith R.; Harrison, Tabitha A.; Newcomb, Polly A.; Hsu, Li; White, Emily; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. [Bien, Stephanie A.; Newcomb, Polly A.; Potter, John D.; White, Emily; Peters, Ulrike] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Gala, Manish; Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Gala, Manish; Chan, Andrew T.] Harvard Med Sch, Boston, MA USA. [Abecasis, Goncalo] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Bezieau, Stephane; Kury, Sebastien] CHU Nantes, Serv Genet Med, Nantes, France. [Brenner, Hermann; Butterbach, Katja; Hoffmeister, Michael] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Brenner, Hermann] German Canc Consortium DKTK, Heidelberg, Germany. [Caan, Bette J.] Kaiser Permanente Med Care Program Northern Calif, Div Res, Oakland, CA USA. [Casey, Graham; Conti, David V.; Haile, Robert W.; Schumacher, Fredrick R.] Univ Southern Calif, Keck Sch Med, Los Angeles, CA USA. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ USA. [Gallinger, Steven] Mt Sinai Hosp, Dept Surg, Toronto, ON, Canada. [Hayes, Richard B.] NYU, Sch Med, Dept Populat Hlth, Div Epidemiol, New York, NY USA. [Hopper, John L.; Jenkins, Mark A.] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Hudson, Thomas J.] Ontario Inst Canc Res, Toronto, ON, Canada. [Hudson, Thomas J.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Hudson, Thomas J.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Leal, Suzanne M.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Nickerson, Deborah A.] Univ Washington, Genome Sci, Seattle, WA 98195 USA. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Seminara, Daniela] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Dept Internal Med, Salt Lake City, UT USA. [Chan, Andrew T.] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. [Berndt, Sonja I.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Du, MM (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA.; Du, MM; Peters, U (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA.; Peters, U (reprint author), Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. EM dumeng@mskcc.org; upeters@fhcrc.org RI Jenkins, Mark/P-7803-2015; Gallinger, Steven/E-4575-2013; Brenner, Hermann/B-4627-2017; OI Jenkins, Mark/0000-0002-8964-6160; Brenner, Hermann/0000-0002-6129-1572; Hayes, Richard/0000-0002-0918-661X; Bien, Stephanie/0000-0002-8713-4583; Hoffmeister, Michael/0000-0002-8307-3197 FU GECCO: National Cancer Institute; GECCO: National Institutes of Health; GECCO: U.S. Department of Health and Human Services [U01 CA137088, R01 CA059045, U01 CA164930]; National Cancer Institute [R25 CA94880, P30 CA008748]; Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); National Cancer Institute, National Institutes of Health [U01 CA122839]; National Institutes of Health: Australasian Colorectal Cancer Family Registry [U01 CA097735]; National Institutes of Health: Ontario Registry for Studies of Familial Colorectal Cancer [U01 CA074783]; National Institutes of Health: Seattle Colorectal Cancer Family Registry [U01 CA074794]; DACHS: German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; COLO2&3: National Institutes of Health [R01 CA60987]; CCFR: National Institutes of Health (RFA) [CA-95-011]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; DALS: National Institutes of Health [R01 CA48998]; NHS; PHS: HPFS by National Institutes of Health [P01 CA 055075, UM1 CA167552, R01 137178, P50 CA 127003]; NHS by the National Institutes of Health [P50 CA 127003, R01 CA137178, P01 CA 087969]; National Institutes of Health [CA42182]; Damon Runyon Clinical investigator Award; MEC: National Institutes of Health [R37 CA54281, P01 CA033619, R01 CA63464]; OFCCR: National Institutes of Health [U01 CA074783]; GL2 grant from Ontario Research Fund; Canadian Institutes of Health Research; Cancer Risk Evaluation (CaRE) Program grant from Canadian Cancer Society Research Institute; Senior Investigator Awards from Ontario Institute for Cancer Research; Ontario Ministry of Research and Innovation; PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) [Z01 CP 010200]; NIH [U01 HG004446]; NIH GEI [U01 HG 004438]; PMH-CCFR: National Institutes of Health [R01 CA076366]; VITAL: National Institutes of Health [K05 CA154337]; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; CORECT: National Cancer Institute, National Institutes of Health under RFA [CA-09-002 (U19 CA148107)]; [K24 DK098311] FX This work was supported by the following: GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045; U01 CA164930), M.D. is supported by grants R25 CA94880 and P30 CA008748 from the National Cancer Institute. ASTERISK: Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC). COLO2&3: National Institutes of Health (R01 CA60987). CCFR: National Institutes of Health (RFA # CA-95-011) and through cooperative agreements with members of the Colon Cancer Family Registry and P.I.s. This genome wide scan was supported by the National Cancer Institute, National Institutes of Health by U01 CA122839. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR. The following Colon CFR centers contributed data to this manuscript and were supported by National Institutes of Health: Australasian Colorectal Cancer Family Registry (U01 CA097735), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), and Seattle Colorectal Cancer Family Registry (U01 CA074794). DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: National Institutes of Health (R01 CA48998 to M.L.S.); HPFS, NHS, and PHS: HPFS by the National Institutes of Health (P01 CA 055075, UM1 CA167552, R01 137178, and P50 CA 127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA 087969 and P50 CA 127003,) and PHS by the National Institutes of Health (CA42182). A.T.C. is also supported by a Damon Runyon Clinical investigator Award and K24 DK098311. MEC: National Institutes of Health (R37 CA54281, P01 CA033619, and R01 CA63464). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section above. As subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. T.J.H. is a recipient of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (Yeager, M et al. Nat Genet 2007 May;39(5):645-9), Colon CGEMS pancreatic cancer scan (PanScan) (Amundadottir, L et al. Nat Genet. 2009 Sep;41(9):986-90 and Petersen, GM et al Nat Genet. 2010 Mar;42(3):2248), and the Lung Cancer and Smoking study. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207v.1p1 and phs000206.v3.; p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH-CCFR: National Institutes of Health (R01 CA076366 to P.A.N.). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. CORECT: National Cancer Institute, National Institutes of Health under RFA #CA-09-002 (U19 CA148107). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in CORECT, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or CORECT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 1 Z9 1 U1 3 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 5 PY 2016 VL 11 IS 7 AR e0157521 DI 10.1371/journal.pone.0157521 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DR3JE UT WOS:000379798700007 PM 27379672 ER PT J AU Walensky, RP AF Walensky, Rochelle P. TI Investing in People Who Inject Drugs: A PrEPonderance of Opportunities SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID USERS C1 [Walensky, Rochelle P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Walensky, RP (reprint author), Massachusetts Gen Hosp, Med Practice Evaluat Ctr, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM rwalensky@partners.org NR 9 TC 0 Z9 0 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 JUL 5 PY 2016 VL 165 IS 1 BP 63 EP 64 DI 10.7326/M16-0788 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DQ5AD UT WOS:000379215800013 ER PT J AU Samuel, BS Rowedder, H Braendle, C Felix, MA Ruvkun, G AF Samuel, Buck S. Rowedder, Holli Braendle, Christian Felix, Marie-Anne Ruvkun, Gary TI Caenorhabditis elegans responses to bacteria from its natural habitats SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Caenorhabditis elegans; host-microbe interactions; ecology ID C. ELEGANS; GUT MICROBIOTA; TRANSLATIONAL INHIBITION; PATHOGEN; ASSOCIATIONS; DIVERSITY; SEQUENCES; HISTORY; MODELS; GENES AB Most Caenorhabditis elegans studies have used laboratory Escherichia coli as diet and microbial environment. Here we characterize bacteria of C. elegans' natural habitats of rotting fruits and vegetation to provide greater context for its physiological responses. By the use of 16S ribosomal DNA (rDNA)-based sequencing, we identified a large variety of bacteria in C. elegans habitats, with phyla Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria being most abundant. From laboratory assays using isolated natural bacteria, C. elegans is able to forage on most bacteria (robust growth on similar to 80% of >550 isolates), although similar to 20% also impaired growth and arrested and/or stressed animals. Bacterial community composition can predict wild C. elegans population states in both rotting apples and reconstructed microbiomes: alpha-Proteobacteria-rich communities promote proliferation, whereas Bacteroidetes or pathogens correlate with non-proliferating dauers. Combinatorial mixtures of detrimental and beneficial bacteria indicate that bacterial influence is not simply nutritional. Together, these studies provide a foundation for interrogating how bacteria naturally influence C. elegans physiology. C1 [Samuel, Buck S.; Rowedder, Holli; Ruvkun, Gary] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Braendle, Christian] Univ Nice Sophia Antipolis, Inst Biol Valrose, INSERM, CNRS, Parc Valrose, F-06108 Nice, France. [Felix, Marie-Anne] Ecole Normale Super, INSERM U1024, CNRS UMR8197, Inst Biol, F-75005 Paris, France. [Samuel, Buck S.] Baylor Coll Med, Dept Mol Virol & Microbiol, Alkek Ctr Metagen & Microbiome Res, Houston, TX 77030 USA. RP Ruvkun, G (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.; Felix, MA (reprint author), Ecole Normale Super, INSERM U1024, CNRS UMR8197, Inst Biol, F-75005 Paris, France. EM felix@biologie.ens.fr; ruvkun@molbio.mgh.harvard.edu OI Samuel, Buck/0000-0002-4347-3997; Braendle, Christian/0000-0003-0203-4581 FU NIH Office of Research Infrastructure Programs [P40 OD010440]; Charles King Trust Senior Postdoctoral Fellowship; Ruth L. Kirchstein National Research Service Award Postdoctoral Fellowship [DK838852]; NIH [AG16636] FX We thank Tony Belicard for help during collection of apples that were used to culture natural bacterial isolates; Isabelle Nuez for 16S sequencing of some bacterial strains; Jonah Larkins-Ford and Annie Conery for help with worm sorting experiments; Chris Carr for technical help with the Ion Torrent sequencing; Fred Ausubel for strains and helpful suggestions; Sarah Marsh for comments on the manuscript; members of the G.R. laboratory, the F. Ausubel laboratory, and the J. Kaplan laboratory for support and suggestions throughout the project; and C. elegans Genetic Stock Center for strains, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). B.S.S. was funded by a Charles King Trust Senior Postdoctoral Fellowship and Ruth L. Kirchstein National Research Service Award Postdoctoral Fellowship (DK838852). This work was also supported by NIH Grant AG16636 (to G.R.). NR 52 TC 7 Z9 7 U1 8 U2 13 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 JUL 5 PY 2016 VL 113 IS 27 BP E3941 EP E3949 DI 10.1073/pnas.1607183113 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2GW UT WOS:000379021700018 PM 27317746 ER PT J AU Su, Y Xia, W Li, J Walz, T Humphries, MJ Vestweber, D Cabanas, C Lu, CF Springer, TA AF Su, Yang Xia, Wei Li, Jing Walz, Thomas Humphries, Martin J. Vestweber, Dietmar Cabanas, Carlos Lu, Chafen Springer, Timothy A. TI Relating conformation to function in integrin alpha(5)beta(1) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID X-RAY-SCATTERING; CRYSTAL-STRUCTURE; MONOCLONAL-ANTIBODIES; EXTRACELLULAR SEGMENT; FIBRONECTIN RECEPTOR; ELECTRON-MICROSCOPY; LEUKOCYTE INTEGRIN; REGULATORY REGION; LIGAND-BINDING; HYBRID DOMAIN AB Whether beta(1) integrin ectodomains visit conformational states similarly to beta(2) and beta(3) integrins has not been characterized. Furthermore, despite a wealth of activating and inhibitory antibodies to beta(1) integrins, the conformational states that these antibodies stabilize, and the relation of these conformations to function, remain incompletely characterized. Using negative-stain electron microscopy, we show that the integrin alpha(5)beta(1) ectodomain adopts extended-closed and extended-open conformations as well as a bent conformation. Antibodies SNAKA51, 8E3, N29, and 9EG7 bind to different domains in the alpha(5) or beta(1) legs, activate, and stabilize extended ectodomain conformations. Antibodies 12G10 and HUTS-4 bind to the beta(1) beta I domain and hybrid domains, respectively, activate, and stabilize the open headpiece conformation. Antibody TS2/16 binds a similar epitope as 12G10, activates, and appears to stabilize an open beta I domain conformation without requiring extension or hybrid domain swing-out. mAb13 and SG/19 bind to the beta I domain and beta I-hybrid domain interface, respectively, inhibit, and stabilize the closed conformation of the headpiece. The effects of the antibodies on cell adhesion to fibronectin substrates suggest that the extended-open conformation of alpha(5)beta(1) is adhesive and that the extended-closed and bent-closed conformations are nonadhesive. The functional effects and binding sites of antibodies and fibronectin were consistent with their ability in binding to alpha(5)beta(1) on cell surfaces to cross-enhance or inhibit one another by competitive or noncompetitive (allosteric) mechanisms. C1 [Su, Yang; Xia, Wei; Li, Jing; Lu, Chafen; Springer, Timothy A.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Su, Yang; Xia, Wei; Li, Jing; Lu, Chafen; Springer, Timothy A.] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Walz, Thomas] Rockefeller Univ, New York, NY 10065 USA. [Humphries, Martin J.] Univ Manchester, Fac Life Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester M13 9PT, Lancs, England. [Vestweber, Dietmar] Max Planck Inst Mol Biomed, D-48149 Munster, Germany. [Cabanas, Carlos] Ctr Biol Mol Severo Ochoa CSIC UAM, Madrid 28049, Spain. RP Springer, TA (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA.; Springer, TA (reprint author), Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM timothy.springer@childrens.harvard.edu FU NIH [HL-108248] FX We thank Li-Zhi Mi for help with EM data collection and processing. This work was supported by NIH Grant HL-108248. NR 45 TC 7 Z9 7 U1 4 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 JUL 5 PY 2016 VL 113 IS 27 BP E3872 EP E3881 DI 10.1073/pnas.1605074113 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2GW UT WOS:000379021700011 PM 27317747 ER PT J AU Takatani, T Shirakawa, J Roe, MW Leech, CA Maier, BF Mirmira, RG Kulkarni, RN AF Takatani, Tomozumi Shirakawa, Jun Roe, Michael W. Leech, Colin A. Maier, Bernhard F. Mirmira, Raghavendra G. Kulkarni, Rohit N. TI IRS1 deficiency protects beta-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation SO SCIENTIFIC REPORTS LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; INSULIN-RECEPTOR; MESSENGER-RNA; REGULATORY SUBUNITS; P38 MAPK; ELONGATION; ACTIVATION; AUTOPHAGY; GROWTH; MICE AB Endoplasmic reticulum (ER) stress is among several pathological features that underlie beta-cell failure in the development of type 1 and type 2 diabetes. Adaptor proteins in the insulin/insulin-like-growth factor-1 signaling pathways, such as insulin receptor substrate-1 (IRS1) and IRS2, differentially impact beta-cell survival but the underlying mechanisms remain unclear. Here we report that beta-cells deficient in IRS1 (IRS1KO) are resistant, while IRS2 deficiency (IRS2KO) makes them susceptible to ER stress-mediated apoptosis. IRS1KOs exhibited low nuclear accumulation of spliced XBP-1 due to its poor stability, in contrast to elevated accumulation in IRS2KO. The reduced nuclear accumulation in IRS1KO was due to protein instability of Xbp1 secondary to proteasomal degradation. IRS1KO also demonstrated an attenuation in their general translation status in response to ER stress revealed by polyribosomal profiling. Phosphorylation of eEF2 was dramatically increased in IRS1KO enabling the beta-cells to adapt to ER stress by blocking translation. Furthermore, significantly high ER calcium (Ca2+) was detected in IRS1KO beta-cells even upon induction of ER stress. These observations suggest that IRS1 could be a therapeutic target for beta-cell protection against ER stress-mediated cell death by modulating XBP-1 stability, protein synthesis, and Ca2+ storage in the ER. C1 [Takatani, Tomozumi; Shirakawa, Jun; Kulkarni, Rohit N.] Harvard Med Sch, Islet Cell & Regenerat Biol, Joslin Diabet Ctr, Dept Med,Brigham & Womens Hosp,Harvard Stem Cell, Boston, MA USA. [Roe, Michael W.; Leech, Colin A.] SUNY Upstate Med Univ, Dept Med, Syracuse, NY 13210 USA. [Maier, Bernhard F.; Mirmira, Raghavendra G.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. [Maier, Bernhard F.; Mirmira, Raghavendra G.] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA. [Mirmira, Raghavendra G.] Indiana Univ Sch Med, Dept Cellular & Integrat Physiol, Dept Biochem & Mol Biol, Dept Med, Indianapolis, IN 46202 USA. RP Kulkarni, RN (reprint author), Harvard Med Sch, Islet Cell & Regenerat Biol, Joslin Diabet Ctr, Dept Med,Brigham & Womens Hosp,Harvard Stem Cell, Boston, MA USA. EM rohit.kulkarni@joslin.harvard.edu OI Shirakawa, Jun/0000-0002-0822-8750 FU Manpei Suzuki Diabetes Foundation; Iacocca Foundation; Japan Society for the Promotion of Science; National Institutes of Health [R01 DK60581, R01 DK67536]; Indiana Diabetes Research Center Core service [P30 DK097512]; [R01 DK103215] FX T.T. was supported by Manpei Suzuki Diabetes Foundation and the Iacocca Foundation. J.S. is supported by the Japan Society for the Promotion of Science. This work was supported by grants from from the National Institutes of Health R01 DK60581 and Indiana Diabetes Research Center Core service (P30 DK097512) (R.G.M), and by grants from the National Institutes of Health R01 DK67536 and in part from R01 DK103215 (R.N.K.). NR 59 TC 1 Z9 1 U1 1 U2 1 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 JUL 5 PY 2016 VL 6 AR 28177 DI 10.1038/srep28177 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ2YI UT WOS:000379069200001 PM 27378176 ER PT J AU Braunwald, E AF Braunwald, Eugene TI Circulation: The Beat Goes On SO CIRCULATION LA English DT Article DE cell therapy; editors; journal; PCSK9 inhibitors; science C1 [Braunwald, Eugene] Harvard Univ, Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp,Sch Med, Boston, MA 02115 USA. [Braunwald, Eugene] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Braunwald, E (reprint author), Brigham & Womens Hosp, 350 Longwood Ave, Boston, MA 02115 USA. EM ebraunwald@partners.org NR 3 TC 1 Z9 1 U1 0 U2 0 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 JUL 5 PY 2016 VL 134 IS 1 BP 6 EP 8 DI 10.1161/CIRCULATIONAHA.116.021747 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DQ0OV UT WOS:000378900300004 PM 27358431 ER PT J AU Bohula, EA Giugliano, RP Ruff, CT Kuder, JF Murphy, SA Antman, EM Braunwald, E AF Bohula, Erin A. Giugliano, Robert P. Ruff, Christian T. Kuder, Julia F. Murphy, Sabina A. Antman, Elliott M. Braunwald, Eugene TI Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial SO CIRCULATION LA English DT Article DE anticoagulants; atrial fibrillation; kidney; thromboembolism; warfarin ID NONVALVULAR ATRIAL-FIBRILLATION; CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; XA INHIBITOR EDOXABAN; MYOCARDIAL-INFARCTION; SYSTEMIC EMBOLISM; WARFARIN; RISK; ANTICOAGULATION; STROKE AB Background: Edoxaban, an oral factor Xa inhibitor with 50% renal clearance, was noninferior to well-managed warfarin for stroke or systemic embolism (S/SE) prevention and reduced bleeding in patients with atrial fibrillation. We evaluated the efficacy and safety of edoxaban versus warfarin across the range of baseline creatinine clearance (CrCl) in the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48) with a focus on the higher-dose edoxaban regimen (HDER) and the upper range of CrCl. Methods: A total of 14 071 patients with atrial fibrillation at moderate to high risk for stroke were randomized to warfarin or HDER (60 mg daily or a 50% dose reduction to 30 mg daily for CrCl 30-50 mL/min, body weight of <= 60 kg, or use of a potent phosphorylated glycoprotein inhibitor). CrCl <30 mL/min was exclusionary. End points of S/SE, International Society on Thrombosis and Haemostasis major bleeding, and the net clinical outcome of S/SE/major bleeding or death were evaluated by intention-to-treat analysis using the prespecified CrCl cut point of 50 mL/min and additional exploratory cut points with the CockcroftGault formula. A sensitivity analysis was performed with the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula for estimating renal function. Results: The relative risk of S/SE with HDER versus warfarin in patients with CrCl > 50 mL/min (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.72-1.04) was similar to that in patients with CrCl <= 50 mL/min (HR, 0.87; 95% CI, 0.65-1.18; P for interaction=0.94). Several exploratory analyses suggested lower relative efficacy for the prevention of S/SE with HDER compared with warfarin at higher levels of CrCl (CrCl <= 50 mL/min: HR, 0.87; 95% CI, 0.65-1.18; CrCl >50-95 mL/min: HR, 0.78; 95% CI, 0.64-0.96; CrCl > 95 mL/min: HR, 1.36; 95% CI, 0.88-2.10; P for interaction=0.08). Bleeding rates were lower at all levels of CrCl with HDER (P for interaction=0.11). Because of the preserved effect on bleeding, the net clinical outcome was more favorable with HDER across the range of CrCl (P for interaction=0.73). Similar findings were observed in the sensitivity analysis using the CKD-EPI formula. Conclusions: Although there was an apparent decrease in relative efficacy to prevent arterial thromboembolism in the upper range of CrCl, the safety and net clinical benefit of HDER compared with warfarin are consistent across the range of renal function. C1 [Bohula, Erin A.; Giugliano, Robert P.; Ruff, Christian T.; Kuder, Julia F.; Murphy, Sabina A.; Antman, Elliott M.; Braunwald, Eugene] Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp,Cardiovasc Div,Dept Med, Boston, MA 02115 USA. RP Bohula, EA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 350 Longwood Ave,First Off Floor, Boston, MA 02115 USA. EM ebohula@partners.org FU Daiichi Sankyo FX The ENGAGE AF-TIMI 48 study was sponsored by Daiichi Sankyo. NR 27 TC 10 Z9 10 U1 1 U2 4 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 JUL 5 PY 2016 VL 134 IS 1 BP 24 EP + DI 10.1161/CIRCULATIONAHA.116.022361 PG 25 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DQ0OV UT WOS:000378900300007 PM 27358434 ER PT J AU Fordyce, CB Hellkamp, AS Lokhnygina, Y Lindner, SM Piccini, JP Becker, RC Berkowitz, SD Breithardt, G Fox, KAA Mahaffey, KW Nessel, CC Singer, DE Patel, MR AF Fordyce, Christopher B. Hellkamp, Anne S. Lokhnygina, Yuliya Lindner, Samuel M. Piccini, Jonathan P. Becker, Richard C. Berkowitz, Scott D. Breithardt, Guenter Fox, Keith A. A. Mahaffey, Kenneth W. Nessel, Christopher C. Singer, Daniel E. Patel, Manesh R. CA ROCKET AF Steering Comm TI On-Treatment Outcomes in Patients With Worsening Renal Function With Rivaroxaban Compared With Warfarin Insights From ROCKET AF SO CIRCULATION LA English DT Article DE anticoagulants; atrial fibrillation; kidney; renal insufficiency ID NONVALVULAR ATRIAL-FIBRILLATION; GLOMERULAR-FILTRATION-RATE; LY RANDOMIZED EVALUATION; FACTOR-XA INHIBITOR; HEART-FAILURE; SERUM CREATININE; SYSTEMIC EMBOLISM; RISK-FACTORS; BASE-LINE; IMPAIRMENT AB Background: Despite rapid clinical adoption of novel anticoagulants, it is unknown whether outcomes differ among patients with worsening renal function (WRF) taking these new drugs compared with warfarin. We aimed to determine whether the primary efficacy (stroke or systemic embolism) and safety (major bleeding and nonmajor clinically relevant bleeding) end points from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial) differed among participants with WRF taking rivaroxaban and those taking warfarin. Methods: After excluding patients without at least 1 follow-up creatinine measurement (n=1624), we included all remaining patients (n=12 612) randomly assigned to either rivaroxaban or dose-adjusted warfarin. Ontreatment WRF (a decrease of > 20% from screening creatinine clearance measurement at any time point during the study) was evaluated as a timedependent covariate in Cox proportional hazards models. Results: Baseline characteristics were generally similar between patients with stable renal function (n=9292) and WRF (n=3320). Rates of stroke or systemic embolism, myocardial infarction, and bleeding were also similar, but WRF patients experienced a higher incidence of vascular death versus stable renal function (2.21 versus 1.41 events per 100 patient-years; P=0.026). WRF patients who were randomized to receive rivaroxaban had a reduction in stroke or systemic embolism compared with those taking warfarin (1.54 versus 3.25 events per 100 patient-years) that was not seen in patients with stable renal function who were randomized to receive rivaroxaban (P=0.050 for interaction). There was no difference in major or nonmajor clinically relevant bleeding among WRF patients randomized to warfarin versus rivaroxaban. Conclusions: Among patients with on-treatment WRF, rivaroxaban was associated with lower rates of stroke and systemic embolism compared with warfarin, without an increase in the composite bleeding end point. C1 [Fordyce, Christopher B.; Hellkamp, Anne S.; Lokhnygina, Yuliya; Lindner, Samuel M.; Piccini, Jonathan P.; Patel, Manesh R.] Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. [Becker, Richard C.] Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. [Berkowitz, Scott D.] Bayer HealthCare Pharmaceut, Whippany, NJ USA. [Breithardt, Guenter] Univ Hosp Munster, Dept Cardiovasc Med, Div Electrophysiol, Munster, Germany. [Fox, Keith A. A.] Univ Edinburgh, Ctr Cardiovasc Sci, Edinburgh EH8 9YL, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. [Mahaffey, Kenneth W.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Nessel, Christopher C.] Janssen Res & Dev, Raritan, NJ USA. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. RP Fordyce, CB (reprint author), Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM christopher.fordyce@duke.edu FU Johnson & Johnson Pharmaceutical Research and Development; Bayer HealthCare FX This work and the ROCKET AF trial were supported by Johnson & Johnson Pharmaceutical Research and Development and Bayer HealthCare. The Duke Clinical Research Institute coordinated the trial, managed the database, and undertook the primary analysis independent of the sponsors. The authors had complete access to the data and were responsible for writing and submitting the manuscript for publication. NR 33 TC 7 Z9 7 U1 3 U2 4 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 JUL 5 PY 2016 VL 134 IS 1 BP 37 EP + DI 10.1161/CIRCULATIONAHA.116.021890 PG 20 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DQ0OV UT WOS:000378900300008 PM 27358435 ER PT J AU El-Jawahri, A Paasche-Orlow, MK Matlock, D Stevenson, LW Lewis, EF Stewart, G Semigran, M Chang, YC Parks, K Walker-Corkery, ES Temel, JS Bohossian, H Ooi, H Mann, E Volandes, AE AF El-Jawahri, Areej Paasche-Orlow, Michael K. Matlock, Dan Stevenson, Lynne Warner Lewis, Eldrin F. Stewart, Garrick Semigran, Marc Chang, Yuchiao Parks, Kimberly Walker-Corkery, Elizabeth S. Temel, Jennifer S. Bohossian, Hacho Ooi, Henry Mann, Eileen Volandes, Angelo E. TI Randomized, Controlled Trial of an Advance Care Planning Video Decision Support Tool for Patients With Advanced Heart Failure SO CIRCULATION LA English DT Article DE heart failure; quality of health care; quality of life ID CANCER; RESUSCITATION; COMMUNICATION; HOSPICE AB Background: Conversations about goals of care and cardiopulmonary resuscitation (CPR)/intubation for patients with advanced heart failure can be difficult. This study examined the impact of a video decision support tool and patient checklist on advance care planning for patients with heart failure. Methods: This was a multisite, randomized, controlled trial of a video-assisted intervention and advance care planning checklist versus a verbal description in 246 patients >= 64 years of age with heart failure and an estimated likelihood of death of >50% within 2 years. Intervention participants received a verbal description for goals of care (life-prolonging care, limited care, and comfort care) and CPR/intubation plus a 6-minute video depicting the 3 levels of care, CPR/intubation, and an advance care planning checklist. Control subjects received only the verbal description. The primary analysis compared the proportion of patients preferring comfort care between study arms immediately after the intervention. Secondary outcomes were CPR/intubation preferences and knowledge (6-item test; range, 0-6) after intervention. Results: In the intervention group, 27 (22%) chose life-prolonging care, 31 (25%) chose limited care, 63 (51%) selected comfort care, and 2 (2%) were uncertain. In the control group, 50 (41%) chose life-prolonging care, 27 (22%) selected limited care, 37 (30%) chose comfort care, and 8 (7%) were uncertain (P<0.001). Intervention participants (compared with control subjects) were more likely to forgo CPR (68% versus 35%; P<0.001) and intubation (77% versus 48%; P<0.001) and had higher mean knowledge scores (4.1 versus 3.0; P<0.001). Conclusions: Patients with heart failure who viewed a video were more informed, more likely to select a focus on comfort, and less likely to desire CPR/intubation compared with patients receiving verbal information only. C1 [El-Jawahri, Areej; Semigran, Marc; Chang, Yuchiao; Parks, Kimberly; Walker-Corkery, Elizabeth S.; Temel, Jennifer S.; Mann, Eileen; Volandes, Angelo E.] Massachusetts Gen Hosp, 55 Fruit St,Yawkey 9E, Boston, MA 02115 USA. [El-Jawahri, Areej; Stevenson, Lynne Warner; Lewis, Eldrin F.; Stewart, Garrick; Semigran, Marc; Chang, Yuchiao; Parks, Kimberly; Walker-Corkery, Elizabeth S.; Temel, Jennifer S.; Volandes, Angelo E.] Harvard Univ, Sch Med, Boston, MA USA. [Paasche-Orlow, Michael K.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Matlock, Dan] Univ Colorado, Sch Med, Aurora, CO USA. [Stevenson, Lynne Warner; Lewis, Eldrin F.; Stewart, Garrick] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Bohossian, Hacho] Newton Wellesley Hosp, Newton, MA USA. [Bohossian, Hacho] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Ooi, Henry] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Ooi, Henry] Nashville Vet Adm Med Ctr, Nashville, TN USA. RP El-Jawahri, A (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Yawkey 9E, Boston, MA 02115 USA. EM ael-jawahri@partners.org FU National Heart, Lung, and Blood Institute [R01 HL 107268] FX This work was supported by grant R01 HL 107268 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute. The sponsor did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation or approval of the manuscript. NR 23 TC 2 Z9 2 U1 4 U2 7 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 JUL 5 PY 2016 VL 134 IS 1 BP 52 EP + DI 10.1161/CIRCULATIONAHA.116.021937 PG 21 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DQ0OV UT WOS:000378900300010 PM 27358437 ER PT J AU Carson, SS Cox, CE Wallenstein, S Hanson, LC Danis, M Tulsky, JA Chai, E Nelson, JE AF Carson, Shannon S. Cox, Christopher E. Wallenstein, Sylvan Hanson, Laura C. Danis, Marion Tulsky, James A. Chai, Emily Nelson, Judith E. TI Effect of Palliative Care-Led Meetings for Families of Patients With Chronic Critical Illness A Randomized Clinical Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PROLONGED MECHANICAL VENTILATION; OF-LIFE CARE; COMMUNICATION-SKILLS; RESOURCE UTILIZATION; DEPRESSION SCALE; HOSPITAL ANXIETY; UNITED-STATES; ILL PATIENTS; ICU; VALIDATION AB IMPORTANCE Family caregivers of patients with chronic critical illness experience significant psychological distress. OBJECTIVE To determine whether family informational and emotional support meetings led by palliative care clinicians improve family anxiety and depression. DESIGN, SETTING, AND PARTICIPANTS A multicenter randomized clinical trial conducted from October 2010 through November 2014 in 4 medical intensive care units (ICUs). Adult patients (aged >= 21 years) requiring 7 days of mechanical ventilation were randomized and their family surrogate decision makers were enrolled in the study. Observers were blinded to group allocation for the measurement of the primary outcomes. INTERVENTIONS At least 2 structured family meetings led by palliative care specialists and provision of an informational brochure (intervention) compared with provision of an informational brochure and routine family meetings conducted by ICU teams (control). There were 130 patients with 184 family surrogate decision makers in the intervention group and 126 patients with 181 family surrogate decision makers in the control group. MAIN OUTCOMES AND MEASURES The primary outcome was Hospital Anxiety and Depression Scale symptom score (HADS; score range, 0[best] to 42[worst]; minimal clinically important difference, 1.5) obtained during 3-month follow-up interviews with the surrogate decision makers. Secondary outcomes included posttraumatic stress disorder experienced by the family and measured by the Impact of Events Scale-Revised (IES-R; total score range, 0 [best] to 88 [worst]), discussion of patient preferences, hospital length of stay, and 90-day survival. RESULTS Among 365 family surrogate decision makers (mean age, 51 years; 71% female), 312 completed the study. At 3 months, there was no significant difference in anxiety and depression symptoms between surrogate decision makers in the intervention group and the control group (adjusted mean HADS score, 12.2 vs 11.4, respectively; between-group difference, 0.8 [95% CI, -0.9 to 2.6]; P = .34). Posttraumatic stress disorder symptoms were higher in the intervention group (adjusted mean IES-R score, 25.9) compared with the control group (adjusted mean IES-R score, 21.3) (between-group difference, 4.60 [95% CI, 0.01 to 9.10]; P = .0495). There was no difference between groups regarding the discussion of patient preferences (intervention, 75%; control, 83%; odds ratio, 0.63[95% CI, 0.34 to 1.16; P = .14]). The median number of hospital days for patients in the intervention vs the control group (19 days vs 23 days, respectively; between-group difference, -4 days [95% CI, -6 to 3 days]; P = .51) and 90-day survival (hazard ratio, 0.95 [95% CI, 0.65 to 1.38], P = .96) were not significantly different. CONCLUSIONS AND RELEVANCE Among families of patients with chronic critical illness, the use of palliative care-led informational and emotional support meetings compared with usual care did not reduce anxiety or depression symptoms and may have increased posttraumatic stress disorder symptoms. These findings do not support routine or mandatory palliative care-led discussion of goals of care for all families of patients with chronic critical illness. C1 [Carson, Shannon S.; Hanson, Laura C.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Cox, Christopher E.] Duke Univ, Med Ctr, Durham, NC USA. [Wallenstein, Sylvan; Chai, Emily] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Danis, Marion] NIH, Bldg 10, Bethesda, MD 20892 USA. [Tulsky, James A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. [Tulsky, James A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. [Nelson, Judith E.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Nelson, Judith E.] Weill Cornell Med Coll, New York, NY USA. RP Carson, SS (reprint author), Univ N Carolina, Sch Med, Div Pulm & Crit Care Med, Marsico Lung Inst,Cecil B Sheps Ctr Hlth Serv Res, 4125 Bioinformat Bldg,CB 7020, Chapel Hill, NC 27599 USA. EM scarson@med.unc.edu FU National Institute of Nursing Research [R01-NR012413] FX This project was funded by grant R01-NR012413 from the National Institute of Nursing Research. NR 36 TC 15 Z9 16 U1 13 U2 15 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 JUL 5 PY 2016 VL 316 IS 1 BP 51 EP 62 DI 10.1001/jama.2016.8474 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DQ2MY UT WOS:000379037600018 PM 27380343 ER PT J AU Blatter, C Meijer, EFJ Nam, AS Jones, D Bouma, BE Padera, TP Vakoc, BJ AF Blatter, Cedric Meijer, Eelco F. J. Nam, Ahhyun S. Jones, Dennis Bouma, Brett E. Padera, Timothy P. Vakoc, Benjamin J. TI In vivo label-free measurement of lymph flow velocity and volumetric flow rates using Doppler optical coherence tomography SO SCIENTIFIC REPORTS LA English DT Article ID RETINAL BLOOD-FLOW; VESSELS; MICE; MICROSCOPY; DISEASE; CANCER; NODES AB Direct in vivo imaging of lymph flow is key to understanding lymphatic system function in normal and disease states. Optical microscopy techniques provide the resolution required for these measurements, but existing optical techniques for measuring lymph flow require complex protocols and provide limited temporal resolution. Here, we describe a Doppler optical coherence tomography platform that allows direct, label-free quantification of lymph velocity and volumetric flow rates. We overcome the challenge of very low scattering by employing a Doppler algorithm that operates on low signal-to-noise measurements. We show that this technique can measure lymph velocity at sufficiently high temporal resolution to resolve the dynamic pulsatile flow in collecting lymphatic vessels. C1 [Blatter, Cedric; Nam, Ahhyun S.; Bouma, Brett E.; Vakoc, Benjamin J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Blatter, Cedric; Meijer, Eelco F. J.; Nam, Ahhyun S.; Jones, Dennis; Bouma, Brett E.; Padera, Timothy P.; Vakoc, Benjamin J.] Harvard Med Sch, Boston, MA 02115 USA. [Meijer, Eelco F. J.; Jones, Dennis; Padera, Timothy P.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Labs Tumor Biol, Ctr Canc, Boston, MA 02114 USA. [Nam, Ahhyun S.] MIT, Dept Mech Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Vakoc, BJ (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA.; Vakoc, BJ (reprint author), Harvard Med Sch, Boston, MA 02115 USA. EM bvakoc@mgh.harvard.edu OI Padera, Timothy/0000-0002-3453-9384 FU Center for Biomedical OCT Research and Translation [P41EB015903]; National Institutes of Health [R01CA163528, DP2OD008780, R21AI097745, R01HL128168, F32CA183465]; National Cancer Institute Federal Share of Proton Income; Swiss National Science Foundation early post-doctoral mobility fellowship [P2SKP2_158640]; Burroughs Wellcome Fund postdoctoral award; UNCF-Merck postdoctoral fellowship FX Research reported in this publication was supported in part by the Center for Biomedical OCT Research and Translation through Grant Number P41EB015903, awarded by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health, by the National Institutes of Health under award numbers R01CA163528 (B.J.V.), DP2OD008780 (T.P.P.), R21AI097745 (T.P.P.), R01HL128168 (T.P.P.) and F32CA183465 (D.J.). The National Cancer Institute Federal Share of Proton Income also supported this work (T.P.P., B.J.V.). Cedric Blatter was supported by a Swiss National Science Foundation early post-doctoral mobility fellowship (P2SKP2_158640). Dennis Jones was supported by a Burroughs Wellcome Fund postdoctoral award and UNCF-Merck postdoctoral fellowship. The authors acknowledge Matthias Geissbuehler for a modified StackReg ImageJ plugin. NR 43 TC 1 Z9 1 U1 4 U2 20 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 JUL 5 PY 2016 VL 6 AR 29035 DI 10.1038/srep29035 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA DQ3BI UT WOS:000379077300001 PM 27377852 ER PT J AU Jaffer, FA O'Gara, PT AF Jaffer, Farouc A. O'Gara, Patrick T. TI Multivessel CAD in Nondiabetic Patients To Operate or to Dilate? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE coronary artery bypass grafting; multivessel disease; percutaneous coronary intervention ID PERCUTANEOUS CORONARY INTERVENTION; ISCHEMIC-HEART-DISEASE; ARTERY-DISEASE; BYPASS-SURGERY; ELUTING STENTS; SYNTAX SCORE; LEFT MAIN; MANAGEMENT; GUIDELINE; DIAGNOSIS C1 [Jaffer, Farouc A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [O'Gara, Patrick T.] Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. RP Jaffer, FA (reprint author), Massachusetts Gen Hosp, Dept Med, Div Cardiol, MGH CVRC, 185 Cambridge St, Boston, MA 02114 USA.; O'Gara, PT (reprint author), Brigham & Womens Hosp, BWH Cardiol, 75 Francis St, Boston, MA 02115 USA. EM fjaffer@mgh.harvard.edu; pogara@partners.org NR 11 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 JUL 5 PY 2016 VL 68 IS 1 BP 37 EP 39 DI 10.1016/j.jacc.2016.05.008 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DP5IB UT WOS:000378528400006 PM 27364048 ER PT J AU English, L Miller, JS Mbusa, R Matte, M Kenney, J Bwambale, S Ntaro, M Patel, P Mulogo, E Stone, GS AF English, Lacey Miller, James S. Mbusa, Rapheal Matte, Michael Kenney, Jessica Bwambale, Shem Ntaro, Moses Patel, Palka Mulogo, Edgar Stone, Geren S. TI Monitoring iCCM referral systems: Bugoye Integrated Community Case Management Initiative (BIMI) in Uganda (vol 15, pg 247, 2016) SO MALARIA JOURNAL LA English DT Correction C1 [English, Lacey] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Miller, James S.] Harvard Med Sch, Boston, MA USA. [Mbusa, Rapheal; Bwambale, Shem] Bugoye Hlth Ctr III, Bugoye, Uganda. [Matte, Michael; Ntaro, Moses; Mulogo, Edgar] Mbarara Univ Sci & Technol, Dept Community Hlth, Mbarara, Uganda. [Kenney, Jessica; Patel, Palka; Stone, Geren S.] Massachusetts Gen Hosp, Global Primary Care Program, Boston, MA 02114 USA. RP English, L (reprint author), Univ N Carolina, Sch Med, Chapel Hill, NC USA. EM Lacey_English@med.unc.edu NR 1 TC 1 Z9 1 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUL 4 PY 2016 VL 15 AR 343 DI 10.1186/s12936-016-1375-6 PG 1 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA DQ1WC UT WOS:000378990100003 ER PT J AU Kubzansky, LD Kim, ES Salinas, J Huffman, JC Kawachi, I AF Kubzansky, Laura D. Kim, Eric S. Salinas, Joel Huffman, Jeff C. Kawachi, Ichiro TI Happiness, health, and mortality Reply SO LANCET LA English DT Letter C1 [Kubzansky, Laura D.; Kim, Eric S.; Kawachi, Ichiro] Harvard Univ, TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Salinas, Joel] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Huffman, Jeff C.] Massachusetts Gen Hosp, Cardiac Psychiat Res Program, Boston, MA 02114 USA. [Huffman, Jeff C.] Massachusetts Gen Hosp, Inpatient Med Psychiat Serv, Boston, MA 02114 USA. RP Kubzansky, LD (reprint author), Harvard Univ, TH Chan Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. EM lkubzans@hsph.harvard.edu NR 7 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUL 2 PY 2016 VL 388 IS 10039 BP 27 EP 27 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA DP9PM UT WOS:000378828400020 PM 27397787 ER PT J AU Djemie, T Weckhuysen, S von Spiczak, S Carvill, GL Jaehn, J Anttonen, AK Brilstra, E Caglayan, HS de Kovel, CG Depienne, C Gaily, E Hamalainen, E Giraldez, BG Gormley, P Guerrero-Lopez, R Guerrini, R Hamalainen, E Hartmann, C Hernandez-Hernandez, L Hjalgrim, H Koeleman, BPC Leguern, E Lehesjoki, AE Lemke, JR Leu, C Marini, C McMahon, JM Mei, D Moller, RS Muhle, H Myers, CT Nava, C Serratosa, JM Sisodiya, SM Stephani, U Striano, P van Kempen, MJA Verbeek, NE Usluer, S Zara, F Palotie, A Mefford, HC Scheffer, IE De Jonghe, P Helbig, I Suls, A AF Djemie, Tania Weckhuysen, Sarah von Spiczak, Sarah Carvill, Gemma L. Jaehn, Johanna Anttonen, Anna-Kaisa Brilstra, Eva Caglayan, Hande S. de Kovel, Carolien G. Depienne, Christel Gaily, Eija Hamalainen, Eija Giraldez, Beatriz G. Gormley, Padhraig Guerrero-Lopez, Rosa Guerrini, Renzo Hamalainen, Eija Hartmann, Corinna Hernandez-Hernandez, Laura Hjalgrim, Helle Koeleman, Bobby P. C. Leguern, Eric Lehesjoki, Anna-Elina Lemke, Johannes R. Leu, Costin Marini, Carla McMahon, Jacinta M. Mei, Davide Moller, Rikke S. Muhle, Hiltrud Myers, Candace T. Nava, Caroline Serratosa, Jose M. Sisodiya, Sanjay M. Stephani, Ulrich Striano, Pasquale van Kempen, Marjan J. A. Verbeek, Nienke E. Usluer, Sunay Zara, Federico Palotie, Aarno Mefford, Heather C. Scheffer, Ingrid E. De Jonghe, Peter Helbig, Ingo Suls, Arvid CA EuroEPINOMICS-RES Dravet Working TI Pitfalls in genetic testing: the story of missed SCN1A mutations SO MOLECULAR GENETICS & GENOMIC MEDICINE LA English DT Article DE Dravet syndrome; epilepsy; genetic screening; next-generation sequencing; Sanger sequencing ID DE-NOVO MUTATIONS; DRAVET SYNDROME; EPILEPTIC ENCEPHALOPATHY; PHENOTYPE AB Background Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations. Methods We sent out a survey to 16 genetic centers performing SCN1A testing. Results We collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation-negative, both due to technical limitations and human errors. Conclusion We illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated. C1 [Djemie, Tania; Weckhuysen, Sarah; Brilstra, Eva; Serratosa, Jose M.; De Jonghe, Peter; Suls, Arvid] VIB, Dept Mol Genet, Neurogenet Grp, Antwerp, Belgium. [Djemie, Tania; Weckhuysen, Sarah; De Jonghe, Peter; Suls, Arvid] Univ Antwerp, Inst Born Bunge, Neurogenet Lab, Antwerp, Belgium. [Weckhuysen, Sarah; Depienne, Christel; Leguern, Eric; Nava, Caroline] UPMC Univ Paris 06, Sorbonne Univ, 91-105 Blvd Hop, F-75013 Paris, France. [Weckhuysen, Sarah; Depienne, Christel; Leguern, Eric; Nava, Caroline] INSERM, CNRS, ICM, UMR 7225,U 1127, 47-83 Blvd Hop, F-75013 Paris, France. [Weckhuysen, Sarah] Grp Hosp Pitie Salpetriere, AP HP, Ctr Reference Epilepsies Rares, Epilepsy Unit, F-75013 Paris, France. [von Spiczak, Sarah; Jaehn, Johanna; Hartmann, Corinna; Muhle, Hiltrud; Stephani, Ulrich] Univ Med Ctr Schleswig Holstein, Dept Neuropediat, Kiel, Germany. [Carvill, Gemma L.; Myers, Candace T.; Mefford, Heather C.] Univ Washington, Dept Pediat, Div Med Genet, Seattle, WA 98195 USA. [Anttonen, Anna-Kaisa; Lehesjoki, Anna-Elina] Folkhalsan Inst Genet, Helsinki, Finland. [Anttonen, Anna-Kaisa] Univ Helsinki, Med & Clin Genet, Helsinki, Finland. [Anttonen, Anna-Kaisa] Helsinki Univ Hosp, Helsinki, Finland. [de Kovel, Carolien G.; Koeleman, Bobby P. C.; van Kempen, Marjan J. A.; Verbeek, Nienke E.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Caglayan, Hande S.; Usluer, Sunay] Bogazici Univ, Dept Mol Biol & Genet, Istanbul, Turkey. [Depienne, Christel; Leguern, Eric; Nava, Caroline] Hop La Pitie Salpetriere, AP HP, Dept Genet, 47-83 Blvd Hop, F-75013 Paris, France. [Gaily, Eija] Helsinki Univ Hosp, Dept Pediat Neurol, Helsinki, Finland. [Hamalainen, Eija] EO Osped Galliera, Genet Lab, Genoa, Italy. [Giraldez, Beatriz G.; Serratosa, Jose M.] Univ Autonoma Madrid, Neurol Lab, Madrid, Spain. [Giraldez, Beatriz G.; Serratosa, Jose M.] Univ Autonoma Madrid, Dept Neurol, Epilepsy Unit, Inst Invest Sanitaria,Fdn Jimenez Diaz, Madrid, Spain. [Giraldez, Beatriz G.; Guerrero-Lopez, Rosa; Serratosa, Jose M.] IIS Fdn Jimenez Diaz, Madrid, Spain. [Giraldez, Beatriz G.; Guerrero-Lopez, Rosa; Serratosa, Jose M.] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain. [Gormley, Padhraig] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Gormley, Padhraig] Harvard Med Sch, Boston, MA 02114 USA. [Gormley, Padhraig; Palotie, Aarno] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Gormley, Padhraig] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Gormley, Padhraig; Hamalainen, Eija] Wellcome Trust Sanger Inst, Hinxton, England. [Guerrini, Renzo; Marini, Carla; Mei, Davide] Univ Florence, A Meyer Childrens Hosp, Pediat Neurol & Neurogenet Unit & Labs, Florence, Italy. [Hamalainen, Eija; Palotie, Aarno] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Hernandez-Hernandez, Laura; Leu, Costin; Sisodiya, Sanjay M.] UCL Inst Neurol, Biomed Res Ctr, NIHR Univ Coll London Hosp, Dept Clin & Expt Epilepsy, London, England. [Hernandez-Hernandez, Laura; Sisodiya, Sanjay M.] Epilepsy Soc, Gerrards Cross, Bucks, England. [Hjalgrim, Helle; Moller, Rikke S.] Danish Epilepsy Ctr, Dept Neurol, Dianalund, Denmark. [Hjalgrim, Helle; Moller, Rikke S.] Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark. [Lehesjoki, Anna-Elina] Univ Helsinki, Res Programs Unit, Mol Neurol, Helsinki, Finland. [Lemke, Johannes R.] Univ Leipzig, Inst Human Genet, Leipzig, Germany. [McMahon, Jacinta M.; Scheffer, Ingrid E.] Univ Melbourne, Dept Med, Epilepsy Res Ctr, Austin Hlth, Melbourne, Vic, Australia. [Striano, Pasquale] Univ Genoa, Pediat Neurol & Muscular Dis Unit, G Gaslini Inst, Dept Neurosci Rehabil Ophthalmol Genet & Maternal, Genoa, Italy. [Zara, Federico] Giannina Gaslini Inst, Dept Neurosci, Neurogenet Lab, Genoa, Italy. [Scheffer, Ingrid E.] Univ Melbourne, Dept Paediat, Parkville, Vic 3052, Australia. [Scheffer, Ingrid E.] Royal Childrens Hosp, Parkville, Vic 3052, Australia. [Scheffer, Ingrid E.] Florey Inst Neurosci & Mental Hlth, Melbourne, Vic 3084, Australia. [De Jonghe, Peter] Univ Antwerp Hosp, Div Neurol, Antwerp, Belgium. [Helbig, Ingo] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA. [Suls, Arvid] Univ Antwerp, Ctr Med Genet, GENOMED, Antwerp, Belgium. RP Suls, A (reprint author), Univ Antwerp, Ctr Med Genet, Campus Drie Eiken,Prins Boudewijnlaan 43, B-2650 Edegem, Belgium. EM arvid.suls@uantwerpen.be FU Assistance Publique des Hopitaux de Paris (AP-HP); Dravet Syndrome UK; Katy Baggott Foundation; Epilepsy Society; International Coordination Action (ICA) [G0E8614N]; EpiPGX (European Union 7th Framework Programme Grant) [279062]; UK Department of Health's NIHR Biomedical Research Centres funding scheme; Folkhalsan Research Foundation; Eurocores program of the European Science Foundation P.D.J. [G.A.136.11.N, FWO/ESF-ECRP]; TUBITAK [110S518]; medical faculty of Kiel University, Germany; French program "Investissements d'avenir" [ANR-10-IAIHU-06]; [HE5415/3-1] FX This study was funded by the following sources: Assistance Publique des Hopitaux de Paris (AP-HP), Dravet Syndrome UK, the Katy Baggott Foundation, the Epilepsy Society, the International Coordination Action (ICA, grant G0E8614N), and EpiPGX (European Union 7th Framework Programme Grant 279062). This work was partly undertaken at UCLH/UCL, which received a proportion of funding from the UK Department of Health's NIHR Biomedical Research Centres funding scheme. This work was supported by Folkhalsan Research Foundation (A-KA, A-EL). Within the Eurocores program of the European Science Foundation P.D.J. (G.A.136.11.N and FWO/ESF-ECRP) and I.H. (HE5415/3-1) received financial support within the EuroEPINOMICS-RES network. H.C. is granted by the TUBITAK project no 110S518. S.v.S, H.M., U.S. and I.H. received funding from the medical faculty of Kiel University, Germany. T.D. is a PhD fellow of the Institute of Science and Technology (IWT). A.S. was a postdoctoral fellow of the Fund for Scientific Research Flanders (FWO). S.W. is supported by French program "Investissements d'avenir" (ANR-10-IAIHU-06). NR 19 TC 3 Z9 3 U1 0 U2 0 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2324-9269 J9 MOL GENET GENOM MED JI Mol. Genet. Genom. Med. PD JUL PY 2016 VL 4 IS 4 BP 457 EP 464 DI 10.1002/mgg3.217 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA EL2KX UT WOS:000394449700009 PM 27465585 ER PT J AU Schoffski, P Choy, E Le Cesne, A Camargo, V Bauer, S Rha, SY Blay, JY D'Adamo, DR Guo, M Maki, RG AF Schoffski, Patrick Choy, Edwin Le Cesne, Axel Camargo, Veridiana Bauer, Sebastian Rha, Sun Young Blay, Jean-Yves D'Adamo, David R. Guo, Matthew Maki, Robert G. TI Phase (ph) 3 study of eribulin (ERI) vs dacarbazine (DTIC) in leiomyosarcoma (LMS) and liposarcoma (LPS) patients (pts) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Japanese-Society-of-Medical-Oncology CY JUL 28-30, 2016 CL Kobe, JAPAN SP Japanese Soc Med Oncol C1 [Schoffski, Patrick] Univ Hosp Leuven, Dept Gen Med Oncol, Leuven, Belgium. [Choy, Edwin] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Le Cesne, Axel] Gustave Roussy, Villejuif, France. [Camargo, Veridiana] Hosp Sirio Libanes, Dept Med Oncol, Sau Paulo, Brazil. [Bauer, Sebastian] West German Canc Ctr, Essen, Germany. [Rha, Sun Young] Severance Hosp, Seoul, South Korea. [Blay, Jean-Yves] Univ Claude Bernard, Lyon, France. [Blay, Jean-Yves] Ctr Leon Berard, Lyon, France. [D'Adamo, David R.; Guo, Matthew] Eisai Inc, Woodcliff Lake, NJ USA. [Maki, Robert G.] Mt Sinai Med Ctr, Tisch Canc Inst, New York, NY 10029 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD JUL 1 PY 2016 VL 27 SU 7 MA PS - 2 PG 1 WC Oncology SC Oncology GA EK4QK UT WOS:000393911700128 ER PT J AU Suzuki, K Kuss, I Smith, MR Fizazi, K AF Suzuki, Kazuhiro Kuss, Iris Smith, Matthew R. Fizazi, Karim TI ARAMIS trial: Efficacy and safety of ODM-201 in men with high-risk nonmetastatic castration-resistant prostate cancer SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Japanese-Society-of-Medical-Oncology CY JUL 28-30, 2016 CL Kobe, JAPAN SP Japanese Soc Med Oncol C1 [Suzuki, Kazuhiro] Gunma Univ, Grad Sch Med, Gunma, Japan. [Suzuki, Kazuhiro] Gunma Univ Hosp, Gunma, Japan. [Kuss, Iris] Bayer Pharma AG, Global Clin Oncol, Berlin, Germany. [Smith, Matthew R.] