FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Yu, WH Lauffenburger, D Alter, G AF Yu, Wen-Han Lauffenburger, Doug Alter, Galit TI Molecular regulation of antigen-specific antibody glycosylation following B cell activation SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [Yu, Wen-Han] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Dept Biol Engn, MIT, Cambridge, MA USA. [Lauffenburger, Doug] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Alter, Galit] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 11 BP 1088 EP 1089 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300019 ER PT J AU Okamoto, R Mandal, K Ling, M Luster, A Sawaya, M Yeates, T Kajihara, Y Kent, S AF Okamoto, Ryo Mandal, Kalyanswer Ling, Morris Luster, Andrew Sawaya, Michael Yeates, Todd Kajihara, Yasuhiro Kent, Stephen TI Biological activities of the homogeneous glycosylated chemokines CCL1 and Ser-CCL1 prepared by total chemical synthesis SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res ID NONGLYCOSYLATED FORMS C1 [Okamoto, Ryo; Kajihara, Yasuhiro; Kent, Stephen] Osaka Univ, Suita, Osaka 565, Japan. [Mandal, Kalyanswer] Univ Chicago, Chicago, IL 60637 USA. [Ling, Morris; Luster, Andrew] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cambridge, MA 02138 USA. NR 2 TC 0 Z9 0 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 91 BP 1118 EP 1119 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300099 ER PT J AU Xu, YX Ashline, D Liu, L Tassa, C Shaw, S Ravid, K Layne, M Reinhold, V Robbins, P AF Xu, Yuxin Ashline, David Liu, Li Tassa, Carlos Shaw, Stanley Ravid, Katya Layne, Matthew Reinhold, Vernon Robbins, Phillips TI The glycosylation-dependent interaction of perlecan core protein with LDL: implications for atherosclerosis SO GLYCOBIOLOGY LA English DT Meeting Abstract CT Joint Meeting of the Society-for-Glycobiology (SFG) and the Japanese-Society-of-Carbohydrate-Research (JSCR) CY NOV 16-19, 2014 CL Honolulu, HI SP Society For Glycobiology, Japanese Soc Carbohydrate Res C1 [Xu, Yuxin] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Xu, Yuxin] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ashline, David; Reinhold, Vernon] Univ New Hampshire, Glyc Ctr, Durham, NH 03824 USA. [Liu, Li; Robbins, Phillips] Boston Univ, Dept Mol & Cell Biol, Henry M Goldman Sch Dent Med, Boston, MA 02215 USA. [Tassa, Carlos; Shaw, Stanley] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Ravid, Katya] Boston Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Layne, Matthew] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD NOV PY 2014 VL 24 IS 11 MA 297 BP 1194 EP 1194 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AT1CI UT WOS:000344670300303 ER PT J AU Elbatarny, M Mollah, S Grabell, J Bae, S Deforest, M Tuttle, A Hopman, W Clark, DS Mauer, AC Bowman, M Riddel, J Christopherson, PA Montgomery, RR Rand, ML Coller, B James, PD AF Elbatarny, M. Mollah, S. Grabell, J. Bae, S. Deforest, M. Tuttle, A. Hopman, W. Clark, D. S. Mauer, A. C. Bowman, M. Riddel, J. Christopherson, P. A. Montgomery, R. R. Rand, M. L. Coller, B. James, P. D. CA Zimmerman Program Investigators TI Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project SO HAEMOPHILIA LA English DT Article DE bleeding questionnaire; bleeding score; ISTH-BAT; normal range ID VON-WILLEBRAND-DISEASE; QUESTIONNAIRE; MULTICENTER; SYMPTOMS; HISTORY AB Bleeding Assessment Tools (BATs) have been developed to aid in the standardized evaluation of bleeding symptoms. The Vicenza Bleeding Questionnaire (BQ), published in 2005, established a common framework and scoring key that has undergone subsequent modification over the years, culminating in the publication of the ISTH-BAT in 2010. Understanding the normal range of bleeding scores is critical when assessing the utility of a BAT. Within the context of The Merging Project, a bioinformatics system was created to facilitate the merging of legacy data derived from four different (but all Vicenza-based) BATs; the MCMDM1-VWD BQ, the Condensed MCMDM-1VWD BQ, the Pediatric Bleeding Questionnaire and the ISTH-BAT. Data from 1040 normal adults and 328 children were included in the final analysis, which showed that the normal range is 0-3 for adult males, 0-5 for adult females and 0-2 in children for both males and females. Therefore, the cut-off for a positive or abnormal BS is 4 in adult males, 6 in adult females and 3 in children. This information can now be used to objectively assess bleeding symptoms as normal or abnormal in future studies. C1 [Elbatarny, M.; Grabell, J.; James, P. D.] Queens Univ, Dept Med, Kingston, ON K7L 3N6, Canada. [Mollah, S.; Mauer, A. C.; Coller, B.] Rockefeller Univ, Lab Blood & Vasc Biol, New York, NY 10021 USA. [Bae, S.; Deforest, M.; Tuttle, A.; Bowman, M.; James, P. D.] Queens Univ, Dept Pathol & Mol Med, Kingston, ON K7L 3N6, Canada. [Hopman, W.; James, P. D.] Queens Univ, Kingston, ON K7L 3N6, Canada. [Clark, D. S.; Rand, M. L.] Hosp Sick Children, Div Haematol Oncol, Toronto, ON M5G 1X8, Canada. [Mauer, A. C.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Riddel, J.] Childrens Hosp Oakland, Div Hematol, Oakland, CA USA. [Christopherson, P. A.; Montgomery, R. R.] Med Coll Wisconsin, Blood Res Inst, Blood Ctr Wisconsin, Milwaukee, WI 53226 USA. [Christopherson, P. A.; Montgomery, R. R.; Zimmerman Program Investigators] Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. RP James, PD (reprint author), Queens Univ, Room 2025 Etherington Hall, Kingston, ON K7L 3N6, Canada. EM jamesp@queensu.ca RI Kerlin, Bryce/E-3369-2011 OI Kerlin, Bryce/0000-0002-1756-8271 FU Canadian Hemophilia Society; Zimmerman Program for the Molecular and Clinical Biology of von Willebrand disease - National Institutes of Health Program Project [HL081588]; National Center for Advancing Translational Sciences (NCATS) [UL1 TR000043]; National Institutes of Health and Translational Science Award (CTSA); C17 Research Network FX This research was funded by a Canadian Hemophilia Society Research Grant and Summer Studentship; the Zimmerman Program for the Molecular and Clinical Biology of von Willebrand disease - National Institutes of Health Program Project Grant HL081588; Grant UL1 TR000043 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health and Translational Science Award (CTSA) and C17 Research Network. NR 7 TC 17 Z9 17 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-8216 EI 1365-2516 J9 HAEMOPHILIA JI Haemophilia PD NOV PY 2014 VL 20 IS 6 BP 831 EP 835 DI 10.1111/hae.12503 PG 5 WC Hematology SC Hematology GA AS8WL UT WOS:000344525800033 PM 25196510 ER PT J AU Friedman, DJ Upadhyay, GA Rajabali, A Altman, RK Orencole, M Parks, KA Moore, SA Park, MY Picard, MH Ruskin, JN Singh, JP Heist, EK AF Friedman, Daniel J. Upadhyay, Gaurav A. Rajabali, Alefiyah Altman, Robert K. Orencole, Mary Parks, Kimberly A. Moore, Stephanie A. Park, Mi Young Picard, Michael H. Ruskin, Jeremy N. Singh, Jagmeet P. Heist, E. Kevin TI Progressive ventricular dysfunction among non responders to cardiac resynchronization therapy: Baseline predictors and associated clinical outcomes SO HEART RHYTHM LA English DT Article DE Remodeling; Heart failure; Cardiac resynchronization therapy; Cardiomyopathy; Biventricular pacing; Ventricular tachycardia; Ventricular fibrillation ID CHRONIC HEART-FAILURE; REVERSE; DEFIBRILLATOR; CARE AB BACKGROUND Cardiac resynchronization therapy (CRT) nonresponders have poor outcomes. The significance of progressive ventricular dysfunction among nonresponders remains unclear. OBJECTIVE We sought to define predictors of and clinical outcomes associated with progressive ventricular dysfunction despite CRT. METHODS We conducted an analysis of 328 patients undergoing CRT with defibrillator for standard indications. On the basis of 6-month echocardiograms, we classified patients as responders (those with a >= 5% increase in ejection fraction) and progressors (those with a >= 5% decrease in ejection fraction), and all others were defined as nonprogressors. Coprimary end points were 3-year (1) heart failure, left ventricular assist device (LVAD), transplantation, or death and (2) ventricular tachycardia (VT) or ventricular fibrillation (VF). RESULTS MuLtivariable predictors of progressive ventricular dysfunction were aldosterone antagonist use (hazard ratio [HR] 0.23; P = .008), prior valve surgery (HR 3.3; P = .005), and QRS duration (HR 0.98; P = .02). More favorable changes in ventricular function were associated with Lower incidences of heart failure, LVAD, transplantation, or death (70% vs 54% vs 330/e; P < .0001) and VT or VF (66% vs 38% vs 28%; P = .001) for progressors, nonprogressors, and responders, respectively. After multivariable adjustment, progressors remained at increased risk of heart failure, LVAD, transplantation, or death (HR 2.14; P = .0029) and VT or VF (HR 2.03; P = .046) as compared with nonprogressors. Responders were at decreased risk of heart failure, LVAD, transplantation, or death (HR 0.44; P < .0001) and VT or VF (0.51; P = .015) as compared with nonprogressors. CONCLUSION Patients with progressive deterioration in ventricular function despite CRT represent a high-risk group of nonresponders at increased risk of worsened clinical outcomes. C1 [Friedman, Daniel J.] Duke Univ Hosp, Div Cardiol, Durham, NC USA. [Upadhyay, Gaurav A.; Rajabali, Alefiyah; Orencole, Mary; Ruskin, Jeremy N.; Singh, Jagmeet P.; Heist, E. Kevin] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Altman, Robert K.] Mt Sinai St Lukes Roosevelt Hosp, Al Sabah Arrhythmia Inst, New York, NY USA. [Parks, Kimberly A.; Moore, Stephanie A.] Massachusetts Gen Hosp, Heart Failure & Cardiac Transplantat Unit, Boston, MA 02114 USA. [Park, Mi Young] Hallym Univ, Dongtan Sacred Hosp, Dept Cardiol, Hwaseong, South Korea. [Picard, Michael H.] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. RP Heist, EK (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St, Boston, MA 02114 USA. EM kheist@partners.org OI Orencole, Mary/0000-0002-7862-2796; Picard, Michael/0000-0002-9264-3243; Friedman, Daniel /0000-0001-5791-1954 FU National Cardiovascular Data Registry; Biotronik; Sorin; St Jude Medical; Boston Scientific; Sarin FX Dr Friedman has received research support from the National Cardiovascular Data Registry. Dr Heist has received honoraria from Biotronik, Boston Scientific, Sorin, and St Jude Medical; research grants from Biotronik, Sorin, and St Jude Medical; and consulting fees from Boston Scientific, Sarin, and St Jude Medical. Dr Ruskin has served as an advisor or consultant for Astellas/Cardiorne, Biosense Webster, CardioFocus, CardioInsight, CryoCath, Medtronic, Pfizer, Porto la, and Third Rock Ventures; has received fellowship support from Biosense Webster, Boston Scientific, Medronic, and St Jude Medical; has received honoraria from Med-IQ; and owns equity in Porto la. Dr Parks has received consultant fees from Thoratec and honoraria from Biotronik and Sorin. Dr Singh has received research grants from St Jude Medical, Medtronic, Boston Scientific, and Biotronik; consulting fees from Boston Scientific, Biotronik, St Jude Medical, Medtronic, CardioInsight, Thoratec, and Biosense Webster; and honoraria from Medtronic, Biotronik, Guidant, St Jude Medical, and Sorin. Dr Upadhyay has received salary support from the Max Schaldach Fellowship of the Heart Rhythm Society. NR 17 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD NOV PY 2014 VL 11 IS 11 BP 1991 EP 1998 DI 10.1016/j.hrthm.2014.08.005 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AS8DI UT WOS:000344480000022 PM 25106864 ER PT J AU Larson, ER Porterfield, JE Sagar, S Marmol-Velez, J Panday, M Escobedo, D Michalek, J Ouyang, YJ Valvano, JW Pearce, JA Feldman, MD AF Larson, Erik R. Porterfield, John E. Sagar, Sandeep Marmol-Velez, Juan Panday, Manoj Escobedo, Daniel Michalek, Joel Ouyang, Yongjian Valvano, Jonathan W. Pearce, John A. Feldman, Marc D. TI Admittance to detect alterations in left ventricular stroke volume SO HEART RHYTHM LA English DT Article DE Shock reduction; Biventricular pacing/defibrillation; Ventricular tachycardia; Ventricular fibrillation; Inappropriate shocks ID CARDIOVERTER-DEFIBRILLATOR SHOCKS; CONDUCTANCE CATHETER; INAPPROPRIATE; THERAPY; MORTALITY; TRIAL AB BACKGROUND Implantable cardioverter-defibrillators monitor intracardiac electrograms (EGMs) to discriminate between ventricular and supraventricular tachycardias. The incidence of inappropriate shocks remains high because of misclassification of the tachycardia in an otherwise hemodynamically stable individual. Coupling EGMs with an assessment of left ventricular (LV) stroke volume (SV) could help in gauging hemodynamics during an arrhythmia and reducing inappropriate shocks. OBJECTIVE The purpose of this study was to use the admittance method to accurately derive LV SV. METHODS Ultrasonic flow probe and LV endocardial crystals were used in canines (n = 12) as the standard for LV SV. Biventricular pacing leads were inserted to obtain admittance measurements. A tetrapolar, complex impedance measurement was made between the Bi-V leads. The real and imaginary components of impedance were used to discard the myocardial component from the blood component to derive instantaneous blood conductance (G(b)). Alterations in SV were measured during right ventricular pacing, dopamine infusion, and inferior vena cava occlusion. RESULTS G(b) tracks steady-state changes in SV more accurately than traditional magnitude (ie. IYI, without removal of the muscle signal) during right ventricular pacing and dopamine infusion (P = .004). Instantaneous LV volume also was tracked more accurately by G(b) than vertical bar Y vertical bar in the subset of subjects that underwent inferior vena cava occlusions (n = 5, P = .025). Finite element modeling demonstrates that admittance shifts more sensitivity of the measurement to the LV blood chamber as the mechanism for improvement (see Online Appendix). CONCLUSION Monitoring LV SV is possible using the admittance method with biventricular pacing leads. The technique could be piggybacked to complement EGMs to determine if arrhythmias are hemodynamically unstable. C1 [Larson, Erik R.; Valvano, Jonathan W.; Pearce, John A.] Univ Texas Austin, Dept Elect Engn, Austin, TX 78712 USA. [Porterfield, John E.; Feldman, Marc D.] Admittance Technol, Austin, TX USA. [Sagar, Sandeep; Marmol-Velez, Juan; Panday, Manoj; Escobedo, Daniel; Feldman, Marc D.] Univ Texas Hlth Sci Ctr San Antonio, Div Cardiol, San Antonio, TX 78229 USA. [Michalek, Joel; Ouyang, Yongjian] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Feldman, Marc D.] South Texas Vet Hlth Care Syst, Dept Vet Affairs, San Antonio, TX USA. RP Feldman, MD (reprint author), Univ Texas Hlth Sci Ctr San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78248 USA. EM feldmanm@uthscsa.edu OI Marmol-Velez, Juan/0000-0002-7450-9817 FU Janey and Dolph Briscoe Center for Cardiovascular Research; CTSA [UL1RR025767] FX Support was provided by the Janey and Dolph Briscoe Center for Cardiovascular Research and a CTSA grant (UL1RR025767). Supplies were provided by Transonic Systems and St. Jude Medical. NR 20 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 EI 1556-3871 J9 HEART RHYTHM JI Heart Rhythm PD NOV PY 2014 VL 11 IS 11 BP 2075 EP 2083 DI 10.1016/j.hrthm.2014.06.034 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AS8DI UT WOS:000344480000034 PM 24981870 ER PT J AU Gaskins, AJ Afeiche, MC Hauser, R Williams, PL Gillman, MW Tanrikut, C Petrozza, JC Chavarro, JE AF Gaskins, A. J. Afeiche, M. C. Hauser, R. Williams, P. L. Gillman, M. W. Tanrikut, C. Petrozza, J. C. Chavarro, J. E. TI Paternal physical and sedentary activities in relation to semen quality and reproductive outcomes among couples from a fertility center SO HUMAN REPRODUCTION LA English DT Article DE physical activity; semen quality; male fertility; assisted reproduction ID ACTIVE MEN; EXERCISE; HORMONE; PROFILE; INTENSITIES; INFERTILITY; PARAMETERS; VOLUME AB Is paternal physical activity associated with semen quality parameters and with outcomes of infertility treatment? Among men presenting for infertility treatment, weightlifting and outdoor activities were associated with higher sperm concentrations but not with greater reproductive success. Higher physical activity is related to better semen quality but no studies to date have investigated whether it predicts greater reproductive success. The Environment and Reproductive Health (EARTH) Study is an on-going prospective cohort study which enrolls subfertile couples presenting at Massachusetts General Hospital (2005-2013). In total, 231 men provided 433 semen samples and 163 couples underwent 421 IVF or intrauterine insemination cycles. Leisure time spent in physical and sedentary activities over the past year was self-reported using a validated questionnaire. We used mixed models to analyze the association of physical and sedentary activities with semen quality and with clinical pregnancy and live birth rates. Men in this cohort engaged in a median of 3.2 h/week of moderate-to-vigorous activities. Men in the highest quartile of moderate-to-vigorous activity had 43% (95% confidence interval (CI) 9, 87%) higher sperm concentrations than men in the lowest quartile (P-trend = 0.04). Men in the highest category of outdoor activity (a parts per thousand yen1.5 h/week) and weightlifting (a parts per thousand yen2 h/week) had 42% (95% CI 10, 84%) and 25% (95% CI -10, 74%) higher sperm concentrations, respectively, compared with men in the lowest category (0 h/week) (P-trend = 0.04 and 0.02). Conversely, men who reported bicycling a parts per thousand yen1.5 h/week had 34% (95% CI 4, 55%) lower sperm concentrations compared with men who reported no bicycling (P-trend = 0.05). Paternal physical and sedentary activities were not related to clinical pregnancy or live birth rates following infertility treatment. The generalizability of the findings on live birth rates to populations not undergoing infertility treatment is limited. Certain types of physical activity, specifically weightlifting and outdoor activities, may improve semen quality but may not lead to improved success of infertility treatments. Further research is needed in other non-clinical populations. The authors are supported by NIH grants R01-ES009718, ES000002, P30-DK046200, T32-DK007703-16 and ES022955 T32-HD060454. None of the authors has any conflicts of interest to declare. C1 [Gaskins, A. J.; Afeiche, M. C.; Gillman, M. W.; Chavarro, J. E.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Gaskins, A. J.; Hauser, R.; Williams, P. L.; Chavarro, J. E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hauser, R.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Williams, P. L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Gillman, M. W.] Harvard Univ, Sch Med, Dept Populat Med, Harvard Pilgrim Hlth Care Inst, Boston, MA 02115 USA. [Tanrikut, C.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Hauser, R.; Tanrikut, C.; Petrozza, J. C.; Chavarro, J. E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hauser, R.; Petrozza, J. C.] Massachusetts Gen Hosp, Vincent Obstet & Gynecol, Boston, MA 02114 USA. [Chavarro, J. E.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. RP Gaskins, AJ (reprint author), Harvard Univ, Sch Publ Hlth, Bldg 2 3rd Floor,655 Huntington Ave, Boston, MA 02115 USA. EM ajg219@mail.harvard.edu FU NIH [R01-ES009718, R01-ES022955, ES000002, P30-DK046200, T32-DK007703-16, T32-HD060454] FX The authors are supported by NIH grants R01-ES009718, R01-ES022955, ES000002, P30-DK046200, T32-DK007703-16 and T32-HD060454. The funding sources had no influence on the study design, data analysis, writing of the report or the decision to submit the findings of the present study for publication. NR 33 TC 7 Z9 7 U1 1 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 EI 1460-2350 J9 HUM REPROD JI Hum. Reprod. PD NOV PY 2014 VL 29 IS 11 BP 2575 EP 2582 DI 10.1093/humrep/deu212 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AT1EJ UT WOS:000344675700028 PM 25164027 ER PT J AU Gockley, AA Rauh-Hain, JA del Carmen, MG AF Gockley, Allison A. Rauh-Hain, J. Alejandro del Carmen, Marcela G. TI Uterine Leiomyosarcoma A Review Article SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Review DE Leiomyosarcoma; Uterine tumor; Review ID GYNECOLOGIC-ONCOLOGY-GROUP; GEMCITABINE PLUS DOCETAXEL; PROGNOSTIC-FACTORS; SARCOMA; SURVIVAL; RADIOTHERAPY; PATTERNS; THERAPY; IMPACT AB Uterine leiomyosarcomas (LMSs) are rare aggressive tumors, with high recurrence rates, even when confined to the uterine corpus at the time of diagnosis. These tumors are large myometrial masses, which typically spread hematogenously. Patients present with vague symptoms similar to those of patients with leiomyomas. Most patients are diagnosed with LMS postoperatively. In the presence of metastatic disease, complete surgical cytoreduction should be attempted when feasible. Lymphadenectomy should be performed only in patients with nodes suspected of harboring metastatic disease and as part of a cytoreductive effort. There are conflicting data to support adjuvant chemotherapy or radiation therapy for early-stage disease. Patients with advanced-stage disease should receive gemcitabine and docetaxel adjuvant chemotherapy. Patients with recurrent disease are candidates for a wide variety of second-line treatments, of which many are investigational. Although prognosis remains dismal, ongoing studies are investigating the role of advanced imaging, multimodality treatment, prognostic nomograms, and unique biomedical pathways to increase understanding of LMS and improve therapeutic options for patients. C1 [Gockley, Allison A.; Rauh-Hain, J. Alejandro; del Carmen, Marcela G.] Vincent Obstet & Gynecol, Div Gynecol Oncol, Boston, MA USA. RP del Carmen, MG (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 25 TC 7 Z9 8 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD NOV PY 2014 VL 24 IS 9 BP 1538 EP 1542 DI 10.1097/IGC.0000000000000290 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AT0FE UT WOS:000344611800005 PM 25304676 ER PT J AU Berek, JS Edwards, RP Parker, LP DeMars, LR Herzog, TJ Lentz, SS Morris, RT Akerley, WL Holloway, RW Method, MW Plaxe, SC Walker, JL Friccius-Quecke, H Krasner, CN AF Berek, Jonathan S. Edwards, Robert P. Parker, Lynn P. DeMars, Leslie R. Herzog, Thomas J. Lentz, Samuel S. Morris, Robert T. Akerley, Wallace L. Holloway, Robert W. Method, Michael W. Plaxe, Steven C. Walker, Joan L. Friccius-Quecke, Hilke Krasner, Carolyn N. TI Catumaxomab for the Treatment of Malignant Ascites in Patients With Chemotherapy-Refractory Ovarian Cancer A Phase II Study SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Catumaxomab; Trifunctional antibody; Malignant ascites; Ovarian cancer ID CELL ADHESION MOLECULE; TRIFUNCTIONAL ANTIBODY CATUMAXOMAB; EPCAM X ANTI-CD3; BISPECIFIC ANTIBODY; ACCESSORY CELLS; EP-CAM; EXPRESSION; OVEREXPRESSION; ACTIVATION; EFFUSIONS AB Objective: The aim of this study was to investigate the efficacy and safety of intraperitoneal catumaxomab in heavily pretreated patients with chemotherapy-refractory ovarian cancer and recurrent symptomatic malignant ascites. Methods: The study is a single-arm open-label multicenter US phase II study. Patients received 4 three-hour intraperitoneal catumaxomab infusions (10, 20, 50, and 150 Kg within 10 days). The primary end point was the percentage of patients with at least a 4-fold increase in the puncture-free interval (PuFI) relative to the pretreatment interval. The main secondary end points were puncture-free survival, overall survival, ascites symptoms, and safety. Time to first therapeutic puncture (TTPu) was analyzed post hoc. Results: Forty patients were screened, and 32 patients (80%) were treated. Seven patients (23%) achieved the primary end point. The median PuFI was prolonged 2-fold from 12 to 27.5 days. The median TTPu was prolonged 4-fold from 12 to 52 days. The median puncture-free survival and overall survival were 29.5 and 111 days, respectively. Nineteen patients (59%) required puncture after catumaxomab treatment. Ascites symptoms improved in most of the 13 predefined categories. At study end, most symptoms were still improved compared with screening. The most frequent treatment-related adverse events were related to cytokine release (vomiting, nausea, pyrexia, fatigue, and chills) or intraperitoneal administration (abdominal pain). Transient increases in liver parameters and transient decreases in blood lymphocytes were regularly observed but were generally without clinical relevance. Conclusions: Catumaxomab prolonged PuFI and TTPu had a beneficial effect on quality of life, as shown by the improvement in ascites symptoms, and had an acceptable safety profile, which is consistent with its mode of action. C1 [Berek, Jonathan S.] Stanford Univ, Sch Med, Div Gynecol Oncol,Dept Obstet & Gynecol, Stanford Womens Canc Ctr,Stanford Canc Inst, Stanford, CA 94305 USA. [Edwards, Robert P.] UPMC, Magee Womens Hosp, Pittsburgh, PA USA. [Parker, Lynn P.] Univ Louisville, James Graham Brown Canc Ctr, Louisville, KY 40292 USA. [DeMars, Leslie R.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Herzog, Thomas J.] Columbia Univ, Ctr Canc, New York, NY USA. [Lentz, Samuel S.] WFU Baptist Med Ctr, Winston Salem, NC USA. [Morris, Robert T.] Wayne State Univ, Barbara Ann Karmanos Canc Ctr, Detroit, MI USA. [Akerley, Wallace L.] Huntsman Canc Inst, Salt Lake City, UT USA. [Holloway, Robert W.] Florida Hosp, Inst Canc, Orlando, FL USA. [Method, Michael W.] Northern Indiana Canc Res Consortium, South Bend, IN USA. [Plaxe, Steven C.] Univ Calif San Diego, San Diego, CA 92103 USA. [Walker, Joan L.