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Fizazi, Karim] Inst Gustave Roussy, Dept Canc Med, Villejuif, France. NR 0 TC 0 Z9 0 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD JUL 1 PY 2016 VL 27 SU 7 MA PF1-091 PG 1 WC Oncology SC Oncology GA EK4QK UT WOS:000393911700257 ER PT J AU Florez, JC AF Florez, Jose C. TI Precision Medicine in Diabetes: Is It Time? SO DIABETES CARE LA English DT Article ID INSULIN-RESISTANCE; PREVENTION PROGRAM; GENOMIC MEDICINE; LIFE-STYLE; METFORMIN; HYPERGLYCEMIA; PREDICTION; MANAGEMENT; MUTATIONS; VARIANTS C1 [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Metab Program, Cambridge, MA 02142 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Florez, Jose C.] Harvard Med Sch, Dept Med, Boston, MA 02115 USA. RP Florez, JC (reprint author), Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA.; Florez, JC (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.; Florez, JC (reprint author), Broad Inst, Metab Program, Cambridge, MA 02142 USA.; Florez, JC (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.; Florez, JC (reprint author), Harvard Med Sch, Dept Med, Boston, MA 02115 USA. EM jcflorez@partners.org FU Massachusetts General Hospital Scholars Award FX J.C.F. is supported by a Massachusetts General Hospital Scholars Award. NR 27 TC 4 Z9 4 U1 0 U2 0 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 JUL PY 2016 VL 39 IS 7 BP 1085 EP 1088 DI 10.2337/dc16-0586 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500013 PM 27289125 ER PT J AU Pandharipande, PV Herts, BR Gore, RM Mayo-Smith, WW Harvey, HB Megibow, AJ Berland, LL AF Pandharipande, Pari V. Herts, Brian R. Gore, Richard M. Mayo-Smith, William W. Harvey, H. Benjamin Megibow, Alec J. Berland, Lincoln L. TI Rethinking Normal: Benefits and Risks of Not Reporting Harmless Incidental Findings SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Incidental finding; health policy; medical decision making ID WHITE PAPER; COMMITTEE II; PELVIC CT; RENAL CYSTS; CLASSIFICATION-SYSTEM; MRI; RECOMMENDATIONS; DISEASE; BURDEN; MASSES AB The authors explore the benefits and risks of not reporting imaging findings that do not have clinical relevance, with the goal of developing recommendations to reduce their reporting. The authors review the example of incidentally detected, simple renal cysts (Bosniak category I), including medicolegal conditions required for such a shift in reporting practices to be acceptable. The authors propose four potential criteria for not reporting clinically unimportant findings and recommend that these criteria be debated in other contexts, so that they can be refined and implemented. C1 [Pandharipande, Pari V.; Harvey, H. Benjamin] Massachusetts Gen Hosp, Dept Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. [Pandharipande, Pari V.; Harvey, H. Benjamin] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Herts, Brian R.] Cleveland Clin, Dept Radiol, Cleveland, OH 44106 USA. [Gore, Richard M.] NorthShore Univ Hlth Syst, Dept Radiol, Evanston, IL USA. [Mayo-Smith, William W.] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Megibow, Alec J.] NYU, Dept Radiol, Langone Med Ctr, 560 1St Ave, New York, NY 10016 USA. [Berland, Lincoln L.] Univ Alabama Birmingham, Dept Radiol, Birmingham, AL USA. RP Pandharipande, PV (reprint author), Massachusetts Gen Hosp, Dept Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM pari@mgh-ita.org NR 22 TC 7 Z9 7 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD JUL PY 2016 VL 13 IS 7 BP 764 EP 767 DI 10.1016/j.jacr.2016.03.017 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DZ6SF UT WOS:000385991500006 PM 27162042 ER PT J AU Smith, AK Ritchie, CS Miao, YH Boscardin, WJ Wallhagen, ML AF Smith, Alexander K. Ritchie, Christine S. Miao, Yinghui Boscardin, W. John Wallhagen, Margaret L. TI Self-Reported Hearing in the Last 2 Years of Life in Older Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE hearing loss; end of life; population-based studies ID LONGITUDINAL ANALYSIS; UNITED-STATES; AID USE; CARE; IMPAIRMENT; PREVALENCE; COMMUNICATION; EPIDEMIOLOGY; QUALITY; PATIENT AB OBJECTIVES: To assess the prevalence and correlates of self-reported hearing loss during the last 2 years of life. DESIGN: Observational cohort study. SETTING: The Health and Retirement Study (HRS), a longitudinal nationally representative cohort of adults aged 50 and older (2000-13). PARTICIPANTS: Older adults (N = 5,895, mean age at death 78, 53% female, 20% nonwhite). MEASUREMENTS: The HRS interview closest to death was used (mean 12.2 months before death). Participants rated their hearing (excellent, very good, good, fair, poor) and indicated whether they used hearing aids. The prevalence and correlates of fair and poor ratings are described, adjusted for age and sex. RESULTS: Thirty-two percent (95% confidence interval (CI) = 31-34%) of all participants and 60% (95% CI = 57-64%) of the 7% of participants who used hearing aids rated their hearing as fair or poor. The prevalence of fair or poor hearing was highest in participants interviewed closest to death (29% 19-24 months before death, 36% 1-6 months before death, P for trend = .01). Correlates of fair or poor hearing during the last 2 years of life included age at death (50-59, 22%; 60-69, 21%; 70-79, 26%; 80-89, 38%; >= 90, 50%), sex (men 35%, women 30%), race and ethnicity (Hispanic 42%, white 33%), wealth (lowest quartile 38%, highest quartile 27%), history of heart disease (yes 38%, no 27%), activity of daily living dependence (yes 42%, no 26%), difficulty taking medications (yes 46%, no 29%), and probable dementia (yes 44%, no 24%). CONCLUSION: Self-reported hearing loss increases during the last 2 years of life and is associated with physical and social vulnerability. C1 [Smith, Alexander K.; Ritchie, Christine S.; Boscardin, W. John] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Smith, Alexander K.; Miao, Yinghui; Boscardin, W. John] Univ Calif San Francisco, Vet Affairs Med Ctr, Geriatr Palliat & Extended Care, San Francisco, CA 94143 USA. [Ritchie, Christine S.] Univ Calif San Francisco, Jewish Home San Francisco, San Francisco, CA 94143 USA. [Miao, Yinghui; Boscardin, W. John] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Wallhagen, Margaret L.] Univ Calif San Francisco, Dept Physiol Nursing, San Francisco, CA USA. RP Smith, AK (reprint author), UCSF, Div Geriatr, San Francisco VA Med Ctr, Med, 4150 Clement St 181G, San Francisco, CA 94121 USA. EM aksmith@ucsf.edu FU National Institute on Aging [1K23AG040772]; American Federation for Aging Research FX Dr. Wallhagen serves on the board of the Hearing Loss Association of America. Dr. Smith was funded by a K23 Beeson award from the National Institute on Aging (1K23AG040772) and the American Federation for Aging Research. NR 23 TC 1 Z9 1 U1 0 U2 0 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 JUL PY 2016 VL 64 IS 7 BP 1486 EP 1491 DI 10.1111/jgs.14145 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA DW3NN UT WOS:000383548400015 ER PT J AU Pepke-Zaba, J Jais, X Channick, R AF Pepke-Zaba, Joanna Jais, Xavier Channick, Richard TI Medical Therapy in Chronic Thromboembolic Pulmonary Hypertension SO ANNALS OF THE AMERICAN THORACIC SOCIETY LA English DT Article DE pulmonary circulation; thromboembolism; vasodilator agents; riociguat; pulmonary vascular resistance AB Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but life-threatening condition resulting from unresolved thromboembolic obstructions. Pulmonary endarterectomy surgery is currently the standard of treatment, as it is potentially curative; however, not all cases are amenable to surgical intervention due to distal distribution of the organized thromboembolic material or the presence of comorbidities. Up to one-third of patients have persistent or recurrent pulmonary hypertension after pulmonary endarterectomy. In addition to the occlusive organized thromboembolic material, there is a small-vessel vasculopathy in nonoccluded parts of the pulmonary circulation that is histologically similar to that described in pulmonary arterial hypertension. This observation has led to frequent off-license use of approved pulmonary arterial hypertension therapies in CTEPH. Small uncontrolled trials have investigated prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors in CTEPH with mixed results. A phase III study of the endothelin receptor antagonist bosentan met only one of its two coprimary end points. The first large randomized controlled trial showing a positive treatment effect was the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase Stimulator Trial (CHEST). This study led to the licensing of riociguat for use in inoperable or persistent recurrent CTEPH. Rigorous randomized controlled trials of medical therapy for CTEPH are needed, and several are underway or planned. In the future, outcomes research may be facilitated by identification of novel end points specific to CTEPH. C1 [Pepke-Zaba, Joanna] Papworth Hosp, Pulm Vasc Dis Unit, Cambridge CB23 3RE, England. [Jais, Xavier] Univ Paris Sud, Bicetre Hosp, Dept Pulmonol, Le Kremlin Bicetre, France. [Channick, Richard] Massachusetts Gen Hosp, Pulm Hypertens & Thromboendarterect Program, Boston, MA 02114 USA. RP Pepke-Zaba, J (reprint author), Papworth Hosp, Pulm Vasc Dis Unit, Cambridge CB23 3RE, England. EM joanna.pepkezaba@papworth.nhs.uk NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1546-3222 EI 2325-6621 J9 ANN AM THORAC SOC JI Ann. Am. Thoracic Society PD JUL PY 2016 VL 13 SU 3 BP S248 EP S254 DI 10.1513/AnnalsATS.201512-802AS PG 7 WC Respiratory System SC Respiratory System GA EJ2HU UT WOS:000393031500007 PM 27571006 ER PT J AU Paulus, YM Butler, NJ AF Paulus, Yannis M. Butler, Nicholas J. TI Spectral-Domain Optical Coherence Tomography, Wide-Field Photography, and Fundus Autofluorescence Correlation of Posterior Ophthalmomyiasis Interna SO OPHTHALMIC SURGERY LASERS & IMAGING RETINA LA English DT Article AB Posterior ophthalmomyiasis interna is a rare, potentially devastating infestation of the posterior segment by fly larvae. The authors report the first demonstration of spectral-domain optical coherence tomography (SD-OCT) (Spectralis; Heidelberg Engineering, Heidelberg, Germany), wide-field angiography (Optos, Dunfermline, Scotland) and photography, and fundus autofluorescence with temporal progression during a period of 6 months. A 12-year-old white female presented with acute, painless vision loss with hand motions visual acuity. No larva was visible, so she was treated with oral ivermectin. Visual acuity improved to 20/80. OCT demonstrated hyporeflective spaces of the outer retina and retinal pigment epithelium, which resolved during 1-month period with improved ellipsoid layer by 6 months. Fundus autofluorescence demonstrated linear hypoautofluorescent tracks. C1 [Paulus, Yannis M.] Univ Michigan, Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. [Butler, Nicholas J.] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Butler, Nicholas J.] VA Boston Healthcare Syst, Boston, MA USA. RP Paulus, YM (reprint author), 1000 Wall St, Ann Arbor, MI 48105 USA. EM ypaulus@med.umich.edu FU Heed Ophthalmic Foundation FX Supported in part by the Heed Ophthalmic Foundation Fellows Grant (YMP). NR 8 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 2325-8160 EI 2325-8179 J9 OSLI RETINA JI Ophthalmic Surg. Lasers Imag. Retin. PD JUL PY 2016 VL 47 IS 7 BP 682 EP 685 DI 10.3928/23258160-20160707-13 PG 4 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA EJ3FP UT WOS:000393098300013 PM 27434903 ER PT J AU Yeung, CM Lozano-Calderon, SA Allar, B Naqvi, M Gebhardt, MC Anderson, ME AF Yeung, Caleb M. Lozano-Calderon, Santiago A. Allar, Benjamin Naqvi, Manahil Gebhardt, Mark C. Anderson, Megan E. TI Ipsilateral Nonvascularized Autograft and Periosteal Repair for the Treatment of Pediatric Tumors of the Distal Fibula SO ORTHOPEDICS LA English DT Article ID RECONSTRUCTION; RESECTION; SURVIVAL; SARCOMA; GRAFT AB Resection of the distal fibula is used to treat malignant or benign locally aggressive tumors involving this region. Current reconstructive techniques are limited by undesirable functional deficits. The authors present a partretrospective and part-prospective case-comparison of 2 patient groups (study and control) treated for malignant or benign locally aggressive primary bone tumors of the distal fibula. Patients in the study group underwent a novel surgical technique involving distal transportation of the ipsilateral proximal portion of the fibula after periosteal dissection and osteotomy with subsequent proximal periosteal reconstruction. Patients in the control group underwent other limb-salvage or amputation procedures. Patients were evaluated at follow-up appointments for oncologic, radiographic, and functional outcomes. The groups had similar demographic and perioperative data. Operative time was longer in the study group. Radiographic union occurred in 75% of the study group vs 50% of the control group. Musculoskeletal Tumor Society scores were similar between groups. According to American Foot and Ankle scores, activity limitations and support requirements were greater in the study group; according to Foot and Ankle Disability Index scores, patients in the control group reported more difficulty with squatting. All patients in the study group were without recurrence at follow-up. One patient in the control group had recurrence of disease. Complications occurred in 3 of 4 study group patients and in all control group patients. With the authors' technique for distal fibular reconstruction involving transporting the ipsilateral remaining proximal fibula as a nonvascularized autograft, the regenerative capability of the periosteum allows for restoration of the proximal fibula, preserving osseous stock. C1 [Yeung, Caleb M.; Lozano-Calderon, Santiago A.; Allar, Benjamin; Naqvi, Manahil; Gebhardt, Mark C.; Anderson, Megan E.] Boston Childrens Hosp, Dept Orthopaed, Boston, MA USA. [Lozano-Calderon, Santiago A.; Gebhardt, Mark C.; Anderson, Megan E.] Harvard MIT, Beth Israel Deaconess Med Ctr, Cambridge, MA USA. [Yeung, Caleb M.] Harvard MIT, Div Hlth Sci & Technol, Cambridge, MA USA. [Lozano-Calderon, Santiago A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. RP Lozano-Calderon, SA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. EM slozanocalderon@mgh.harvard.edu NR 16 TC 1 Z9 1 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0147-7447 EI 1938-2367 J9 ORTHOPEDICS JI Orthopedics PD JUL-AUG PY 2016 VL 39 IS 4 BP E687 EP E694 DI 10.3928/01477447-20160419-03 PG 8 WC Orthopedics SC Orthopedics GA EJ3IJ UT WOS:000393105500015 PM 27111078 ER PT J AU Maison, S Liberman, LD Liberman, MC AF Maison, Stephane Liberman, Leslie D. Liberman, M. Charles TI Type II Cochlear Ganglion Neurons Do Not Drive the Olivocochlear Reflex: Re-Examination of the Cochlear Phenotype in Peripherin Knock-Out Mice SO ENEURO LA English DT Article DE olivocochlear reflex; feedback; peripherin; hair cells; cochlea ID GUINEA-PIG COCHLEA; AIDED 3-DIMENSIONAL RECONSTRUCTION; SPIRAL GANGLION; HAIR-CELLS; EFFERENT INNERVATION; HORSERADISH-PEROXIDASE; RECIPROCAL SYNAPSES; AFFERENT NEURONS; AUDITORY-NERVE; ADULT CATS AB The cochlear nerve includes a small population of unmyelinated sensory fibers connecting outer hair cells to the brain. The functional role of these type II afferent neurons is controversial, because neurophysiological data are sparse. A recent study (Froud et al., 2015) reported that targeted deletion of peripherin, a type of neurofilament, eliminated type II afferents and inactivated efferent feedback to the outer hair cells, thereby suggesting that type II afferents were the sensory drive to this sound-evoked, negative-feedback reflex, the olivocochlear pathway. Here, we re-evaluated the cochlear phenotype in mice from the peripherin knock-out line and show that (1) type II afferent terminals are present in normal number and (2) olivocochlear suppression of cochlear responses is absent even when this efferent pathway is directly activated by shocks. We conclude that type II neurons are not the sensory drive for the efferent reflex and that peripherin deletion likely causes dysfunction of synaptic transmission between olivocochlear terminals and their peripheral targets. C1 [Maison, Stephane; Liberman, M. Charles] Harvard Med Sch, Dept Otol & Laryngol, Boston, MA 02115 USA. [Maison, Stephane; Liberman, Leslie D.; Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, 243 Charles St, Boston, MA 02114 USA. RP Liberman, MC (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, 243 Charles St, Boston, MA 02114 USA. EM Charles_Liberman@meei.harvard.edu NR 46 TC 1 Z9 1 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD JUL-AUG PY 2016 VL 3 IS 4 AR UNSP e0207 DI 10.1523/ENEURO.0207-16.2016 PG 11 WC Neurosciences SC Neurosciences & Neurology GA EH7BV UT WOS:000391928700041 ER PT J AU Sloas, DC Zhuo, R Xue, HB Chambers, AR Kolaczyk, E Polley, DB Sen, K AF Sloas, David C. Zhuo, Ran Xue, Hongbo Chambers, Anna R. Kolaczyk, Eric Polley, Daniel B. Sen, Kamal TI Interactions across Multiple Stimulus Dimensions in Primary Auditory Cortex SO ENEURO LA English DT Article DE auditory; evolutionary algorithm; generalized additive model; integration; sensory ID MACAQUE INFEROTEMPORAL CORTEX; RECEPTIVE-FIELDS; NATURAL SOUNDS; CORTICAL-NEURONS; CAT; RESPONSES; REPRESENTATION; OPTIMIZATION; ORGANIZATION; SELECTIVITY AB Although sensory cortex is thought to be important for the perception of complex objects, its specific role in representing complex stimuli remains unknown. Complex objects are rich in information along multiple stimulus dimensions. The position of cortex in the sensory hierarchy suggests that cortical neurons may integrate across these dimensions to form a more gestalt representation of auditory objects. Yet, studies of cortical neurons typically explore single or few dimensions due to the difficulty of determining optimal stimuli in a high dimensional stimulus space. Evolutionary algorithms (EAs) provide a potentially powerful approach for exploring multidimensional stimulus spaces based on real-time spike feedback, but two important issues arise in their application. First, it is unclear whether it is necessary to characterize cortical responses to multidimensional stimuli or whether it suffices to characterize cortical responses to a single dimension at a time. Second, quantitative methods for analyzing complex multidimensional data from an EA are lacking. Here, we apply a statistical method for nonlinear regression, the generalized additive model (GAM), to address these issues. The GAM quantitatively describes the dependence between neural response and all stimulus dimensions. We find that auditory cortical neurons in mice are sensitive to interactions across dimensions. These interactions are diverse across the population, indicating significant integration across stimulus dimensions in auditory cortex. This result strongly motivates using multidimensional stimuli in auditory cortex. Together, the EA and the GAM provide a novel quantitative paradigm for investigating neural coding of complex multidimensional stimuli in auditory and other sensory cortices. C1 [Sloas, David C.; Sen, Kamal] Boston Univ, Hearing Res Ctr, Boston, MA 02215 USA. [Sloas, David C.; Sen, Kamal] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Zhuo, Ran; Xue, Hongbo; Kolaczyk, Eric] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Chambers, Anna R.; Polley, Daniel B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Polley, Daniel B.] Harvard Med Sch, Dept Otolaryngol, Boston, MA 02115 USA. RP Sen, K (reprint author), Boston Univ, Hearing Res Ctr, Boston, MA 02215 USA.; Sen, K (reprint author), Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. EM kamalsen@bu.edu NR 35 TC 0 Z9 0 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 2373-2822 J9 ENEURO JI eNeuro PD JUL-AUG PY 2016 VL 3 IS 4 DI 10.1523/ENEURO.0124-16.2016 PG 7 WC Neurosciences SC Neurosciences & Neurology GA EH7BV UT WOS:000391928700024 ER PT J AU Furie, R Merrill, J Werth, V Khamashta, M Kalunian, K Brohawn, P Illei, G Drappa, J Wang, L Yoo, S AF Furie, R. Merrill, J. Werth, V. Khamashta, M. Kalunian, K. Brohawn, P. Illei, G. Drappa, J. Wang, L. Yoo, S. TI ANIFROLUMAB, AN ANTI-INTERFERON-ALPHA RECEPTOR MONOCLONAL ANTIBODY, IN MODERATE TO SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract DE Efficacy; Clinical trial; Low disease activity C1 [Furie, R.] Northwell Hlth, Great Neck, NY USA. [Merrill, J.] Oklahoma Med Res Fdn, 825 NE 13th St, Oklahoma City, OK 73104 USA. [Werth, V.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Werth, V.] Univ Penn, Philadelphia, PA 19104 USA. [Khamashta, M.] Graham Hughes Lupus Res Lab, Div Womens Hlth, London, England. [Kalunian, K.] UCSD Sch Med, La Jolla, CA USA. [Brohawn, P.; Illei, G.; Drappa, J.; Wang, L.] MedImmune, Gaithersburg, MD USA. [Yoo, S.] Regenxbio, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X EI 1593-098X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD JUL-AUG PY 2016 VL 34 IS 4 SU 99 MA S2:03 BP S4 EP S4 PG 1 WC Rheumatology SC Rheumatology GA EF4IT UT WOS:000390289700005 ER PT J AU Merrill, J Furie, R Werth, V Khamashta, M Drappa, J Wang, L Illei, G AF Merrill, J. Furie, R. Werth, V. Khamashta, M. Drappa, J. Wang, L. Illei, G. TI ANIFROLUMAB REDUCES DISEASE ACTIVITY IN MULTIPLE ORGAN DOMAINS IN MODERATE TO SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract DE novel therapy; interferon; efficacy C1 [Merrill, J.] Oklahoma Med Res Fdn, 825 NE 13th St, Oklahoma City, OK 73104 USA. [Furie, R.] Northwell Hlth, Great Neck, NY USA. [Werth, V.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Werth, V.] Univ Penn, Philadelphia, PA 19104 USA. [Khamashta, M.] Graham Hughes Lupus Res Lab, Div Womens Hlth, London, England. [Drappa, J.; Wang, L.; Illei, G.] MedImmune, Gaithersburg, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X EI 1593-098X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD JUL-AUG PY 2016 VL 34 IS 4 SU 99 MA S2:04 BP S4 EP S4 PG 1 WC Rheumatology SC Rheumatology GA EF4IT UT WOS:000390289700006 ER PT J AU Ogino, S Nishihara, R AF Ogino, Shuji Nishihara, Reiko TI All Biomedical and Health Science Researchers, Including Laboratory Physicians and Scientists, Need Adequate Education and Training in Study Design and Statistics SO CLINICAL CHEMISTRY LA English DT News Item C1 [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Div MPE Mol Pathol Epidemiol, 450 Brookline Ave,DFCI Rm M422, Boston, MA 02215 USA. [Ogino, Shuji] Harvard Med Sch, Boston, MA USA. [Ogino, Shuji; Nishihara, Reiko] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji; Nishihara, Reiko] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Nishihara, Reiko] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Nishihara, Reiko] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Ogino, S (reprint author), Brigham & Womens Hosp, Dept Pathol, Div MPE Mol Pathol Epidemiol, 450 Brookline Ave,DFCI Rm M422, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu FU NCI NIH HHS [K07 CA190673, R35 CA197735] NR 2 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD JUL PY 2016 VL 62 IS 7 BP 1039 EP 1040 DI 10.1373/clinchem.2016.257873 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA EF2CL UT WOS:000390132000023 PM 27354573 ER PT J AU Boas, DA Sakadzic, S Selb, J Farzam, P Franceschini, MA Carp, SA AF Boas, David A. Sakadzic, Sava Selb, Juliette Farzam, Parisa Franceschini, Maria Angela Carp, Stefan A. TI Establishing the diffuse correlation spectroscopy signal relationship with blood flow SO NEUROPHOTONICS LA English DT Article DE diffuse correlation spectroscopy; blood flow; Monte Carlo; photon migration ID OPTICAL-PROPERTIES; WAVE SPECTROSCOPY; RADIATIVE-TRANSFER; VALIDATION; TISSUE; MEDIA; CELLS; SUSPENSIONS; SCATTERING; LIGHT AB Diffuse correlation spectroscopy (DCS) measurements of blood flow rely on the sensitivity of the temporal autocorrelation function of diffusively scattered light to red blood cell (RBC) mean square displacement (MSD). For RBCs flowing with convective velocity v(RBC), the autocorrelation is expected to decay exponentially with (v(RBC)(tau))(2), where tau is the delay time. RBCs also experience shear-induced diffusion with a diffusion coefficient D-shear and an MSD of 6D(shear)tau. Surprisingly, experimental data primarily reflect diffusive behavior. To provide quantitative estimates of the relative contributions of convective and diffusive movements, we performed Monte Carlo simulations of light scattering through tissue of varying vessel densities. We assumed laminar vessel flow profiles and accounted for shear-induced diffusion effects. In agreement with experimental data, we found that diffusive motion dominates the correlation decay for typical DCS measurement parameters. Furthermore, our model offers a quantitative relationship between the RBC diffusion coefficient and absolute tissue blood flow. We thus offer, for the first time, theoretical support for the empirically accepted ability of the DCS blood flow index (BFi) to quantify tissue perfusion. We find BFi to be linearly proportional to blood flow, but with a proportionality modulated by the hemoglobin concentration and the average blood vessel diameter. (C) The Authors. C1 [Boas, David A.; Sakadzic, Sava; Selb, Juliette; Farzam, Parisa; Franceschini, Maria Angela; Carp, Stefan A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, MGH HST Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Boas, DA (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, MGH HST Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM dboas@nmr.mgh.harvard.edu FU NCI NIH HHS [R01 CA187595]; NIBIB NIH HHS [P41 EB015896]; NINDS NIH HHS [R01 NS091230, R21 NS093259] NR 36 TC 3 Z9 3 U1 1 U2 1 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-423X EI 2329-4248 J9 NEUROPHOTONICS JI Neurophotonics PD JUL-SEP PY 2016 VL 3 IS 3 AR 031412 DI 10.1117/1.NPh.3.3.031412 PG 9 WC Neurosciences; Optics SC Neurosciences & Neurology; Optics GA EF8MG UT WOS:000390582600012 PM 27335889 ER PT J AU Cassano, P Petrie, SR Hamblin, MR Henderson, TA Iosifescu, DV AF Cassano, Paolo Petrie, Samuel R. Hamblin, Michael R. Henderson, Theodore A. Iosifescu, Dan V. TI Review of transcranial photobiomodulation for major depressive disorder: targeting brain metabolism, inflammation, oxidative stress, and neurogenesis SO NEUROPHOTONICS LA English DT Review DE near-infrared radiation; photobiomodulation; low-level laser therapy; major depressive disorder; metabolism; inflammation; neurogenesis; oxidative stress; near-infrared; NILT; low-level light therapy ID LEVEL LASER THERAPY; NEAR-INFRARED LIGHT; MAGNETIC-RESONANCE-SPECTROSCOPY; ADULT HIPPOCAMPAL NEUROGENESIS; TERM NEUROLOGICAL DEFICITS; GLUCOSE-METABOLISM; NEUROTHERA EFFECTIVENESS; ISCHEMIC-STROKE; EMBOLIC STROKES; NITRIC-OXIDE AB We examined the use of near-infrared and red radiation (photobiomodulation, PBM) for treating major depressive disorder (MDD). While still experimental, preliminary data on the use of PBM for brain disorders are promising. PBM is low-cost with potential for wide dissemination; further research on PBM is sorely needed. We found clinical and preclinical studies via PubMed search (2015), using the following keywords: "near-infrared radiation," "NIR," "low-level light therapy," "low-level laser therapy," or "LLLT" plus "depression." We chose clinically focused studies and excluded studies involving near-infrared spectroscopy. In addition, we used PubMed to find articles that examine the link between PBM and relevant biological processes including metabolism, inflammation, oxidative stress, and neurogenesis. Studies suggest the processes aforementioned are potentially effective targets for PBM to treat depression. There is also clinical preliminary evidence suggesting the efficacy of PBM in treating MDD, and comorbid anxiety disorders, suicidal ideation, and traumatic brain injury. Based on the data collected to date, PBM appears to be a promising treatment for depression that is safe and well-tolerated. However, large randomized controlled trials are still needed to establish the safety and effectiveness of this new treatment for MDD. (C) The Authors. C1 [Cassano, Paolo; Petrie, Samuel R.] Massachusetts Gen Hosp, Depress Clin & Res Program, One Bowdoin Sq,6th Floor, Boston, MA 02114 USA. [Cassano, Paolo] Harvard Med Sch, Dept Psychiat, 401 Pk Dr, Boston, MA 02215 USA. [Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, 50 Blossom St, Boston, MA 02114 USA. [Hamblin, Michael R.] Harvard Med Sch, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Henderson, Theodore A.] Synapt Space, 3979 East Arapahoe Rd, Littleton, CO 80122 USA. [Henderson, Theodore A.] Neurolaser Fdn, Suite 420,215 South Wadsworth, Lakewood, CO 80226 USA. [Iosifescu, Dan V.] Mt Sinai Sch Med, Mood & Anxiety Disorders Program, 1428 Madison Ave, New York, NY 10029 USA. [Iosifescu, Dan V.] Mt Sinai Sch Med, Dept Psychiat & Neurosci, 1 Gustave L Levy Pl, New York, NY 10029 USA. RP Cassano, P (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, One Bowdoin Sq,6th Floor, Boston, MA 02114 USA.; Cassano, P (reprint author), Harvard Med Sch, Dept Psychiat, 401 Pk Dr, Boston, MA 02215 USA. EM pcassano@mgh.harvard.edu NR 96 TC 3 Z9 3 U1 4 U2 21 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-423X EI 2329-4248 J9 NEUROPHOTONICS JI Neurophotonics PD JUL-SEP PY 2016 VL 3 IS 3 AR 031404 DI 10.1117/1.NPh.3.3.031404 PG 10 WC Neurosciences; Optics SC Neurosciences & Neurology; Optics GA EF8MG UT WOS:000390582600004 PM 26989758 ER PT J AU Maione, AG Smith, A Kashpur, O Yanez, V Knight, E Mooney, DJ Md, AV Tomic-Canic, M Garlick, JA AF Maione, Anna G. Smith, Avi Kashpur, Olga Yanez, Vanessa Knight, Elana Mooney, David J. Veves, Aristidis Tomic-Canic, Marjana Garlick, Jonathan A. TI Altered ECM deposition by diabetic foot ulcer-derived fibroblasts implicates fibronectin in chronic wound repair SO WOUND REPAIR AND REGENERATION LA English DT Article ID VENOUS LEG ULCERS; EXTRACELLULAR-MATRIX; CELLULAR INFILTRATE; REGENERATION; CONTRACTION; COLLAGEN AB Current chronic wound treatments often fail to promote healing of diabetic foot ulcers (DFU), leading to amputation and increased patient morbidity. A critical mediator of proper wound healing is the production, assembly, and remodeling of the extracellular matrix (ECM) by fibroblasts. However, little is known about how these processes are altered in fibroblasts within the DFU microenvironment. Thus, we investigated the capacity of multiple, primary DFU-derived fibroblast strains to express, produce, and assemble ECM proteins compared to diabetic patient-derived fibroblasts and healthy donor-derived fibroblasts. Gene expression microarray analysis showed differential expression of ECM and ECM-regulatory genes by DFU-derived fibroblasts which translated to functional differences in a 3D in vitro ECM tissue model. DFU-derived fibroblasts produced thin, fibronectin-rich matrices, and responded abnormally when challenged with transforming growth factor-beta, a key regulator of matrix production during healing. These results provide novel evidence that DFU-derived fibroblasts contribute to the defective matrices of DFUs and chronic wound pathogenesis. C1 [Maione, Anna G.; Smith, Avi; Kashpur, Olga; Yanez, Vanessa; Knight, Elana; Garlick, Jonathan A.] Tufts Univ, Sch Dent Med, Dept Oral & Maxillofacial Pathol Oral Med & Crani, 55 Kneeland St,South Cove,Room 116, Boston, MA 02111 USA. [Mooney, David J.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Mooney, David J.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Veves, Aristidis] Harvard Med Sch, Microcirculat Lab, Boston, MA USA. [Veves, Aristidis] Harvard Med Sch, Joslin Beth Israel Deaconess Foot Ctr, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Tomic-Canic, Marjana] Univ Miami, Miller Sch Med, Wound Healing & Regenerat Med Res Program, Dept Dermatol & Cutaneous Surg, Miami, FL 33136 USA. RP Garlick, JA (reprint author), Tufts Univ, Sch Dent Med, Dept Oral & Maxillofacial Pathol Oral Med & Crani, 55 Kneeland St,South Cove,Room 116, Boston, MA 02111 USA. EM jonathan.garlick@tufts.edu FU National Institute of Health (NIH) [DK098055-06A1] FX This work was supported by grant #DK098055-06A1 to Jonathan A. Garlick from National Institute of Health (NIH). NR 31 TC 1 Z9 1 U1 2 U2 2 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 JUL-AUG PY 2016 VL 24 IS 4 BP 630 EP 643 DI 10.1111/wrr.12437 PG 14 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA EE1SX UT WOS:000389364500002 PM 27102877 ER PT J AU Bale, TA Abedalthagafi, M Bi, WL Kang, YJ Merrill, P Dunn, IF Dubuc, A Charbonneau, SK Brown, L Ligon, AH Ramkissoon, SH Ligon, KL AF Bale, Tejus A. Abedalthagafi, Malak Bi, Wenya Linda Kang, Yun Jee Merrill, Parker Dunn, Ian F. Dubuc, Adrian Charbonneau, Sarah K. Brown, Loreal Ligon, Azra H. Ramkissoon, Shakti H. Ligon, Keith L. TI Genomic characterization of recurrent high-grade astroblastoma SO CANCER GENETICS LA English DT Article DE Astroblastoma; aCGH; NGS; GBM; SETD2 ID GLIOMAS; GLIOBLASTOMA; EPENDYMOMA; FEATURES; TUMORS; MEDULLOBLASTOMA; CLASSIFICATION; NEUROGENESIS; MUTATIONS; SURVIVAL AB Astroblastomas are rare primary brain tumors, diagnosed based on histologic features. Not currently assigned a WHO grade, they typically display indolent behavior, with occasional variants taking a more aggressive course. We characterized the immunohistochemical characteristics, copy number (high-resolution array comparative genomic hybridization, OncoCopy) and mutational profile (targeted next-generation exome sequencing, OncoPanel) of a cohort of seven biopsies from four patients to identify recurrent genomic events that may help distinguish astroblastomas from other more common high-grade gliomas. We found that tumor histology was variable across patients and between primary and recurrent tumor samples. No common molecular features were identified among the four tumors. Mutations commonly observed in astrocytic tumors (IDH1/2, TP53, ATRX, and PTEN) or ependymoma were, not identified. However one case with rapid clinical progression displayed mutations more commonly associated with GBM (NF1(N1054H/K63 star), PIK3CA(R38H) and ERG(A403T)). Conversely, another case, originally classified as glioblastoma with nine-year survival before recurrence, lacked a GBM mutational profile. Other mutations frequently seen in lower grade gliomas (BCOR, BCORL1, ERBB3, MYB, ATM) were also present in several tumors. Copy number changes were variable across tumors. Our findings indicate that astroblastomas have variable growth patterns and morphologic features, posing significant challenges to accurate classification in the absence of diagnostically specific copy number alterations and molecular features. Their histopathologic overlap with glioblastoma will likely confound the observation of long-term GBM "survivors". Further genomic profiling is needed to determine whether these tumors represent a distinct entity and to guide management strategies. C1 [Bale, Tejus A.; Abedalthagafi, Malak; Merrill, Parker; Dubuc, Adrian; Ligon, Azra H.; Ramkissoon, Shakti H.; Ligon, Keith L.] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Abedalthagafi, Malak; Kang, Yun Jee; Charbonneau, Sarah K.; Brown, Loreal; Ramkissoon, Shakti H.; Ligon, Keith L.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Abedalthagafi, Malak] King Fahad Med City, Dept Pathol, Riyadh, Saudi Arabia. [Bi, Wenya Linda; Dunn, Ian F.] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA USA. RP Ligon, KL (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA.; Ligon, KL (reprint author), Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. EM keith_ligon@dfci.harvard.edu FU King Abdulaziz City for Science and Technology (KACST), Saudi Arabia FX The authors would like to thank the members of the Ligon lab for helpful discussions. The authors would like to thank Marian Slaney and Sebastian Valentin for the technical assistance with tissue processing and the Center for Advanced Molecular Diagnostic lab members for the genetic testing. This study was supported by the King Abdulaziz City for Science and Technology (KACST), Saudi Arabia (M.A.). NR 39 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 2210-7762 EI 2210-7770 J9 CANCER GENET-NY JI Cancer Genet. PD JUL-AUG PY 2016 VL 209 IS 7-8 BP 321 EP 330 DI 10.1016/j.cancergen.2016.06.002 PG 10 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA EA8EF UT WOS:000386867400003 PM 27425854 ER PT J AU Ruderman, L Ehrlich, DB Roy, A Pietrzak, RH Harpaz-Rotem, I Levy, I AF Ruderman, Lital Ehrlich, Daniel B. Roy, Alicia Pietrzak, Robert H. Harpaz-Rotem, Ilan Levy, Ifat TI POSTTRAUMATIC STRESS SYMPTOMS AND AVERSION TO AMBIGUOUS LOSSES IN COMBAT VETERANS SO DEPRESSION AND ANXIETY LA English DT Article DE PTSD; decision making; uncertainty; ambiguity; aversion; anxious arousal ID DECISION-MAKING; PSYCHOLOGICAL DISTRESS; PREFRONTAL CORTEX; UNCERTAINTY; DISORDER; RISK; RDOC; HYPERAROUSAL; FRAMEWORK; BEHAVIOR AB Background: Psychiatric symptoms typically cut across traditional diagnostic categories. In order to devise individually tailored treatments, there is a need to identify the basic mechanisms that underlie these symptoms. Behavioral economics provides a framework for studying these mechanisms at the behavioral level. Here, we utilized this framework to examine a widely ignored aspect of trauma-related symptomatology-individual uncertainty attitudes-in combat veterans with and without posttraumatic stress disorder (PTSD). Methods: Fifty-seven combat veterans, including 30 with PTSD and 27 without PTSD, completed a risk and ambiguity decision-making task that characterizes individual uncertainty attitudes, distinguishing between attitudes toward uncertain outcomes with known ("risk") and unknown ("ambiguity") probabilities, and between attitudes toward uncertain gains and uncertain losses. Participants' choices were used to estimate risk and ambiguity attitudes in the gain and loss domains. Results: Veterans with PTSD were more averse to ambiguity, but not risk, compared to veterans without PTSD, when making choices between possible losses, but not gains. The degree of aversion was associated with anxious arousal (e.g., hypervigilance) symptoms, as well as with the degree of combat exposure. Moreover, ambiguity attitudes fully mediated the association between combat exposure and anxious arousal symptoms. Conclusions: These results provide a foundation for prospective studies of the causal association between ambiguity attitudes and trauma-related symptoms, as well as etiologic studies of the neural underpinnings of these behavioral outcomes. More generally, these results demonstrate the potential of neuroeconomic and behavioral economic techniques for devising objective and incentive-compatible diagnostic tools, and investigating the etiology of psychiatric disorders. (C) 2016 Wiley Periodicals, Inc. C1 [Ruderman, Lital; Ehrlich, Daniel B.; Levy, Ifat] Yale Sch Med, Sect Comparat Med, POB 208016, New Haven, CT 06520 USA. [Roy, Alicia; Pietrzak, Robert H.; Harpaz-Rotem, Ilan; Levy, Ifat] US Dept Vet Affairs, Natl Ctr PTSD, New Haven, CT USA. [Roy, Alicia; Pietrzak, Robert H.; Harpaz-Rotem, Ilan] Yale Sch Med, Dept Psychiat, New Haven, CT USA. [Levy, Ifat] Yale Sch Med, Dept Neurosci, New Haven, CT USA. RP Levy, I (reprint author), Yale Sch Med, Sect Comparat Med, POB 208016, New Haven, CT 06520 USA. EM ifat.levy@yale.edu FU National Institute of Mental Health [R21MH102634]; Clinical Neurosciences Division of the U.S. Department of Veterans Affairs National Center for PTSD FX Contract grant sponsor: National Institute of Mental Health (to I. L. and I. H.-R.); Contract grant number: R21MH102634; Contract grant sponsor: Clinical Neurosciences Division of the U.S. Department of Veterans Affairs National Center for PTSD. NR 39 TC 0 Z9 0 U1 2 U2 3 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 JUL PY 2016 VL 33 IS 7 BP 606 EP 613 DI 10.1002/da.22494 PG 8 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA DW5TD UT WOS:000383708900005 PM 27000639 ER PT J AU Gordon, LB Kieran, MW Kleinman, ME Misteli, T AF Gordon, Leslie B. Kieran, Mark W. Kleinman, Monica E. Misteli, Tom TI The decision-making process and criteria in selecting candidate drugs for progeria clinical trials SO EMBO MOLECULAR MEDICINE LA English DT Editorial Material ID HUTCHINSON-GILFORD PROGERIA AB Hutchinson-Gilford progeria syndrome (progeria) is an extremely rare premature aging disease with a population prevalence of 1 in 20 million. Nevertheless, propelled by the discovery of a causal mutation in the lamin A/C gene (LMNA) (De Sandre-Giovannoli et al, 2003; Eriksson et al, 2003) and strong patient advocacy (Gordon & Gordon, 2014), progeria has rapidly become a vibrant field of study, attracting a wide range of researchers from basic cell biologists to clinicians. C1 [Gordon, Leslie B.; Kleinman, Monica E.] Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Gordon, Leslie B.; Kleinman, Monica E.] Harvard Med Sch, Boston, MA 02115 USA. [Gordon, Leslie B.] Brown Univ, Dept Pediat, Hasbro Childrens Hosp, Providence, RI 02912 USA. [Gordon, Leslie B.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Kieran, Mark W.] Dana Farber Canc Inst, Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA 02115 USA. [Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Gordon, LB (reprint author), Boston Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA.; Gordon, LB (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Gordon, LB (reprint author), Brown Univ, Dept Pediat, Hasbro Childrens Hosp, Providence, RI 02912 USA.; Gordon, LB (reprint author), Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. EM leslie_gordon@brown.edu NR 8 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1757-4676 EI 1757-4684 J9 EMBO MOL MED JI EMBO Mol. Med. PD JUL PY 2016 VL 8 IS 7 BP 685 EP 687 DI 10.15252/emmm.201606280 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA DW4SC UT WOS:000383632300001 PM 27234439 ER PT J AU Boikos, SA Pappo, AS Killian, JK LaQuaglia, MP Weldon, CB George, S Trent, JC von Mehren, M Wright, JA Schiffman, JD Raygada, M Pacak, K Meltzer, PS Miettinen, MM Stratakis, C Janeway, KA Helman, LJ AF Boikos, Sosipatros A. Pappo, Alberto S. Killian, J. Keith LaQuaglia, Michael P. Weldon, Chris B. George, Suzanne Trent, Jonathan C. von Mehren, Margaret Wright, Jennifer A. Schiffman, Josh D. Raygada, Margarita Pacak, Karel Meltzer, Paul S. Miettinen, Markku M. Stratakis, Constantine Janeway, Katherine A. Helman, Lee J. TI Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic SO JAMA ONCOLOGY LA English DT Article ID SUCCINATE-DEHYDROGENASE; GERMLINE MUTATIONS; IDH2 MUTATIONS; KIT; PDGFRA; GENES; GIST; GENETICS; IMATINIB; CANCER AB IMPORTANCE Wild-type (WT) gastrointestinal stromal tumors (GISTs), which lack KIT and PDGFRA gene mutations, are the primary form of GIST in children and occasionally occur in adults. They respond poorly to standard targeted therapy. Better molecular and clinical characterization could improve management. OBJECTIVE To evaluate the clinical and tumor genomic features of WT GIST. DESIGN, SETTING, AND PARTICIPANTS Patients enrolled in an observational study at the National Institutes of Health starting in 2008 and were evaluated in a GIST clinic held once or twice yearly. Patients provided access to existing medical records and tumor specimens. Self-referred or physician-referred patients younger than 19 years with GIST or 19 years or older with known WT GIST (no mutations in KIT or PDGFRA) were recruited; 116 patients with WT GIST were enrolled, and 95 had adequate tumor specimen available. Tumors were characterized by immunohistochemical analysis (IHC) for succinate dehydrogenase (SDH) subunit B, sequencing of SDH genes, and determination of SDHC promoter methylation. Testing of germline SDH genes was offered to consenting patients and families. MAIN OUTCOMES AND MEASURES For classification, tumors were characterized by SDHA, B, C, or D (SDHX) mutations and other genetic and epigenetic alterations, including presence of mutations in germline. Clinical characteristics were categorized. RESULTS Wild-type GIST specimens from 95 patients (median age, 23 [range, 7-78] years; 70% female) were classified into 3 molecular subtypes: SDH-competent (n = 11), defined by detection of SDHB by IHC; and 2 types of SDH-deficient GIST (n = 84). Of SDH-deficient tumors, 63 (67%) had SDH mutations, and in 31 of 38 (82%), the SDHX mutation was also present in germline. Twenty-one (22%) SDH-deficient tumors had methylation of the SDHC promoter leading to silencing of expression. Mutations in known cancer-associated pathways were identified in 9 of 11 SDH-competent tumors. Among patients with SDH-mutant tumors, 62% were female (39 of 63), median (range) age was 23 (7-58) years, and approximately 30% presented with metastases (liver [12 of 58], peritoneal [6 of 58], lymph node [15 of 23]). SDHC-epimutant tumors mostly affected young females (20 of 21; median [range] age, 15 [8-50] years), and approximately 40% presented with metastases (liver [7 of 19], peritoneal [1 of 19], lymph node [3 of 8]). SDH-deficient tumors occurred only in the stomach and had an indolent course. CONCLUSIONS AND RELEVANCE An observational study of WT GIST permitted the evaluation of a large number of patients with this rare disease. Three molecular subtypes with implications for prognosis and clinical management were identified. C1 [Boikos, Sosipatros A.; Helman, Lee J.] NCI, Pediat Oncol Branch, Ctr Canc Res, 9000 Rockville Pike,Bldg 31,Room 3A11, Bethesda, MD 20892 USA. [Boikos, Sosipatros A.] Virginia Commonwealth Univ, Massey Canc Ctr, Sarcoma & Rare Tumors Program, Div Hematol Oncol & Palliat Care, Richmond, VA 23284 USA. [Pappo, Alberto S.] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA. [Killian, J. Keith; Meltzer, Paul S.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [LaQuaglia, Michael P.] Mem Sloan Kettering Canc Ctr, Pediat Surg Serv, 1275 York Ave, New York, NY 10021 USA. [Weldon, Chris B.] Boston Childrens Hosp, Dept Surg, Boston, MA USA. [George, Suzanne] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Trent, Jonathan C.] Univ Miami, Div Hematol Oncol, Dept Med, Sylvester Comprehens Canc Ctr, Miami, FL USA. [von Mehren, Margaret] Fox Chase Canc Ctr, Div Hematol Oncol, 7701 Burholme Ave, Philadelphia, PA 19111 USA. [Wright, Jennifer A.; Schiffman, Josh D.] Huntsman Canc Inst, Pediat Hematol & Oncol, Salt Lake City, UT USA. [Raygada, Margarita] Natl Inst Child Hlth & Human Dev, Div Intramural Res, Bethesda, MD USA. [Pacak, Karel] Natl Inst Child Hlth & Human Dev, Sect Med Neuroendocrinol, Bethesda, MD USA. [Miettinen, Markku M.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Stratakis, Constantine] NICHHD, Sect Endocrinol & Genet, Bethesda, MD 20892 USA. [Janeway, Katherine A.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. RP Helman, LJ (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, 9000 Rockville Pike,Bldg 31,Room 3A11, Bethesda, MD 20892 USA. EM helmanl@nih.gov FU intramural National Cancer Institute (NCI), National Institutes of Health (NIH) FX The study was funded by the intramural National Cancer Institute (NCI), National Institutes of Health (NIH). NR 33 TC 8 Z9 8 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JUL PY 2016 VL 2 IS 7 BP 922 EP 928 DI 10.1001/jamaoncol.2016.0256 PG 7 WC Oncology SC Oncology GA DW5RK UT WOS:000383704300016 PM 27011036 ER PT J AU Piotrowska, Z Sequist, LV AF Piotrowska, Zofia Sequist, Lecia V. TI Treatment of EGFR-Mutant Lung Cancers After Progression in Patients Receiving First-Line EGFR Tyrosine Kinase Inhibitors A Review SO JAMA ONCOLOGY LA English DT Review ID RANDOMIZED PHASE-3 TRIAL; ACQUIRED-RESISTANCE; OPEN-LABEL; NSCLC-PATIENTS; MET AMPLIFICATION; TARGETED THERAPY; T790M MUTATION; ASIAN PATIENTS; NEVER-SMOKERS; TKI THERAPY AB IMPORTANCE Patients with EGFR-mutant lung cancer benefit from treatment with EGFR inhibitors such as erlotinib, gefitinib, and afatinib, but outcomes are limited by the eventual development of resistance to these agents. Over half of patients acquire a secondary T790M mutation in EGFR at the time of progression and a substantial minority develops resistance through other mechanisms. Multiple treatment strategies are now available to patients whose disease has progressed on their initial EGFR inhibitor, including therapies targeting both T790M, and non-T790M-mediated resistance. OBSERVATIONS This review summarizes information about and current treatment strategies for patients with EGFR-mutant lung cancer whose disease progresses on their initial EGFR inhibitor, including those with T790M and other types of acquired resistance. Postprogression therapy should be tailored based on identified resistance mechanisms, sites, and pace of disease progression, and patient preference. Biopsy and genotyping of resistant tissue or plasma are essential to identifying resistance mechanisms and selecting the most appropriate treatment when patients' disease progresses during treatment with an initial EGFR inhibitor. Third-generation EGFR inhibitors are generally preferred for patients with T790M-positive resistance, whereas standard chemotherapy and clinical trials are preferred for those without T790M. For select patients, treatment can be continued beyond progression and local ablative therapies can be used to target sites of oligoprogression. CONCLUSIONS AND RELEVANCE Treatment for patients who progress on their initial EGFR inhibitor should be tailored to identified resistance mechanisms and sites of progression. Emerging reports about resistance to third-generation EGFR inhibitors will lay the groundwork for overcoming the next generation of resistance, and further research is needed to develop more effective therapies. C1 [Piotrowska, Zofia; Sequist, Lecia V.] Harvard Med Sch, Boston, MA USA. [Piotrowska, Zofia; Sequist, Lecia V.] Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. RP Piotrowska, Z (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. EM zpiotrowska@partners.org NR 61 TC 2 Z9 2 U1 3 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2374-2445 J9 JAMA ONCOL JI JAMA Oncol. PD JUL PY 2016 VL 2 IS 7 BP 948 EP 954 DI 10.1001/jamaoncol.2016.0333 PG 7 WC Oncology SC Oncology GA DW5RK UT WOS:000383704300020 PM 27196961 ER PT J AU Shimizu, M Joyashiki, E Noda, H Watanabe, T Okazaki, M Nagayasu, M Adachi, K Tamura, T Potts, JT Gardella, TJ Kawabe, Y AF Shimizu, Masaru Joyashiki, Eri Noda, Hiroshi Watanabe, Tomoyuki Okazaki, Makoto Nagayasu, Miho Adachi, Kenji Tamura, Tatsuya Potts, John T., Jr. Gardella, Thomas J. Kawabe, Yoshiki TI Pharmacodynamic Actions of a Long-Acting PTH Analog (LA-PTH) in Thyroparathyroidectomized (TPTX) Rats and Normal Monkeys SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE HYPOPARATHYROIDISM; LONG-ACTING PTH ANALOG; PTH RECEPTOR; HORMONE REPLACEMENT THERAPY; THYROPARATHYROIDECTOMIZED RATS; CALCIUM HOMEOSTASIS ID PARATHYROID-HORMONE RECEPTOR; RANDOMIZED CROSSOVER TRIAL; REPLACEMENT THERAPY; FOLLOW-UP; HYPOPARATHYROIDISM; CONFORMATIONS; SELECTIVITY; GENERATION; EFFICACY; BINDING AB Hypoparathyroidism is a disease of chronic hypocalcemia and hyperphosphatemia due to a deficiency of parathyroid hormone (PTH). PTH and analogs of the hormone are of interest as potential therapies. Accordingly, we examined the pharmacological properties of a long-acting PTH analog, [Ala1,3,12,18,22, Gln10, Arg11, Trp14, Lys26]-PTH(1-14)/ PTHrP(15-36) (LA-PTH) in thyroparathyroidectomized (TPTX) rats, a model of HP, as well as in normal monkeys. In TPTX rats, a single intravenous administration of LA-PTH at a dose of 0.9 nmol/kg increased serum calcium (sCa) and decreased serum phosphate (sPi) to near-normal levels for longer than 48 hours, whereas PTH(1-34) and PTH(1-84), each injected at a dose 80-fold higher than that used for LA-PTH, increased sCa and decreased sPi only modestly and transiently (< 6 hours). LA-PTH also exhibited enhanced and prolonged efficacy versus PTH(1-34) and PTH(1-84) for elevating sCa when administered subcutaneously (s.c.) into monkeys. Daily s.c. administration of LA-PTH (1.8 nmol/kg) into TPTX rats for 28 days elevated sCa to near normal levels without causing hypercalciuria or increasing bone resorption markers, a desirable goal in the treatment of hypoparathyroidism. The results are supportive of further study of long-acting PTH analogs as potential therapies for patients with hypoparathyroidism. (C) 2016 American Society for Bone and Mineral Research. C1 [Shimizu, Masaru; Joyashiki, Eri; Noda, Hiroshi; Watanabe, Tomoyuki; Okazaki, Makoto; Nagayasu, Miho; Adachi, Kenji; Tamura, Tatsuya; Kawabe, Yoshiki] Chugai Pharmaceut Co Ltd, Div Res, 1-135 Komakado, Shizuoka, Japan. [Watanabe, Tomoyuki; Potts, John T., Jr.; Gardella, Thomas J.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Shimizu, M (reprint author), Chugai Pharmaceut Co Ltd, Div Res, 1-135 Komakado, Shizuoka, Japan. EM shimizumsr@chugai-pharm.co.jp FU Chugai Pharmaceutical Co., Ltd.; NIH grant NIDDK [11794, AR066261] FX This work was supported by Chugai Pharmaceutical Co., Ltd.; and was partially supported by NIH grant NIDDK 11794 (to TJG and JTP), and AR066261 (to TJG). We thank the staff of Chugai Research Institute for Medical Science, Inc., for the technical assistance of in vivo studies. NR 30 TC 4 Z9 4 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 EI 1523-4681 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUL PY 2016 VL 31 IS 7 BP 1405 EP 1412 DI 10.1002/jbmr.2811 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DW5VP UT WOS:000383715800009 PM 26865415 ER PT J AU Petrillo, LA Ritchie, CS AF Petrillo, Laura A. Ritchie, Christine S. TI The challenges of symptom management for patients with multimorbidity in research and practice: A thematic review SO PROGRESS IN PALLIATIVE CARE LA English DT Review DE Multimorbidity; Symptom management; Palliative care ID MULTIPLE CHRONIC CONDITIONS; QUALITY-OF-LIFE; OLDER-ADULTS; PALLIATIVE CARE; PHYSICAL FUNCTION; COMORBIDITY; PREVALENCE AB Introduction: Multimorbidity, the presence of multiple coexisting diseases or conditions, afflicts the majority of older adults, and is associated with increased mortality and healthcare utilization. In addition, multimorbidity negatively impacts quality of life and increases symptom burden. Yet, there is a dearth of evidence on how to best manage symptoms in patients with multimorbidity. Methods: We conducted a thematic review of approaches to symptom management in multimorbidity. Results: Research in this area has been hampered by inconsistent definitions of multimorbidity and challenges in outcome measurement. Investigations of symptom management strategies in specific disease states, like cancer, typically exclude medically complex patients. In the absence of evidence, the American Geriatrics Society's recommendations for the care of adults with multimorbidity provide a useful starting point for clinicians. We present a case to demonstrate how the AGS recommendations can be tailored to the situation of symptom management in patients with multimorbidity. We also present suggestions for future research directions. Discussion: Multimorbidity is an incredibly common and overlooked problem in our healthcare system, and only stands to increase in relevance as patients live longer and have the opportunity to accrue a greater burden of chronic illness. A comprehensive approach to patients with multimorbidity includes focusing on patient preferences, carefully interpreting the available evidence (including both the benefits and potential harms), and thinking critically about the burden of any treatment. Taking time to elicit patient goals and preferences, and apprise patients of their prognosis if they want to know, are especially important in symptom management discussions with patients with multimorbidity. C1 [Petrillo, Laura A.