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Friccius-Quecke, Hilke] Neovii Biotech GmbH, Munich, Germany. [Krasner, Carolyn N.] Massachusetts Gen Hosp, Dana Farber Harvard Canc Ctr, Boston, MA 02114 USA. RP Berek, JS (reprint author), Stanford Univ, Sch Med, 300 Pasteur Dr,Room HG332, Stanford, CA 94305 USA. EM jberek@stanford.edu FU Neovii Biotech GmbH, Munich, Germany FX This study (NCT00326885) was sponsored by Neovii (formerly Fresenius) Biotech GmbH, Munich, Germany. NR 30 TC 11 Z9 12 U1 0 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 NOV PY 2014 VL 24 IS 9 BP 1583 EP 1589 DI 10.1097/IGC.0000000000000286 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AT0FE UT WOS:000344611800011 PM 25254563 ER PT J AU Mangili, G Lorusso, D Brown, J Pfisterer, J Massuger, L Vaughan, M Ngan, HYS Golfier, F Sekharan, PK Charry, RC Poveda, A Kim, JW Xiang, Y Berkowtiz, R Seckl, MJ AF Mangili, Giorgia Lorusso, Domenica Brown, Jubilee Pfisterer, Jacobus Massuger, Leon Vaughan, Michelle Ngan, Hextan Y. S. Golfier, Francois Sekharan, Paradan K. Charry, Rafael Cortes Poveda, Andres Kim, Jae-Weon Xiang, Yang Berkowtiz, Ross Seckl, Michael J. TI Trophoblastic Disease Review for Diagnosis and Management A Joint Report From the International Society for the Study of Trophoblastic Disease, European Organisation for the Treatment of Trophoblastic Disease, and the Gynecologic Cancer InterGroup SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Review DE Gestational trophoblastic disease; Management; Diagnosis; Review ID SINGLE-AGENT METHOTREXATE; FACTOR SCORING SYSTEM; MOLAR PREGNANCY; NEOPLASIA; CHEMOTHERAPY; TUMORS; RESISTANCE; ETOPOSIDE; LUNG; HCG AB Objective: The objective of this study was to provide a consensus review on gestational trophoblastic disease diagnosis and management from the combined International Society for the Study of Trophoblastic Disease, European Organisation for the Treatment of Trophoblastic Disease, and the Gynecologic Cancer InterGroup. Methods: A joint committee representing various groups reviewed the literature obtained from PubMed searches. Results and Conclusions: Guidelines were constructed on the basis of literature review. After initial diagnosis in local centers, centralization of pathology review and ongoing care is recommended to achieve the best outcomes. C1 [Mangili, Giorgia] IRCCS San Raffaele Hosp, Dept Gynecol & Obstet, Milan, Italy. [Lorusso, Domenica] Univ Cattolica Sacro Cuore, Dept Gynecol Oncol, I-00168 Rome, Italy. [Brown, Jubilee] Univ Texas MD Anderson Canc Ctr, Gynecol Oncol Grp, Houston, TX 77030 USA. [Pfisterer, Jacobus] AGO Study Grp, Gynecol Oncol Ctr, Kiel, Germany. [Massuger, Leon] Radboud Univ Nijmegen Med Ctr, Dept Obstet & Gynaecol, Nijmegen, Netherlands. [Vaughan, Michelle] ANZGOG, Camperdown, NSW, Australia. [Ngan, Hextan Y. S.] Univ Hong Kong, Queen Mary Hosp, Dept Obstet & Gynecol, Hong Kong, Hong Kong, Peoples R China. [Golfier, Francois] Hosp Civils Lyon, Ctr Reference Malad Trophoblast, Lyon, France. [Sekharan, Paradan K.] Coll Med, Inst Maternal & Child Hlth, Dept Obstet & Gynecol, Calicut, Kerala, India. [Charry, Rafael Cortes] Cent Univ Venezuela, Univ Hosp Caracas, GTD Unit, Caracas, Venezuela. [Poveda, Andres] Fdn Inst Valenciano Oncol, Spanish Ovarian Canc Res Grp GEICO, Valencia, Spain. [Kim, Jae-Weon] Seoul Natl Univ Hosp, Korean Gynaecol Oncol Grp, Seoul 110744, South Korea. [Xiang, Yang] Chinese Acad Med Sci, Dept Obstet & Gynecol, Peking Union Med Coll Hosp, Beijing 100730, Peoples R China. [Xiang, Yang] Peking Union Med Coll, Beijing 100021, Peoples R China. [Berkowtiz, Ross] Harvard Univ, Brigham & Womens Hosp, Div Gynecol Oncol, Dept Obstet & Gynecol,Dana Farber Canc Inst,Sch M, Boston, MA 02115 USA. [Seckl, Michael J.] Charing Cross Campus Imperial Coll London, Charing Cross Trophoblast Dis Ctr, Dept Histopathol, London, England. [Seckl, Michael J.] Charing Cross Campus Imperial Coll London, Charing Cross Trophoblast Dis Ctr, Dept Med Oncol, London, England. RP Seckl, MJ (reprint author), Charing Cross Hosp, Dept Med Oncol, Charing Cross Trophoblast Dis Ctr, Campus Imperial Coll London,Fulham Palace Rd, London W6 8RF, England. EM m.seckl@imperial.ac.uk RI Massuger, Leon/H-8072-2014; Lorusso, Domenica/K-6523-2016 OI Lorusso, Domenica/0000-0003-0981-0598 FU NCI NIH HHS [P30 CA016672] NR 30 TC 21 Z9 24 U1 5 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD NOV PY 2014 VL 24 IS 9 SU 3 BP S109 EP S116 DI 10.1097/IGC.0000000000000294 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AT0FS UT WOS:000344613200021 PM 25341573 ER PT J AU Sagae, S Susumu, N Viswanathan, AN Aoki, D Backes, FJ Provencher, DM Vaughan, M Creutzberg, CL Kurzeder, C Kristensen, G Lee, C Kurtz, JE Glasspool, RM Small, W AF Sagae, Satoru Susumu, Nobuyuki Viswanathan, Akila N. Aoki, Daisuke Backes, Floor J. Provencher, Diane M. Vaughan, Michelle Creutzberg, Carien L. Kurzeder, Christian Kristensen, Gunnar Lee, Chulmin Kurtz, Jean-Emmanuel Glasspool, Rosalind M. Small, William, Jr. TI Gynecologic Cancer InterGroup (GCIG) Consensus Review for Uterine Serous Carcinoma SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Review DE Uterine serous carcinoma; GCIG; Review ID ADVANCED ENDOMETRIAL CARCINOMA; WHOLE-ABDOMINAL IRRADIATION; PHASE-III TRIAL; STAGE-I; ONCOLOGY-GROUP; CLEAR-CELL; SURVIVAL OUTCOMES; PAPILLARY; CHEMOTHERAPY; DOXORUBICIN AB Objectives: Uterine serous carcinoma (USC) represents a rare and aggressive histologic subtype of endometrial cancer, associated with a poor prognosis. This article critically reviews the literature pertinent to the epidemiology, pathology, molecular biology, diagnosis, management, and perspectives of patients with USC. Methods: As one of a series of The Gynecologic Cancer InterGroup (GCIG) Rare Tumor Working Group in London, November 2013, we discussed about USC many times with various experts among international GCIG groups. Results: Both USC and approximately 25% of high-grade endometrioid tumors represent extensive copy number alterations, few DNA methylation changes, low estrogen and progesterone levels, and frequent P53mutations. Uterine serous carcinoma shares molecular characteristics with ovarian serous and basal-like breast carcinomas. In addition to optimal surgery, platinum-and taxane-based chemotherapy should be considered in the treatment of both early-and advanced-stage disease. The combination of radiation and chemotherapy appears to be associated with the highest survival rates. The role of radiation therapy in the management of this disease, with a high propensity for distant failures, remains elusive. Conclusions: Uterine serous carcinoma is a unique and biologically aggressive subtype of endometrial cancer and should be studied as a distinct entity. Futures studies should identify the optimized chemotherapy and radiation regimens, sequence of therapy and schedule, and the role of targeted biologic therapy. C1 [Sagae, Satoru] JR Sapporo Hosp, Dept Obstet & Gynecol, Sapporo, Hokkaido 0600033, Japan. [Susumu, Nobuyuki; Aoki, Daisuke] Keio Univ, Sch Med, Dept Obstet & Gynecol, Tokyo 160, Japan. [Viswanathan, Akila N.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Backes, Floor J.] Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. [Provencher, Diane M.] Ctr Hosp Univ Montreal, Montreal, PQ, Canada. [Vaughan, Michelle] Christchurch Hosp, Dept Oncol, Canterbury, New Zealand. [Creutzberg, Carien L.] Leiden Univ, Dept Clin Oncol, Med Ctr, Leiden, Netherlands. [Kurzeder, Christian] Kliniken Essen Mitte KEM AGO, Dept Gynecol & Gynecol Oncol, Essen, Germany. [Kristensen, Gunnar] Norwegian Radium Hosp, Oslo, Norway. [Lee, Chulmin] Inje Univ, Sanggye Paik Hosp, Dept Obstet & Gynecol, Seoul, South Korea. [Kurtz, Jean-Emmanuel] Hop Univ Strasbourg, Dept Hematol & Oncol, Strasbourg, France. [Glasspool, Rosalind M.] Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland. [Small, William, Jr.] Loyola Univ, Stritch Sch Med, Dept Radiat Oncol, Chicago, IL 60611 USA. RP Sagae, S (reprint author), JR Sapporo Hosp, Dept Obstet & Gynecol, Chuou Ku, North 3 East 1, Sapporo, Hokkaido 0600033, Japan. EM s-sagae@jrhokkaido.co.jp RI Kurtz, Jean-Emmanuel/R-3286-2016; OI Backes, Floor/0000-0002-9225-6913; Glasspool, Rosalind/0000-0002-5000-1680 NR 30 TC 16 Z9 16 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X EI 1525-1438 J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD NOV PY 2014 VL 24 IS 9 SU 3 BP S83 EP S89 DI 10.1097/IGC.0000000000000264 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AT0FS UT WOS:000344613200017 PM 25341586 ER PT J AU Xia, YM Gupta, GK Castano, AP Mroz, P Avci, P Hamblin, MR AF Xia, Yumin Gupta, Gaurav K. Castano, Ana P. Mroz, Pawel Avci, Pinar Hamblin, Michael R. TI CpG oligodeoxynucleotide as immune adjuvant enhances photodynamic therapy response in murine metastatic breast cancer SO JOURNAL OF BIOPHOTONICS LA English DT Article DE breast cancer; CpG oligodeoxynucleotide; dendritic cells; photodynamic therapy ID NF-KAPPA-B; ANTITUMOR IMMUNITY; DENDRITIC CELLS; SUPPRESSOR-CELLS; TLR9 AGONISTS; TUMOR; IMMUNOTHERAPY; ACTIVATION; DISEASE; MODEL AB Breast cancer is the most common cause of cancer death in women. The side effects and complications following current breast cancer therapy can be devastating. Moreover, the prognosis in late stages of the diseases is usually poor. Photodynamic therapy (PDT) is a promising cancer treatment modality that is capable of both local tumor destruction and immune stimulation. However, treatment with PDT alone is often non-curative due to tumor-induced immune cell dysfunction and immune suppression. This phenomenon has motivated a new approach by combining immunostimulants with PDT to enhance anti-tumor immunity. In the present study, we investigated PDT mediated by verteporfin and 690 nm light delivered 15 min later, in combination with an immunomodulation approach using CpG oligodeoxynucleotide for the treatment of 4T1 metastatic breast cancer in a BALB/c immunocompetent mouse model. In vitro, CpG primed immature dendritic cells (DC) via toll like receptor 9 to phagocytose PDT killed tumor cells leading to DC maturation and activation. Peritumoral injection of CpG after PDT in mice gave improved local tumor control and a survival advantage compared to either treatment alone (p < 0.05). CpG may be a valuable dendritic cell targeted immunoadjuvant to combine with PDT. ((c) 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) C1 [Xia, Yumin; Gupta, Gaurav K.; Castano, Ana P.; Mroz, Pawel; Avci, Pinar; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Xia, Yumin; Gupta, Gaurav K.; Castano, Ana P.; Mroz, Pawel; Avci, Pinar; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Avci, Pinar] Semmelweis Univ, Sch Med, Dept Dermatol Dermatooncol & Venerol, H-1085 Budapest, Hungary. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu OI Hamblin, Michael/0000-0001-6431-4605 FU NCI NIH HHS [R01 CA083882]; NIAID NIH HHS [R01 AI050875] NR 51 TC 10 Z9 11 U1 3 U2 19 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1864-063X EI 1864-0648 J9 J BIOPHOTONICS JI J. Biophotonics PD NOV PY 2014 VL 7 IS 11-12 BP 897 EP 905 DI 10.1002/jbio.201300072 PG 9 WC Biochemical Research Methods; Biophysics; Optics SC Biochemistry & Molecular Biology; Biophysics; Optics GA AT0WB UT WOS:000344651800005 PM 23922221 ER PT J AU Bose, A Upadhyay, GA Kandala, J Heist, EK Mela, T Parks, KA Singh, JP AF Bose, Abhishek Upadhyay, Gaurav A. Kandala, Jagdesh Heist, Edwin K. Mela, Theofanie Parks, Kimberly A. Singh, Jagmeet P. TI Does Prior Valve Surgery Change Outcome in Patients Treated with Cardiac Resynchronization Therapy? SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Article DE coronary artery bypass surgery; cardiac resynchronization therapy; cardiac valve surgery; heart failure; heart transplant ID PERMANENT PACEMAKER IMPLANTATION; VENTRICULAR SYSTOLIC FUNCTION; HEART-FAILURE PATIENTS; ATRIAL-FIBRILLATION; RISK-FACTORS; ATRIOVENTRICULAR-CONDUCTION; CARDIOPULMONARY BYPASS; AORTIC-STENOSIS; FOLLOW-UP; REPLACEMENT AB Impact of Prior Valve Surgery in CRT Patients AimsCardiac valve surgery (CVS) has been implicated as a potential barrier to optimal response after cardiac resynchronization therapy (CRT) though prospective data regarding outcome remains limited. We sought to determine CRT response in patients with a prior history of CVS. Methods and ResultsWe performed a retrospective analysis of a prospectively acquired cohort of CRT patients with history of CVS. Echocardiographic response was evaluated at baseline and 6 months. The coprimary endpoints were time to first heart failure (HF) hospitalization and a composite of all-cause mortality, transplantation and left ventricular assist device (LVAD) assessed over a 3-year follow-up period. The study group consisted of 569 patients undergoing CRT. Of these, 86 patients had a history of CVS (46.5% aortic, 37.2% mitral, 16.3% combined, and tricuspid), and were compared to 483 patients with no history of CVS. Baseline clinical and echocardiographic characteristics were not significantly different between the groups except for a higher incidence of atrial fibrillation (AF; 74.4% vs. 55.3%; P = 0.001), coronary artery bypass surgery (CABG; 58.1% vs. 38.7%; P = 0.001), and longer QRS duration (167.6 29.3 milliseconds vs. 159.4 +/- 27.5 milliseconds; P = 0.01) in those with prior CVS. Survival with respect to HF hospitalization and composite outcome was comparable in both groups. Echocardiographic response (improvement in left ventricular ejection fraction of 10%) was similar. No difference in clinical or echocardiographic outcome was found by type of valve surgery performed. ConclusionDespite a higher incidence of AF, CABG, and longer QRS duration, history of CVS is not associated with worse clinical or echocardiographic outcome after CRT. C1 [Bose, Abhishek; Upadhyay, Gaurav A.; Kandala, Jagdesh; Heist, Edwin K.; Mela, Theofanie; Singh, Jagmeet P.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Corrigan Minehan Inst, Ctr Heart, Boston, MA 02114 USA. [Parks, Kimberly A.] Massachusetts Gen Hosp, Heart Failure & Cardiac Transplant Program, Corrigan Minehan Inst, Ctr Heart, Boston, MA 02114 USA. RP Upadhyay, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv,Heart Ctr, Boston, MA 02114 USA. EM gaupadhyay@partners.org FU Max Schaldach Fellowship Award of the Heart Rhythm Society; Biotronik; Sorin; St. Jude Medical; Boston Scientific; Thoratec Inc.; Medtronic FX Dr. Upadhyay reports receiving salary support from the Max Schaldach Fellowship Award of the Heart Rhythm Society. Dr. Heist reports receiving honoraria from Biotronik, Boston Scientific, Sorin, and St. Jude Medical; research grants from Biotronik, Sorin, and St. Jude Medical; and consulting fees from Boston Scientific, Sorin, and St. Jude Medical. Dr. Mela reports receiving honoraria from Medtronic Inc., Biotronik, and St. Jude Medical. Dr. Parks reports receiving consulting fees from Thoratec Inc. and honoraria from Biotronik and Sorin. Dr. Singh reports serving as an advisor or consultant for Biotronik, Boston Scientific, Medtronic, Sorin, St. Jude Medical, Respicardia, and CardioInsight; serving as a speaker or a member of a speakers bureau for Biotronik, Boston Scientific, Sorin, and St. Jude Medical; and receiving grants for clinical research from Biotronik, Boston Scientific, Medtronic, and St. Jude Medical. Other authors: No disclosures. NR 38 TC 1 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-3873 EI 1540-8167 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD NOV PY 2014 VL 25 IS 11 BP 1206 EP 1213 DI 10.1111/jce.12469 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AS7ZL UT WOS:000344470300010 PM 24903306 ER PT J AU Lerman, J Everett, L Cote, CJ AF Lerman, Jerrold Everett, Lucy Cote, Charles J. TI Correspondence on "Clinical Characterization of Gastroenteritis-Related Seizures in Children: Impact of Fever and Serum Sodium Levels" Response SO JOURNAL OF CHILD NEUROLOGY LA English DT Letter C1 [Lerman, Jerrold] SUNY Buffalo, Women & Childrens Hosp Buffalo, Buffalo, NY 14260 USA. [Lerman, Jerrold] Univ Rochester, Rocester, NY USA. [Everett, Lucy] Massachusetts Gen Hosp, MassGen Hosp Children, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Cote, Charles J.] Massachusetts Gen Hosp, MassGen Hosp Children, Dept Anesthesia & Crit Care, Div Pediat Anesthesia, Boston, MA 02114 USA. RP Lerman, J (reprint author), SUNY Buffalo, Women & Childrens Hosp Buffalo, Buffalo, NY 14260 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD NOV PY 2014 VL 29 IS 11 BP 1580 EP 1580 DI 10.1177/0883073813510604 PG 1 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AT0XB UT WOS:000344655400034 PM 24282182 ER PT J AU Pineiro, ML Roberts, AM Waxler, JL Mullett, JE Pober, BR McDougle, CJ AF Pineiro, Mildred Lopez Roberts, Antoinette M. Waxler, Jessica L. Mullett, Jennifer E. Pober, Barbara R. McDougle, Christopher J. TI N-Acetylcysteine for Neuropsychiatric Symptoms in a Woman With Williams Syndrome SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE Williams syndrome; N-acetylcysteine; behavior; glutamate; neuropsychiatric ID DOUBLE-BLIND; 2 CHILDREN; METHYLPHENIDATE; DISORDER; INDIVIDUALS; GLUTAMATE AB Williams syndrome is a relatively rare genetic disorder caused by the hemizygous microdeletion of a region in chromosome 7q11.23. Individuals with Williams syndrome typically present with a highly social, overfriendly, and empathic personality. Comorbid medical and neuropsychiatric disorders are common. Reports of effective pharmacological treatment of associated neuropsychiatric disorders are limited. The authors describe the successful treatment of interfering anger, aggression, and hair-pulling with N-acetylcysteine in a 19-year-old woman with Williams syndrome. The neuropsychiatric symptoms emerged 1 week following an upper gastrointestinal endoscopy, for which fentanyl, midazolam, and propofol were used as anesthetics. The patient's treatment course and hypothesized mechanisms underlying the clinical presentation and symptom resolution are described. C1 [Pineiro, Mildred Lopez] Geisel Sch Med Dartmouth, Lebanon, NH USA. [Waxler, Jessica L.; Pober, Barbara R.; McDougle, Christopher J.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Mullett, Jennifer E.; McDougle, Christopher J.] Massachusetts Gen Hosp, Lurie Ctr Autism, Lexington, MA USA. [Pober, Barbara R.; McDougle, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. [Pober, Barbara R.] Quinnipiac Univ, Netter Sch Med, Dept Med Sci, Middletown, CT USA. [McDougle, Christopher J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP McDougle, CJ (reprint author), Lurie Ctr Autism, One Maguire Rd, Lexington, MA 02421 USA. EM cmcdougle@partners.org NR 15 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 EI 1708-8283 J9 J CHILD NEUROL JI J. Child Neurol. PD NOV PY 2014 VL 29 IS 11 BP NP135 EP NP138 DI 10.1177/0883073813512025 PG 4 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AT0XB UT WOS:000344655400002 PM 24396132 ER PT J AU Lourenco, TGB Heller, D Silva-Boghossian, CM Cotton, SL Paster, BJ Colombo, APV AF Baeta Lourenco, Talita Gomes Heller, Debora Silva-Boghossian, Carina Maciel Cotton, Sean L. Paster, Bruce J. Vieira Colombo, Ana Paula TI Microbial signature profiles of periodontally healthy and diseased patients SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Article DE aggressive periodontitis; biofilm; chronic periodontitis; gingivitis; microarray analysis; microbiota ID AGGRESSIVE PERIODONTITIS; IDENTIFICATION MICROARRAY; REFRACTORY PERIODONTITIS; SUBGINGIVAL MICROBIOTA; BACTERIAL DIVERSITY; ORAL MICROFLORA; COMMUNITY; INDIVIDUALS; GINGIVITIS; BIOFILMS AB AimTo determine microbial profiles that discriminate periodontal health from different forms of periodontal diseases. MethodsSubgingival biofilm was obtained from patients with periodontal health (27), gingivitis (11), chronic periodontitis (35) and aggressive periodontitis (24), and analysed for the presence of >250 species/phylotypes using HOMIM. Microbial differences among groups were examined by Mann-Whitney U-test. Regression analyses were performed to determine microbial risk indicators of disease. ResultsPutative and potential new periodontal pathogens were more prevalent in subjects with periodontal diseases than periodontal health. Detection of Porphyromonas endodontalis/Porphyromonas spp. (OR 9.5 [1.2-73.1]) and Tannerella forsythia (OR 38.2 [3.2-450.6]), and absence of Neisseria polysaccharea (OR 0.004 [0-0.15]) and Prevotella denticola (OR 0.014 [0-0.49], p<0.05) were risk indicators of periodontal disease. Presence of Aggregatibacter actinomycetemcomitans (OR 29.4 [3.4-176.5]), Cardiobacterium hominis (OR 14.9 [2.3-98.7]), Peptostreptococcaceae sp. (OR 35.9 [2.7-483.9]), P.alactolyticus (OR 31.3 [2.1-477.2]), and absence of Fretibacterium spp. (OR 0.024 [0.002-0.357]), Fusobacterium naviforme/Fusobacterium nucleatum ss vincentii (OR 0.015 [0.001-0.223]), Granulicatella adiacens/Granulicatella elegans (OR 0.013 [0.001-0.233], p<0.05) were associated with aggressive periodontitis. ConclusionThere were specific microbial signatures of the subgingival biofilm that were able to distinguish between microbiomes of periodontal health and diseases. Such profiles may be used to establish risk of disease. C1 [Baeta Lourenco, Talita Gomes; Heller, Debora; Silva-Boghossian, Carina Maciel; Vieira Colombo, Ana Paula] Univ Fed Rio de Janeiro, Inst Microbiol, BR-21941 Rio De Janeiro, Brazil. [Heller, Debora; Silva-Boghossian, Carina Maciel] Univ Fed Rio de Janeiro, Div Grad Periodont, Dept Dent Clin, BR-21941 Rio De Janeiro, Brazil. [Heller, Debora] Goldman Sch Med, Dept Oral Biol, Boston, MA USA. [Cotton, Sean L.; Paster, Bruce J.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Paster, Bruce J.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Colombo, APV (reprint author), Univ Fed Rio de Janeiro, CCS, Inst Microbiol, Paulo de Goes Bloco 1,Lab I2-03, BR-21941902 Rio de Janeiro, RJ, Brazil. EM apcolombo@micro.ufrj.br RI Silva-Boghossian, Carina M./G-9440-2012 OI Silva-Boghossian, Carina M./0000-0002-4500-4350 FU National Council for Scientific and Technological Development CNPq; Coordination of Improvement of Higher Education Personnel (CAPES), Brasilia, Brazil; Foundation for Research Financial Support in the State of Rio de Janeiro (FAPERJ), Rio de Janeiro, Brazil; National Institutes of Health [DE021565] FX The authors declare that they have no conflict of interests regarding this study. This work was supported in part by National Council for Scientific and Technological Development CNPq, and Coordination of Improvement of Higher Education Personnel (CAPES), Brasilia, Brazil; Foundation for Research Financial Support in the State of Rio de Janeiro (FAPERJ), Rio de Janeiro, Brazil and a grant from The National Institutes of Health, DE021565 (BP). NR 40 TC 26 Z9 26 U1 1 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0303-6979 EI 1600-051X J9 J CLIN PERIODONTOL JI J. Clin. Periodontol. PD NOV PY 2014 VL 41 IS 11 BP 1027 EP 1036 DI 10.1111/jcpe.12302 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AS8CH UT WOS:000344477400001 PM 25139407 ER PT J AU Hooper, DC Hirsch, MS AF Hooper, David C. Hirsch, Martin S. TI Clarification Regarding Novel Clostridium botulinum Toxin Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter C1 [Hooper, David C.; Hirsch, Martin S.] Massachusetts Gen Hosp, Div Infect Dis, Cambridge, MA 02139 USA. RP Hirsch, MS (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 65 Landsdowne St,Rm 419, Cambridge, MA 02139 USA. EM mshirsch@partners.org NR 3 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD NOV 1 PY 2014 VL 210 IS 9 BP 1517 EP 1518 DI 10.1093/infdis/jiu270 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AT0ER UT WOS:000344610600023 PM 24808388 ER PT J AU Hillblom, D Schueth, A Robertson, SM Topor, L Low, G AF Hillblom, Douglas Schueth, Anthony Robertson, Scott M. Topor, Laura Low, Greg TI The Impact of Information Technology on Managed Care Pharmacy: Today and Tomorrow SO JOURNAL OF MANAGED CARE PHARMACY LA English DT Editorial Material ID ELECTRONIC HEALTH RECORD AB Understanding the use of health information technology (HIT) and its implications is crucial for the future of managed care pharmacy. Information is the cornerstone of providing and managing care, and the ability to exchange data is easier and more complicated than ever before. In this commentary, a subset of the Academy of Managed Care Pharmacy Healthcare Information Technology Advisory Council addresses how HIT supports managed care today and its anticipated evolution, with a focus on quality, patient safety, communication, and efficiency. Among the tools and functions reviewed are electronic health records, electronic prescribing, health information exchange, electronic prior authorization, pharmacists as care team members, formularies, prescription drug abuse, and policy levers to address these issues. Copyright (C) 2014, Academy of Managed Care Pharmacy. All rights reserved. C1 [Hillblom, Douglas] OptumRx, Profess Practice & Pharm Policy, Sacramento, CA 95826 USA. [Schueth, Anthony] Point Care Partners LLC, Coral Springs, FL USA. [Robertson, Scott M.] Kaiser Permanente, Pasadena, CA USA. [Topor, Laura] Granada Hlth, Minnetonka, MN USA. [Low, Greg] Massachusetts Gen Hosp, MGPO Pharm, Boston, MA 02114 USA. RP Hillblom, D (reprint author), OptumRx, Profess Practice & Pharm Policy, 8880 Cal Ctr Dr,Ste 300, Sacramento, CA 95826 USA. EM douglas.hillblom@optum.com NR 48 TC 1 Z9 1 U1 2 U2 5 PU ACAD MANAGED CARE PHARMACY PI ALEXANDRIA PA 100 N PITT ST, 400, ALEXANDRIA, VA 22314-3134 USA SN 1083-4087 J9 J MANAGE CARE PHARM JI J. Manag. Care Pharm. PD NOV PY 2014 VL 20 IS 11 BP 1073 EP 1079 PG 7 WC Health Care Sciences & Services; Pharmacology & Pharmacy SC Health Care Sciences & Services; Pharmacology & Pharmacy GA AS8RF UT WOS:000344515200001 PM 25351968 ER PT J AU Haggerty, G Forlenza, N Poland, C Ray, S Zodan, J Mehra, A Goyal, A Baity, MR Siefert, CJ Sobin, S Leite, D Sinclair, SJ AF Haggerty, Greg Forlenza, Nicholas Poland, Charlotte Ray, Sagarika Zodan, Jennifer Mehra, Ashwin Goyal, Ajay Baity, Matthew R. Siefert, Caleb J. Sobin, Sean Leite, David Sinclair, Samuel J. TI Assessing Overall Functioning With Adolescent Inpatients SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE Overall functioning; GAF; SOS-10; SCORS-G; adolescent; inpatient; assessment ID SCHWARTZ OUTCOME SCALE-10; GLOBAL ASSESSMENT SCALE; LENGTH-OF-STAY; MENTAL-HEALTH; INITIAL-VALIDATION; CONSTRUCT-VALIDITY; PREDICTING LENGTH; AXIS-II; PERSONALITY; CHILDREN AB The current study sought to evaluate the validity and reliability of a brief measure of overall functioning for adolescents. Clinicians were asked to complete the Overall Functioning Scale (OFS) for 72 adolescents consecutively admitted to the adolescent psychiatric inpatient service of a community safety net medical center. The results revealed that this new measure is related to the patients' length of stay, clinician-rated measures of social cognition and object relations, Global Assessment of Functioning (GAF) score at admission, as well as global rating of engagement in individual psychotherapy. The results also showed that the OFS was related to the patients' history of nonsuicidal self-harm as well as treatment outcome as assessed by measures of psychological health and well-being as well as symptoms. Hierarchical regressions reveal that the OFS shows incremental validity greater than the admission GAF score in predicting length of stay. The results also showed that the OFS demonstrates interrater reliability in the excellent range (intraclass correlation coefficient(1,2)) of 0.88. Clinical implications of the use of this tool and areas of future research are discussed. C1 [Haggerty, Greg; Forlenza, Nicholas; Poland, Charlotte; Ray, Sagarika; Zodan, Jennifer; Mehra, Ashwin; Goyal, Ajay] Nassau Univ, Med Ctr, Von Tauber Inst Global Psychiat, Dept Psychiat & Behav Sci, E Meadow, NY 11554 USA. [Baity, Matthew R.] Alliant Int Univ, Dept Psychol, Sacramento, CA USA. [Siefert, Caleb J.] Univ Michigan Dearborn, Dept Psychol, Dearborn, MI USA. [Sobin, Sean] Long Isl Univ, Dept Psychol, Brookville, NY USA. [Leite, David] Liberty Univ, Dept Psychol, Lynchburg, VA USA. [Sinclair, Samuel J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp,Psychol Evalut & Res Lab, Boston, MA 02115 USA. RP Haggerty, G (reprint author), Nassau Univ, Med Ctr, 2201 Hempstead Tpke,Box 48, E Meadow, NY 11554 USA. EM ghag541@aol.com FU American Psychoanalytic Association; NIMH [1R21MH097781-01A1] FX This study was supported in part by a grant awarded to the first author from the American Psychoanalytic Association and by NIMH Grant No. 1R21MH097781-01A1, received by the first author. NR 44 TC 0 Z9 0 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 EI 1539-736X J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD NOV PY 2014 VL 202 IS 11 BP 822 EP 828 DI 10.1097/NMD.0000000000000200 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AT4XB UT WOS:000344944300009 PM 25259948 ER PT J AU Shepard, JA Vajda, K Nyer, M Clarke, W Gonder-Frederick, L AF Shepard, Jaclyn A. Vajda, Karen Nyer, Maren Clarke, William Gonder-Frederick, Linda TI Understanding the Construct of Fear of Hypoglycemia in Pediatric Type 1 Diabetes SO JOURNAL OF PEDIATRIC PSYCHOLOGY LA English DT Article DE anxiety; diabetes; quality of life ID SUBCUTANEOUS INSULIN INFUSION; POOR GLYCEMIC CONTROL; YOUNG-CHILDREN; EMOTIONAL DISTRESS; FIT INDEXES; PARENTS; ADOLESCENTS; MELLITUS; FATHERS; MOTHERS AB ObjectiveaEuro integral Fear of hypoglycemia (FoH) can be a significant barrier to glycemic control in pediatric type 1 diabetes (T1D). This study aimed to explore underlying constructs of the Hypoglycemia Fear Survey (HFS) for parents (PHFS) and children (CHFS).aEuro integral MethodsaEuro integral Data were aggregated from five studies of 259 youth with T1D and 250 parents. Exploratory Factor Analysis was used to determine the underlying factors of the CHFS and PHFS.aEuro integral ResultsaEuro integral Similar four-factor solutions were found for the CHFS and PHFS. Both subscales consisted of two factors: Behavior Subscale (1) behaviors used to keep blood glucose (BG) high to prevent hypoglycemia (Maintain High BG) and (2) other actions to avoid hypoglycemia (Avoidance); Worry Subscale (1) concerns about helplessness (Helplessness) and (2) negative social consequences associated with hypoglycemia (Social Consequences).aEuro integral ConclusionsaEuro integral These constructs provide a more comprehensive understanding of pediatric FoH and have implications for interventions aimed at reducing FoH in this population. C1 [Shepard, Jaclyn A.; Vajda, Karen; Gonder-Frederick, Linda] Univ Virginia, Dept Psychiat & Neurobehav Sci, Charlottesville, VA 22908 USA. [Nyer, Maren] Harvard Univ, Depress Clin & Res Program, Massachusetts Gen Hosp, Dept Psychiat,Med Sch, Cambridge, MA 02138 USA. [Clarke, William] Univ Virginia, Dept Pediat, Charlottesville, VA 22908 USA. RP Gonder-Frederick, L (reprint author), Univ Virginia, Sch Med, Behav Med Ctr, Box 800223, Charlottesville, VA 22908 USA. EM Lag3g@virginia.edu FU NIDDK NIH HHS [R21DK080896] NR 38 TC 7 Z9 7 U1 1 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-8693 EI 1465-735X J9 J PEDIATR PSYCHOL JI J. Pediatr. Psychol. PD NOV-DEC PY 2014 VL 39 IS 10 BP 1115 EP 1125 DI 10.1093/jpepsy/jsu068 PG 11 WC Psychology, Developmental SC Psychology GA AT0IU UT WOS:000344620900007 PM 25214644 ER PT J AU Pan, C Zhou, Y Dator, R Ginghina, C Zhao, YC Movius, J Peskind, E Zabetian, CP Quinn, J Galasko, D Stewart, T Shi, M Zhang, J AF Pan, Catherine Zhou, Yong Dator, Romel Ginghina, Carmen Zhao, Yanchun Movius, James Peskind, Elaine Zabetian, Cyrus P. Quinn, Joseph Galasko, Douglas Stewart, Tessandra Shi, Min Zhang, Jing TI Targeted Discovery and Validation of Plasma Biomarkers of Parkinson's Disease SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE Parkinsons disease; targeted mass spectrometry; peripheral biomarkers; selected reaction monitoring ID BLOOD-BRAIN-BARRIER; ALPHA-SYNUCLEIN; PRION PROTEIN; NEURODEGENERATIVE DISEASES; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; MASS-SPECTROMETRY; GROWTH-FACTOR; GLYCOPROTEINS; PROTEOMICS AB Despite extensive research, an unmet need remains for protein biomarkers of Parkinson's disease (PD) in peripheral body fluids, especially blood, which is easily accessible clinically. The discovery of such biomarkers is challenging, however, due to the enormous complexity and huge dynamic range of human blood proteins, which are derived from nearly all organ systems, with those originating specifically from the central nervous system (CNS) being exceptionally low in abundance. In this investigation of a relatively large cohort (similar to 300 subjects), selected reaction monitoring (SRM) assays (a targeted approach) were used to probe plasma peptides derived from glycoproteins previously found to be altered in the CNS based on PD diagnosis or severity. Next, the detected peptides were interrogated for their diagnostic sensitivity and specificity as well as the correlation with PD severity, as determined by the Unified Parkinson's Disease Rating Scale (UPDRS). The results revealed that 12 of the 50 candidate glycopeptides were reliably and consistently identified in plasma samples, with three of them displaying significant differences among diagnostic groups. A combination of four peptides (derived from PRNP, HSPG2, MEGF8, and NCAM1) provided an overall area under curve (AUC) of 0.753 (sensitivity: 90.4%; specificity: 50.0%). Additionally, combining two peptides (derived from MEGF8 and ICAM1) yielded significant correlation with PD severity, that is, UPDRS (r = 0.293, p = 0.004). The significance of these results is at least two-fold: (1) it is possible to use a targeted approach to identify otherwise very difficult to detect CNS related biomarkers in peripheral blood and (2) the novel biomarkers, if validated in independent cohorts, can be employed to assist with clinical diagnosis of PD as well as monitoring disease progression. C1 [Pan, Catherine; Dator, Romel; Ginghina, Carmen; Zhao, Yanchun; Movius, James; Stewart, Tessandra; Shi, Min; Zhang, Jing] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98104 USA. [Pan, Catherine] Inarian Neurodiagnost, Mercer Isl, WA 98040 USA. [Zhou, Yong] Inst Syst Biol, Seattle, WA 98109 USA. [Peskind, Elaine] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Peskind, Elaine] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Zabetian, Cyrus P.