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Ritchie, Christine S.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. RP Petrillo, LA (reprint author), San Francisco VA Med Ctr, San Francisco, CA 94121 USA. EM laura.petrillo@ucsf.edu NR 37 TC 0 Z9 0 U1 2 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0969-9260 EI 1743-291X J9 PROG PALLIAT CARE JI Prog. Palliat. Care PD JUL PY 2016 VL 24 IS 5 BP 262 EP 267 DI 10.1080/09699260.2016.1192320 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DW4AE UT WOS:000383583400002 ER PT J AU Rong, SS Chen, LJ Pang, CP AF Rong, Shi Song Chen, Li Jia Pang, Chi Pui TI Myopia Genetics-The Asia-Pacific Perspective SO ASIA-PACIFIC JOURNAL OF OPHTHALMOLOGY LA English DT Review DE myopia; refractive error; gene; genetics; ethnicity ID GENOME-WIDE ASSOCIATION; HIGH-GRADE MYOPIA; STATIONARY NIGHT BLINDNESS; RECESSIVE HIGH MYOPIA; DOMINANT HIGH MYOPIA; HAN CHINESE POPULATION; TIME SPENT OUTDOORS; CHILDRENS EYE SIZE; REFRACTIVE ERROR; SUSCEPTIBILITY LOCUS AB Myopia is a major cause of visual impairment worldwide. In particular, high myopia is associated with serious blinding complications, including retinal detachment, chorioretinal degeneration, and choroidal neovascularization. Myopia is multifactorial in etiology, resulting from the interaction of environmental and genetic risk factors. During the past 2 decades, a large number of gene loci and variants have been identified for myopia. There are more than 20 myopia-associated loci spanning all chromosomes. Earlier findings were obtained mainly from family linkage analyses and candidate gene studies, and more recent results are principally from genome-wide association studies and exome sequencing. Some genetic associations have been successfully validated and replicated in populations of different geographic localities and ethnicities, but some have not. Compared with Whites, Asian populations-in particular Japanese, Korean, and Chinese-have a much higher prevalence of myopia, especially high myopia. Both genetic and environmental factors contribute to such ethnic variations. This review attempts to summarize and compare the allelic frequencies of gene variants known to be associated with myopia in different ethnic groups, especially in the Asia-Pacific region. C1 [Rong, Shi Song; Chen, Li Jia; Pang, Chi Pui] Chinese Univ Hong Kong, Hong Kong Eye Hosp, Dept Ophthalmol & Visual Sci, 147 K Argyle St, Kowloon, Hong Kong, Peoples R China. [Rong, Shi Song] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Pang, CP (reprint author), Chinese Univ Hong Kong, Hong Kong Eye Hosp, Dept Ophthalmol & Visual Sci, 147 K Argyle St, Kowloon, Hong Kong, Peoples R China. EM cppang@cuhk.edu.hk NR 105 TC 2 Z9 3 U1 7 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2162-0989 J9 ASIA-PAC J OPHTHALMO JI Asia-Pac. J. Ophthalmol. PD JUL-AUG PY 2016 VL 5 IS 4 BP 236 EP 244 DI 10.1097/APO.0000000000000224 PG 9 WC Ophthalmology SC Ophthalmology GA ED6NQ UT WOS:000388972700004 PM 27488065 ER PT J AU Mihos, CG Pineda, AM Horvath, SA Santana, O AF Mihos, Christos G. Pineda, Andres M. Horvath, Sofia A. Santana, Orlando TI Anterior Mitral Leaflet Augmentation for Ischemic Mitral Regurgitation Performed Via a Right Thoracotomy Approach SO INNOVATIONS-TECHNOLOGY AND TECHNIQUES IN CARDIOTHORACIC AND VASCULAR SURGERY LA English DT Article DE Anterior leaflet augmentation; Functional mitral regurgitation; Ischemic cardiomyopathy; Ischemic mitral regurgitation; Pericardial patch ID VALVE SURGERY; DYSFUNCTION; DISEASE AB Ischemic mitral regurgitation (MR) after myocardial infarction is associated with poor long-term survival, and the optimal treatment strategy remains debated. The most common repair technique used is a restrictive annuloplasty. However, up to 15% to 30% of patients experience recurrent MR owing to progressive left ventricular remodeling and geometric distortion of the mitral valve apparatus. Anterior mitral leaflet augmentation using a pericardial patch, in combination with a true-sized mitral annuloplasty, has been proposed as an adjunctive technique to increase the durability of valve repair for ischemic MR. Herein, we describe 2 cases of anterior mitral leaflet augmentation with annuloplasty repair for severe ischemic MR via a minimally invasive right thoracotomy, and review the literature regarding patient selection and clinical outcomes of this technique. C1 [Mihos, Christos G.] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, 55 Fruit St, Boston, MA 02140 USA. [Pineda, Andres M.; Horvath, Sofia A.; Santana, Orlando] Columbia Univ, Div Cardiol, Mt Sinai Heart Inst, Miami Beach, FL USA. RP Mihos, CG (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, 55 Fruit St, Boston, MA 02140 USA. EM cmihos@mgh.harvard.edu NR 16 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1556-9845 EI 1559-0879 J9 INNOVATIONS JI Innovations PD JUL-AUG PY 2016 VL 11 IS 4 BP 298 EP 300 PG 3 WC Surgery SC Surgery GA ED6CQ UT WOS:000388942800013 PM 27612148 ER PT J AU Yeomans, PD Ross, RJ AF Yeomans, Peter D. Ross, Richard J. TI Removing Barriers in the Assessment of Combat-Related Post-traumatic Stress Disorder SO MILITARY MEDICINE LA English DT Editorial Material ID VETERANS AB While the Veterans Health Administration continues to treat Vietnam War Veterans, approximately two million service men and women have returned from Iraq and Afghanistan. However, our treatments can only be as effective as the quality of our clinical assessment. Disclosure of trauma is facilitated when the type of trauma is present in the sociocultural environment of patient and clinician. Topics that once were deemed too shameful for inquiry, specifically, childhood abuse, domestic violence, sexual abuse, and military sexual trauma are now part of a standard assessment. Similarly, the standard clinical assessment of combat Veterans should include specific queries that address the darkest underside of wartime experiences. C1 [Yeomans, Peter D.; Ross, Richard J.] Philadelphia Vet Affairs Med, Behav Hlth Serv, 3900 Woodland Ave, Philadelphia, PA 19104 USA. [Ross, Richard J.] Univ Penn, Perelman Sch Med, Dept Psychiat, 3535 Market St, Philadelphia, PA 19104 USA. RP Yeomans, PD (reprint author), Philadelphia Vet Affairs Med, Behav Hlth Serv, 3900 Woodland Ave, Philadelphia, PA 19104 USA. NR 8 TC 0 Z9 0 U1 1 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD JUL PY 2016 VL 181 IS 7 BP 625 EP 626 DI 10.7205/MILMED-D-15-00182 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA DW5LT UT WOS:000383687400006 PM 27391614 ER PT J AU Heinz, AJ Pennington, DL Cohen, N Schmeling, B Lasher, BA Schrodek, E Batki, SL AF Heinz, Adrienne J. Pennington, David L. Cohen, Nicole Schmeling, Brandi Lasher, Brooke A. Schrodek, Emily Batki, Steven L. TI Relations Between Cognitive Functioning and Alcohol Use, Craving, and Post-Traumatic Stress: An Examination Among Trauma-Exposed Military Veterans With Alcohol Use Disorder SO MILITARY MEDICINE LA English DT Article ID SUBSTANCE USE DISORDERS; COMPULSIVE DRINKING SCALE; RANDOMIZED CLINICAL-TRIAL; RISK TASK BART; EXECUTIVE FUNCTION; PREFRONTAL CORTEX; PSYCHOMETRIC PROPERTIES; TREATMENT OUTCOMES; TREATMENT RESPONSE; WORKING-MEMORY AB Cognitive dysfunction is commonly observed among individuals with alcohol use disorder (AUD) and trauma exposure and is, in turn, associated with worse clinical outcomes. Accordingly, disruptions in cognitive functioning may be conceptualized as a trans-disease phenomenon representing a potential high-yield target for intervention. Less is known though about how different cognitive functions covary with alcohol use, craving, and post-traumatic stress symptom severity among trauma-exposed individuals with AUD. Sixty-eight male and female trauma-exposed military veterans with AUD, entering treatment trials to reduce alcohol use, completed measures assessing alcohol use and craving, post-traumatic stress symptom severity, and cognitive functioning. In multivariate models, after controlling for post-traumatic stress symptom severity, poorer learning and memory was associated with higher alcohol consumption and higher risk taking/impulsivity was associated with stronger preoccupations with alcohol and compulsions to drink. Alcohol consumption and craving, but not performance on cognitive tests, were positively associated with post-traumatic stress symptom severity. Findings suggest that interventions to strengthen cognitive functioning might be used as a preparatory step to augment treatments for AUD. Clinicians are encouraged to consider a standard assessment of cognitive functioning, in addition to post-traumatic stress symptom severity, in treatment planning and delivery for this vulnerable and high-risk population. C1 [Heinz, Adrienne J.; Cohen, Nicole] Palo Alto Vet Affairs Hlth Care Syst, Ctr Innovat Implementat, Natl Ctr Posttraumat Stress Disorder, 795 Willow Rd, Menlo Pk, CA 94025 USA. [Pennington, David L.; Lasher, Brooke A.; Schrodek, Emily; Batki, Steven L.] San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. [Pennington, David L.; Lasher, Brooke A.; Schrodek, Emily; Batki, Steven L.] Univ Calif San Francisco, Dept Psychiat, 500 Parnassus Ave, San Francisco, CA 94143 USA. [Pennington, David L.] Northern Calif Inst Res & Educ, 4150 Clement St 151NC, San Francisco, CA 94121 USA. [Schmeling, Brandi] Palo Alto Univ, 1791 Arastradero Rd, Palo Alto, CA 94304 USA. RP Heinz, AJ (reprint author), Palo Alto Vet Affairs Hlth Care Syst, Ctr Innovat Implementat, Natl Ctr Posttraumat Stress Disorder, 795 Willow Rd, Menlo Pk, CA 94025 USA. FU Department of Defense [W81XWH-05-2-0094, W81XWH-12-2-0137, W81XWH-11-2-0245]; National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health [UCSF-CTSI UL1 RR024131]; VA Rehabilitation Research and Development (RR&D) Career Development Award-2 [1IK2RX001492-01A1] FX This project was supported by Department of Defense W81XWH-05-2-0094, W81XWH-12-2-0137, and W81XWH-11-2-0245 (SLB), the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health UCSF-CTSI UL1 RR024131, which were administered by the Northern California Institute for Research and Education, and with resources of the Veterans Affairs Medical Center, San Francisco, California. Support was also provided by a VA Rehabilitation Research and Development (RR&D) Career Development Award-2 (1IK2RX001492-01A1) granted to Dr. Heinz. NR 97 TC 0 Z9 0 U1 10 U2 10 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 JUL PY 2016 VL 181 IS 7 BP 663 EP 671 DI 10.7205/MILMED-D-15-00228 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DW5LT UT WOS:000383687400012 PM 27391620 ER PT J AU Edwards-Stewart, A Smolenski, DJ Reger, GM Bush, N Workman, DE AF Edwards-Stewart, Amanda Smolenski, Derek J. Reger, Greg M. Bush, Nigel Workman, Don E. TI An Analysis of Personal Technology Use by Service Members and Military Behavioral Health Providers SO MILITARY MEDICINE LA English DT Article ID SMARTPHONE; SOLDIERS; IPHONE AB Personal technology use is ubiquitous in the United States today and technology, in general, continues to change the face of health care. However, little is known about the personal technology use of military service members and the behavioral health care providers that treat them. This study reports the technology use of 1,101 active duty service members and 45 behavioral health care providers at a large military installation. Participants reported Internet usage; ownership of smartphones, tablets, and e-readers; usage of mobile applications (apps); and basic demographic information. Compared with providers, service members reported higher rates of smartphone ownership, were more likely to own Android smartphones than iPhones, and spent more time gaming. Both groups spent a comparable amount of time using social media. With the exception of gaming, however, differences between service members and providers were not statistically significant when demographics were matched and controlled. Among service members, younger respondents (18-34) were statistically more likely than older respondents (35-58) to own smartphones, spend time gaming, and engage in social media. Our findings can help inform provider's technology-based education and intervention of their patients and guide the development of new technologies to support the psychological health of service members. C1 [Edwards-Stewart, Amanda; Smolenski, Derek J.; Bush, Nigel; Workman, Don E.] Natl Ctr Telehlth & Technol T2, 9933 West Hayes St, Tacoma, WA 98431 USA. [Reger, Greg M.] VA Puget Sound, Dept Vet Affairs, 9600 Vet Dr, Tacoma, WA 98493 USA. RP Edwards-Stewart, A (reprint author), Natl Ctr Telehlth & Technol T2, 9933 West Hayes St, Tacoma, WA 98431 USA. NR 28 TC 1 Z9 1 U1 2 U2 2 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD JUL PY 2016 VL 181 IS 7 BP 701 EP 709 DI 10.7205/MILMED-D-15-00041 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA DW5LT UT WOS:000383687400017 PM 27391625 ER PT J AU Athalye, PS Sekeljic, NJ Ilic, MM Tonyushkin, AA Notaros, BM AF Athalye, Pranav S. Sekeljic, Nada J. Ilic, Milan M. Tonyushkin, Alexey A. Notaros, Branislav M. TI Subject-loaded quadrifilar helical-antenna RF coil with high B-1(+) field uniformity and large FOV for 3-T MRI SO CONCEPTS IN MAGNETIC RESONANCE PART B-MAGNETIC RESONANCE ENGINEERING LA English DT Article DE B-1(+) field uniformity; high-field 3-T MRI systems; magnetic resonance imaging (MRI); quadrifilar helical-antenna coil; RF body coils ID COAXIAL WAVE-GUIDE; ULTRAHIGH FIELDS; HOMOGENEITY; EFFICIENCY; STRENGTH AB A novel method for excitation of RF B-1 field in high-field (3-T) magnetic resonance imaging (MRI) systems using a subject-loaded quadrifilar helical antenna as an RF coil is proposed, evaluated, and demonstrated. Design, analysis, characterization, and evaluation of the novel coil when situated in a 3-T MRI bore and loaded with different phantoms are performed and cross-validated by extensive numerical simulations using multiple computational electromagnetics techniques. The results for the quadrifilar helical-antenna RF body coil show (a) strong field penetration in the entire phantoms; (b) excellent right-hand circular polarization (RCP); (c) high spatial uniformity of RCP RF magnetic field, B-1(+), throughout the phantoms; (d) large field of view (FOV); (e) good transmit efficiency; and (f) low local specific absorption rate (SAR). The examples show that the new RF coil provides substantially better B-1(+)-field uniformity and much larger FOV than any of the previously reported numerical and experimental results for the existing RF coil designs at 3 T in literature that enable comparison. In addition, helical RF body coils of different lengths can, for instance, easily provide an excellent RCP and highly uniform B-1(+)-field within the MRI maximum FOV length of 50cm, and even 100cm. The proposed MRI RF coil yields a remarkable improvement in the field uniformity in the longitudinal direction, for various phantoms, with comparable efficiency and SAR levels. C1 [Athalye, Pranav S.; Sekeljic, Nada J.; Ilic, Milan M.; Notaros, Branislav M.] Colorado State Univ, Dept Elect & Comp Engn, Ft Collins, CO 80523 USA. [Sekeljic, Nada J.] Intel Corp, Hillsboro, OR 97124 USA. [Ilic, Milan M.] Univ Belgrade, Sch Elect Engn, Belgrade, Serbia. [Tonyushkin, Alexey A.] Univ Massachusetts, Dept Phys, Boston, MA 02125 USA. [Tonyushkin, Alexey A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. RP Notaros, BM (reprint author), Colorado State Univ, Dept Elect & Comp Engn, Ft Collins, CO 80523 USA. EM notaros@colostate.edu FU National Science Foundation [ECCS-1307863]; Serbian Ministry of Education, Science, and Technological Development [TR-32005] FX This work was supported by the National Science Foundation under grant ECCS-1307863 and by the Serbian Ministry of Education, Science, and Technological Development under grant TR-32005. NR 39 TC 0 Z9 0 U1 7 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-5031 EI 1552-504X J9 CONCEPT MAGN RESON B JI Concepts Magn. Reson. Part B PD JUL PY 2016 VL 46 IS 3 BP 106 EP 117 DI 10.1002/cmr.b.21326 PG 12 WC Chemistry, Physical; Instruments & Instrumentation; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Chemistry; Instruments & Instrumentation; Physics; Spectroscopy GA EC0GP UT WOS:000387777500001 ER PT J AU Ponte, PR Somerville, JG Adams, JM AF Ponte, Patricia Reid Somerville, Jackie G. Adams, Jeffrey M. TI Assuring the Capture of Standardized Nursing Data: A Call to Action for Chief Nursing Officers SO INTERNATIONAL JOURNAL OF NURSING KNOWLEDGE LA English DT Editorial Material C1 [Ponte, Patricia Reid] Dana Farber Canc Inst, Patient Care Serv DFCI, Boston, MA 02115 USA. [Ponte, Patricia Reid] Dana Farber Canc Inst, Oncol Nursing & Clin Serv BWH, Boston, MA 02115 USA. [Somerville, Jackie G.] Brigham & Womens Hosp, Patient Care Serv, 75 Francis St, Boston, MA 02115 USA. [Adams, Jeffrey M.] Workforce Outcomes Res & Leadership Dev Inst WORL, Boston, MA USA. [Adams, Jeffrey M.] Robert Wood Johnson Fdn, AONE ASU Interprofess Fellowship Innovat Hlth Lea, Princeton, NJ 08543 USA. RP Adams, JM (reprint author), Workforce Outcomes Res & Leadership Dev Inst WORL, Boston, MA USA.; Adams, JM (reprint author), Robert Wood Johnson Fdn, AONE ASU Interprofess Fellowship Innovat Hlth Lea, Princeton, NJ 08543 USA. EM jeffrey.m.adams@asu.edu NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-3087 EI 2047-3095 J9 INT J NURS KNOWL JI Int. J. Nurs. Knowl. PD JUL PY 2016 VL 27 IS 3 BP 127 EP 128 DI 10.1111/2047-3095.12136 PG 2 WC Nursing SC Nursing GA EC7IP UT WOS:000388310800001 ER PT J AU Christakopoulos, GE Karmpaliotis, D Alaswad, K Yeh, RW Jaffer, FA Wyman, RM Lombardi, W Grantham, JA Kandzari, DA Lembo, N Moses, JW Kirtane, A Parikh, M Green, P Finn, M Garcia, S Doing, A Patel, M Bahadorani, J Christopoulos, G Karatasakis, A Thompson, CA Banerjee, S Brilakis, ES AF Christakopoulos, Georgios E. Karmpaliotis, Dimitri Alaswad, Khaldoon Yeh, Robert W. Jaffer, Farouc A. Wyman, R. Michael Lombardi, William Grantham, J. Aaron Kandzari, David A. Lembo, Nicholas Moses, Jeffrey W. Kirtane, Ajay Parikh, Manish Green, Philip Finn, Matthew Garcia, Santiago Doing, Anthony Patel, Mitul Bahadorani, John Christopoulos, Georgios Karatasakis, Aris Thompson, Craig A. Banerjee, Subhash Brilakis, Emmanouil S. TI Contrast Utilization During Chronic Total Occlusion Percutaneous Coronary Intervention: Insights From a Contemporary Multicenter Registry SO JOURNAL OF INVASIVE CARDIOLOGY LA English DT Article DE percutaneous coronary intervention; chronic total occlusion; contrast volume; radiation; complications; air kerma; fluoroscopy ID IN-STENT RESTENOSIS; ACUTE-RENAL-FAILURE; INDUCED NEPHROPATHY; US REGISTRY; HYBRID APPROACH; PROCEDURAL OUTCOMES; SUCCESS; SCORE; VALIDATION; PREVENTION AB Background. Administration of a large amount of contrast volume during chronic total occlusion (CTO) percutaneous coronary intervention (PCI) may lead to contrast-induced nephropathy. Methods. We examined the association of clinical, angiographic and procedural variables with contrast volume administered during 1330 CTO-PCI procedures performed at 12 experienced United States centers. Results. Technical and procedural success was 90% and 88%, respectively, and mean contrast volume was 289 +/- 138 mL. Approximately 33% of patients received >320 mL of contrast (high contrast utilization group). On univariable analysis, male gender (P=.01), smoking (P=.01), prior coronary artery bypass graft surgery (P=.04), moderate or severe calcification (P=.01), moderate or severe tortuosity (P=.04), proximal cap ambiguity (P=.01), distal cap at a bifurcation (P<.001), side branch at the proximal cap (P<.001), blunt/no stump (P=.01), occlusion length (P<.001), higher J-CTO score (P=.02), use of antegrade dissection and reentry or retrograde approach (P<.001), ad hoc CTO-PCI (P=.04), dual arterial access (P<.001), and 8 Fr guide catheters (P<.001) were associated with higher contrast volume; conversely, diabetes mellitus (P=.01) and in-stent restenosis (P=.01) were associated with lower contrast volume. On multivariable analysis, moderate/severe calcification (P=.04), distal cap at a bifurcation (P<.001), ad hoc CTO-PCI (P<.001), dual arterial access (P=.01), 8 Fr guide catheters (P=.02), and use of antegrade dissection/reentry or the retrograde approach (P<.001) were independently associated with higher contrast use, whereas diabetes (P=.02), larger target vessel diameter (P=.03), and presence of "interventional" collaterals (P<.001) were associated with lower contrast utilization. Conclusions. Several baseline clinical, angiographic, and procedural characteristics are associated with higher contrast volume administration during CTO-PCI. C1 [Christakopoulos, Georgios E.; Christopoulos, Georgios; Karatasakis, Aris; Banerjee, Subhash; Brilakis, Emmanouil S.] VA North Texas Healthcare Syst, Dallas, TX USA. [Christakopoulos, Georgios E.; Christopoulos, Georgios; Karatasakis, Aris; Banerjee, Subhash; Brilakis, Emmanouil S.] UT Southwestern Med Ctr, Dallas, TX USA. [Karmpaliotis, Dimitri; Moses, Jeffrey W.; Kirtane, Ajay; Parikh, Manish; Green, Philip; Finn, Matthew] Columbia Univ, New York, NY USA. [Alaswad, Khaldoon] Henry Ford Hosp, Detroit, MI 48202 USA. [Yeh, Robert W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yeh, Robert W.] Harvard Med Sch, Boston, MA USA. [Jaffer, Farouc A.; Wyman, R. Michael] Torrance Mem Med Ctr, Torrance, CA USA. [Lombardi, William] Univ Washington, Seattle, WA 98195 USA. [Grantham, J. Aaron] Mid Amer Heart Inst, Kansas City, MO USA. [Kandzari, David A.; Lembo, Nicholas] Piedmt Heart Inst, Atlanta, GA USA. [Garcia, Santiago] Minneapolis VA Healthcare Syst, Minneapolis, MN USA. [Garcia, Santiago] Univ Minnesota, Minneapolis, MN USA. [Doing, Anthony] Med Ctr Rockies, Loveland, CO USA. [Patel, Mitul; Bahadorani, John] VA San Diego Healthcare Syst, San Diego, CA USA. [Patel, Mitul; Bahadorani, John] Univ Calif San Diego, San Diego, CA 92103 USA. [Thompson, Craig A.] Boston Sci, Natick, MA USA. RP Brilakis, ES (reprint author), Dallas VA Med Ctr 111A, 4500 South Lancaster Rd, Dallas, TX 75216 USA. EM esbrilakis@gmail.com FU National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR001105] FX Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001105. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 33 TC 1 Z9 1 U1 1 U2 1 PU H M P COMMUNICATIONS PI MALVERN PA 83 GENERAL WARREN BLVD, STE 100, MALVERN, PA 19355 USA SN 1042-3931 EI 1557-2501 J9 J INVASIVE CARDIOL JI J. Invasive Cardiol. PD JUL PY 2016 VL 28 IS 7 BP 288 EP 294 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EC9EO UT WOS:000388447300008 PM 27342206 ER PT J AU Lorsakul, A El Fakhri, G Worstell, W Ouyang, JS Rakvongthai, Y Laine, AF Li, QZ AF Lorsakul, Auranuch El Fakhri, Georges Worstell, William Ouyang, Jinsong Rakvongthai, Yothin Laine, Andrew F. Li, Quanzheng TI Numerical observer for atherosclerotic plaque classification in spectral computed tomography SO JOURNAL OF MEDICAL IMAGING LA English DT Article DE numerical observer; channelized Hotelling observer; spectral computed tomography; classification task; plaque imaging; image quality assessment ID DUAL-ENERGY CT; LESION DETECTION; IMAGE QUALITY; CAROTID ATHEROSCLEROSIS; DETECTION PERFORMANCE; GOLD NANOPARTICLES; HOTELLING-OBSERVER; DATA SETS; IN-VIVO; CORONARY AB Spectral computed tomography (SCT) generates better image quality than conventional computed tomography (CT). It has overcome several limitations for imaging atherosclerotic plaque. However, the literature evaluating the performance of SCT based on objective image assessment is very limited for the task of discriminating plaques. We developed a numerical-observer method and used it to assess performance on discrimination vulnerable-plaque features and compared the performance among multienergy CT (MECT), dual-energy CT (DECT), and conventional CT methods. Our numerical observer was designed to incorporate all spectral information and comprised two-processing stages. First, each energy-window domain was preprocessed by a set of localized channelized Hotelling observers (CHO). In this step, the spectral image in each energy bin was decorrelated using localized prewhitening and matched filtering with a set of Laguerre-Gaussian channel functions. Second, the series of the intermediate scores computed from all the CHOs were integrated by a Hotelling observer with an additional prewhitening and matched filter. The overall signal-to-noise ratio (SNR) and the area under the receiver operating characteristic curve (AUC) were obtained, yielding an overall discrimination performance metric. The performance of our new observer was evaluated for the particular binary classification task of differentiating between alternative plaque characterizations in carotid arteries. A clinically realistic model of signal variability was also included in our simulation of the discrimination tasks. The inclusion of signal variation is a key to applying the proposed observer method to spectral CT data. Hence, the task-based approaches based on the signal-known-exactly/background-known-exactly (SKE/BKE) framework and the clinical-relevant signal-known-statistically/background-known-exactly (SKS/BKE) framework were applied for analytical computation of figures of merit (FOM). Simulated data of a carotid-atherosclerosis patient were used to validate our methods. We used an extended cardiac-torso anthropomorphic digital phantom and three simulated plaque types (i.e., calcified plaque, fatty-mixed plaque, and iodine-mixed blood). The images were reconstructed using a standard filtered backprojection (FBP) algorithm for all the acquisition methods and were applied to perform two different discrimination tasks of: (1) calcified plaque versus fatty-mixed plaque and (2) calcified plaque versus iodine-mixed blood. MECT outperformed DECT and conventional CT systems for all cases of the SKE/BKE and SKS/BKE tasks (all p < 0.01). On average of signal variability, MECT yielded the SNR improvements over other acquisition methods in the range of 46.8% to 65.3% (all p < 0.01) for FBP-Ramp images and 53.2% to 67.7% (all p < 0.01) for FBP-Hanning images for both identification tasks. This proposed numerical observer combined with our signal variability framework is promising for assessing material characterization obtained through the additional energy-dependent attenuation information of SCT. These methods can be further extended to other clinical tasks such as kidney or urinary stone identification applications. (C) 2016 Society of Photo-Optical Instrumentation Engineers (SPIE) C1 [Lorsakul, Auranuch; El Fakhri, Georges; Ouyang, Jinsong; Rakvongthai, Yothin; Li, Quanzheng] Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Gordon Ctr Med Imaging, 55 Fruit St,White 427, Boston, MA 02114 USA. [Lorsakul, Auranuch; Laine, Andrew F.] Columbia Univ, Dept Biomed Engn, 1210 Amsterdam Ave, New York, NY 10027 USA. [El Fakhri, Georges; Ouyang, Jinsong; Li, Quanzheng] Harvard Med Sch, Dept Radiol, 25 Shattuck St, Boston, MA 02115 USA. [Worstell, William] PhotoDiagnost Syst Inc, 85 Swanson Rd, Boxboro, MA 01719 USA. [Rakvongthai, Yothin] Chulalongkorn Univ, Dept Radiol, Fac Med, 1873 Rama 4 Rd, Bangkok 10330, Thailand. RP Li, QZ (reprint author), Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Gordon Ctr Med Imaging, 55 Fruit St,White 427, Boston, MA 02114 USA.; Li, QZ (reprint author), Harvard Med Sch, Dept Radiol, 25 Shattuck St, Boston, MA 02115 USA. EM li.quanzheng@mgh.harvard.edu NR 66 TC 0 Z9 0 U1 0 U2 0 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 2329-4302 EI 2329-4310 J9 J MED IMAGING JI J. Med. Imaging PD JUL-SEP PY 2016 VL 3 IS 3 AR 035501 DI 10.1117/1.JMI.3.3.035501 PG 18 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA EC6FO UT WOS:000388232100013 ER PT J AU Shimada, SL Allison, JJ Rosen, AK Feng, H Houston, TK AF Shimada, Stephanie L. Allison, Jeroan J. Rosen, Amy K. Feng, Hua Houston, Thomas K. TI Sustained Use of Patient Portal Features and Improvements in Diabetes Physiological Measures SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE personal health records; diabetes mellitus; type 2; self care; HbA1c; cholesterol; LDL; blood pressure; veterans ID PERSONAL HEALTH RECORDS; SHARED MEDICAL-RECORD; CROSS-SECTIONAL ANALYSIS; ADHERENCE; SYSTEM; CARE; COMMUNICATION; MANAGEMENT AB Background: Personal health records (PHRs) have the potential to improve patient self-management for chronic conditions such as diabetes. However, evidence is mixed as to whether there is an association between PHR use and improved health outcomes. Objective: The aim of this study was to evaluate the association between sustained use of specific patient portal features (Web-based prescription refill and secure messaging-SM) and physiological measures important for the management of type 2 diabetes. Methods: Using a retrospective cohort design, including Veterans with diabetes registered for the My Health e Vet patient portal who had not yet used the Web-based refill or SM features and who had at least one physiological measure (HbA1c, low-density lipoprotein (LDL) cholesterol, blood pressure) in 2009-2010 (baseline) that was above guideline recommendations (N=111,686), we assessed portal use between 2010 and 2014. We calculated the odds of achieving control of each measure by 2013 to 2014 (follow-up) by years of using each portal feature, adjusting for demographic and clinical characteristics associated with portal use. Results: By 2013 to 2014, 34.13% (38,113/111,686) of the cohort was using Web-based refills, and 15.75% (17,592/111,686) of the cohort was using SM. Users were slightly younger (P<.001), less likely to be eligible for free care based on economic means (P<.001), and more likely to be women (P<.001). In models adjusting for both features, patients with uncontrolled HbA1c at baseline who used SM were significantly more likely than nonusers to achieve glycemic control by follow-up if they used SM for 2 years (odds ratio-OR=1.24, CI: 1.14-1.34) or 3 or more years (OR=1.28, CI: 1.12-1.45). However, there was no significant association between Web-based refill use and glycemic control. Those with uncontrolled blood pressure at baseline who used Web-based refills were significantly more likely than nonusers to achieve control at follow-up with 2 (OR=1.07, CI: 1.01-1.13) or 3 (OR=1.08, CI: 1.02-1.14) more years of Web-based refill use. Both features were significantly associated with improvements in LDL cholesterol levels at follow-up. Conclusions: Although rates of use of the refill function were higher within the population, sustained SM use had a greater impact on HbA1c. Evaluations of patient portals should consider that individual components may have differential effects on health improvements. C1 [Shimada, Stephanie L.; Feng, Hua; Houston, Thomas K.] Edith Nourse Rogers Mem Vet Hosp, Ctr Healthcare Org & Implementat Res, 200 Springs Rd,Bldg 70 152, Bedford, MA 01730 USA. [Shimada, Stephanie L.] Boston Univ, Sch Publ Hlth, Dept Hlth Law Policy & Management, Boston, MA USA. [Shimada, Stephanie L.; Allison, Jeroan J.; Feng, Hua; Houston, Thomas K.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Div Hlth Informat & Implementat Sci, Worcester, MA USA. [Rosen, Amy K.] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA USA. [Rosen, Amy K.] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA. RP Shimada, SL (reprint author), Edith Nourse Rogers Mem Vet Hosp, Ctr Healthcare Org & Implementat Res, 200 Springs Rd,Bldg 70 152, Bedford, MA 01730 USA. EM Stephanie.Shimada@va.gov OI Shimada, Stephanie/0000-0002-6517-5122 FU Department of Veterans Affairs Health Services Research and Development Service [CDA 10-210]; VA eHealth QUERI [EHQ 10-190] FX Dr. Shimada was supported by a Career Development Award (CDA 10-210) from the Department of Veterans Affairs Health Services Research and Development Service and the VA eHealth QUERI (EHQ 10-190). The contents do not represent the views of the US Department of Veterans Affairs or the US Government. NR 35 TC 0 Z9 0 U1 2 U2 2 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 JUL PY 2016 VL 18 IS 7 AR e179 DI 10.2196/jmir.5663 PG 13 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA EC9WS UT WOS:000388495600017 PM 27369696 ER PT J AU Cauley, RP Liao, EC AF Cauley, Ryan P. Liao, Eric C. TI Deepithelialization and Extended Dermal Apposition: A Technique for Closure of High-risk Incisions in Breast Reconstruction SO PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN LA English DT Editorial Material C1 [Cauley, Ryan P.; Liao, Eric C.] Harvard Med Sch, Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA USA. RP Liao, EC (reprint author), Harvard Med Sch, Massachusetts Gen Hosp, Surg & Genet, 15 Parkman St, Boston, MA 02114 USA. EM cliao@partners.org NR 5 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2169-7574 J9 PRS-GLOB OPEN JI PRS-GLOB. OPEN PD JUL PY 2016 VL 4 IS 7 AR e802 DI 10.1097/GOX.0000000000000791 PG 2 WC Surgery SC Surgery GA EC7ZN UT WOS:000388359800014 PM 27536481 ER PT J AU Kortlever, JTP Janssen, SJ Molleman, J Hageman, MGJS Ring, D AF Kortlever, Joost T. P. Janssen, Stein J. Molleman, Jeroen Hageman, Michiel G. J. S. Ring, David TI Discrete Pathophysiology is Uncommon in Patients with Nonspecific Arm Pain SO ARCHIVES OF BONE AND JOINT SURGERY-ABJS LA English DT Article DE Arm; Discrete; Nonspecific; Pain; Pathophysiology ID EXTREMITY MUSCULOSKELETAL DISORDERS; UPPER-LIMB DISORDERS; PSYCHOSOCIAL FACTORS; GENERAL-POPULATION; CONTROLLED-TRIAL; FOREARM PAIN; PRIMARY-CARE; RISK-FACTORS; FOLLOW-UP; PREVALENCE AB Background: Nonspecific symptoms are common in all areas of medicine. Patients and caregivers can be frustrated when an illness cannot be reduced to a discrete pathophysiological process that corresponds with the symptoms. We therefore asked the following questions: 1) Which demographic factors and psychological comorbidities are associated with change from an initial diagnosis of nonspecific arm pain to eventual identification of discrete pathophysiology that corresponds with symptoms? 2) What is the percentage of patients eventually diagnosed with discrete pathophysiology, what are those pathologies, and do they account for the symptoms? Methods: We evaluated 634 patients with an isolated diagnosis of nonspecific upper extremity pain to see if discrete pathophysiology was diagnosed on subsequent visits to the same hand surgeon, a different hand surgeon, or any physician within our health system for the same pain. Results: There were too few patients with discrete pathophysiology at follow-up to address the primary study question. Definite discrete pathophysiology that corresponded with the symptoms was identified in subsequent evaluations by the index surgeon in one patient (0.16% of all patients) and cured with surgery (nodular fasciitis). Subsequent doctors identified possible discrete pathophysiology in one patient and speculative pathophysiology in four patients and the index surgeon identified possible discrete pathophysiology in four patients, but the five discrete diagnoses accounted for only a fraction of the symptoms. Conclusion: Nonspecific diagnoses are not harmful. Prospective randomized research is merited to determine if nonspecific, descriptive diagnoses are better for patients than specific diagnoses that imply pathophysiology in the absence of discrete verifiable pathophysiology. C1 [Kortlever, Joost T. P.; Janssen, Stein J.; Molleman, Jeroen; Hageman, Michiel G. J. S.; Ring, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ring, D (reprint author), Univ Texas Austin, Dell Med Sch, Austin, TX 78712 USA. EM Dring@partners.org NR 44 TC 0 Z9 0 U1 0 U2 0 PU MASHHAD UNIV MED SCIENCES PI MASHHAD PA VICE-CHANCELLOR FOR RES CTR OFF IJBMS, DANESHGAH ST, PO BOX 9138813944 - 445, MASHHAD, 00000, IRAN SN 2345-4644 EI 2345-461X J9 ARCH BONE JT SURG-AB JI Arch. Bone Jt. Surg.-ABJS PD JUL PY 2016 VL 4 IS 3 BP 213 EP 219 PG 7 WC Orthopedics SC Orthopedics GA EC4KU UT WOS:000388098900003 PM 27517064 ER PT J AU ter Meulen, DP Nota, SPFT Hageman, MGJS Ring, DC AF ter Meulen, Dirk P. Nota, Sjoerd P. F. T. Hageman, Michiel G. J. S. Ring, David C. TI Progression of Heterotopic Ossification around the Elbow after Trauma SO ARCHIVES OF BONE AND JOINT SURGERY-ABJS LA English DT Article DE Disease progression; Elbow; Heterotopic; Injuries; Ossification ID RADIATION-THERAPY; RISK-FACTORS AB Background: This study addresses the null hypothesis that there is no expansion of heterotopic ossification (HO) in the elbow beyond what can be seen early on. Methods: The area of HO was measured on lateral radiographs of 38 consecutive patients that had operative treatment of HO between 2000 and 2013. Measurements from radiographs obtained between 3 to 7 weeks were compared to measurements from radiographs made 3 months or more after injury. Results: There was no significant difference between the average area of HO on the first (median 2.8 square centimeters, Q1: 1.5, Q3: 5.1) and later radiographs (median of 2.8 square centimeters, Q1: 1.4, Q3: 5.0) (P = 0.99). Conclusion: According to our results the area of HO does not expand beyond what can be seen early in the disease process. C1 [ter Meulen, Dirk P.; Nota, Sjoerd P. F. T.; Hageman, Michiel G. J. S.; Ring, David C.] Massachusetts Gen Hosp, Hand Surg Serv, Boston, MA 02114 USA. RP Ring, DC (reprint author), 1400 Barbara Jordan Blvd 1-114, Austin, TX 78723 USA. EM david.ring@austin.utexas.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU MASHHAD UNIV MED SCIENCES PI MASHHAD PA VICE-CHANCELLOR FOR RES CTR OFF IJBMS, DANESHGAH ST, PO BOX 9138813944 - 445, MASHHAD, 00000, IRAN SN 2345-4644 EI 2345-461X J9 ARCH BONE JT SURG-AB JI Arch. Bone Jt. Surg.-ABJS PD JUL PY 2016 VL 4 IS 3 BP 228 EP 230 PG 3 WC Orthopedics SC Orthopedics GA EC4KU UT WOS:000388098900006 PM 27517067 ER PT J AU Hamilton, HK Lilly, E Arndt, KA Dover, JS AF Hamilton, Heather K. Lilly, Evelyn Arndt, Kenneth A. Dover, Jeffrey S. TI No Difference in Psychotropic Medication Use in Cosmetic and General Dermatology Patients SO JOURNAL OF DRUGS IN DERMATOLOGY LA English DT Article ID PREVALENCE; DISORDERS; SURGERY AB Background: Patients presenting for appearance-related concerns are often perceived as being more difficult (ie, more needy, more difficult to satisfy) than patients presenting for medical dermatologic problems. While the reasons for this perception are many, some hypothesize that this may be related to a higher rate of anxiety, depression, or body image issues among these patients. Objective: To determine the prevalence of psychotropic medication use in cosmetic dermatology patients compared to the prevalence of such medication use in general dermatology patients. Methods & Materials: The study was a retrospective chart review of female patients, 18 or older, new to a private practice. Exclusion criteria included dermatologic disorders with known psychosocial comorbidity. Psychotropic medication use was recorded. Results:The percentage of subjects in the medical group (n=156) who reported using psychotropic medications was 22.2% compared to 26.8% in the cosmetic group (n=154; P=0.09). Conclusion: The prevalence of psychotropic medication use among all dermatology patients in our practice was relatively high, but there was no statistically significant difference in the rate of psychotropic medication use in cosmetic dermatology patients compared to general dermatology patients. C1 [Hamilton, Heather K.; Lilly, Evelyn; Arndt, Kenneth A.; Dover, Jeffrey S.] SkinCare Physicians, Chestnut Hill, MA 02467 USA. [Hamilton, Heather K.; Lilly, Evelyn; Arndt, Kenneth A.; Dover, Jeffrey S.] Yale Univ, Sch Med, 333 Cedar St, New Haven, CT 06520 USA. [Lilly, Evelyn] Harvard Med Sch, Boston, MA USA. [Lilly, Evelyn] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hamilton, HK (reprint author), SkinCare Physicians, Chestnut Hill, MA 02467 USA.; Hamilton, HK (reprint author), Yale Univ, Sch Med, 333 Cedar St, New Haven, CT 06520 USA. EM heatheraklein@yahoo.com NR 12 TC 0 Z9 0 U1 0 U2 0 PU JOURNAL OF DRUGS IN DERMATOLOGY PI NEW YORK PA 377 PARK AVE SOUTH, 6TH FLOOR, NEW YORK, NY 10016 USA SN 1545-9616 J9 J DRUGS DERMATOL JI J. Drugs Dermatol. PD JUL PY 2016 VL 15 IS 7 BP 858 EP 861 PG 4 WC Dermatology SC Dermatology GA EC2IQ UT WOS:000387935800007 PM 27391636 ER PT J AU Maree, AO Margey, RJ Selzer, F Bajrangee, A Jneid, H Marroquin, OC Mulukutla, SR Laskey, WK Jacobs, AK AF Maree, Andrew O. Margey, Ronan J. Selzer, Faith Bajrangee, Amrit Jneid, Hani Marroquin, Oscar C. Mulukutla, Suresh R. Laskey, Warren K. Jacobs, Alice K. TI Renal insufficiency, bleeding and prescription of dischargemedication in patients undergoing percutaneous coronary intervention in the National Heart, Lung, and Blood Institute (NHLBI) Dynamic Registry SO CARDIOVASCULAR REVASCULARIZATION MEDICINE LA English DT Article DE Renal insufficiency; Percutaneous coronary intervention; Cardiovascular medication; Antiplatelet ID DRUG-ELUTING STENTS; CHRONIC KIDNEY-DISEASE; ST-SEGMENT ELEVATION; GLOBAL REGISTRY; OUTCOMES; EVENTS; ERA; MORTALITY; GRACE AB Aims: To establish the relationship between renal insufficiency, bleeding and prescription of cardiovascular medication. Methods and results: This was a prospective, multi-center, cohort study of consecutive patients undergoing PCI during three NHLBI Dynamic Registry recruitment waves. Major and minor bleeding, access site bleeding and rates of prescription of cardiovascular medication at discharge were determined based on estimated glomerular filtration rate (eGFR). Renal insufficiency was an independent predictor of major adverse cardiovascular events (MACE). Bleeding events and access site bleeding requiring transfusion were significantly associated with degrees of renal insufficiency (p < 0.001). There was an incremental decline in prescription of cardiovascular medication at discharge proportionate to the degree of renal impairment (aspirin, thienopyridine, statin, coumadin (overall p < 0.001), beta blocker (overall p = 0.003), ACE inhibitor (overall p = 0.02). Bleeders were less likely to be discharged on a thienopyridine (95.4% versus 89.9% for bleeding, p < 0.001 and 95.3% versus 87.9% for access site bleeding, p= 0.005), but not aspirin (96.3% versus 96.2%, p= 0.97 and 96.3% versus 93.6%, p= 0.29 respectively). Failure to prescribe anti-platelet therapy at discharge was strongly associated with increased MACE at one year. Conclusions: Renal insufficiency is associated with bleeding in patients undergoing PCI. Patients with renal insufficiency are less likely to receive recommended discharge pharmacotherapy. (C) 2016 Elsevier Inc. All rights reserved. C1 [Maree, Andrew O.; Jacobs, Alice K.] Boston Med Ctr, Div Cardiol, Boston, MA USA. [Maree, Andrew O.; Jacobs, Alice K.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Margey, Ronan J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Margey, Ronan J.] Harvard Med Sch, Boston, MA USA. [Selzer, Faith] Univ Pittsburgh, Div Cardiol, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Maree, Andrew O.; Bajrangee, Amrit] St James Hosp, Div Cardiol, Dublin, Ireland. [Maree, Andrew O.; Bajrangee, Amrit] Trinity Coll Dublin, Dublin, Ireland. [Jneid, Hani] Michael E DeBakey VA Med Ctr, Div Cardiol, Houston, TX USA. [Jneid, Hani] Baylor Coll Med, Houston, TX 77030 USA. [Marroquin, Oscar C.; Mulukutla, Suresh R.] Univ Pittsburgh, Med Ctr, Div Cardiol, Pittsburgh, PA 15260 USA. [Laskey, Warren K.] Univ New Mexico, Sch Med, Div Cardiol, Albuquerque, NM 87131 USA. RP Maree, AO (reprint author), St James Hosp, CREST Directorate, Div Cardiol, Dublin 8, Ireland. EM andrew.maree@gmail.com NR 14 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1553-8389 EI 1878-0938 J9 CARDIOVASC REVASCULA JI Cardiovasc. Revascularization Med. PD JUL-AUG PY 2016 VL 17 IS 5 BP 302 EP 307 DI 10.1016/j.carrev.2016.03.002 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA9KS UT WOS:000386963300003 PM 27053436 ER PT J AU Dallalzadeh, LO Go, AS Chang, YC Borowsky, LH Fang, MC Singer, DE AF Dallalzadeh, Liane O. Go, Alan S. Chang, Yuchiao Borowsky, Leila H. Fang, Margaret C. Singer, Daniel E. TI Stability of High-Quality Warfarin Anticoagulation in a Community-Based Atrial Fibrillation Cohort: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE anticoagulants; arrhythmia; embolism; prevention; risk factors ID NORMALIZED RATIO CONTROL; STABLE INR CONTROL; STROKE PREVENTION; ORAL ANTICOAGULANTS; RANDOMIZED-TRIALS; THERAPY; OUTCOMES; DABIGATRAN; EDOXABAN; EFFICACY AB Background-Warfarin reduces ischemic stroke risk in atrial fibrillation (AF) but increases bleeding risk. Novel anticoagulants challenge warfarin as stroke-preventive therapy for AF. They are available at fixed doses but are more costly. Warfarin anticoagulation at a time in therapeutic range (TTR) >= 70% is similarly as effective and safe as novel anticoagulants. It is unclear whether AF patients with TTR >= 70% will remain stably anticoagulated and avoid the need to switch to a novel anticoagulant. We assessed stability of warfarin anticoagulation in AF patients with an initial TTR >= 70%. Methods and Results-Within the community-based Anticoagulation and Risk Factors in AF (ATRIA) cohort followed from 1996 to 2003, we identified 2841 new warfarin users who continued warfarin over 9 months. We excluded months 1 to 3 to achieve a stable dose. For the 987 patients with TTR >= 70% in an initial 6-month period (TTR1; months 4-9), we described the distribution of TTR2 (months 10-15) and assessed multivariable correlates of persistent TTR >= 70%. Of patients with TTR1 >= 70%, 57% persisted with TTR2 >= 70% and 16% deteriorated to TTR2 <50%. Only initial TTR1 >= 90% (adjusted odds ratio 1.47, 95% CI 1.07-2.01) independently predicted TTR2 >= 70%. Heart failure was moderately associated with marked deterioration (TTR2 <50%); adjusted odds ratio 1.45, 95% CI 1.00-2.10. Conclusions-Nearly 60% of AF patients with high-quality TTR1 on warfarin maintained TTR >= 70% over the next 6 months. A minority deteriorated to very poor TTR. Patient features did not strongly predict TTR in the second 6-month period. Our analyses support watchful waiting for AF patients with initial high-quality warfarin anticoagulation before considering alternative anticoagulants. C1 [Dallalzadeh, Liane O.; Chang, Yuchiao; Singer, Daniel E.] Harvard Med Sch, Boston, MA USA. [Go, Alan S.] Kaiser Permanente Northern Calif, Div Res, Oakland, CA USA. [Go, Alan S.] Univ Calif San Francisco, Dept Med Epidemiol & Biostat, San Francisco, CA 94143 USA. [Fang, Margaret C.] Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94143 USA. [Go, Alan S.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Chang, Yuchiao; Borowsky, Leila H.; Singer, Daniel E.] Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. RP Singer, DE (reprint author), Massachusetts Gen Hosp, Div Gen Internal Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM desinger@mgh.harvard.edu FU National Institute on Aging [R01 AG15478]; National Heart, Lung, and Blood Institute [RC2HL101589, U19 HL091179]; Eliot B. and Edith C. Shoolman Fund of the Massachusetts General Hospital (Boston, MA) FX This study was supported by the National Institute on Aging (R01 AG15478), the National Heart, Lung, and Blood Institute (RC2HL101589 and U19 HL091179) and the Eliot B. and Edith C. Shoolman Fund of the Massachusetts General Hospital (Boston, MA). The funding sources had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; or in preparation, review or approval of the manuscript. NR 37 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e003482 DI 10.1161/JAHA.116.003482 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800036 ER PT J AU Eisen, A Ruff, CT Braunwald, E Nordio, F Corbalan, R Dalby, A Dorobantu, M Mercuri, M Lanz, H Rutman, H Wiviott, SD Antman, EM Giugliano, RP AF Eisen, Alon Ruff, Christian T. Braunwald, Eugene Nordio, Francesco Corbalan, Ramon Dalby, Anthony Dorobantu, Maria Mercuri, Michele Lanz, Hans Rutman, Howard Wiviott, Stephen D. Antman, Elliott M. Giugliano, Robert P. TI Sudden Cardiac Death in Patients With Atrial Fibrillation: Insights From the ENGAGE AF-TIMI 48 Trial SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE atrial fibrillation; sudden cardiac death ID RISK STRATIFICATION; PREDICTING STROKE; COMPETING-RISK; DIGOXIN USE; EPIDEMIOLOGY; WARFARIN; ASSOCIATION; VALIDATION; EDOXABAN; OUTCOMES AB Background-Recent findings suggest that atrial fibrillation is associated with sudden cardiac death (SCD). We examined the incidence, characteristics, and factors associated with SCD in patients with atrial fibrillation. Methods and Results-SCD was defined as witnessed death <= 60 minutes from the onset of new symptoms or unwitnessed death 1 to 24 hours after being observed alive, without another known cause of death. Predictors of SCD were examined using multivariate competing risks models. Over 2.8 years (median), 2349 patients died (40.5 per 1000 patient-years), of which 1668 (71%) were cardiovascular deaths. SCD was the most common cause of cardiovascular death (n=749; median age 73 years; 70.6% male). Most SCD events occurred out of hospital (92.8%) and without prior symptoms (66.0%). Predictors of SCD included low ejection fraction, heart failure, and prior myocardial infarction (P<0.001 for each). Additional significant baseline predictors of SCD, but not of other causes of death, included male sex, electrocardiographic left ventricular hypertrophy, higher heart rate, nonuse of beta blockers, and use of digitalis. The latter was associated with SCD in patients with or without heart failure (adjusted hazard ratio 1.55 [95% CI 1.29-1.86] and 1.56 [95% CI 1.14-2.11], respectively; P-interaction=0.73). The rate of SCD was numerically but not statistically lower with edoxaban (1.20% per year with lower dose edoxaban; 1.28% per year with higher dose edoxaban) compared with warfarin (1.40% per year). Conclusion-SCD is the most common cause of cardiovascular death in patients with atrial fibrillation and has several distinct predictors, some of which are modifiable. These findings may be considered in planning research and treatment strategies for patients with atrial fibrillation. C1 [Eisen, Alon; Ruff, Christian T.; Braunwald, Eugene; Nordio, Francesco; Wiviott, Stephen D.; Antman, Elliott M.; Giugliano, Robert P.