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Zabetian, Cyrus P.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98195 USA. [Quinn, Joseph] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Galasko, Douglas] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. RP Zhang, J (reprint author), Univ Washington, Sch Med, Dept Pathol, 325 9th Ave,HMC 359635, Seattle, WA 98104 USA. EM zhangj@uw.edu RI Shi, Min/G-6165-2012; OI Shi, Min/0000-0002-6901-2558; Zabetian, Cyrus/0000-0002-7739-4306 FU University of Washington's Proteomics Resource [UWPR95794]; [R43NS065553]; [AG033398]; [AG05131]; [ES004696-5897]; [ES007033-6364]; [ES016873]; [ES019277]; [NS057567]; [NS062684]; [NS060252]; [NS062684-6221]; [NS082137] FX We deeply appreciate the generous participation and donation of samples by the patients in this study. The project described was supported by Award Number R43NS065553 (to C.P.) as well as Award Numbers AG033398, AG05131, ES004696-5897, ES007033-6364, ES016873, ES019277, NS057567, NS062684, NS060252, NS062684-6221, and NS082137 (to J.Z.). It was also partially supported by the University of Washington's Proteomics Resource (UWPR95794). The content is solely the responsibility of the authors and does not necessarily represent the official views of any funding agency. NR 58 TC 9 Z9 9 U1 6 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD NOV PY 2014 VL 13 IS 11 BP 4535 EP 4545 DI 10.1021/pr500421v PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AT0PA UT WOS:000344636500006 PM 24853996 ER PT J AU Gbormittah, FO Lee, LY Taylor, K Hancock, WS Iliopoulos, O AF Gbormittah, Francisca O. Lee, Ling Y. Taylor, KyOnese Hancock, William S. Iliopoulos, Othon TI Comparative Studies of the Proteome, Glycoproteome, and N-Glycome of Clear Cell Renal Cell Carcinoma Plasma before and after Curative Nephrectomy SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE Glycoproteomics; glycomics; N-glycans; lectins; multi-lectin affinity chromatography ID D-BINDING PROTEIN; BREAST-CANCER PATIENTS; CHROMATOGRAPHY M-LAC; AFFINITY-CHROMATOGRAPHY; STRUCTURAL-ANALYSIS; MASS-SPECTROMETRY; SIALIC-ACID; SERUM; GLYCOSYLATION; EXPRESSION AB Clear cell renal cell carcinoma is the most prevalent of all reported kidney cancer cases, and currently there are no markers for early diagnosis. This has stimulated great research interest recently because early detection of the disease can significantly improve the low survival rate. Combining the proteome, glycoproteome, and N-glycome data from clear cell renal cell carcinoma plasma has the potential of identifying candidate markers for early diagnosis and prognosis and/or to monitor disease recurrence. Here, we report on the utilization of a multi-dimensional fractionation approach (12P-M-LAC) and LCMS/MS to comprehensively investigate clear cell renal cell carcinoma plasma collected before (disease) and after (non-disease) curative nephrectomy (n = 40). Proteins detected in the subproteomes were investigated via label-free quantification. Protein abundance analysis revealed a number of low-level proteins with significant differential expression levels in disease samples, including HSPG2, CD146, ECM1, SELL, SYNE1, and VCAM1. Importantly, we observed a strong correlation between differentially expressed proteins and clinical status of the patient. Investigation of the glycoproteome returned 13 candidate glycoproteins with significant differential M-LAC column binding. Qualitative analysis indicated that 62% of selected candidate glycoproteins showed higher levels (upregulation) in M-LAC bound fraction of disease samples. This observation was further confirmed by released N-glycans data in which 53% of identified N-glycans were present at different levels in plasma in the disease vs non-disease samples. This striking result demonstrates the potential for significant protein glycosylation alterations in clear cell renal cell carcinoma cancer plasma. With future validation in a larger cohort, information derived from this study may lead to the development of clear cell renal cell carcinoma candidate biomarkers. C1 [Gbormittah, Francisca O.; Taylor, KyOnese; Hancock, William S.] Northeastern Univ, Barnett Inst, Boston, MA 02115 USA. [Gbormittah, Francisca O.; Taylor, KyOnese; Hancock, William S.] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Lee, Ling Y.] Macquarie Univ, Dept Chem, Sydney, NSW 2109, Australia. [Lee, Ling Y.] Macquarie Univ, Dept Biomol Sci, Sydney, NSW 2109, Australia. [Iliopoulos, Othon] Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Res, Charlestown, MA 02129 USA. [Iliopoulos, Othon] Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. RP Hancock, WS (reprint author), Northeastern Univ, Barnett Inst, 360 Huntington Ave, Boston, MA 02115 USA. EM wi.hancock@neu.edu; oiliopoulos@partners.org FU Early Detection Research Network from National Cancer Institute (NCI) [1U01CA152653-01] FX This work was supported by the Early Detection Research Network grant no. 1U01CA152653-01 from the National Cancer Institute (NCI). NR 56 TC 4 Z9 4 U1 3 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD NOV PY 2014 VL 13 IS 11 BP 4889 EP 4900 DI 10.1021/pr500591e PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AT0PA UT WOS:000344636500036 PM 25184692 ER PT J AU Taneja, AK Torriani, M Simeone, FJ AF Taneja, Atul K. Torriani, Martin Simeone, F. Joseph TI Septic Arthritis and Osteomyelitis of the Hip by Candida albicans SO JOURNAL OF RHEUMATOLOGY LA English DT Editorial Material ID PATIENT C1 [Taneja, Atul K.] Hosp Israelita Albert Einstein, Hosp Coracao & Teleimagem, Diagnost Ctr,Div Musculoskeletal Radiol, Div Musculoskeletal Imaging,Imaging Dept, Sao Paulo, Brazil. [Torriani, Martin; Simeone, F. Joseph] Massachusetts Gen Hosp, Div Musculoskeletal Imaging & Intervent, Boston, MA 02114 USA. [Torriani, Martin; Simeone, F. Joseph] Harvard Univ, Sch Med, Boston, MA USA. RP Taneja, AK (reprint author), Hosp Israelita Albert Einstein, Dept Imagem, Av Albert Einstein 627, BR-05652900 Sao Paulo, Brazil. EM taneja@einstein.br RI Taneja, Atul/N-3133-2014 OI Taneja, Atul/0000-0002-4655-2033 NR 5 TC 1 Z9 2 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 365 BLOOR ST E, STE 901, TORONTO, ONTARIO M4W 3L4, CANADA SN 0315-162X EI 1499-2752 J9 J RHEUMATOL JI J. Rheumatol. PD NOV PY 2014 VL 41 IS 11 BP 2270 EP 2270 DI 10.3899/jrheum.140354 PG 1 WC Rheumatology SC Rheumatology GA AT0AI UT WOS:000344598900026 PM 25362708 ER PT J AU Nabors, LB Portnow, J Ammirati, M Brem, H Brown, P Butowski, N Chamberlain, MC DeAngelis, LM Fenstermaker, RA Friedman, A Gilbert, MR Hattangadi-Gluth, J Hesser, D Holdhoff, M Junck, L Lawson, R Loeffler, JS Moots, PL Mrugala, MM Newton, HB Raizer, JJ Recht, L Shonka, N Shrieve, DC Sills, AK Swinnen, LJ Tran, D Tran, N Vrionis, FD Wen, PY McMillian, NR Ho, M AF Nabors, Louis Burt Portnow, Jana Ammirati, Mario Brem, Henry Brown, Paul Butowski, Nicholas Chamberlain, Marc C. DeAngelis, Lisa M. Fenstermaker, Robert A. Friedman, Allan Gilbert, Mark R. Hattangadi-Gluth, Jona Hesser, Deneen Holdhoff, Matthias Junck, Larry Lawson, Ronald Loeffler, Jay S. Moots, Paul L. Mrugala, Maciej M. Newton, Herbert B. Raizer, Jeffrey J. Recht, Lawrence Shonka, Nicole Shrieve, Dennis C. Sills, Allen K., Jr. Swinnen, Lode J. David Tran Nam Tran Vrionis, Frank D. Wen, Patrick Yung McMillian, Nicole R. Ho, Maria TI Central Nervous System Cancers, Version 2.2014 Featured Updates to the NCCN Guidelines SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID WHOLE-BRAIN RADIOTHERAPY; STEREOTACTIC RADIOSURGERY; PROGNOSTIC-FACTORS; INTRACRANIAL METASTASES; CEREBRAL METASTASES; SURGICAL RESECTION; RADIATION-THERAPY; BREAST-CANCER; MANAGEMENT; CARCINOMA AB The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases. C1 [Nabors, Louis Burt] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35203 USA. [Portnow, Jana] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Ammirati, Mario; Newton, Herbert B.] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Ammirati, Mario; Newton, Herbert B.] Ohio State Univ, Ctr Comprehens Canc, Solove Res Inst, Columbus, OH 43210 USA. [Brem, Henry; Holdhoff, Matthias; Swinnen, Lode J.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Sidney, BC, Canada. [Brown, Paul; Gilbert, Mark R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Butowski, Nicholas] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Chamberlain, Marc C.; Mrugala, Maciej M.] Univ Washington, Seattle Canc Care Alliance, Seattle, WA 98195 USA. [DeAngelis, Lisa M.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Fenstermaker, Robert A.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Hattangadi-Gluth, Jona] UC San Diego Moores Canc Ctr, La Jolla, CA 92093 USA. [Hesser, Deneen] Amer Brain Tumor Assoc, Chicago, IL USA. [Junck, Larry] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Lawson, Ronald] Univ Tennessee, Hlth Sci Ctr, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Loeffler, Jay S.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Moots, Paul L.; Sills, Allen K., Jr.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Raizer, Jeffrey J.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Recht, Lawrence] Stanford Comprehens Canc Ctr, Stanford, CA 94305 USA. [Shonka, Nicole] Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE USA. [Shrieve, Dennis C.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [David Tran] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO 63110 USA. [David Tran] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Nam Tran; Vrionis, Frank D.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Wen, Patrick Yung] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [McMillian, Nicole R.; Ho, Maria] Natl Comprehens Canc Network, Ft Washington, PA USA. RP Nabors, LB (reprint author), Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35203 USA. RI Gilbert, Mark/J-7494-2016 OI Gilbert, Mark/0000-0003-2556-9722 FU Eisai, Inc.; Millennium: The Takeda Oncology Company; Teva Pharmaceuticals; Bayer HealthCare Pharmaceuticals Inc.; Celgene Corporation; Endo Pharmaceuticals and HealthTronics; Genentech; ARIAD Pharmaceuticals, Inc. FX Supported by educational grants from Eisai, Inc.; Millennium: The Takeda Oncology Company; Teva Pharmaceuticals; Bayer HealthCare Pharmaceuticals Inc.; Celgene Corporation; Endo Pharmaceuticals and HealthTronics; Genentech; and ARIAD Pharmaceuticals, Inc. NR 32 TC 17 Z9 18 U1 0 U2 6 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD NOV PY 2014 VL 12 IS 11 BP 1517 EP 1523 PG 7 WC Oncology SC Oncology GA AS8RP UT WOS:000344516200005 PM 25361798 ER PT J AU Denlinger, CS Ligibel, JA Are, M Baker, KS Demark-Wahnefried, W Dizon, D Friedman, DL Goldman, M Jones, L King, A Ku, GH Kvale, E Langbaum, TS Leonardi-Warren, K McCabe, MS Melisko, M Montoya, JG Mooney, K Morgan, MA Moslehi, JJ O'Connor, T Overholser, L Paskett, ED Peppercorn, J Raza, M Rodriguez, MA Syrjala, KL Urba, SG Wakabayashi, MT Zee, P McMillian, NR Freedman-Cass, DA AF Denlinger, Crystal S. Ligibel, Jennifer A. Are, Madhuri Baker, K. Scott Demark-Wahnefried, Wendy Dizon, Don Friedman, Debra L. Goldman, Mindy Jones, Lee King, Allison Ku, Grace H. Kvale, Elizabeth Langbaum, Terry S. Leonardi-Warren, Kristin McCabe, Mary S. Melisko, Michelle Montoya, Jose G. Mooney, Kathi Morgan, Mary Ann Moslehi, Javid J. O'Connor, Tracey Overholser, Linda Paskett, Electra D. Peppercorn, Jeffrey Raza, Muhammad Rodriguez, M. Alma Syrjala, Karen L. Urba, Susan G. Wakabayashi, Mark T. Zee, Phyllis McMillian, Nicole R. Freedman-Cass, Deborah A. TI Survivorship: Screening for Cancer and Treatment Effects, Version 2.2014 Clinical Practice Guidelines in Oncology SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Review ID QUALITY-OF-LIFE; SF AB The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for common physical and psychosocia I consequences of cancer and cancer treatment. This portion of the guidelines describes recommendations regarding screening for the effects of cancer and its treatment. The panel created a sample screening tool, specifically for use in combination with the NCCN Guidelines for Survivorship, to guide providers to topics that require more in-depth assessment. Effective screening and assessment can help providers deliver necessary and comprehensive survivorship care. C1 [Denlinger, Crystal S.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Ligibel, Jennifer A.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02215 USA. [Are, Madhuri] Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE USA. [Baker, K. Scott; Syrjala, Karen L.] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, Seattle, WA USA. [Demark-Wahnefried, Wendy; Kvale, Elizabeth] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL USA. [Dizon, Don] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Friedman, Debra L.; Moslehi, Javid J.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Goldman, Mindy; Melisko, Michelle] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Jones, Lee; McCabe, Mary S.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [King, Allison] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO USA. [King, Allison] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Ku, Grace H.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA USA. [Langbaum, Terry S.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Sidney, BC, Canada. [Leonardi-Warren, Kristin; Overholser, Linda] Univ Colorado, Ctr Canc, Boulder, CO 80309 USA. [Montoya, Jose G.] Stanford Canc Inst, Stanford, CA USA. [Mooney, Kathi] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Morgan, Mary Ann] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [O'Connor, Tracey] Roswell Pk Canc Inst, Buffalo, NY USA. [Paskett, Electra D.] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Paskett, Electra D.] Ohio State Univ, Ctr Comprehens Canc, Solove Res Inst, Columbus, OH 43210 USA. [Peppercorn, Jeffrey] Duke Canc Inst, Durham, NC USA. [Raza, Muhammad] Univ Tennessee, Hlth Sci Ctr, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Rodriguez, M. Alma] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Urba, Susan G.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Wakabayashi, Mark T.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Zee, Phyllis] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. RP Denlinger, CS (reprint author), Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. FU National Cancer Institute; American Cancer Society; Harvest for Health Gardening Project for Breast Cancer Survivors; Nutrigenomic Link between Alpha-Linolenic Acid and Aggressive Prostate Cancer; Bayer HealthCare; Genentech, Inc.; ImClone Systems Incorporated; MedImmune Inc.; OncoMed Pharmaceuticals; Astex Pharmaceuticals; Merrimack Pharmaceuticals; Pfizer Inc.; Celldex Therapeutics; Galena Biopharma; University of Utah; Millennium Pharmaceuticals, Inc.; Accleron, Inc.; Merck Co., Inc.; Amgen Inc.; Ortho Biotech Products, L.P.; Philips/Respironics FX Wendy Demark-Wahnefried, PhD, RD National Cancer Institute; American Cancer Society; Harvest for Health Gardening Project for Breast Cancer Survivors; and Nutrigenomic Link between Alpha-Linolenic Acid and Aggressive Prostate Cancer; Crystal S. Denlinger, MD Bayer HealthCare; Genentech, Inc.; ImClone Systems Incorporated; MedImmune Inc.; OncoMed Pharmaceuticals; Astex Pharmaceuticals; Merrimack Pharmaceuticals; and Pfizer Inc.; Michelle Melisko, MD Genentech, Inc.; Celldex Therapeutics; and Galena Biopharma; Kathi Mooney, RN, PhD University of Utah; Javid J. Moslehi, MD Millennium Pharmaceuticals, Inc.; and Accleron, Inc.; Electra D. Paskett, PhD Merck & Co., Inc.; M. Alma Rodriguez, MD Amgen Inc.; and Ortho Biotech Products, L.P.; Phyllis Zee, MD Philips/Respironics NR 6 TC 2 Z9 2 U1 0 U2 3 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD NOV PY 2014 VL 12 IS 11 BP 1526 EP 1530 PG 5 WC Oncology SC Oncology GA AS8RP UT WOS:000344516200006 PM 25361799 ER PT J AU O'Brien, S Radich, JP Abboud, CN Akhtari, M Altman, JK Berman, E Curtin, P DeAngelo, DJ Deininger, M Devine, S Fathi, AT Gotlib, J Jagasia, M Kropf, P Moore, JO Pallera, A Reddy, VVB Shah, NP Smith, BD Snyder, DS Wetzler, M Gregory, K Sundar, H AF O'Brien, Susan Radich, Jerald P. Abboud, Camille N. Akhtari, Mojtaba Altman, Jessica K. Berman, Ellin Curtin, Peter DeAngelo, Daniel J. Deininger, Michael Devine, Steven Fathi, Amir T. Gotlib, Jason Jagasia, Madan Kropf, Patricia Moore, Joseph O. Pallera, Arnel Reddy, Vishnu V. B. Shah, Neil P. Smith, B. Douglas Snyder, David S. Wetzler, Meir Gregory, Kristina Sundar, Hema TI Chronic Myelogenous Leukemia, Version 1.2015 Clinical Practice Guidelines in Oncology SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Review ID CHRONIC MYELOID-LEUKEMIA; STEM-CELL TRANSPLANTATION; DONOR LYMPHOCYTE INFUSIONS; TYROSINE KINASE INHIBITORS; BONE-MARROW-TRANSPLANTATION; POLYMERASE-CHAIN-REACTION; TERM-FOLLOW-UP; PULMONARY ARTERIAL-HYPERTENSION; ACUTE LYMPHOBLASTIC-LEUKEMIA; CHROMOSOME-POSITIVE LEUKEMIA AB Chronic myelogenous leukemia (CML) is usually diagnosed in the chronic phase. Untreated chronic phase CML will eventually progress to advanced phase (accelerated or blast phase) CML. Tyrosine kinase inhibitors (TKIs) have been shown to induce favorable response rates in patients with accelerated and blast phase CML. The addition of TKIs to chemotherapy has also been associated with improved outcomes in patients with blast phase CML. Allogeneic hematopoietic stem cell transplant remains a potentially curative option for patients with advanced phase CML, although treatment with a course of TKIs will be beneficial as a bridge to transplant. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with advanced phase CML. C1 [O'Brien, Susan] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Radich, Jerald P.] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, Seattle, WA USA. [Abboud, Camille N.] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO USA. [Abboud, Camille N.] Univ Washington, Sch Med, Seattle, WA USA. [Akhtari, Mojtaba] Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE USA. [Altman, Jessica K.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Berman, Ellin] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Curtin, Peter] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA USA. [DeAngelo, Daniel J.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Deininger, Michael] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Devine, Steven] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Devine, Steven] Solove Res Inst, Columbus, OH USA. [Fathi, Amir T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Gotlib, Jason] Stanford Canc Inst, Stanford, CA 94305 USA. [Jagasia, Madan] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Kropf, Patricia] Fox Chase Canc Ctr, Philadelphia, PA USA. [Moore, Joseph O.] Duke Canc Inst, Durham, NC USA. [Pallera, Arnel] Univ Tennessee, Hlth Sci Ctr, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Reddy, Vishnu V. B.] Univ Alabama, Ctr Comprehens Canc, Tuscaloosa, AL 35487 USA. [Shah, Neil P.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Smith, B. Douglas] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Sidney, BC, Canada. [Snyder, David S.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Wetzler, Meir] Roswell Pk Canc Inst, Buffalo, NY USA. RP O'Brien, S (reprint author), Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. OI Reddy, Vishnu/0000-0001-5474-3289 FU Eli Lilly and Company; Merck Co., Inc.; Novartis Pharmaceuticals Corporation; Teva; ARIAD Pharmaceuticals, Inc.; Boehringer Ingelheim GmbH; Bristol-Myers Squibb Company; Millennium Pharmaceuticals, Inc.; Agios; Ambit; Astellas; Cyclacel; Epizyme; Lilly Pharmaceuticals; Talon; Pfizer Inc.; Ariad Pharmaceuticals; Onconova; Celgene Corporation; Gilead; Genzyme Corporation; Genentech, Inc.; Infinity; Morphosys; CSL-Behring; NCI; MedPace; OSU; Prime Oncology FX Camille N. Abboud, MD Eli Lilly and Company; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; and Teva; Jessica K. Altman, MD ARIAD Pharmaceuticals, Inc.; Boehringer Ingelheim GmbH; Bristol-Myers Squibb Company; Millennium Pharmaceuticals, Inc.; Agios; Ambit; Astellas; Cyclacel; Epizyme; Lilly Pharmaceuticals; Talon; and Pfizer Inc.; Ellin Berman, MD ARIAD Pharmaceuticals, Inc.; Novartis Pharmaceuticals Corporation; and Ariad Pharmaceuticals; Peter Curtin, MD Onconova; Michael Deininger, MD, PhD ARIAD Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; Celgene Corporation; Novartis Pharmaceuticals Corporation; and Gilead; Steven Devine, MD Genzyme Corporation; Joseph O. Moore, MD ARIAD Pharmaceuticals, Inc.; Genentech, Inc.; and Novartis Pharmaceuticals Corporation; Susan O'Brien, MD Ariad; Infinity; and Morphosys; Jerald P. Radich, MD Novartis Pharmaceuticals Corporation; Neil P. Shah, MD, PhD ARIAD Pharmaceuticals, Inc.; and Bristol-Myers Squibb Company; B. Douglas Smith, MD Bristol-Myers Squibb Company; Merck & Co., Inc.; CSL-Behring; and Pfizer Inc.; David S. Snyder, MD Bristol-Myers Squibb Company; and Novartis Pharmaceuticals Corporation; Meir Wetzler, MD Bristol-Myers Squibb Company; NCI; Cyclacel; MedPace; OSU; and Prime Oncology NR 158 TC 16 Z9 17 U1 1 U2 7 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD NOV PY 2014 VL 12 IS 11 BP 1590 EP 1609 PG 20 WC Oncology SC Oncology GA AS8RP UT WOS:000344516200013 PM 25361806 ER PT J AU Venook, AP Arcila, ME Benson, AB Berry, DA Camidge, DR Carlson, RW Choueiri, TK Guild, V Kalemkerian, GP Kurzrock, R Lovly, CM McKee, AE Morgan, RJ Olszanski, AJ Redman, MW Stearns, V McClure, J Birkeland, ML AF Venook, Alan P. Arcila, Maria E. Benson, Al B., III Berry, Donald A. Camidge, David Ross Carlson, Robert W. Choueiri, Toni K. Guild, Valerie Kalemkerian, Gregory P. Kurzrock, Razelle Lovly, Christine M. McKee, Amy E. Morgan, Robert J. Olszanski, Anthony J. Redman, Mary W. Stearns, Vered McClure, Joan Birkeland, Marian L. TI NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article ID CELL LUNG-CANCER; HER2-POSITIVE BREAST-CANCER; FACTOR RECEPTOR MUTATIONS; DOSE-ESCALATION TRIAL; PHASE-II TRIAL; C-KIT PROTEIN; COLORECTAL-CANCER; OVARIAN-CANCER; MONOCLONAL-ANTIBODY; SOLID TUMORS AB Defining treatment-susceptible or -resistant populations of patients with cancer through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies, because potential patient populations are divided into ever smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists, and information developers. C1 [Venook, Alan P.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Arcila, Maria E.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Benson, Al B., III] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Berry, Donald A.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Camidge, David Ross] Univ Colorado, Ctr Canc, Boulder, CO 80309 USA. [Carlson, Robert W.] Stanford Canc Inst, Fox Chase Canc Ctr, Natl Comprehens Canc Network, Stanford, CA USA. [Choueiri, Toni K.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Guild, Valerie] Aim Melanoma Fdn, Richmond, CA USA. [Kalemkerian, Gregory P.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Kurzrock, Razelle] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Lovly, Christine M.] Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Morgan, Robert J.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Olszanski, Anthony J.] Fox Chase Canc Ctr, Philadelphia, PA USA. [Redman, Mary W.] Fred Hutchinson Canc Res Center, Seattle Canc Care Alliance, Seattle, WA USA. [Stearns, Vered] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Sidney, BC, Canada. RP Venook, AP (reprint author), Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. FU Boehringer Ingelheim Pharmaceuticals, Inc.; Celgene Corporation; Dendreon; Helsinn; Novartis Oncology; Xcenda, an AmerisourceBergen Consulting Services company; Astellas Pharma US, Inc.; Biodesix; Gilead Sciences, Inc.; Incyte Corporation; Janssen; Medivation Inc.; Millennium: The Takeda Oncology Company; TEVA Oncology; Onyx Pharmaceuticals, Inc.; Abbott Molecular and ImmunoGen, Inc. FX This NCCN Working Group Report was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc.; Celgene Corporation; Dendreon; Helsinn; Novartis Oncology; and Xcenda, an AmerisourceBergen Consulting Services company. It was also supported by Astellas Pharma US, Inc.; Biodesix; Gilead Sciences, Inc.; Incyte Corporation; Janssen; Medivation Inc.; Millennium: The Takeda Oncology Company; TEVA Oncology; and Onyx Pharmaceuticals, Inc., an Amgen subsidiary; by grants from Abbott Molecular and ImmunoGen, Inc.; and by an educational donation provided by Amgen. NR 118 TC 5 Z9 5 U1 1 U2 6 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD NOV PY 2014 VL 12 IS 11 BP 1629 EP 1649 PG 21 WC Oncology SC Oncology GA AS8RP UT WOS:000344516200015 PM 25361808 ER PT J AU Ahmed, M Solbiati, L Brace, CL Breen, DJ Callstrom, MR Charboneau, JW Chen, MH Choi, BI de Baere, T Dodd, GD Gervais, DA Gianfelice, D Gillams, AR Lee, FT Leen, E Lencioni, R Littrup, PJ Livraghi, T Lu, DS McGahan, JP Meloni, MF Nikolic, B Pereira, PL Liang, P Rhim, H Rose, SC Salem, R Sofocleous, CT Solomon, SB Soulen, MC Tanaka, M Vogl, TJ Wood, BJ Goldberg, SN AF Ahmed, Muneeb Solbiati, Luigi Brace, Christopher L. Breen, David J. Callstrom, Matthew R. Charboneau, J. William Chen, Min-Hua Choi, Byung Ihn de Baere, Thierry Dodd, Gerald D., III Gervais, Debra A. Gianfelice, David Gillams, Alice R. Lee, Fred T., Jr. Leen, Edward Lencioni, Riccardo Littrup, Peter J. Livraghi, Tito Lu, David S. McGahan, John P. Meloni, Maria Franca Nikolic, Boris Pereira, Philippe L. Liang, Ping Rhim, Hyunchul Rose, Steven C. Salem, Riad Sofocleous, Constantinos T. Solomon, Stephen B. Soulen, Michael C. Tanaka, Masatoshi Vogl, Thomas J. Wood, Bradford J. Goldberg, S. Nahum CA Int Working Grp Image-Guided Tumor TI Image-Guided Tumor Ablation: Standardization of Terminology and Reporting Criteria-A 10-Year Update SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID PERCUTANEOUS RADIOFREQUENCY ABLATION; RENAL-CELL CARCINOMA; VIVO PORCINE LIVER; TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION; IRREVERSIBLE ELECTROPORATION ABLATION; CONTRAST-ENHANCED ULTRASOUND; INTERNALLY COOLED ELECTRODES; LONG-TERM SURVIVAL; QUALITY-OF-LIFE; HEPATOCELLULAR-CARCINOMA AB Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes. C1 [Ahmed, Muneeb] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Solbiati, Luigi] Osped Generale, Dept Radiol, Busto Arsizio, Italy. [Brace, Christopher L.] Univ Wisconsin, Dept Radiol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Brace, Christopher L.