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc Med, Boston, MA USA. [Eisen, Alon; Ruff, Christian T.; Braunwald, Eugene; Nordio, Francesco; Wiviott, Stephen D.; Antman, Elliott M.; Giugliano, Robert P.] Harvard Med Sch, Dept Med, Boston, MA USA. [Corbalan, Ramon] Hosp Clin Pontificia Univ Catolica Chile, Santiago, Chile. [Dalby, Anthony] Milpark Hosp, Johannesburg, South Africa. [Dorobantu, Maria] Carol Davila Univ Med & Pharm, Emergency Clin Hosp, Bucharest, Romania. [Mercuri, Michele; Lanz, Hans; Rutman, Howard] Daiichi Sankyo, Parsippany, NJ USA. RP Giugliano, RP (reprint author), TIMI Study Grp, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. EM rgiugliano@partners.org FU AstraZeneca; Eisai; Intarcia; Johnson Johnson; Bristol Myers Squibb; Merck amp; Co.; Daiichi Sankyo; Glaxo Smith Kline; Sanofi Aventis; Duke University; Novartis; Amgen Daiichi Sankyo; Merck; Eli Lilly and Company; Boehringer Ingelheim; Merck Co; Medicines Co.; Medscape; Bayer; Menarini International; Sanofi; Boehringer Ingelheim Pharmaceuticals, Inc; Sanofi-Aventis; Daiichi Sankyo Inc.; Daiichi Sankyo.; AngelMed; Janssen Pharmaceuticals; Xoma; ICON Clinical Research; Boston Clinical Research Institute; American College of Cardiology; Amgen; Boehringer-Ingelheim; Bristol-Myers Squibb Company; CVS Caremark; GlaxoSmithKline; Lexicon; Pfizer; Portola; St Jude Medical FX Christian Ruff discloses consultant fees/honoraria: Boehringer Ingelheim, Daiichi Sankyo; research/research grants: AstraZeneca, Eisai, Intarcia. Eugene Braunwald discloses consultant fees/honoraria: Merck & Co (no compensation), The Medicines Co., Medscape, Bayer, Daiichi Sankyo, Menarini International, Sanofi, Novartis (uncompensated); research/research grants: AstraZeneca, Johnson & Johnson, Bristol Myers Squibb, Merck & amp; Co., Daiichi Sankyo, Glaxo Smith Kline, Sanofi Aventis, Duke University and Novartis. Anthony Dalby discloses consultant fees/honoraria: Boehringer Ingelheim Pharmaceuticals, Inc, Sanofi-Aventis; speakers bureau: Bayer Healthcare Pharmaceuticals. Michele Mercuri discloses salary: Daiichi Sankyo Inc. Hans Joachim Lanz discloses salary: Daiichi Sankyo Inc. Howard Rutman discloses salary: Daiichi Sankyo. Stephen Wiviott discloses consultant fees: AstraZeneca, Bristol-Myers Squibb, Eisai, Arena Pharmaceuticals, Eli Lilly, Daiichi Sankyo, Aegerion, AngelMed, Janssen Pharmaceuticals, Xoma, ICON Clinical Research, and Boston Clinical Research Institute and grant support through his institution from AstraZeneca, Bristol-Myers Squibb, Eisai, Arena Pharmaceuticals, Merck, Eli Lilly, Daiichi Sankyo, and Sanofi. Elliott Antman discloses research/research grants: AstraZeneca, Daiichi Sankyo, Eli Lilly and Company. Robert Giugliano discloses consultant fees/honoraria: American College of Cardiology, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb Company, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Lexicon, Merck, Pfizer, Portola, St Jude Medical; research/research grants: Amgen Daiichi Sankyo and Merck to his institution. The remaining authors have no disclosures to report. NR 26 TC 1 Z9 1 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e003735 DI 10.1161/JAHA.116.003735 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800059 ER PT J AU Guo, FJ Garvey, WT AF Guo, Fangjian Garvey, W. Timothy TI Trends in Cardiovascular Health Metrics in Obese Adults: National Health and Nutrition Examination Survey (NHANES), 1988-2014 SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE blood pressure; glucose; lipids; obesity; risk factor ID BODY-MASS INDEX; WEIGHT-LOSS THERAPY; METABOLIC SYNDROME; INSULIN-RESISTANCE; UNITED-STATES; US ADULTS; MYOCARDIAL-INFARCTION; DISEASE RISK; PREVALENCE; OVERWEIGHT AB Background-No study has quantified trends in the prevalence of cardiovascular disease risk factors and cardiovascular health metrics among obese people in the United States in recent years. Methods and Results-We examined the secular changes in cardiovascular health metrics and key cardiovascular disease risk factors among obese adults (aged >= 20 years) in the United States. We included 18 626 obese adults (body mass index >= 30) from the National Health and Nutrition Examination Survey (NHANES) III and NHANES 1999-2014. Among those obese adults, there were decreases in mean systolic blood pressure, diastolic blood pressure, and total cholesterol levels and increases in mean high-density lipoprotein cholesterol levels and mean hemoglobin A1c levels. Prevalence of blood pressure health and lipid health remained stable during the period 1988-2014, whereas prevalence of blood glucose health decreased significantly during this period. Prevalence of freedom from cardiovascular disease risk factors remained stable at approximate to 15% among the adult obese population during the period 1988-2014, whereas prevalence of presence of all 3 risk factors increased from 16.4% to 22.4% during this period, commensurate with a decline in those with 1 to 2 risk factors (from 69.6% to 62.4%). Conclusions-During the past 3 decades, blood pressure health and blood lipid health remained stable or improved, whereas blood glucose health deteriorated among adult obese population. This resulted in an overall decrease in cardiovascular health status among obese adults and greater risk of type 2 diabetes mellitus. The data argue for interventions targeted to those obese persons who are metabolically unhealthy to stem rising rates of diabetes mellitus. C1 [Guo, Fangjian] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Guo, Fangjian] Univ Texas Med Branch, Ctr Interdisciplinary Res Womens Hlth, Galveston, TX 77555 USA. [Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Garvey, W. Timothy] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Guo, FJ (reprint author), Univ Texas Med Branch, Ctr Interdisciplinary Res Womens Hlth, Dept Obstet & Gynecol, 301 Univ Blvd, Galveston, TX 77555 USA. EM guofangjian@gmail.com; garveyt@uab.edu OI Guo, Fangjian/0000-0003-3729-2724 FU Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) at the National Institutes of Health (NIH) [T32HD055163]; Merit Review program of the Department of Veterans Affairs, National Institutes of Health [DK-038765, DK-083562]; UAB Diabetes Research Center [P60-DK079626]; National Center for Health Statistics Centers for Disease Control and Prevention FX Dr Guo is currently a postdoctoral fellow supported by an institutional training grant (National Research Service Award T32HD055163) from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) at the National Institutes of Health (NIH). This study is supported by the Merit Review program of the Department of Veterans Affairs, National Institutes of Health (DK-038765 and DK-083562), and the UAB Diabetes Research Center (P60-DK079626). Role of the Sponsors: All data from NHANES used in this study were collected by the National Center for Health Statistics Centers for Disease Control and Prevention. NR 47 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e003619 DI 10.1161/JAHA.116.003619 PG 20 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800050 ER PT J AU Kidd, SK Bonaca, MP Braunwald, E De Ferrari, GM Lewis, BS Merlini, PA Murphy, SA Scirica, BM White, HD Morrow, DA AF Kidd, Stephen K. Bonaca, Marc P. Braunwald, Eugene De Ferrari, Gaetano M. Lewis, Basil S. Merlini, Piera A. Murphy, Sabina A. Scirica, Benjamin M. White, Harvey D. Morrow, David A. TI Universal Classification System Type of Incident Myocardial Infarction in Patients With Stable Atherosclerosis: Observations From Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE atherosclerosis; cardiovascular disease; myocardial infarction; platelet inhibitor ID TRITON-TIMI 38; CARDIOVASCULAR DEATH; AMERICAN-COLLEGE; TRIAL; CORONARY; DEFINITION; VORAPAXAR; REDUCTION; PRASUGREL; RISK AB Background-Our dual aims were as follows: (1) to classify new or recurrent myocardial infarctions (MI) in patients with stable atherosclerosis using the Universal Definition of MI classification system; and (2) to characterize the effects of vorapaxar, a first-in-class platelet protease-activated receptor -1 antagonist, on new or recurrent MI. Methods and Results-We analyzed data from TRA 2 degrees P-TIMI 50, a multinational, randomized, double-blind, placebo-controlled trial of vorapaxar. This analysis included 20 770 patients with previous MI or peripheral arterial disease without a history of transient ischemic attack or stroke. Each new or recurrent MI after randomization that met the trial end point definition was further categorized according to the European Society of Cardiology, American College of Cardiology, American Heart Association, World Heart Federation Universal Definition classification of type and size. Of 1095 incident MIs, 77% were spontaneous (Type 1), with a smaller number (9.8%) of secondary MIs (Type 2). Vorapaxar reduced Type 1 MI (hazard ratio [HR] 0.84, CI 0.73-0.98, P=0.024), with a similar pattern for Type 2 MI (HR 0.74, CI 0.49-1.10, P=0.13). Notably, vorapaxar showed a consistent pattern of reduction across size of MIs, including MIs in the highest Universal MI size class (>= 10x upper reference limit, HR 0.83, CI 0.70-0.98, P=0.025). As such, there was a significant reduction in larger, spontaneous MIs (Type 1, >= 10x upper reference limit, HR 0.81, CI 0.67-0.99, P=0.036), and a consistent pattern with respect to fatal MI (HR 0.66, CI 0.39-1.11, P=0.12). Conclusions-Among stable patients with established atherosclerosis, the most common type of incident MI is spontaneous MI, and the reduction in MI with vorapaxar was consistent across MIs of varying type and size, including spontaneous infarctions >= 10x upper reference limit. C1 [Bonaca, Marc P.; Braunwald, Eugene; Murphy, Sabina A.; Scirica, Benjamin M.; Morrow, David A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, TIMI Study Grp,Cardiovasc Div, Boston, MA USA. [Kidd, Stephen K.; Bonaca, Marc P.; Braunwald, Eugene; Scirica, Benjamin M.; Morrow, David A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. [De Ferrari, Gaetano M.] Univ Pavia, Dept Mol Med, I-27100 Pavia, Italy. [De Ferrari, Gaetano M.] Fdn IRCCS Policlin San Matteo, Dept Cardiol, Pavia, Italy. [Lewis, Basil S.] Technion, Lady Davis Carmel Med Ctr, Haifa, Israel. [Lewis, Basil S.] Technion, Ruth & Bruce Rappaport Sch Med, Haifa, Israel. [Merlini, Piera A.] Azienda Osped Niguarda Ca Granda, Div Cardiol 4, Milan, Italy. [White, Harvey D.] Auckland City Hosp, Green Lane Cardiovasc Serv, West Auckland, New Zealand. RP Morrow, DA (reprint author), Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. FU Merck and Co. FX The TRA 2 degrees P-TIMI 50 trial was funded by Merck and Co. NR 16 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e003237 DI 10.1161/JAHA.116.003237 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800021 ER PT J AU Menard, MT Farber, A Assmann, SF Choudhry, NK Conte, MS Creager, MA Dake, MD Jaff, MR Kaufman, JA Powell, RJ Reid, DM Siami, FS Sopko, G White, CJ Rosenfield, K AF Menard, Matthew T. Farber, Alik Assmann, Susan F. Choudhry, Niteesh K. Conte, Michael S. Creager, Mark A. Dake, Michael D. Jaff, Michael R. Kaufman, John A. Powell, Richard J. Reid, Diane M. Siami, Flora Sandra Sopko, George White, Christopher J. Rosenfield, Kenneth TI Design and Rationale of the Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) Trial SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE atherosclerosis; cost-effectiveness; critical limb ischemia; endovascular; outcome; quality; stent treatment; surgery ID PERIPHERAL ARTERIAL-DISEASE; COST-EFFECTIVENESS ANALYSIS; LEG BASIL TRIAL; LOWER-EXTREMITY; THREATENING ISCHEMIA; AMPUTATION-FREE; SAPHENOUS-VEIN; TASK-FORCE; BYPASS; ANGIOPLASTY AB Background-Critical limb ischemia (CLI) is increasing in prevalence, and remains a significant source of mortality and limb loss. The decision to recommend surgical or endovascular revascularization for patients who are candidates for both varies significantly among providers and is driven more by individual preference than scientific evidence. Methods and Results-The Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) Trial is a prospective, randomized, multidisciplinary, controlled, superiority trial designed to compare treatment efficacy, functional outcomes, quality of life, and cost in patients undergoing best endovascular or best open surgical revascularization. Approximately 140 clinical sites in the United States and Canada will enroll 2100 patients with CLI who are candidates for both treatment options. A pragmatic trial design requires consensus on patient eligibility by at least 2 investigators, but leaves the choice of specific procedural strategy within the assigned revascularization approach to the individual treating investigator. Patients with suitable single-segment of saphenous vein available for potential bypass will be randomized within Cohort 1 (n=1620), while patients without will be randomized within Cohort 2 (n= 480). The primary efficacy end point of the trial is Major Adverse Limb Event-Free Survival. Key secondary end points include Re-intervention and Amputation-Free-Survival and Amputation Free-Survival. Conclusions-The BEST-CLI trial is the first randomized controlled trial comparing endovascular therapy to open surgical bypass in patients with CLI to be carried out in North America. This landmark comparative effectiveness trial aims to provide Level I data to clarify the appropriate role for both treatment strategies and help define an evidence-based standard of care for this challenging patient population. C1 [Menard, Matthew T.] Brigham & Womens Hosp, Div Vasc & Endovasc Surg, 75 Francis St, Boston, MA 02115 USA. [Choudhry, Niteesh K.] Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA. [Farber, Alik] Boston Med Ctr, Div Vasc & Endovasc Surg, Boston, MA USA. [Assmann, Susan F.; Siami, Flora Sandra] New England Res Inst, 9 Galen St, Watertown, MA 02172 USA. [Conte, Michael S.] Univ Calif San Francisco, Med Ctr, Div Vasc & Endovasc Surg, San Francisco, CA USA. [Creager, Mark A.] Dartmouth Hitchcock Med Ctr, Dartmouth Hitchcock Heart & Vasc Ctr, Lebanon, NH 03766 USA. [Powell, Richard J.] Dartmouth Hitchcock Med Ctr, Div Vasc Surg, Lebanon, NH 03766 USA. [Dake, Michael D.] Stanford Hosp & Clin, Dept Cardiothorac Surg, Stanford, CA USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Fireman Vasc Ctr, Boston, MA 02114 USA. [Rosenfield, Kenneth] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Kaufman, John A.] Dotter Intervent Inst OHSU, Portland, OR USA. [Reid, Diane M.; Sopko, George] NHLBI, Bldg 10, Bethesda, MD 20892 USA. [White, Christopher J.] Ochsner Med Ctr, Dept Cardiol, New Orleans, LA USA. RP Menard, MT (reprint author), Brigham & Womens Hosp, Dept Vasc Surg, 75 Francis St, Boston, MA 02115 USA. EM mmenard@partners.org FU National Heart, Lung, and Blood Institute [U01HL107407, U01HL107352, U01HL115662] FX This trial is funded by National Heart, Lung, and Blood Institute through grant numbers U01HL107407, U01HL107352, and U01HL115662. NR 42 TC 6 Z9 7 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e003219 DI 10.1161/JAHA.116.003219 PG 21 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800018 ER PT J AU van't Hof, FNG Ruigrok, YM Lee, CH Ripke, S Anderson, G de Andrade, M Baas, AF Blankensteijn, JD Bottinger, EP Bown, MJ Broderick, J Bijlenga, P Carrell, DS Crawford, DC Crosslin, DR Ebeling, C Eriksson, JG Fornage, M Foroud, T von und zu Fraunberg, M Friedrich, CM Gaal, EI Gottesman, O Guo, DC Harrison, SC Hernesniemi, J Hofman, A Inoue, I Jaaskelainen, JE Jones, GT Kiemeney, LALM Kivisaari, R Ko, N Koskinen, S Kubo, M Kullo, IJ Kuivaniemi, H Kurki, MI Laakso, A Lai, D Leal, SM Lehto, H LeMaire, SA Low, SK Malinowski, J McCarty, CA Milewicz, DM Mosley, TH Nakamura, Y Nakaoka, H Niemela, M Pacheco, J Peissig, PL Pera, J Rasmussen-Torvik, L Ritchie, MD Rivadeneira, F van Rij, AM Santos-Cortez, RLP Saratzis, A Slowik, A Takahashi, A Tromp, G Uitterlinden, AG Verma, SS Vermeulen, SH Wang, GT Han, B Rinkel, GJE de Bakker, PIW AF van't Hof, Femke N. G. Ruigrok, Ynte M. Lee, Cue Hyunkyu Ripke, Stephan Anderson, Graig de Andrade, Mariza Baas, Annette F. Blankensteijn, Jan D. Bottinger, Erwin P. Bown, Matthew J. Broderick, Joseph Bijlenga, Philippe Carrell, David S. Crawford, Dana C. Crosslin, David R. Ebeling, Christian Eriksson, Johan G. Fornage, Myriam Foroud, Tatiana von und zu Fraunberg, Mikael Friedrich, Christoph M. Gaal, Emilia I. Gottesman, Omri Guo, Dong-Chuan Harrison, Seamus C. Hernesniemi, Juha Hofman, Albert Inoue, Ituro Jaaskelainen, Juha E. Jones, Gregory T. Kiemeney, Lambertus A. L. M. Kivisaari, Riku Ko, Nerissa Koskinen, Seppo Kubo, Michiaki Kullo, Iftikhar J. Kuivaniemi, Helena Kurki, Mitja I. Laakso, Aki Lai, Dongbing Leal, Suzanne M. Lehto, Hanna LeMaire, Scott A. Low, Siew-Kee Malinowski, Jennifer McCarty, Catherine A. Milewicz, Dianna M. Mosley, Thomas H. Nakamura, Yusuke Nakaoka, Hirofumi Niemela, Mika Pacheco, Jennifer Peissig, Peggy L. Pera, Joanna Rasmussen-Torvik, Laura Ritchie, Marylyn D. Rivadeneira, Fernando van Rij, Andre M. Santos-Cortez, Regie Lyn P. Saratzis, Athanasios Slowik, Agnieszka Takahashi, Atsushi Tromp, Gerard Uitterlinden, Andre G. Verma, Shefali S. Vermeulen, Sita H. Wang, Gao T. Han, Buhm Rinkel, Gabriel J. E. de Bakker, Paul I. W. CA Aneurysm Consortium Vasc Res Consortium New Zealand TI Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE abdominal aortic aneurysm; genome wide association study; intracranial aneurysm; thoracic aortic aneurysm ID GENOME-WIDE ASSOCIATION; AORTIC-ANEURYSMS; SEQUENCE VARIANT; SUSCEPTIBILITY; LINKAGE; LOCI; PATHOGENESIS; METAANALYSIS; DISSECTIONS; IMPUTATION AB Background-Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. Methods and Results-We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single-nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]= 1.11; P=4.1 x 10(-5)) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1 x 10(-3)). Conclusions-Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication. C1 [van't Hof, Femke N. G.; Ruigrok, Ynte M.; Rinkel, Gabriel J. E.] Univ Med Ctr Utrecht, Utrecht Stroke Ctr, Dept Neurol & Neurosurg, Rudolf Magnus Inst Neurosci, Utrecht, Netherlands. [Baas, Annette F.] Univ Med Ctr Utrecht, Dept Med Genet, Ctr Mol Med, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Epidemiol, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Ripke, Stephan] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ripke, Stephan] Harvard Med Sch, Boston, MA USA. [Lee, Cue Hyunkyu; Han, Buhm] Univ Ulsan, Coll Med, Dept Convergence Med, Seoul, South Korea. [Lee, Cue Hyunkyu; Han, Buhm] Asan Med Ctr, Asan Inst Life Sci, Seoul, South Korea. [Ripke, Stephan] Charite, Dept Psychiat & Psychotherapy, Berlin, Germany. [Anderson, Graig] Univ Sydney, George Inst Int Hlth, Sydney, NSW 2006, Australia. [de Andrade, Mariza; Kullo, Iftikhar J.] Mayo Clin, Rochester, NY USA. [Blankensteijn, Jan D.] Vrije Univ Amsterdam Med Ctr, Dept Vasc Surg, Amsterdam, Netherlands. [Bottinger, Erwin P.; Gottesman, Omri] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Bown, Matthew J.; Saratzis, Athanasios] Univ Leicester, Dept Cardiovasc Sci, Leicester LE1 7RH, Leics, England. [Bown, Matthew J.; Saratzis, Athanasios] Univ Leicester, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester LE1 7RH, Leics, England. [Broderick, Joseph] Univ Cincinnati, Sch Med, Dept Neurol, Cincinnati, OH USA. [Bijlenga, Philippe] Hop Univ Geneve, Geneva, Switzerland. [Bijlenga, Philippe] Fac Med Geneva, Geneva, Switzerland. [Carrell, David S.] Grp Hlth Res Inst, Seattle, WA USA. [Crawford, Dana C.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Inst Computat Biol, Cleveland, OH 44106 USA. [Crawford, Dana C.; Malinowski, Jennifer] Vanderbilt Univ, Ctr Human Genet Res, 221 Kirkland Hall, Nashville, TN 37235 USA. [Crosslin, David R.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Ebeling, Christian] Fraunhofer Inst Algorithmen & Wissensch Rechnen, St Augustin, Germany. [Eriksson, Johan G.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Helsinki Univ Hosp, Helsinki, Finland. [Gaal, Emilia I.] FIMM, Helsinki, Finland. Univ Helsinki, FIN-00014 Helsinki, Finland. [von und zu Fraunberg, Mikael] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [von und zu Fraunberg, Mikael] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA. [Foroud, Tatiana; Lai, Dongbing] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [von und zu Fraunberg, Mikael; Jaaskelainen, Juha E.; Kurki, Mitja I.] Kuopio Univ Hosp, Neurosurg NeuroCtr, Kuopio, Finland. [Friedrich, Christoph M.] Univ Appl Sci & Arts, Dept Comp Sci, Dortmund, Germany. [Gaal, Emilia I.; Laakso, Aki] Dept Chron Dis Prevent, Publ Hlth Genom Unit, Helsinki, Finland. [Koskinen, Seppo] Natl Inst Hlth & Welf, Dept Hlth Funct Capac & Welf, Helsinki, Finland. [Gaal, Emilia I.; Hernesniemi, Juha; Kivisaari, Riku; Lehto, Hanna; Niemela, Mika] Univ Helsinki, Cent Hosp, Dept Neurosurg, Helsinki, Finland. [Harrison, Seamus C.] Univ Leicester, Dept Cardiovasc Sci, Leicester LE1 7RH, Leics, England. [Hofman, Albert; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Inoue, Ituro; Nakaoka, Hirofumi] Natl Inst Genet, Div Human Genet, Mishima, Shizuoka, Japan. [Jones, Gregory T.; van Rij, Andre M.] Univ Otago, Dept Surg, Dunedin, New Zealand. [Kiemeney, Lambertus A. L. M.; Vermeulen, Sita H.] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands. [LeMaire, Scott A.] Baylor Coll Med, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [LeMaire, Scott A.] Texas Heart Inst, Houston, TX 77025 USA. [Guo, Dong-Chuan; Milewicz, Dianna M.] Univ Texas Med Sch Houston, Dept Internal Med, Houston, TX USA. [Ko, Nerissa] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Kubo, Michiaki; Low, Siew-Kee; Takahashi, Atsushi] RIKEN, Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan. [Kuivaniemi, Helena; Tromp, Gerard] Geisinger Hlth Syst, Sigfried & Janet Weis Ctr Res, Danville, PA USA. [Kuivaniemi, Helena] Temple Univ, Dept Surg, Sch Med, Philadelphia, PA 19122 USA. [Kurki, Mitja I.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kurki, Mitja I.] Broad Inst, Med & Populat Genet Program, Boston, MA USA. [Leal, Suzanne M.; Santos-Cortez, Regie Lyn P.; Wang, Gao T.] Baylor Coll Med, Ctr Stat Genet, Houston, TX 77030 USA. [Malinowski, Jennifer] Yale Sch Med, Dept Surg, New Haven, CT USA. [McCarty, Catherine A.] Essentia Inst Rural Hlth, Div Res, Duluth, MN USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Nakamura, Yusuke] Univ Chicago, Dept Med, Sect Hematol & Oncol, Chicago, IL 60637 USA. [Pacheco, Jennifer] Northwestern Univ, Feinberg Sch Med, Ctr Genet Med, Chicago, IL 60611 USA. [Rasmussen-Torvik, Laura] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Peissig, Peggy L.] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA. [Pera, Joanna; Slowik, Agnieszka] Jagiellonian Univ, Dept Neurol, Krakow, Poland. [Ritchie, Marylyn D.; Verma, Shefali S.] Penn State Univ, Ctr Syst Genom, University Pk, PA 16802 USA. [Kuivaniemi, Helena; Tromp, Gerard] Univ Stellenbosch, Dept Biomed Sci, Tygerberg, South Africa. RP de Bakker, PIW (reprint author), Univ Med Ctr Utrecht, Dept Med Genet, Univ Weg 100, NL-3584 CG Utrecht, Netherlands.; de Bakker, PIW (reprint author), Univ Med Ctr Utrecht, Dept Epidemiol, Univ Weg 100, NL-3584 CG Utrecht, Netherlands. EM pdebakker@umcutrecht.nl RI Bown, Matthew/P-1957-2016; Bijlenga, Philippe/S-1049-2016; OI Bown, Matthew/0000-0002-6180-3611; Bijlenga, Philippe/0000-0002-3586-2757; Deloukas, Panos/0000-0001-9251-070X; Lindholt, Jes/0000-0001-9536-4488 FU Dutch Heart Foundation (NHS) [2008B004]; clinical fellowship grant of the Netherlands Organization for Scientific Research (NWO) [40-00703-98-13533]; Dr E. Dekker Program of the Netherlands Heart Foundation [2009T001]; HEFCE Clinical Senior Lecturer Fellowship; Familial Intracranial Aneurysm (FIA) [R01NS39512, R03NS083468]; Instrumentarium Science Foundation, Finland; Finnish Foundation for Cardiovascular Research; University of Eastern Finland; National Institutes of Health (NIH) [P50-HL083794]; Netherlands Organization of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO); Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; Municipality of Rotterdam; Ministry of Education, Culture, Sports, Sciences and Technology, Japan; National Health and Medical Research Council (NHMRC), Australia; Health Research Council of New Zealand [08-75, 14-155]; Jagiellonian University Medical College [K/ZDS/001456]; National Heart, Lung, and Blood Institute [HHSN268 201100005C, HHSN268201100006C, HHSN26820110000 7C, HHSN268201100008C, HHSN268201100009C, HHSN2 68201100010C, HHSN268201100011C, HHSN26820 110012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; NIH [P50-HL083794, HHSN268200625226C, R01-HL62594, UL1RR024148, K08-HL080085]; 6th framework program of the European Commission [FP6-IST-2004-027703]; Wellcome Trust [084695, 076113, 085475]; Pennsylvania Commonwealth Universal Research Enhancement Program; Geisinger Clinical Research Fund; American Heart Association; Ben Franklin Technology Development Fund of Pennsylvania; NHGRI; NIGMS [U01HG004438, U01HG004424, U01HG004610, U01HG006375, U01HG 004608, U01HG006389, U01HG04599, U01HG006379, U01HG004609, U01HG006388, U01HG04603, U01HG006378, U01HG006385, U01HG006382, U01HG006380]; Vanderbilt University Medical Center's BioVU; National Center for Research Resources at National Center for Advancing Translational Sciences [UL1 RR024975-01, 2 UL1 TR000445-06]; Doris Duke Charitable Trust; Vivian L. Smith Foundation; TexGen Foundation; Thoracic Surgery Foundation for Research and Education; NIH [CTSA] [UL1RR025758]; [UL1RR025005]; [R01-HL70825] FX van 't Hof is supported by a grant of the Dutch Heart Foundation (NHS; Project No. 2008B004). Ruigrok is supported by a clinical fellowship grant of the Netherlands Organization for Scientific Research (NWO; Project No. 40-00703-98-13533). Baas is supported by a grant from the Dr E. Dekker Program of the Netherlands Heart Foundation 2009T001). Bown is supported by a HEFCE Clinical Senior Lecturer Fellowship. Broderick is supported by a Familial Intracranial Aneurysm (FIA) grant (R01NS39512). Foroud is supported by an FIA grant (R03NS083468). Kubo is funded by the Instrumentarium Science Foundation, Finland, and by the Finnish Foundation for Cardiovascular Research, University of Eastern Finland. Saratzis is an NIHR Academic Clinical Lecturer. Milewicz is supported by grants from the National Institutes of Health (NIH; P50-HL083794).; The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, and RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS data sets are supported by the Netherlands Organization of Scientific Research NWO Investments (No. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO), Netherlands Consortium for Healthy Aging (NCHA; Project No. 050-060-810). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam.; The Japanese IA GWAS (named "Japan 2" in this study) was conducted as part of the Biobank Japan Project that was supported by the Ministry of Education, Culture, Sports, Sciences and Technology, Japan.; For the "USA+" IA GWAS, infrastructure was partly supported by Grant No. UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. This study was also supported by the National Health and Medical Research Council (NHMRC), Australia, and the Health Research Council of New Zealand. Additional funding was provided by a grant from Jagiellonian University Medical College K/ZDS/001456. The study also contains data from Atherosclerosis Risk in Communities, which is performed as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268 201100005C, HHSN268201100006C, HHSN26820110000 7C, HHSN268201100008C, HHSN268201100009C, HHSN2 68201100010C, HHSN268201100011C, and HHSN26820 110012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Neurocognitive data were collected by U01 HL096812, HL096814, HL096899, HL096902, and HL096917 with previous brain MRI examinations funded by R01-HL70825.; The @neurIST project is supported by the 6th framework program of the European Commission (www.aneurist.org) FP6-IST-2004-027703.; AAA GWAS data provided by the Aneurysm Consortium were funded by the Wellcome Trust (Award No. 084695) and makes use of data generated by the WTCCC. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the WTCCC project was provided by the Wellcome Trust under awards 076113 and 085475. Funding for the New Zealand project was provided by the Health Research Council of New Zealand (08-75, 14-155). The Geisinger project was funded, in part, by the Pennsylvania Commonwealth Universal Research Enhancement Program, the Geisinger Clinical Research Fund, the American Heart Association, and the Ben Franklin Technology Development Fund of Pennsylvania. The eMERGE Network is funded by the NHGRI, with additional funding from the NIGMS through the following grants: U01HG004438 to Johns Hopkins University; U01HG004424 to The Broad Institute; U01HG004438 to CIDR; U01HG004610 and U01HG006375 to Group Health Cooperative; U01HG 004608 to Marshfield Clinic; U01HG006389 to Essentia Institute of Rural Health; U01HG04599 and U01HG006379 to Mayo Clinic; U01HG004609 and U01HG006388 to Northwestern University; U01HG04603 and U01HG006378 to Vanderbilt University; U01HG006385 to the Coordinating Center; U01HG006382 to Geisinger Health System; and U01HG006380 to Icahn School of Medicine Mount Sinai. Vanderbilt's data set(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU, which is supported by institutional funding and by the National Center for Research Resources (Grant UL1 RR024975-01; which is now at the National Center for Advancing Translational Sciences: Grant 2 UL1 TR000445-06).; The project that created the data regarding the TAA cohort was supported by grants from the NIH (P50-HL083794 and R01-HL62594; UL1RR024148 and UL1RR025758 [CTSA]; K08-HL080085), as well as the Doris Duke Charitable Trust, the Vivian L. Smith Foundation, the TexGen Foundation, and the Thoracic Surgery Foundation for Research and Education. NR 46 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e002603 DI 10.1161/JAHA.115.002603 PG 19 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800009 ER PT J AU Wu, C Arora, P AF Wu, Connie Arora, Pankaj TI Noncoding Genome-Wide Association Studies Variant for Obesity: Inroads Into Mechanism An Overview From the AHA's Council on Functional Genomics and Translational Biology SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Editorial Material DE adipocyte; epigenetics; genome-wide association study; obesity ID ADULT OBESITY; CHILDHOOD C1 [Wu, Connie] Harvard Med Sch, Dept Med, Cardiovasc Res Ctr, Massachusetts Gen Hosp, Boston, MA USA. [Wu, Connie] Harvard Med Sch, Dept Anesthesia, Anesthesia Ctr Crit Care Res Crit Care & Pain Med, Massachusetts Gen Hosp, Boston, MA USA. [Arora, Pankaj] Univ Alabama Birmingham, Dept Med, Div Cardiol, 1808 7th Ave S,BDB 201, Birmingham, AL 35294 USA. RP Wu, C (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Anesthesia Ctr Crit Care Res, 55 Fruit St,GRB 444, Boston, MA 02114 USA.; Arora, P (reprint author), Univ Alabama Birmingham, Div Cardiol, 1808 7th Ave S,BDB 201, Birmingham, AL 35294 USA. EM parora@uabmc.edu NR 11 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD JUL PY 2016 VL 5 IS 7 AR e003060 DI 10.1161/JAHA.115.003060 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA EA6CT UT WOS:000386713800012 ER PT J AU Kacmarek, RM Vilar, J Blanch, L AF Kacmarek, Robert M. Vilar, Jesus Blanch, Lluis TI Cycle asynchrony: always a concern during pressure ventilation! SO MINERVA ANESTESIOLOGICA LA English DT Editorial Material ID MECHANICAL VENTILATION C1 [Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, 55 Fruit St, Boston, MA 01460 USA. [Kacmarek, Robert M.] Harvard Univ, Dept Anesthesiol, Boston, MA 02115 USA. [Vilar, Jesus; Blanch, Lluis] Inst Salud Carlos II, CIBER Enfermedades Resp, Madrid, Spain. [Vilar, Jesus] Hosp Univ Dr Negrin, Res Unit, Multidisciplinary Organ Dysfunct Evaluat Res Netw, Las Palmas Gran Canaria, Spain. [Blanch, Lluis] Univ Autonoma Barcelona, Crit Care Ctr, Corp Sanitaria Univ Parc Tauli, Inst Invest Innovacio Parc Tauli, Sabadell, Spain. RP Kacmarek, RM (reprint author), Massachusetts Gen Hosp, Dept Resp Care, 55 Fruit St, Boston, MA 01460 USA. EM rkacmarek@partners.org NR 10 TC 1 Z9 1 U1 0 U2 0 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0375-9393 EI 1827-1596 J9 MINERVA ANESTESIOL JI Minerva Anestesiol. PD JUL PY 2016 VL 82 IS 7 BP 728 EP 730 PG 3 WC Anesthesiology; Critical Care Medicine SC Anesthesiology; General & Internal Medicine GA EA8MK UT WOS:000386888700002 PM 26859156 ER PT J AU Elgin, C Nuhi, V Johnson, RH AF Elgin, Cristina Nuhi, Veldana Johnson, Ralph H. TI Comparison of decentralized versus centralized pharmacist management of patients with atrial fibrillation treated with direct oral anticoagulants (DOACs). SO PHARMACOTHERAPY LA English DT Meeting Abstract CT American-College-of-Clinical-Pharmacy (ACCP) Virtual Poster Symposium CY MAY 18-19, 2016 CL ELECTR NETWORK SP Amer Coll Clin Pharm C1 [Elgin, Cristina; Nuhi, Veldana; Johnson, Ralph H.] Ralph H Johnson VA Med Ctr, Dept Pharm, Charleston, SC 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 0277-0008 EI 1875-9114 J9 PHARMACOTHERAPY JI Pharmacotherapy PD JUL PY 2016 VL 36 IS 7 MA 5 BP E85 EP E85 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DW4EP UT WOS:000383595600008 ER PT J AU Gauthier, J Griffith, J AF Gauthier, Joshua Griffith, June TI Implementation and evaluation of an overdose education and naloxone distribution (OEND) program. SO PHARMACOTHERAPY LA English DT Meeting Abstract CT American-College-of-Clinical-Pharmacy (ACCP) Virtual Poster Symposium CY MAY 18-19, 2016 CL ELECTR NETWORK SP Amer Coll Clin Pharm C1 [Gauthier, Joshua] Tuscaloosa VA Med Ctr, Tuscaloosa, AL USA. [Griffith, June] Tuscaloosa VA Med Ctr, US Dept Vet Affairs, Tuscaloosa, AL USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-0008 EI 1875-9114 J9 PHARMACOTHERAPY JI Pharmacotherapy PD JUL PY 2016 VL 36 IS 7 MA 148 BP E126 EP E126 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DW4EP UT WOS:000383595600145 ER PT J AU Im, EP Griffith, J Hamilton, D AF Im, Eun Pyung Griffith, June Hamilton, Debora TI Opioid safety initiative: clinical pharmacy intervention. SO PHARMACOTHERAPY LA English DT Meeting Abstract CT American-College-of-Clinical-Pharmacy (ACCP) Virtual Poster Symposium CY MAY 18-19, 2016 CL ELECTR NETWORK SP Amer Coll Clin Pharm C1 [Im, Eun Pyung; Griffith, June; Hamilton, Debora] US Dept Vet Affairs, Tuscaloosa VA Med Ctr, Tuscaloosa, AL 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 0277-0008 EI 1875-9114 J9 PHARMACOTHERAPY JI Pharmacotherapy PD JUL PY 2016 VL 36 IS 7 MA 138 BP E123 EP E124 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DW4EP UT WOS:000383595600136 ER PT J AU Morgan, J Griffith, J AF Morgan, Joni Griffith, June TI Quality improvement project regarding posttraumatic stress disorder (PTSD) and benzodiazepines as part of the Psychotropic Drug Safety Initiative ( PDSI). SO PHARMACOTHERAPY LA English DT Meeting Abstract CT American-College-of-Clinical-Pharmacy (ACCP) Virtual Poster Symposium CY MAY 18-19, 2016 CL ELECTR NETWORK SP Amer Coll Clin Pharm C1 [Morgan, Joni; Griffith, June] Tuscaloosa VA Med Ctr, US Dept Vet Affairs, Tuscaloosa, AL 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 0277-0008 EI 1875-9114 J9 PHARMACOTHERAPY JI Pharmacotherapy PD JUL PY 2016 VL 36 IS 7 MA 147 BP E126 EP E126 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA DW4EP UT WOS:000383595600144 ER PT J AU Garza-Mayers, AC McClurkin, M Smith, GP AF Garza-Mayers, Anna Cristina McClurkin, Michael Smith, Gideon P. TI Review of treatment for discoid lupus erythematosus SO DERMATOLOGIC THERAPY LA English DT Review DE discoid; lupus; chronic cutaneous; therapeutics ID CUTANEOUS LUPUS; DOUBLE-BLIND; MYCOPHENOLATE-MOFETIL; CONTROLLED-TRIAL; EFFICACY; THERAPY; SMOKING; SAFETY; HYDROXYCHLOROQUINE; INFLAMMATION AB Discoid lupus erythematosus (DLE) is a chronic cutaneous disease characterized by inflammatory plaques that, in the absence of prompt diagnosis and treatment, may lead to disfiguring scarring and skin atrophy. However, there is limited evidence for which treatments are most effective. Currently, no medications have been approved specifically for the treatment of DLE. Many of the drugs described in the literature were developed for use in other immune disorders. This review will summarize current therapeutic options for DLE and their supporting evidence with discussion of prevention, topical measures, physical modalities, and systemic therapies, including newer potential therapies. C1 [Garza-Mayers, Anna Cristina; McClurkin, Michael; Smith, Gideon P.] Harvard Med Sch, Boston, MA USA. [Garza-Mayers, Anna Cristina; Smith, Gideon P.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Smith, GP (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. EM gpsmith@mgh.harvard.edu FU NIGMS NIH HHS [T32 GM007753] NR 50 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1396-0296 EI 1529-8019 J9 DERMATOL THER JI Dermatol. Ther. PD JUL-AUG PY 2016 VL 29 IS 4 BP 274 EP 283 DI 10.1111/dth.12358 PG 10 WC Dermatology SC Dermatology GA DZ8AW UT WOS:000386091700015 PM 27073142 ER PT J AU Effing, TW Vercoulen, JH Bourbeau, J Trappenburg, J Lenferink, A Cafarella, P Coultas, D Meek, P van der Valk, P Bischoff, EWMA Bucknall, C Dewan, NA Early, F Fan, V Frith, P Janssen, DJA Mitchell, K Morgan, M Nici, L Patel, I Walters, H Rice, KL Singh, S Zuwallack, R Benzo, R Goldstein, R Partridge, MR van der Palen, J AF Effing, Tanja W. Vercoulen, Jan H. Bourbeau, Jean Trappenburg, Jaap Lenferink, Anke Cafarella, Paul Coultas, David Meek, Paula van der Valk, Paul Bischoff, Erik W. M. A. Bucknall, Christine Dewan, Naresh A. Early, Frances Fan, Vincent Frith, Peter Janssen, Daisy J. A. Mitchell, Katy Morgan, Mike Nici, Linda Patel, Irem Walters, Haydn Rice, Kathryn L. Singh, Sally Zuwallack, Richard Benzo, Roberto Goldstein, Roger Partridge, Martyn R. van der Palen, Job TI Definition of a COPD self-management intervention: International Expert Group consensus SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; MOTIVATION AB There is an urgent need for consensus on what defines a chronic obstructive pulmonary disease (COPD) self-management intervention. We aimed to obtain consensus regarding the conceptual definition of a COPD self-management intervention by engaging an international panel of COPD self-management experts using Delphi technique features and an additional group meeting. In each consensus round the experts were asked to provide feedback on the proposed definition and to score their level of agreement (1=totally disagree; 5=totally agree). The information provided was used to modify the definition for the next consensus round. Thematic analysis was used for free text responses and descriptive statistics were used for agreement scores. In total, 28 experts participated. The consensus round response rate varied randomly over the five rounds (ranging from 48% (n=13) to 85% (n=23)), and mean definition agreement scores increased from 3.8 (round 1) to 4.8 (round 5) with an increasing percentage of experts allocating the highest score of 5 (round 1: 14% (n=3); round 5: 83% (n=19)). In this study we reached consensus regarding a conceptual definition of what should be a COPD self-management intervention, clarifying the requisites for such an intervention. Operationalisation of this conceptual definition in the near future will be an essential next step. C1 [Effing, Tanja W.; Cafarella, Paul; Frith, Peter] Southern Adelaide Local Hlth Network, Dept Resp Med, Adelaide, SA, Australia. [Effing, Tanja W.; Cafarella, Paul; Frith, Peter] Flinders Univ S Australia, Sch Med, Adelaide, SA 5001, Australia. [Vercoulen, Jan H.] Radboud Univ Nijmegen, Med Ctr, Dept Med Psychol, NL-6525 ED Nijmegen, Netherlands. [Vercoulen, Jan H.] Radboud Univ Nijmegen, Med Ctr, Dept Pulm Dis, NL-6525 ED Nijmegen, Netherlands. [Bourbeau, Jean] McGill Univ, McGill Univ Hlth Ctr, Res Inst, Resp Epidemiol & Clin Res Unit, Montreal, PQ, Canada. [Trappenburg, Jaap] Univ Med Ctr Utrecht, Dept Rehabil Nursing Sci & Sports, Utrecht, Netherlands. [Lenferink, Anke; van der Valk, Paul; van der Palen, Job] Med Spectrum Twente, Dept Pulm Med, Enschede, Netherlands. [Coultas, David] Oregon Hlth & Sci Univ, VA Portland Hlth Care Syst, Portland, OR 97201 USA. [Coultas, David] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Meek, Paula] Univ Colorado, Coll Nursing, Aurora, CO USA. [Bischoff, Erik W. M. A.] Radboud Univ Nijmegen, Med Ctr, Dept Primary & Community Care, Nijmegen, Netherlands. [Bucknall, Christine] Glasgow Royal Infirm, Dept Resp Med, Glasgow G4 0SF, Lanark, Scotland. [Dewan, Naresh A.] Creighton Univ, Div Pulm Crit Care & Sleep Med, Omaha, NE 68178 USA. [Dewan, Naresh A.] Omaha Vet Affairs Med Ctr, Omaha, NE USA. [Early, Frances] Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Ctr Self Management Support, Cambridge, England. [Fan, Vincent] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Fan, Vincent] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Janssen, Daisy J. A.] CIRO, Ctr Expertise Chron Organ Failure, Dept Res & Educ, Horn, Netherlands. [Mitchell, Katy; Singh, Sally] Univ Hosp Leicester, Ctr Exercise & Rehabil Sci, Leicester, Leics, England. [Morgan, Mike] Univ Hosp Leicester NHS Trust, Glenfield Hosp, Dept Resp Med, Leicester, Leics, England. [Nici, Linda] Providence Vet Adm Med Ctr, Dept Pulm & Crit Care, Providence, RI USA. [Patel, Irem] Kings Coll Hosp NHS Trust, Dept Resp Med, London, England. [Walters, Haydn] Univ Tasmania, Sch Med, CRE Chron Resp Dis, Hobart, Tas, Australia. [Rice, Kathryn L.] VA Med Ctr, Dept Med, Pulm Sect, Minneapolis, MN USA. [Rice, Kathryn L.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Zuwallack, Richard] St Francis Hosp & Med Ctr, Dept Pulm & Crit Care, Hartford, CT USA. [Benzo, Roberto] Mayo Clin, Mindful Breathing Lab, Rochester, MN USA. [Goldstein, Roger] Univ Toronto, West Pk Healthcare, Toronto, ON, Canada. [Partridge, Martyn R.] Imperial Coll, Natl Heart & Lung Inst, London, England. [van der Palen, Job] Univ Twente, Dept Res Methodol Measurement & Data Anal, POB 217, NL-7500 AE Enschede, Netherlands. RP Effing, TW (reprint author), Repatriat Gen Hosp, Dept Resp Med, Daws Rd, Daw Pk, SA 5041, Australia. EM tanja.effing@health.sa.gov.au NR 23 TC 5 Z9 5 U1 2 U2 2 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD JUL PY 2016 VL 48 IS 1 BP 46 EP 54 DI 10.1183/13993003.00025-2016 PG 9 WC Respiratory System SC Respiratory System GA DZ6FK UT WOS:000385956800011 PM 27076595 ER PT J AU Brizzi, K Deki, S Tshering, L Clark, SJ Nirola, DK Patenaude, BN McKenzie, ED McLane, HC Cash, SS Dorji, C Mateen, FJ AF Brizzi, Kate Deki, Sonam Tshering, Lhab Clark, Sarah J. Nirola, Damber K. Patenaude, Bryan N. McKenzie, Erica D. McLane, Hannah C. Cash, Sydney S. Dorji, Chencho Mateen, Farrah J. TI Knowledge, attitudes and practices regarding epilepsy in the Kingdom of Bhutan SO INTERNATIONAL HEALTH LA English DT Article DE Awareness; Bhutan; Epilepsy; Neurology; Social stigma; Traditional medicine ID STIGMA-SCALE; HEALTH; PERCEPTION; PEOPLE AB To assess the knowledge, attitudes and practices of epilepsy among healthcare workers (HCWs) and people with epilepsy (PWE) living in Bhutan. A survey with similar questions was distributed to HCWs and PWE (2014-2015). Responses were compared between the two groups. A Stigma Scale in Epilepsy Score was tested for an independent association with patient age, sex, years of education and presence of seizure freedom using regression models. PWE (n=177), when compared to HCWs (n=75), were more likely to believe that epilepsy is contagious; epilepsy results from karma or past actions; PWE need help in school; and people with epilepsy have spiritual powers (p < 0.05 for each comparison). Among people with epilepsy, a higher stigma score was independently associated with lower educational attainment (p=0.006) and presence of a seizure in the prior year (p=0.013), but not age, sex or anti-epileptic drug side effects. While knowledge of epilepsy was overall fairly high, PWE more often held certain stigmatizing beliefs, including theories of contagion and a relationship between seizures and spiritual powers. Higher educational level and seizure freedom were associated with lower stigma, underscoring their importance in stigma reduction. C1 [Brizzi, Kate; Clark, Sarah J.; McKenzie, Erica D.; Cash, Sydney S.; Mateen, Farrah J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Deki, Sonam; Tshering, Lhab; Nirola, Damber K.; Dorji, Chencho] Jigme Dorji Wangchuck Natl Referral Hosp, Dept Psychiat, Thimphu, Bhutan. [Patenaude, Bryan N.; McLane, Hannah C.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. [Cash, Sydney S.; Mateen, Farrah J.] Harvard Med Sch, Boston, MA USA. RP Mateen, FJ (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA.; Mateen, FJ (reprint author), Harvard Med Sch, Boston, MA USA. EM fmateen@partners.org FU Grand Challenges Canada, Partners Center for Expertise in Global Health. FX Grand Challenges Canada, Partners Center for Expertise in Global Health. NR 16 TC 1 Z9 1 U1 2 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1876-3413 EI 1876-3405 J9 INT HEALTH JI Int. Health PD JUL PY 2016 VL 8 IS 4 BP 286 EP 291 DI 10.1093/inthealth/ihw017 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DZ7QG UT WOS:000386060300010 PM 27160683 ER PT J AU Brink, JA AF Brink, James A. TI Providing Higher Value Care Through Population Health Management: What Is the Radiologist's Role? SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 [Brink, James A.] Massachusetts Gen Hosp, 55 Fruit St,FND-216, Boston, MA 02114 USA. RP Brink, JA (reprint author), Massachusetts Gen Hosp, 55 Fruit St,FND-216, Boston, MA 02114 USA. EM jabrinke@partners.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD JUL PY 2016 VL 13 IS 7 BP 759 EP 760 DI 10.1016/j.jacr.2016.06.001 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DZ6SF UT WOS:000385991500001 PM 27378540 ER PT J AU Sheehan, SE Coburn, JA Singh, H Vanness, DJ Sittig, DF Moberg, DP Safdar, N Lee, KS Brunner, MC AF Sheehan, Scott E. Coburn, John A. Singh, Hardeep Vanness, David J. Sittig, Dean F. Moberg, D. Paul Safdar, Nasia Lee, Kenneth S. Brunner, Michael C. TI Reducing Unnecessary Shoulder MRI Examinations Within a Capitated Health Care System: A Potential Role for Shoulder Ultrasound SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Shoulder; MRI; ultrasound; utilization; costs ID CLINICAL DECISION-SUPPORT; ROTATOR CUFF TEARS; PHYSICIAN ORDER ENTRY; LONG HEAD; UTILIZATION MANAGEMENT; METAANALYSIS; RADIOLOGY; ACCURACY; JOINT; PAIN AB Purpose: MRI is frequently overused. The aim of this study was to analyze shoulder MRI ordering practices within a capitated health care system and explore the potential effects of shoulder ultrasound substitution. Methods: We reviewed medical records of 237 consecutive shoulder MRI examinations performed in 2013 at a Department of Veterans Affairs tertiary care hospital. Using advanced imaging guidelines, we assessed ordering appropriateness of shoulder MRI and estimated the proportion of examinations for which musculoskeletal ultrasound could have been an acceptable substitute, had it been available. We then reviewed MRI findings and assessed if ultrasound with preceding radiograph would have been adequate for diagnosis, based on literature reports of shoulder ultrasound diagnostic performance. Results: Of the 237 examinations reviewed, 106 (45%) were deemed to be inappropriately ordered, most commonly because of an absent preceding radiograph (n = 98; 92%). Nonorthopedic providers had a higher frequency of inappropriate ordering (44%) relative to orthopedic specialists (17%) (P = .016; odds ratio = 3.15, 95% confidence interval = 1.24-8.01). In the 237 examinations, ultrasound could have been the indicated advanced imaging modality for 157 (66%), and most of these (133/157; 85%) could have had all relevant pathologies characterized when combined with radiographs. Regardless of indicated modality, ultrasound could have characterized 80% of all cases ordered by nonorthopedic providers and 50% of cases ordered by orthopedic specialists (P = .007). Conclusions: Advanced shoulder imaging is often not ordered according to published appropriateness criteria. While nonorthopedic provider orders were more likely to be inappropriate, inappropriateness persisted among orthopedic providers. A combined ultrasound and radiograph evaluation strategy could accurately characterize shoulder pathologies for most cases. C1 [Sheehan, Scott E.; Coburn, John A.; Vanness, David J.; Moberg, D. Paul; Safdar, Nasia; Lee, Kenneth S.; Brunner, Michael C.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. [Coburn, John A.; Vanness, David J.; Moberg, D. Paul; Lee, Kenneth S.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Singh, Hardeep] Michael E DeBakey VA Med Ctr, Houston VA Ctr Innovat Qual Effectiveness & Safet, Houston, TX USA. [Singh, Hardeep] Baylor Coll Med, Houston, TX 77030 USA. [Sittig, Dean F.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. RP Sheehan, SE (reprint author), William S Middleton Mem Vet Adm Med Ctr, Dept Radiol 114, 2500 Overlook Terrace, Madison, WI 53705 USA. EM ssheehan@uwhealth.org NR 52 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 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD JUL PY 2016 VL 13 IS 7 BP 780 EP 787 DI 10.1016/j.jacr.2016.03.015 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DZ6SF UT WOS:000385991500009 PM 27162045 ER PT J AU Rao, S Rao, S Rincon, S Caruso, P Ptak, T Raja, AS Prabhakar, AM Harvey, HB AF Rao, Sevith Rao, Sishir Rincon, Sandra Caruso, Paul Ptak, Thomas Raja, Ali S. Prabhakar, Anand M. Harvey, H. Benjamin TI Assessment of Pediatric Neurotrauma Imaging Appropriateness at a Level I Pediatric Trauma Center SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Radiology; appropriateness criteria; CT; MRI; head trauma; TBI; utilization; diagnostic radiation; Image Gently; pediatrics; concussion ID BLUNT HEAD TRAUMA; COMPUTED-TOMOGRAPHY; EMERGENCY-DEPARTMENT; RADIATION-EXPOSURE; CHILDREN; CRITERIA; INJURY; CHILDHOOD; QUICK; SCANS AB Purpose: The aim of this study was to assess the prevalence of appropriate neuroimaging on the basis of the ACR Appropriateness Criteria among pediatric patients presenting after head trauma to a level I emergency department. Methods: A retrospective emergency department record review was performed for patients <18 years of age undergoing head CT or MRI for the indication "head trauma" between January 2013 and December 2014. Clinical history and symptoms were compared with the ACR Appropriateness Criteria; the indication was deemed appropriate for ratings of >= 7. Patients were analyzed by age, gender, presentation, imaging obtained, follow-up, treatment, and outcomes. Results: Among 207 patients, 120 (58%) were imaged with CT and 107 (52%) with MRI; 20 patients underwent both CT and MRI. One hundred eighty-seven patients (90.3%) were appropriately imaged, with 90.0% of CT studies (108 of 120) deemed appropriate and 91.6% of MRI studies (98 of 107) deemed appropriate. Younger patients were more likely to be inappropriately imaged with CT or MRI than older patients (P = .02 and P < .01, respectively). Patients undergoing CT were older (mean age 9.9 +/- 5.8 years) and more likely to be male (85.2%) than those undergoing MRI (5.6 +/- 5.6 years and 55.1%, respectively) (P < .01 and P < .001, respectively). The diagnostic yield of positive imaging findings for intracranial trauma was significantly lower in the MRI group (P < .01), and patients undergoing MRI were significantly more likely to return to baseline with conservative management (P < .01). Conclusions: Most pediatric patients undergoing neuroimaging for head trauma did so appropriately per ACR guidelines and had symptom resolution with conservative management. The minority not imaged appropriately represent a target for quality improvement efforts. C1 [Rao, Sevith; Rao, Sishir; Rincon, Sandra; Caruso, Paul; Ptak, Thomas; Prabhakar, Anand M.; Harvey, H. Benjamin] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Raja, Ali S.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Rao, Sevith; Rao, Sishir; Rincon, Sandra; Caruso, Paul; Ptak, Thomas; Raja, Ali S.; Prabhakar, Anand M.; Harvey, H. Benjamin] Harvard Med Sch, Boston, MA USA. [Harvey, H. Benjamin] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Harvey, H. Benjamin] ACR Appropriateness Criteria Expert Panel Neurol, Boston, MA USA. RP Harvey, HB (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, Dept Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM hbharvey@mgh.harvard.edu NR 22 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 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD JUL PY 2016 VL 13 IS 7 BP 788 EP 793 DI 10.1016/j.jacr.2016.02.022 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DZ6SF UT WOS:000385991500010 PM 27084071 ER PT J AU Hanley, M Ahmed, O Chandra, A Gage, KL Gerhard-Herman, MD Ginsburg, M Gornik, HL Johnson, PT Oliva, IB Ptak, T Steigner, ML Strax, R Rybicki, FJ Dill, KE AF Hanley, Michael Ahmed, Osmanuddin Chandra, Ankur Gage, Kenneth L. Gerhard-Herman, Marie D. Ginsburg, Michael Gornik, Heather L. Johnson, Pamela T. Oliva, Isabel B. Ptak, Thomas Steigner, Michael L. Strax, Richard Rybicki, Frank J. Dill, Karin E. TI ACR Appropriateness Criteria Clinically Suspected Pulmonary Arteriovenous Malformation SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Appropriateness Criteria; pulmonary arteriovenous malformations; hereditary hemorrhagic telangiectasia; Osler-Weber-Rendu syndrome; transthoracic echocardiography; chest CT ID HEREDITARY HEMORRHAGIC TELANGIECTASIA; TO-LEFT SHUNT; CONTRAST ECHOCARDIOGRAPHY; MR-ANGIOGRAPHY; CT; EMBOLIZATION; UPDATE AB Pulmonary arteriovenous malformations are often included in the differential diagnosis of common clinical presentations, including hypoxemia, hemoptysis, brain abscesses, and paradoxical stroke, as well as affecting 30% to 50% of patients with hereditary hemorrhagic telangiectasia (HHT). Various imaging studies are used in the diagnostic and screening settings, which have been reviewed by the ACR Appropriateness Criteria Vascular Imaging Panel. Pulmonary arteriovenous malformation screening in patients with HHT is commonly performed with transthoracic echocardiographic bubble study, followed by CT for positive cases. Although transthoracic echocardiographic bubble studies and radionuclide perfusion detect right-to-left shunts, they do not provide all of the information needed for treatment planning and may remain positive after embolization. Pulmonary angiography is appropriate for preintervention planning but not as an initial test. MR angiography has a potential role in younger patients with HHT who may require lifelong surveillance, despite lower spatial resolution compared with CT. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three 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 in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. C1 [Hanley, Michael] Univ Virginia Hlth Syst, POB 800170, Charlottesville, VA 22908 USA. [Ahmed, Osmanuddin] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Chandra, Ankur] Scripps Green Hosp, La Jolla, CA USA. [Chandra, Ankur] Soc Vasc Surg, San Diego, CA USA. [Gage, Kenneth L.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Gerhard-Herman, Marie D.; Steigner, Michael L.] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. [Gerhard-Herman, Marie D.; Gornik, Heather L.; Steigner, Michael L.] Amer Coll Cardiol, Washington, DC USA. [Ginsburg, Michael] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Gornik, Heather L.] Cleveland Clin, Inst Heart & Vasc, Cleveland, OH 44106 USA. [Johnson, Pamela T.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Oliva, Isabel B.] Univ Arizona, Coll Med, Tucson, AZ USA. [Ptak, Thomas] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Strax, Richard] Baylor Coll Med, Houston, TX 77030 USA. [Rybicki, Frank J.] Univ Ottawa, Ottawa Hosp, Res Inst, Ottawa, ON, Canada. [Rybicki, Frank J.] Univ Ottawa, Dept Radiol, Ottawa, ON, Canada. [Dill, Karin E.] Univ Chicago, Chicago, IL 60637 USA. RP Hanley, M (reprint author), Univ Virginia Hlth Syst, POB 800170, Charlottesville, VA 22908 USA. EM mhanley@virginia.edu NR 22 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 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD JUL PY 2016 VL 13 IS 7 BP 796 EP 800 DI 10.1016/j.jacr.2016.03.020 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DZ6SF UT WOS:000385991500012 PM 27209598 ER PT J AU Chang, SY Lo, CS Zhao, XP Liao, MC Chenier, I Bouley, R Ingelfinger, JR Chan, JSD Zhang, SL AF Chang, Shiao-Ying Lo, Chao-Sheng Zhao, Xin-Ping Liao, Min-Chun Chenier, Isabelle Bouley, Richard Ingelfinger, Julie R. Chan, John S. D. Zhang, Shao-Ling TI Overexpression of angiotensinogen downregulates aquaporin 1 expression via modulation of Nrf2-HO-1 pathway in renal proximal tubular cells of transgenic mice SO JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM LA English DT Article DE Aquaporin-1; Nrf2; intrarenal renin-angiotensin system; hypertension; kidney injury ID NA+/H+ EXCHANGER 3; WATER CHANNELS; BLOOD-PRESSURE; ENDOTHELIAL-CELLS; HEME OXYGENASE; RAT; HYPERTENSION; APOPTOSIS; SYSTEM; KIDNEY AB Introduction: We aimed to examine the regulation of aquaporin 1 expression in an angiotensinogen transgenic mouse model, focusing on underlying mechanisms. Methods: Male transgenic mice overexpressing rat angiotensinogen in their renal proximal tubular cells (RPTCs) and rat immortalised RPTCs stably transfected with rat angiotensinogen cDNA were used. Results: Angiotensinogen-transgenic mice developed hypertension and nephropathy, changes that were either partially or completely attenuated by treatment with losartan or dual renin-angiotensin system blockade (losartan and perindopril), respectively, while hydralazine prevented hypertension but not nephropathy. Decreased expression of aquaporin 1 and heme oxygenase-1 and increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and sodium-hydrogen exchanger 3 were observed in RPTCs of angiotensinogen-transgenic mice and in angiotensinogen-transfected immortalised RPTCs. These parameters were normalised by dual renin-angiotensin system blockade. Both in vivo and in vitro studies identified a novel mechanism in which angiotensinogen overexpression in RPTCs enhances the cytosolic accumulation of Nrf2 via the phosphorylation of pGSK3 beta Y216. Consequently, lower intranuclear Nrf2 levels are less efficient to trigger heme oxygenase-1 expression as a defence mechanism, which subsequently diminishes aquaporin 1 expression in RPTCs. Conclusions: Angiotensinogen-mediated downregulation of aquaporin 1 and Nrf2 signalling may play an important role in intrarenal renin-angiotensin system-induced hypertension and kidney injury. C1 [Chang, Shiao-Ying; Lo, Chao-Sheng; Zhao, Xin-Ping; Liao, Min-Chun; Chenier, Isabelle; Chan, John S. D.; Zhang, Shao-Ling] CRCHUM, Montreal, PQ, Canada. [Bouley, Richard] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Bouley, Richard; Ingelfinger, Julie R.] Harvard Med Sch, Boston, MA USA. [Ingelfinger, Julie R.] Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. RP Zhang, SL (reprint author), CRCHUM, Montreal, PQ, Canada. EM shao.ling.zhang@umontreal.ca FU Kidney Foundation of Canada [KFOC130032]; Canadian Diabetes Association [OG-3-13-4073-SZ, DS-3-13-4408-SC]; Canadian Institutes of Health Research [MOP-10688, MOP-84363, MOP-142378] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by the grants to SLZ from the Kidney Foundation of Canada (grant number KFOC130032) and Canadian Diabetes Association (grant number OG-3-13-4073-SZ) as well as grants to JSDC and SLZ from the Canadian Institutes of Health Research (grant numbers MOP-10688, MOP-84363 and MOP-142378). SYC is the recipient of a Canadian Diabetes Association doctoral research award (grant number DS-3-13-4408-SC). NR 51 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1470-3203 EI 1752-8976 J9 J RENIN-ANGIO-ALDO S JI J. Renin-Angiotensin-Aldosterone Syst. PD JUL-SEP PY 2016 VL 17 IS 3 AR UNSP 1470320316668737 DI 10.1177/1470320316668737 PG 12 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA DZ4PY UT WOS:000385842200017 ER PT J AU Mbanze, I Moschovis, PP Malhotra, A AF Mbanze, Irina Moschovis, Peter P. Malhotra, Atul TI The American Thoracic Society Global Scholars Program SO JOURNAL OF THORACIC DISEASE LA English DT Editorial Material ID CRITICAL-CARE MEDICINE; INCOME COUNTRIES; NEXT-GENERATION; PULMONARY; EDUCATION C1 [Mbanze, Irina] Maputo Cent Hosp, Dept Med, Div Cardiol, Maputo, Mozambique. [Moschovis, Peter P.] Massachusetts Gen Hosp, Div Pulm, Boston, MA 02114 USA. [Moschovis, Peter P.] Massachusetts Gen Hosp, Div Crit Care Med, Boston, MA 02114 USA. [Moschovis, Peter P.] Massachusetts Gen Hosp, Div Pediat Global Hlth, Boston, MA 02114 USA. [Malhotra, Atul] Univ Calif San Diego, Div Pulm Crit Care & Sleep Med, La Jolla, CA 92093 USA. RP Malhotra, A (reprint author), Univ Calif San Diego, Div Pulm Crit Care & Sleep Med, La Jolla, CA 92093 USA. EM amalhotra@ucsd.edu FU NHLBI NIH HHS [K24 HL132105, R01 HL085188, R01 HL081823, R21 HL121794, R01 HL119201, F32 HL124951] NR 10 TC 0 Z9 0 U1 0 U2 0 PU PIONEER BIOSCIENCE PUBL CO PI HONG KONG PA 9A GOLD SHINE TOWER, 346-348 QUEEN'S RD CENTRAL, SHEUNG WAN, HONG KONG, 00000, PEOPLES R CHINA SN 2072-1439 EI 2077-6624 J9 J THORAC DIS JI J. Thorac. Dis. PD JUL PY 2016 VL 8 SU 7 BP S586 EP S587 DI 10.21037/jtd.2016.07.46 PG 2 WC Respiratory System SC Respiratory System GA DY9FK UT WOS:000385438900020 PM 27606102 ER PT J AU Rho, M Camacho-Soto, A Cheng, A Havran, M Morone, NE Rodriguez, E Shega, J Weiner, DK AF Rho, Monica Camacho-Soto, Alejandra Cheng, Abby Havran, Mark Morone, Natalia E. Rodriguez, Eric Shega, Joseph Weiner, Debra K. TI Deconstructing Chronic Low Back Pain in the Older Adult-Step by Step Evidence and Expert-Based Recommendations for Evaluation and Treatment. Part VIII: Lateral Hip and Thigh Pain SO PAIN MEDICINE LA English DT Article DE Lateral Hip Pain; Greater Trochanteric Pain Syndrome; Chronic Low Back Pain; Thigh Pain; Iliotibial Band Pain; Lumbar Radiculopathy; Lumbar Radiculitis; Hip Osteoarthritis; Lumbar Spinal Stenosis; Meralgia Paresthetica; Diagnostic Algorithm; Elderly ID LUMBAR DISC HERNIATION; NERVE STRETCH TEST; ILIOTIBIAL BAND; NONOPERATIVE TREATMENT; MERALGIA-PARESTHETICA; OSTEOARTHRITIS; RUNNERS; RADICULOPATHY; IMPINGEMENT; FLEXIBILITY AB Objective. This article presents an evidence-based algorithm to assist primary care providers with the diagnosis and management of lateral hip and thigh pain in older adults. It is part of a series that focuses on coexisting pain patterns and contributors to chronic low back pain (CLBP) in the aging population. The objective of the series is to encourage clinicians to take a holistic approach when evaluating and treating CLBP in older adults. Methods. A content expert panel and a primary care panel collaboratively used the modified Delphi approach to iteratively develop an evidence-based diagnostic and treatment algorithm. The panelists included physiatrists, geriatricians, internists, and physical therapists who treat both civilians and Veterans, and the algorithm was developed so that all required resources are available within the Veterans Health Administration system. An illustrative patient case was chosen from one of the author's clinical practices to demonstrate the reasoning behind principles presented in the algorithm. Results. An algorithm was developed which logically outlines evidence-based diagnostic and therapeutic recommendations for lateral hip and thigh pain in older adults. A case is presented which highlights the potential complexities of identifying the true pain generator and the importance of implementing proper treatment. Conclusions. Lateral hip and thigh pain in older adults can contribute to and coexist with CLBP. Distinguishing the true cause(s) of pain from potentially a myriad of asymptomatic degenerative changes can be challenging, but a systematic approach can assist in identifying and treating some of the most common causes. C1 [Rho, Monica; Cheng, Abby] Northwestern Univ, McGaw Med Ctr, Rehabil Inst Chicago, Dept Phys Med & Rehabil, Chicago, IL 60611 USA. [Camacho-Soto, Alejandra] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Havran, Mark] VA Cent Iowa Hlth Care Syst, Extended Care & Rehab, Des Moines, IA USA. [Havran, Mark] Des Moines Univ, Des Moines, IA USA. [Morone, Natalia E.; Weiner, Debra K.] Vet Affairs Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Morone, Natalia E.] Univ Pittsburgh, Ctr Res Hlth Care, Div Gen Internal Med, Pittsburgh, PA USA. [Morone, Natalia E.; Weiner, Debra K.] Univ Pittsburgh, Sch Med, Clin & Translat Sci Inst, Pittsburgh, PA USA. [Rodriguez, Eric; Weiner, Debra K.] Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA USA. [Shega, Joseph] VITAS Healthcare, Miami, FL USA. [Weiner, Debra K.] Dept Psychiat, Pittsburgh, PA USA. [Weiner, Debra K.] Dept Anesthesiol, Pittsburgh, PA USA. RP Weiner, DK (reprint author), VA Pittsburgh Healthcare Syst, Univ Dr,Bldg 30,00GR, Pittsburgh, PA 15240 USA. EM debra.weiner@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Rehabilitation Research and Development Service FX This material is based on work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Rehabilitation Research and Development Service. Drs. Monica Rho and Alejandra Camacho-Soto are co-first authors. NR 45 TC 0 Z9 0 U1 8 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1526-2375 EI 1526-4637 J9 PAIN MED JI Pain Med. PD JUL PY 2016 VL 17 IS 7 BP 1249 EP 1260 DI 10.1093/pm/pnw111 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA DZ1WK UT WOS:000385632100008 ER PT J AU Lampert, RC Nesbitt, TR Chuang, SK Ziccardi, VB AF Lampert, Robert C. Nesbitt, Travis R. Chuang, Sung-Kiang Ziccardi, Vincent B. TI Management of endodontic injuries to the inferior alveolar nerve SO QUINTESSENCE INTERNATIONAL LA English DT Article DE endodontic injuries; external neurolysis; inferior alveolar nerve repair; internal neurolysis ID MICROSURGERY; PARESTHESIA; REPAIR; CEMENT; DAMAGE AB Objective: Functional sensory recovery from microsurgical intervention for inferior alveolar nerve (IAN) injuries resulting from endodontic treatment were evaluated using a retrospective chart review. Other variables assessed included time from injury to surgery as well as other factors which improved functional neurosensory recovery (FSR). Method and Materials: This case series of seven patients evaluated the outcome of IAN microsurgery following endodontic-related nerve injuries. All patients were referred, evaluated, and operated on by the primary investigator (VBZ). Surgical intervention consisted of external and/or internal neurolysis with irrigation of the mandibular canal and decompression of the affected IAN as well as allogeneic nerve graft in one patient. Preoperative and postoperative sensory levels were recorded and FSR was assessed using the Medical Research Council scale. Results: Seven subjects with a mean age of 35.57 years (range 22 to 55 years old) opted to undergo trigeminal nerve microsurgery for management of their IAN injury resulting from endodontic treatment of mandibular molar teeth. Six women and one man were included in this population. The majority of subjects presented with an initial chief complaint of dysesthesia and hypoesthesia. The mean interval between nerve injury and surgical treatment was 15 weeks (range 1 to 40 weeks). All patients had preoperative sensory level of S0, S1, or S2+, and achieved FSR following surgery. Two patients had postoperative sensory level of S3, four patients had a postoperative sensory level of S3+, and one had a postoperative sensory level of S4 (complete recovery). Conclusions: The results of this study suggest that trigeminal nerve microsurgery for the surgical treatment of endodontic injuries to the IAN can improve neurosensory function. Surgical intervention in this study was beneficial to alleviate neurosensory deficits and symptoms for those injuries to the IAN caused by endodontic treatment. C1 [Lampert, Robert C.; Ziccardi, Vincent B.] Rutgers Sch Dent Med, Dept Oral & Maxillofacial Surg, Newark, NJ USA. [Nesbitt, Travis R.] Brookdale Univ Hosp & Med Ctr, Dept Oral & Maxillofacial Surg, Brooklyn, NY USA. [Chuang, Sung-Kiang] Harvard Sch Dent Med, Dept Oral & Maxillofacial Surg, Boston, MA USA. [Chuang, Sung-Kiang] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP Ziccardi, VB (reprint author), Dept Oral & Maxillofacial Surg, 110 Bergen St,Room B854, Newark, NJ 07103 USA. EM ziccarvb@sdm.rutgers.edu NR 23 TC 0 Z9 0 U1 0 U2 0 PU QUINTESSENCE PUBLISHING CO INC PI HANOVER PARK PA 4350 CHANDLER DRIVE, HANOVER PARK, IL 60133 USA SN 0033-6572 EI 1936-7163 J9 QUINTESSENCE INT JI Quintessence Int. PD JUL-AUG PY 2016 VL 47 IS 7 BP 581 EP 587 DI 10.3290/j.qi.a36176 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA DW0VV UT WOS:000383362000005 PM 27319813 ER PT J AU Nigwekar, SU Sprague, SM AF Nigwekar, Sagar U. Sprague, Stuart M. TI We Do Too Many Parathyroidectomies for Calciphylaxis SO SEMINARS IN DIALYSIS LA English DT Article ID HEMODIALYSIS; NECROSIS; OUTCOMES; DISEASE AB Calciphylaxis, a disorder of dermal arteriolar calcification with a distinct predilection for patients with advanced kidney disease, remains an enigmatic condition that challenges clinicians. Observations regarding positive associations between levels of circulating parathyroid hormone (PTH) and the risk of calciphylaxis, combined with experimental data suggesting a pathogenic role of secondary hyperparathyroidism in vascular calcification, have led to the assumption that reducing PTH levels will improve the outcomes in patients with calciphylaxis. This editorial communicates the contemporary data regarding surgical parathyroidectomy as a treatment option for these patients. We raise concerns regarding the quality of available data and discuss the direction of future comparative effectiveness research in this field. C1 [Nigwekar, Sagar U.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Sprague, Stuart M.] Univ Chicago, Pritzker Sch Med, NorthShore Univ HealthSyst, Div Nephrol & Hypertens, Evanston, IL USA. RP Sprague, SM (reprint author), Div Nephrol & Hypertens, 2650 Ridge Ave, Evanston, IL 60201 USA. EM stuartmsprague@gmail.com NR 13 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-0959 EI 1525-139X J9 SEMIN DIALYSIS JI Semin. Dial. PD JUL-AUG PY 2016 VL 29 IS 4 BP 312 EP 314 DI 10.1111/sdi.12502 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA DZ1QB UT WOS:000385611800021 PM 27082830 ER PT J AU Patel, MS Volpp, KG Rosin, R Bellamy, SL Small, DS Fletcher, MA Osman-Koss, R Brady, JL Haff, N Lee, SM Wesby, L Hoffer, K Shuttleworth, D Taylor, DH Hilbert, V Zhu, JS Yang, L Wang, XM Asch, DA AF Patel, Mitesh S. Volpp, Kevin G. Rosin, Roy Bellamy, Scarlett L. Small, Dylan S. Fletcher, Michele A. Osman-Koss, Rosemary Brady, Jennifer L. Haff, Nancy Lee, Samantha M. Wesby, Lisa Hoffer, Karen Shuttleworth, David Taylor, Devon H. Hilbert, Victoria Zhu, Jingsan Yang, Lin Wang, Xingmei Asch, David A. TI A Randomized Trial of Social Comparison Feedback and Financial Incentives to Increase Physical Activity SO AMERICAN JOURNAL OF HEALTH PROMOTION LA English DT Article DE physical activity; social comparison; performance feedback; teams; financial incentives; behavioral economics; connected health ID CORONARY-HEART-DISEASE; HEALTH BEHAVIOR-CHANGE; WEARABLE DEVICES; IMPROVE HEALTH; WEIGHT-LOSS; US ADULTS; ALL-CAUSE; METAANALYSIS; RISK; ECONOMICS AB Purpose: To compare the effectiveness of different combinations of social comparison feedback and financial incentives to increase physical activity. Design: Randomized trial (Clinicaltrials.gov number, NCT02030080). Setting: Philadelphia, Pennsylvania. Participants: Two hundred eighty-six adults. Interventions: Twenty-six weeks of weekly feedback on team performance compared to the 50th percentile (n = 100) or the 75th percentile (n = 64) and 13 weeks of weekly lottery-based financial incentive plus feedback on team performance compared to the 50th percentile (n = 80) or the 75th percentile (n = 44) followed by 13 weeks of only performance feedback. Measures: Mean proportion of participant-days achieving the 7000-step goal during the 13-week intervention. Analysis: Generalized linear mixed models adjusting for repeated measures and clustering by team. Results: Compared to the 75th percentile without incentives during the intervention period, the mean proportion achieving the 7000-step goal was significantly greater for the 50th percentile with incentives group (0.45 vs 0.27, difference: 0.18, 95% confidence interval [CI]: 0.04 to 0.32; P = .012) but not for the 75th percentile with incentives group (0.38 vs 0.27, difference: 0.11, 95% CI: -0.05 to 0.27; P = .19) or the 50th percentile without incentives group (0.30 vs 0.27, difference: 0.03, 95% CI: -0.10 to 0.16; P = .67). Conclusion: Social comparison to the 50th percentile with financial incentives was most effective for increasing physical activity. C1 [Patel, Mitesh S.; Volpp, Kevin G.; Bellamy, Scarlett L.; Yang, Lin; Wang, Xingmei; Asch, David A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Patel, Mitesh S.; Volpp, Kevin G.; Small, Dylan S.; Asch, David A.] Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. [Patel, Mitesh S.; Volpp, Kevin G.; Wesby, Lisa; Hoffer, Karen; Shuttleworth, David; Taylor, Devon H.; Hilbert, Victoria; Zhu, Jingsan; Asch, David A.] Univ Penn, LDI Ctr Hlth Incent & Behav Econ, Philadelphia, PA 19104 USA. [Patel, Mitesh S.; Volpp, Kevin G.; Rosin, Roy; Asch, David A.] Univ Penn Hlth Syst, Ctr Hlth Care Innovat, Philadelphia, PA USA. [Patel, Mitesh S.; Volpp, Kevin G.; Asch, David A.] Crescenz Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Fletcher, Michele A.; Osman-Koss, Rosemary; Brady, Jennifer L.] Univ Penn, Univ Penn Hlth Syst, Philadelphia, PA 19104 USA. [Haff, Nancy] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lee, Samantha M.] Columbia Univ, Dept Med, Med Ctr, New York, NY USA. RP Patel, MS (reprint author), 1312b Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM mpatel@upenn.edu FU National Institute on Aging [RC4 AG039114]; Department of Veteran Affairs; Robert Wood Johnson Foundation; CVS Caremark; Humana; Discovery (South Africa); Merck FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was funded by the National Institute on Aging (RC4 AG039114) to Drs Asch and Volpp. Dr Patel was supported in part by the Department of Veteran Affairs and the Robert Wood Johnson Foundation. Dr. Volpp also has received consulting income from CVS Caremark and research funding from Humana, CVS Caremark, Discovery (South Africa), and Merck, none of which are related to the work described in this manuscript. NR 49 TC 0 Z9 0 U1 11 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0890-1171 EI 2168-6602 J9 AM J HEALTH PROMOT JI Am. J. Health Promot. PD JUL-AUG PY 2016 VL 30 IS 6 BP 416 EP 424 DI 10.1177/0890117116658195 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA DS7DY UT WOS:000380944300002 PM 27422252 ER PT J AU Liu, J Wang, PP Douglas, SL Tate, JM Sham, S Lloyd, SG AF Liu, Jian Wang, Peipei Douglas, Samuel L. Tate, Joshua M. Sham, Simon Lloyd, Steven G. TI Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE diet; myocardial ischemia-reperfusion injury; insulin; metabolism ID KETONE-BODY METABOLISM; PERFUSED RAT-HEART; LOW-FLOW ISCHEMIA; ACID OXIDATION; MITOCHONDRIAL METABOLISM; GLUCOSE-TOLERANCE; KETOGENIC DIET; OBESE RATS; INJURY; RESISTANCE AB High-fat, low-carbohydrate Diet (HFLCD) impairs the myocardial response to ischemia-reperfusion, but the underlying mechanisms remain elusive. We sought to determine the magnitude of diet-induced alterations in intrinsic properties of the myocardium (including insulin sensitivity and substrate oxidation) and circulating substrate and insulin differences resulting from diet, leading to this impaired response. Rats were fed HFLCD (60% kcal from fat/30% protein/10% carbohydrate) or control diet (CONT) (16%/19%/65%) for 2 wk. Isolated hearts underwent global low-flow ischemia followed by reperfusion (I/R). Carbon-13 NMR spectroscopy was used to determine myocardial substrate TCA cycle entry. Myocardial insulin sensitivity was assessed as dose-response of Akt phosphorylation. There was a significant effect of HFLCD and I/R with both these factors leading to an increase in free fatty acid (FFA) oxidation and a decrease in carbohydrate or ketone oxidation. Following I/R, HFLCD led to decreased ketone and increased FFA oxidation; the recovery of left ventricular (LV) function was decreased in HFLCD and was negatively correlated with FFA oxidation and positively associated with ketone oxidation. HFLCD also resulted in reduced insulin sensitivity. Under physiologic ranges, there were no direct effects of buffer insulin and ketone levels on oxidation of any substrate and recovery of cardiac function after I/R. An insulinketone interaction exists for myocardial substrate oxidation characteristics. We conclude that the impaired recovery of function after ischemia-reperfusion with HFLCD is largely due to intrinsic diet effects on myocardial properties, rather than to diet effect on circulating insulin or substrate levels. C1 [Liu, Jian; Douglas, Samuel L.; Tate, Joshua M.; Sham, Simon; Lloyd, Steven G.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Wang, Peipei] Natl Univ Singapore, Natl Univ Hlth Syst, Cardiovasc Res Inst, Singapore, Singapore. [Lloyd, Steven G.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Lloyd, SG (reprint author), Univ Alabama Birmingham, Div Cardiovasc Dis, Dept Med, D-101 Cardiac MRI,1808 7th Ave South, Birmingham, AL 35294 USA. EM slloyd@uabmc.edu FU American Heart Association [0735212N]; National Institute of Diabetes and Digestive and Kidney Diseases [P30 DK-056336] FX This work was supported in part by American Heart Association Scientist Development Grant 0735212N and by National Institute of Diabetes and Digestive and Kidney Diseases P30 DK-056336. NR 48 TC 0 Z9 0 U1 4 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUL PY 2016 VL 311 IS 1 BP H1 EP H10 DI 10.1152/ajpheart.00809.2015 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA DY3CZ UT WOS:000384969700001 PM 27199129 ER PT J AU McClatchey, PM Schafer, M Hunter, KS Reusch, JEB AF McClatchey, P. Mason Schafer, Michal Hunter, Kendall S. Reusch, Jane E. B. TI The endothelial glycocalyx promotes homogenous blood flow distribution within the microvasculature SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE glycocalyx; microvascular perfusion; perfusion heterogeneity; oxygen delivery ID CHRONIC HEART-FAILURE; TRANSIT-TIME HETEROGENEITY; SKELETAL-MUSCLE; METABOLIC SYNDROME; PERFUSION HETEROGENEITY; EXERCISE CAPACITY; IN-VIVO; CAPILLARY HEMODYNAMICS; INSULIN-RESISTANCE; BARRIER PROPERTIES AB Many common diseases involve impaired tissue perfusion, and heterogeneous distribution of blood flow in the microvasculature contributes to this pathology. The physiological mechanisms regulating homogeneity/heterogeneity of microvascular perfusion are presently unknown. Using established empirical formulations for blood viscosity modeling in vivo (blood vessels) and in vitro (glass tubes), we showed that the in vivo formulation predicts more homogenous perfusion of microvascular networks at the arteriolar and capillary levels. Next, we showed that the more homogeneous blood flow under simulated in vivo conditions can be explained by changes in red blood cell interactions with the vessel wall. Finally, we demonstrated that the presence of a spacefilling, semipermeable layer (such as the endothelial glycocalyx) at the vessel wall can account for the changes of red blood cell interactions with the vessel wall that promote homogenous microvascular perfusion. Collectively, our results indicate that the mechanical properties of the endothelial glycocalyx promote homogeneous microvascular perfusion. Preservation or restoration of normal glycocalyx properties may be a viable strategy for improving tissue perfusion in a variety of diseases. C1 [McClatchey, P. Mason; Reusch, Jane E. B.] Univ Colorado, Div Endocrinol, Anschutz Med Campus, Aurora, CO USA. [McClatchey, P. Mason; Reusch, Jane E. B.] Denver Vet Affairs Med Ctr, Dept Med, Denver, CO USA. [McClatchey, P. Mason; Schafer, Michal; Hunter, Kendall S.; Reusch, Jane E. B.] Univ Colorado, Dept Bioengn, Anschutz Med Campus, Aurora, CO USA. [Schafer, Michal; Hunter, Kendall S.] Childrens Hosp Colorado, Div Cardiol, Dept Pediat, Aurora, CO USA. [Reusch, Jane E. B.] Univ Colorado, Sch Med, Ctr Womens Hlth Res, Aurora, CO USA. RP Reusch, JEB (reprint author), 12801 E 17th Ave,MS 8106, Aurora, CO 80045 USA. EM jane.reusch@ucdenver.edu FU Colorado Clinical and Translational Sciences Institute [UL1-RR-025780]; Center for Women's Health Research; Veterans Affairs Merit Review; Department of Bioengineering FX This work was supported by Colorado Clinical and Translational Sciences Institute-UL1-RR-025780 (to J. E. B. Reusch, M. Schafer, K. S. Hunter, and P. M. McClatchey), the Center for Women's Health Research (to J. E. B. Reusch), Veterans Affairs Merit Review (to J. E. B. Reusch), and the Department of Bioengineering (to P. M. McClatchey). NR 63 TC 0 Z9 0 U1 2 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUL PY 2016 VL 311 IS 1 BP H168 EP H176 DI 10.1152/ajpheart.00132.2016 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA DY3CZ UT WOS:000384969700017 PM 27199117 ER PT J AU Firth, PG AF Firth, Paul G. TI Of Penguins, Pinnipeds, and Poisons Anesthesia on Elephant Island SO ANESTHESIOLOGY LA English DT Article ID CHLOROFORM AB Although Ernest Shackleton's Endurance Antarctic expedition of 1914 to 1916 is a famous epic of survival, the medical achievements of the two expedition doctors have received little formal examination. Marooned on Elephant Island after the expedition ship sank, Drs. Macklin and McIlroy administered a chloroform anesthetic to crew member Perce Blackborow to amputate his frostbitten toes. As the saturated vapor pressure of chloroform at 0 degrees C is 71.5 mmHg and the minimum alveolar concentration is 0.5% of sea-level atmospheric pressure (3.8 mmHg), it would have been feasible to induce anesthesia at a low temperature. However, given the potentially lethal hazards of a light chloroform anesthetic, an adequate and constant depth of anesthesia was essential. The pharmacokinetics of the volatile anesthetic, administered via the open-drop technique in the frigid environment, would have been unfamiliar to the occasional anesthetist. To facilitate vaporization of the chloroform, the team burned penguin skins and seal blubber under overturned lifeboats to increase the ambient temperature from -0.5 degrees to 26.6 degrees C. Chloroform degrades with heat to chlorine and phosgene, but buildup of these poisonous gases did not occur due to venting of the confined space by the stove chimney. The anesthetic went well, and the patient-and all the ship's crew-survived to return home. C1 [Firth, Paul G.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. RP Firth, PG (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM pfirth@partners.org NR 36 TC 1 Z9 1 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD JUL PY 2016 VL 125 IS 1 BP 25 EP 33 DI 10.1097/ALN.0000000000001151 PG 9 WC Anesthesiology SC Anesthesiology GA DY2JO UT WOS:000384919100014 PM 27148920 ER PT J AU Zaremba, S Shin, CH Hutter, MM Malviya, SA Grabitz, SD MacDonald, T Diaz-Gil, D Ramachandran, SK Hess, D Malhotra, A Eikermann, M AF Zaremba, Sebastian Shin, Christina H. Hutter, Matthew M. Malviya, Sanjana A. Grabitz, Stephanie D. MacDonald, Teresa Diaz-Gil, Daniel Ramachandran, Satya Krishna Hess, Dean Malhotra, Atul Eikermann, Matthias TI Continuous Positive Airway Pressure Mitigates Opioid-induced Worsening of Sleep-disordered Breathing Early after Bariatric Surgery SO ANESTHESIOLOGY LA English DT Article ID RANDOMIZED-CONTROLLED-TRIAL; PREVENT PULMONARY COMPLICATIONS; INDUCED RESPIRATORY DEPRESSION; NATIONWIDE INPATIENT SAMPLE; MORBIDLY OBESE-PATIENTS; POWER SPECTRAL-ANALYSIS; Y GASTRIC BYPASS; WEIGHT-LOSS; ADAPTIVE SERVOVENTILATION; POSTOPERATIVE HYPOXEMIA AB Background: Bariatric surgery patients are vulnerable to sleep-disordered breathing (SDB) early after recovery from surgery and anesthesia. The authors hypothesized that continuous positive airway pressure (CPAP) improves postoperative oxygenation and SDB and mitigates opioid-induced respiratory depression. Methods: In a randomized crossover trial, patients after bariatric surgery received 30% oxygen in the postanesthesia care unit (PACU) under two conditions: atmospheric pressure and CPAP (8 to 10 cm H2O). During 1 h of each treatment, breathing across cortical arousal states was analyzed using polysomnography and spirometry. Arousal state and respiratory events were scored in accordance with American Academy of Sleep Medicine guidelines. Data on opioid boluses in the PACU were collected. The primary and secondary outcomes were the apnea hypopnea index (AHI) and apnea after self-administration of opioids in the PACU. Linear mixed model analysis was used to compare physiologic measures of breathing. Results: Sixty-four percent of the 33 patients with complete postoperative polysomnography data demonstrated SDB (AHI greater than 5/h) early after recovery from anesthesia. CPAP treatment decreased AHI (8 +/- 2/h vs. 25 +/- 5/h, P < 0.001), decreased oxygen desaturations (5 +/- 10/h vs. 16 +/- 20/h, P < 0.001), and increased the mean oxygen saturation by 3% (P = 0.003). CPAP significantly decreased the respiratory-depressant effects observed during wakefulness-sleep transitions without affecting hemodynamics. The interaction effects between CPAP treatment and opioid dose for the dependent variables AHI (P < 0.001), inspiratory flow (P = 0.002), and minute ventilation (P = 0.015) were significant. Conclusions: This pharmacophysiologic interaction trial shows that supervised CPAP treatment early after surgery improves SDB and ameliorates the respiratory-depressant effects of opioids without undue hemodynamic effects. C1 [Zaremba, Sebastian; Shin, Christina H.; Malviya, Sanjana A.; Grabitz, Stephanie D.; MacDonald, Teresa; Diaz-Gil, Daniel; Eikermann, Matthias] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Hutter, Matthew M.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Hess, Dean] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Resp Care, Boston, MA USA. [Zaremba, Sebastian] Univ Bonn, Dept Neurol, Sleep Med, Bonn, Germany. [Zaremba, Sebastian] Helmholtz Assoc, German Ctr Neurodegenerat Dis DZNE, Bonn, Germany. [Ramachandran, Satya Krishna] Univ Michigan, Sch Med, Dept Anesthesiol, Ann Arbor, MI USA. [Malhotra, Atul] Univ Calif San Diego, Dept Med, Div Pulm & Crit Care Med, La Jolla, CA 92093 USA. [Eikermann, Matthias] Univ Hosp Essen, Dept Anesthesia & Crit Care, Essen, Germany. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anaesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM meikermann@partners.org RI Ramachandran, Satya Krishna/P-6636-2016 OI Ramachandran, Satya Krishna/0000-0002-7176-6375 FU ResMed Foundation, La Jolla, California; National Institutes of Health (Bethesda, Maryland) [R01 HL085188, K24 HL093218] FX Supported by a research grant titled "Consequences of Obstructive Sleep Apnea on Respiratory Function following Weight-loss Surgery: A Randomized Controlled Trial" from the ResMed Foundation, La Jolla, California (to Dr. Eikermann); and the National Institutes of Health (Bethesda, Maryland) grants R01 HL085188 and K24 HL093218 (to Dr. Malhotra). NR 67 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD JUL PY 2016 VL 125 IS 1 BP 92 EP 104 DI 10.1097/ALN.0000000000001160 PG 13 WC Anesthesiology SC Anesthesiology GA DY2JO UT WOS:000384919100021 PM 27171827 ER PT J AU Turner, JA Fitzsimons, MG Pardo, MC Hawkins, JL Huang, YM Rudolph, MDD Keyes, MA Howard-Quijano, KJ Naim, NZ Buckley, JC Grogan, TR Steadman, RH AF Turner, Judi A. Fitzsimons, Michael G. Pardo, Manuel C., Jr. Hawkins, Joy L. Huang, Yue Ming Rudolph, Maria D. D. Keyes, Mary A. Howard-Quijano, Kimberly J. Naim, Natale Z. Buckley, Jack C. Grogan, Tristan R. Steadman, Randolph H. TI Effect of Performance Deficiencies on Graduation and Board Certification Rates A 10-yr Multicenter Study of Anesthesiology Residents SO ANESTHESIOLOGY LA English DT Article ID RESIDENCY PROGRAM DIRECTORS; MEDICINE RESIDENCY; NATIONAL-SURVEY; RISK RESIDENTS; REMEDIATION; EXPERIENCE; PROBATION; DISMISSAL; OUTCOMES; LEARNER AB Background: This multicenter, retrospective study was conducted to determine how resident performance deficiencies affect graduation and board certification. Methods: Primary documents pertaining to resident performance were examined over a 10-yr period at four academic anesthesiology residencies. Residents entering training between 2000 and 2009 were included, with follow-up through February 2016. Residents receiving actions by the programs' Clinical Competency Committee were categorized by the area of deficiency and compared to peers without deficiencies. Results: A total of 865 residents were studied (range: 127 to 275 per program). Of these, 215 residents received a total of 405 actions from their respective Clinical Competency Committee. Among those who received an action compared to those who did not, the proportion graduating differed (93 vs. 99%, respectively, P < 0.001), as did the proportion achieving board certification (89 vs. 99%, respectively, P < 0.001). When a single deficiency in an Essential Attribute (e.g., ethical, honest, respectful behavior; absence of impairment) was identified, the proportion graduating dropped to 55%. When more than three Accreditation Council for Graduate Medical Education Core Competencies were deficient, the proportion graduating also dropped significantly. Conclusions: Overall graduation and board certification rates were consistently high in residents with no, or isolated, deficiencies. Residents deficient in an Essential Attribute, or multiple competencies, are at high risk of not graduating or achieving board certification. More research is needed on the effectiveness and selective deployment of remediation efforts, particularly for high-risk groups. C1 [Turner, Judi A.; Huang, Yue Ming; Keyes, Mary A.; Howard-Quijano, Kimberly J.; Naim, Natale Z.; Buckley, Jack C.; Steadman, Randolph H.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol & Perioperat Med, Los Angeles, CA 90095 USA. [Grogan, Tristan R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med Stat Core, Los Angeles, CA 90095 USA. [Rudolph, Maria D. D.] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Simulat Ctr, Los Angeles, CA 90095 USA. [Fitzsimons, Michael G.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Pardo, Manuel C., Jr.] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. [Hawkins, Joy L.] Univ Colorado, Sch Med, Dept Anesthesiol, Denver, CO USA. RP Steadman, RH (reprint author), RRUMC, Dept Anesthesiol & Perioperat Med, Box 957403,757 Westwood Blvd,Suite 3325, Los Angeles, CA 90095 USA. EM rsteadman@mednet.ucla.edu FU Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California; Department of Anesthesia, Critical Care and Pain Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts; Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California; Department of Anesthesiology, University of Colorado School of Medicine, Denver, Colorado; National Institutes of Health/National Center for Advancing Translational Science UCLA Clinical and Translational Science Institute [UL1TR000124] FX This study was supported by the authors' institutions: Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California; Department of Anesthesia, Critical Care and Pain Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts; Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California; and Department of Anesthesiology, University of Colorado School of Medicine, Denver, Colorado. Statistical analyses described were partially supported by National Institutes of Health/National Center for Advancing Translational Science UCLA Clinical and Translational Science Institute grant number UL1TR000124. NR 23 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD JUL PY 2016 VL 125 IS 1 BP 221 EP 229 DI 10.1097/ALN.0000000000001142 PG 9 WC Anesthesiology SC Anesthesiology GA DY2JO UT WOS:000384919100034 PM 27119434 ER PT J AU Gerbaud, E Weisz, G Tanaka, A Kashiwagi, M Shimizu, T Wang, L Souza, C Bouma, BE Suter, MJ Shishkov, M Ughi, GJ Halpern, EF Rosenberg, M Waxman, S Moses, JW Mintz, GS Maehara, A Tearney, GJ AF Gerbaud, Edouard Weisz, Giora Tanaka, Atsushi Kashiwagi, Manabu Shimizu, Takehisa Wang, Lin Souza, Christiano Bouma, Brett E. Suter, Melissa J. Shishkov, Milen Ughi, Giovanni J. Halpern, Elkan F. Rosenberg, Mireille Waxman, Sergio Moses, Jeffrey W. Mintz, Gary S. Maehara, Akiko Tearney, Guillermo J. TI Multi-laboratory inter-institute reproducibility study of IVOCT and IVUS assessments using published consensus document definitions SO EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING LA English DT Article DE Reproducibility; Intravascular ultrasound imaging; Optical frequency domain imaging; Optical coherence tomography ID OPTICAL COHERENCE TOMOGRAPHY; INTRAVASCULAR ULTRASOUND; INTEROBSERVER VARIABILITY; INTRACORONARY ULTRASOUND; OCT; INTRAOBSERVER; ACQUISITION; STANDARDS; IMAGE AB Aims The aim of this study was to investigate the reproducibility of intravascular optical coherence tomography (IVOCT) assessments, including a comparison to intravascular ultrasound (IVUS). Intra-observer and inter-observer variabilities of IVOCT have been previously described, whereas inter-institute reliability in multiple laboratories has never been systematically studied. Methods and results In 2 independent laboratories with intravascular imaging expertise, 100 randomized matched data sets of IVOCT and IVUS images were analysed by 4 independent observers according to published consensus document definitions. Intraobserver, inter-observer, and inter-institute variabilities of IVOCT qualitative and quantitative measurements vs. IVUS measurements were assessed. Minor inter-and intra-observer variability of both imaging techniques was observed for detailed qualitative and geometric analysis, except for inter-observer mixed plaque identification on IVUS (kappa = 0.70) and for inter-observer fibrous cap thickness measurement reproducibility on IVOCT (ICC = 0.48). The magnitude of inter-institute measurement differences for IVOCT was statistically significantly less than that for IVUS concerning lumen cross-sectional area (CSA), maximum and minimum lumen diameters, stent CSA, and maximum and minimum stent diameters (P < 0.001, P < 0.001, P < 0.001, P = 0.02, P < 0.001, and P = 0.01, respectively). Minor interinstitute measurement variabilities using both techniques were also found for plaque identification. Conclusion In the measurement of lumen CSA, maximum and minimum lumen diameters, stent CSA, and maximum and minimum stent diameters by analysts from two different laboratories, reproducibility of IVOCT was more consistent than that of IVUS. C1 [Gerbaud, Edouard; Tanaka, Atsushi; Kashiwagi, Manabu; Bouma, Brett E.; Suter, Melissa J.; Shishkov, Milen; Ughi, Giovanni J.; Rosenberg, Mireille; Tearney, Guillermo J.] Massachusetts Gen Hosp, Harvard Med Sch, BHX604A, Boston, MA 02114 USA. [Gerbaud, Edouard; Tanaka, Atsushi; Kashiwagi, Manabu; Bouma, Brett E.; Suter, Melissa J.; Shishkov, Milen; Ughi, Giovanni J.; Rosenberg, Mireille; Tearney, Guillermo J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, BHX604A, Boston, MA 02114 USA. [Weisz, Giora; Shimizu, Takehisa; Wang, Lin; Souza, Christiano; Moses, Jeffrey W.; Mintz, Gary S.; Maehara, Akiko] Columbia Univ, Med Ctr, New York, NY USA. [Weisz, Giora; Shimizu, Takehisa; Wang, Lin; Souza, Christiano; Moses, Jeffrey W.; Mintz, Gary S.; Maehara, Akiko] Cardiovasc Res Fdn, New York, NY USA. [Halpern, Elkan F.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Waxman, Sergio] Lahey Clin Med Ctr, Dept Cardiol, Burlington, MA 01803 USA. [Tearney, Guillermo J.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA USA. [Tearney, Guillermo J.] Harvard Med Sch, Dept Pathol, Boston, MA USA. [Tearney, Guillermo J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Tearney, GJ (reprint author), Massachusetts Gen Hosp, Harvard Med Sch, BHX604A, Boston, MA 02114 USA.; Tearney, GJ (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, BHX604A, Boston, MA 02114 USA.; Tearney, GJ (reprint author), Harvard Mit Div Hlth Sci & Technol, Cambridge, MA USA.; Tearney, GJ (reprint author), Harvard Med Sch, Dept Pathol, Boston, MA USA.; Tearney, GJ (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM gtearney@partners.org OI Ughi, Giovanni J./0000-0003-3354-0698 FU NIH [R01HL076398] FX The research was funded in part by NIH R01HL076398. NR 21 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 2047-2404 EI 2047-2412 J9 EUR HEART J-CARD IMG JI Eur. Heart J.-Cardiovasc. Imaging PD JUL 1 PY 2016 VL 17 IS 7 BP 756 EP 764 DI 10.1093/ehjci/jev229 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DX9OP UT WOS:000384725300010 PM 26377904 ER PT J AU Schoenhagen, P Ghoshhajra, B Achenbach, S Abbara, S AF Schoenhagen, Paul Ghoshhajra, Brian Achenbach, Stephan Abbara, Suhny TI Interpretation of 'incidental' cardiovascular findings in standard chest CTs impact of evolving scanner technology on educational requirements SO JOURNAL OF CARDIOVASCULAR COMPUTED TOMOGRAPHY LA English DT Editorial Material ID CARDIAC COMPUTED-TOMOGRAPHY; IMAGE QUALITY; ANGIOGRAPHY; IDENTIFICATION; DISEASE; AORTA C1 [Schoenhagen, Paul] Cleveland Clin, Cleveland, OH 44106 USA. [Ghoshhajra, Brian] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Achenbach, Stephan] Univ Erlangen Nurnberg, Erlangen, Germany. [Abbara, Suhny] Univ Texas Southwestern Med Ctr Dallas, Dallas, TX 75390 USA. RP Schoenhagen, P (reprint author), Cleveland Clin, Cardiovasc Imaging, Desk J1-4 24,9500 Euclid Ave, Cleveland, OH 44195 USA. EM schoenp1@ccf.org NR 20 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-5925 J9 J CARDIOVASC COMPUT JI J. Cardiovasc. Comput. Tomogr. PD JUL-AUG PY 2016 VL 10 IS 4 BP 289 EP 290 DI 10.1016/j.jcct.2016.04.004 PG 2 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA DY3SN UT WOS:000385014800004 PM 27145695 ER PT J AU Hoge, WS Polimeni, JR AF Hoge, W. Scott Polimeni, Jonathan R. TI Dual-Polarity GRAPPA for Simultaneous Reconstruction and Ghost Correction of Echo Planar Imaging Data SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE Nyquist ghost correction; parallel imaging; fMRI; artifact correction; oblique ghosts; GESTE ID PARALLEL ACQUISITIONS GRAPPA; PHASE CORRECTION; FUNCTIONAL MRI; EPI; ARTIFACTS AB Purpose: The purpose of this study was to seek improved image quality from accelerated echo planar imaging (EPI) data, particularly at ultrahigh fields. Certain artifacts in EPI reconstructions can be attributed to nonlinear phase differences between data acquired using frequency-encoding gradients of alternating polarity. These errors appear near regions of local susceptibility gradients and typically cannot be corrected with conventional Nyquist ghost correction (NGC) methods. Methods: We propose a new reconstruction method that integrates ghost correction into the parallel imaging data recovery process. This is achieved through a pair of generalized auto-calibrating partially parallel acquisitions (GRAPPA) kernels that operate directly on the measured EPI data. The proposed dual-polarity GRAPPA (DPG) method estimates missing k-space data while simultaneously correcting inherent EPI phase errors. Results: Simulation results showed that standard NGC is incapable of correcting higher-order phase errors, whereas the DPG kernel approach successfully removed these errors. The presence of higher-order phase errors near regions of local susceptibility gradients was demonstrated with in vivo data. DPG reconstructions of in vivo 3T and 7T EPI data acquired near these regions showed a marked improvement over conventional methods. Conclusion: This new parallel imaging method for reconstructing accelerated EPI data shows better resilience to inherent EPI phase errors, resulting in higher image quality in regions where higher-order EPI phase errors commonly occur. (C) 2015 Wiley Periodicals, Inc. C1 [Hoge, W. Scott] Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. [Hoge, W. Scott] Harvard Med Sch, Boston, MA USA. [Polimeni, Jonathan R.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Hoge, WS (reprint author), Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. EM shoge@bwh.harvard.edu FU Functional Neuroimaging Laboratory, Brigham and Women's Hospital; National Institute of Biomedical Imaging and Bioengineering [K01-EB011498, R01-EB019437]; Athinoula A. Martinos Center for Biomedical Imaging FX Grant sponsor: Functional Neuroimaging Laboratory, Brigham and Women's Hospital; Grant sponsor: National Institute of Biomedical Imaging and Bioengineering; Grant number: K01-EB011498, R01-EB019437; Grant sponsor: Athinoula A. Martinos Center for Biomedical Imaging. NR 25 TC 1 Z9 1 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2016 VL 76 IS 1 BP 32 EP 44 DI 10.1002/mrm.25839 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY3MK UT WOS:000384996900003 PM 26208304 ER PT J AU Han, F Zhou, ZW Rapacchi, S Nguyen, KL Finn, JP Hu, P AF Han, Fei Zhou, Ziwu Rapacchi, Stanislas Nguyen, Kim-Lien Finn, J. Paul Hu, Peng TI Segmented Golden Ratio Radial Reordering with Variable Temporal Resolution for Dynamic Cardiac MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE golden ratio; cardiac MRI; RF golden angle radial; segmented k-space ID RETROSPECTIVE RECONSTRUCTION; CINE IMAGES; K-SPACE; ANGIOGRAPHY; MOTION AB Purpose: Golden ratio (GR) radial reordering allows for retrospective choice of temporal resolution by providing a near-uniform k-space sampling within any reconstruction window. However, when applying GR to electrocardiogram (ECG)-gated cardiac imaging, the k-space coverage may not be as uniform because a single reconstruction window is broken into several temporally isolated ones. The goal of this study was to investigate the image artifacts caused by applying GR to ECG-gated cardiac imaging and to propose a segmented GR method to address this issue. Methods: Computer simulation and phantom experiments were used to evaluate the image artifacts resulting from three k-space sampling patterns (ie, uniform radial, conventional GR, and segmented GR). Two-and three-dimensional cardiac cine images were acquired in seven healthy subjects. Imaging artifacts due to k-space sampling nonuniformity were graded on a 5-point scale by an experienced cardiac imaging reader. Results: Segmented GR provides more uniform k-space sampling that is independent of heart-rate variation than conventional GR. Cardiac cine images using segmented GR have significantly higher and more reliable image quality than conventional GR. Conclusion: Segmented GR successfully addresses the non-uniform sampling that occurs with combining conventional GR with ECG gating. This technique can potentially be applied to any ECG-gated cardiac imaging application to allow for retrospective selection of a reconstruction window. (C) 2015 Wiley Periodicals, Inc. C1 [Han, Fei; Zhou, Ziwu; Rapacchi, Stanislas; Nguyen, Kim-Lien; Finn, J. Paul; Hu, Peng] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol Sci, Los Angeles, CA 90095 USA. [Han, Fei; Zhou, Ziwu] Univ Calif Los Angeles, Dept Bioengn, Los Angeles, CA USA. [Hu, Peng] Univ Calif Los Angeles, Biomed Phys Interdept Grad Program, Los Angeles, CA USA. [Nguyen, Kim-Lien] VA Greater Los Angeles Healthcare Syst, Div Cardiol, Los Angeles, CA USA. [Nguyen, Kim-Lien] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Hu, P (reprint author), Dept Radiol Sci, 300 UCLA Med Plaza Suite B119, Los Angeles, CA 90095 USA. EM penghu@mednet.ucla.edu OI Nguyen, Kim-Lien/0000-0002-8854-2976 FU National Institutes of Health [1R01HL127153] FX Grant sponsor: National Institutes of Health; Grant number: 1R01HL127153. NR 20 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2016 VL 76 IS 1 BP 94 EP 103 DI 10.1002/mrm.25861 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY3MK UT WOS:000384996900008 PM 26243442 ER PT J AU Farivar, R Grigorov, F van der Kouwe, AJ Wald, LL Keil, B AF Farivar, Reza Grigorov, Filip van der Kouwe, Andre J. Wald, Lawrence L. Keil, Boris TI Dense, Shape-Optimized Posterior 32-Channel Coil for Submillimeter Functional Imaging of Visual Cortex at 3T SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE magnetic resonance imaging; phased-array; fMRI; parallel imaging; shape optimization; ocular dominance columns; functional MRI; orientation columns; accelerated EPI ID OCULAR DOMINANCE COLUMNS; SURFACE-BASED ANALYSIS; PHASED-ARRAY; HEAD COIL; BRAIN; MRI; NOISE; FMRI; DESIGN; TESLA AB Purpose: Functional neuroimaging of small cortical patches such as columns is essential for testing computational models of vision, but imaging from cortical columns at conventional 3T fields is exceedingly difficult. By targeting the visual cortex exclusively, we tested whether combined optimization of shape, coil placement, and electronics would yield the necessary gains in signal-to-noise ratio (SNR) for submillimeter visual cortex functional MRI (fMRI). Method: We optimized the shape of the housing to a population-averaged atlas. The shape was comfortable without cushions and resulted in the maximally proximal placement of the coil elements. By using small wire loops with the least number of solder joints, we were able to maximize the Q factor of the individual elements. Finally, by planning the placement of the coils using the brain atlas, we were able to target the arrangement of the coil elements to the extent of the visual cortex. Results: The combined optimizations led to as much as two-fold SNR gain compared with a whole-head 32-channel coil. This gain was reflected in temporal SNR as well and enabled fMRI mapping at 0.75 mm resolutions using a conventional GRAPPA-accelerated gradient echo echo planar imaging. Conclusion: Integrated optimization of shape, electronics, and element placement can lead to large gains in SNR and empower submillimeter fMRI at 3T. (C) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. C1 [Farivar, Reza; Grigorov, Filip] McGill Univ, Dept Ophthalmol, McGill Vis Res Unit, Montreal, PQ, Canada. [van der Kouwe, Andre J.; Wald, Lawrence L.; Keil, Boris] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [van der Kouwe, Andre J.; Wald, Lawrence L.; Keil, Boris] Harvard Med Sch, Boston, MA USA. [Wald, Lawrence L.] MIT, Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Farivar, R (reprint author), Royal Victoria Hosp, McGill Vis Res Unit, Room H4-14,687 Pine Ave West, Montreal, PQ H3A 1A1, Canada. EM reza.farivar@mcgill.ca FU National Institutes of Health [P41RR14075]; Research Institute of the McGill University Health Centre FX Grant sponsor: National Institutes of Health; Grant number: P41RR14075; Grant sponsor: Research Institute of the McGill University Health Centre (internal award to Reza Farivar). NR 30 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2016 VL 76 IS 1 BP 321 EP 328 DI 10.1002/mrm.25815 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY3MK UT WOS:000384996900032 PM 26218835 ER PT J AU Mahmood, Z McDaniel, P Guerin, B Keil, B Vester, M Adalsteinsson, E Wald, LL Daniel, L AF Mahmood, Zohaib McDaniel, Patrick Guerin, Bastien Keil, Boris Vester, Markus Adalsteinsson, Elfar Wald, Lawrence L. Daniel, Luca TI General Design Approach and Practical Realization of Decoupling Matrices for Parallel Transmission Coils SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE decoupling matrix; robust decoupling; parallel transmit coils; parallel transmission; power efficiency ID RF PULSE DESIGN; PHASED-ARRAY; SAR REDUCTION; GLOBAL SAR; 8 CHANNELS; LOCAL SAR; EXCITATION; POWER; MRI; CONSTRAINTS AB Purpose: In a coupled parallel transmit (pTx) array, the power delivered to a channel is partially distributed to other channels because of coupling. This power is dissipated in circulators resulting in a significant reduction in power efficiency. In this study, a technique for designing robust decoupling matrices interfaced between the RF amplifiers and the coils is proposed. The decoupling matrices ensure that most forward power is delivered to the load without loss of encoding capabilities of the pTx array. Theory and Methods: The decoupling condition requires that the impedance matrix seen by the power amplifiers is a diagonal matrix whose entries match the characteristic impedance of the power amplifiers. In this work, the impedance matrix of the coupled coils is diagonalized by a successive multiplication by its eigenvectors. A general design procedure and software are developed to generate automatically the hardware that implements diagonalization using passive components. Results: The general design method is demonstrated by decoupling two example parallel transmit arrays. Our decoupling matrices achieve better than -20 db decoupling in both cases. Conclusion: A robust framework for designing decoupling matrices for pTx arrays is presented and validated. The proposed decoupling strategy theoretically scales to any arbitrary number of channels. (C) 2015 Wiley Periodicals, Inc. C1 [Mahmood, Zohaib; McDaniel, Patrick; Adalsteinsson, Elfar; Daniel, Luca] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Guerin, Bastien; Keil, Boris; Wald, Lawrence L.] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Vester, Markus] Siemens AG, Healthcare Sect, Imaging & Therapy Div, Erlangen, Germany. [Adalsteinsson, Elfar; Wald, Lawrence L.] Harvard MIT Div Hlth Sci Technol, Cambridge, MA USA. [Adalsteinsson, Elfar; Wald, Lawrence L.