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Biomed Engn, Madison, WI USA. [Brace, Christopher L.] Univ Wisconsin, Dept Med Phys, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Breen, David J.] Southampton Univ Hosp, Dept Radiol, Southampton, Hants, England. [Callstrom, Matthew R.; Charboneau, J. William] Mayo Clin, Dept Radiol, Rochester, MN USA. [Chen, Min-Hua] Peking Univ, Sch Oncol, Dept Ultrasound, Beijing 100871, Peoples R China. [Choi, Byung Ihn] Seoul Natl Univ Hosp, Dept Radiol, Seoul 110744, South Korea. [de Baere, Thierry] Inst Cancerol Gustave Roussy, Dept Imaging, Villejuif, France. [Dodd, Gerald D., III] Univ Colorado Anschutz Med Campus, Sch Med, Dept Radiol, Aurora, CO USA. Rhode Isl Hosp, Dept Diagnost Fladiol, Providence, RI USA. [Gervais, Debra A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Gianfelice, David] Univ Hlth Network, Laval, PQ, Canada. [Gillams, Alice R.] London Clin, Dept Imaging, London, England. [Lee, Fred T., Jr.] Univ Wisconsin Hosp & Clin, Dept Radiol, Madison, WI 53792 USA. [Leen, Edward] Royal Infirm, Dept Radiol, Glasgow G31 2ER, Lanark, Scotland. [Lencioni, Riccardo] Univ Pisa, Pisa Univ Hosp, Cisanello Hosp, Dept Diagnost Imaging & Intervent, Pisa, Italy. [Lencioni, Riccardo] Univ Pisa, Sch Med, I-56100 Pisa, Italy. [Littrup, Peter J.] Wayne State Univ, Karmonos Canc Inst, Dept Radiol, Detroit, MI USA. [Lu, David S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol, Los Angeles, CA 90095 USA. [McGahan, John P.] Univ Calif Davis, Med Ctr, Ctr Ambulatory Care, Dept Radiol, Sacramento, CA 95817 USA. [Meloni, Maria Franca] Osped Valduce, Dept Radiol, Como, Italy. [Nikolic, Boris] Albert Einstein Med Ctr, Dept Radiol, Philadelphia, PA 19141 USA. [Pereira, Philippe L.] Heidelberg Univ, Acad Hosp, Clin Radiol Minimally Invas Therapies & Nucl Med, Heilbronn, Germany. [Liang, Ping] Chinese Peoples Liberat Army Gen Hosp, Dept Intervent Ultrasound, Beijing, Peoples R China. [Rhim, Hyunchul] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Diagnost Radiol, Seoul, South Korea. [Rose, Steven C.] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. [Salem, Riad] Northwestern Univ, Dept Radiol, Chicago, IL USA. [Sofocleous, Constantinos T.; Solomon, Stephen B.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Soulen, Michael C.] Hosp Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Tanaka, Masatoshi] Yokokura Hosp, Dept Hepatol, Miyama, Japan. [Vogl, Thomas J.] Goethe Univ Frankfurt, Univ Hosp Frankfurt, Inst Diagnost & Intervent Radiol, D-60054 Frankfurt, Germany. [Wood, Bradford J.] NIH, Bethesda, MD 20892 USA. [Goldberg, S. Nahum] Hadassah Hebrew Univ, Med Ctr, Dept Radiol ImageGuided Therapy, Jerusalem, Israel. [Goldberg, S. Nahum] Hadassah Hebrew Univ, Med Ctr, Intervent Oncol Unit, Jerusalem, Israel. RP Ahmed, M (reprint author), Beth Israel Deaconess Med Ctr, Dept Radiol, 1 Deaconess Rd,WCC-308B, Boston, MA 02215 USA. EM mahmed@bidmc.harvard.edu OI Dupuy, Damian/0000-0003-0524-5982 FU NeuWave Medical; University of Wisconsin; Galil Medical; Siemens Medical; GE Medical; Thermedical; Samsung Electronics; Terumo; HS-Medical; Boston-Scientific; BSD Medical; Covidien; Covidien/Valleylab; Endocare; Ethicon Endo-Surgery; Philips; Celon Olympus; Siemens Medical Solutions; GE Healthcare; AngioDyamics; Guerbet LLC; BTG; Merit Medical; Sirtex; Cooperative Research and Development Agreement (CRADA) Philips Healthcare; CRADA Biocompatibles BTG; CRADA Perfint; CRADA Celsion; CRADA Invivo; AngioDynamics; Cosman Medical FX M.A. No relevant conflicts of interest to disclose. L.S. No relevant conflicts of interest to disclose. C.L.B. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: received consultancy fees from NeuWave Medical, author and institution received payment for patents (planned, pending, or issued) from University of Wisconsin and NeuWave Medical, received payment for stock/stock options from NeuWave Medical Other relationships: none to disclose. D.J.B. Financial activities related to the present article: paid for occasional proctoring by Galli Medical. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. M.R.C. Financial activities related to the present article: none to disclose. Financial activities not related to the present article. received grants from Galil Medical, Siemens Medical, GE Medical, Thermedical. Other relationships: none to disclose. J.W.C. No relevant conflicts of interest to disclose. M.H.C. No relevant conflicts of interest to disclose. B.I.C. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: institution received a research grant from Samsung Electronics. Other relationships: none to disclose. T.d.B. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: received personal fees from Terumo, a grant from HS-Medical, and payment for travel to a meeting from Boston-Scientific. Other relationships: none to disclose. G.D.D. No relevant conflicts of interest to disclose. D.E.D. Financial activities related to the present article. none to disclose. Financial activities not related to the present article: paid for board membership by BSD Medical, received consultancy fees from BSD Medical and Covidien, received grants or has grants pending from NeuWave Medical, received payment for lectures including service on speakers bureaus from BSD Medical, was paid royalties by Springer Verlag and UpToDate, received stock or stock options from BSD Medical. Other relationships: none to disclose. D.A.G. Financial activities related to the present article: none to disclose. Financial activities not related to the present article. received a research grant from Covidien/Valleylab. Other relationships: none to disclose. D.G. No relevant conflicts of interest to disclose. A.R.G. Financial activities related to the present article: received consulting fee or honorarium from Covidien, received fees for participatient in review activities such as data monitoring boards, statistical analysis, end point committees, and the like from Covidien Financial activities not related to the present article: was paid for board membership, consultancy, and lectures including service on speakers bureaus by Covidien Other relationships: none to disclose. F.T.L. Financial activities related to the present article: received payment from NeuWave Medical. Financial activities not related to the present article: received royalties from Covidien, is a stockholder and on the Board of Directors for NeuWave Medical, has a patent on the Switching Controller with royalties paid from Covidien, has multiple patents on heat-based thermal therapies for microwave ablation systems licensed to NeuWave Medical. Other relationships: none to disclose. E.L. No relevant conflicts of interest to disclose. R.L. No relevant conflicts of interest to disclose. P.J.L.; No relevant conflicts of interest to disclose T.L. No relevant conflicts of interest to disclose. D.S.L. Financial activities related to the present article. none to disclose. Financial activities not related to the present article: institution received grants or has grants pending from Endocare and Ethicon Endo-Surgery, received payment for lectures including service on speakers bureaus from Philips. Other relationships: none to disclose. J.P.M. No relevant conflicts of interest to disclose. M.F.M. No relevant conflicts of interest to disclose. B.N. No relevant conflicts of interest to disclose. P.L.P. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: received a grant from Celon Olympus; fees for conferences from Siemens Medical Solutions; consultant's honoraries from Terumo Europe, Terumo Germany, and Microsulis; materials from AngioDynamics. Other relationships: none to disclose. P.L. No relevant conflicts of interest to disclose. H.R. No relevant conflicts of interest to disclose. S.C.R. No relevant conflicts of interest to disclose. R.S. No relevant conflicts of interest to disclose. C.T.S. No relevant conflicts of interest to disclose. S.B.S. Financial activities related to the present article: institution received a grant from GE Healthcare, author received consulting fee or honorarium from AngioDyamics, Covidien, and GE Healthcare. Financial activities not related to the present article: none to disclose. Other relationships: none to disclose. M.C.S. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: author received consultancy fees from Guerbet LLC, BTG, Merit Medical; institution received grants or has grants pending from Guerbet LLC and BTG; author received payment for lectures including service on speakers bureaus from Sirtex; author received royalties from Cambridge University Press. Other relationships: none to disclose. M.T. No relevant conflicts of interest to disclose. T.J.V. No relevant conflicts of interest to disclose. B.J.W. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: institution received grants or has grants pending from Cooperative Research and Development Agreement (CRADA) Philips Healthcare, CRADA Biocompatibles BTG, CRADA Perfint, CRADA Celsion, CRADA Invivo; the National Institutes of Health has intellectual property in the field. Other relationships: none to disclose. S.N.G. Financial activities related to the present article. institution received a grant for sponsored research from AngioDynamics; author received consulting fee or honorarium from AngioDynamics. Financial activities not related to the present article: author received consultancy fees from Cosman Medical and institution received grants or has grants pending from Cosman Medical. Other relationships: none to disclose. NR 99 TC 58 Z9 58 U1 5 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 EI 1535-7732 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD NOV PY 2014 VL 25 IS 11 BP 1691 EP 1705 DI 10.1016/j.jvir.2014.08.027 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA AT1UZ UT WOS:000344720500005 PM 25442132 ER PT J AU Conrad, MF Michalczyk, MJ Opalacz, A Patel, VI LaMuraglia, GM Cambria, RP AF Conrad, Mark F. Michalczyk, Michael J. Opalacz, Arissa Patel, Virendra I. LaMuraglia, Glenn M. Cambria, Richard P. TI The natural history of asymptomatic severe carotid artery stenosis SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID JUXTALUMINAL HYPOECHOIC AREA; VASCULAR-SURGERY; INTRAPLAQUE HEMORRHAGE; HEART-ASSOCIATION; ULTRASOUND IMAGES; PLAQUES PREDICTS; ISCHEMIC EVENTS; STROKE RISK; PROGRESSION; ENDARTERECTOMY AB Background: Although level 1 evidence supports carotid endarterectomy (CEA) for stroke prevention in patients with asymptomatic severe carotid artery stenosis (ASCAS; >70%), medical therapy alone has been promulgated by some as equally effective. The goal of this study was to determine the natural history of medically treated patients with ASCAS. Methods: Patients with ASCAS from 2005 to 2006 were identified in a health network database. Patients were included if the initial therapeutic plan involved medical therapy alone (usually because of comorbidities or patient preference). Study end points included: ipsilateral neurologic symptoms (INS) of transient ischemic attack and/or stroke, death, and INS and/or death. Results: There were 126 carotid arteries identified in 115 patients. Using standard duplex velocity criteria, 88 (70%) had severe (70%-89%) and 38 (30%) had very severe stenoses (VSS; 90%-99%). The average age was 73.5 years, demographic characteristics included: 66% hypertension, 64% coronary artery disease, 30% diabetes, 5% chronic kidney disease (CKD), and 86% were taking a statin drug (28% had a low-density lipoprotein level <100 mg/dL). There were 31 patients (24.6%) who developed INS during a mean follow-up of 27 months; most (23 of 31; 74%) occurred within 12 months of the initial duplex ultrasound examination; 14 (45%) were strokes. The 5-year actuarial freedom from INS was 70.1 +/- 5%. Multivariate predictors of INS included: VSS (hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.56-6.76; P = .002), CKD (HR, 6.25; 95% CI, 2.05-19.2; P = . 001), and age (HR, 0.94; 95% CI, 0.91-0.98; P = . 001). There were 41 patients (33%) who underwent eventual carotid revascularization (32 CEA, nine stent); 23 of 41 (56%) were performed for INS and 18 (44%) for plaque progression. Overall 5-year actuarial survival was 69.8% +/- 4.1%. Multivariate predictors of death included: age (HR, 1.06; 95% CI, 1.03-1.1; P = .0001), chronic obstructive pulmonary disease (HR, 1.92; 95% CI, 1.08-3.41; P = . 03), and diabetes (HR, 5.08; 95% CI, 2.86-9.01; P < .0001). The 5-year actuarial freedom from INS and/or death was 54 +/- 4.4%. Multivariate predictors of INS and/or death were: VSS (HR, 1.98; 95% CI, 1.22-3.23; P = .006), CKD (HR, 5.46; 95% CI, 2.12-14.08; P = .0004), and diabetes (HR, 2.6; 95% CI, 1.59-4.24; P = .0001). Statin use was not protective against INS or death in this cohort. Conclusions: Medically managed patients with ASCAS develop INS early, especially in patients with VSS. Medical therapy with aspirin and statins failed to control ASCAS, thus validating the role of CEA in these patients as promulgated in multiple current treatment guidelines. C1 [Conrad, Mark F.] Massachusetts Gen Hosp, Dept Surg, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Conrad, MF (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Vasc & Endovasc Surg, 15 Parkman St,WAC 440, Boston, MA 02114 USA. EM mconrad@partners.org NR 43 TC 14 Z9 14 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD NOV PY 2014 VL 60 IS 5 BP 1218 EP 1225 DI 10.1016/j.jvs.2014.05.047 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA AS8TO UT WOS:000344521100016 PM 25041986 ER PT J AU Quick, ED Leser, JS Clarke, P Tyler, KL AF Quick, Eamon D. Leser, J. Smith Clarke, Penny Tyler, Kenneth L. TI Activation of Intrinsic Immune Responses and Microglial Phagocytosis in an Ex Vivo Spinal Cord Slice Culture Model of West Nile Virus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; CD8(+) T-CELLS; JAPANESE ENCEPHALITIS; IN-VITRO; BRAIN; NEURONS; MINOCYCLINE; INNATE; PATHOGENESIS; REPLICATION AB West Nile virus (WNV) is a neurotropic flavivirus that causes significant neuroinvasive disease involving the brain and/or spinal cord. Experimental mouse models of WNV infection have established the importance of innate and adaptive immune responses in controlling the extent and severity of central nervous system (CNS) disease. However, differentiating between immune responses that are intrinsic to the CNS and those that are dependent on infiltrating inflammatory cells has proven difficult. We used a murine ex vivo spinal cord slice culture (SCSC) model to determine the innate immune processes specific to the CNS during WNV infections. By 7 days after ex vivo infection of SCSCs, the majority of neurons and a substantial percentage of astrocytes were infected with WNV, resulting in apoptotic cell death and astrogliosis. Microglia, the resident immune cells of the CNS, were activated by WNV infection, as exemplified by their amoeboid morphology, the development of filopodia and lamellipodia, and phagocytosis of WNV-infected cells and debris. Microglial cell activation was concomitant with increased expression of pro-inflammatory cytokines and chemokines, including CXCL10, CXCL1, CCL5, CCL3, CCL2, tumor necrosis factor alpha (TNF-alpha), TNF-related apoptosis-inducing ligand (TRAIL), and interleukin-6 (IL-6). The application of minocycline, an inhibitor of neuro-inflammation, altered the WNV-induced proinflammatory cytokine/chemokine expression profile, with inhibited production of CCL5, CCL2, and IL-6. Our findings establish that CNS-resident cells have the capacity to initiate a robust innate immune response against WNV infection in the absence of infiltrating inflammatory cells and systemic immune responses. IMPORTANCE There are no specific treatments of proven efficacy available for WNV neuroinvasive disease. A better understanding of the pathogenesis of WNV CNS infection is crucial for the rational development of novel therapies. Development of a spinal cord slice culture (SCSC) model facilitates the study of WNV pathogenesis and allows investigation of the intrinsic immune responses of the CNS. Our studies demonstrate that robust CNS innate immune responses, including microglial activation and proinflammatory cytokine/chemokine production, develop independently of contributions from the peripheral immune system and CNS-infiltrating inflammatory cells. C1 [Quick, Eamon D.; Tyler, Kenneth L.] Univ Colorado Denver, Neurosci Program, Aurora, CO USA. [Leser, J. Smith; Clarke, Penny; Tyler, Kenneth L.] Univ Colorado Denver, Dept Neurol, Aurora, CO 80045 USA. [Tyler, Kenneth L.] Univ Colorado Denver, Dept Immunol & Microbiol, Aurora, CO USA. [Tyler, Kenneth L.] Univ Colorado Denver, Dept Infect Dis, Aurora, CO USA. [Tyler, Kenneth L.] Univ Colorado Denver, Dept Med, Aurora, CO USA. [Tyler, Kenneth L.] Denver VA Med Ctr, Denver, CO USA. RP Clarke, P (reprint author), Univ Colorado Denver, Dept Neurol, Aurora, CO 80045 USA. EM Penny.Clarke@ucdenver.edu OI Tyler, Kenneth/0000-0003-3294-5888 FU NIH [R01 NS076512, R21/R33 AI101064]; VA merit grant FX The study described in this publication was supported by NIH grants R01 NS076512 (to K.L.T.) and R21/R33 AI101064 (to K.L.T.) and by a VA merit grant (to K.L.T.). K. L. Tyler is also supported by the Reuler-Lewin Family Professorship. NR 72 TC 8 Z9 8 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2014 VL 88 IS 22 BP 13005 EP 13014 DI 10.1128/JVI.01994-14 PG 10 WC Virology SC Virology GA AT3CG UT WOS:000344812500007 PM 25165111 ER PT J AU Cohen, K Altfeld, M Alter, G Stamatatos, L AF Cohen, Kristen Altfeld, Marcus Alter, Galit Stamatatos, Leonidas TI Early Preservation of CXCR5(+) PD-1(+) Helper T Cells and B Cell Activation Predict the Breadth of Neutralizing Antibody Responses in Chronic HIV-1 Infection SO JOURNAL OF VIROLOGY LA English DT Article ID SIMIAN/HUMAN IMMUNODEFICIENCY VIRUS; CXC CHEMOKINE RECEPTOR-5; FOLLICULAR HELPER; GERMINAL CENTER; MONOCLONAL-ANTIBODIES; IN-VITRO; IMMUNE-RESPONSES; PASSIVE TRANSFER; ICOS DEFICIENCY; SHIV CHALLENGE AB Much is known about the characteristics of broadly neutralizing antibodies (bNAbs) generated during HIV-1 infection, but little is known about immunological mechanisms responsible for their development in only a minority of those infected by HIV-1. By monitoring longitudinally a cohort of HIV-1-infected subjects, we observed that the preservation of CXCR5(+) CD4(+) T helper cell frequencies and activation status of B cells during the first year of infection correlates with the maximum breadth of plasma neutralizing antibody responses during chronic infection independently of viral load. Although, during the first year of infection, no differences were observed in the abilities of peripheral CXCR5(+) CD4(+) T helper cells to induce antibody secretion by autologous naive B cells, higher frequencies of class-switched antibodies were detected in cocultures of CXCR5(+) CD4(+) T and B cells from the subjects who later developed broadly neutralizing antibody responses than those who did not. Furthermore, B cells from the former subjects had higher expression of AICDA than B cells from the latter subjects, and transcript levels correlated with the frequency of CXCR5(+) CD4(+) T cells. Thus, the early preservation of CXCR5(+) CD4(+) T cells and B cell function are central to the development of bNAbs. Our study provides a possible explanation for their infrequent generation during HIV-1 infection. IMPORTANCE Broadly neutralizing antibodies are developed by HIV-1-infected subjects, but so far (and despite intensive efforts over the past 3 decades) they have not been elicited by immunization. Understanding how bNAbs are generated during natural HIV-1 infection and why only some HIV-1-infected subjects generate such antibodies will assist our efforts to elicit bNAbs by immunization. CXCR5(+) PD-1(+) CD4(+) T cells are critical for the development of high-affinity antigen-specific antibody responses. In our study, we found that the HIV-1-infected subjects who develop bNAbs have a higher frequency of peripheral CXCR5(+) PD-1(+) CD4(+) T cells in early infection and also that this frequency mirrored what was observed in uninfected subjects and correlated with the level of B cell activation across subjects. Our study highlights the critical role helper T cell function has in the elicitation of broadly neutralizing antibody responses in the context of HIV infection. C1 [Cohen, Kristen; Stamatatos, Leonidas] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Cohen, Kristen; Stamatatos, Leonidas] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Altfeld, Marcus; Alter, Galit] Massachusetts Gen Hosp, MIT & Harvard, MGH, Ragon Inst, Boston, MA 02114 USA. [Altfeld, Marcus] Heinrich Pette Inst, Hamburg, Germany. RP Stamatatos, L (reprint author), Seattle Biomed Res Inst, 4 Nickerson St, Seattle, WA 98109 USA. EM leo.stamatatos@seattlebiomed.org FU NIAID [R01AI081625] FX These studies were supported by NIAID R01AI081625. NR 67 TC 19 Z9 20 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2014 VL 88 IS 22 BP 13310 EP 13321 DI 10.1128/JVI.02186-14 PG 12 WC Virology SC Virology GA AT3CG UT WOS:000344812500032 PM 25210168 ER PT J AU Landes, SD Ardelt, M Vaillant, GE Waldinger, RJ AF Landes, Scott D. Ardelt, Monika Vaillant, George E. Waldinger, Robert J. TI Childhood Adversity, Midlife Generativity, and Later Life Well-Being SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article DE Adjustment to aging; Adversarial childhood; Generativity; Later life health; Longitudinal study ID STRESS-RELATED GROWTH; CUMULATIVE ADVANTAGE; POSTTRAUMATIC GROWTH; EMPIRICAL-EVIDENCE; HUMAN RESILIENCE; ADULT HEALTH; TRAUMA; DISADVANTAGE; PERSPECTIVES; PERSONALITY AB Objectives. Prior studies confirm that after experiencing childhood adversity, resilient adults can recover and engage in generative growth. This study explored the long-term effects of childhood adversity (assessed as harsh parenting and/or childhood poverty) on successful aging for individuals who either achieved or failed to achieve Erikson's psychosocial developmental stage of generativity in midlife. Method. The study utilized a sample of 636 men from the Harvard Sample and Inner City Cohort of the 73-year longitudinal Study of Adult Development. Nested ordinary least squares regression models were used to test the mediating and moderating effects of midlife generativity on later life health and adjustment to aging. Results. Men who experienced childhood adversity were less likely than men with no childhood adversity to achieve generativity in midlife. Although achievement of generativity was associated with better later life health and adjustment to aging, it neither mediated nor moderated the negative relation between childhood poverty and later life health outcomes. However, for men who experienced an adversarial childhood, achievement of generativity mediated and moderated adjustment to aging. Discussion. Results suggest that psychosocial growth in adulthood can compensate for the long-term negative effects of an adversarial childhood on adjustment to aging, but not for later life health. C1 [Landes, Scott D.] Univ N Florida, Dept Sociol Anthropol & Social Work, Jacksonville, FL 32224 USA. [Ardelt, Monika] Univ Florida, Dept Sociol & Criminol & Law, Gainesville, FL USA. [Vaillant, George E.; Waldinger, Robert J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Vaillant, George E.; Waldinger, Robert J.] Harvard Univ, Sch Med, Boston, MA USA. RP Landes, SD (reprint author), Univ N Florida, Dept Sociol Anthropol & Social Work, 1 UNF Dr, Jacksonville, FL 32224 USA. EM scott.landes@unf.edu FU NIA NIH HHS [R01 AG045230] NR 67 TC 4 Z9 5 U1 7 U2 30 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5014 EI 1758-5368 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD NOV PY 2014 VL 69 IS 6 BP 942 EP 952 DI 10.1093/geronb/gbu055 PG 11 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA AT1BE UT WOS:000344667300014 PM 24870028 ER PT J AU Ramalingam, SS Janne, PA Mok, T O'Byrne, K Boyer, MJ Von Pawel, J Pluzanski, A Shtivelband, M Docampo, LI Bennouna, J Zhang, H Liang, JQ Doherty, JP Taylor, I Mather, CB Goldberg, Z O'Connell, J Paz-Ares, L AF Ramalingam, Suresh S. Jaenne, Pasi A. Mok, Tony O'Byrne, Kenneth Boyer, Michael J. Von Pawel, Joachim Pluzanski, Adam Shtivelband, Mikhail Iglesias Docampo, Lara Bennouna, Jaafar Zhang, Hui Liang, Jane Q. Doherty, Jim P. Taylor, Ian Mather, Cecile B. Goldberg, Zelanna O'Connell, Joseph Paz-Ares, Luis TI Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial SO LANCET ONCOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; GEFITINIB; EGFR; INHIBITOR; CHEMOTHERAPY; PF-00299804; MUTATIONS; RESISTANCE AB Background Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study. Methods In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. Findings Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2.6 months (95% CI 1.9-2.8) in both the dacomitinib group and the erlotinib group (stratifi ed hazard ratio [HR] 0.941, 95% CI 0.802-1.104, one-sided log-rank p= 0.229). For patients with wild-type KRAS, median progression-free survival was 2.6 months for dacomitinib (95% CI 1.9-2.9) and erlotinib (95% CI 1.9-3.0; stratifi ed HR 1.022, 95% CI 0.834-1.253, one-sided p=0.587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [<1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib. Interpretation Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations. C1 [Ramalingam, Suresh S.] Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA 30322 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mok, Tony] Chinese Univ Hong Kong, Dept Clin Oncol, State Key Lab South China, Hong Kong Canc Inst, Shatin, Hong Kong, Peoples R China. [O'Byrne, Kenneth] Princess Alexandra Hosp, Woolloongabba, Qld 4102, Australia. [Boyer, Michael J.] Chris OBrien Lifehouse Royal Prince Alfred Hosp, Sydney, NSW, Australia. [Von Pawel, Joachim] Asklepios Fachkliniken, Munich, Germany. [Pluzanski, Adam] Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Pluzanski, Adam] Inst Oncol, Warsaw, Poland. [Shtivelband, Mikhail] Ironwood Canc & Res Ctr, Chandler, AZ USA. [Iglesias Docampo, Lara] Hosp Univ 12 Octubre, Dept Med Oncol, Madrid, Spain. [Bennouna, Jaafar] Inst Cancerol Ouest, Nantes, France. [Zhang, Hui] Pfizer China Res & Dev, Shanghai, Peoples R China. [Liang, Jane Q.; Taylor, Ian; Mather, Cecile B.] Pfizer Oncol, Groton, CT USA. [Doherty, Jim P.; O'Connell, Joseph] Pfizer Oncol, New York, NY USA. [Goldberg, Zelanna] Pfizer Oncol, San Diego, CA USA. [Paz-Ares, Luis] Univ Hosp Virgen del Rocio, Seville, Spain. RP Ramalingam, SS (reprint author), Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA 30322 USA. EM ssramal@emory.edu RI bennouna, jaafar/K-9350-2015; IBIS, NUEVAS TERAPIA/P-3415-2015 FU NCI NIH HHS [U10 CA180864] NR 16 TC 31 Z9 33 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD NOV PY 2014 VL 15 IS 12 BP 1369 EP 1378 DI 10.1016/S1470-2045(14)70452-8 PG 10 WC Oncology SC Oncology GA AS9ER UT WOS:000344546400048 PM 25439691 ER PT J AU Rajkumar, SV Dimopoulos, MA Palumbo, A Blade, J Merlini, G Mateos, MV Kumar, S Hillengass, J Kastritis, E Richardson, P Landgren, O Paiva, B Dispenzieri, A Weiss, B Leleu, X Zweegman, S Lonial, S Rosinol, L Zamagni, E Jagannath, S Sezer, O Kristinsson, SY Caers, J Usmani, SZ Lahuerta, JJ Johnsen, HE Beksac, M Cavo, M Goldschmidt, H Terpos, E Kyle, RA Anderson, KC Durie, BGM San Miguel, JF AF Rajkumar, S. Vincent Dimopoulos, Meletios A. Palumbo, Antonio Blade, Joan Merlini, Giampaolo Mateos, Maria-Victoria Kumar, Shaji Hillengass, Jens Kastritis, Efstathios Richardson, Paul Landgren, Ola Paiva, Bruno Dispenzieri, Angela Weiss, Brendan Leleu, Xavier Zweegman, Sonja Lonial, Sagar Rosinol, Laura Zamagni, Elena Jagannath, Sundar Sezer, Orhan Kristinsson, Sigurdur Y. Caers, Jo Usmani, Saad Z. Lahuerta, Juan Jose Johnsen, Hans Erik Beksac, Meral Cavo, Michele Goldschmidt, Hartmut Terpos, Evangelos Kyle, Robert A. Anderson, Kenneth C. Durie, Brian G. M. San Miguel, Jesus F. TI International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma SO LANCET ONCOLOGY LA English DT Review ID LIGHT-CHAIN RATIO; MULTIPARAMETER FLOW-CYTOMETRY; MARROW PLASMA-CELLS; LENALIDOMIDE PLUS DEXAMETHASONE; UNDETERMINED SIGNIFICANCE MGUS; POSITRON-EMISSION-TOMOGRAPHY; EARLY TREATMENT STRATEGIES; INDEPENDENT RISK-FACTOR; MONOCLONAL GAMMOPATHY; IMAGING TECHNIQUES AB This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any differences in outcome that might occur as a result of the new disease definition. C1 [Rajkumar, S. Vincent; Kumar, Shaji; Dispenzieri, Angela; Kyle, Robert A.] Mayo Clin, Div Hematol, Rochester, MN 55905 USA. [Dimopoulos, Meletios A.; Kastritis, Efstathios; Terpos, Evangelos] Univ Athens, Sch Med, Dept Clin Therapeut, GR-11527 Athens, Greece. [Palumbo, Antonio] Univ Turin, Azienda Osped Univ Citta Salute & Sci Torino, Div Hematol, Myeloma Unit, Turin, Italy. [Blade, Joan; Rosinol, Laura] Hosp Clin Barcelona, Barcelona, Spain. [Merlini, Giampaolo] Univ Hosp Policlin San Matteo, Amyloidosis Ctr, Pavia, Italy. [Mateos, Maria-Victoria] Univ Hosp Salamanca, IBSAL, Salamanca, Spain. [Hillengass, Jens; Goldschmidt, Hartmut] Heidelberg Univ, Dept Hematol Oncol & Rheumatol, Heidelberg, Germany. [Richardson, Paul; Anderson, Kenneth C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Landgren, Ola] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Paiva, Bruno; San Miguel, Jesus F.] Univ Navarra Clin, Ctr Invest Med Aplicada, Pamplona, Spain. [Weiss, Brendan] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Leleu, Xavier] Univ Hosp Lille, Lille, France. [Zweegman, Sonja] Vrije Univ Amsterdam Med Ctr, Dept Hematol, Amsterdam, Netherlands. [Lonial, Sagar] Emory Univ, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Zamagni, Elena; Cavo, Michele] Univ Bologna, Seragnoli Inst Hematol, Sch Med, Bologna, Italy. [Jagannath, Sundar] Mt Sinai Canc Inst, New York, NY USA. [Sezer, Orhan] Mem Hosp, Istanbul, Turkey. [Kristinsson, Sigurdur Y.] Karolinska Univ Hosp, Karolinska Inst, Stockholm, Sweden. [Caers, Jo] CHU Liege, Dept Hematol, Liege, Belgium. [Usmani, Saad Z.] Carolinas HealthCare Syst, Levine Canc Inst, Charlotte, NC USA. [Lahuerta, Juan Jose] Hosp Univ 12 Octubre, Serv Hematol, Madrid, Spain. [Johnsen, Hans Erik] Aalborg Univ Hosp, Dept Haematol, Aalborg, Denmark. [Beksac, Meral] Ankara Univ, Sch Med, TR-06100 Ankara, Turkey. [Durie, Brian G. M.] Cedars Sinai Comprehens Canc Ctr, Los Angeles, CA USA. RP Rajkumar, SV (reprint author), Mayo Clin, Div Hematol, 200 First St SW, Rochester, MN 55905 USA. EM rajkumar.vincent@mayo.edu RI Kumar, Shaji/A-9853-2008; Merlini, Giampaolo/A-3817-2008; Kristinsson, Sigurdur /M-2910-2015; OI Kumar, Shaji/0000-0001-5392-9284; Merlini, Giampaolo/0000-0001-7680-3254; Kristinsson, Sigurdur /0000-0002-4964-7476; CAVO, MICHELE/0000-0003-4514-3227; Dispenzieri, Angela/0000-0001-8780-9512 FU Celgene; Ortho Biotech; Onyx; Amgen; Bristol-Myers Squibb; Genmab A/S; Janssen-Cilag; Millennium Pharmaceuticals; Onyx Pharmaceuticals; Sanofi Aventis; Array BioPharma; Janssen; Millennium Takeda; Millennium; Novartis; Cephalon/Teva; Abbvie; Pfizer; Jannsen; Research and Development; Sanofi; Jansen-Cilag FX MAD reports personal fees from Celgene, Ortho Biotech, and Onyx. AP reports personal fees from Amgen, Bristol-Myers Squibb, Genmab A/S, Janssen-Cilag, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Celgene, Sanofi Aventis, and Array BioPharma. JB reports personal fees from Celgene and Janssen. GM reports personal fees from Millennium Takeda. SK reports grants from Celgene, Millennium, Novartis, Cephalon/Teva, Abbvie, and Onyx. PR has been a member of advisory committees for Millennium, Celgene, Johnson & Johnson, and Novartis. BP has received honoraria from Millennium, Celgene, Janssen, and The Binding Site Group Ltd. AD reports grants from Celgene, Millennium, Pfizer, and Jannsen. BW reports grants and personal fees from Janssen Research and Development, personal fees from Celgene and Onyx, and grants from Millennium. SZ reports grants from Celgene, Janssen, and Millennium. SL reports personal fees from Millennium, Celgene, Novartis, Onyx, Sanofi, Janssen, and Bristol-Myers Squibb. LR has received honoraria from Janssen and Celgene. EZ reports grants from Jansen-Cilag and Celgene. SJ has been a consultant for Celgene, Sanofi, and Bristol-Myers Squibb. OS reports personal fees from Celgene and Janssen. MB is in the speakers bureau for Celgene, Janssen-Cilag and Amgen, and serves on advisory boards for Janssen-Cilag, Bristol-Myers Squibb, and Novartis. MC reports personal fees from Janssen, Celgene, Millennium, Onyx, and Bristol-Myers Squibb. KCA reports personal fees from Celgene, Millennium, Gilead, Sanofi Aventis, and Onyx. All other authors declare no competing interests. NR 100 TC 264 Z9 284 U1 20 U2 59 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD NOV PY 2014 VL 15 IS 12 BP E538 EP E548 PG 11 WC Oncology SC Oncology GA AS9ER UT WOS:000344546400022 PM 25439696 ER PT J AU Chong, CR Wirth, LJ Nishino, M Chen, AB Sholl, LM Kulke, MH McNamee, CJ Janne, PA Johnson, BE AF Chong, Curtis R. Wirth, Lori J. Nishino, Mizuki Chen, Aileen B. Sholl, Lynette M. Kulke, Matthew H. McNamee, Ciaran J. Jaenne, Pasi A. Johnson, Bruce E. TI Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors SO LUNG CANCER LA English DT Article DE Typical carcinoid; Atypical carcinoid; DIPNECH ID CELL LUNG-CANCER; NEUROENDOCRINE TUMORS; BRONCHIAL CARCINOIDS; OCTREOTIDE; CISPLATIN; RADIANT-2; SURVIVAL; PHASE-3 AB Objectives: The optimal management of locally advanced and metastatic pulmonary carcinoid tumors remains to be determined. Materials and methods: A retrospective review was conducted on patients with typical and atypical pulmonary carcinoid tumors treated at our institutions between 1990 and 2012. Results: 300 patients were identified with pulmonary carcinoid, (80 patients with atypical carcinoid), of whom 29 presented with metastatic disease (16 atypical). Of evaluable patients, 26 (41%) with stages I-III atypical carcinoid tumors recurred at a median time of 3.7 years (range, 0.4-32), compared to 3 (1%) patients with typical carcinoid (range, 8-12.3). 39 patients were treated with chemotherapy, including 30 patients with metastatic disease (27 atypical), and 7 patients were treated with adjuvant platinum etoposide chemoradiation (6 atypical, 1 typical, 6 stage IIIA, 1 stage JIB). At a median follow-up of 2 years there were 2 recurrences in the 7 patients receiving adjuvant treatment. Median survival after diagnosis of metastatic disease for patients with atypical pulmonary carcinoid was 3.3 years with a 5-year survival of 24%. Treatment regimens showing efficacy in pulmonary carcinoid include 15 patients treated with octreotide-based therapies (10% response rate (RR), 70% disease control rate (DCR), 15 month median progression-free survival (PFS)), 13 patients treated with etoposide + platinum (23% RR, 69% DCR, 7 month median PFS), and 14 patients treated with temozolomide-based therapies (14% RR, 57% DCR, 10 month median PFS). 8 of 10 patients with octreotide-avid disease treated with an octreotide-based regimen experienced disease control (1 partial response, 7 stable disease) for a median of 18 months (range 6-72 months). Conclusions: These results support our previous finding that a subset of pulmonary carcinoid tumors are responsive to chemotherapy. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Chong, Curtis R.; Jaenne, Pasi A.; Johnson, Bruce E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Wirth, Lori J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Nishino, Mizuki] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02215 USA. [Nishino, Mizuki; Chen, Aileen B.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Chen, Aileen B.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02215 USA. [Sholl, Lynette M.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. [Kulke, Matthew H.] Dana Farber Canc Inst, Ctr Gastrointestinal Oncol, Boston, MA 02215 USA. [McNamee, Ciaran J.] Brigham & Womens Hosp, Div Thorac Surg, Boston, MA 02215 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM Bruce_Johnson@dfci.harvard.edu FU Conquer Cancer Foundation of ASCO Young Investigator Award; American Cancer Society [PF-14-020-01-CDD]; Uniting Against Lung Cancer; National Cancer Institute [1K23CA157631] FX This work was funded by a Conquer Cancer Foundation of ASCO Young Investigator Award, a postdoctoral fellowship, PF-14-020-01-CDD from the American Cancer Society, and a grant from Uniting Against Lung Cancer to C.R.C. Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the American Society of Clinical Oncology or the Conquer Cancer Foundation. M.N. was supported by 1K23CA157631 (National Cancer Institute). The authors express appreciation for a gift supporting the study to the Dana-Farber Cancer Institute from the Gallup Foundation. NR 34 TC 14 Z9 14 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD NOV PY 2014 VL 86 IS 2 BP 241 EP 246 DI 10.1016/j.lungcan.2014.08.012 PG 6 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AS7LU UT WOS:000344438400023 PM 25218177 ER PT J AU Zhao, N Wilkerson, MD Shah, U Yin, XY Wang, AY Hayward, MC Roberts, P Lee, CB Parsons, AM Thorne, LB Haithcock, BE Grilley-Olson, JE Stinchcombe, TE Funkhouser, WK Wong, KK Sharpless, NE Hayes, DN AF Zhao, Ni Wilkerson, Matthew D. Shah, Usman Yin, Xiaoying Wang, Anyou Hayward, Michele C. Roberts, Patrick Lee, Carrie B. Parsons, Alden M. Thorne, Leigh B. Haithcock, Benjamin E. Grilley-Olson, Juneko E. Stinchcombe, Thomas E. Funkhouser, William K. Wong, Kwok-Kin Sharpless, Norman E. Hayes, D. Neil TI Alterations of LKB1 and KRAS and risk of brain metastasis: Comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma SO LUNG CANCER LA English DT Article DE NSCLC; Brain Metastasis; Prognostic model; LKB1; KRAS ID PROPHYLACTIC CRANIAL IRRADIATION; FOLLOW-UP; SOMATIC MUTATIONS; LKB1/STK11 GENE; BREAST-CANCER; INACTIVATION; ADENOCARCINOMA; TRIALS AB Background: Brain metastases are one of the most malignant complications of lung cancer and constitute a significant cause of cancer related morbidity and mortality worldwide. Recent years of investigation suggested a role of LKB1 in NSCLC development and progression, in synergy with KRAS alteration. In this study, we systematically analyzed how LKB1 and KRAS alteration, measured by mutation, gene expression (GE) and copy number (CN), are associated with brain metastasis in NSCLC. Materials and methods: Patients treated at University of North Carolina Hospital from 1990 to 2009 with NSCLC provided frozen, surgically extracted tumors for analysis. GE was measured using Agilent 44,000 custom-designed arrays, CN was assessed by Affymetrix GeneChip Human Mapping 250K Sty Array or the Genome-Wide Human SNP Array 6.0 and gene mutation was detected using ABI sequencing. Integrated analysis was conducted to assess the relationship between these genetic markers and brain metastasis. A model was proposed for brain metastasis prediction using these genetic measurements. Results: 17 of the 174 patients developed brain metastasis. LKB1 wild type tumors had significantly higher LKB1 CN (p < 0.001) and GE (p = 0.002) than the LKB1 mutant group. KRAS wild type tumors had significantly lower KR/IS GE (p<0.001) and lower CN, although the latter failed to be significant (p = 0.295). Lower LKB1 CN (p = 0.039) and KRAS mutation (p = 0.007) were significantly associated with more brain metastasis. The predictive model based on nodal (N) stage, patient age, LKB1 CN and KRAS mutation had a good prediction accuracy, with area under the ROC curve of 0.832 (p < 0.001). Conclusion: LKB1 CN in combination with KRAS mutation predicted brain metastasis in NSCLC. (C) 2014 The Authors. Published by Elsevier Ireland Ltd. C1 [Zhao, Ni; Yin, Xiaoying; Wang, Anyou; Hayward, Michele C.; Roberts, Patrick; Lee, Carrie B.; Thorne, Leigh B.; Grilley-Olson, Juneko E.; Stinchcombe, Thomas E.; Funkhouser, William K.; Sharpless, Norman E.; Hayes, D. Neil] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Zhao, Ni] Univ N Carolina, Gilling Sch Global Publ Hlth, Dept Biostat, Chapel Hill, NC 27599 USA. [Shah, Usman] Lehigh Valley Hlth Network, Div Hematol Oncol, Dept Med, Allentown, PA USA. [Lee, Carrie B.; Grilley-Olson, Juneko E.; Stinchcombe, Thomas E.; Sharpless, Norman E.; Hayes, D. Neil] Univ N Carolina, Multidisciplinary Thorac Oncol Program, Div Hematol Oncol, Dept Internal Med, Chapel Hill, NC 27599 USA. [Parsons, Alden M.; Haithcock, Benjamin E.] Univ N Carolina, Div Cardiothorac Surg, Dept Surg, Chapel Hill, NC 27599 USA. [Thorne, Leigh B.; Funkhouser, William K.] Univ N Carolina, UNC Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Wong, Kwok-Kin] Harvard Univ, Sch Med, Dept Med, Dana Farber Canc Inst, Cambridge, MA 02138 USA. [Sharpless, Norman E.] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27599 USA. [Wilkerson, Matthew D.] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27599 USA. RP Hayes, DN (reprint author), Univ N Carolina, Sch Med, UNC Lineberger Comprehens Canc Ctr, CB 7295,450 West Dr, Chapel Hill, NC 27599 USA. EM hayes@med.unc.edu RI Zhao, Ni/P-9086-2014; OI Zhao, Ni/0000-0002-7762-3949; Wang, Anyou/0000-0002-4981-3606 FU Thomas G. Labreque Foundation, through Joan's Legacy Foundation; Clinical/Translational Award from the UNC Lineberger Comprehensive Cancer Center FX This study was supported by the Thomas G. Labreque Foundation, through Joan's Legacy Foundation and by a Clinical/Translational Award from the UNC Lineberger Comprehensive Cancer Center. NR 35 TC 10 Z9 10 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 EI 1872-8332 J9 LUNG CANCER JI Lung Cancer PD NOV PY 2014 VL 86 IS 2 BP 255 EP 261 DI 10.1016/j.lungcan.2014.08.013 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AS7LU UT WOS:000344438400025 PM 25224251 ER PT J AU Kaneko-Tarui, T Commandeur, AE Patterson, AL DeKuiper, JL Petillo, D Styer, AK Teixeira, JM AF Kaneko-Tarui, Tomoko Commandeur, Arno E. Patterson, Amanda L. DeKuiper, Justin L. Petillo, David Styer, Aaron K. Teixeira, Jose M. TI Hyperplasia and fibrosis in mice with conditional loss of the TSC2 tumor suppressor in Mullerian duct mesenchyme-derived myometria SO MOLECULAR HUMAN REPRODUCTION LA English DT Article DE uterine fibroid; mTOR; tumourigenesis; infertility; TSC2 ID TUBEROUS SCLEROSIS; UTERINE LEIOMYOMA; PROGESTERONE-RECEPTOR; ENDOMETRIAL CANCER; BETA-CATENIN; FIBROIDS; DELETION; GENE; PREGNANCY; PATHWAY AB Uterine leiomyomata are the most common tumors found in the female reproductive tract. Despite the high prevalence and associated morbidities of these benign tumors, little is known about the molecular basis of uterine leiomyoma development and progression. Loss of the Tuberous Sclerosis 2 (TSC2) tumor suppressor has been proposed as a mechanism important for the etiology of uterine leiomyomata based on the Eker rat model. However, conflicting evidence showing increased TSC2 expression has been reported in human uterine leiomyomata, suggesting that TSC2 might not be involved in the pathogenesis of this disorder. We have produced mice with conditional deletion of the Tsc2 gene in the myometria to determine whether loss of TSC2 leads to leiomyoma development in murine uteri. Myometrial hyperplasia and increased collagen deposition was observed in Tsc2(cKO) mice compared with control mice, but no leiomyomata were detected by post-natal week 24. Increased signaling activity of mammalian target of rapamycin complex 1, which is normally repressed by TSC2, was also detected in the myometria of Tsc2(cKO) mice. Treatment of the mutant mice with rapamycin significantly inhibited myometrial expansion, but treatment with the progesterone receptor modulator, mifepristone, did not. The ovaries of the Tsc2(cKO) mice appeared normal, but half the mice were infertile and most of the other half became infertile after a single litter, which was likely due to oviductal blockage. Our study shows that although TSC2 loss alone does not lead to leiomyoma development, it does lead to myometrial hyperplasia and fibrosis. C1 [Kaneko-Tarui, Tomoko; Commandeur, Arno E.; Styer, Aaron K.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Vincent Ctr Reprod Biol,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Patterson, Amanda L.; DeKuiper, Justin L.; Petillo, David; Teixeira, Jose M.] Michigan State Univ, Coll Human Med, Dept Obstet Gynecol & Reprod Biol, Grand Rapids, MI 49503 USA. RP Teixeira, JM (reprint author), Michigan State Univ, 333 Bostwick Ave NE,4018A, Grand Rapids, MI 49503 USA. EM jose.teixeira@hc.msu.edu OI Teixeira, Jose/0000-0002-6438-5064 FU Bayer Grant4Targets Program; A. David Mazzone Research Awards Program; National Institutes of Health [HD072489] FX These studies were supported by the Bayer Grant4Targets Program to J.M.T., the A. David Mazzone Research Awards Program to A. K. S. and J.M.T., and by the National Institutes of Health (HD072489 to J.M.T.). NR 42 TC 2 Z9 2 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1360-9947 EI 1460-2407 J9 MOL HUM REPROD JI Mol. Hum. Reprod. PD NOV PY 2014 VL 20 IS 11 BP 1126 EP 1134 DI 10.1093/molehr/gau077 PG 9 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA AT0HW UT WOS:000344618500008 PM 25189766 ER PT J AU Rotstein, BH Wey, HY Shoup, TM Wilson, AA Liang, SH Hooker, JM Vasdev, N AF Rotstein, Benjamin H. Wey, Hsiao-Ying Shoup, Timothy M. Wilson, Alan A. Liang, Steven H. Hooker, Jacob M. Vasdev, Neil TI PET Imaging of Fatty Acid Amide Hydrolase with [F-18]DOPP in Nonhuman Primates SO MOLECULAR PHARMACEUTICS LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO EVALUATION; NERVOUS-SYSTEM; ANANDAMIDE; INHIBITOR; BRAIN; PF-04457845; FAAH; ENDOCANNABINOIDS; SELECTIVITY AB Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [C-11]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [18F]DOPP ([18F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising 18F-labeled analogue based on rodent studies. The goal of this work is to evaluate [18F]DOPP in nonhuman primates to support its clinical translation. High specific activity [18F]DOPP (56 Ci center dot?mol1) was administered intravenously (iv) to three baboons (2M/1F, 34 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 ?g/kg iv, 10 min prior to [18F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ?95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [18F]DOPP covalently links to the active site of FAAH. Consistent with previous findings for [11C]CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter ?k3 was therefore used to evaluate whole brain (WB) and regional binding of [18F]DOPP. Pretreatment studies showed inhibition of ?k3 across all brain regions (WB baseline: 0.112 mL/cm3/min; 300 ?g/kg URB597: 0.058 mL/cm3/min), suggesting that [18F]DOPP binding is specific for FAAH, consistent with previous rodent data. C1 [Rotstein, Benjamin H.; Shoup, Timothy M.; Liang, Steven H.; Vasdev, Neil] Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Rotstein, Benjamin H.; Shoup, Timothy M.; Liang, Steven H.; Vasdev, Neil] Massachusetts Gen Hosp, Ctr Adv Med Imaging Sci, Boston, MA 02114 USA. [Rotstein, Benjamin H.; Wey, Hsiao-Ying; Shoup, Timothy M.; Liang, Steven H.; Hooker, Jacob M.; Vasdev, Neil] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Wey, Hsiao-Ying; Hooker, Jacob M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Wilson, Alan A.] Univ Toronto, Ctr Addict & Mental Hlth, Res Imaging Ctr, Toronto, ON M5T 1R8, Canada. [Wilson, Alan A.] Univ Toronto, Dept Psychiat, Toronto, ON M5T 1R8, Canada. RP Hooker, JM (reprint author), Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. EM hooker@nmr.mgh.harvard.edu; vasdev.neil@mgh.harvard.edu OI Rotstein, Benjamin/0000-0001-9707-9357 FU Natural Sciences and Engineering Research Council of Canada (NSERC); Harvard/MGH Nuclear Medicine Training Program from the Department of Energy [DE-SC0008430]; NIH [1R21M1-1094424, 1K01DA038000-01] FX We thank David F. Lee, Jr., and Dr. Ronald Moore for assistance with radioisotope production, Dr. Ronald Borra, Shirley Hsu, Grae Arabasz, and Helen Deng for assistance with PET/MR imaging experiments, and Dr. Ramesh Neelamegam for assistance with plasma protein binding experiments. We thank Dr. Dustin Wooten for helpful discussions. B.H.R. is a Natural Sciences and Engineering Research Council of Canada (NSERC) Postdoctoral Fellow. H.-Y.W. is supported by the Harvard/MGH Nuclear Medicine Training Program from the Department of Energy (DE-SC0008430). This work was supported in part by NIH Grants: 1R21M1-1094424 (A.A.W.) and 1K01DA038000-01 (S.H.L.). NR 35 TC 6 Z9 6 U1 2 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1543-8384 J9 MOL PHARMACEUT JI Mol. Pharm. PD NOV PY 2014 VL 11 IS 11 BP 3832 EP 3838 DI 10.1021/mp500316h PG 7 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA AS5JP UT WOS:000344307700007 PM 25004399 ER PT J AU Stroupe, KT Weaver, FM Cao, LS Ippolito, D Barton, BR Burnett-Zeigler, IE Holloway, RG Vickrey, BG Simuni, T Follett, KA AF Stroupe, Kevin T. Weaver, Frances M. Cao, Lishan Ippolito, Dolores Barton, Brandon R. Burnett-Zeigler, Inger E. Holloway, Robert G. Vickrey, Barbara G. Simuni, Tanya Follett, Kenneth A. TI Cost of Deep Brain Stimulation for the Treatment of Parkinson's Disease by Surgical Stimulation Sites SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; cost; deep brain stimulation ID RANDOMIZED CONTROLLED-TRIAL; SUBTHALAMIC NUCLEUS; MEDICAL THERAPY; GLOBUS-PALLIDUS; UNCERTAINTY AB ObjectiveTo assess costs and effectiveness of deep brain stimulation (DBS) of the internal globus pallidum (GPi) versus subthalamic nucleus (STN) from the provider and societal perspectives for Parkinson's disease (PD) patients in a multicenter randomized trial. MethodsAll costs from randomization to 36 months were included. Costs were from Department of Veterans Affairs (VA) and Medicare databases and clinical trial data. Quality adjusted life years (QALYs) were from Quality of Well Being questionnaires. ResultsProvider costs were similar for the 144 GPi and 130 STN patients (GPi: $138,044 vs. STN: $131,822; difference = $6,222, 95% confidence interval [CI]: -$42,125 to $45,343). Societal costs were also similar (GPi: $171,061 vs. STN: $167,706; difference = $3,356, 95% CI: -$57,371 to $60,294). The GPi patients had nonsignificantly more QALYs. ConclusionsThe QALYs and costs were similar; the level of uncertainty given the sample size suggests that these factors should not direct treatment or resource allocation decisions in selecting or making available either procedure for eligible PD patients. (c) 2014 International Parkinson and Movement Disorder Society C1 [Stroupe, Kevin T.; Weaver, Frances M.; Cao, Lishan; Ippolito, Dolores] Hines VA Hosp, Ctr Management Complex Chron Healthcare, Hines, IL USA. [Stroupe, Kevin T.; Weaver, Frances M.] Loyola Univ Stritch Sch Med, Maywood, IL USA. [Barton, Brandon R.] Rush Univ Med Ctr, Chicago, IL USA. [Barton, Brandon R.] Jesse Brown VA Med Ctr, Chicago, IL USA. [Burnett-Zeigler, Inger E.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Holloway, Robert G.] Univ Rochester Med Ctr, Rochester, NY USA. [Vickrey, Barbara G.] VA Southwest PADRECC, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Vickrey, Barbara G.] UCLA Dept Neurol, Los Angeles, CA USA. [Simuni, Tanya] Northwestern Univ, Parkinsons Dis & Movement Disorders Ctr, Chicago, IL 60611 USA. [Follett, Kenneth A.] Univ Nebraska Sch Med, Omaha, NE USA. RP Stroupe, KT (reprint author), Edward Hines Jr VA Hosp, Ctr Innovat Complex Chron Care, 5000 South 5th Ave 151H, Hines, IL 60141 USA. EM Kevin.Stroupe@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service [IIR 08-124-2]; VA Research Career Scientist Award FX This study was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (Project Number: IIR 08-124-2). Dr. Weaver was also supported by a VA Research Career Scientist Award. NR 25 TC 8 Z9 8 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD NOV PY 2014 VL 29 IS 13 BP 1666 EP 1674 DI 10.1002/mds.26029 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA AT0TT UT WOS:000344648400014 PM 25220042 ER PT J AU Li, N Fassl, A Chick, J Inuzuka, H Li, XY Mansour, MR Liu, LJ Wang, HZ King, B Shaik, S Gutierrez, A Ordureau, A Otto, T Kreslavsky, T Baitsch, L Bury, L Meyer, CA Ke, N Mulry, KA Kluk, MJ Roy, M Kim, S Zhang, XW Geng, Y Zagozdzon, A Jenkinson, S Gale, RE Linch, DC Zhao, JJ Mullighan, CG Harper, JW Aster, JC Aifantis, I von Boehmer, H Gygi, SP Wei, WY Look, AT Sicinski, P AF Li, Na Fassl, Anne Chick, Joel Inuzuka, Hiroyuki Li, Xiaoyu Mansour, Marc R. Liu, Lijun Wang, Haizhen King, Bryan Shaik, Shavali Gutierrez, Alejandro Ordureau, Alban Otto, Tobias Kreslavsky, Taras Baitsch, Lukas Bury, Leah Meyer, Clifford A. Ke, Nan Mulry, Kristin A. Kluk, Michael J. Roy, Moni Kim, Sunkyu Zhang, Xiaowu Geng, Yan Zagozdzon, Agnieszka Jenkinson, Sarah Gale, Rosemary E. Linch, David C. Zhao, Jean J. Mullighan, Charles G. Harper, J. Wade Aster, Jon C. Aifantis, Iannis von Boehmer, Harald Gygi, Steven P. Wei, Wenyi Look, A. Thomas Sicinski, Piotr TI Cyclin C is a haploinsufficient tumour suppressor SO NATURE CELL BIOLOGY LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; RNA-POLYMERASE-II; SQUAMOUS-CELL CARCINOMA; IN-SITU HYBRIDIZATION; UBIQUITIN LIGASE; TRANSCRIPTIONAL ACTIVATION; GENE AMPLIFICATION; NOTCH-1 MUTATIONS; DEPENDENT KINASE; ALLELIC LOSS AB Cyclin C was cloned as a growth-promoting G(1) cyclin, and was also shown to regulate gene transcription. Here we report that in vivo cyclin C acts as a haploinsufficient tumour suppressor, by controlling Notch1 oncogene levels. Cyclin C activates an 'orphan' CDK19 kinase, as well as CDK8 and CDK3. These cyclin-C-CDK complexes phosphorylate the Notch1 intracellular domain (ICN1) and promote ICN1 degradation. Genetic ablation of cyclin C blocks ICN1 phosphorylation in vivo, thereby elevating ICN1 levels in cyclin-C-knockout mice. Cyclin C ablation or heterozygosity collaborates with other oncogenic lesions and accelerates development of T-cell acute lymphoblastic leukaemia (T-ALL). Furthermore, the cyclin C encoding gene CCNC is heterozygously deleted in a significant fraction of human T-ALLs, and these tumours express reduced cyclin C levels. We also describe point mutations in human T-ALL that render cyclin-C-CDK unable to phosphorylate ICN1. Hence, tumour cells may develop different strategies to evade inhibition by cyclin C. C1 [Li, Na; Fassl, Anne; Liu, Lijun; Wang, Haizhen; Otto, Tobias; Baitsch, Lukas; Bury, Leah; Ke, Nan; Mulry, Kristin A.; Geng, Yan; Zagozdzon, Agnieszka; Zhao, Jean J.; Sicinski, Piotr] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Li, Na; Fassl, Anne; Liu, Lijun; Wang, Haizhen; Otto, Tobias; Bury, Leah; Ke, Nan; Mulry, Kristin A.; Geng, Yan; Zagozdzon, Agnieszka; Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Chick, Joel; Ordureau, Alban; Harper, J. Wade; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Inuzuka, Hiroyuki; Shaik, Shavali; Wei, Wenyi] Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Li, Xiaoyu; Kreslavsky, Taras; von Boehmer, Harald] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Li, Xiaoyu; Kreslavsky, Taras; von Boehmer, Harald] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Mansour, Marc R.; Gutierrez, Alejandro; Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Mansour, Marc R.; Gutierrez, Alejandro; Look, A. Thomas] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Mansour, Marc R.; Gutierrez, Alejandro; Look, A. Thomas] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Mansour, Marc R.; Jenkinson, Sarah; Gale, Rosemary E.; Linch, David C.] UCL, Dept Haematol, London WC1E 6BT, England. [King, Bryan; Aifantis, Iannis] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA. [King, Bryan; Aifantis, Iannis] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Baitsch, Lukas; Zhao, Jean J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Meyer, Clifford A.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Meyer, Clifford A.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Kluk, Michael J.; Roy, Moni; Aster, Jon C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kim, Sunkyu] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. [Zhang, Xiaowu] Cell Signaling Technol Inc, Danvers, MA 01923 USA. [Mullighan, Charles G.] St Jude Res Hosp, Dept Pathol, Memphis, TN 38105 USA. RP Sicinski, P (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM peter_sicinski@dfci.harvard.edu RI Ordureau, Alban/C-7558-2012; OI Ordureau, Alban/0000-0002-4924-8520; Mullighan, Charles/0000-0002-1871-1850 FU American Syrian Lebanese Associated Charities of St. Jude Children's Research Hospital [P01 CA109901, R01 CA083688, GM094777, R01 AG011085] FX We thank S. Blacklow, T. Sanda, T. Roberts, E. Sicinska, I. Kalaszczynska, S. Bukarac and D. Payne-Turner for help at different stages of the project. This work was supported by grants P01 CA109901 (to P.S., H.v.B. and A.T.L.), R01 CA083688 (to P.S.), GM094777 (to W.W.), American Syrian Lebanese Associated Charities of St. Jude Children's Research Hospital (to C.G.M.), and R01 AG011085 (to J.W.H.). C.G.M. is a St. Baldrick's Scholar and Pew Scholar NR 71 TC 24 Z9 24 U1 5 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD NOV PY 2014 VL 16 IS 11 BP 1080 EP + DI 10.1038/ncb3046 PG 25 WC Cell Biology SC Cell Biology GA AT2EF UT WOS:000344744000007 PM 25344755 ER PT J AU Ke, YG Ong, LL Sun, W Song, J Dong, MD Shih, WM Yin, P AF Ke, Yonggang Ong, Luvena L. Sun, Wei Song, Jie Dong, Mingdong Shih, William M. Yin, Peng TI DNA brick crystals with prescribed depths SO NATURE CHEMISTRY LA English DT Article ID SINGLE-STRANDED-DNA; NANOSCALE SHAPES; GOLD NANOPARTICLES; BLOCK-COPOLYMERS; FOLDING DNA; ARRAYS; NANOSTRUCTURES; JUNCTIONS; DESIGN; ORIGAMI AB The ability to assemble functional materials with precise spatial arrangements is important for applications ranging from protein crystallography to photovoltaics. Here, we describe a general framework for constructing two-dimensional crystals with prescribed depths and sophisticated three-dimensional features. The crystals are self-assembled from single-stranded DNA components called DNA bricks. We demonstrate the experimental construction of DNA brick crystals that can grow to micrometre size in their lateral dimensions with precisely controlled depths up to 80 nm. They can be designed to pack DNA helices at angles parallel or perpendicular to the plane of the crystal and to display user-specified sophisticated three-dimensional nanoscale features, such as continuous or discontinuous cavities and channels. C1 [Ke, Yonggang; Ong, Luvena L.; Sun, Wei; Shih, William M.; Yin, Peng] Harvard Univ, Wyss Inst Biologically Inspired Engn, Boston, MA 02115 USA. [Ke, Yonggang; Shih, William M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Ke, Yonggang; Shih, William M.