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. RP Mahmood, Z (reprint author), MIT, Off 36-732,77 Massachusetts Ave, Cambridge, MA 02139 USA. FU National Science Foundation [1227020-EEC]; Semiconductor Research Corporation [TASK 2436.001]; NIH [R01EB0006847, R01EB007942, P41EB015896] FX Grant sponsor: National Science Foundation; Grant number: 1227020-EEC; Grant sponsor: the Semiconductor Research Corporation; Grant number: TASK 2436.001; Grant sponsor: NIH; Grant numbers: R01EB0006847, R01EB007942, P41EB015896. NR 55 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUL PY 2016 VL 76 IS 1 BP 329 EP 339 DI 10.1002/mrm.25855 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY3MK UT WOS:000384996900033 PM 26228386 ER PT J AU Lemieux, JE Tran, AD Freimark, L Schaffner, SF Goethert, H Andersen, KG Bazner, S Li, A McGrath, G Sloan, L Vannier, E Milner, D Pritt, B Rosenberg, E Telford, S Bailey, JA Sabeti, PC AF Lemieux, Jacob E. Tran, Alice D. Freimark, Lisa Schaffner, Stephen F. Goethert, Heidi Andersen, Kristian G. Bazner, Suzane Li, Amy McGrath, Graham Sloan, Lynne Vannier, Edouard Milner, Dan Pritt, Bobbi Rosenberg, Eric Telford, Sam, III Bailey, Jeffrey A. Sabeti, Pardis C. TI A global map of genetic diversity in Babesia microti reveals strong population structure and identifies variants associated with clinical relapse SO NATURE MICROBIOLOGY LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; CYTOCHROME-B; IMMUNOCOMPROMISED PATIENTS; ATOVAQUONE-RESISTANCE; RIBOSOMAL MUTATIONS; HYBRID SELECTION; UNITED-STATES; INFECTION; PARASITES; AZITHROMYCIN AB Human babesiosis caused by Babesia microti is an emerging tick-borne zoonosis of increasing importance due to its rising incidence and expanding geographic range(1). Infection with this organism, an intraerythrocytic parasite of the phylum Apicomplexa, causes a febrile syndrome similar to malaria(2). Relapsing disease is common among immunocompromised and asplenic individuals(3,4) and drug resistance has recently been reported(5). To investigate the origin and genetic diversity of this parasite, we sequenced the complete genomes of 42 B. microti samples from around the world, including deep coverage of clinical infections at endemic sites in the continental USA. Samples from the continental USA segregate into a Northeast lineage and a Midwest lineage, with subsequent divergence of subpopulations along geographic lines. We identify parasite variants that associate with relapsing disease, including amino acid substitutions in the atovaquone-binding regions of cytochrome b (cytb) and the azithromycin-binding region of ribosomal protein subunit L4 (rpl4). Our results shed light on the origin, diversity and evolution of B. microti, suggest possible mechanisms for clinical relapse, and create the foundation for further research on this emerging pathogen. C1 [Lemieux, Jacob E.; Freimark, Lisa; Schaffner, Stephen F.; Andersen, Kristian G.; Sabeti, Pardis C.] Broad Inst MIT Div Hlth Sci, Cambridge, MA 02142 USA. [Lemieux, Jacob E.; Freimark, Lisa; Schaffner, Stephen F.; Andersen, Kristian G.; Sabeti, Pardis C.] MIT, Cambridge, MA 02142 USA. [Lemieux, Jacob E.; Bazner, Suzane; McGrath, Graham; Rosenberg, Eric] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Tran, Alice D.; Bailey, Jeffrey A.] Univ Massachusetts, Sch Med, Program Bioinformat & Integrat Biol, Worcester, MA 01605 USA. [Goethert, Heidi; Telford, Sam, III] Tufts Sch Vet Med, North Grafton, MA 01536 USA. [Andersen, Kristian G.] Scripps Res Inst, La Jolla, CA 92037 USA. [Li, Amy] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Sloan, Lynne; Pritt, Bobbi] Mayo Clin, Dept Pathol, Rochester, MN 55905 USA. [Vannier, Edouard] Tufts Med Ctr, Div Geog Med & Infect Dis, Boston, MA 02111 USA. [Milner, Dan] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. [Rosenberg, Eric] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Bailey, Jeffrey A.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. [Sabeti, Pardis C.] MIT Div Hlth Sci & Univ, Dept Evolutionary & Organism Biol, Cambridge, MA 02138 USA. RP Sabeti, PC (reprint author), Broad Inst MIT Div Hlth Sci, Cambridge, MA 02142 USA.; Sabeti, PC (reprint author), MIT, Cambridge, MA 02142 USA.; Sabeti, PC (reprint author), MIT Div Hlth Sci & Univ, Dept Evolutionary & Organism Biol, Cambridge, MA 02138 USA. EM pardis@broadinstitute.org RI Schaffner, Stephen/D-1189-2011 FU Broad Institute SPARC programme; Bill and Melinda Gates Foundation; Howard Hughes Medical Institute; Infectious Disease Society of America; MIT Division of Health Sciences and/MIT Division of Health Sciences and Technology Research Assistantship; NIH MSTP [T32GM007753]; NIH [U01AI109656, R41AI078631]; Evelyn Lilly Lutz Foundation; Dorothy Harrison Egan Foundation; National Research Fund for Tick-Borne Diseases FX The authors thank R. Tewhey, A. Piantadosi and J. Maguire for feedback and advice, and J. Robbins, J. Katz, J. Gelfand and T. Wieczorek for discussions and assistance with sample collection. The authors acknowledge members of the parasitology and haematology laboratories at Massachusetts General Hospital and Brigham and Women's Hospital for assistance with case identification. P.C.S. and this work are supported by the Broad Institute SPARC programme and the Bill and Melinda Gates Foundation and the Howard Hughes Medical Institute. This work was supported in part by an Infectious Disease Society of America Medical Scholars award, a MIT Division of Health Sciences and/MIT Division of Health Sciences and Technology Research Assistantship to J.E.L. and NIH MSTP grants T32GM007753 to J.E.L. and A.L. S.T. and H.K.G. are supported by NIH U01AI109656 and R41AI078631 and by grants from the Evelyn Lilly Lutz Foundation, the Dorothy Harrison Egan Foundation and the Bill and Melinda Gates Foundation. E.V. was supported by a grant from the National Research Fund for Tick-Borne Diseases. NR 50 TC 3 Z9 3 U1 6 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND EI 2058-5276 J9 NAT MICROBIOL JI NAT. MICROBIOL PD JUL PY 2016 VL 1 IS 7 AR 16079 DI 10.1038/NMICROBIOL.2016.79 PG 7 WC Microbiology SC Microbiology GA DW4IF UT WOS:000383605700015 PM 27572973 ER PT J AU Nierenberg, AA AF Nierenberg, Andrew A. TI Why We Sleep SO PSYCHIATRIC ANNALS LA English DT Editorial Material C1 [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Psychiat, Boston, MA 02114 USA. [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA. [Nierenberg, Andrew A.] Massachusetts Gen Hosp, MGH Res Inst, Training & Educ, Boston, MA 02114 USA. [Nierenberg, Andrew A.] Harvard Med Sch, Psychiat, Boston, MA 02115 USA. RP Nierenberg, AA (reprint author), Massachusetts Gen Hosp, Psychiat, Boston, MA 02114 USA.; Nierenberg, AA (reprint author), Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA.; Nierenberg, AA (reprint author), Massachusetts Gen Hosp, MGH Res Inst, Training & Educ, Boston, MA 02114 USA.; Nierenberg, AA (reprint author), Harvard Med Sch, Psychiat, Boston, MA 02115 USA. EM psyann@Healio.com NR 2 TC 0 Z9 0 U1 2 U2 2 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 EI 1938-2456 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD JUL PY 2016 VL 46 IS 7 BP 381 EP 381 DI 10.3928/00485713-20160520-01 PG 1 WC Psychiatry SC Psychiatry GA DY3VF UT WOS:000385022600001 ER PT J AU Patino, M Prochowski, A Agrawal, MD Simeone, FJ Gupta, R Hahn, PF Sahani, DV AF Patino, Manuel Prochowski, Andrea Agrawal, Mukta D. Simeone, Frank J. Gupta, Rajiv Hahn, Peter F. Sahani, Dushyant V. TI Material Separation Using Dual-Energy CT: Current and Emerging Applications SO RADIOGRAPHICS LA English DT Article ID VIRTUAL NONENHANCED IMAGES; ACUTE PULMONARY-EMBOLISM; ADDITIONAL SPECTRAL FILTRATION; EFFECTIVE ATOMIC NUMBER; RENAL STONE COMPOSITION; COMPUTED-TOMOGRAPHY; DIAGNOSTIC PERFORMANCE; MULTIDETECTOR CT; MATERIAL DENSITY; LIVER FIBROSIS AB Dual-energy (DE) computed tomography (CT) offers the opportunity to generate material-specific images on the basis of the atomic number Z and the unique mass attenuation coefficient of a particular material at different x-ray energies. Material-specific images provide qualitative and quantitative information about tissue composition and contrast media distribution. The most significant contribution of DE CT-based material characterization comes from the capability to assess iodine distribution through the creation of an image that exclusively shows iodine. These iodine-specific images increase tissue contrast and amplify subtle differences in attenuation between normal and abnormal tissues, improving lesion detection and characterization in the abdomen. In addition, DE CT enables computational removal of iodine influence from a CT image, generating virtual noncontrast images. Several additional materials, including calcium, fat, and uric acid, can be separated, permitting imaging assessment of metabolic imbalances, elemental deficiencies, and abnormal deposition of materials within tissues. The ability to obtain material-specific images from a single, contrast-enhanced CT acquisition can complement the anatomic knowledge with functional information, and may be used to reduce the radiation dose by decreasing the number of phases in a multiphasic CT examination. DE CT also enables generation of energy-specific and virtual monochromatic images. Clinical applications of DE CT leverage both material-specific images and virtual monochromatic images to expand the current role of CT and overcome several limitations of single-energy CT. (C) RSNA, 2016. C1 [Patino, Manuel; Prochowski, Andrea; Agrawal, Mukta D.; Simeone, Frank J.; Gupta, Rajiv; Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging, 55 Fruit St, Boston, MA 02114 USA. [Hahn, Peter F.] Massachusetts Gen Hosp, Dept Abdominal Imaging & Intervent, 55 Fruit St, Boston, MA 02114 USA. Harvard Med Sch, 55 Fruit St, Boston, MA 02114 USA. RP Sahani, DV (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging, 55 Fruit St, Boston, MA 02114 USA. EM dsahani@mgh.harvard.edu NR 99 TC 1 Z9 1 U1 1 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD JUL-AUG PY 2016 VL 36 IS 4 BP 1087 EP 1105 DI 10.1148/rg.2016150220 PG 19 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA DY3YG UT WOS:000385033800011 PM 27399237 ER PT J AU Barnett, PG Schmitt, SK Yu, W Goetz, MB Ohl, ME Asch, SM AF Barnett, Paul G. Schmitt, Susan K. Yu, Wei Goetz, Matthew Bidwell Ohl, Michael E. Asch, Steven M. TI How Will New Guidelines Affect CD4 Testing in Veterans With HIV? SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE HIV; CD4 testing; veterans; guidelines; cost ID ANTIRETROVIRAL THERAPY; INFECTED PATIENTS; CELL COUNT; SUPPRESSION AB Background. Guidelines now recommend limited use of routine CD4 cell count testing in human immunodeficiency virus (HIV)-infected patients with successful viral control who are not immunocompromised. Methods. CD4 and viral load tests for patients receiving HIV care from the US Department of Veterans Affairs during 2009-2013 were evaluated to determine trends in CD4 testing frequency and the number, cost, and results of CD4 tests considered optional under the guidelines. Results. There were 28 530 individuals with sufficient testing to be included. At the time of the last CD4 test, 19.8% of the cohort was eligible for optional monitoring and 15.6% for minimal monitoring. CD4 testing frequency declined by 10.8% over 4 years, reducing the direct cost of testing by US$196 000 per year. Full implementation of new treatment guidelines could reduce CD4 testing a further 28.9%, an additional annual savings of US$600 000. CD4 tests conducted during periods of potentially reduced monitoring were rarely <200 cells/mu L: 1.1% of the tests conducted when minimal monitoring was recommended and just 0.3% of tests conducted when optional monitoring was recommended were less than this value. Conclusions. Reduced CD4 monitoring of HIV-infected patients would result in modest cost savings and likely reduce patient anxiety, with little or no impact on the quality of care. Veterans Affairs has made substantial progress in reducing the frequency of optional CD4 testing, but further reductions may still be warranted. C1 [Barnett, Paul G.; Schmitt, Susan K.; Yu, Wei] Vet Affairs Palo Alto Hlth Care Syst, Hlth Econ Resource Ctr, Menlo Pk, CA USA. [Barnett, Paul G.] Univ Calif San Francisco, Dept Psychiat, Treatment Res Ctr, San Francisco, CA USA. [Barnett, Paul G.; Yu, Wei; Asch, Steven M.] Vet Affairs Palo Alto Hlth Care Syst, Ctr Innovat Implementat, Menlo Pk, CA USA. [Goetz, Matthew Bidwell] Univ Calif Los Angeles, Infect Dis Sect, Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90024 USA. [Goetz, Matthew Bidwell] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Ohl, Michael E.] Univ Iowa, Ctr Comprehens Access & Delivery Res & Evaluat, Iowa City Vet Affairs Med Ctr, Dept Internal Med,Carver Coll Med, Iowa City, IA 52242 USA. [Asch, Steven M.] Stanford Univ, Sch Med, Dept Gen Med Disciplines, Stanford, CA 94305 USA. RP Barnett, PG (reprint author), VA Palo Alto Hlth Care Syst, Hlth Econ Resource Ctr, 795 Willow Rd 152 MPD, Menlo Pk, CA 94025 USA. EM paul.barnett@va.gov FU Quality Enhancement Research Initiative; Health Services Research and Development Service of the US Department of Veterans Affairs FX This work was supported by the Quality Enhancement Research Initiative and the Health Services Research and Development Service of the US Department of Veterans Affairs. NR 18 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2016 VL 63 IS 1 BP 96 EP 100 DI 10.1093/cid/ciw194 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA DT1FH UT WOS:000381226600019 PM 27045125 ER PT J AU Garvey, WT Mechanick, JI Brett, EM Garber, AJ Hurley, DL Jastreboff, AM Nadolsky, K Pessah-Pollack, R Plodkowski, R AF Garvey, W. Timothy Mechanick, Jeffrey I. Brett, Elise M. Garber, Alan J. Hurley, Daniel L. Jastreboff, Ania M. Nadolsky, Karl Pessah-Pollack, Rachel Plodkowski, Raymond CA AACE ACE Obesity Clinical Practice TI AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITY SO ENDOCRINE PRACTICE LA English DT Article ID BODY-MASS INDEX; POLYCYSTIC-OVARY-SYNDROME; NONALCOHOLIC FATTY-LIVER; RANDOMIZED-CONTROLLED-TRIAL; TYPE-2 DIABETES-MELLITUS; GASTROESOPHAGEAL-REFLUX DISEASE; BINGE-EATING DISORDER; OBSTRUCTIVE SLEEP-APNEA; PLACEBO-CONTROLLED TRIAL; LIFE-STYLE INTERVENTION AB Objective: Development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and the American College of Endocrinology (ACE) Board of Trustees and adheres to published AACE protocols for the standardized production of clinical practice guidelines (CPGs). Methods: Recommendations are based on diligent review of clinical evidence with transparent incorporation of subjective factors. Results: There are 9 broad clinical questions with 123 recommendation numbers that include 160 specific statements (85 [53.1%] strong [Grade A]; 48 [30.0%] intermediate [Grade B], and 11 [6.9%] weak [Grade C], with 16 [10.0%] based on expert opinion [Grade D]) that build a comprehensive medical care plan for obesity. There were 133 (83.1%) statements based on strong (best evidence level [BEL] 1 = 79 [49.4%]) or intermediate (BEL 2 = 54 [33.7%]) levels of scientific substantiation. There were 34 (23.6%) evidence-based recommendation grades (Grades A-C = 144) that were adjusted based on subjective factors. Among the 1,790 reference citations used in this CPG, 524 (29.3%) were based on strong (evidence level [EL] 1), 605 (33.8%) were based on intermediate (EL 2), and 308 (17.2%) were based on weak (EL 3) scientific studies, with 353 (19.7%) based on reviews and opinions (EL 4). Conclusion: The final recommendations recognize that obesity is a complex, adiposity-based chronic disease, where management targets both weight-related complications and adiposity to improve overall health and quality of life. The detailed evidence-based recommendations allow for nuanced clinical decision-making that addresses real-world medical care of patients with obesity, including screening, diagnosis, evaluation, selection of therapy, treatment goals, and individualization of care. The goal is to facilitate high-quality care of patients with obesity and provide a rational, scientific approach to management that optimizes health outcomes and safety. C1 [Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Garvey, W. Timothy] UAB Diabet Res Ctr, Birmingham, AL USA. [Garvey, W. Timothy] Birmingham VA Med Ctr, Birmingham, AL USA. [Mechanick, Jeffrey I.] Icahn Sch Med Mt Sinai, Metab Support, New York, NY 10029 USA. [Mechanick, Jeffrey I.] Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, Med, New York, NY 10029 USA. [Brett, Elise M.] Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. [Garber, Alan J.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Garber, Alan J.] Baylor Coll Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Garber, Alan J.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Hurley, Daniel L.] Mayo Clin, Med, Rochester, MN USA. [Jastreboff, Ania M.] Yale Univ, Sch Med, Internal Med, Endocrinol,Pediat,Pediat Endocrinol, New Haven, CT USA. [Nadolsky, Karl] Walter Reed Natl Mil Med Ctr, Diabet Obes & Metab Inst, Bethesda, MD USA. [Pessah-Pollack, Rachel] Mt Sinai Sch Med, ProHlth Care Associates, Div Endocrinol, Lake Success, NY USA. [Plodkowski, Raymond] Scripps Clin, Ctr Weight Management, Div Endocrinol Diabet & Metab, San Diego, CA USA. RP Garvey, WT (reprint author), Amer Assoc Clin Endocrinologists, 245 Riverside Ave,Suite 200, Jacksonville, FL 32202 USA. EM publications@aace.com NR 1790 TC 10 Z9 10 U1 26 U2 26 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD JUL PY 2016 VL 22 SU 3 BP 1 EP 203 DI 10.4158/EP161365.GL PG 203 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DX3NJ UT WOS:000384279500001 PM 27219496 ER PT J AU Garvey, WT Mechanick, JI Brett, EM Garber, AJ Hurley, DL Jastreboff, AM Nadolsky, K Pessah-Pollack, R Plodkowski, R AF Garvey, W. Timothy Mechanick, Jeffrey I. Brett, Elise M. Garber, Alan J. Hurley, Daniel L. Jastreboff, Ania M. Nadolsky, Karl Pessah-Pollack, Rachel Plodkowski, Raymond CA AACE ACE Obesity Clinical Practice TI AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITY SO ENDOCRINE PRACTICE LA English DT Article ID CARDIOVASCULAR-DISEASE RISK; WEIGHT-LOSS DIETS; RANDOMIZED CONTROLLED-TRIAL; IMPROVING PRIMARY-CARE; BODY-MASS INDEX; MEDITERRANEAN DIET; METABOLIC SYNDROME; MACRONUTRIENT COMPOSITION; STANDARDIZED PRODUCTION; INSULIN SENSITIVITY AB Objective: Development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and the American College of Endocrinology (ACE) Board of Trustees and adheres to published AACE protocols for the standardized production of clinical practice guidelines (CPGs). Methods: Recommendations are based on diligent review of clinical evidence with transparent incorporation of subjective factors. Results: There are 9 broad clinical questions with 123 recommendation numbers that include 160 specific statements (85 [53.1%] strong [Grade A], 48 [30.0%] intermediate [Grade B], and 11 [6.9%] weak [Grade C], with 16 [10.0%] based on expert opinion [Grade D]) that build a comprehensive medical care plan for obesity. There were 133 (83.1%) statements based on strong (best evidence level [BEL] 1 = 79 [49.4%]) or intermediate (BEL 2 = 54 [33.7%]) levels of scientific substantiation. There were 34 (23.6%) evidence-based recommendation grades (Grades A-C = 144) that were adjusted based on subjective factors. Among the 1,788 reference citations used in this CPG, 524 (29.3%) were based on strong (evidence level [EL] 1), 605 (33.8%) were based on intermediate (EL 2), and 308 (17.2%) were based on weak (EL 3) scientific studies, with 351 (19.6%) based on reviews and opinions (EL 4). Conclusion: The final recommendations recognize that obesity is a complex, adiposity-based chronic disease, where management targets both weight-related complications and adiposity to improve overall health and quality of life. The detailed evidence-based recommendations allow for nuanced clinical decision-making that addresses real-world medical care of patients with obesity, including screening, diagnosis, evaluation, selection of therapy, treatment goals, and individualization of care. The goal is to facilitate high-quality care of patients with obesity and provide a rational, scientific approach to management that optimizes health outcomes and safety. C1 [Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Garvey, W. Timothy] UAB Diabet Res Ctr, Birmingham, AL 35294 USA. [Garvey, W. Timothy] Birmingham VA Med Ctr, Birmingham, AL 35233 USA. [Mechanick, Jeffrey I.] Icahn Sch Med Mt Sinai, Metab Support, New York, NY 10029 USA. [Mechanick, Jeffrey I.] Icahn Sch Med Mt Sinai, Med, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. [Brett, Elise M.] Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. [Garber, Alan J.] Baylor Coll Med, Dept Med Biochem & Mol Biol, Houston, TX 77030 USA. [Garber, Alan J.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Hurley, Daniel L.] Mayo Clin, Med, Rochester, MN USA. [Jastreboff, Ania M.] Yale Univ, Sch Med, Internal Med Endocrinol Pediat Pediat Endocrinol, New Haven, CT USA. [Nadolsky, Karl] Walter Reed Natl Mil Med Ctr, Diabet Obes & Metab Inst, Bethesda, MD USA. [Pessah-Pollack, Rachel] Mt Sinai Sch Med, New York, NY USA. [Pessah-Pollack, Rachel] ProHealth Care Associates, Div Endocrinol, Lake Success, NY USA. [Plodkowski, Raymond] Scripps Clin, Div Endocrinol Diabet & Metab, Ctr Weight Management, San Diego, CA USA. RP Garvey, WT (reprint author), Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA.; Garvey, WT (reprint author), UAB Diabet Res Ctr, Birmingham, AL 35294 USA.; Garvey, WT (reprint author), Birmingham VA Med Ctr, Birmingham, AL 35233 USA. EM publications@aace.com NR 75 TC 5 Z9 5 U1 3 U2 3 PU AMER ASSOC CLINICAL ENDOCRINOLOGISTS PI JACKSONVILLE PA 245 RIVERSIDE AVENUE, STE 200, JACKSONVILLE, FL 32202 USA SN 1530-891X EI 1934-2403 J9 ENDOCR PRACT JI Endocr. Pract. PD JUL PY 2016 VL 22 IS 7 BP 842 EP 884 DI 10.4158/EP161356.ESGL PG 43 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DX3NI UT WOS:000384279400011 PM 27472012 ER PT J AU Heidenreich, PA Sahay, A Oliva, N Gholami, P Lin, S Mittman, BS Rumsfeld, JS AF Heidenreich, Paul A. Sahay, Anju Oliva, Nancy Gholami, Parisa Lin, Shoutzu Mittman, Brian S. Rumsfeld, John S. TI Impact of the Hospital to Home Initiative on Readmissions in the VA Health Care System SO QUALITY MANAGEMENT IN HEALTH CARE LA English DT Article DE heart failure; quality of care; readmission; transition of care ID HEART-FAILURE; INTERVENTIONS; METAANALYSIS; RATES AB Background: Hospital to Home (H2H) is a national quality improvement initiative sponsored by the Institute for Healthcare Improvement and the American College of Cardiology, with the goal of reducing readmission for patients hospitalized with heart disease. We sought to determine the impact of H2H within the Veterans Affairs (VA) health care system. Methods: Using a controlled interrupted time series, we determined the association of VA hospital enrollment in H2H with the primary outcome of 30-day all-cause readmission following a heart failure hospitalization. VA heart failure providers were surveyed to determine quality improvement projects initiated in response to H2H. Secondary outcomes included initiation of recommended H2H projects, follow-up within 7 days, and total hospital days at 30 days and 1 year. Results: Sixty-five of 104 VA hospitals (66%) enrolled in the national H2H initiative. Hospital characteristic associated with H2H enrollment included provision of tertiary care, academic affiliation, and greater use of home monitoring. There was no significant difference in mean 30-day readmission rates (20.0% 5.0% for H2H vs 19.3% +/- 5.9% for non-H2H hospitals; P = .48) The mean fraction of patients with a cardiology visit within 7 days was slightly higher for H2H hospitals (3.0% +/- 2.4% for H2H vs 2.0% +/- 1.9% for non-H2H hospitals; P = .05). Patients discharged from H2H hospitals had fewer mean hospitals days during the following year (7.6% +/- 2.6% for H2H vs 9.2% +/- 3.0 for non-H2H; P = .01) early after launch of H2H, but the effect did not persist. Conclusions: VA hospitals enrolling in H2H had slightly more early follow-up in cardiology clinic but no difference in 30-day readmission rates compared with hospitals not enrolling in H2H. C1 [Heidenreich, Paul A.; Sahay, Anju; Oliva, Nancy; Gholami, Parisa; Lin, Shoutzu] Vet Adm Palo Alto Hlth Care Syst, 111C,3801 Ave, Palo Alto, CA 94303 USA. [Mittman, Brian S.] Greater Los Angeles VA Hlth Care Syst, Los Angeles, CA USA. [Rumsfeld, John S.] Eastern Colorado VA Hlth Care Syst, Denver, CO USA. RP Heidenreich, PA (reprint author), Vet Adm Palo Alto Hlth Care Syst, 111C,3801 Ave, Palo Alto, CA 94303 USA. EM heiden@stanford.edu FU Veterans Administration's Quality Enhancement and Research Initiative [04-326, SDP 09-160] FX This study was supported by grants from the Veterans Administration's Quality Enhancement and Research Initiative 04-326 and SDP 09-160. NR 11 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1063-8628 EI 1550-5154 J9 QUAL MANAG HEALTH CA JI Qual. Manag. Health Care PD JUL-SEP PY 2016 VL 25 IS 3 BP 129 EP 133 DI 10.1097/QMH.0000000000000105 PG 5 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA DX1OI UT WOS:000384136300002 PM 27367213 ER PT J AU Berretta, P Patel, HJ Gleason, TG Sundt, TM Myrmel, T Desai, N Korach, A Panza, A Bavaria, J Khoynezhad, A Woznicki, E Montgomery, D Isselbacher, EM Di Bartolomeo, R Fattori, R Nienaber, CA Eagle, KA Trimarchi, S Di Eusanio, M AF Berretta, Paolo Patel, Himanshu J. Gleason, Thomas G. Sundt, Thoralf M. Myrmel, Truls Desai, Nimesh Korach, Amit Panza, Antonello Bavaria, Joe Khoynezhad, Ali Woznicki, Elise Montgomery, Dan Isselbacher, Eric M. Di Bartolomeo, Roberto Fattori, Rossella Nienaber, Christoph A. Eagle, Kim A. Trimarchi, Santi Di Eusanio, Marco TI IRAD experience on surgical type A acute dissection patients: results and predictors of mortality SO ANNALS OF CARDIOTHORACIC SURGERY LA English DT Article DE Type A aortic dissection; aorta; international registry of acute aortic dissection (IRAD); aortic surgery ID ACUTE-AORTIC-DISSECTION; INTERNATIONAL-REGISTRY; CLINICAL CHARACTERISTICS; ROOT REPLACEMENT; RISK-FACTORS; MANAGEMENT; OUTCOMES; REPAIR; MALPERFUSION; INSIGHTS AB Type A acute aortic dissection (TAAD) is a disease that has a catastrophic impact on a patient's life and emergent surgery represents a key goal of early treatment. Despite continuous improvements in imaging techniques, medical therapy and surgical management, early mortality in patients undergoing TAAD repair still remains high, ranging from 17% to 26%. In this setting, the International Registry of Acute Aortic Dissection (IRAD), the largest worldwide registry for acute aortic dissection, was established to assess clinical characteristics, management and outcomes of TAAD patients. The present review aimed to evaluate and comment on outcomes of TAAD surgery as reported from IRAD series. C1 [Berretta, Paolo; Di Eusanio, Marco] G Mazzini Hosp, Div Cardiac Surg, Teramo, Italy. [Patel, Himanshu J.] Univ Michigan Hlth Syst, Cardiac Surg, Ann Arbor, MI USA. [Gleason, Thomas G.] Univ Pittsburgh, Div Cardiothorac Surg, Pittsburgh, PA USA. [Sundt, Thoralf M.; Isselbacher, Eric M.] Massachusetts Gen Hosp, Thorac Aort Ctr, Boston, MA 02114 USA. [Myrmel, Truls] Univ Tromso Hosp, Dept Thorac & Cardiovasc Surg, Tromso, Norway. [Desai, Nimesh; Bavaria, Joe] Univ Penn, Sch Med, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. [Korach, Amit] Hadassah Hebrew Univ Med Ctr, Dept Cardiothorac Surg, Jerusalem, Israel. [Panza, Antonello] Univ Hosp San Giovanni di Dio & Ruggi dAragona, Dept Cardiol & Cardiac Surg, Salerno, Italy. [Khoynezhad, Ali] Cedars Sinai Med Ctr, Div Cardiothorac Surg, Los Angeles, CA 90048 USA. [Woznicki, Elise; Montgomery, Dan; Eagle, Kim A.] Univ Michigan Hlth Syst, Cardiovasc Ctr, Ann Arbor, MI USA. [Di Bartolomeo, Roberto] Univ Bologna, S Orsola Malpighi Hosp, Dept Cardiac Surg, I-40126 Bologna, Italy. [Fattori, Rossella] San Salvatore Hosp, Intervent Cardiol Unit, Pesaro, Italy. [Nienaber, Christoph A.] Royal Brompton & Harefield NHS Trust, Cardiol & Aort Ctr, London, England. [Trimarchi, Santi] IRCCS Policlin San Donato, Thorac Aort Res Ctr, San Donato Milanese, Italy. RP Di Eusanio, M (reprint author), G Mazzini Hosp, Dept Cardiac Surg, Piazza Italia, I-64100 Teramo, Italy. EM marco.dieusanio@aslteramo.it NR 38 TC 1 Z9 2 U1 0 U2 0 PU AME PUBL CO PI SHEUNG WAN PA ROOM 604 6-F HOLLYWOOD CENTER, 77-91, QUEENS ROAD, SHEUNG WAN, HONG KONG 00000, PEOPLES R CHINA SN 2225-319X EI 2304-1021 J9 ANN CARDIOTHORAC SUR JI Ann. Cardiothorac. Surg. PD JUL PY 2016 VL 5 IS 4 BP 346 EP 351 DI 10.21037/acs.2016.05.10 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA DW0TX UT WOS:000383356800009 PM 27563547 ER PT J AU Fussner, LA Hummel, AM Schroeder, DR Silva, F Cartin-Ceba, R Snyder, MR Hoffman, GS Kallenberg, CGM Langford, CA Merkel, PA Monach, PA Seo, P Spiera, RF St Clair, EW Tchao, NK Stone, JH Specks, U AF Fussner, Lynn A. Hummel, Amber M. Schroeder, Darrell R. Silva, Francisco Cartin-Ceba, Rodrigo Snyder, Melissa R. Hoffman, Gary S. Kallenberg, Cees G. M. Langford, Carol A. Merkel, Peter A. Monach, Paul A. Seo, Philip Spiera, Robert F. St Clair, E. William Tchao, Nadia K. Stone, John H. Specks, Ulrich CA Rituximab ANCA-Associated Vasculit TI Factors Determining the Clinical Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3 SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID ANCA-ASSOCIATED VASCULITIS; TERM-FOLLOW-UP; WEGENERS-GRANULOMATOSIS; DISEASE-ACTIVITY; POLYANGIITIS WEGENERS; SYSTEMIC VASCULITIS; TREATMENT RESISTANCE; REMISSION-INDUCTION; CAPTURE-ELISA; RELAPSE AB Objective. Relapse following remission is common in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), particularly with ANCAs directed at proteinase 3 (PR3). This study was undertaken to evaluate the association of an increase in PR3-ANCA level with subsequent relapse. Methods. Data from the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial were used. Starting from the time of achieving complete remission, serialmeasurements by direct and capture enzyme-linked immunosorbent assays (ELISAs) were analyzed in 93 patients with PR3-ANCA, using Cox proportional hazards regression. Results. An increase in PR3-ANCA level was identified in 58 of 93 subjects (62.4%) by direct ELISA and in 59 of 93 (63.4%) by capture ELISA. Relapses occurred in 55 of 93 subjects (59.1%), with 25 and 21 occurring within 1 year after an increase by direct ELISA and capture ELISA, respectively. An increase by direct ELISA was associated with subsequent severe relapses (hazard ratio [HR] 4.57; P < 0.001), particularly in patients presenting with renal involvement (HR 7.94; P < 0.001) and alveolar hemorrhage (HR 24.19; P < 0.001). Both assays identified increased risk for severe relapse in the rituximab group (HR 5.80; P50.002 for direct ELISA andHR 4.54; P50.007 for capture ELISA) but not the cyclophosphamide/azathioprine group (P=0.103 and P=0.197, respectively). Conclusion. The association of an increase in PR3-ANCA level with the risk of subsequent relapse is partially affected by the PR3-ANCA detection methodology, disease phenotype, and remission induction treatment. An increase in PR3-ANCA level during complete remission conveys an increased risk of relapse, particularly severe relapse, among patients with renal involvement or alveolar hemorrhage and those treated with rituximab. Serial measurements of PR3-ANCA may be informative in this subset of patients, but the risk of relapse must be weighed carefully against the risks associated with therapy. C1 [Fussner, Lynn A.; Hummel, Amber M.; Schroeder, Darrell R.; Cartin-Ceba, Rodrigo; Snyder, Melissa R.; Specks, Ulrich] Mayo Clin, Rochester, MN USA. [Fussner, Lynn A.; Hummel, Amber M.; Schroeder, Darrell R.; Cartin-Ceba, Rodrigo; Snyder, Melissa R.; Specks, Ulrich] Mayo Fdn Med Educ & Res, Rochester, MN USA. [Silva, Francisco] Univ Desarrollo, Santiago, Chile. [Hoffman, Gary S.; Langford, Carol A.] Cleveland Clin Fdn, Cleveland, OH USA. [Kallenberg, Cees G. M.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Merkel, Peter A.] Univ Penn, Philadelphia, PA 19104 USA. [Monach, Paul A.] Boston Univ, Med Ctr, Boston, MA USA. [Monach, Paul A.] VA Boston Healthcare Syst, Boston, MA USA. [Seo, Philip] Johns Hopkins Univ, Baltimore, MD USA. [Spiera, Robert F.] Hosp Special Surg, 535 E 70th St, New York, NY 10021 USA. [St Clair, E. William] Duke Univ, Med Ctr, Durham, NC USA. [Tchao, Nadia K.] Immune Tolerance Network, San Francisco, CA USA. [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Specks, U (reprint author), Mayo Clin, Div Pulm & Crit Care Med, 200 First St SW,Stabile Bldg 8-56, Rochester, MN 55905 USA. EM specks.ulrich@mayo.edu FU NIH (National Center for Advancing Translational Sciences Clinical and Translational Science Award [CTSA]) [UL1-TR-000135]; Immune Tolerance Network (NIH) [N01-AI-15416, ITN021AI]; National Institute of Allergy and Infectious Diseases, NIH; Juvenile Diabetes Research Foundation; Genentech; Biogen Idec; Arthritis Foundation; NIH [CTSA 1-UL1-RR-024150-01, CTSA UL1-RR-025005, K23-AR-052820, K24-AR-049185, CTSA UL1-RR-025771, M01-RR-00533, K24-AR-02224, UL1-TR-000439] FX Supported by the NIH (National Center for Advancing Translational Sciences Clinical and Translational Science Award [CTSA] UL1-TR-000135). Enzyme-linked immunosorbent assay kits for antineutrophil cytoplasmic antibody (ANCA) testing were provided by Euroimmun (Lubeck, Germany). Data for the current study were obtained from the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial, which was performed with the support of the Immune Tolerance Network (NIH contract N01-AI-15416, protocol number ITN021AI), an international clinical research consortium headquartered at the University of California and supported by the National Institute of Allergy and Infectious Diseases, NIH, and the Juvenile Diabetes Research Foundation. Genentech and Biogen Idec provided the study medications and partial funding for the RAVE trial. At the Mayo Clinic and Foundation, Johns Hopkins University, Boston University, and the Cleveland Clinic, the RAVE trial was supported by the NIH (Mayo Clinic: National Center for Research Resources CTSA 1-UL1-RR-024150-01; Johns Hopkins University: National Center for Research Resources CTSA UL1-RR-025005 and career development awards K23-AR-052820 to Dr. Seo and K24-AR-049185 to Dr. Stone; Boston University: National Center for Research Resources CTSA UL1-RR-025771, grant M01-RR-00533, and career development award K24-AR-02224 to Dr. Merkel; Cleveland Clinic: National Center for Advancing Translational Sciences grant UL1-TR-000439). The RAVE trial at Boston University was also supported by the Arthritis Foundation (Investigator Award to Dr. Monach). NR 52 TC 8 Z9 8 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD JUL PY 2016 VL 68 IS 7 BP 1700 EP 1710 DI 10.1002/art.39637 PG 11 WC Rheumatology SC Rheumatology GA DW2UO UT WOS:000383497500018 PM 26882078 ER PT J AU Fenske, TS Ahn, KW Graff, TM DiGilio, A Bashir, Q Kamble, RT Ayala, E Bacher, U Brammer, JE Cairo, M Chen, A Chen, YB Chhabra, S D'Souza, A Farooq, U Freytes, C Ganguly, S Hertzberg, M Inwards, D Jaglowski, S Kharfan-Dabaja, MA Lazarus, HM Nathan, S Pawarode, A Perales, MA Reddy, N Seo, S Sureda, A Smith, SM Hamadani, M AF Fenske, Timothy S. Ahn, Kwang W. Graff, Tara M. DiGilio, Alyssa Bashir, Qaiser Kamble, Rammurti T. Ayala, Ernesto Bacher, Ulrike Brammer, Jonathan E. Cairo, Mitchell Chen, Andy Chen, Yi-Bin Chhabra, Saurabh D'Souza, Anita Farooq, Umar Freytes, Cesar Ganguly, Siddhartha Hertzberg, Mark Inwards, David Jaglowski, Samantha Kharfan-Dabaja, Mohamed A. Lazarus, Hillard M. Nathan, Sunita Pawarode, Attaphol Perales, Miguel-Angel Reddy, Nishitha Seo, Sachiko Sureda, Anna Smith, Sonali M. Hamadani, Mehdi TI Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE DLBCL; prognostic score; allogeneic transplantation; prior autologous transplan ID B-CELL LYMPHOMA; CONDITIONING REGIMENS; REDUCED-INTENSITY; PREDICT SURVIVAL; IMPACT; RITUXIMAB; GRAFT; OUTCOMES; ORIGIN AB For diffuse large B-cell lymphoma (DLBCL) patients progressing after autologous haematopoietic cell transplantation (autoHCT), allogeneic HCT (alloHCT) is often considered, although limited information is available to guide patient selection. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 503 patients who underwent alloHCT after disease progression/relapse following a prior autoHCT. The 3-year probabilities of non-relapse mortality, progression/relapse, progression-free survival (PFS) and overall survival (OS) were 30, 38, 31 and 37% respectively. Factors associated with inferior PFS on multivariate analysis included Karnofsky performance status (KPS) <80, chemoresistance, autoHCT to alloHCT interval <1-year and myeloablative conditioning. Factors associated with worse OS on multivariate analysis included KPS<80, chemoresistance and myeloablative conditioning. Three adverse prognostic factors were used to construct a prognostic model for PFS, including KPS<80 (4 points), autoHCT to alloHCT interval <1-year (2 points) and chemoresistant disease at alloHCT (5 points). This CIBMTR prognostic model classified patients into four groups: low-risk (0 points), intermediate-risk (2-5 points), high-risk (6-9 points) or very high-risk (11 points), predicting 3-year PFS of 40, 32, 11 and 6%, respectively, with 3-year OS probabilities of 43, 39, 19 and 11% respectively. In conclusion, the CIBMTR prognostic model identifies a subgroup of DLBCL patients experiencing long-term survival with alloHCT after a failed prior autoHCT. C1 [Fenske, Timothy S.; Hamadani, Mehdi] Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Milwaukee, WI 53226 USA. [Ahn, Kwang W.; DiGilio, Alyssa; D'Souza, Anita; Hamadani, Mehdi] Med Coll Wisconsin, Dept Med, CIBMTR, Milwaukee, WI 53226 USA. [Ahn, Kwang W.] Med Coll Wisconsin, Div Biostat, Inst Hlth & Soc, Milwaukee, WI 53226 USA. [Graff, Tara M.] Med Oncol Hematol Associates, Des Moines, IA USA. [Bashir, Qaiser; Brammer, Jonathan E.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Stem Cell Transplantat, Houston, TX 77030 USA. [Kamble, Rammurti T.] Baylor Coll Med, Div Hematol & Oncol, Ctr Cell & Gene Therapy, Houston, TX 77030 USA. [Ayala, Ernesto; Kharfan-Dabaja, Mohamed A.] H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA. [Bacher, Ulrike] Univ Med Goettingen, Dept Haematol Oncol, Gottingen, Germany. [Bacher, Ulrike] Univ Canc Ctr Hamburg, Interdisciplinary Clin Stem Cell Transplantat, Hamburg, Germany. [Cairo, Mitchell] New York Med Coll, Dept Pediat, Div Pediat Hematol Oncol & Stem Cell Transplantat, Valhalla, NY 10595 USA. [Chen, Andy] Oregon Hlth & Sci Univ, Ctr Hematol Malignancies, Portland, OR 97201 USA. [Chen, Yi-Bin] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Chhabra, Saurabh] Med Univ South Carolina, Div Hematol Oncol, Charleston, SC USA. [Farooq, Umar] Univ Iowa Hosp & Clin, Dept Oncol & Blood Marrow Transplantat, Iowa City, IA 52242 USA. [Freytes, Cesar] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Freytes, Cesar] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Ganguly, Siddhartha] Univ Kansas, Med Ctr, Div Hematol Oncol, Blood & Marrow Transplantat, Kansas City, KS 66103 USA. [Hertzberg, Mark] Prince Wales Hosp, Dept Haematol, Randwick, NSW, Australia. [Inwards, David] Mayo Clin, Div Hematol, Rochester, MN USA. [Jaglowski, Samantha] Ohio State Univ, Med Ctr, Div Hematol, Columbus, OH 43210 USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Cleveland, OH USA. [Nathan, Sunita] Rush Univ, Dept Hematol, Med Ctr, Chicago, IL 60612 USA. [Pawarode, Attaphol] Univ Michigan, Sch Med, Dept Internal Med, Blood & Marrow Transplantat Program,Div Hematol O, Ann Arbor, MI USA. [Perales, Miguel-Angel] Mem Sloan Kettering Canc Ctr, Dept Med, Adult Bone Marrow Transplantat Serv, 1275 York Ave, New York, NY 10021 USA. [Reddy, Nishitha] Vanderbilt Univ, Med Ctr, Div Hematol Oncol, Nashville, TN USA. [Seo, Sachiko] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, 1124 Columbia St, Seattle, WA 98104 USA. [Sureda, Anna] Hosp Duran I Reynals, Serv Hematol, Inst Catala Oncol, Barcelona, Spain. [Sureda, Anna] European Grp Blood & Marrow Transplantat, Barcelona, Spain. [Smith, Sonali M.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. RP Hamadani, M (reprint author), Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, 9200 W Wisconsin Ave,Suite C5500, Milwaukee, WI 53226 USA. EM mhamadani@mcw.edu FU Public Health Service Grant/Cooperative Agreement from the National Cancer Institute (NCI) [U24-CA076518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases (NIAID); NHLBI [5U10HL069294]; NCI; Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]; Office of Naval Research [N00014-13-1-0039, N00014-14-1-0028]; Actinium Pharmaceuticals; Allos Therapeutics, Inc.; Amgen, Inc.; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc.; Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; Remedy Informatics; Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; TerumoBCT; Teva Neuroscience, Inc.; THERAKOS, Inc.; University of Minnesota; University of Utah; Wellpoint, Inc. FX Morgan Geronime for administrative Support. The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.;*Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick's Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience, Inc.; *THERAKOS, Inc.; University of Minnesota; University of Utah; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government. *Corporate Members. NR 26 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUL PY 2016 VL 174 IS 2 BP 235 EP 248 DI 10.1111/bjh.14046 PG 14 WC Hematology SC Hematology GA DW6PP UT WOS:000383773700006 PM 26989808 ER PT J AU Rosenthal, A Kumar, S Hofmeister, C Laubach, J Vij, R Dueck, A Gano, K Stewart, AK AF Rosenthal, Allison Kumar, Shaji Hofmeister, Craig Laubach, Jacob Vij, Ravi Dueck, Amylou Gano, Katherine Stewart, A. Keith TI A Phase Ib Study of the combination of the Aurora Kinase Inhibitor Alisertib (MLN8237) and Bortezomib in Relapsed Multiple Myeloma SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Letter DE multiple myeloma; alisertib; aurora kinase; bortezomib; relapse ID ADVANCED SOLID TUMORS C1 [Rosenthal, Allison; Dueck, Amylou; Gano, Katherine; Stewart, A. Keith] Mayo Clin, Scottsdale, AZ 85259 USA. [Kumar, Shaji] Mayo Clin, Rochester, MN USA. [Hofmeister, Craig] Ohio State, James Canc Ctr, Columbus, OH USA. [Laubach, Jacob] Dana Farber Canc Inst, Boston, MA 02115 USA. [Vij, Ravi] Washington Univ, St Louis, MO USA. RP Stewart, AK (reprint author), Mayo Clin, Scottsdale, AZ 85259 USA. EM stewart.keith@mayo.edu RI Hofmeister, Craig/E-3256-2011 OI Hofmeister, Craig/0000-0003-4816-1607 FU NCI NIH HHS [P30 CA016672, P30 CA016058] NR 8 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUL PY 2016 VL 174 IS 2 BP 323 EP 325 DI 10.1111/bjh.13765 PG 3 WC Hematology SC Hematology GA DW6PP UT WOS:000383773700016 PM 26403323 ER PT J AU Balbach, ST Orkin, SH AF Balbach, Sebastian T. Orkin, Stuart H. TI An Achilles' Heel for MLL-Rearranged Leukemias: Writers and Readers of H3 Lysine 36 Dimethylation SO CANCER DISCOVERY LA English DT Editorial Material ID HEMATOPOIETIC STEM-CELLS; MEDIATED TRANSFORMATION; DOT1L AB Histone H3 lysine 36 dimethylation (H3K36me2), a modification associated with transcriptional activation, is required for mixed-lineage leukemia-dependent transcription and leukemic transformation. In this issue of Cancer Discovery, Zhu and colleagues map the network of readers, writers, and erasers of H3K36me2 and uncover the ASH1L histone methyltransferase as a novel target for therapeutic intervention. (C) 2016 AACR. C1 [Balbach, Sebastian T.; Orkin, Stuart H.] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA. [Balbach, Sebastian T.; Orkin, Stuart H.] Harvard Med Sch, Boston, MA USA. [Orkin, Stuart H.] Harvard Stem Cell Inst, Cambridge, MA USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM Stuart_Orkin@dfci.harvard.edu RI Balbach, Sebastian/A-1107-2009 OI Balbach, Sebastian/0000-0003-0212-5758 NR 11 TC 0 Z9 0 U1 0 U2 0 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 JUL PY 2016 VL 6 IS 7 BP 700 EP 702 DI 10.1158/2159-8290.CD-16-0564 PG 3 WC Oncology SC Oncology GA DW0TC UT WOS:000383354500021 PM 27371576 ER PT J AU Kim, E Ilic, N Shrestha, Y Zou, LH Kamburov, A Zhu, C Yang, XP Lubonja, R Tran, N Nguyen, C Lawrence, MS Piccioni, F Bagul, M Doench, JG Chouinard, CR Wu, XY Hogstrom, L Natoli, T Tamayo, P Horn, H Corsello, SM Lage, K Root, DE Subramanian, A Golub, TR Getz, G Boehm, JS Hahn, WC AF Kim, Eejung Ilic, Nina Shrestha, Yashaswi Zou, Lihua Kamburov, Atanas Zhu, Cong Yang, Xiaoping Lubonja, Rakela Tran, Nancy Nguyen, Cindy Lawrence, Michael S. Piccioni, Federica Bagul, Mukta Doench, John G. Chouinard, Candace R. Wu, Xiaoyun Hogstrom, Larson Natoli, Ted Tamayo, Pablo Horn, Heiko Corsello, Steven M. Lage, Kasper Root, David E. Subramanian, Aravind Golub, Todd R. Getz, Gad Boehm, Jesse S. Hahn, William C. TI Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles SO CANCER DISCOVERY LA English DT Article ID PROSTATE-CANCER; MISSENSE MUTATIONS; TUMOR-SUPPRESSOR; SOMATIC MUTATIONS; LUNG-CANCER; PTEN; GENOME; GENES; SPOP; RAS AB Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles, including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic. One rare KRAS allele, D33E, displayed tumorigenicity and constitutive activation of known RAS effector pathways. By comparing gene expression changes induced upon expression of wild-type and mutant alleles, we inferred the activity of specific alleles. Because alleles found to be mutated only once in 5,338 tumors rendered cells tumorigenic, these observations underscore the value of integrating genomic information with functional studies. SIGNIFICANCE: Experimentally inferring the functional status of cancer-associated mutations facilitates the interpretation of genomic information in cancer. Pooled in vivo screen and gene expression profiling identified functional variants and demonstrated that expression of rare variants induced tumorigenesis. Variant phenotyping through functional studies will facilitate defining key somatic events in cancer. (C) 2016 AACR. C1 [Kim, Eejung; Ilic, Nina; Shrestha, Yashaswi; Zou, Lihua; Kamburov, Atanas; Zhu, Cong; Yang, Xiaoping; Lubonja, Rakela; Tran, Nancy; Nguyen, Cindy; Lawrence, Michael S.; Piccioni, Federica; Bagul, Mukta; Doench, John G.; Chouinard, Candace R.; Wu, Xiaoyun; Hogstrom, Larson; Natoli, Ted; Tamayo, Pablo; Horn, Heiko; Corsello, Steven M.; Lage, Kasper; Root, David E.; Subramanian, Aravind; Golub, Todd R.; Getz, Gad; Boehm, Jesse S.; Hahn, William C.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Kim, Eejung; Ilic, Nina; Corsello, Steven M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Zou, Lihua; Kamburov, Atanas; Getz, Gad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Zou, Lihua; Kamburov, Atanas; Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Tamayo, Pablo] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Horn, Heiko; Lage, Kasper] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Golub, Todd R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Hahn, WC (reprint author), Dana Farber Canc Inst, Med Oncol, Dana 1538,450 Brookline Ave, Boston, MA 02215 USA. EM william_hahn@dfci.harvard.edu FU Samsung Scholarship; Susan G. Komen Postdoctoral Fellowship [PDF12230602]; European Molecular Biology Laboratory; Conquer Cancer Foundation of ASCO Young Investigator Award; U.S. NCI grant [U01 CA176058]; Carlos Slim Foundation in Mexico FX This study was supported by a Samsung Scholarship (to E. Kim), Susan G. Komen Postdoctoral Fellowship PDF12230602 (to N. Ilic), a long-term postdoctoral fellowship from the European Molecular Biology Laboratory (to A. Kamburov), a Conquer Cancer Foundation of ASCO Young Investigator Award (to S.M. Corsello), and U.S. NCI grant U01 CA176058 (to W.C. Hahn). This work was conducted as part of the Slim Initiative for Genomic Medicine, a project funded by the Carlos Slim Foundation in Mexico. NR 58 TC 9 Z9 9 U1 1 U2 1 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 JUL PY 2016 VL 6 IS 7 BP 714 EP 726 DI 10.1158/2159-8290.CD-16-0160 PG 13 WC Oncology SC Oncology GA DW0TC UT WOS:000383354500023 PM 27147599 ER PT J AU Saha, SK Gordan, JD Kleinstiver, BP Vu, P Najem, MS Yeo, JC Shi, L Kato, Y Levin, RS Webber, JT Damon, LJ Egan, RK Greninger, P McDermott, U Garnett, MJ Jenkins, RL Rieger-Christ, KM Sullivan, TB Hezel, AF Liss, AS Mizukami, Y Goyal, L Ferrone, CR Zhu, AX Joung, JK Shokat, KM Benes, CH Bardeesy, N AF Saha, Supriya K. Gordan, John D. Kleinstiver, Benjamin P. Vu, Phuong Najem, Mortada S. Yeo, Jia-Chi Shi, Lei Kato, Yasutaka Levin, Rebecca S. Webber, James T. Damon, Leah J. Egan, Regina K. Greninger, Patricia McDermott, Ultan Garnett, Mathew J. Jenkins, Roger L. Rieger-Christ, Kimberly M. Sullivan, Travis B. Hezel, Aram F. Liss, Andrew S. Mizukami, Yusuke Goyal, Lipika Ferrone, Cristina R. Zhu, Andrew X. Joung, J. Keith Shokat, Kevan M. Benes, Cyril H. Bardeesy, Nabeel TI Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma SO CANCER DISCOVERY LA English DT Article ID KINASE INHIBITOR SELECTIVITY; UNKNOWN PRIMARY SITE; MYELOID-LEUKEMIA; TARGETED THERAPY; BILIARY CANCER; BCR-ABL; RESISTANCE; POTENT; CELLS; IDH1 AB Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver bile duct malignancy exhibiting frequent isocitrate dehydrogenase (IDH1/IDH2) mutations. Through a high-throughput drug screen of a large panel of cancer cell lines, including 17 biliary tract cancers, we found that IDH mutant (IDHm) ICC cells demonstrate a striking response to the multikinase inhibitor dasatinib, with the highest sensitivity among 682 solid tumor cell lines. Using unbiased proteomics to capture the activated kinome and CRISPR/Cas9-based genome editing to introduce dasatinib-resistant "gatekeeper" mutant kinases, we identified SRC as a critical dasatinib target in IDHm ICC. Importantly, dasatinib-treated IDHm xenografts exhibited pronounced apoptosis and tumor regression. Our results show that IDHm ICC cells have a unique dependency on SRC and suggest that dasatinib may have therapeutic benefit against IDHm ICC. Moreover, these proteomic and genome-editing strategies provide a systematic and broadly applicable approach to define targets of kinase inhibitors underlying drug responsiveness. SIGNIFICANCE: IDH mutations define a distinct subtype of ICC, a malignancy that is largely refractory to current therapies. Our work demonstrates that IDHm ICC cells are hypersensitive to dasatinib and critically dependent on SRC activity for survival and proliferation, pointing to new therapeutic strategies against these cancers. (C) 2016 AACR. C1 [Saha, Supriya K.; Vu, Phuong; Najem, Mortada S.; Yeo, Jia-Chi; Shi, Lei; Kato, Yasutaka; Damon, Leah J.; Egan, Regina K.; Greninger, Patricia; Mizukami, Yusuke; Goyal, Lipika; Ferrone, Cristina R.; Zhu, Andrew X.; Benes, Cyril H.; Bardeesy, Nabeel] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Gordan, John D.; Webber, James T.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Kleinstiver, Benjamin P.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, Charlestown, MA USA. [Kleinstiver, Benjamin P.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA USA. [Kleinstiver, Benjamin P.; Joung, J. Keith] Harvard Med Sch, Dept Pathol, Boston, MA USA. [Levin, Rebecca S.; Shokat, Kevan M.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. [McDermott, Ultan; Garnett, Mathew J.] Wellcome Trust Sanger Inst, Hinxton, England. [Jenkins, Roger L.] Lahey Hosp & Med Ctr, Dept Transplantat, Burlington, MA USA. [Rieger-Christ, Kimberly M.; Sullivan, Travis B.] Lahey Hosp & Med Ctr, Dept Translat Res, Burlington, MA USA. [Hezel, Aram F.] Univ Rochester, Sch Med, Rochester, NY USA. [Liss, Andrew S.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Liss, Andrew S.] Massachusetts Gen Hosp, Andrew L Warshaw MD Inst Pancreat Canc Res, Boston, MA 02114 USA. [Liss, Andrew S.] Harvard Med Sch, Boston, MA 02114 USA. [Mizukami, Yusuke] Sapporo Higashi Tokushukai Hosp, Ctr Clin & Biomed Res, Sapporo, Hokkaido, Japan. [Shokat, Kevan M.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. RP Bardeesy, N (reprint author), Massachusetts Gen Hosp, 185 Cambridge St,CPZN 4216, Boston, MA 02114 USA.; Benes, CH (reprint author), CNY 149 Room 7401,149 13th St, Charlestown, MA 02129 USA. EM cbenes@mgh.harvard.edu; nelbardeesy@partners.org OI McDermott, Ultan/0000-0001-9032-4700; Webber, James/0000-0001-8594-9888 FU Translational Research Award from the V Foundation; Target Cancer Foundation; Gallagher Chair in Gastrointestinal Cancer Research at Massachusetts General Hospital; NCI-Mentored Clinical Scientist Research Career Development Award [1K08CA194268-01]; DF/HCC GI SPORE [P50CA127003]; American Cancer Society Postdoctoral Grant; Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship; Wellcome Trust [102696]; NIH Director's Pioneer Award [DP1 GM105378]; Editas Medicine; Hera Testing Laboratories; Poseida Therapeutics; Transposagen Biopharmaceuticals FX This work was supported by a Translational Research Award from the V Foundation to N. Bardeesy, C.H. Benes, and A.X. Zhu, and by a grant from Target Cancer Foundation to N. Bardeesy. N. Bardeesy is the holder of the Gallagher Chair in Gastrointestinal Cancer Research at Massachusetts General Hospital. S.K. Saha is supported by an NCI-Mentored Clinical Scientist Research Career Development Award (1K08CA194268-01). N. Bardeesy and S.K. Saha are supported by the DF/HCC GI SPORE (P50CA127003). J.D. Gordan was supported by an American Cancer Society Postdoctoral Grant. K.M. Shokat is a Howard Hughes Medical Institute Investigator. B.P. Kleinstiver was supported by a Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship. C.H. Benes, U. McDermott, and M.J. Garnett are supported by a grant from the Wellcome Trust (102696). J.K. Joung is supported by an NIH Director's Pioneer Award (DP1 GM105378) and is a consultant for Horizon Discovery. J.K. Joung has financial interests in Editas Medicine, Hera Testing Laboratories, Poseida Therapeutics, and Transposagen Biopharmaceuticals. J.K. Joung's interests were reviewed and are managed by Massachusetts General Hospital and Partners Health-Care in accordance with their conflict of interest policies. NR 45 TC 2 Z9 2 U1 4 U2 4 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 JUL PY 2016 VL 6 IS 7 BP 727 EP 739 DI 10.1158/2159-8290.CD-15-1442 PG 13 WC Oncology SC Oncology GA DW0TC UT WOS:000383354500024 PM 27231123 ER PT J AU Patnaik, A Rosen, LS Tolaney, SM Tolcher, AW Goldman, JW Gandhi, L Papadopoulos, KP Beeram, M Rasco, DW Hilton, JF Nasir, A Beckmann, RP Schade, AE Fulford, AD Nguyen, TS Martinez, R Kulanthaivel, P Li, LQ Frenzel, M Cronier, DM Chan, EM Flaherty, KT Wen, PY Shapiro, GI AF Patnaik, Amita Rosen, Lee S. Tolaney, Sara M. Tolcher, Anthony W. Goldman, Jonathan W. Gandhi, Leena Papadopoulos, Kyriakos P. Beeram, Muralidhar Rasco, Drew W. Hilton, John F. Nasir, Aejaz Beckmann, Richard P. Schade, Andrew E. Fulford, Angie D. Nguyen, Tuan S. Martinez, Ricardo Kulanthaivel, Palaniappan Li, Lily Q. Frenzel, Martin Cronier, Damien M. Chan, Edward M. Flaherty, Keith T. Wen, Patrick Y. Shapiro, Geoffrey I. TI Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors SO CANCER DISCOVERY LA English DT Article ID KINASE 4/6 INHIBITOR; CYCLIN-DEPENDENT KINASES; PD 0332991; ANTITUMOR-ACTIVITY; DOSE-ESCALATION; OVARIAN-CANCER; PHASE-I; PROLIFERATION; COMBINATION; PALBOCICLIB AB We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin-dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumorspecific cohorts for breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor-positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting >= 6 months. SIGNIFICANCE: Abemaciclib represents the first selective inhibitor of CDK4 and CDK6 with a safety profile allowing continuous dosing to achieve sustained target inhibition. This first-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. (C) 2016 AACR. C1 [Patnaik, Amita; Tolcher, Anthony W.; Papadopoulos, Kyriakos P.; Beeram, Muralidhar; Rasco, Drew W.] South Texas Accelerated Res Therapeut, 4383 Med Dr, San Antonio, TX 78229 USA. [Rosen, Lee S.; Goldman, Jonathan W.] Univ Calif Los Angeles, Los Angeles, CA USA. [Tolaney, Sara M.; Gandhi, Leena; Hilton, John F.; Wen, Patrick Y.; Shapiro, Geoffrey I.