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Ong, Luvena L.] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Sun, Wei; Yin, Peng] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Song, Jie; Dong, Mingdong] Aarhus Univ, Ctr DNA Nanotechnol, Interdisciplinary Nanosci Ctr iNANO, DK-8000 Aarhus C, Denmark. RP Ke, YG (reprint author), Georgia Inst Technol, Wallace H Coulter Dept Biomed Engn, Atlanta, GA 30322 USA. EM yonggang.ke@emory.edu; py@hms.harvard.edu RI Dong, Mingdong/B-3341-2010; OI Dong, Mingdong/0000-0002-2025-2171; /0000-0001-5317-3018 FU ONR [N000141110914, N000141010827, N000141410610, N000141310593, N000014091118, N000141010241]; ARO [W911NF1210238]; NSF CAREER Award [CCF1054898]; NSF Expedition in Computing Award [CCF1317291]; NSF [CCF1162459, CMMI1333215, CMMI1334109, CMMI1344915]; NIH Director's New Innovator Award [1DP2OD007292, 1DP2OD004641]; Wyss Institute Faculty Startup Fund; Wyss Institute Faculty Grant; ARO MURI grant [W911NF1210420]; NSF Graduate Research Fellowship; AUFF from Aarhus University; Niels Bohr Foundation from The Royal Danish Academy of Science; National Research Foundation; Villum Foundation FX This work is supported by ONR Young Investigator Program Award N000141110914, ONR Grants N000141010827, N000141410610 and N000141310593, ARO Grant W911NF1210238, NSF CAREER Award CCF1054898, NSF Expedition in Computing Award CCF1317291, NSF Grants CCF1162459, CMMI1333215, CMMI1334109 and CMMI1344915, NIH Director's New Innovator Award 1DP2OD007292 and a Wyss Institute Faculty Startup Fund to P.Y., and by a Wyss Institute Faculty Grant, ARO MURI grant W911NF1210420, ONR Grants N000014091118 and N000141010241 and NIH Director's New Innovator Award 1DP2OD004641 to W.M.S. L.L.O. is supported by an NSF Graduate Research Fellowship. J.S. acknowledges AUFF funding from Aarhus University and the Niels Bohr Foundation from The Royal Danish Academy of Science. M. D. acknowledges financial support from the Danish National Research Foundation and the Villum Foundation. NR 48 TC 42 Z9 42 U1 8 U2 82 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1755-4330 EI 1755-4349 J9 NAT CHEM JI Nat. Chem. PD NOV PY 2014 VL 6 IS 11 BP 994 EP 1002 DI 10.1038/NCHEM.2083 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA AS8BS UT WOS:000344476000013 PM 25343605 ER PT J AU Wong, IY Javaid, S Wong, EA Perk, S Haber, DA Toner, M Irimia, D AF Wong, Ian Y. Javaid, Sarah Wong, Elisabeth A. Perk, Sinem Haber, Daniel A. Toner, Mehmet Irimia, Daniel TI Collective and individual migration following the epithelial-mesenchymal transition SO NATURE MATERIALS LA English DT Article ID CANCER-CELL INVASION; EXPRESSION; MODEL; CYTOSKELETON; CONFINEMENT; METASTASIS; ADHESION; BEHAVIOR; SNAIL; EMT AB During cancer progression, malignant cells in the tumour invade surrounding tissues. This transformation of adherent cells to a motile phenotype has been associated with the epithelial-mesenchymal transition (EMT). Here, we show that EMT-activated cells migrate through micropillar arrays as a collectively advancing front that scatters individual cells. Individual cells with few neighbours dispersed with fast, straight trajectories, whereas cells that encountered many neighbours migrated collectively with epithelial biomarkers. We modelled these emergent dynamics using a physical analogy to phase transitions during binary-mixture solidification, and validated it using drug perturbations, which revealed that individually migrating cells exhibit diminished chemosensitivity. Our measurements also indicate a degree of phenotypic plasticity as cells interconvert between individual and collective migration. The study of multicellular behaviours with single-cell resolution should enable further quantitative insights into heterogeneous tumour invasion. C1 [Wong, Ian Y.; Wong, Elisabeth A.; Perk, Sinem; Toner, Mehmet; Irimia, Daniel] Harvard Univ, Sch Med, Massachusetts Gen Hosp, BioMEMS Resource Ctr,Dept Surg, Charlestown, MA 02129 USA. [Javaid, Sarah; Haber, Daniel A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Irimia, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, BioMEMS Resource Ctr,Dept Surg, Charlestown, MA 02129 USA. EM dirimia@hms.harvard.edu OI Irimia, Daniel/0000-0001-7347-2082; Wong, Ian Y/0000-0002-9439-2548 FU Merck Fellowship of the Damon Runyon Cancer Research Foundation [DRG-2065-10]; Howard Hughes Medical Institute; National Institutes of Health [CA129933, EB002503, CA135601, GM092804] FX We thank J. Taunton for the gift of FMK-MEA, A. Besser and G. Danuser for assistance with cell tracking, and O. Hurtado for assistance with fabrication. This work was supported by the Merck Fellowship of the Damon Runyon Cancer Research Foundation (DRG-2065-10) to I.Y.W., the Howard Hughes Medical Institute to D. A. H., as well as the National Institutes of Health under CA129933 to D. A. H., EB002503 (BioMEMS Resource Center) to M. T., and CA135601 and GM092804 to D.I. NR 48 TC 29 Z9 30 U1 5 U2 38 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1476-1122 EI 1476-4660 J9 NAT MATER JI Nat. Mater. PD NOV PY 2014 VL 13 IS 11 BP 1063 EP 1071 DI 10.1038/NMAT4062 PG 9 WC Chemistry, Physical; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Materials Science; Physics GA AS8AC UT WOS:000344471900015 PM 25129619 ER PT J AU Moverare-Skrtic, S Henning, P Liu, XW Nagano, K Saito, H Borjesson, AE Sjogren, K Windahl, SH Farman, H Kindlund, B Engdahl, C Koskela, A Zhang, FP Eriksson, EE Zaman, F Hammarstedt, A Isaksson, H Bally, M Kassem, A Lindholm, C Sandberg, O Aspenberg, P Savendahl, L Feng, JQ Tuckermann, J Tuukkanen, J Poutanen, M Baron, R Lerner, UH Gori, F Ohlsson, C AF Moverare-Skrtic, Sofia Henning, Petra Liu, Xianwen Nagano, Kenichi Saito, Hiroaki Borjesson, Anna E. Sjogren, Klara Windahl, Sara H. Farman, Helen Kindlund, Bert Engdahl, Cecilia Koskela, Antti Zhang, Fu-Ping Eriksson, Emma E. Zaman, Farasat Hammarstedt, Ann Isaksson, Hanna Bally, Marta Kassem, Ali Lindholm, Catharina Sandberg, Olof Aspenberg, Per Savendahl, Lars Feng, Jian Q. Tuckermann, Jan Tuukkanen, Juha Poutanen, Matti Baron, Roland Lerner, Ulf H. Gori, Francesca Ohlsson, Claes TI Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures SO NATURE MEDICINE LA English DT Article ID RECEPTOR-RELATED PROTEIN-5; BETA-CATENIN; TYROSINE KINASE; MINERAL DENSITY; GENOME-WIDE; SOST GENE; DIFFERENTIATION; MASS; ACTIVATION; CELLS AB The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need. C1 [Moverare-Skrtic, Sofia; Henning, Petra; Borjesson, Anna E.; Sjogren, Klara; Windahl, Sara H.; Farman, Helen; Kindlund, Bert; Engdahl, Cecilia; Lindholm, Catharina; Poutanen, Matti; Lerner, Ulf H.; Ohlsson, Claes] Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med, Gothenburg, Sweden. [Liu, Xianwen; Nagano, Kenichi; Saito, Hiroaki; Baron, Roland; Gori, Francesca] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Liu, Xianwen] Sichuan Univ, West China Hosp Stomatol, State Key Lab Oral Dis, Sichuan, Peoples R China. [Liu, Xianwen] Sichuan Univ, West China Hosp Stomatol, Dept Oral & Maxillofacial Surg, Sichuan, Peoples R China. [Koskela, Antti; Tuukkanen, Juha] Univ Oulu, Med Res Ctr, Dept Anat & Cell Biol, Oulu, Finland. [Zhang, Fu-Ping; Poutanen, Matti] Univ Turku, Inst Biomed, Dept Physiol, Turku Ctr Dis Modeling, Turku, Finland. [Eriksson, Emma E.; Zaman, Farasat; Savendahl, Lars] Karolinska Inst, Pediat Endocrinol Unit, Dept Womens & Childrens Hlth, Stockholm, Sweden. [Zaman, Farasat] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Hammarstedt, Ann] Univ Gothenburg, Sahlgrenska Acad, Lundberg Lab Diabet Res, Dept Mol & Clin Med, Gothenburg, Sweden. [Isaksson, Hanna] Lund Univ, Dept Biomed Engn, Lund, Sweden. [Isaksson, Hanna] Lund Univ, Dept Orthoped, Lund, Sweden. [Bally, Marta] Chalmers, Dept Appl Phys, Div Biol Phys, S-41296 Gothenburg, Sweden. [Kassem, Ali] Umea Univ, Umea, Sweden. [Sandberg, Olof; Aspenberg, Per] Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden. [Feng, Jian Q.] Texas A&M Hlth Sci Ctr, Baylor Coll Dent, Dept Biomed Sci, Dallas, TX USA. [Tuckermann, Jan] Univ Ulm, Inst Gen Zool & Endocrinol, D-89069 Ulm, Germany. [Baron, Roland; Gori, Francesca] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Endocrine Unit, Boston, MA USA. RP Ohlsson, C (reprint author), Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Inst Med, Gothenburg, Sweden. EM roland_baron@hsdm.harvard.edu; ulf.lerner@odont.umu.se; francesca_gori@hsdm.harvard.edu; claes.ohlsson@medic.gu.se RI Isaksson, Hanna/L-1340-2015; Bally, Marta/G-8744-2011; OI Isaksson, Hanna/0000-0002-9690-8907; Kassem, Ali/0000-0002-1820-8518; Bally, Marta/0000-0002-5865-8302; Engdahl, Cecilia/0000-0002-8914-0178 FU Swedish Research Council; Swedish Foundation for Strategic Research, COMBINE; Avtal om Lakarutbildning och Forskning/Lakarutbildningsavtalet (ALF/LUA) research grant in Gothenburg, Linkoping University, Swedish National Graduate School in Odontological Sciences; Lundberg Foundation; Torsten and Ragnar Soderberg's Foundation; Swedish Rheumatism Association; Royal 80 Year Fund of King Gustav V; Novo Nordisk Foundation; German Research Foundation [SPP 1468 Tu220/6]; University of Turku and Biocenter Finland; US National Institutes of Health [R01AR064724] FX We are grateful to C. Uggla, M. Petersson, A. Hansevi, A. Lie, I. Lundgren, B. Aleksic and the staff at the Turku Center for Disease Modeling (TCDM) for technical assistance. We thank M. Johansson at Bergman Labora for help with photographing the embryos. We thank R. Brommage (Lexicon Pharmaceuticals Inc.) for providing the Wnt164-/-,exon 1-3 mice. This study was supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, COMBINE, the Avtal om Lakarutbildning och Forskning/Lakarutbildningsavtalet (ALF/LUA) research grant in Gothenburg, Linkoping University, Swedish National Graduate School in Odontological Sciences, the Lundberg Foundation, the Torsten and Ragnar Soderberg's Foundation, the Swedish Rheumatism Association, the Royal 80 Year Fund of King Gustav V, the Novo Nordisk Foundation and the German Research Foundation (SPP 1468 Tu220/6, Immunobone). The work at TCDM was supported by funding provided by University of Turku and Biocenter Finland. This work was supported in part by a grant to R.B. from the US National Institutes of Health (R01AR064724). The HSDM micro-CT core facility performed the micro-CT analyses of the Wnt16-/-,exon 1-3 mice. NR 48 TC 37 Z9 38 U1 6 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD NOV PY 2014 VL 20 IS 11 BP 1279 EP 1288 DI 10.1038/nm.3654 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AT1XM UT WOS:000344724300017 PM 25306233 ER PT J AU Sistigu, A Yamazaki, T Vacchelli, E Chaba, K Enot, DP Adam, J Vitale, I Goubar, A Baracco, EE Remedios, C Fend, L Hannani, D Aymeric, L Ma, Y Niso-Santano, M Kepp, O Schultze, JL Tuting, T Belardelli, F Bracci, L La Sorsa, V Ziccheddu, G Sestili, P Urbani, F Delorenzi, M Lacroix-Triki, M Quidville, V Conforti, R Spano, JP Pusztai, L Poirier-Colame, V Delaloge, S Penault-Llorca, F Ladoire, S Arnould, L Cyrta, J Dessoliers, MC Eggermont, A Bianchi, ME Pittet, M Engblom, C Pfirschke, C Preville, X Uze, G Schreiber, RD Chow, MT Smyth, MJ Proietti, E Andre, F Kroemer, G Zitvogel, L AF Sistigu, Antonella Yamazaki, Takahiro Vacchelli, Erika Chaba, Kariman Enot, David P. Adam, Julien Vitale, Ilio Goubar, Aicha Baracco, Elisa E. Remedios, Catarina Fend, Laetitia Hannani, Dalil Aymeric, Laetitia Ma, Yuting Niso-Santano, Mireia Kepp, Oliver Schultze, Joachim L. Tueting, Thomas Belardelli, Filippo Bracci, Laura La Sorsa, Valentina Ziccheddu, Giovanna Sestili, Paola Urbani, Francesca Delorenzi, Mauro Lacroix-Triki, Magali Quidville, Virginie Conforti, Rosa Spano, Jean-Philippe Pusztai, Lajos Poirier-Colame, Vichnou Delaloge, Suzette Penault-Llorca, Frederique Ladoire, Sylvain Arnould, Laurent Cyrta, Joanna Dessoliers, Marie-Charlotte Eggermont, Alexander Bianchi, Marco E. Pittet, Mikael Engblom, Camilla Pfirschke, Christina Preville, Xavier Uze, Gilles Schreiber, Robert D. Chow, Melvyn T. Smyth, Mark J. Proietti, Enrico Andre, Fabrice Kroemer, Guido Zitvogel, Laurence TI Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy SO NATURE MEDICINE LA English DT Article ID TOLL-LIKE RECEPTOR-3; DOUBLE-STRANDED-RNA; BREAST-CANCER; IMMUNE-RESPONSES; ANTICANCER CHEMOTHERAPY; DENDRITIC CELLS; RIG-I; INNATE; TUMORS; GENE AB Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-alpha and IFN-beta receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking TIr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy. C1 [Sistigu, Antonella; Yamazaki, Takahiro; Vacchelli, Erika; Adam, Julien; Goubar, Aicha; Baracco, Elisa E.; Remedios, Catarina; Fend, Laetitia; Hannani, Dalil; Aymeric, Laetitia; Ma, Yuting; Niso-Santano, Mireia; Kepp, Oliver; Quidville, Virginie; Conforti, Rosa; Poirier-Colame, Vichnou; Delaloge, Suzette; Cyrta, Joanna; Dessoliers, Marie-Charlotte; Andre, Fabrice; Kroemer, Guido; Zitvogel, Laurence] Gustave Roussy Canc Campus, Villejuif, France. [Sistigu, Antonella; Yamazaki, Takahiro; Remedios, Catarina; Fend, Laetitia; Hannani, Dalil; Aymeric, Laetitia; Conforti, Rosa; Poirier-Colame, Vichnou; Zitvogel, Laurence] INSERM, U1015, Villejuif, France. [Sistigu, Antonella; Yamazaki, Takahiro; Vacchelli, Erika; Baracco, Elisa E.; Remedios, Catarina; Hannani, Dalil; Aymeric, Laetitia; Ma, Yuting; Niso-Santano, Mireia; Kepp, Oliver; Eggermont, Alexander; Andre, Fabrice; Zitvogel, Laurence] Univ Paris Saclay, Fac Med, Le Kremlin Bicetre, France. [Sistigu, Antonella; Belardelli, Filippo; Bracci, Laura; La Sorsa, Valentina; Ziccheddu, Giovanna; Sestili, Paola; Urbani, Francesca] Ist Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, Italy. [Vacchelli, Erika; Chaba, Kariman; Enot, David P.; Baracco, Elisa E.; Ma, Yuting; Niso-Santano, Mireia; Kepp, Oliver; Kroemer, Guido] INSERM, U848, Villejuif, France. [Chaba, Kariman; Enot, David P.; Kroemer, Guido] Ctr Rech Cordeliers, Equipe Labellisee Ligue Nationale Canc 11, Paris, France. [Chaba, Kariman; Enot, David P.; Kroemer, Guido] Univ Paris 05, Sorbonne Paris Cite, Paris, France. [Adam, Julien; Delaloge, Suzette; Andre, Fabrice] Gustave Roussy Canc Campus, Dept Biol & Pathol, Villejuif, France. [Adam, Julien; Andre, Fabrice] Gustave Roussy Canc Campus, Dept Med Oncol, Villejuif, France. [Vitale, Ilio] Regina Elena Inst Canc Res, Rome, Italy. [Goubar, Aicha; Dessoliers, Marie-Charlotte; Andre, Fabrice] INSERM, U981, Villejuif, France. [Fend, Laetitia; Preville, Xavier] Transgene SA, Illkirch Graffenstaden, France. [Schultze, Joachim L.] Univ Bonn, Lab Genom & Immunoregulat Life & Med Sci LIMES, Bonn, Germany. [Tueting, Thomas] Univ Hosp Bonn, Dept Dermatol, Lab Expt Dermatol, Bonn, Germany. [Delorenzi, Mauro] SIB, Lausanne, Switzerland. [Delorenzi, Mauro] Ecole Polytech Fed Lausanne, Sch Life Sci, ISREC, Natl Ctr Competence Res NCCR Mol Oncol, Lausanne, Switzerland. [Delorenzi, Mauro] CHU Vaudois, Dept Format & Rech, Lausanne, Switzerland. [Lacroix-Triki, Magali] Ctr Claudius Regaud, Dept Pathol, Toulouse, France. [Conforti, Rosa; Poirier-Colame, Vichnou] Ctr Clin Invest Biotherapies Canc CICBT 507, Villejuif, France. [Conforti, Rosa; Spano, Jean-Philippe] Hop La Pitie Salpetriere, Dept Med Oncol, Paris, France. [Pusztai, Lajos] Yale Univ, Sch Med, New Haven, CT USA. [Penault-Llorca, Frederique] Univ Auvergne, EA ERTICa 4677, Dept Pathol, Jean Perrin Ctr, Clermont Ferrand, France. [Ladoire, Sylvain; Arnould, Laurent] Ctr Georges Francois Leclerc, Dept Med Oncol, Dijon, France. [Ladoire, Sylvain; Arnould, Laurent] INSERM, Fac Med CRI 866, Dijon, France. [Ladoire, Sylvain; Arnould, Laurent] Univ Burgundy, Dijon, France. [Bianchi, Marco E.] San Raffaele Univ & Sci Inst, Milan, Italy. [Pittet, Mikael; Engblom, Camilla; Pfirschke, Christina] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Pittet, Mikael; Engblom, Camilla; Pfirschke, Christina] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Uze, Gilles] Univ Montpellier 2, CNRS, UMR5235, Montpellier, France. [Schreiber, Robert D.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Chow, Melvyn T.; Smyth, Mark J.] Queensland Inst Med Res, Herston, Qld 4006, Australia. [Smyth, Mark J.] Univ Queensland, Sch Med, Herston, Qld, Australia. [Sistigu, Antonella; Yamazaki, Takahiro; Vacchelli, Erika; Kroemer, Guido] Gustave Roussy Canc Campus, Metabol Platform, Villejuif, France. [Kroemer, Guido] Hop Europeen Georges, AP HP, Paris, France. RP Zitvogel, L (reprint author), Univ Paris Saclay, Fac Med, Le Kremlin Bicetre, France. EM kroemer@orange.fr; laurence.zitvogel@gustaveroussy.fr RI LACROIX-TRIKI, Magali/P-7184-2014; Smyth, Mark/H-8709-2014; Schultze, Joachim/D-7794-2011; BRACCI, LAURA/J-8777-2016; OI LACROIX-TRIKI, Magali/0000-0002-7157-3960; Smyth, Mark/0000-0001-7098-7240; Schultze, Joachim/0000-0003-2812-9853; BRACCI, LAURA/0000-0002-2535-4353; PROIETTI, ENRICO/0000-0001-9023-2072; VITALE, ILIO/0000-0002-5918-1841; Niso-Santano, Mireia/0000-0002-6506-422X; Sistigu, Antonella/0000-0002-2528-1238 FU Ligue Nationale contre le Cancer (Equipes labellisees); Site de Recherche Integree sur le Cancer (IRIC) Socrates; ISREC Foundation; Agence Nationale pour la Recherche (ANR AUTOPH, ANR Emergence); European Commission (ArtForce); European Research Council Advanced Investigator Grant; Fondation pour la Recherche Medicale (FRM); Institut National du Cancer (INCa); Fondation de France; Canceropole Ile-de-France; Fondation Bettencourt-Schueller; LabEx Immuno-Oncology and the Paris Alliance of Cancer Research Institutes; Ligue Nationale contre le Cancer; Fondation Association-pour-la-Recherche curie Cancer; National Health and Medical Research Council (NH&MRC) Australia Fellowship; Victorian Cancer Agency; Associazione Italiana Ricerca contro II Cancro (AIRC) [MFAG_13058]; Deutsche Forschungsgemeinschaft (DFG) [PF809/1-1]; Boerhinger Ingelheim; Association Vie et Cancer; Institut national du Cancer et la Direction Generale de l'Offre de Soins-INSERM [6043] FX We acknowledge L. Galluzzi for help with preparation of the manuscript. We thank P. Rameau, Y. Lecluse and M. Sanchez for assistance with FAGS experiments, G. Schiavoni and G. D'Agostino (Istituto Superiore di Sanita) for recombinant Ifn-alpha 1, our colleagues from the Gustave Roussy Cancer Center and the Istituto Superiore di Sanita animal facilities, P. Gonin, M. Macchia and E. Cardarelli. We acknowledge P. Vielh for his help with immunohistochemical analyses and G. Stoll for his support in statistical analyses. G.K. and L.Z. are supported by the Ligue Nationale contre le Cancer (Equipes labellisees), Site de Recherche Integree sur le Cancer (IRIC) Socrates, the ISREC Foundation, Agence Nationale pour la Recherche (ANR AUTOPH, ANR Emergence), the European Commission (ArtForce), a European Research Council Advanced Investigator Grant (to G.K.), the Fondation pour la Recherche Medicale (FRM), the Institut National du Cancer (INCa), the Fondation de France, Canceropole Ile-de-France, the Fondation Bettencourt-Schueller, the LabEx Immuno-Oncology and the Paris Alliance of Cancer Research Institutes. A.S. is supported by Ligue Nationale contre le Cancer: D.H. was supported-by Fondation Association-pour-la-Recherche curie Cancer. M.J.S. was supported by a National Health and Medical Research Council (NH&MRC) Australia Fellowship and Program Grant and a grant from the Victorian Cancer Agency. E.P. and L.B. were supported by Associazione Italiana Ricerca contro II Cancro (AIRC) (MFAG_13058). C.P. was supported by the Deutsche Forschungsgemeinschaft (DFG) PF809/1-1. C.E. was supported by Boerhinger Ingelheim. F.A. was supported by Association Vie et Cancer. J.A. was supported by Institut national du Cancer et la Direction Generale de l'Offre de Soins-INSERM 6043. NR 60 TC 129 Z9 134 U1 5 U2 44 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD NOV PY 2014 VL 20 IS 11 BP 1301 EP 1309 DI 10.1038/nm.3708 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AT1XM UT WOS:000344724300019 PM 25344738 ER PT J AU Tichauer, KM Samkoe, KS Gunn, JR Kanick, SC Hoopes, PJ Barth, RJ Kaufman, PA Hasan, T Pogue, BW AF Tichauer, Kenneth M. Samkoe, Kimberley S. Gunn, Jason R. Kanick, Stephen C. Hoopes, P. Jack Barth, Richard J. Kaufman, Peter A. Hasan, Tayyaba Pogue, Brian W. TI Microscopic lymph node tumor burden quantified by macroscopic dual-tracer molecular imaging SO NATURE MEDICINE LA English DT Article ID GROWTH-FACTOR RECEPTOR; BREAST-CANCER; IN-VIVO; CORRESPONDING METASTASES; HER3 EXPRESSION; EGFR; DIFFERENTIATION; TISSUES AB Lymph node biopsy is employed in many cancer surgeries to identify metastatic disease and to determine cancer stage, yet morbidity and diagnostic delays associated with lymph node biopsy could be avoided if noninvasive imaging of nodal involvement were reliable. Molecular imaging has potential in this regard; however, variable delivery and nonspecific uptake of imaging tracers have made conventional approaches ineffective clinically. Here we present a method of correcting for nonspecific uptake with injection of a second untargeted tracer that allows for quantification of tumor burden in lymph nodes. We confirmed the approach in an athymic mouse model of metastatic human breast cancer by targeting epidermal growth factor receptor, a cell surface receptor overexpressed by many cancers. We observed a significant correlation between in vivo (dual-tracer) and ex vivo measures of tumor burden (r = 0.97, P < 0.01), with an ultimate sensitivity of approximately 200 cells (potentially more sensitive than conventional lymph node biopsy). C1 [Tichauer, Kenneth M.] IIT, Dept Biomed Engn, Chicago, IL 60616 USA. [Samkoe, Kimberley S.; Hoopes, P. Jack; Barth, Richard J.; Pogue, Brian W.] Geisel Sch Med, Dept Surg, Hanover, NH USA. [Gunn, Jason R.; Kanick, Stephen C.; Hoopes, P. Jack; Pogue, Brian W.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Kaufman, Peter A.] Geisel Sch Med, Dept Med, Lebanon, NH USA. [Hasan, Tayyaba; Pogue, Brian W.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Tichauer, KM (reprint author), IIT, Dept Biomed Engn, Chicago, IL 60616 USA. EM ktichaue@iit.edu; brian.w.pogue@dartmouth.edu FU US National Institutes of Health [R01 CA109558, R01 CA156177, U54 CA151662]; Canadian Institutes of Health Research postdoctoral fellowship FX This work was sponsored by US National Institutes of Health research grants R01 CA109558, R01 CA156177, and U54 CA151662 as well as a the Canadian Institutes of Health Research postdoctoral fellowship for K.M.T. NR 34 TC 21 Z9 21 U1 4 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD NOV PY 2014 VL 20 IS 11 BP 1348 EP 1353 DI 10.1038/nm.3732 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA AT1XM UT WOS:000344724300026 PM 25344739 ER PT J AU Bar-Nur, O Brumbaugh, J Verheul, C Apostolou, E Pruteanu-Malinici, I Walsh, RM Ramaswamy, S Hochedlinger, K AF Bar-Nur, Ori Brumbaugh, Justin Verheul, Cassandra Apostolou, Effie Pruteanu-Malinici, Iulian Walsh, Ryan M. Ramaswamy, Sridhar Hochedlinger, Konrad TI Small molecules facilitate rapid and synchronous iPSC generation SO NATURE METHODS LA English DT Article ID PLURIPOTENT STEM-CELLS; SOMATIC-CELLS; HUMAN FIBROBLASTS; DEFINED FACTORS; VITAMIN-C; MOUSE; DIFFERENTIATION; MECHANISMS; CONVERSION; INDUCTION AB The reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) upon overexpression of OCT4, KLF4, SOX2 and c-MYC (OKSM) provides a powerful system to interrogate basic mechanisms of cell fate change. However, iPSC formation with standard methods is typically protracted and inefficient, resulting in heterogeneous cell populations. We show that exposure of OKSM-expressing cells to both ascorbic acid and a GSK3-beta inhibitor (AGi) facilitates more synchronous and rapid iPSC formation from several mouse cell types. AGi treatment restored the ability of refractory cell populations to yield iPSC colonies, and it attenuated the activation of developmental regulators commonly observed during the reprogramming process. Moreover, AGi supplementation gave rise to chimera-competent iPSCs after as little as 48 h of OKSM expression. Our results offer a simple modification to the reprogramming protocol, facilitating iPSC induction at unparalleled efficiencies and enabling dissection of the underlying mechanisms in more homogeneous cell populations. C1 [Bar-Nur, Ori; Brumbaugh, Justin; Verheul, Cassandra; Apostolou, Effie; Pruteanu-Malinici, Iulian; Walsh, Ryan M.; Ramaswamy, Sridhar; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Bar-Nur, Ori; Brumbaugh, Justin; Verheul, Cassandra; Apostolou, Effie; Walsh, Ryan M.; Ramaswamy, Sridhar; Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA USA. [Bar-Nur, Ori; Brumbaugh, Justin; Verheul, Cassandra; Apostolou, Effie; Walsh, Ryan M.; Hochedlinger, Konrad] Howard Hughes Med Inst, Chevy Chase, MD USA. [Bar-Nur, Ori; Brumbaugh, Justin; Verheul, Cassandra; Apostolou, Effie; Walsh, Ryan M.; Hochedlinger, Konrad] Dept Stem Cell & Regenerat Biol, Cambridge, MA USA. [Pruteanu-Malinici, Iulian; Ramaswamy, Sridhar; Hochedlinger, Konrad] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Pruteanu-Malinici, Iulian; Ramaswamy, Sridhar] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Hochedlinger, K (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM khochedlinger@mgh.harvard.edu FU Gruss-Lipper postdoctoral fellowship; US National Institutes of Health (NIH) [R01HD058013]; Howard Hughes Medical Institute; MGH Executive Committee on Research; NIH [1F32HD078029-01A1] FX We thank members of the Hochedlinger lab for helpful suggestions and critical reading of the manuscript. We thank M. Borkent for providing study material and to A. Foudi and D. Kramer for scientific discussion. We thank L. Prickett, M. Weglarz and K. Folz-Donahue at the Massachusetts General Hospital/Harvard Stem Cell Institute flow cytometry core. O.B.-N. was supported by a Gruss-Lipper postdoctoral fellowship. Support to K.H. was from the US National Institutes of Health (NIH; R01HD058013) and the Howard Hughes Medical Institute. J.B. is grateful for support from the Tosteson Fund for Medical Discovery Post-doctoral Fellowship by the MGH Executive Committee on Research and NIH (1F32HD078029-01A1). NR 41 TC 28 Z9 29 U1 1 U2 27 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 NOV PY 2014 VL 11 IS 11 BP 1170 EP 1176 DI 10.1038/NMETH.3142 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AS9SA UT WOS:000344580600025 PM 25262205 ER PT J AU Sachdev, PS Blacker, D Blazer, DG Ganguli, M Jeste, DV Paulsen, JS Petersen, RC AF Sachdev, Perminder S. Blacker, Deborah Blazer, Dan G. Ganguli, Mary Jeste, Dilip V. Paulsen, Jane S. Petersen, Ronald C. TI Classifying neurocognitive disorders: the DSM-5 approach SO NATURE REVIEWS NEUROLOGY LA English DT Review ID MILD COGNITIVE IMPAIRMENT; ALZHEIMERS ASSOCIATION WORKGROUPS; DIAGNOSTIC-CRITERIA; FRONTOTEMPORAL DEMENTIA; NATIONAL INSTITUTE; VASCULAR DEMENTIA; DISEASE; RECOMMENDATIONS; GUIDELINES AB Neurocognitive disorders-including delirium, mild cognitive impairment and dementia-are characterized by decline from a previously attained level of cognitive functioning. These disorders have diverse clinical characteristics and aetiologies, with Alzheimer disease, cerebrovascular disease, Lewy body disease, frontotemporal degeneration, traumatic brain injury, infections, and alcohol abuse representing common causes. This diversity is reflected by the variety of approaches to classifying these disorders, with separate groups determining criteria for each disorder on the basis of aetiology. As a result, there is now an array of terms to describe cognitive syndromes, various definitions for the same syndrome, and often multiple criteria to determine a specific aetiology. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) provides a common framework for the diagnosis of neurocognitive disorders, first by describing the main cognitive syndromes, and then defining criteria to delineate specific aetiological subtypes of mild and major neurocognitive disorders. The DSM-5 approach builds on the expectation that clinicians and research groups will welcome a common language to deal with the neurocognitive disorders. As the use of these criteria becomes more widespread, a common international classification for these disorders could emerge for the first time, thus promoting efficient communication among clinicians and researchers. C1 [Sachdev, Perminder S.] Univ New S Wales, Prince Wales Hosp, Ctr Hlth Brain Ageing, Sch Psychiat, Randwick, NSW 2031, Australia. [Blacker, Deborah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Blazer, Dan G.] Duke Univ, Duke Inst Brain Sci, Durham, NC 27710 USA. [Ganguli, Mary] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Jeste, Dilip V.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Paulsen, Jane S.] Univ Iowa, Carver Coll Med, Iowa City, IA 52242 USA. [Petersen, Ronald C.] Mayo Clin, Rochester, MN 55905 USA. RP Sachdev, PS (reprint author), Univ New S Wales, Prince Wales Hosp, Ctr Hlth Brain Ageing, Sch Psychiat, Barker St, Randwick, NSW 2031, Australia. EM p.sachdev@unsw.edu.au RI MORAN, CATHERINE/C-9539-2015; OI Sachdev, Perminder/0000-0002-9595-3220 FU National Institute on Aging, the National Institutes of Health; Department of Health and Human Services, USA [K07 AG044395]; National Institute of Mental Health, USA [R01 MH099987]; Sam and Rose Stein Institute for Research on Aging; National Health and Medical Research Council of Australia [568969] FX The authors would like to thank Prof. Igor Grant, the members of the DSM-5 Task Force and the other Work Groups, as well as many external advisers and consultants who provided invaluable input to the development of the classification. M.G. was supported in part by the National Institute on Aging, the National Institutes of Health, and the Department of Health and Human Services, USA (grant K07 AG044395). D.V.J. was supported in part by the National Institute of Mental Health, USA (grant R01 MH099987), and by the Sam and Rose Stein Institute for Research on Aging. P.S. was supported in part by the National Health and Medical Research Council of Australia (grant 568969). NR 34 TC 26 Z9 27 U1 1 U2 35 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 EI 1759-4766 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD NOV PY 2014 VL 10 IS 11 BP 634 EP 642 DI 10.1038/nrneurol.2014.181 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA AT2LU UT WOS:000344767200006 PM 25266297 ER PT J AU Hsu, JJ Katz, R Ix, JH de Boer, IH Kestenbaum, B Shlipak, MG AF Hsu, Jeffrey J. Katz, Ronit Ix, Joachim H. de Boer, Ian H. Kestenbaum, Bryan Shlipak, Michael G. TI Association of fibroblast growth factor-23 with arterial stiffness in the Multi-Ethnic Study of Atherosclerosis SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE ABI; arterial elasticity; arterial stiffness; FGF-23; pulse pressure ID CHRONIC KIDNEY-DISEASE; ANKLE-BRACHIAL INDEX; CARDIOVASCULAR EVENTS; PULSE PRESSURE; ALL-CAUSE; MORTALITY; CALCIFICATION; HEART; RISK; COMMUNITY AB Serum fibroblast growth factor-23 (FGF-23) is associated with cardiovascular disease (CVD), yet the mechanisms remain uncertain. Our objective was to determine whether higher FGF-23 concentrations are associated with arterial stiffness. In this cross-sectional study, serum FGF-23 concentrations were measured in 5977 participants without known CVD in the Multi-Ethnic Study of Atherosclerosis. The primary outcomes of interest were large (LAE) and small artery elasticity (SAE), pulse pressure and ankle-brachial index (ABI) > 1.30. LAE and SAE were measured by pulse contour analysis of the radial artery. Pulse pressure was measured with an automated sphygmomanometer using the average of two resting blood pressure measurements. ABI was calculated as the ratio of the ankle and brachial systolic blood pressures. Serum FGF-23 concentrations were not significantly associated with LAE [relative difference (RD) per doubling: 0%; 95% confidence interval (CI): -2-1%], SAE (RD per doubling: 0%; 95% CI: -3-2%), pulse pressure (beta per doubling: 0.44; 95% CI: -0.31-1.19), or a high ABI (odds ratio per doubling: 1.14; 95% CI: 0.84-1.55). Findings were similar irrespective of chronic kidney disease status. Higher serum FGF-23 concentrations are not associated with arterial stiffness, as measured by pulse pressure, LAE, SAE or high ABI, in a community-based population without CVD. C1 [Hsu, Jeffrey J.; Shlipak, Michael G.] Univ Calif San Francisco, San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA 94143 USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Med, Div Nephrol, La Jolla, CA 92093 USA. [Katz, Ronit] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [de Boer, Ian H.; Kestenbaum, Bryan] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. RP Shlipak, MG (reprint author), Univ Calif San Francisco, San Francisco VA Med Ctr, Div Gen Internal Med, San Francisco, CA 94143 USA. EM michael.shlipak@ucsf.edu FU National Institute on Aging (NIA) [5R01-AG-027002-06]; National Heart, Lung and Blood Institute [5R01-AG-027002-06]; UCSF Department of Medicine FX The authors thank the other investigators, the staff and the participants of MESA for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. This research was supported by grants 5R01-AG-027002-06 from the National Institute on Aging (NIA) and R01-HL-096875 from the National Heart, Lung and Blood Institute, and the UCSF Department of Medicine. NR 33 TC 9 Z9 12 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 EI 1460-2385 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD NOV PY 2014 VL 29 IS 11 BP 2099 EP 2105 DI 10.1093/ndt/gfu101 PG 7 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA AT0KP UT WOS:000344625400019 PM 24782533 ER PT J AU Reardon, DA Freeman, G Wu, C Chiocca, EA Wucherpfennig, KW Wen, PY Fritsch, EF Curry, WT Sampson, JH Dranoff, G AF Reardon, David A. Freeman, Gordon Wu, Catherine Chiocca, E. Antonio Wucherpfennig, Kai W. Wen, Patrick Y. Fritsch, Edward F. Curry, William T., Jr. Sampson, John H. Dranoff, Glenn TI Immunotherapy advances for glioblastoma SO NEURO-ONCOLOGY LA English DT Review DE glioblastoma; immune checkpoint; immunosuppression; immunotherapy; vaccine ID GROWTH-FACTOR RECEPTOR; CENTRAL-NERVOUS-SYSTEM; REGULATORY T-CELLS; NEWLY-DIAGNOSED GLIOBLASTOMA; CHIMERIC-ANTIGEN-RECEPTOR; ANTITUMOR IMMUNE-RESPONSES; RESISTANT PROSTATE-CANCER; COLONY-STIMULATING FACTOR; RELAPSED MALIGNANT GLIOMA; DOSE-ESCALATION TRIAL AB Survival for patients with glioblastoma, the most common high-grade primary CNS tumor, remains poor despite multiple therapeutic interventions including intensifying cytotoxic therapy, targeting dysregulated cell signaling pathways, and blocking angiogenesis. Exciting, durable clinical benefits have recently been demonstrated for a number of other challenging cancers using a variety of immunotherapeutic approaches. Much modern research confirms that the CNS is immunoactive rather than immunoprivileged. Preliminary results of clinical studies demonstrate that varied vaccine strategies have achieved encouraging evidence of clinical benefit for glioblastoma patients, although multiple variables will likely require systematic investigation before optimal outcomes are realized. Initial preclinical studies have also revealed promising results with other immunotherapies including cell-based approaches and immune checkpoint blockade. Clinical studies to evaluate a wide array of immune therapies for malignant glioma patients are being rapidly developed. Important considerations going forward include optimizing response assessment and identifiying correlative biomarkers for predict therapeutic benefit. Finally, the potential of complementary combinatorial immunotherapeutic regimens is highly exciting and warrants expedited investigation. C1 [Reardon, David A.; Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Freeman, Gordon; Wu, Catherine; Wucherpfennig, Kai W.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Reardon, David A.; Wu, Catherine] Dana Farber Brigham & Womens Canc Ctr, Dept Med Oncol, Boston, MA USA. [Chiocca, E. Antonio] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Wen, Patrick Y.] Brigham & Womens Hosp, Div Neurooncol, Dept Neurol, Boston, MA 02115 USA. [Sampson, John H.] Duke Univ, Med Ctr, Div Neurosurg, Dept Surg, Durham, NC 27710 USA. [Curry, William T., Jr.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Wu, Catherine; Fritsch, Edward F.; Dranoff, Glenn] Dana Farber Brigham & Womens Canc Ctr, Dept Med Oncol, Boston, MA USA. [Wu, Catherine; Fritsch, Edward F.; Dranoff, Glenn] Dana Farber Brigham & Womens Canc Ctr, Canc Vaccine Ctr, Boston, MA USA. [Dranoff, Glenn] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Reardon, DA (reprint author), Dana Farber Canc Inst, Ctr Neurooncol, 450 Brookline Ave, Boston, MA 02215 USA. EM david_reardon@dfci.harvard.edu FU Celldex Therapeutics; Bristol-= 60 y, codeleted), class IV (age 43-59 y, not codeleted, not frontal lobe tumor or age 60-69 y, not codeleted), and class V (age >= 70 y, not codeleted). Survival differences were highly significant (P<.0001), with medians ranging from 9.3 years (95% CI: 8.4-16.0) for class I to 0.6 years (95% CI: 0.5-0.9) for class V. Conclusions. These 5 distinct classification groups were defined using prognostic factors typically obtained during routine management of patients with anaplastic oligodendroglial tumors. Validation in a prospective clinical trial may better differentiate patients with respect to treatment outcome. C1 [Iwamoto, Fabio M.; Abrey, Lauren E.; DeAngelis, Lisa M.; Lassman, Andrew B.] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10021 USA. [Jhanwar, Suresh C.; Rosenblum, Marc K.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Panageas, Katherine S.; Reiner, Anne S.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Brain Tumor Ctr, New York, NY 10021 USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, Los Angeles, CA USA. [Aldape, Kenneth D.; Rivera, Andreana L.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Eichler, April F.; Louis, David N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Eichler, April F.; Louis, David N.] Harvard Univ, Sch Med, Boston, MA USA. [Paleologos, Nina A.] Univ Chicago, Pritzker Sch Med, NorthShore Univ Hlth Syst, Evanston Hosp,Kellogg Canc Ctr, Evanston, IL USA. [Fisher, Barbara J.] London Reg Canc Program, London, ON, Canada. [Ashby, Lynn S.] Barrow Neurol Inst, Phoenix, AZ 85013 USA. [Cairncross, J. Gregory; Urgoiti, Gloria B. Roldan] Univ Calgary, Calgary, AB, Canada. [Wen, Patrick Y.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wen, Patrick Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ligon, Keith L.] Brigham & Womens Hosp, Ctr Mol Oncol Pathol, Dana Farber Canc Inst, Childrens Hosp Boston, Boston, MA 02115 USA. [Schiff, David] Univ Virginia Hlth Syst, Charlottesville, VA USA. [Robins, H. Ian; Rocque, Brandon G.] Univ Wisconsin, Madison, WI USA. [Chamberlain, Marc C.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Chamberlain, Marc C.] Univ Washington, Seattle Canc Care Alliance, Seattle, WA 98195 USA. [Mason, Warren P.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Weaver, Susan A.] Albany Med Ctr, Albany, NY USA. [Green, Richard M.] Kaiser Permanente, Los Angeles Med Ctr, Los Angeles, CA USA. [Kamar, Francois G.] Clemenceau Med Ctr, Beirut, Lebanon. [Kamar, Francois G.] Univ St Esprit de Kaslik, Byblos, Lebanon. RP Lassman, AB (reprint author), Columbia Univ, Med Ctr, 710 W 168th St, New York, NY 10032 USA. EM ABL7@cumc.columbia.edu OI Reiner, Anne/0000-0002-1258-6112; kamar , francois/0000-0001-8470-5515 FU [P30 CA008748]; [P30 CA013696-40] FX Funding for development of the initial dataset was described previously. In addition, K. S. P. and A. S. R. were supported in part by P30 CA008748 and A. B. L. in part by P30 CA013696-40. Funding sources had no access to patient data and no role in conceiving or designing the study or in data collection, analysis, or interpretation of results. NR 38 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 IS 11 BP 1541 EP 1546 DI 10.1093/neuonc/nou083 PG 6 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AT0MX UT WOS:000344631200013 PM 24997140 ER PT J AU Aizer, AA Arvold, ND Catalano, P Claus, EB Golby, AJ Johnson, MD Al-Mefty, O Wen, PY Reardon, DA Lee, EQ Nayak, L Rinne, ML Beroukhim, R Weiss, SE Ramkissoon, SH Abedalthagafi, M Santagata, S Dunn, IF Alexander, BM AF Aizer, Ayal A. Arvold, Nils D. Catalano, Paul Claus, Elizabeth B. Golby, Alexandra J. Johnson, Mark D. Al-Mefty, Ossama Wen, Patrick Y. Reardon, David A. Lee, Eudocia Q. Nayak, Lakshmi Rinne, Mikael L. Beroukhim, Rameen Weiss, Stephanie E. Ramkissoon, Shakti H. Abedalthagafi, Malak Santagata, Sandro Dunn, Ian F. Alexander, Brian M. TI Adjuvant radiation therapy, local recurrence, and the need for salvage therapy in atypical meningioma SO NEURO-ONCOLOGY LA English DT Article DE atypical meningioma; radiation; recurrence; salvage ID FRACTIONATED STEREOTACTIC RADIOTHERAPY; GROSS-TOTAL RESECTION; ANAPLASTIC MENINGIOMAS; CLINICAL ARTICLE; INTRACRANIAL MENINGIOMAS; NONBENIGN MENINGIOMAS; RADIOSURGERY; OUTCOMES AB Background. The impact of adjuvant radiation in patients with atypical meningioma remains poorly defined. We sought to determine the impact of adjuvant radiation therapy in this population. Methods. We identified 91 patients with World Health Organization grade II (atypical) meningioma managed at Dana-Farber/Brigham and Women's Cancer Center between 1997 and 2011. A propensity score model incorporating age at diagnosis, gender, Karnofsky performance status, tumor location, tumor size, reason for diagnosis, and era of treatment was constructed using logistic regression for the outcome of receipt versus nonreceipt of radiation therapy. Propensity scores were then used as continuous covariates in a Cox proportional hazards model to determine the adjusted impact of adjuvant radiation therapy on both local recurrence and the combined endpoint of use of salvage therapy and death due to progressive meningioma. Results. The median follow-up in patients without recurrent disease was 4.9 years. After adjustment for pertinent confounding variables, radiation therapy was associated with decreased local recurrence in those undergoing gross total resection (hazard ratio, 0.25; 95% CI, 0.07-0.96; P=.04). No differences in overall survival were seen in patients who did and did not receive radiation therapy. Conclusion. Patients who have had a gross total resection of an atypical meningioma should be considered for adjuvant radiation therapy given the improvement in local control. Multicenter, prospective trials are required to definitively evaluate the potential impact of radiation therapy on survival in patients with atypical meningioma. C1 [Aizer, Ayal A.] Brigham & Womens Hosp, Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Arvold, Nils D.; Alexander, Brian M.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02215 USA. [Catalano, Paul] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Claus, Elizabeth B.; Golby, Alexandra J.; Johnson, Mark D.; Al-Mefty, Ossama; Dunn, Ian F.] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Wen, Patrick Y.; Reardon, David A.; Lee, Eudocia Q.; Nayak, Lakshmi; Rinne, Mikael L.; Beroukhim, Rameen] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02215 USA. [Weiss, Stephanie E.] Fox Chase Canc Ctr, Dept Radiat Oncol, Philadelphia, PA 19111 USA. [Ramkissoon, Shakti H.; Santagata, Sandro] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Alexander, BM (reprint author), Dana Farber Brigham & Womens Canc Ctr, Dept Radiat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM bmalexander@lroc.harvard.edu NR 22 TC 13 Z9 13 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 IS 11 BP 1547 EP 1553 DI 10.1093/neuonc/nou098 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AT0MX UT WOS:000344631200014 PM 24891451 ER PT J AU Chen, TC Chen, PP Francis, BA Junk, AK Smith, SD Singh, K Lin, SC AF Chen, Teresa C. Chen, Philip P. Francis, Brian A. Junk, Anna K. Smith, Scott D. Singh, Kuldev Lin, Shan C. TI Pediatric Glaucoma Surgery A Report by the American Academy of Ophthalmology SO OPHTHALMOLOGY LA English DT Article ID PRIMARY CONGENITAL GLAUCOMA; DIODE-LASER CYCLOPHOTOCOAGULATION; CHRONIC CHILDHOOD UVEITIS; AHMED VALVE IMPLANTATION; TERM-FOLLOW-UP; 1ST 2 YEARS; MITOMYCIN-C; 360-DEGREES TRABECULOTOMY; PRIMARY TRABECULECTOMY; SURGICAL TECHNIQUE AB Objective: To review the current published literature to evaluate the success rates and long-term problems associated with surgery for pediatric glaucoma. Methods: Literature searches of the PubMed and Cochrane Library databases were last conducted in May 2012. The search yielded 838 potentially relevant citations, of which 273 were in non-English languages. The titles and abstracts of these articles were reviewed by the authors, and 364 were selected for possible further review. Members of the Ophthalmic Technology Assessment Committee Glaucoma Panel reviewed the full text of these articles and used the 36 that met inclusion and exclusion criteria for this Ophthalmic Technology Assessment. There were no studies on the topic that provided level I evidence. The assessment included only level II and level III studies. Results: Surgeons treat pediatric glaucoma most commonly with goniotomy, trabeculotomy, trabeculectomy, combined trabeculotomy and trabeculectomy, tube shunt surgery, cyclodestruction, and deep sclerectomy. Certain surgical options seem better for specific diagnoses, such as primary congenital glaucoma, aphakic glaucoma, and glaucomas associated with other ocular or systemic anomalies. Conclusions: There are many surgical options for the treatment of the pediatric glaucomas. The relative efficacy of these various procedures for particular diagnoses and clinical situations should be weighed against the specific risks associated with the procedures for individual patients. (C) 2014 by the American Academy of Ophthalmology. C1 [Chen, Teresa C.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Glaucoma Serv, Boston, MA USA. [Chen, Philip P.] Univ Washington, Dept Ophthalmol, Seattle, WA 98195 USA. [Francis, Brian A.] Univ Calif Los Angeles, David Geffen Sch Med, Doheny Eye Inst, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Junk, Anna K.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Smith, Scott D.] Cleveland Clin Abu Dhabi, Abu Dhabi, U Arab Emirates. [Singh, Kuldev] Stanford Univ, Sch Med, Stanford, CA USA. [Lin, Shan C.] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA USA. RP Chen, TC (reprint author), Amer Acad Ophthalmol, Qual Care & Knowledge Base Dev, POB 7424, San Francisco, CA 94120 USA. FU American Academy of Ophthalmology FX Funded without commercial support by the American Academy of Ophthalmology. NR 51 TC 12 Z9 12 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2014 VL 121 IS 11 BP 2107 EP 2115 DI 10.1016/j.ophtha.2014.05.010 PG 9 WC Ophthalmology SC Ophthalmology GA AS8DM UT WOS:000344480400014 PM 25066765 ER PT J AU Fernandes, J Austen, WG AF Fernandes, Justin Austen, William G., Jr. TI Reply: Prevention of Capsular Contracture with Photochemical Tissue Passivation SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Letter C1 [Fernandes, Justin; Austen, William G., Jr.] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. RP Austen, WG (reprint author), Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, 15 Parkman St,WAC 435, Boston, MA 02114 USA. EM wausten@partners.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD NOV PY 2014 VL 134 IS 5 BP 849E EP 850E DI 10.1097/PRS.0000000000000628 PG 2 WC Surgery SC Surgery GA AS9EN UT WOS:000344546000026 PM 25347665 ER PT J AU Goldstein, JM Cherkerzian, S Seidman, LJ Donatelli, JAL Remington, AG Tsuang, MT Hornig, M Buka, SL AF Goldstein, J. M. Cherkerzian, S. Seidman, L. J. Donatelli, J. -A. L. Remington, A. G. Tsuang, M. T. Hornig, M. Buka, S. L. TI Prenatal maternal immune disruption and sex-dependent risk for psychoses SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Fetal programming; inflammation; psychoses; schizophrenia; sex differences ID PITUITARY-ADRENAL AXIS; NEW-ENGLAND FAMILY; BRAIN-DEVELOPMENT; ANIMAL-MODELS; PROINFLAMMATORY CYTOKINES; INFLAMMATORY RESPONSE; ADULT SCHIZOPHRENIA; STEROID-HORMONES; NERVOUS-SYSTEM; FETAL-BRAIN AB Background. Previous studies suggest that abnormalities in maternal immune activity during pregnancy alter the offspring's brain development and are associated with increased risk for schizophrenia (SCZ) dependent on sex. Method. Using a nested case-control design and prospectively collected prenatal maternal sera from which interleukin (IL)-1 beta, IL-8, IL-6, tumor necrosis factor (TNF)-alpha and IL-10 were assayed, we investigated sex-dependent associations between these cytokines and 88 psychotic cases [SCZ=44; affective psychoses (AP)=44] and 100 healthy controls from a pregnancy cohort followed for >40 years. Analyses included sex-stratified non-parametric tests adjusted for multiple comparisons to screen cytokines associated with SCZ risk, followed by deviant subgroup analyses using generalized estimating equation (GEE) models. Results. There were higher prenatal IL-6 levels among male SCZ than male controls, and lower TNF-alpha levels among female SCZ than female controls. The results were supported by deviant subgroup analyses with significantly more SCZ males with high IL-6 levels (>highest quartile) compared with controls [odd ratio (OR)(75)=3.33, 95% confidence interval (CI) 1.13-9.82], and greater prevalence of low TNF-alpha levels (2.5, >4.0, and >6.5 ng/mL). METHODS We conducted a cross-sectional study of 323,426 men aged >= 65 years who had a screening PSA test in 2003 at a Veterans Affairs facility. The primary predictor was the use of statin medications at the time of index screening PSA test. The main outcome was the screening PSA value. Poisson regressions were performed to calculate adjusted relative risks for having an abnormal screening PSA result according to statin usage. RESULTS Percentages of men with PSA results exceeding commonly used thresholds of >2.5, >4.0, and >6.5 ng/mL were 21.0%, 7.6%, and 1.6%, respectively. These percentages decreased with statin use, increasing statin dose, duration of statin use, and potency of the statin. For example, after adjusting for age, the percentage of men having a PSA level >4.0 ng/mL ranged from 8.2% in non-statin users to 6.2% in men prescribed with >40 mg of simvastatin dose. Adjusted relative risks of having a PSA level >4.0 ng/mL were 0.89 (95% confidence interval [CI], 0.86-0.93), 0.87 (95% CI, 0.84-0.91), and 0.83 (95% CI, 0.80-0.87), respectively for men on simvastatin dose of 5-20, >20-40, and >40 mg vs non-statin users. CONCLUSION Statin use is associated with a reduction in the probability that an older man will have an abnormal screening PSA result, regardless of the PSA threshold. This reduction is more pronounced with higher statin dose, longer statin duration, and higher statin potency. (C) 2014 Elsevier Inc. C1 Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94121 USA. Univ Calif San Francisco, San Francisco VA Med Ctr, San Francisco, CA 94121 USA. Duke Univ, Durham VA Med Ctr, Durham, NC USA. Duke Univ, Duke Prostate Ctr, Durham, NC USA. Univ New Mexico, New Mexico VA Hlth Care Syst, Albuquerque, NM 87131 USA. Univ New Mexico, Dept Med, Albuquerque, NM 87131 USA. RP Shi, Y (reprint author), Univ Calif San Francisco, VA Med Ctr, Div Geriatr, 181G,4150 Clement St, San Francisco, CA 94121 USA. EM Ying.Shi2@va.gov FU National Cancer Institute at the National Institutes of Health [R01 CA134425]; National Institute on Aging at the National Institutes of Health [K24AG041180, K24CA160653]; New Mexico Veterans Affairs Health Care System FX This work was supported by grant R01 CA134425 from the National Cancer Institute at the National Institutes of Health (Louise C. Walter, Stephen J. Freedland, and Richard M. Hoffman), by grant K24AG041180 from the National Institute on Aging at the National Institutes of Health (Louise C. Walter), by grant K24CA160653 from the National Cancer Institute at the National Institutes of Health (Stephen J. Freedland), and by the New Mexico Veterans Affairs Health Care System (Richard M. Hoffman). NR 29 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD NOV PY 2014 VL 84 IS 5 BP 1058 EP 1064 DI 10.1016/j.urology.2014.06.069 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AS8CU UT WOS:000344478700024 PM 25443902 ER PT J AU Shi, Y Boscardin, WJ Walter, LC AF Shi, Ying Boscardin, W. John Walter, Louise C. TI Statin Medications Are Associated With a Lower Probability of Having an Abnormal Screening Prostate-specific Antigen Result REPLY SO UROLOGY LA English DT Editorial Material C1 [Shi, Ying] San Francisco VA Med Ctr, Div Geriatr, San Francisco, CA 94121 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Shi, Y (reprint author), San Francisco VA Med Ctr, Div Geriatr, San Francisco, CA 94121 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD NOV PY 2014 VL 84 IS 5 BP 1065 EP 1065 DI 10.1016/j.urology.2014.06.072 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA AS8CU UT WOS:000344478700026 PM 25443904 ER PT J AU Zhang, Q Siroky, M Yang, JH Zhao, ZH Azadzoi, K AF Zhang, Qi Siroky, Mike Yang, Jing-Hua Zhao, Zuohui Azadzoi, Kazem TI Effects of Ischemia and Oxidative Stress on Bladder Purinoceptors Expression SO UROLOGY LA English DT Article ID PURINERGIC RECEPTOR EXPRESSION; URINARY-TRACT SYMPTOMS; P2X RECEPTORS; DETRUSOR OVERACTIVITY; ATROPINE-RESISTANT; RAT; CONTRACTIONS; PRESSURE; CULTURES; RELEASE AB OBJECTIVE To study the effects of chronic ischemia on bladder purinoceptors. A close correlation between bladder ischemia and lower urinary tract symptoms has been reported. Purinoceptors contribute to important aspects of bladder function including sensation, neural signaling, and voiding contraction. Our goal was to examine purinoceptors expression in the ischemic overactive bladder. MATERIALS AND METHODS Moderate bladder ischemia was produced in rabbits by creating bilateral iliac artery atherosclerosis. After 8 weeks, bladder blood flow was measured, and cystometrograms were obtained. Bladder tissues from 8-week ischemic and age-matched control bladders were processed for the analysis of oxidative stress markers, P2X and P2Y purinoceptors expression, and transmission electron microscopy. RESULTS Arterial atherosclerosis significantly decreased bladder blood flow. Markers of oxidative stress characterized by increased levels of advanced oxidation protein products and malondialdehyde were evident in the ischemic bladder tissues. Chronic ischemia and oxidative stress decreased the bladder capacity and increased spontaneous bladder contractions. Bladder pressure at micturition and intravesical pressure rise during contractions tended to be greater in the ischemic bladder but did not reach significance. Transmission electron microscopy showed smooth muscle cell and microvasculature structural damage and diffuse fibrosis. These changes in the ischemic bladder were associated with significant increases in purinoceptors P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7 expression. The P2Y isoforms were not expressed in the rabbit bladder. CONCLUSION Structural and functional changes in the chronically ischemic bladder were associated with upregulation of P2X receptor isoforms. Increased P2X expression may play a role in ischemia-induced bladder overactivity and noncompliance. C1 [Zhang, Qi; Siroky, Mike; Yang, Jing-Hua; Zhao, Zuohui; Azadzoi, Kazem] Boston Univ, Sch Med, VA Boston Healthcare Syst, Dept Urol, Boston, MA 02130 USA. RP Azadzoi, K (reprint author), Boston Univ, VA Boston Healthcare Syst, Sch Med, Bldg 1A,Room 315 151,150 South Huntington Ave, Boston, MA 02130 USA. EM kazadzoi@bu.edu FU grant BLR&D MERIT from U.S. Department of Veterans Affairs [1I01BX001428-01A1] FX This study was supported by grant BLR&D MERIT 1I01BX001428-01A1 from the U.S. Department of Veterans Affairs. NR 30 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD NOV PY 2014 VL 84 IS 5 AR 1249.e1 DI 10.1016/j.urology.2014.07.023 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AS8CU UT WOS:000344478700077 PM 25219364 ER PT J AU Pang, J Borjeson, TM Muthupalani, S Ducore, RM Carr, CA Feng, Y Sullivan, MP Cristofaro, V Luo, J Lindstrom, JM Fox, JG AF Pang, J. Borjeson, T. M. Muthupalani, S. Ducore, R. M. Carr, C. A. Feng, Y. Sullivan, M. P. Cristofaro, V. Luo, J. Lindstrom, J. M. Fox, J. G. TI Megaesophagus in a Line of Transgenic Rats: A Model of Achalasia SO VETERINARY PATHOLOGY LA English DT Article DE achalasia; esophagus; imaging; immunohistochemistry; megaesophagus; muscle studies; Pvrl3; ultrastructure; rat ID LOWER ESOPHAGEAL SPHINCTER; ACQUIRED MYASTHENIA-GRAVIS; MYENTERIC GANGLIAL CELLS; NITRIC-OXIDE SYNTHASE; RIGHT AORTIC-ARCH; CONGENITAL ACHALASIA; OUTFLOW OBSTRUCTION; RISK-FACTORS; MUTANT MICE; DOGS AB Megaesophagus is defined as the abnormal enlargement or dilatation of the esophagus, characterized by a lack of normal contraction of the esophageal walls. This is called achalasia when associated with reduced or no relaxation of the lower esophageal sphincter (LES). To date, there are few naturally occurring models for this disease. A colony of transgenic (Pvrl3-Cre) rats presented with megaesophagus at 3 to 4 months of age; further breeding studies revealed a prevalence of 90% of transgene-positive animals having megaesophagus. Affected rats could be maintained on a total liquid diet long term and were shown to display the classic features of dilated esophagus, closed lower esophageal sphincter, and abnormal contractions on contrast radiography and fluoroscopy. Histologically, the findings of muscle degeneration, inflammation, and a reduced number of myenteric ganglia in the esophagus combined with ultrastructural lesions of muscle fiber disarray and mitochondrial changes in the striated muscle of these animals closely mimic that seen in the human condition. Muscle contractile studies looking at the response of the lower esophageal sphincter and fundus to electrical field stimulation, sodium nitroprusside, and L-nitro-L-arginine methyl ester also demonstrate the similarity between megaesophagus in the transgenic rats and patients with achalasia. No primary cause for megaesophagus was found, but the close parallel to the human form of the disease, as well as ease of care and manipulation of these rats, makes this a suitable model to better understand the etiology of achalasia as well as study new management and treatment options for this incurable condition. C1 [Pang, J.; Borjeson, T. M.; Muthupalani, S.; Ducore, R. M.; Feng, Y.; Fox, J. G.] MIT, Div Comparat Med, Cambridge, MA 02139 USA. [Carr, C. A.] MIT, Picower Inst Learning & Memory, RIKEN MIT Ctr Neural Circuit Genet, Cambridge, MA 02139 USA. [Sullivan, M. P.; Cristofaro, V.