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Nasir, Aejaz; Beckmann, Richard P.; Schade, Andrew E.; Fulford, Angie D.; Nguyen, Tuan S.; Martinez, Ricardo; Kulanthaivel, Palaniappan; Li, Lily Q.; Frenzel, Martin; Cronier, Damien M.; Chan, Edward M.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hilton, John F.] Univ Ottawa, Ottawa, ON, Canada. RP Patnaik, A (reprint author), South Texas Accelerated Res Therapeut, 4383 Med Dr, San Antonio, TX 78229 USA.; Shapiro, GI (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Early Drug Dev Ctr, Mayer 446,450 Brookline Ave, Boston, MA 02215 USA. EM amita.patnaik@start.stoh.com; geoffrey_shapiro@dfci.harvard.edu FU Eli Lilly and Company FX All funding was provided by Eli Lilly and Company. NR 47 TC 17 Z9 18 U1 5 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD JUL PY 2016 VL 6 IS 7 BP 740 EP 753 DI 10.1158/2159-8290.CD-16-0095 PG 14 WC Oncology SC Oncology GA DW0TC UT WOS:000383354500025 PM 27217383 ER PT J AU Stone, JH AF Stone, J. H. TI IgG4-related disease: pathophysiologic insights drive emerging treatment approaches SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Article; Proceedings Paper CT 18th International Symposium on Advances in Targeted Therapies CY MAR 16-20, 2016 CL Palma de Mallorca, SPAIN DE IgG4-related disease; cytotoxic T cell; SLAMF7; plasmablast ID AUTOIMMUNE PANCREATITIS; RITUXIMAB THERAPY; SYSTEMIC-DISEASE; STATEMENT AB IgG4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect essentially any organ. The disease shows similar histopathology findings across organ systems, consisting of a lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. IgG4 itself appears to be a reactive phenomenon rather than the primary disease driver. Recent investigations have focused on the interactions between cells of the B cell lineage and a novel CD4(+) SLAMF7(+) cytotoxic T cells capable of promoting fibrosis. Plasmablasts appear to play a crucial role along with B cells in the presentation of antigen to this T cell. IgG4-RD is marked by responsiveness to glucocorticoids, but frequent disease relapse, the inability to taper glucocorticoids completely, and steroid toxicity are problematic. Targeted treatment approaches against the B cell lineage appear promising, and therapeutic efforts focused upon the CD4(+) SLAMF7(+) cytotoxic T cell may also be feasible. C1 [Stone, J. H.] Massachusetts Gen Hosp, Rheumatol Clin Yawkey 2, 55 Fruit St, Boston, MA 02114 USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Rheumatol Clin Yawkey 2, 55 Fruit St, Boston, MA 02114 USA. EM jhstone@partners.org NR 21 TC 0 Z9 0 U1 2 U2 2 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X EI 1593-098X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD JUL-AUG PY 2016 VL 34 IS 4 SU 98 BP S66 EP S68 PG 3 WC Rheumatology SC Rheumatology GA DW8TI UT WOS:000383928000016 ER PT J AU Cefalu, WT Boulton, AJM Tamborlane, WV Moses, RG LeRoith, D Greene, EL Hu, FB Bakris, G Wylie-Rosett, J Rosenstock, J Weinger, K Blonde, L de Groot, M Rich, SS D'Alessio, D Riddle, MC Reynolds, L AF Cefalu, William T. Boulton, Andrew J. M. Tamborlane, William V. Moses, Robert G. LeRoith, Derek Greene, Eddie L. Hu, Frank B. Bakris, George Wylie-Rosett, Judith Rosenstock, Julio Weinger, Katie Blonde, Lawrence de Groot, Mary Rich, Stephen S. D'Alessio, David Riddle, Matthew C. Reynolds, Lyn TI Diabetes Care: "Lagniappe" and "Seeing Is Believing"! SO DIABETES CARE LA English DT Editorial Material ID METABOLIC SURGERY; MANAGEMENT C1 [Cefalu, William T.] Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Boulton, Andrew J. M.] Univ Manchester, Manchester Diabet Ctr, Manchester, Lancs, England. [Tamborlane, William V.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Moses, Robert G.] ISLHD, Wollongong, NSW, Australia. [LeRoith, Derek] Icahn Sch Med Mt Sinai, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. [Greene, Eddie L.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA. [Hu, Frank B.] Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Hu, Frank B.] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Bakris, George] Univ Chicago Med, ASH Comprehens Hypertens Ctr, Dept Med, Div Endocrinol Diabet & Metab, Chicago, IL USA. [Wylie-Rosett, Judith] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Rosenstock, Julio] Med City, Dallas Diabet & Endocrine Ctr, Dallas, TX USA. [Weinger, Katie] Harvard Med Sch, Joslin Diabet Ctr, Boston, MA USA. [Blonde, Lawrence] Ochsner Med Ctr, Ochsner Diabet Clin Res Unit, Frank Riddick Diabet Inst, Dept Endocrinol, New Orleans, LA USA. [de Groot, Mary] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Rich, Stephen S.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [D'Alessio, David] Duke Univ, Div Endocrinol Diabet & Metab, Durham, NC USA. [Riddle, Matthew C.] Oregon Hlth & Sci Univ, Div Endocrinol Diabet & Clin Nutr, Portland, OR 97201 USA. [Reynolds, Lyn] Amer Diabet Assoc, Indianapolis, IN USA. RP Cefalu, WT (reprint author), Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. EM cefaluwt@pbrc.edu FU NCCIH NIH HHS [P50 AT002776]; NIGMS NIH HHS [U54 GM104940] NR 19 TC 1 Z9 1 U1 4 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2016 VL 39 IS 7 BP 1069 EP 1071 DI 10.2337/dc16-0891 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500008 PM 27631957 ER PT J AU Russell, SJ Beck, RW AF Russell, Steven J. Beck, Roy W. TI Design Considerations for Artificial Pancreas Pivotal Studies SO DIABETES CARE LA English DT Article ID SEVERE HYPOGLYCEMIC EVENTS; EXCHANGE CLINIC REGISTRY; GLYCATED ALBUMIN; GLYCEMIC CONTROL; GLUCOSE; TYPE-1; COMPLICATIONS; MANAGEMENT; IMPACT; TRIAL AB The development of artificial pancreas systems has evolved to the point that pivotal studies designed to assess efficacy and safety are in progress or soon to be initiated. These pivotal studies are intended to provide the necessary data to gain clearance from the U.S. Food and Drug Administration, coverage by payers, and adoption by patients and clinicians. Although there will not be one design that is appropriate for every system, there are certain aspects of protocol design that will be considerations in all pivotal studies designed to assess efficacy and safety. One key aspect of study design is the intervention to be used by the control group. A case can be made that the control group should use the currently available best technology, which is sensor-augmented pump therapy. However, an equally, if not more, compelling case can be made that the control intervention should be usual care. In this Perspective, we elaborate on this issue and provide a pragmatic approach to the design of clinical trials of artificial pancreas systems. C1 [Russell, Steven J.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Beck, Roy W.] Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. RP Beck, RW (reprint author), Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. EM rbeck@jaeb.org FU Dexcom; Tandem Diabetes; Eli Lilly; Sanofi; Animas; Tandem; Bigfoot Biomedical FX S.J.R. reports pending patent applications for a blood glucose control system assigned to Partners HealthCare and Massachusetts General Hospital; reports receiving loaned equipment, support in kind, and/or technical assistance from Dexcom, Tandem Diabetes, and Eli Lilly; reports honoraria for lectures from Tandem Diabetes, Dexcom, Sanofi, and Eli Lilly; reports consulting fees from Sanofi; and reports serving on the scientific advisory boards for Tandem Diabetes and Companion Medical. R.W.B. reports that his nonprofit employer has received consultant payments on his behalf from Animas, Tandem, and Bigfoot Biomedical with no personal compensation to him and grant funds from Dexcom. No other potential conflicts of interest relevant to this article were reported. NR 29 TC 6 Z9 6 U1 1 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 JUL PY 2016 VL 39 IS 7 BP 1161 EP 1167 DI 10.2337/dc15-2449 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500023 PM 27330125 ER PT J AU Maahs, DM Buckingham, BA Castle, JR Cinar, A Damiano, ER Dassau, E DeVries, JH Doyle, FJ Griffen, SC Haidar, A Heinemann, L Hovorka, R Jones, TW Kollman, C Kovatchev, B Levy, BL Nimri, R O'Neal, DN Philip, M Renard, E Russell, SJ Weinzimer, SA Zisser, H Lum, JW AF Maahs, David M. Buckingham, Bruce A. Castle, Jessica R. Cinar, Ali Damiano, Edward R. Dassau, Eyal DeVries, J. Hans Doyle, Francis J., III Griffen, Steven C. Haidar, Ahmad Heinemann, Lutz Hovorka, Roman Jones, Timothy W. Kollman, Craig Kovatchev, Boris Levy, Brian L. Nimri, Revital O'Neal, David N. Philip, Moshe Renard, Eric Russell, Steven J. Weinzimer, Stuart A. Zisser, Howard Lum, John W. TI Outcome Measures for Artificial Pancreas Clinical Trials: A Consensus Report SO DIABETES CARE LA English DT Article ID AMERICAN-DIABETES-ASSOCIATION; SEVERE HYPOGLYCEMIC EVENTS; CONTINUOUS GLUCOSE MONITOR; FREE-LIVING CONDITIONS; LOOP INSULIN DELIVERY; CLOSED-LOOP; POSITION STATEMENT; TYPE-1; ACCURACY; SYSTEMS AB Research on and commercial development of the artificial pancreas (AP) continue to progress rapidly, and the AP promises to become a part of clinical care. In this report, members of the JDRF Artificial Pancreas Project Consortium in collaboration with the wider AP community 1) advocate for the use of continuous glucose monitoring glucose metrics as outcome measures in AP trials, in addition to HbA(1c), and 2) identify a short set of basic, easily interpreted outcome measures to be reported in AP studies whenever feasible. Consensus on a broader range of measures remains challenging; therefore, reporting of additional metrics is encouraged as appropriate for individual AP studies or study groups. Greater consistency in reporting of basic outcome measures may facilitate the interpretation of study results by investigators, regulatory bodies, health care providers, payers, and patients themselves, thereby accelerating the widespread adoption of AP technology to improve the lives of people with type 1 diabetes. C1 [Maahs, David M.] Univ Colorado, Sch Med, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA. [Buckingham, Bruce A.] Stanford Univ, Dept Pediat Endocrinol, Div Pediat Endocrinol & Diabet, Stanford, CA 94305 USA. [Castle, Jessica R.] Oregon Hlth & Sci Univ, Dept Med, Harold Schnitzer Diabet Hlth Ctr, Div Endocrinol, Portland, OR 97201 USA. [Cinar, Ali] IIT, Dept Chem & Biol Engn, Chicago, IL 60616 USA. [Damiano, Edward R.; Russell, Steven J.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Dassau, Eyal; Doyle, Francis J., III; Zisser, Howard] Univ Calif Santa Barbara, Dept Chem Engn, Santa Barbara, CA 93106 USA. [Dassau, Eyal; Doyle, Francis J., III] Harvard Univ, Harvard John A Paulson Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [DeVries, J. Hans] Univ Amsterdam, Acad Med Ctr, Dept Endocrinol, Amsterdam, Netherlands. [Griffen, Steven C.] JDRF, New York, NY USA. [Haidar, Ahmad] McGill Univ, Dept Biomed Engn, Montreal, PQ, Canada. [Haidar, Ahmad] McGill Univ, Div Endocrinol, Montreal, PQ, Canada. [Heinemann, Lutz] Profil Inst Metab Res, Neuss, Germany. [Hovorka, Roman] Univ Cambridge, Wellcome Trust Med Res Clin Inst Metab Sci, Cambridge, England. [Jones, Timothy W.] Univ Western Australia, Telethon Kids Inst, Perth, WA, Australia. [Kollman, Craig; Lum, John W.] Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. [Kovatchev, Boris] Univ Virginia, Charlottesville, VA USA. [Levy, Brian L.] Johnson & Johnson Diabet Care Co, Wayne, PA USA. [Nimri, Revital; Philip, Moshe] Tel Aviv Univ, Jesse Z & Sara Lea Shafer Inst Endocrinol & Diabe, Schneider Childrens Med Ctr Israel, Natl Ctr Childhood Diabet,Sackler Fac Med, Petah Tiqwa, Israel. [O'Neal, David N.] Univ Melbourne, St Vincents Hosp Melbourne, Dept Med, Fitzroy, Vic, Australia. [Renard, Eric] Univ Montpellier, Dept Endocrinol Diabet & Nutr, Montpellier Univ Hosp,UMR 5203,U1191, Clin Invest Ctr 1411,INSERM,Inst Funct Genom,CNRS, Montpellier, France. [Russell, Steven J.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Russell, Steven J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Russell, Steven J.] Harvard Med Sch, Boston, MA USA. [Weinzimer, Stuart A.] Yale Univ, Sch Med, New Haven, CT USA. RP Lum, JW (reprint author), Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. EM jlum@jaeb.org RI Hovorka, Roman/J-4123-2016; OI Hovorka, Roman/0000-0003-2901-461X; DeVries, J. Hans/0000-0001-9196-9906 FU Abbott; Insulet; Medtronic; Dexcom; Roche Diagnostics; JDRF; Sanofi; Tandem Diabetes Care; Novo Nordisk; National Institutes of Health (NIH); Automated Glucose Control LLC; Animas Corp.; Johnson Johnson; NIH; Eli Lilly; B. Braun; Profil; Diabetes UK; Sanofi-Aventis; National Institute of Diabetes and Digestive and Kidney Diseases; European Commission; National Institute for Health Research Efficacy and Mechanism Evaluation Programme; Becton, Dickson, and Co.; Merck; Andromeda; Bristol-Myers Squibb; Kamada; Pfizer; AstraZeneca; NG Solutions Ltd.; Nutriteen Professionals Ltd.; A. Menarini Diagnostics; Cellnovo; LifeScan FX D.M.M. reports personal fees from Abbott and Insulet and research support from Medtronic, Dexcom, and Roche Diagnostics. B.A.B. reports grant support from JDRF, Medtronic, and Dexcom; personal fees from Medtronic, Sanofi, Tandem Diabetes Care, and Novo Nordisk; and other support from Roche Diagnostics, Dexcom, and Abbott. J.R.C. has a significant financial interest in Pacific Diabetes Technologies, Inc., a company that may have a commercial interest in the results of this research and technology. This potential conflict of interest has been reviewed and managed by Oregon Health & Science University. A.C. reports personal fees from Medtronic and a patent "Automatic insulin pumps using recursive multivariable models and adaptive control algorithms" (#US8690820) issued. E.R.D. reports a patent "Fully automated control system for type 1 diabetes" (#US7806854) issued, grants from JDRF and the National Institutes of Health (NIH), and personal fees from Automated Glucose Control LLC and Animas Corp. J.H.D. reports grants from Medtronic and personal fees from Johnson & Johnson and Sanofi. F.J.D. reports grants from JDRF and NIH and personal fees from Automated Glucose Control LLC and Animas Corp. A.H. owns intellectual property in the field of artificial pancreas (dosing algorithm). A.H. has received consultant and speaker honoraria from SNELL Medical Communication and the Diabetic Children's Foundation and research support from Medtronic. R.H. reports personal fees from Medtronic, Eli Lilly, Novo Nordisk, B. Braun, Sanofi, and Profil and grants from JDRF and Diabetes UK. In addition, R.H. has a patent "Substance monitoring and control in human R.H. reports personal fees from Medtronic, Eli Lilly, Novo Nordisk, B. Braun, Sanofi-Aventis, and Profil, as well as grants from JDRF, Diabetes UK, the National Institute of Diabetes and Digestive and Kidney Diseases, European Commission 7th Framework Programme for Research and Technological Development, and National Institute for Health Research Efficacy and Mechanism Evaluation Programme. In addition, R.H. has a patent "Substance monitoring and control in human or animal bodies" (#US9089305) license, a patent "Overnight closed-loop insulin delivery with model predictive control and glucose measurement error model" (#US8585637) issued, a patent "A system for insulin delivery using glucose regulation and measurement error models" (#US8062249) issued, and a patent "Substance monitoring and control in human or animal bodies" (#US8977504) licensed. T.W.J. reports personal fees and nonfinancial support from Medtronic and personal fees from Novo Nordisk and Animas Corp. B.K. reports grants from Becton, Dickson, and Co. and Sanofi, personal fees from Sanofi, and nonfinancial support from Animas Corp., Roche Diagnostics, and Tandem Diabetes Care. In addition, B.K. has a patent "CGM-based prevention of hypoglycemia via hypoglycemia risk assessment and smooth reduction of insulin delivery" (#US8562587), with royalties paid to Animas Corp.; a patent "Method and apparatus for modular power management and protection of critical services in ambulatory medical devices" (PCT/US12/43883), licensed to TypeZero Technologies; and a patent "Unified platform for monitoring and control of blood glucose levels in diabetic patients" (PCT/US12/43910), licensed to TypeZero Technologies. R.H. is a shareholder in TypeZero Technologies. B.L.L. reports other support from LifeScan and Animas Corp. R.N. reports grants from JDRF and other support from Novo Nordisk and DreaMed Diabetes Ltd. D.N.O.; reports grants and personal fees from Medtronic, Roche Diagnostics, Sanofi, and Novo Nordisk. M.P. report grants from Medtronic, Novo Nordisk, Roche Diagnostics, Eli Lilly, Merck, Andromeda, Sanofi, Bristol-Myers Squibb, Kamada, Pfizer, AstraZeneca, NG Solutions Ltd., and Nutriteen Professionals Ltd.; personal fees from Medtronic, Novo Nordisk, Eli Lilly, Sanofi, and Pfizer; and other support from Medtronic, Novo Nordisk, Roche Diagnostics, CGM3 Ltd., NG Solutions Ltd., DreaMed Diabetes Ltd., and Nutriteen Professionals Ltd. M.P. has a patent "Method and system for automatic monitoring of diabetes related treatments" (#US20120123234 A1) pending. E.R. reports personal fees from A. Menarini Diagnostics, Cellnovo, Eli Lilly, Johnson & Johnson, Animas Corp., LifeScan, Medtronic, Novo Nordisk, Abbott, Roche Diagnostics, Dexcom, and Sanofi and nonfinancial support from Abbott, Roche Diagnostics, Dexcom, and Insulet. S.J.R. reports personal fees from Dexcom, Tandem Diabetes Care, Sanofi, Eli Lilly, and Novo Nordisk; nonfinancial support from Eli Lilly, SweetSpot Diabetes, International Biomedical, Abbott, Insulet, and Medtronic; and other support from Companion Medical. S.J.R. has patents pending on aspects of bionic pancreas. S.A.W. reports grants from Medtronic and personal fees from Medtronic, Insulet, and Tandem Diabetes Care. H.Z. reports grants from NIH and JDRF. No other potential conflicts of interest relevant to this article were reported. NR 41 TC 8 Z9 8 U1 5 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2016 VL 39 IS 7 BP 1175 EP 1179 DI 10.2337/dc15-2716 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500025 PM 27330126 ER PT J AU Cefalu, WT Buse, JB Tuomilehto, J Fleming, GA Ferrannini, E Gerstein, HC Bennett, PH Ramachandran, A Raz, I Rosenstock, J Kahn, SE AF Cefalu, William T. Buse, John B. Tuomilehto, Jaakko Fleming, G. Alexander Ferrannini, Ele Gerstein, Hertzel C. Bennett, Peter H. Ramachandran, Ambady Raz, Itamar Rosenstock, Julio Kahn, Steven E. TI Update and Next Steps for Real-World Translation of Interventions for Type 2 Diabetes Prevention: Reflections From a Diabetes Care Editors' Expert Forum SO DIABETES CARE LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; LIFE-STYLE INTERVENTION; RANDOMIZED-CONTROLLED-TRIAL; CORONARY-HEART-DISEASE; 10-YEAR FOLLOW-UP; BETA-CELL FUNCTION; DA QING IGT; FASTING GLUCOSE; INSULIN-SECRETION; PROGRAM OUTCOMES AB The International Diabetes Federation estimates that 415 million adults worldwide now have diabetes and 318 million have impaired glucose tolerance. These numbers are expected to increase to 642 million and 482 million, respectively, by 2040. This burgeoning pandemic places an enormous burden on countries worldwide, particularly resource-poor regions. Numerous landmark trials evaluating both intensive lifestyle modification and pharmacological interventions have persuasively demonstrated that type 2 diabetes can be prevented or its onset can be delayed in high-risk individuals with impaired glucose tolerance. However, key challenges remain, including how to scale up such approaches for widespread translation and implementation, how to select appropriately from various interventions and tailor them for different populations and settings, and how to ensure that preventive interventions yield clinically meaningful, cost-effective outcomes. In June 2015, a Diabetes Care Editors' Expert Forum convened to discuss these issues. This article, an outgrowth of the forum, begins with a summary of seminal prevention trials, followed by a discussion of considerations for selecting appropriate populations for intervention and the clinical implications of the various diagnostic criteria for prediabetes. The authors outline knowledge gaps in need of elucidation and explore a possible new avenue for securing regulatory approval of a prevention-related indication for metformin, as well as specific considerations for future pharmacological interventions to delay the onset of type 2 diabetes. They conclude with descriptions of some innovative, pragmatic translational initiatives already under way around the world. C1 [Cefalu, William T.] Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. [Buse, John B.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland. [Tuomilehto, Jaakko] Dasman Diabet Inst, Dasman, Kuwait. [Tuomilehto, Jaakko] King Abdulaziz Univ, Saudi Diabet Res Grp, Jeddah, Saudi Arabia. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Fleming, G. Alexander] Kinexum, Harpers Ferry, WV USA. [Ferrannini, Ele] CNR, Inst Clin Physiol, Pisa, Italy. [Gerstein, Hertzel C.] McMaster Univ, Hamilton, ON, Canada. [Gerstein, Hertzel C.] Hamilton Hlth Sci, Hamilton, ON, Canada. [Bennett, Peter H.] NIH, Phoenix, AZ USA. [Ramachandran, Ambady] India Diabet Res Fdn, Madras, Tamil Nadu, India. [Bennett, Peter H.] Dr A Ramachandrans Diabet Hosp, Madras, Tamil Nadu, India. [Raz, Itamar] Hadassah Hebrew Univ Hosp, Dept Internal Med, Diabet Unit, Jerusalem, Israel. [Rosenstock, Julio] Med City, Dallas Diabet & Endocrine Ctr, Dallas, TX USA. [Rosenstock, Julio] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. RP Cefalu, WT (reprint author), Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. EM william.cefalu@pbrc.edu OI Kahn, Steven/0000-0001-7307-9002 FU National Institutes of Health (NIH) [1U54-GM-104940]; NIH [P50-AT-002776] FX Writing and editing support services for this article were provided by Debbie Kendall of Kendall Editorial in Richmond, VA. The Editorial Committee recognizes that the work of the journal and contributions such as this Expert Forum would not be possible without the dedicated work and continued support of many individuals. Specifically, the planning, logistics, and funding of the meeting and the incredible editorial support would not have been possible without the tireless efforts of Chris Kohler and his staff at the ADA Publishing office. In addition, the Editorial Committee thanks Lyn Reynolds and her staff in the ADA editorial office for support and Anne Gooch at the Pennington Biomedical Research Center for her valuable assistance in helping to organize the Expert Forum. W.T.C. is supported in part by National Institutes of Health (NIH) grant 1U54-GM-104940, which funds the Louisiana Clinical and Translational Science Center, and NIH grant P50-AT-002776. NR 138 TC 5 Z9 5 U1 2 U2 2 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 JUL PY 2016 VL 39 IS 7 BP 1186 EP 1201 DI 10.2337/dc16-0873 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500027 PM 27631469 ER PT J AU Piccolo, RS Subramanian, SV Pearce, N Florez, JC McKinlay, JB AF Piccolo, Rebecca S. Subramanian, S. V. Pearce, Neil Florez, Jose C. McKinlay, John B. TI Relative Contributions of Socioeconomic, Local Environmental, Psychosocial, Lifestyle/Behavioral, Biophysiological, and Ancestral Factors to Racial/Ethnic Disparities in Type 2 Diabetes SO DIABETES CARE LA English DT Article ID HEALTH BACH SURVEY; GENETIC ANCESTRY; PHYSICAL-ACTIVITY; AFRICAN-AMERICAN; HBA(1C) LEVELS; RISK; ACCELEROMETER; ASSOCIATION; IMPUTATION; ADMIXTURE AB OBJECTIVE Racial/ethnic minorities in the U.S. have a higher prevalence of type 2 diabetes mellitus (T2DM) than white adults. While many independent risk factors for T2DM have been identified, these determinants are often viewed in isolation without considering the joint contributions of competing risk factors. The objective of this study was to assess the relative contributions of six domains of influence to racial/ethnic disparities in T2DM. RESEARCH DESIGN AND METHODS Cross-sectional analyses were conducted using the Boston Area Community Health III Survey (2010-2012), the third wave of a population-based sample of men and women from three racial/ethnic groups (black, Hispanic, white) living in Boston, Massachusetts (N = 2,764). Prevalent diabetes was defined by self-report of T2DM, fasting glucose >125mg/dL, or HbA(1c) >= 6.5%. Structural equation models were constructed to evaluate the direct effects of each conceptual domain of influence on T2DM prevalence, as well as their indirect effects on the race/ethnicity-T2DM relationship. All direct and indirect pathways were included. RESULTS The final model indicated that 38.9% and 21.8% of the total effect of black race and Hispanic ethnicity, respectively, on T2DM prevalence was mediated by the socioeconomic, environmental, psychosocial, and lifestyle/behavioral risk scores. The largest mediating influence was the socioeconomic risk score, which explained 21.8% and 26.2% of the total effect of black race and Hispanic ethnicity, respectively. CONCLUSIONS Our study found that socioeconomic factors had the greatest impact on explaining the excess prevalence of T2DM among racial/ethnic minorities. C1 [Piccolo, Rebecca S.; Pearce, Neil] London Sch Hyg & Trop Med, London, England. [Subramanian, S. V.] Harvard Univ, Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Harvard Med Sch, Boston, MA USA. [McKinlay, John B.] New England Res Inst, Dept Epidemiol, 9 Galen St, Watertown, MA 02172 USA. RP Piccolo, RS (reprint author), London Sch Hyg & Trop Med, London, England. EM rebecca.piccolo@lshtm.ac.uk FU National Institutes of Diabetes and Digestive and Kidney Diseases [DK056842, DK080786] FX This study was supported by grants from the National Institutes of Diabetes and Digestive and Kidney Diseases (DK056842 and DK080786). NR 36 TC 3 Z9 3 U1 9 U2 9 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 JUL PY 2016 VL 39 IS 7 BP 1208 EP 1217 DI 10.2337/dc15-2255 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500029 PM 27330127 ER PT J AU Hering, BJ Clarke, WR Bridges, ND Eggerman, TL Alejandro, R Bellin, MD Chaloner, K Czarniecki, CW Goldstein, JS Hunsicker, LG Kaufman, DB Korsgren, O Larsen, CP Luo, XR Markmann, JF Naji, A Oberholzer, J Posselt, AM Rickels, MR Ricordi, C Robien, MA Senior, PA Shapiro, AMJ Stock, PG Turgeon, NA AF Hering, Bernhard J. Clarke, William R. Bridges, Nancy D. Eggerman, Thomas L. Alejandro, Rodolfo Bellin, Melena D. Chaloner, Kathryn Czarniecki, Christine W. Goldstein, Julia S. Hunsicker, Lawrence G. Kaufman, Dixon B. Korsgren, Olle Larsen, Christian P. Luo, Xunrong Markmann, James F. Naji, Ali Oberholzer, Jose Posselt, Andrew M. Rickels, Michael R. Ricordi, Camillo Robien, Mark A. Senior, Peter A. Shapiro, A. M. James Stock, Peter G. Turgeon, Nicole A. CA Clinical Islet Transplantation Con TI Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia SO DIABETES CARE LA English DT Article ID EXCHANGE CLINIC REGISTRY; INSULIN PUMP THERAPY; PANCREAS TRANSPLANTATION; GLYCEMIC CONTROL; CURRENT STATE; AWARENESS; ADULTS; MELLITUS; OUTCOMES; IDDM AB OBJECTIVE Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50-80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment. RESEARCH DESIGN AND METHODS This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA(1c) <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant. RESULTS The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA(1c) level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients. CONCLUSIONS Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs. C1 [Hering, Bernhard J.; Bellin, Melena D.] Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN 55455 USA. [Hering, Bernhard J.] Univ Minnesota, Dept Surg, Box 242 UMHC, Minneapolis, MN 55455 USA. [Clarke, William R.; Chaloner, Kathryn; Hunsicker, Lawrence G.] Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA. [Bridges, Nancy D.; Czarniecki, Christine W.; Goldstein, Julia S.; Robien, Mark A.] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. [Eggerman, Thomas L.] NIDDK, NIH, Bethesda, MD 20892 USA. [Alejandro, Rodolfo; Ricordi, Camillo] Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA. [Bellin, Melena D.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Kaufman, Dixon B.] Univ Wisconsin, Dept Surg, Div Transplantat, Madison, WI USA. [Korsgren, Olle] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Larsen, Christian P.; Turgeon, Nicole A.] Emory Univ, Emory Transplant Ctr, Atlanta, GA 30322 USA. [Luo, Xunrong] Northwestern Univ, Feinberg Sch Med, Comprehens Transplant Ctr, Chicago, IL 60611 USA. [Markmann, James F.] Harvard Med Sch, Massachusetts Gen Hosp, Div Transplant Surg, Boston, MA USA. [Naji, Ali; Rickels, Michael R.] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Naji, Ali; Rickels, Michael R.] Univ Penn, Perelman Sch Med, Dept Surg, Philadelphia, PA 19104 USA. [Naji, Ali; Rickels, Michael R.] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Oberholzer, Jose] Univ Illinois Hosp & Hlth Sci Syst, Div Transplantat, Chicago, IL USA. [Posselt, Andrew M.; Stock, Peter G.] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Senior, Peter A.; Shapiro, A. M. James] Univ Alberta, Clin Islet Transplant Program, Edmonton, AB, Canada. [Senior, Peter A.; Shapiro, A. M. James] Univ Alberta, Fac Med & Dent, Edmonton, AB, Canada. RP Hering, BJ (reprint author), Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN 55455 USA.; Hering, BJ (reprint author), Univ Minnesota, Dept Surg, Box 242 UMHC, Minneapolis, MN 55455 USA. EM bhering@umn.edu OI Ricordi, Camillo/0000-0001-8092-7153 FU National Institute of Allergy and Infectious Diseases; National Institute for Diabetes and Digestive and Kidney Diseases [U01-AI-089317, U01-AI-089316, U01-AI-065191, U01-DK-085531, 5U01-DK-070431-10, U01-DK-070431, U01-DK070460, U01-AI-065193, U01-DK-070430, U01-AI-065192]; General Clinical Research Center Awards and Clinical and Translational Science Awards [UL1-TR-000454, 5UL1-RR-025741, 8UL1-TR-000150, UL1-TR-000004, UL1-TR-000050, 1UL1-TR-000460, 5M01-RR-000400, UL1-TR-000114, M01-RR-00040, UL1-TR-000003]; National Institute of Allergy and Infectious Diseases of the National Institutes of Health [NO1-AI-15416, UM1-AI-109565] FX This research was supported by grants from the National Institute of Allergy and Infectious Diseases and the National Institute for Diabetes and Digestive and Kidney Diseases to the following institutions: Emory University (Atlanta, GA), U01-AI-089317; Northwestern University (Evanston, IL), U01-AI-089316; University of Alberta(Edmonton, Alberta, Canada), U01-AI-065191; University of California, San Francisco (San Francisco, CA) U01-DK-085531; University of Illinois, Chicago(Chicago, IL), 5U01-DK-070431-10; University of Iowa (Iowa City, IA), U01-DK-070431; University of Miami (Miami, FL), U01-DK070460; University of Minnesota (Minneapolis, MN), U01-AI-065193; University of Pennsylvania (Philadelphia, PA), U01-DK-070430; and Uppsala University (Uppsala, Sweden), U01-AI-065192. In addition, the study was supported by the following General Clinical Research Center Awards and Clinical and Translational Science Awards: to Emory University, UL1-TR-000454; Northwestern University, 5UL1-RR-025741 and 8UL1-TR-000150; University of California, San Francisco, UL1-TR-000004; University of Illinois, Chicago, UL1-TR-000050; University of Miami, 1UL1-TR-000460; University of Minnesota, 5M01-RR-000400 and UL1-TR-000114; and University of Pennsylvania, M01-RR-00040 and UL1-TR-000003. TrialShare, a public database maintained by the Immune Tolerance Network, is supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers NO1-AI-15416 and UM1-AI-109565. NR 40 TC 19 Z9 19 U1 3 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 JUL PY 2016 VL 39 IS 7 BP 1230 EP 1240 DI 10.2337/dc15-1988 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500032 PM 27208344 ER PT J AU Celeng, C Maurovich-Horvat, P Ghoshhajra, BB Merkely, B Leiner, T Takx, RAP AF Celeng, Csilla Maurovich-Horvat, Pal Ghoshhajra, Brian B. Merkely, Bela Leiner, Tim Takx, Richard A. P. TI Prognostic Value of Coronary Computed Tomography Angiography in Patients With Diabetes: A Meta-analysis SO DIABETES CARE LA English DT Article ID AMERICAN-HEART-ASSOCIATION; ARTERY-DISEASE; CT ANGIOGRAPHY; CARDIOVASCULAR-DISEASE; CARDIAC EVENTS; FOLLOW-UP; RISK; MELLITUS; INDIVIDUALS; POPULATION AB OBJECTIVE The usefulness of coronary computed tomography angiography (CTA) for the evaluation of coronary artery disease (CAD) in patients with diabetes is ambiguous. We therefore performed a meta-analysis of studies reporting event rates and hazard ratios (HR) to determine the prognostic value of CTA in this patient population. RESEARCH DESIGN AND METHODS We searched PubMed and Embase up to November 2015. Study subjects' characteristics, events (all-cause mortality or cardiac death, nonfatal myocardial infarction, unstable angina pectoris, stroke, revascularization), and events excluding revascularization were collected. We calculated the prevalence of obstructive and nonobstructive CAD on CTA, annualized event rates, and pooled unadjusted and adjusted HR using a generic inverse random model. RESULTS Eight studies were eligible for inclusion into this meta-analysis, with 6,225 participants (56% male; weighted age, 61 years) with a follow-up period ranging from 20 to 66 months. The prevalence of obstructive CAD, nonobstructive CAD, and no CAD was 38%, 36%, and 25%, respectively. The annualized event rate was 17.1% for obstructive CAD, 4.5% for nonobstructive CAD, and 0.1% for no CAD. Obstructive and nonobstructive CAD were associated with an increased HR of 5.4 and 4.2, respectively. A higher HR for obstructive CAD was observed in studies including revascularization compared with those that did not (7.3 vs. 3.7, P = 0.124). CONCLUSIONS CTA in patients with diabetes allows for safely ruling out future events, and the detection of CAD could allow for the identification of high-risk patients in whom aggressive risk factor modification, medical surveillance, or elective revascularization could potentially improve survival. C1 [Celeng, Csilla; Maurovich-Horvat, Pal; Merkely, Bela] Semmelweis Univ, Heart & Vasc Ctr, MTA SE Cardiovasc Imaging Res Grp, Budapest, Hungary. [Ghoshhajra, Brian B.; Takx, Richard A. P.] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Div Cardiovasc Imaging, Boston, MA 02114 USA. [Ghoshhajra, Brian B.; Takx, Richard A. P.] Harvard Med Sch, Boston, MA 02115 USA. [Leiner, Tim; Takx, Richard A. P.] Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. RP Takx, RAP (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Div Cardiovasc Imaging, Boston, MA 02114 USA.; Takx, RAP (reprint author), Harvard Med Sch, Boston, MA 02115 USA.; Takx, RAP (reprint author), Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. EM r.a.p.takx@umcutrecht.nl FU Van Leersum Grant of the Royal Netherlands Academy of Arts and Sciences FX R.A.P.T. is supported by Van Leersum Grant of the Royal Netherlands Academy of Arts and Sciences. NR 35 TC 0 Z9 1 U1 0 U2 0 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 JUL PY 2016 VL 39 IS 7 BP 1274 EP 1280 DI 10.2337/dc16-0281 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500037 PM 27330128 ER PT J AU Arnold, SV Inzucchi, SE McGuire, DK Mehta, SN Goyal, A Sperling, LS Maddox, TM Einhorn, D Wong, ND Ratner, RE Hammar, N Fenici, P Sheehan, JJ Wong, JL Kosiborod, M AF Arnold, Suzanne V. Inzucchi, Silvio E. McGuire, Darren K. Mehta, Sanjeev N. Goyal, Abhinav Sperling, Laurence S. Maddox, Thomas M. Einhorn, Daniel Wong, Nathan D. Ratner, Robert E. Hammar, Niklas Fenici, Peter Sheehan, John J. Wong, Jennifer L. Kosiborod, Mikhail TI Evaluating the Quality of Comprehensive Cardiometabolic Care for Patients With Type 2 Diabetes in the US: The Diabetes Collaborative Registry SO DIABETES CARE LA English DT Letter ID CLINICAL-PRACTICE; ASSOCIATION; GUIDELINES; MORTALITY; MELLITUS; BURDEN C1 [Arnold, Suzanne V.; Kosiborod, Mikhail] St Lukes Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Arnold, Suzanne V.; Kosiborod, Mikhail] Univ Missouri, Kansas City, MO 64110 USA. [Inzucchi, Silvio E.] Yale Univ, Sch Med, New Haven, CT USA. [McGuire, Darren K.] Univ Texas Southwestern Med Ctr, Dallas, TX USA. [Mehta, Sanjeev N.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Goyal, Abhinav; Sperling, Laurence S.] Emory Univ, Sch Med, Atlanta, GA USA. [Maddox, Thomas M.] VA Eastern Colorado Hlth Care Syst, Denver, CO USA. [Maddox, Thomas M.] Univ Colorado, Sch Med, Denver, CO USA. [Einhorn, Daniel] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. [Wong, Nathan D.] Univ Calif Irvine, Sch Med, Irvine, CA 92717 USA. [Ratner, Robert E.] Amer Diabet Assoc, Alexandria, VA USA. [Hammar, Niklas] AstraZeneca, Molndal, Sweden. [Fenici, Peter] AstraZeneca, Rome, Italy. [Sheehan, John J.] AstraZeneca, Ft Washington, PA USA. [Wong, Jennifer L.] Amer Coll Cardiol Fdn, Washington, DC USA. RP Kosiborod, M (reprint author), St Lukes Mid Amer Heart Inst, Kansas City, MO 64111 USA.; Kosiborod, M (reprint author), Univ Missouri, Kansas City, MO 64110 USA. EM mkosiborod@saint-lukes.org NR 20 TC 0 Z9 0 U1 0 U2 0 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 JUL PY 2016 VL 39 IS 7 BP E99 EP E101 DI 10.2337/dc16-0585 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA DT3YG UT WOS:000381416500005 PM 27222504 ER PT J AU Davis, M Aviki, E Rauh-Hain, JA Worley, M Berkowitz, R Schorge, J Muto, M Sisodia, RC Horowitz, N del Carmen, M AF Davis, Michelle Aviki, Emeline Rauh-Hain, J. Alejandro Worley, Michael, Jr. Berkowitz, Ross Schorge, John Muto, Michael Sisodia, Rachel Clark Horowitz, Neil del Carmen, Marcela TI Investigating the Impact of Body Mass Index on Intraperitoneal Chemotherapy Outcomes in Ovarian and Fallopian Tube Cancer SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Ovarian cancer; Intraperitoneal chemotherapy; Obesity ID GYNECOLOGIC-ONCOLOGY-GROUP; CYTOREDUCTIVE SURGERY; OBESITY; WOMEN; COMPLICATIONS; APPENDICEAL; MANAGEMENT; CISPLATIN; SURVIVAL; DISEASE AB Objectives: The aim of this study was to investigate the impact of body mass index (BMI) on completion, complications, and clinical outcomes of intraperitoneal (IP) chemotherapy in patients with advanced-stage ovarian cancer. Methods: Patients with optimally cytoreduced International Federation of Gynecology and Obstetrics stage IIIC ovarian cancer treated with IP chemotherapy were retrospectively identified using an institutional review boardYapproved database. Clinical data were abstracted from the longitudinal medical record. Survival estimates were calculated using the Kaplan-Meier method. Results: Ninety-two patients (35.5%) completed at least one cycle of IP chemotherapy. For these patients, there was no difference in histology, surgical complexity, or degree of cytoreduction based on BMI. Sixty-five percent of normal weight, 70% of overweight, and 59.1% of obese women completed 6 cycles (P = 0.697). There was also no significant difference in IP chemotherapy complications (P = 0.303). Body mass index had no impact on disease-free survival (P = 0.44) or overall survival, with a median overall survival of 68.5 months for normal weight, 65.9 months for overweight, and 61.7 months for obese women (P = 0.25). However, on multivariate analysis, obesity had an odds ratio of 2.92 (P = 0.02) for mortality. There was a trend toward treatment with intravenous chemotherapy (84.2%) over IP (15.8%) in patients with class II obesity (P = 0.06). Discussion: There was no difference in completion of IP chemotherapy or complications with respect to BMI; however, there was a trend away from treatment with IP therapy in extreme obesity. These data suggest that IP chemotherapy is feasible in obese patients without incurring increased morbidity. C1 [Davis, Michelle; Aviki, Emeline; Berkowitz, Ross; Muto, Michael; Horowitz, Neil] Harvard Med Sch, Brigham & Womens Hosp, Div Gynecol Oncol, Boston, MA USA. [Aviki, Emeline; Rauh-Hain, J. Alejandro; Schorge, John; Sisodia, Rachel Clark; del Carmen, Marcela] Harvard Med Sch, Massachusetts Gen Hosp, Vincent Obstet & Gynecol, Div Gynecol Oncol, Boston, MA USA. [Worley, Michael, Jr.] St Peters Univ Hosp, New Brunswick, NJ USA. RP del Carmen, M (reprint author), Massachusetts Gen Hosp, Vincent Obstet & Gynecol, Div Gynecol Oncol, 55 Fruit St,Yawkey 9 E, Boston, MA 02114 USA. EM mdelcarmen@partners.org NR 28 TC 1 Z9 1 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD JUL PY 2016 VL 26 IS 6 BP 1033 EP 1040 DI 10.1097/IGC.0000000000000729 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DW9CV UT WOS:000383953500008 PM 27206282 ER PT J AU Simmons, AR Clarke, CH Badgwell, DB Lu, Z Sokoll, LJ Lu, KH Zhang, Z Bast, RC Skates, SJ AF Simmons, Archana R. Clarke, Charlotte H. Badgwell, Donna B. Lu, Zhen Sokoll, Lori J. Lu, Karen H. Zhang, Zhen Bast, Robert C., Jr. Skates, Steven J. TI Validation of a Biomarker Panel and Longitudinal Biomarker Performance for Early Detection of Ovarian Cancer SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Ovarian cancer; Early detection; Multiple marker; Longitudinal biomarker ID RANDOMIZED CONTROLLED-TRIAL; STATISTICS; MORTALITY; PROSTATE; LUNG AB Objectives: Longitudinal multimarker combinations have the potential to improve sensitivity while maintaining the high specificity required for the early detection of ovarian cancer. The use of multiple markers to improve sensitivity over cancer antigen 125 (CA125) in longitudinal algorithms for early ovarian cancer detection requires the selection of markers with optimal discriminatory power and low longitudinal variance relative to disease-initiated changes. Our objective was to identify a multimarker panel suitable for ovarian cancer, where each individual marker has its own baseline, permitting longitudinal algorithm development. Materials and Methods: In this retrospective study, we measured CA125, human epididymis protein 4 (HE4), matrix metalloproteinase-7 (MMP-7), CA72-4, CA19-9, CA15-3, carcinoembryonic antigen, and soluble vascular cell adhesion molecule (sVCAM) concentrations using immunoassays in pretreatment sera from 142 stage I ovarian cancer cases and 5 annual samples each from 217 healthy controls. After random division into training and validation sets, all possible biomarker combinations were explored exhaustively using linear classifiers to identify the panel with the greatest sensitivity for stage I disease at a high specificity of 98%. To evaluate longitudinal performance of the individual markers, the within-person over time and the between-person coefficient of variation (CV) were estimated. Hierarchical modeling across women of log-concentrations enabled the borrowing of information across subjects to moderate variance estimates given the small number of observations per subject. Results: The 4-marker panel comprising CA125, HE4, MMP-7, and CA72-4 performed with the highest sensitivity (83.2%) at 98% specificity. The within-person CVs were lower for CA125, HE4, MMP-7, and CA72-4 (15%, 25%, 25%, and 21%, respectively) compared with their corresponding between-person CV (49%, 20%, 35%, and 84%, respectively) indicating baselines in healthy volunteers. After simple log-transformations, the within volunteer variation across volunteers was modeled with a normal distribution permitting parsimonious hierarchical modeling. Conclusions: The multiplex panel chosen is suitable for the early detection of ovarian cancer and the individual markers have their own baseline permitting longitudinal algorithm development. C1 [Simmons, Archana R.; Clarke, Charlotte H.; Badgwell, Donna B.; Lu, Zhen; Bast, Robert C., Jr.] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Sokoll, Lori J.; Zhang, Zhen] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Lu, Karen H.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Skates, Steven J.] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. RP Bast, RC (reprint author), Univ Texas MD Anderson Canc Ctr, 1400 Pressler St,Unit 1439, Houston, TX 77230 USA. EM rbast@mdanderson.org RI Bast, Robert/E-6585-2011 OI Bast, Robert/0000-0003-4621-8462 FU MD Anderson SPORE in Ovarian Cancer NCI [P50 CA83639]; Shared Resources of the MD Anderson CCSG NCI [P30 CA16672]; Cancer Prevention and Research Institute of Texas [RP101382]; Ovarian Cancer Research Fund; National Foundation for Cancer Research FX This study was supported in part by a grant from the MD Anderson SPORE in Ovarian Cancer NCI P50 CA83639 grant; the Shared Resources of the MD Anderson CCSG NCI P30 CA16672 grant; the Cancer Prevention and Research Institute of Texas grant RP101382; the Ovarian Cancer Research Fund; the National Foundation for Cancer Research; and philanthropic support from the Zarrow Foundation and Stuart and Gaye Lynn Zarrow, Golfers Against Cancer, the Kaye Yow Foundation, and the Mossy Family Foundation. Cancer antigen 72-4 reagents were provided by Roche Diagnostics. NR 16 TC 2 Z9 2 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD JUL PY 2016 VL 26 IS 6 BP 1070 EP 1077 DI 10.1097/IGC.0000000000000737 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DW9CV UT WOS:000383953500013 PM 27206285 ER PT J AU Chuang, LT Randall, TC Denny, L Johnston, CM Schmeler, KM Covens, AL Cibula, D Bookman, MA Rawal, S DePetrillo, D Nam, JH Goodman, A Naik, R Manchanda, R Gaffney, DK Small, W Creutzberg, C Rattray, C Kesic, V Paraja, R Eiken, M Belleson, K Coleman, RL Barakat, RR Trimble, EL Quinn, M AF Chuang, Linus T. Randall, Thomas C. Denny, Lynette Johnston, Carolyn M. Schmeler, Kathleen M. Covens, Allan L. Cibula, David Bookman, Michael A. Rawal, Sudhir DePetrillo, Denny Nam, Joo-Hyun Goodman, Annekathryn Naik, Raj Manchanda, Ranjit Gaffney, David K. Small, William, Jr. Creutzberg, Carien Rattray, Carole Kesic, Vesna Paraja, Rene Eiken, Mary Belleson, Kristin Coleman, Robert L. Barakat, Richard R. Trimble, Edward L. Quinn, Michael TI Sister Society Meeting on Global Education Development and Collaboration Meeting Report SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Sister society; Low- and middle-income countries; Global education; Collaboration ID GYNECOLOGIC ONCOLOGY; HEALTH; SURGERY AB Objectives: To identify common barriers to teaching and training and to identify strategies that would be useful in developing future training programs in gynecologic oncology in low- and middle-income countries. Methods: There is a lack of overall strategy to meet the needs of education and training in gynecologic oncology in low- and middle-income countries, the leaderships of sister societies and global health volunteers met at the European Society of Gynecologic Oncology in October 23, 2015. The challenges of the training programs supported by gynecologic oncology societies, major universities and individual efforts were presented and discussed. Strategies to improve education and training were identified. Results: Major challenges include language barriers, limited surgical equipment, inadequate internet access, lack of local support for sustainability in training programs, inadequate pathology and radiation oncology, finance and a global deficiency in identifying sites and personnel in partnering or developing training programs. The leaderships identified various key components including consultation with the local Ministry of Health, local educational institutions; inclusion of the program into existing local programs, a needs assessment, and the development of curriculum and regional centers of excellence. Conclusions: Proper preparation of training sites and trainers, the development of global curriculum, the establishment of centers of excellence, and the ability to measure outcomes are important to improve education and training in gynecologic oncology in low- and middle- income countries. C1 [Chuang, Linus T.] Icahn Sch Med Mt Sinai, 1176 Fifth Ave,Box 1173, New York, NY 10029 USA. [Randall, Thomas C.; Goodman, Annekathryn] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Denny, Lynette] Univ Cape Town, Schuur Hosp, ZA-7700 Rondebosch, South Africa. [Johnston, Carolyn M.] Univ Michigan, Ann Arbor, MI 48109 USA. [Schmeler, Kathleen M.; Coleman, Robert L.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Covens, Allan L.] Univ Toronto, Odette Canc Ctr, Toronto, ON M5S 1A1, Canada. [Cibula, David] Charles Univ Prague, Prague, Czech Republic. [Cibula, David] Gen Univ Hosp, Prague, Czech Republic. [Bookman, Michael A.] US Oncol Network, The Woodlands, TX USA. [Rawal, Sudhir] Rajiv Gandhi Canc Inst, New Delhi, India. [DePetrillo, Denny] Univ Toronto, CAREpath Canada, Toronto, ON M5S 1A1, Canada. [Nam, Joo-Hyun] Univ Ulsan, Coll Med, Seoul, South Korea. [Naik, Raj] Queen Elizabeth Hosp, Gateshead, England. [Manchanda, Ranjit] Queen Mary Univ London, Barts Canc Inst, London, England. [Gaffney, David K.] Univ Utah, Huntsman Canc Hosp, Salt Lake City, UT 84112 USA. [Small, William, Jr.] Loyola Univ, Stritch Sch Med, Chicago, IL 60611 USA. [Creutzberg, Carien] Leiden Univ, Med Ctr, Leiden, Netherlands. [Rattray, Carole] Univ West Indies, Mona Campus, Kingston, Jamaica. [Kesic, Vesna] Clin Ctr Serbia, Belgrade, Serbia. [Paraja, Rene] Inst Cancerol Amer, Antioquia, Colombia. [Eiken, Mary] Int Gynecol Canc Soc, Louisville, KY USA. [Belleson, Kristin] Soc Gynecol Oncol, Chicago, IL USA. [Barakat, Richard R.] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. [Trimble, Edward L.] NCI, Bethesda, MD 20892 USA. [Quinn, Michael] Royal Womens Hosp, Melbourne, Vic, Australia. RP Chuang, LT (reprint author), Icahn Sch Med Mt Sinai, 1176 Fifth Ave,Box 1173, New York, NY 10029 USA. EM linus.chuang@mssm.edu OI Cibula, David/0000-0001-6387-9356 FU NCI NIH HHS [P30 CA008748] NR 6 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD JUL PY 2016 VL 26 IS 6 BP 1186 EP 1188 DI 10.1097/IGC.0000000000000735 PG 3 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA DW9CV UT WOS:000383953500030 PM 27327155 ER PT J AU Wilens, T Zulauf, C Martelon, M Morrison, NR Simon, A Carrellas, NW Yule, A Anselmo, R AF Wilens, Timothy Zulauf, Courtney Martelon, MaryKate Morrison, Nicholas R. Simon, Andrew Carrellas, Nicholas W. Yule, Amy Anselmo, Rayce TI Nonmedical Stimulant Use in College Students: Association With Attention-Deficit/Hyperactivity Disorder and Other Disorders SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article DE Attention-Deficit/Hyperactivity Disorder; Substance-Related Disorders ID ADHD MEDICATION USE; PRESCRIPTION STIMULANTS; ILLICIT USE; DOUBLE-BLIND; ADOLESCENTS; MOTIVES; PREVALENCE; DIVERSION; CHILDREN; MISUSE AB Objective: The nonmedical use of stimulants (misuse) in the college setting remains of utmost public health and clinical concern. The objective of this study was to evaluate comprehensively the characteristics of college students who misused stimulants, attending to rates of attention-deficit/hyperactivity disorder (ADHD), other psychopathology, and substance use disorders. Methods: The data presented are from a cross-sectional study of college students who misused prescription stimulant medications (not including cocaine or methamphetamine) and controls (college students without stimulant misuse). Between May 2010 and May 2013, college students were assessed blindly for psychopathology and substance use disorder by way of Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P) and completion of self-report questionnaires. Results: The analysis included 198 controls (mean +/- SD age = 20.7 +/- 2.6 years) and 100 stimulant misusers (20.7 +/- 1.7 years). Misusers, when compared to controls, were more likely to endorse alcohol, drug, alcohol + drug, and any substance use disorder (all P values <.01). When a subset of stimulant misusers (n = 58) was examined, 67% had a full or subthreshold prescription stimulant use disorder. Misusers also had higher rates of conduct disorder (10% vs 3%; P = .02) and ADHD (including subthreshold cases; 27% vs 16%; P = .02) in addition to lower Global Assessment of Functioning score (P < .01). Higher rates of misuse of immediate-release-relative to extended-release-stimulants were reported. Conclusions: Our data suggest that, compared to controls, college students who misuse stimulant medications are more likely to have ADHD, conduct disorder, stimulant and other substance use disorder, and overall dysfunction. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Wilens, Timothy; Zulauf, Courtney; Martelon, MaryKate; Morrison, Nicholas R.; Simon, Andrew; Carrellas, Nicholas W.; Yule, Amy] Massachusetts Gen Hosp, Div Child Psychiat, Pediat Psychopharmacol Program, Boston, MA 02114 USA. [Wilens, Timothy; Yule, Amy; Anselmo, Rayce] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Wilens, Timothy; Yule, Amy; Anselmo, Rayce] Harvard Med Sch, Boston, MA USA. RP Wilens, T (reprint author), Massachusetts Gen Hosp, Child Psychiat Serv, 55 Fruit St,YAW 6A, Boston, MA 02114 USA. EM twilens@partners.org FU NIH [K24 DA016264] FX This work was supported by an NIH K24 DA016264 grant to Dr Wilens. NR 40 TC 0 Z9 0 U1 4 U2 4 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 JUL PY 2016 VL 77 IS 7 BP 940 EP 947 DI 10.4088/JCP.14m09559 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DW6XY UT WOS:000383795900021 PM 27464314 ER PT J AU Gracious, BL Fontanella, CA Phillips, GS Bridge, JA Marcus, SC Campo, JV AF Gracious, Barbara L. Fontanella, Cynthia A. Phillips, Gary S. Bridge, Jeffrey A. Marcus, Steven C. Campo, John V. TI Antidepressant Exposure and Risk of Fracture Among Medicaid-Covered Youth SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article DE Antidepressants; Child and Adolescent Psychiatry ID SEROTONIN-REUPTAKE INHIBITORS; BONE-MINERAL DENSITY; PEDIATRIC OFFICIAL POSITIONS; DEPRESSIVE SYMPTOMS; ADOLESCENTS; CHILDREN; WOMEN; GROWTH; RECOMMENDATIONS; OSTEOPOROSIS AB Objective: This study examines the association between antidepressant use and risk of fracture in depressed youth and assesses whether fracture incidence varies over the course of antidepressant treatment. Method: A retrospective cohort analysis of Ohio Medicaid claims data was conducted for youth ages 6-17 years with a new episode of ICD-9-diagnosed depression from 2001-2009. The primary outcome variable was time to fracture. Fracture rates were compared between depressed youth treated with antidepressant medication and untreated depressed youth. Time categories of no use, past use, and current use were compared. Results: Of 50,673 depressed youths, 5,872 (11.6%) experienced a fracture. Of those who had a fracture, 2,228 (37.9%) were exposed to antidepressants, 80% of which were selective serotonin reuptake inhibitors. The adjusted hazard ratio (HR) was 3% higher in those currently prescribed antidepressants (HR = 1.03; 95% CI, 1.00-1.06; P = .03). The risk ratio (RR) for adjusted fracture rates per 10,000 persons was twice as high during the first 30 days of antidepressant use compared to the other time periods (RR = 2.0; 95% CI, 1.2-3.3; P = .007). The number of fractures for those with past antidepressant use did not differ from those with no history of antidepressant use. Conclusions: Antidepressant use may be associated with a small but significant increase in fracture risk, particularly within the first 30 days of treatment. Findings underscore a need for additional prospective and mechanistic research. Prescribers should consider other risks for fracture in antidepressant-treated youth, particularly disability and the concomitant use of other medications that increase fracture risk. (C) Copyright 2016 Physicians Postgraduate Press, Inc. C1 [Gracious, Barbara L.; Fontanella, Cynthia A.; Campo, John V.] Ohio State Univ, Dept Psychiat & Behav Hlth, Wexner Med Ctr, Columbus, OH 43210 USA. [Gracious, Barbara L.; Bridge, Jeffrey A.] Nationwide Childrens Hosp, Res Inst, Ctr Innovat Pediat Practice, Columbus, OH USA. [Phillips, Gary S.] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Bridge, Jeffrey A.] Ohio State Univ, Dept Pediat, Columbus, OH 43210 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. RP Gracious, BL (reprint author), Nationwide Childrens Hosp, 700 Childrens Dr,J West 4923, Columbus, OH 43205 USA. EM Barbara.Gracious@nationwidechildrens.org FU National Center for Research Resources [UL1RR025755]; Jeffrey Research Fellowship at the Department of Psychiatry and Behavioral Health; Nationwide Children's Hospital; Ohio State University FX This project was supported by Award Number UL1RR025755 from the National Center for Research Resources, for the statistical support by Mr Phillips. Dr Gracious' salary for the project was supported by The Jeffrey Research Fellowship at the Department of Psychiatry and Behavioral Health, Nationwide Children's Hospital and The Ohio State University. NR 37 TC 0 Z9 0 U1 3 U2 3 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD JUL PY 2016 VL 77 IS 7 BP 950 EP + DI 10.4088/JCP.15m09828 PG 11 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA DW6XY UT WOS:000383795900023 ER PT J AU Frey, LJ Bernstam, EV Denny, JC AF Frey, Lewis J. Bernstam, Elmer V. Denny, Joshua C. TI Precision medicine informatics SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Editorial Material ID ELECTRONIC HEALTH RECORDS; GENOME-WIDE ASSOCIATION; GENOTYPE; DISEASE; SYSTEMS; IMPLEMENTATION; MELANOMA; THERAPY; NETWORK; SUPPORT C1 [Frey, Lewis J.] Med Univ South Carolina, Biomed Informat Ctr, Dept Publ Hlth Sci, Charleston, SC 29425 USA. [Frey, Lewis J.] Ralph H Johnson Dept Vet Affairs Med Ctr, Hlth Equ & Rural Outreach Innovat Ctr, Charleston, SC 29401 USA. [Bernstam, Elmer V.] Univ Texas Hlth Sci Ctr Houston, Sch Biomed Informat, Houston, TX 77030 USA. [Bernstam, Elmer V.] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Div Gen Internal Med, Sch Med, Houston, TX 77030 USA. [Denny, Joshua C.] Vanderbilt Univ, Dept Biomed Informat, 221 Kirkland Hall, Nashville, TN 37235 USA. [Denny, Joshua C.] Vanderbilt Univ, Dept Med, Nashville, TN USA. RP Frey, LJ (reprint author), Med Univ South Carolina, Biomed Informat Ctr, Dept Publ Hlth Sci, Charleston, SC 29425 USA.; Frey, LJ (reprint author), Ralph H Johnson Dept Vet Affairs Med Ctr, Hlth Equ & Rural Outreach Innovat Ctr, Charleston, SC 29401 USA. FU National Institutes of Health (NIH) [1R01GM108346-01, U54-GM104941]; Health Equity and Rural Outreach Innovation Center [CIN 13-418]; Hollings Cancer Center at the Medical University of South Carolina [P30 CA138313]; National Cancer Institute (NCI) [U01 CA180964]; Sheikh Bin Zayed Al Nahyan Foundation; Cancer Prevention Research Institute of Texas Precision Oncology Decision Support Core [RP150535]; National Center for Advancing Translational Sciences (NCATS) [UL1 TR000371]; Bosarge Foundation; MD Anderson Cancer Center [NCI P30 CA016672]; NIH [R01 LM 010685, R01 GM 103859, R01 GM 105688] FX The work of L.J.F. was supported in part by National Institutes of Health (NIH) grants 1R01GM108346-01 and U54-GM104941, Health Equity and Rural Outreach Innovation Center grant CIN 13-418, and funding from the Hollings Cancer Center's support grant P30 CA138313 at the Medical University of South Carolina. The work of E.V.B. was supported by National Cancer Institute (NCI) U01 CA180964, the Sheikh Bin Zayed Al Nahyan Foundation, the Cancer Prevention Research Institute of Texas Precision Oncology Decision Support Core RP150535, National Center for Advancing Translational Sciences (NCATS) grant UL1 TR000371 (Center for Clinical and Translational Sciences), the Bosarge Foundation, and an MD Anderson Cancer Center support grant (NCI P30 CA016672). The work of J.C.D. was supported by R01 LM 010685, R01 GM 103859, and R01 GM 105688 from the NIH. NR 72 TC 1 Z9 2 U1 5 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL PY 2016 VL 23 IS 4 BP 668 EP 670 DI 10.1093/jamia/ocw053 PG 3 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA DW6SS UT WOS:000383782100002 PM 27274018 ER PT J AU Chavez, A Tuttle, M Pruitt, BW Ewen-Campen, B Chari, R Ter-Ovanesyan, D Haque, SJ Cecchi, RJ Kowal, EJK Buchthal, J Housden, BE Perrimon, N Collins, JJ Church, G AF Chavez, Alejandro Tuttle, Marcelle Pruitt, Benjamin W. Ewen-Campen, Ben Chari, Raj Ter-Ovanesyan, Dmitry Haque, Sabina J. Cecchi, Ryan J. Kowal, Emma J. K. Buchthal, Joanna Housden, Benjamin E. Perrimon, Norbert Collins, James J. Church, George TI Comparison of Cas9 activators in multiple species SO NATURE METHODS LA English DT Article ID TRANSCRIPTION FACTORS; GENE-EXPRESSION; GENOME; SYSTEM; DNA; CRISPR-CAS9; COMPLEX; ENDONUCLEASE; TECHNOLOGIES; CRISPR/CAS9 AB Several programmable transcription factors exist based on the versatile Cas9 protein, yet their relative potency and effectiveness across various cell types and species remain unexplored. Here, we compare Cas9 activator systems and examine their ability to induce robust gene expression in several human, mouse, and fly cell lines. We also explore the potential for improved activation through the combination of the most potent activator systems, and we assess the role of cooperativity in maximizing gene expression. C1 [Chavez, Alejandro; Tuttle, Marcelle; Pruitt, Benjamin W.; Ter-Ovanesyan, Dmitry; Cecchi, Ryan J.; Kowal, Emma J. K.; Buchthal, Joanna; Collins, James J.; Church, George] Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA. [Chavez, Alejandro] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Chavez, Alejandro; Ewen-Campen, Ben; Chari, Raj; Ter-Ovanesyan, Dmitry; Housden, Benjamin E.; Perrimon, Norbert; Church, George] Harvard Med Sch, Dept Genet, Boston, MA USA. [Haque, Sabina J.] Middlebury Coll, Dept Mol Biol & Biochem, Middlebury, VT 05753 USA. [Haque, Sabina J.] Middlebury Coll, Dept Math, Middlebury, VT 05753 USA. [Perrimon, Norbert] Harvard Med Sch, Howard Hughes Med Inst, Boston, MA USA. [Collins, James J.] MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Collins, James J.] MIT, Synthet Biol Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Collins, James J.] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. [Collins, James J.] Broad Inst & Harvard, Cambridge, MA USA. RP Chavez, A; Church, G (reprint author), Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA.; Chavez, A (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA.; Chavez, A; Church, G (reprint author), Harvard Med Sch, Dept Genet, Boston, MA USA. EM alex.chavez@wyss.harvard.edu; gchurch@genetics.med.harvard.edu OI Pruitt, Benjamin/0000-0001-7532-7081; Kowal, Emma/0000-0002-8992-7608; Housden, Benjamin/0000-0001-9134-4279; Ewen-Campen, Ben/0000-0002-4326-3033 FU US National Institutes of Health (NIH) National Human Genome Research Institute [P50 HG005550]; Wyss Institute for Biologically Inspired Engineering; National Cancer Institute [5T32CA009216-34]; Banting postdoctoral fellowship from the Canadian Institutes of Health Research; Defense Threat Reduction Agency [HDTRA1-14-1-0006]; NIH under Ruth L. Kirschstein National Research Service Award from the NIH General Medical Sciences Division [F32GM113395] FX We would like to thank S. Vora, A. Tung, M.K. Cromer, and all the members of the Church and Collins labs for helpful discussions and technical assistance. G.C. acknowledges support from US National Institutes of Health (NIH) National Human Genome Research Institute grant P50 HG005550 and from the Wyss Institute for Biologically Inspired Engineering. In addition, A.C. was funded by National Cancer Institute grant 5T32CA009216-34, R.C. was funded by a Banting postdoctoral fellowship from the Canadian Institutes of Health Research, and J.J.C. was supported by Defense Threat Reduction Agency grant HDTRA1-14-1-0006. B.E.-C. acknowledges funding from the NIH under Ruth L. Kirschstein National Research Service Award F32GM113395 from the NIH General Medical Sciences Division. We would also like to thank J. Lee (Cold Spring Harbor, Cold Spring Harbor, NY), P. Mali (UCSD, La Jolla, CA), and S. Shipman (Harvard Medical School, Boston, MA) for gifting us cell lines. NR 40 TC 16 Z9 17 U1 10 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 EI 1548-7105 J9 NAT METHODS JI Nat. Methods PD JUL PY 2016 VL 13 IS 7 BP 563 EP + DI 10.1038/NMETH.3871 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA DW6XK UT WOS:000383794500013 PM 27214048 ER PT J AU Essa, MM Akbar, M Khan, MAS AF Essa, Musthafa Mohamed Akbar, Mohammed Khan, Mohammed Abdul Sattar TI Beneficial effects of date palm fruits on neurodegenerative diseases SO NEURAL REGENERATION RESEARCH LA English DT Editorial Material ID DIETARY SUPPLEMENTATION; ANTIOXIDANT ACTIVITY; ALZHEIMERS-DISEASE; AMYLOID-BETA C1 [Essa, Musthafa Mohamed] Sultan Qaboos Univ, Coll Agr & Marine Sci, Dept Food Sci & Nutr, Muscat, Oman. [Essa, Musthafa Mohamed] Sultan Qaboos Univ, Ageing & Dementia Res Grp, Muscat, Oman. [Akbar, Mohammed] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Khan, Mohammed Abdul Sattar] Massachusetts Gen Hosp, Shriners Hosp Children, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Khan, Mohammed Abdul Sattar] Harvard Med Sch, Boston, MA USA. RP Essa, MM (reprint author), Sultan Qaboos Univ, Coll Agr & Marine Sci, Dept Food Sci & Nutr, Muscat, Oman.; Essa, MM (reprint author), Sultan Qaboos Univ, Ageing & Dementia Res Grp, Muscat, Oman. EM drmdessa@gmail.com NR 15 TC 0 Z9 0 U1 2 U2 2 PU MEDKNOW PUBLICATIONS & MEDIA PVT LTD PI MUMBAI PA B-9, KANARA BUSINESS CENTRE, OFF LINK RD, GHAKTOPAR-E, MUMBAI, 400075, INDIA SN 1673-5374 EI 1876-7958 J9 NEURAL REGEN RES JI Neural Regen. Res. PD JUL PY 2016 VL 11 IS 7 BP 1071 EP 1072 DI 10.4103/1673-5374.187032 PG 2 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA DW6YW UT WOS:000383798300015 PM 27630684 ER PT J AU Brugger, SD Bomar, L Lemon, KP AF Brugger, Silvio D. Bomar, Lindsey Lemon, Katherine P. TI Commensal-Pathogen Interactions along the Human Nasal Passages SO PLOS PATHOGENS LA English DT Article ID BIOSYNTHETIC GENE CLUSTERS; UPPER RESPIRATORY-TRACT; HUMAN SKIN MICROBIOME; ACUTE OTITIS-MEDIA; STAPHYLOCOCCUS-AUREUS; COMMUNITIES; DIVERSITY; CHILDREN; DISEASE; COLONIZATION C1 [Brugger, Silvio D.; Bomar, Lindsey; Lemon, Katherine P.] Forsyth Inst, Dept Microbiol, Cambridge, MA 02142 USA. [Brugger, Silvio D.; Bomar, Lindsey] Harvard Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA USA. [Lemon, Katherine P.] Harvard Med Sch, Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. RP Lemon, KP (reprint author), Forsyth Inst, Dept Microbiol, Cambridge, MA 02142 USA.; Lemon, KP (reprint author), Harvard Med Sch, Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. EM klemon@forsyth.org FU National Institutes of Health through the National Institute of Allergy and Infectious Diseases [R01 AI101018]; National Institute of General Medical Sciences [R01 GM117174]; McIntosh Foundation; Swiss National Science Foundation; Swiss Foundation for Grants in Biology and Medicine [P3SMP3_155315] FX This work was supported by the National Institutes of Health through the National Institute of Allergy and Infectious Diseases R01 AI101018 (KPL) and the National Institute of General Medical Sciences R01 GM117174 (KPL), by the McIntosh Foundation (KPL), and by the Swiss National Science Foundation and Swiss Foundation for Grants in Biology and Medicine P3SMP3_155315 (SDB). Funders had no role in the preparation of this manuscript or decision to publish. NR 48 TC 0 Z9 0 U1 3 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 JUL PY 2016 VL 12 IS 7 AR e1005633 DI 10.1371/journal.ppat.1005633 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA DW0XN UT WOS:000383366400004 PM 27389401 ER PT J AU Williams, JS Egede, LE AF Williams, Joni S. Egede, Leonard E. TI The Association Between Multimorbidity and Quality of Life, Health Status and Functional Disability SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE Multimorbidity; Quality of life; Health status; Functional disability; Chronic disease ID MULTIPLE CHRONIC CONDITIONS; PRIMARY-CARE; COMMUNITY SETTINGS; MANAGING PATIENTS; PREVALENCE; VALIDITY; RELIABILITY; MANAGEMENT; ADULTS; SCALES AB Introduction: Approximately 50% of adults have multimorbidity (MM) that is associated with greater disability, poorer quality of life (QOL) and increased psychological distress. This study assessed the association between MM and QOL, health status and functional disability in U.S. adults. Methods: Cross-sectional study of 23,789 patients from 2011 Medical Expenditure Panel Survey was conducted. Mean scores were calculated for QOL (physical component score [PCS] and mental component score [MCS]) and proportions for functional limitation (activities of daily living [ADL]; instrumental ADL [IADL] and physical functioning). Health status was assessed by depression and serious psychological distress. Regression models evaluated associations between MM and QOL, functional health status and functional limitations, while adjusting for confounders. Results: Approximately 53% of 45-64-year-olds and 84% of those =65-years-old had MM. In adjusted models, =3 conditions were significantly associated with poorer outcomes-PCS QOL (b = -9.15; 95% CI: -9.69 to -8.61), MCS QOL ( = -1.98; 95% CI: -2.43 to -1.52), ADL (odds ratio [OR] = 5.80; 95% CI: 2.27-14.8), IADL (OR = 3.99; 95% CI: 2.31-6.88) and physical functioning (OR = 16.8; 95% CI: 12.0-23.6) compared with 1-2 conditions. Depression (PCS QOL: b = -4.02; 95% CI: -4.89 to -3.15; MCS QOL: b = -12.5; 95% CI: -13.2 to -10.9; ADL: OR = 2.49; 95% CI: 1.65-3.76; IADL: OR = 2.65; 95% CI: 1.88-3.72; physical functioning: OR = 2.44; 95% CI: 1.99-2.99) and serious psychological distress (PCS QOL: b = -3.16; 95% CI: -4.30 to -2.03; MCS QOL: b = -11.8; 95% CI: -12.8 to -10.8; ADL: OR = 1.57; 95% CI: 0.95-2.60; IADL: OR = 1.13; 95% CI: 0.80-1.59 and physical functioning: OR = 1.41; 95% CI: 1.11-1.78) were significantly associated with adverse outcomes. Conclusions: In this nationally representative sample of U.S. adults, MM was significantly associated with poorer QOL, functional health status and physical functioning, when adjusting for relevant confounders. A holistic view of the complexities associated with MM must dictate comprehensive care. C1 [Williams, Joni S.; Egede, Leonard E.] Med Univ South Carolina, Ctr Hlth Dispar Res, Dept Med, Charleston, SC USA. [Williams, Joni S.; Egede, Leonard E.] Med Univ South Carolina, Div Gen Internal Med & Geriatr, Dept Med, Charleston, SC USA. [Egede, Leonard E.] Ralph H Johnson Dept Vet Affairs Med Ctr, Hlth Equ & Rural Outreach Innovat Ctr, Charleston, SC USA. RP Egede, LE (reprint author), Med Univ South Carolina, Hlth Equ & Rural Outreach Innovat Ctr, Ctr Hlth Dispar Res, 135 Rutledge Ave,Room 280G,POB 250593, Charleston, SC 29425 USA. EM egedel@musc.edu FU National Institute of Diabetes and Digestive and Kidney Disease [K24DK093699] FX This study was supported by Grant no. K24DK093699 from The National Institute of Diabetes and Digestive and Kidney Disease (PI: Leonard Egede). NR 22 TC 0 Z9 0 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9629 EI 1538-2990 J9 AM J MED SCI JI Am. J. Med. Sci. PD JUL PY 2016 VL 352 IS 1 BP 45 EP 52 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA DV1GB UT WOS:000382667400006 PM 27432034 ER PT J AU Gabrielsen, JS Tanrikut, C AF Gabrielsen, J. S. Tanrikut, C. TI Chronic exposures and male fertility: the impacts of environment, diet, and drug use on spermatogenesis SO ANDROLOGY LA English DT Review DE chronic exposures; diet; drug use; male infertility; pollution; spermatogenesis ID DISINFECTION BY-PRODUCTS; REPRODUCTIVE ENDOCRINE FUNCTION; PLASMA ANTIOXIDANT CAPACITY; ETHYLENE-GLYCOL ETHERS; HUMAN SPERM MOTILITY; MALE GERM-CELLS; ADULT MALE-RATS; SEMEN QUALITY; SEMINAL PLASMA; INFERTILE MEN AB Several recent studies have suggested that sperm concentrations and semen quality have been decreasing over the past several decades in many areas of the world. The etiology of these decreases is currently unknown. Acute events can have significant impacts on spermatogenesis and are often readily identified during the male fertility evaluation. The majority of male factor infertility, however, is idiopathic. Chronic, low-dose exposures to chemicals and nutrients are more difficult to identify, but are extremely prevalent. These exposures have been shown to have dramatic effects on both individual and community health and interest in the cumulative and synergistic impacts of such agents on spermatogenesis has been increasing. While our understanding of these potential hazards is evolving, it is clear that they may significantly influence male reproductive potential. This review explores the literature related to effects of chronic exposures from drug use, dietary intake, and the environment on spermatogenesis in humans and animals. C1 [Gabrielsen, J. S.; Tanrikut, C.] Massachusetts Gen Hosp, Dept Urol, 55 Fruit St,YAW-10A, Boston, MA 02114 USA. RP Tanrikut, C (reprint author), Massachusetts Gen Hosp, Dept Urol, 55 Fruit St,YAW-10A, Boston, MA 02114 USA. EM ctanrikut@partners.org NR 208 TC 2 Z9 2 U1 10 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-2919 EI 2047-2927 J9 ANDROLOGY-US JI Andrology PD JUL PY 2016 VL 4 IS 4 SI SI BP 648 EP 661 DI 10.1111/andr.12198 PG 14 WC Andrology SC Endocrinology & Metabolism GA DV9VT UT WOS:000383291000013 PM 27230702 ER PT J AU Kannan, L Ramos, M Re, A El-Hachem, N Safikhani, Z Gendoo, DMA Davis, S Gomez-Cabrero, D Castelo, R Hansen, KD Carey, VJ Morgan, M Culhane, AC Haibe-Kains, B Waldron, L AF Kannan, Lavanya Ramos, Marcel Re, Angela El-Hachem, Nehme Safikhani, Zhaleh Gendoo, Deena M. A. Davis, Sean Gomez-Cabrero, David Castelo, Robert Hansen, Kasper D. Carey, Vincent J. Morgan, Martin Culhane, Aedin C. Haibe-Kains, Benjamin Waldron, Levi TI Public data and open source tools for multi-assay genomic investigation of disease SO BRIEFINGS IN BIOINFORMATICS LA English DT Article DE multiple assays (multi-assays); public data; bioconductor; integrative genomics; cancer; pharmacogenomics; omics ID BRITISH BIRTH COHORT; CANONICAL CORRELATION-ANALYSIS; GENE-EXPRESSION SIGNATURES; CANCER-CELL LINES; DRUG-SENSITIVITY; WIDE ASSOCIATION; SMALL MOLECULES; COPY NUMBER; TUMOR TYPES; DATA SETS AB Molecular interrogation of a biological sample through DNA sequencing, RNA and microRNA profiling, proteomics and other assays, has the potential to provide a systems level approach to predicting treatment response and disease progression, and to developing precision therapies. Large publicly funded projects have generated extensive and freely available multi-assay data resources; however, bioinformatic and statistical methods for the analysis of such experiments are still nascent. We review multi-assay genomic data resources in the areas of clinical oncology, pharmacogenomics and other perturbation experiments, population genomics and regulatory genomics and other areas, and tools for data acquisition. Finally, we review bioinformatic tools that are explicitly geared toward integrative genomic data visualization and analysis. This review provides starting points for accessing publicly available data and tools to support development of needed integrative methods. C1 [Kannan, Lavanya; Ramos, Marcel] CUNY Hunter Coll, Sch Publ Hlth, New York, NY 10021 USA. [Re, Angela] Univ Trento, Ctr Integrat Biol, Trento, Italy. [El-Hachem, Nehme] Univ Montreal, Montreal, PQ H3C 3J7, Canada. [Safikhani, Zhaleh; Gendoo, Deena M. A.; Haibe-Kains, Benjamin] Princess Margaret Canc Ctr, Toronto, ON, Canada. [Davis, Sean] NCI, NIH, Bethesda, MD 20892 USA. [Gomez-Cabrero, David] Karolinska Inst, Unit Computat Med, S-10401 Stockholm, Sweden. [Castelo, Robert] Univ Pompeu Fabra, Bioinformat & Biostat, Barcelona, Spain. [Hansen, Kasper D.] Johns Hopkins Univ, Biostat, Baltimore, MD 21218 USA. [Carey, Vincent J.] Harvard Med Sch, Med Biostat, Boston, MA USA. [Morgan, Martin] Roswell Pk Canc Inst, Biostat & Bioinformat, Buffalo, NY 14263 USA. [Culhane, Aedin C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Waldron, Levi] CUNY Hunter Coll, Sch Publ Hlth, Biostat, New York, NY 10021 USA. RP Waldron, L (reprint author), 2180 3rd Ave, New York, NY 10040 USA. EM levi.waldron@hunter.cuny.edu RI Castelo, Robert/A-4679-2010; Gasull, Martina/A-6630-2013; OI Castelo, Robert/0000-0003-2229-4508; Haibe-Kains, Benjamin/0000-0002-7684-0079; Waldron, Levi/0000-0003-2725-0694 FU National Cancer Institute [U24CA180996, 1U19 AI111224-01]; National Institute on Minority Health and Health Disparities [MD007599]; NCI Intramural Research Program of the National Institutes of Health; Spanish MINECO [TIN2011-22826]; Gattuso Slaight Personalized Cancer Medicine Fund at Princess Margaret Cancer Centre; Cancer Research Society (Canada); Brain Canada-CIBC Brain Cancer Research Training Award; University of Trento; Breast Cancer Research Program [W81XWH-15-1-0013] FX The authors' work was funded by the National Cancer Institute [U24CA180996 to MM], the National Institute on Minority Health and Health Disparities [MD007599 to LW] and the NCI Intramural Research Program [SD] of the National Institutes of Health. Spanish MINECO grant TIN2011-22826 to RC. BHK was supported by the Gattuso Slaight Personalized Cancer Medicine Fund at Princess Margaret Cancer Centre. ZS was supported by the Cancer Research Society (Canada). DMAG was supported by the Brain Canada-CIBC Brain Cancer Research Training Award AR was supported by the Biotechnology start-up project of the University of Trento. AC was supported by National Cancer Institute 1U19 AI111224-01 and the Assistant Secretary of Defense Health Program, through the Breast Cancer Research Program, Award No. W81XWH-15-1-0013. NR 96 TC 2 Z9 2 U1 8 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1467-5463 EI 1477-4054 J9 BRIEF BIOINFORM JI Brief. Bioinform. PD JUL PY 2016 VL 17 IS 4 SI SI BP 603 EP 615 DI 10.1093/bib/bbv080 PG 13 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DV7XI UT WOS:000383151200005 PM 26463000 ER PT J AU Meng, C Zeleznik, OA Thallinger, GG Kuster, B Gholami, AM Culhane, AC AF Meng, Chen Zeleznik, Oana A. Thallinger, Gerhard G. Kuster, Bernhard Gholami, Amin M. Culhane, Aedin C. TI Dimension reduction techniques for the integrative analysis of multi-omics data SO BRIEFINGS IN BIOINFORMATICS LA English DT Article DE multivariate analysis; multi-omics data integration; dimension reduction; integrative genomics; exploratory data analysis; multi-assay ID CANONICAL CORRELATION-ANALYSIS; PRINCIPAL COMPONENT ANALYSIS; CO-INERTIA ANALYSIS; ACUTE LYMPHOBLASTIC-LEUKEMIA; GENE-EXPRESSION DATA; NONNEGATIVE MATRIX FACTORIZATION; GENOMIC DATA; CROSS-PLATFORM; ONCOGENIC ROLE; R PACKAGE AB State-of-the-art next-generation sequencing, transcriptomics, proteomics and other high-throughput 'omics' technologies enable the efficient generation of large experimental data sets. These data may yield unprecedented knowledge about molecular pathways in cells and their role in disease. Dimension reduction approaches have been widely used in exploratory analysis of single omics data sets. This review will focus on dimension reduction approaches for simultaneous exploratory analyses of multiple data sets. These methods extract the linear relationships that best explain the correlated structure across data sets, the variability both within and between variables (or observations) and may highlight data issues such as batch effects or outliers. We explore dimension reduction techniques as one of the emerging approaches for data integration, and how these can be applied to increase our understanding of biological systems in normal physiological function and disease. C1 [Meng, Chen] Tech Univ Munich, Bernhard Kusters Grp, Applicat Multivariate Methods Integrat Anal Omics, D-80290 Munich, Germany. [Zeleznik, Oana A.] Graz Univ Technol, Gerhard Thallingers Grp, Enhancement Existing Methods & Dev Novel Gene Set, A-8010 Graz, Austria. [Thallinger, Gerhard G.] Graz Univ Technol, A-8010 Graz, Austria. [Kuster, Bernhard] Tech Univ Munich, Prote & Bioanalyt, D-80290 Munich, Germany. [Kuster, Bernhard] Bavarian Biomol Mass Spectrometry Ctr, Freising Weihenstephan, Germany. [Gholami, Amin M.] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA USA. [Culhane, Aedin C.] Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA. [Culhane, Aedin C.] Harvard TH Chan Sch Publ Hlth, Boston, MA USA. RP Culhane, AC (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM aedin@jimmy.harvard.edu RI Kuster, Bernhard/Q-6031-2016; OI Kuster, Bernhard/0000-0002-9094-1677; Thallinger, Gerhard G./0000-0002-2864-5404 FU Austrian Ministry of Science, Research and Economics [OMICS Center HSRSM initiative]; Dana-Farber Cancer Institute BCB Research Scientist Developmental Funds; National Cancer Institute [2P50 CA101942-11]; Breast Cancer Research Program [W81XWH-15-1-0013] FX GGT was supported by the Austrian Ministry of Science, Research and Economics [OMICS Center HSRSM initiative]. AC was supported by Dana-Farber Cancer Institute BCB Research Scientist Developmental Funds, National Cancer Institute 2P50 CA101942-11 and the Assistant Secretary of Defense Health Program, through the Breast Cancer Research Program under Award No. W81XWH-15-1-0013. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. NR 94 TC 2 Z9 2 U1 8 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1467-5463 EI 1477-4054 J9 BRIEF BIOINFORM JI Brief. Bioinform. PD JUL PY 2016 VL 17 IS 4 SI SI BP 628 EP 641 DI 10.1093/bib/bbv108 PG 14 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA DV7XI UT WOS:000383151200007 PM 26969681 ER PT J AU Alexander, EK Faquin, WC Krane, JF AF Alexander, Erik K. Faquin, William C. Krane, Jeffrey F. TI Highlights for the Cytology Community From the 2015 American Thyroid Association Clinical Guidelines on the Management of Thyroid Nodules and Well-Differentiated Thyroid Cancer SO CANCER CYTOPATHOLOGY LA English DT Article ID GENERATION SEQUENCING ASSAY; BETHESDA SYSTEM; DIAGNOSIS; IMPACT; CYTOPATHOLOGY C1 [Alexander, Erik K.] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Thyroid Sect, Boston, MA USA. [Faquin, William C.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Krane, Jeffrey F.] Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RP Krane, JF (reprint author), Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM jkrane@partners.org FU Asuragen Inc; Veracyte Inc.; Asuragen; Veracyte FX Erik K. Alexander has acted as a paid member of the Scientific Advisory Board for Asuragen Inc and as a paid consultant for Veracyte Inc. In addition, his institution has received research support from both Asuragen and Veracyte. NR 16 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1934-662X EI 1934-6638 J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD JUL PY 2016 VL 124 IS 7 BP 453 EP 456 DI 10.1002/cncy.21662 PG 4 WC Oncology; Pathology SC Oncology; Pathology GA DV3YM UT WOS:000382861800003 PM 26618757 ER PT J AU Nishino, M Hoang, MP Della Pelle, P Morales-Oyarvide, V Huynh, TG Mark, EJ Mino-Kenudson, M AF Nishino, Michiya Hoang, Mai P. Della Pelle, Patricia Morales-Oyarvide, Vicente Huynh, Tiffany G. Mark, Eugene J. Mino-Kenudson, Mari TI Napsin A/p40 Antibody Cocktail for Subtyping Non-Small Cell Lung Carcinoma on Cytology and Small Biopsy Specimens SO CANCER CYTOPATHOLOGY LA English DT Article DE adenocarcinoma; cytology; napsin A; non-small cell lung cancer; p40 (Delta Np63); small biopsy; squamous cell carcinoma ID TRANSCRIPTION FACTOR-I; ASPARTIC PROTEINASE; DELTA-NP63 P40; USEFUL MARKER; DOUBLE STAIN; ADENOCARCINOMA; CANCER; P63; DIAGNOSIS; CLASSIFICATION AB BACKGROUND: Subtyping non-small cell lung carcinomas (NSCLC) into adenocarcinoma (ACA) or squamous cell carcinoma (SQCC) is important for treatment and specimen triage for molecular studies. To preserve tissue for molecular studies in cytology/small biopsy specimens, a 2-antibody cocktail for NSCLC subtyping was developed. METHODS: Markers for lung ACA (thyroid transcription factor 1 and napsin A) and SQCC (cytokeratin 5/6 and p40) were evaluated on tissue microarrays (TMAs) with 143 ACA and 98 SQCC specimens. The napsin A/p40 combination was selected for NSCLC subtyping and validated on the TMA as well as on a cohort of cell block/small biopsy specimens from 80 poorly differentiated NSCLCs. RESULTS: Using TMA analysis, the napsin A-positive (1)/p40 +/- immunophenotype identified ACA with 94% sensitivity and 100% specificity, whereas the napsin A (negative)-/p40+ immunophenotype identified SQCC with 100% sensitivity and specificity. On the validation cohort of 80 cell block and small biopsy specimens, the napsin A/p40 cocktail accurately subtyped 63 of 70 NSCLC (90%) as ACA or SQCC using the subsequent surgical resection as reference histology. Of the remaining 17 cases, 15 were classified as NSCLC-not otherwise specified based on a napsin A-/p40- immunophenotype; their corresponding resections were diagnosed as ACA (7 cases), large cell carcinoma (7 cases), or pleomorphic carcinoma (1 case). Two additional large cell carcinoma cases showed a napsin A-/p40+ or napsin A+/p40+ profile in the preoperative cell block/small biopsy sample. CONCLUSIONS: A napsin A/p40 cocktail can accurately subtype NSCLC into ACA and SQCC in most cell block/small biopsy specimens of poorly differentiated NSCLC. In the minority of cases in which the napsin A/p40 immunophenotype is indeterminate, additional stains may be necessary for precise classification. (C) 2016 American Cancer Society. C1 [Nishino, Michiya] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. [Hoang, Mai P.; Della Pelle, Patricia; Morales-Oyarvide, Vicente; Huynh, Tiffany G.; Mark, Eugene J.; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. RP Mino-Kenudson, M (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM mminokenudson@partners.org NR 36 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1934-662X EI 1934-6638 J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD JUL PY 2016 VL 124 IS 7 BP 472 EP 484 DI 10.1002/cncy.21707 PG 13 WC Oncology; Pathology SC Oncology; Pathology GA DV3YM UT WOS:000382861800006 PM 27412420 ER PT J AU Balassanian, R Wool, GD Ono, JC Olejnik-Nave, J Mah, MM Sweeney, BJ Liberman, H Ljung, BM Pitman, MB AF Balassanian, Ronald Wool, Geoffrey D. Ono, Jill C. Olejnik-Nave, Jolanta Mah, Molinda M. Sweeney, Brenda J. Liberman, Hava Ljung, Britt-Marie Pitman, Martha B. TI A Superior Method for Cell Block Preparation for Fine-Needle Aspiration Biopsies SO CANCER CYTOPATHOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAY 01-12, 2014 CL San Diego, CA SP US & Canadian Acad Pathol DE cell block; collodion bag; fine-needle aspiration (FNA) biopsy; HistoGel; saline plasma thrombin AB BACKGROUND: Cell block (CB) techniques for fine-needle aspiration biopsies (FNABs) vary. A direct comparison of CB techniques with statistical validation was performed to identify the best method. METHODS: Three CB techniques were compared: 1) FNAB rinsed in saline and clotted with plasma and thrombin (SPT); 2) FNAB rinsed in formalin and clotted with HistoGel (HG); and 3) FNAB rinsed in formalin, centrifuged, and the pellet captured in a collodion bag (ColB). FNAB was performed on 35 random surgical specimens for smears and each CB technique. A randomized blinded review of hematoxylin and eosin-stained CB slides was performed and each case was scored on a scale of 1 to 3 for cellularity, preservation, and architecture and the overall best CB was identified. Significance was determined by the Mann-Whitney U test for nonparametric ordinal data. RESULTS: The mean cellularity score was 1.71 for SPT (standard deviation [SD], 0.89), 1.68 for HG (SD, 0.67), and 3.0 for ColB (SD, 0). The mean preservation score was 1.31 for SPT (SD, 0.58), 1.54 for HG (SD, 0.70), and 2.91 for ColB (SD, 0.37). The mean architecture score was 1.45 for SPT (SD, 0.70), 1.43 for HG (SD, 0.60), and 2.71 for ColB (SD, 0.57). There was no statistical significance noted between SPT or HG when compared for each category. ColB was found to be superior to both SPT and HG when compared for each category (P<.05). The overall best CB was obtained with ColB in 33 of 35 cases (94%), with SPT proving superior in 1 of 35 cases (3%) and HG superior in 1 of 35 cases (3%). CONCLUSIONS: ColB appears to be a superior technique for CB, yielding greater cellularity, preservation, and architecture in the majority of cases. (C) 2016 American Cancer Society. C1 [Balassanian, Ronald; Mah, Molinda M.; Liberman, Hava; Ljung, Britt-Marie] Univ Calif San Francisco, Dept Pathol, 1825 4th St, San Francisco, CA 94143 USA. [Wool, Geoffrey D.] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA. [Ono, Jill C.] Lab Med Consultants, Las Vegas, NV USA. [Olejnik-Nave, Jolanta; Sweeney, Brenda J.; Pitman, Martha B.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. RP Balassanian, R (reprint author), Univ Calif San Francisco, Dept Pathol, 1825 4th St, San Francisco, CA 94143 USA. EM ronald.balassanian@ucsf.edu NR 14 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1934-662X EI 1934-6638 J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD JUL PY 2016 VL 124 IS 7 BP 508 EP 518 DI 10.1002/cncy.21722 PG 11 WC Oncology; Pathology SC Oncology; Pathology GA DV3YM UT WOS:000382861800010 PM 27105161 ER PT J AU Hove, MJ Stelzer, J Nierhaus, T Thiel, SD Gundlach, C Margulies, DS Van Dijk, KRA Turner, R Keller, PE Merker, B AF Hove, Michael J. Stelzer, Johannes Nierhaus, Till Thiel, Sabrina D. Gundlach, Christopher Margulies, Daniel S. Van Dijk, Koene R. A. Turner, Robert Keller, Peter E. Merker, Bjorn TI Brain Network Reconfiguration and Perceptual Decoupling During an Absorptive State of Consciousness SO CEREBRAL CORTEX LA English DT Article DE brain networks; eigenvector centrality; functional connectivity; shaman; trance ID INTRINSIC FUNCTIONAL CONNECTIVITY; DEFAULT NETWORK; VISUAL-CORTEX; SYSTEM; MIND; ORGANIZATION; FMRI; MRI; FLUCTUATIONS; ARCHITECTURE AB Trance is an absorptive state of consciousness characterized by narrowed awareness of external surroundings and has long been used-for example, by shamans-to gain insight. Shamans across cultures often induce trance by listening to rhythmic drumming. Using functional magnetic resonance imaging (fMRI), we examined the brain-network configuration associated with trance. Experienced shamanic practitioners (n = 15) listened to rhythmic drumming, and either entered a trance state or remained in a nontrance state during 8-min scans. We analyzed changes in network connectivity. Trance was associated with higher eigenvector centrality (i.e., stronger hubs) in 3 regions: posterior cingulate cortex (PCC), dorsal anterior cingulate cortex (dACC), and left insula/operculum. Seed-based analysis revealed increased coactivation of the PCC (a default network hub involved in internally oriented cognitive states) with the dACC and insula (control-network regions involved in maintaining relevant neural streams). This coactivation suggests that an internally oriented neural stream was amplified by the modulatory control network. Additionally, during trance, seeds within the auditory pathway were less connected, possibly indicating perceptual decoupling and suppression of the repetitive auditory stimuli. In sum, trance involved coactive default and control networks, and decoupled sensory processing. This network reconfiguration may promote an extended internal train of thought wherein integration and insight can occur. C1 [Hove, Michael J.; Stelzer, Johannes; Nierhaus, Till; Thiel, Sabrina D.; Gundlach, Christopher; Margulies, Daniel S.; Turner, Robert; Keller, Peter E.] Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany. [Hove, Michael J.] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. [Stelzer, Johannes] Max Planck Inst Biol Cybernet, Tubingen, Germany. [Nierhaus, Till] Free Univ Berlin, Neurocomputat & Neuroimaging Unit, Berlin, Germany. [Van Dijk, Koene R. A.] Harvard Univ, Cambridge, MA 02138 USA. [Keller, Peter E.] Univ Western Sydney, MARCS Inst, Penrith, NSW 1797, Australia. RP Hove, MJ (reprint author), Harvard Med Sch, Dept Psychiat, Room 2660,149 13th St, Charlestown, MA 02129 USA. EM michaeljhove@gmail.com RI Van Dijk, Koene/G-3317-2012; Margulies, Daniel/L-4719-2016; OI Van Dijk, Koene/0000-0001-6137-4282; Margulies, Daniel/0000-0002-8880-9204; Keller, Peter/0000-0001-7579-6515 FU Varela Award from the Mind and Life Institute; National Institute of Mental Health Grant [T32-MH16259]; Max Planck Society FX This work was supported partially by a Varela Award from the Mind and Life Institute and a National Institute of Mental Health Grant (grant number T32-MH16259) to M.J.H. and by the Max Planck Society. NR 69 TC 3 Z9 3 U1 5 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 EI 1460-2199 J9 CEREB CORTEX JI Cereb. Cortex PD JUL PY 2016 VL 26 IS 7 BP 3116 EP 3124 DI 10.1093/cercor/bhv137 PG 9 WC Neurosciences SC Neurosciences & Neurology GA DV8QC UT WOS:000383200500014 PM 26108612 ER PT J AU Javorsky, E Perkins, A Scharf, MJ AF Javorsky, Emilia Perkins, Alexis Scharf, Mark J. TI Resolution of Disseminated Granuloma Annulare With Removal of Surgical Hardware SO CUTIS LA English DT Editorial Material C1 [Javorsky, Emilia; Perkins, Alexis; Scharf, Mark J.] Univ Massachusetts, Med Ctr, Dept Dermatol, Worcester, MA USA. [Javorsky, Emilia] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Scharf, MJ (reprint author), UMMHC, Dept Dermatol, Hahnemann Campus,281 Lincoln St, Worcester, MA 01605 USA. EM Mark.Scharf@umassmemorial.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU QUADRANT HEALTHCOM INC PI PARSIPPANY PA 7 CENTURY DRIVE, STE 302, PARSIPPANY, NJ 07054-4603 USA SN 0011-4162 EI 2326-6929 J9 CUTIS JI Cutis PD JUL PY 2016 VL 98 IS 1 BP E10 EP E11 PG 2 WC Dermatology SC Dermatology GA DV8RD UT WOS:000383203300005 PM 27529714 ER PT J AU Furtek, KJ Kubiak, DW Barra, M Varughese, CA Ashbaugh, CD Koo, S AF Furtek, Kari J. Kubiak, David W. Barra, Megan Varughese, Christy A. Ashbaugh, Cameron D. Koo, Sophia TI High incidence of neutropenia in patients with prolonged ceftaroline exposure SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article ID STAPHYLOCOCCUS-AUREUS BACTEREMIA; ENDOCARDITIS; AGRANULOCYTOSIS; INFECTIONS; THERAPY AB Objectives: We sought to determine the rate of incident neutropenia and identify potential clinical factors associated with incident neutropenia among patients treated with long courses of ceftaroline. Methods: We retrospectively identified adult patients who received ceftaroline for >= 7 days consecutively at two large academic medical centres in Boston, USA between November 2010 and March 2015. Clinical characteristics (age, gender, medication allergies, baseline renal function, duration of ceftaroline exposure, total daily ceftaroline dose, body mass-adjusted ceftaroline dose and development of rash and neutropenia) were recorded and the rate of incident neutropenia was calculated. The Naranjo probability scale was used to assess whether ceftaroline exposure was associated with neutropenia. We assessed whether clinical factors were associated with neutropenia. Results: The overall rate of incident neutropenia was 10%-14% with >= 2 weeks and 21% with >= 3 weeks of ceftaroline exposure. The median duration of ceftaroline exposure [26 days (IQR 22-44; range 13-68) in patients who developed neutropenia and 15 days (IQR 9-29; range 7-64) in patients without neutropenia] was associated with incident neutropenia (P = 0.048). The median total number of ceftaroline doses received [63 (IQR 44-126; range 36-198) by neutropenic patients and 32 (IQR 22-63; range 14-180) by non-neutropenic patients] was also associated with incident neutropenia (P = 0.023). Conclusions: The overall rate of neutropenia was high and associated with duration of ceftaroline exposure and total number of doses received. Close laboratory monitoring is warranted with long-term ceftaroline use. C1 [Furtek, Kari J.] Northeastern Univ, Sch Pharm, Boston, MA 02115 USA. [Furtek, Kari J.; Kubiak, David W.; Barra, Megan] Brigham & Womens Hosp, Dept Pharm, 75 Francis St, Boston, MA 02115 USA. [Varughese, Christy A.] Massachusetts Gen Hosp, Dept Pharm, Boston, MA 02114 USA. [Ashbaugh, Cameron D.; Koo, Sophia] Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. [Ashbaugh, Cameron D.; Koo, Sophia] Harvard Med Sch, Boston, MA USA. RP Furtek, KJ (reprint author), Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. EM kfurtek@gmail.com FU Brigham and Women's Physicians Organization; National Institutes of Health [K23 AI097225] FX This project was funded, in part, by a grant from the Brigham and Women's Physicians Organization. S. K. is supported by a grant from the National Institutes of Health (K23 AI097225). NR 12 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 EI 1460-2091 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD JUL PY 2016 VL 71 IS 7 BP 2010 EP 2013 DI 10.1093/jac/dkw062 PG 4 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA DV9FP UT WOS:000383246000034 PM 27076105 ER PT J AU Rajagopal, M Martin, MJ Santiago, M Lee, W Kos, VN Meredith, T Gilmore, MS Walker, S AF Rajagopal, Mithila Martin, Melissa J. Santiago, Marina Lee, Wonsik Kos, Veronica N. Meredith, Tim Gilmore, Michael S. Walker, Suzanne TI Multidrug Intrinsic Resistance Factors in Staphylococcus aureus Identified by Profiling Fitness within High-Diversity Transposon Libraries SO MBIO LA English DT Article ID SMALL COLONY VARIANTS; PENICILLIN-BINDING PROTEIN; BETA-LACTAM RESISTANCE; CELL-WALL BIOSYNTHESIS; METHICILLIN RESISTANCE; TEICHOIC-ACIDS; FLUOROQUINOLONE RESISTANCE; PEPTIDOGLYCAN HYDROLASE; ANTIMICROBIAL PEPTIDES; ANTIBIOTIC-RESISTANCE AB Staphylococcus aureus is a leading cause of life-threatening infections worldwide. The MIC of an antibiotic against S. aureus, as well as other microbes, is determined by the affinity of the antibiotic for its target in addition to a complex interplay of many other cellular factors. Identifying nontarget factors impacting resistance to multiple antibiotics could inform the design of new compounds and lead to more-effective antimicrobial strategies. We examined large collections of transposon insertion mutants in S. aureus using transposon sequencing (Tn-Seq) to detect transposon mutants with reduced fitness in the presence of six clinically important antibiotics-ciprofloxacin, daptomycin, gentamicin, linezolid, oxacillin, and vancomycin. This approach allowed us to assess the relative fitness of many mutants simultaneously within these libraries. We identified pathways/genes previously known to be involved in resistance to individual antibiotics, including graRS and vraFG (graRS/vraFG), mprF, and fmtA, validating the approach, and found several to be important across multiple classes of antibiotics. We also identified two new, previously uncharacterized genes, SAOUHSC_01025 and SAOUHSC_01050, encoding polytopic membrane proteins, as important in limiting the effectiveness of multiple antibiotics. Machine learning identified similarities in the fitness profiles of graXRS/vraFG, SAOUHSC_01025, and SAOUHSC_01050 mutants upon antibiotic treatment, connecting these genes of unknown function to modulation of crucial cell envelope properties. Therapeutic strategies that combine a known antibiotic with a compound that targets these or other intrinsic resistance factors may be of value for enhancing the activity of existing antibiotics for treating otherwise-resistant S. aureus strains. IMPORTANCE Bacterial resistance to every major class of antibiotics has emerged, and we are entering a "post-antibiotic era" where relatively minor infections can lead to serious complications or even death. The utility of an antibiotic for a specific pathogen is limited by both intrinsic and acquired factors. Identifying the repertoire of intrinsic resistance factors of an antibiotic for Staphylococcus aureus, a leading cause of community-and hospital-acquired infections, would inform the design of new drugs as well as the identification of compounds that enhance the activity of existing drugs. To identify factors that limit the activity of antibiotics against S. aureus, we used Tn-Seq to simultaneously assess fitness of transposon mutants in every nonessential gene in the presence of six clinically important antibiotics. This work provides an efficient approach for identifying promising targets for drugs that can enhance susceptibility or restore sensitivity to existing antibiotics. C1 [Rajagopal, Mithila; Santiago, Marina; Lee, Wonsik; Meredith, Tim; Gilmore, Michael S.; Walker, Suzanne] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Rajagopal, Mithila] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Martin, Melissa J.; Kos, Veronica N.; Gilmore, Michael S.] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. [Meredith, Tim] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. RP Gilmore, MS; Walker, S (reprint author), Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA.; Gilmore, MS (reprint author), Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. EM Michael_Gilmore@meei.harvard.edu; Suzanne_Walker@hms.harvard.edu FU Institut Merieux; HHS \ National Institutes of Health (NIH) [P01 AI083214, U19 AI109764] FX This work, including the efforts of Melissa J. Martin, Veronica Kos, and Michael S. Gilmore, was funded by Institut Merieux. This work, including the efforts of Mithila Rajagopal, Melissa J. Martin, Marina Santiago, Wonsik Lee, Veronica Kos, Timothy C. Meredith, Michael S. Gilmore, and Suzanne Walker, was funded by HHS vertical bar National Institutes of Health (NIH) (P01 AI083214). This work, including the efforts of Mithila Rajagopal, Marina Santiago, Wonsik Lee, Timothy C. Meredith, and Suzanne Walker, was funded by HHS vertical bar National Institutes of Health (NIH) (U19 AI109764). NR 83 TC 0 Z9 0 U1 6 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2016 VL 7 IS 4 AR e00950-16 DI 10.1128/mBio.00950-16 PG 11 WC Microbiology SC Microbiology GA DW1YQ UT WOS:000383440500039 ER PT J AU Selleck, EM Gilmore, MS AF Selleck, Elizabeth M. Gilmore, Michael S. TI Oxygen as a Virulence Determinant in Polymicrobial Infections SO MBIO LA English DT Editorial Material ID BACTERIAL; SALMONELLA; HOST AB Infections caused by multiple organisms, or polymicrobial infections, are likely more common than is broadly appreciated. Interaction among microbial communities (and with their host) can change the infection landscape by subverting immunity, providing nutrients and inhibiting competing microbes. Stacy et al. (A. Stacy, D. Fleming, R. J. Lamont, K. P. Rumbaugh, and M. Whiteley, mBio 7: e00782-16, 2016, http://dx.doi.org/10.1128/mBio.00782-16) described a novel mechanism that results in synergistic growth of oral microbes Aggregatibacter actinomycetemcomitans and Streptococcus gordonii. The authors used whole-genome fitness profiling by transposon sequencing (Tn-seq) to identify genes differentially required for growth in vitro versus in a mono-or coinfection in a thigh abscess model. They found that coinfection with S. gordonii allowed A. actinomycetemcomitans to shift from an anaerobic to an aerobic mode of growth. This shift involved the production of a terminal electron acceptor H2O2 by S. gordonii and increased A. actinomycetemcomitans persistence-an interaction termed "crossrespiration." C1 [Selleck, Elizabeth M.; Gilmore, Michael S.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Selleck, Elizabeth M.; Gilmore, Michael S.] Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. RP Gilmore, MS (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. EM Michael_Gilmore@meei.harvard.edu NR 15 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD JUL-AUG PY 2016 VL 7 IS 4 AR e01249 DI 10.1128/mBio.01249-16 PG 3 WC Microbiology SC Microbiology GA DW1YQ UT WOS:000383440500076 ER PT J AU Sheehan, KB Martin, M Lesser, CF Isberg, RR Newton, ILG AF Sheehan, Kathy B. Martin, MaryAnn Lesser, Cammie F. Isberg, Ralph R. Newton, Irene L. G. TI Identification and Characterization of a Candidate Wolbachia pipientis Type IV Effector That Interacts with the Actin Cytoskeleton SO MBIO LA English DT Article ID STEM-CELL NICHE; ADP-RIBOSYLATING TOXIN; SECRETION SYSTEMS; BINDING-PROTEIN; ALPHA-SYNUCLEIN; SACCHAROMYCES-CEREVISIAE; INVASIVE SALMONELLA; FILAMENT NUCLEATION; FILARIAL NEMATODES; VIRULENCE PROTEINS AB Many bacteria live as intracellular symbionts, causing persistent infections within insects. One extraordinarily common infection is that of Wolbachia pipientis, which infects 40% of insect species and induces reproductive effects. The bacteria are passed from generation to generation both vertically (through the oocyte) and horizontally (by environmental transmission). Maintenance of the infection within Drosophila melanogaster is sensitive to the regulation of actin, as Wolbachia inefficiently colonizes strains hemizygous for the profilin or villin genes. Therefore, we hypothesized that Wolbachia must depend on the host actin cytoskeleton. In this study, we identify and characterize a Wolbachia protein (WD0830) that is predicted to be secreted by the bacterial parasite. Expression of WD0830 in a model eukaryote (the yeast Saccharomyces cerevisiae) induces a growth defect associated with the appearance of aberrant, filamentous structures which colocalize with rhodamine-phalloidin-stained actin. Purified WD0830 bundles actin in vitro and cosediments with actin filaments, suggesting a direct interaction of the two proteins. We characterized the expression of WD0830 throughout Drosophila development and found it to be upregulated in third-instar larvae, peaking in early pupation, during the critical formation of adult tissues, including the reproductive system. In transgenic flies, heterologously expressed WD0830 localizes to the developing oocyte. Additionally, overexpression of WD0830 results in increased Wolbachia titers in whole flies, in stage 9 and 10 oocytes, and in embryos, compared to controls, suggesting that the protein may facilitate Wolbachia's replication or transmission. Therefore, this candidate secreted effector may play a role in Wolbachia's infection of and persistence within host niches. IMPORTANCE The obligate intracellular Wolbachia pipientis is a ubiquitous alphaproteobacterial symbiont of arthropods and nematodes and is related to the rickettsial pathogens Ehrlichia spp. and Anaplasma spp. Studies of Wolbachia cell biology suggest that this bacterium relies on ho