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, West Roxbury, MA USA. [Luo, J.; Lindstrom, J. M.] Univ Penn, Sch Med, Dept Neurosci, Philadelphia, PA 19104 USA. RP Fox, JG (reprint author), MIT, Div Comparat Med, 77 Massachusetts Ave,16-825, Cambridge, MA 02139 USA. EM jgfox@mit.edu OI Ducore, Rebecca/0000-0001-5223-2266 FU National Institutes of Health [T32OD011141, P30ES002109] FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the National Institutes of Health (grant numbers T32OD011141 and P30ES002109). NR 90 TC 1 Z9 1 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0300-9858 EI 1544-2217 J9 VET PATHOL JI Vet. Pathol. PD NOV PY 2014 VL 51 IS 6 BP 1187 EP 1200 DI 10.1177/0300985813519136 PG 14 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA AT1GQ UT WOS:000344681800018 PM 24457157 ER PT J AU Shi, M Liu, CQ Cook, TJ Bullock, KM Zhao, YC Ginghina, C Li, YF Aro, P Dator, R He, CM Hipp, MJ Zabetian, CP Peskind, E Hu, SC Quinn, JF Galasko, DR Banks, WA Zhang, J AF Shi, Min Liu, Changqin Cook, Travis J. Bullock, Kristin M. Zhao, Yanchun Ginghina, Carmen Li, Yanfei Aro, Patrick Dator, Romel He, Chunmei Hipp, Michael J. Zabetian, Cyrus P. Peskind, Elaine R. Hu, Shu-Ching Quinn, Joseph F. Galasko, Douglas R. Banks, William A. Zhang, Jing TI Plasma exosomal alpha-synuclein is likely CNS-derived and increased in Parkinson's disease SO ACTA NEUROPATHOLOGICA LA English DT Article DE Parkinson's disease; Exosome; alpha-synuclein; Biomarker; Plasma ID BLOOD-BRAIN-BARRIER; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; LEWY BODIES; NERVOUS-SYSTEM; AMYLOID-BETA; BIOMARKER; DJ-1; MICROVESICLES; REABSORPTION AB Extracellular alpha-synuclein is important in the pathogenesis of Parkinson's disease (PD) and also as a potential biomarker when tested in the cerebrospinal fluid (CSF). The performance of blood plasma or serum alpha-synuclein as a biomarker has been found to be inconsistent and generally ineffective, largely due to the contribution of peripherally derived alpha-synuclein. In this study, we discovered, via an intracerebroventricular injection of radiolabeled alpha-synuclein into mouse brain, that CSF alpha-synuclein was readily transported to blood, with a small portion being contained in exosomes that are relatively specific to the central nervous system (CNS). Consequently, we developed a technique to evaluate the levels of alpha-synuclein in these exosomes in individual plasma samples. When applied to a large cohort of clinical samples (267 PD, 215 controls), we found that in contrast to CSF alpha-synuclein concentrations, which are consistently reported to be lower in PD patients compared to controls, the levels of plasma exosomal alpha-synuclein were substantially higher in PD patients, suggesting an increased efflux of the protein to the peripheral blood of these patients. Furthermore, although no association was observed between plasma exosomal and CSF alpha-synuclein, a significant correlation between plasma exosomal alpha-synuclein and disease severity (r = 0.176, p = 0.004) was observed, and the diagnostic sensitivity and specificity achieved by plasma exosomal alpha-synuclein were comparable to those determined by CSF alpha-synuclein. Further studies are clearly needed to elucidate the mechanism involved in the transport of CNS alpha-synuclein to the periphery, which may lead to a more convenient and robust assessment of PD clinically. C1 [Shi, Min; Zhao, Yanchun; Ginghina, Carmen; Aro, Patrick; Dator, Romel; Hipp, Michael J.; Zhang, Jing] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA. [Liu, Changqin] Xiamen Univ, Affiliated Hosp 1, Dept Endocrinol & Diabet, Xiamen 361003, Fujian, Peoples R China. [Cook, Travis J.; Li, Yanfei] Univ Washington, Dept Environm & Occupat Hlth Sci, Sch Publ Hlth, Seattle, WA 98195 USA. [Bullock, Kristin M.; Zabetian, Cyrus P.; Hu, Shu-Ching; Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Bullock, Kristin M.; Banks, William A.] Univ Washington, Sch Med, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. [He, Chunmei] Xiamen Univ, Affiliated Hosp 1, Dept Endocrinol & Diabet, Xiamen Diabet Inst, Xiamen 361003, Fujian, Peoples R China. [Zabetian, Cyrus P.; Hu, Shu-Ching] Vet Affairs Puget Sound Hlth Care Syst, Parkinsons Dis Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Zabetian, Cyrus P.; Hu, Shu-Ching] Univ Washington, Dept Neurol, Sch Med, Seattle, WA 98195 USA. [Peskind, Elaine R.] Univ Washington, Dept Psychiat & Behav Sci, Sch Med, Seattle, WA 98195 USA. [Peskind, Elaine R.] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Quinn, Joseph F.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Galasko, Douglas R.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. RP Zhang, J (reprint author), Univ Washington, Sch Med, Dept Pathol, 325 9th Ave,HMC Box 359635, Seattle, WA 98195 USA. EM mshi70@u.washington.edu; zhangj@u.washington.edu RI Shi, Min/G-6165-2012 OI Shi, Min/0000-0002-6901-2558 FU National Institutes of Health (NIH) [U01 NS082137, P42 ES004696-5897, P30 ES007033-6364, R01 AG033398, R01 ES016873, R01 ES019277, R01 NS057567, P50 NS062684-6221, R01 NS065070, P50 AG005131]; NIH [P50 AG003156-30]; National Institute of Neurological Disorders and Stroke/NIH [R21 NS085425]; University of Washington's Proteomics Resource [UWPR95794] FX We thank Drs. Honglian Li and Sangwoo Jung for their kind help on EM method development, and Dr. Ane Korff for her assistance in Western blot confirmation. We also deeply appreciate the patients and participants for their generous participation and donation of samples. This study was supported by generous grants from the National Institutes of Health (NIH) (U01 NS082137, P42 ES004696-5897, P30 ES007033-6364, R01 AG033398, R01 ES016873, R01 ES019277, R01 NS057567, and P50 NS062684-6221 to JZ, R01 NS065070 to CPZ, and P50 AG005131 to DRG), and partially by a pilot study award from the NIH-sponsored ADRC at the UW (P50 AG003156-30) and a National Institute of Neurological Disorders and Stroke/NIH award R21 NS085425 to MS. It was also supported in part by the University of Washington's Proteomics Resource (UWPR95794). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. NR 73 TC 43 Z9 44 U1 4 U2 26 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD NOV PY 2014 VL 128 IS 5 BP 639 EP 650 DI 10.1007/s00401-014-1314-y PG 12 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA AS1RL UT WOS:000344058200003 PM 24997849 ER PT J AU Bechet, D Gielen, GGH Korshunov, A Pfister, SM Rousso, C Faury, D Fiset, PO Benlimane, N Lewis, PW Lu, C Allis, CD Kieran, MW Ligon, KL Pietsch, T Ellezam, B Albrecht, S Jabado, N AF Bechet, Denise Gielen, Gerrit G. H. Korshunov, Andrey Pfister, Stefan M. Rousso, Caterina Faury, Damien Fiset, Pierre-Olivier Benlimane, Naciba Lewis, Peter W. Lu, Chao Allis, C. David Kieran, Mark W. Ligon, Keith L. Pietsch, Torsten Ellezam, Benjamin Albrecht, Steffen Jabado, Nada TI Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas SO ACTA NEUROPATHOLOGICA LA English DT Article DE K27M; Histone 3 variants; IHC; K27 trimethylation; High-grade astrocytomas ID INTRINSIC PONTINE GLIOMA; ACTIVATING ACVR1 MUTATIONS; PEDIATRIC GLIOBLASTOMA; DISTINCT SUBGROUPS; SOMATIC MUTATIONS; K27M MUTATION; MEDULLOBLASTOMA; H3F3A; TUMORS; EXPRESSION AB Studies in pediatric high-grade astrocytomas (HGA) by our group and others have uncovered recurrent somatic mutations affecting highly conserved residues in histone 3 (H3) variants. One of these mutations leads to analogous p.Lys27Met (K27M) mutations in both H3.3 and H3.1 variants, is associated with rapid fatal outcome, and occurs specifically in HGA of the midline in children and young adults. This includes diffuse intrinsic pontine gliomas (80 %) and thalamic or spinal HGA (> 90 %), which are surgically challenging locations with often limited tumor material available and critical need for specific histopathological markers. Here, we analyzed formalin-fixed paraffin-embedded tissues from 143 pediatric HGA and 297 other primary brain tumors or normal brain. Immunohistochemical staining for H3K27M was compared to tumor genotype, and also compared to H3 tri-methylated lysine 27 (H3K27me3) staining, previously shown to be drastically decreased in samples carrying this mutation. There was a 100 % concordance between genotype and immunohistochemical analysis of H3K27M in tumor samples. Mutant H3K27M was expressed in the majority of tumor cells, indicating limited intra-tumor heterogeneity for this specific mutation within the limits of our dataset. Both H3.1 and H3.3K27M mutants were recognized by this antibody while non-neoplastic elements, such as endothelial and vascular smooth muscle cells or lymphocytes, did not stain. H3K27me3 immunoreactivity was largely mutually exclusive with H3K27M positivity. These results demonstrate that mutant H3K27M can be specifically identified with high specificity and sensitivity using an H3K27M antibody and immunohistochemistry. Use of this antibody in the clinical setting will prove very useful for diagnosis, especially in the context of small biopsies in challenging midline tumors and will help orient care in the context of the extremely poor prognosis associated with this mutation. C1 [Bechet, Denise; Jabado, Nada] McGill Univ, Dept Expt Med, Montreal, PQ H3Z 2Z3, Canada. [Bechet, Denise; Jabado, Nada] McGill Univ, Dept Human Genet, Montreal, PQ H3Z 2Z3, Canada. [Gielen, Gerrit G. H.; Pietsch, Torsten] Univ Bonn, Med Ctr, Inst Neuropathol, D-53127 Bonn, Germany. [Korshunov, Andrey] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, Heidelberg, Germany. [Pfister, Stefan M.] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany. [Rousso, Caterina; Faury, Damien; Jabado, Nada] McGill Univ, Dept Pediat, Ctr Hlth, Montreal Childrens Hosp, Montreal, PQ H3Z 2Z3, Canada. [Fiset, Pierre-Olivier; Albrecht, Steffen] McGill Univ, Montreal Childrens Hosp, Ctr Hlth, Dept Pathol, Montreal, PQ H3Z 2Z3, Canada. [Lewis, Peter W.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Biomol Chem, Madison, WI USA. [Lu, Chao; Allis, C. David] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10021 USA. [Kieran, Mark W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Pediat Hematol Oncol,Dept Pediat Oncol,Boston, Boston, MA 02115 USA. [Ligon, Keith L.] Harvard Univ, Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Ellezam, Benjamin] Univ Montreal, Dept Pathol, CHU Ste Justine, Montreal, PQ H3C 3J7, Canada. [Ellezam, Benjamin] Hop Ste Justine, Montreal, PQ, Canada. [Albrecht, Steffen] Montreal Childrens Hosp, Montreal, PQ H3H 1P3, Canada. RP Jabado, N (reprint author), McGill Univ, Dept Expt Med, 4060 Ste Catherine West,PT239, Montreal, PQ H3Z 2Z3, Canada. EM Benjamin.ellezam@umontreal.ca; steffen.albrecht@hotmail.com; nada.jabado@mcgill.ca RI Gielen, Gerrit /B-4244-2015; Pfister, Stefan/F-6860-2013; OI Pfister, Stefan/0000-0002-5447-5322; Lewis, Peter/0000-0002-9816-7823; Kieran, Mark/0000-0003-2184-7692 FU Genome Canada; Genome Quebec; Institute for Cancer Research of the Canadian Institutes for Health Research (CIHR) McGill University; Montreal Children's Hospital Foundation; Chercheur Clinicien Senior Award; T.D. Trust/Montreal Children's Hospital Foundation FX This work was performed within the context of the I-CHANGE consortium (International Childhood Astrocytoma iNntegrated Genomics and Epigenomics consortium) and supported by funding from Genome Canada, Genome Quebec, The Institute for Cancer Research of the Canadian Institutes for Health Research (CIHR) McGill University and the Montreal Children's Hospital Foundation. N. Jabado is a member of the Penny Cole lab and the recipient of a Chercheur Clinicien Senior Award. D. B. is supported by a studentship from the T.D. Trust/Montreal Children's Hospital Foundation. The authors would like to thank Leonie Michael for critical reading of the manuscript. NR 26 TC 23 Z9 25 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD NOV PY 2014 VL 128 IS 5 BP 733 EP 741 DI 10.1007/s00401-014-1337-4 PG 9 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA AS1RL UT WOS:000344058200010 PM 25200321 ER PT J AU Behlau, I Martin, KV Martin, JN Naumova, EN Cadorette, JJ Sforza, JT Pineda, R Dohlman, CH AF Behlau, Irmgard Martin, Kathryn V. Martin, Jacqueline N. Naumova, Elena N. Cadorette, James J. Sforza, J. Tammy Pineda, Roberto, II Dohlman, Claes H. TI Infectious endophthalmitis in Boston keratoprosthesis: incidence and prevention SO ACTA OPHTHALMOLOGICA LA English DT Article DE Boston keratoprosthesis; endophthalmitis; ocular infections; ocular prophylaxis ID COAGULASE-NEGATIVE STAPHYLOCOCCI; UNIVERSITY-OF-CALIFORNIA; STEVENS-JOHNSON-SYNDROME; I KERATOPROSTHESIS; TYPE-1 KERATOPROSTHESIS; PERMANENT KERATOPROSTHESIS; CORNEAL TRANSPLANTATION; CATARACT-SURGERY; GLAUCOMA; OUTCOMES AB PurposeTo determine the cumulative worldwide incidence of infectious endophthalmitis and associated vision loss after Boston keratoprosthesis (B-KPro) Type I/II implantation and to propose both safe and inexpensive prophylactic antibiotic regimens. MethodsTwo retrospective methods were used to determine the incidence, visual outcomes and aetiologies of infectious endophthalmitis associated with the B-KPro divided per decade: (i) systematic review of the literature from 1990 through January 2013 and (ii) a surveillance survey sent to all surgeons who implanted B-KPros through 2010 with 1-year minimum follow-up. In addition, a single-Boston surgeon 20-year experience was examined. ResultsFrom 1990 through 2010, there were 4729 B-KPros implanted worldwide by 209 U.S. surgeons and 159 international surgeons. The endophthalmitis cumulative mean incidence declined from 12% during its first decade of use to about 3% during its second decade in the Unites States and about 5% internationally during the second decade. There remains a large incidence range both in the United States (1-12.5%) and internationally (up to 17%). Poor compliance with daily topical antibiotics is an important risk factor. While Gram-positive organisms remained dominant, fungal infections emerged during the second decade. ConclusionsDaily prophylactic topical antibiotics have dramatically reduced the endophthalmitis incidence. Although Gram-positive organisms are the most common aetiology, antimicrobials must be inclusive of Gram-negative organisms. Selection of prophylactic regimens should be tailored to local antibiotic susceptibility patterns, be cost-effective, and should not promote the emergence of antimicrobial resistance. An example of a broad-spectrum, low-cost prophylactic option for non-autoimmune patients includes trimethoprim/polymyxinB once daily. C1 [Behlau, Irmgard; Martin, Kathryn V.; Martin, Jacqueline N.; Pineda, Roberto, II; Dohlman, Claes H.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, Boston, MA USA. [Behlau, Irmgard] Tufts Univ, Sch Med, Tufts Sackler Grad Sch Biomed Sci, Boston, MA 02111 USA. [Behlau, Irmgard] Harvard Univ, Sch Med, Mt Auburn Hosp, Div Infect Dis,Dept Med, Cambridge, MA 02138 USA. [Behlau, Irmgard] Tufts Univ, Sch Med, Newton Wellesley Hosp, Div Infect Dis,Dept Med, Newton, MA USA. [Naumova, Elena N.] Tufts Univ, Sch Engn, Tufts Initiat Forecasting & Modeling Infect Dis I, Medford, MA 02155 USA. [Cadorette, James J.] Massachusetts Eye & Ear Infirm, Henry Whittier Porter Bacteriol Lab, Boston, MA 02114 USA. [Sforza, J. Tammy] Massachusetts Eye & Ear Infirm, Dept Pharm, Boston, MA 02114 USA. RP Behlau, I (reprint author), Tufts Univ, Sch Med, Dept Mol Biol & Microbiol & Ophthalmol, Tufts Sackler Grad Sch Biomed Sci, M&V 429,136 Harrison Ave, Boston, MA 02111 USA. EM irmgard.behlau@tufts.edu FU Fight for Sight; MEEI B-KPro Fund FX This work was made possible by the generous support of Fight for Sight Grant-In-Aid (IB) and MEEI B-KPro Fund. NR 79 TC 13 Z9 13 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-375X EI 1755-3768 J9 ACTA OPHTHALMOL JI Acta Ophthalmol. PD NOV PY 2014 VL 92 IS 7 BP e546 EP e555 DI 10.1111/aos.12309 PG 10 WC Ophthalmology SC Ophthalmology GA AS3FN UT WOS:000344162700007 PM 24460594 ER PT J AU Sahin, I Azab, F Mishima, Y Moschetta, M Tsang, B Glavey, SV Manier, S Zhang, Y Sacco, A Roccaro, AM Azab, AK Ghobrial, IM AF Sahin, Ilyas Azab, Feda Mishima, Yuji Moschetta, Michele Tsang, Brian Glavey, Siobhan V. Manier, Salomon Zhang, Yu Sacco, Antonio Roccaro, Aldo M. Azab, Abdel Kareem Ghobrial, Irene M. TI Targeting survival and cell trafficking in multiple myeloma and Waldenstrom macroglobulinemia using pan-class I PI3K inhibitor, buparlisib SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MTOR INHIBITOR; PHOSPHOINOSITIDE 3-KINASES; SYNERGISTIC ACTIVITY; MAMMALIAN TARGET; AKT PATHWAY; NVP-BKM120; IDELALISIB; RAPAMYCIN; COMBINATION AB The phosphatidylinositol-3 kinase (PI3K) pathway is activated in multiple myeloma (MM) and Waldenstrom Macroglobulenima (WM), and plays a crucial role in tumor progression and drug resistance. In this study, we characterized the role of pan-class I PI3K inhibition on cell trafficking and survival of MM and WM cells. We tested the effect of pan-class I PI3K inhibition by siRNA silencing or pharmacologic inhibition with buparlisib on MM cell survival, apoptosis and cell cycle in vitro and tumor growth and mobilization of MM cells in vivo. We then evaluated buparlisib-dependent mechanisms of induced MM cell mobilization. Moreover, the effect of buparlisib on cell survival, apoptosis, and adhesion of WM cells to bone marrow stromal cells (BMSCs) has been evaluated. We showed that buparlisib induced toxicity in MM cells, supported by induction of apoptosis and cell cycle arrest. Buparlisib was also found to reduce tumor progression in vivo. Importantly, buparlisib enhanced MM cell mobilization in vivo which was driven by decreased adhesion of MM cells to BMSCs and increased chemotaxis via up-regulation of CXCR4 expression. Similar to its effects on MM cells, buparlisib also induced cell survival and apoptosis, and decreased adhesion in WM cells. These data highlight the critical contribution of class I PI3K signaling to the regulation of survival and cell dissemination in B-cell malignancies. Am. J. Hematol. 89:1030-1036, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Sahin, Ilyas; Azab, Feda; Mishima, Yuji; Moschetta, Michele; Tsang, Brian; Glavey, Siobhan V.; Manier, Salomon; Zhang, Yu; Sacco, Antonio; Roccaro, Aldo M.; Azab, Abdel Kareem; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Azab, Feda; Azab, Abdel Kareem] Washington Univ St Louis, Sch Med, Div Canc Biol, Dept Radiat Oncol, St Louis, MO USA. RP Ghobrial, IM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu RI Sacco, Antonio/K-4681-2016; OI Sacco, Antonio/0000-0003-2945-9416; Roccaro, Aldo/0000-0002-1872-5128 FU International Waldenstrom Macroglobulinemia Foundation, Kirsch Lab; Heje Fellowship [R01CA154648, 1R01F0003743] FX Contract grant sponsor: International Waldenstrom Macroglobulinemia Foundation, Kirsch Lab (to W. M.), and Heje Fellowship (to W. M.); Contract grant numbers: R01CA154648; 1R01F0003743. NR 49 TC 6 Z9 6 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD NOV PY 2014 VL 89 IS 11 BP 1030 EP 1036 DI 10.1002/ajh.23814 PG 7 WC Hematology SC Hematology GA AS1BA UT WOS:000344010100008 PM 25060991 ER PT J AU Hasserjian, RP Campigotto, F Klepeis, V Fu, B Wang, SA Bueso-Ramos, C Cascio, MJ Rogers, HJ Hsi, ED Soderquist, C Bagg, A Yan, J Ochs, R Orazi, A Moore, F Mahmoud, A George, TI Foucar, K Odem, J Booth, C Morice, W DeAngelo, DJ Steensma, D Stone, RM Neuberg, D Arber, DA AF Hasserjian, Robert Paul Campigotto, Federico Klepeis, Veronica Fu, Bin Wang, Sa A. Bueso-Ramos, Carlos Cascio, Michael Joseph Rogers, Heesun Joyce Hsi, Eric Darryl Soderquist, Craig Bagg, Adam Yan, Jiong Ochs, Rachel Orazi, Attilio Moore, Frank Mahmoud, Amer George, Tracy Irene Foucar, Kathryn Odem, Jamie Booth, Cassie Morice, William DeAngelo, Daniel J. Steensma, David Stone, Richard Maury Neuberg, Donna Arber, Daniel Alan TI De novo acute myeloid leukemia with 20-29% blasts is less aggressive than acute myeloid leukemia with >= 30% blasts in older adults: a Bone Marrow Pathology Group study SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID CONVENTIONAL CARE REGIMENS; AML-TYPE CHEMOTHERAPY; MYELODYSPLASTIC SYNDROMES; REFRACTORY-ANEMIA; SCORING SYSTEM; INTENSIVE CHEMOTHERAPY; ELDERLY-PATIENTS; OPEN-LABEL; PHASE-III; SURVIVAL AB It is controversial whether acute myeloid leukemia (AML) patients with 20-29% bone marrow (BM) blasts, formerly referred to as refractory anemia with excess blasts in transformation (RAEBT), should be considered AML or myelodysplastic syndrome (MDS) for the purposes of treatment and prognostication. We retrospectively studied 571 de novo AML in patients aged > 50 years, including 142 RAEBT and 429 with 30% blasts (AML30), as well as 151 patients with 10-19% BM blasts (RAEB2). RAEBT patients were older and had lower white blood count, but higher hemoglobin, platelet count, and karyotype risk scores compared to AML30, while these features were similar to RAEB2. FLT3 and NPM1 mutations and monocytic morphology occurred more commonly in AML30 than in RAEBT. RAEBT patients were treated less often with induction therapy than AML30, whereas allogeneic stem cell transplant frequency was similar. The median and 4-year OS of RAEBT patients were longer than those of AML30 patients (20.5 vs 12.0 months and 28.6% vs 20.4%, respectively, P=0.003); this difference in OS was manifested in patients in the intermediate UKMRC karyotype risk group, whereas OS of RAEBT patients and AML30 patients in the adverse karyotype risk group were not significantly different. Multivariable analysis showed that RAEBT (P<0.0001), hemoglobin (P=0.005), UKMRC karyotype risk group (P=0.002), normal BM karyotype (P=0.004), treatment with induction therapy (P<0.0001), and stem cell transplant (P<0.0001) were associated with longer OS. Our findings favor considering de novo RAEBT as a favorable prognostic subgroup of AML. Am. J. Hematol. 89:E193-E199, 2014. (c) 2014 Wiley Periodicals, Inc. C1 [Hasserjian, Robert Paul; Klepeis, Veronica] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Campigotto, Federico; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Fu, Bin; Wang, Sa A.; Bueso-Ramos, Carlos] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA. [Cascio, Michael Joseph; Arber, Daniel Alan] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Rogers, Heesun Joyce; Hsi, Eric Darryl] Cleveland Clin, Dept Pathol, Cleveland, OH 44106 USA. [Soderquist, Craig; Bagg, Adam] Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA. [Yan, Jiong; Ochs, Rachel; Orazi, Attilio] Weill Cornell Med Coll, Dept Pathol, New York, NY USA. [Moore, Frank; Mahmoud, Amer; George, Tracy Irene; Foucar, Kathryn] Univ New Mexico, Hlth Sci Ctr, Dept Pathol, Albuquerque, NM 87131 USA. [Odem, Jamie; Booth, Cassie; Morice, William] Mayo Clin, Dept Pathol, Rochester, MN USA. [DeAngelo, Daniel J.; Steensma, David; Stone, Richard Maury] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Hasserjian, RP (reprint author), Massachusetts Gen Hosp, Dept Pathol, WRN244,55 Fruit St, Boston, MA 02114 USA. EM rhasserjian@partners.org OI Cascio, Michael/0000-0002-5537-7740 NR 29 TC 8 Z9 9 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD NOV PY 2014 VL 89 IS 11 BP E193 EP E199 DI 10.1002/ajh.23808 PG 7 WC Hematology SC Hematology GA AS1BA UT WOS:000344010100001 PM 25042343 ER PT J AU Batal, I Schlossman, RL Safa, K Rennke, HG Campenot, ES AF Batal, Ibrahim Schlossman, Robert L. Safa, Kassem Rennke, Helmut G. Campenot, Eric S. TI Anemia, Fatigue, and Late-Failing Kidney Transplant SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material C1 [Batal, Ibrahim; Rennke, Helmut G.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Batal, Ibrahim; Schlossman, Robert L.; Safa, Kassem; Rennke, Helmut G.] Harvard Univ, Sch Med, Boston, MA USA. [Schlossman, Robert L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Safa, Kassem] Brigham & Womens Hosp, Div Renal, Boston, MA 02115 USA. [Campenot, Eric S.] Columbia Univ, Dept Pathol & Cell Biol, Med Ctr, New York, NY 10032 USA. [Campenot, Eric S.] New York Presbyterian Hosp, New York, NY USA. RP Batal, I (reprint author), Columbia Univ, Dept Pathol & Cellular Biol, 630 W 168th St, New York, NY 10032 USA. EM ib2349@columbia.edu NR 4 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD NOV PY 2014 VL 64 IS 5 BP XVI EP XIX DI 10.1053/j.ajkd.2014.06.032 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA AS4IM UT WOS:000344237900002 PM 25344006 ER PT J AU Kalim, S Karumanchi, SA Thadhani, RI Berg, AH AF Kalim, Sahir Karumanchi, S. Ananth Thadhani, Ravi I. Berg, Anders H. TI Protein Carbamylation in Kidney Disease: Pathogenesis and Clinical Implications SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Carbamylation; uremia; posttranslational protein modification (PTM); pathophysiology; chronic kidney disease (CKD); end-stage renal disease (ESRD); cyanate; urea; inflammation; carbamoylation ID LOW-DENSITY-LIPOPROTEIN; CHRONIC-RENAL-FAILURE; SICKLE-CELL DISEASE; HEMOGLOBIN A(1C) LEVELS; ENDOTHELIAL-CELLS; UREMIC PATIENTS; SODIUM CYANATE; PLASMA-PROTEIN; AMINO-ACID; GLUTAMATE DEHYDROGENASE AB Carbamylation describes a nonenzymatic posttranslational protein modification mediated by cyanate, a dissociation product of urea. When kidney function declines and urea accumulates, the burden of carbamylation naturally increases. Free amino acids may protect proteins from carbamylation, and protein carbamylation has been shown to increase in uremic patients with amino acid deficiencies. Carbamylation reactions are capable of altering the structure and functional properties of certain proteins and have been implicated directly in the underlying mechanisms of various disease conditions. A broad range of studies has demonstrated how the irreversible binding of urea-derived cyanate to proteins in the human body causes inappropriate cellular responses leading to adverse outcomes such as accelerated atherosclerosis and inflammation. Given carbamylation's relationship to urea and the evidence that it contributes to disease pathogenesis, measurements of carbamylated proteins may serve as useful quantitative biomarkers of time-averaged urea concentrations while also offering risk assessment in patients with kidney disease. Moreover, the link between carbamylated proteins and disease pathophysiology creates an enticing therapeutic target for reducing the rate of carbamylation. This article reviews the biochemistry of the carbamylation reaction, its role in specific diseases, and the potential diagnostic and therapeutic implications of these findings based on recent advances. (C) 2014 by the National Kidney Foundation, Inc. C1 [Kalim, Sahir; Thadhani, Ravi I.] Massachusetts Gen Hosp, Div Nephrol, Dept Med, Boston, MA USA. [Kalim, Sahir; Karumanchi, S. Ananth; Thadhani, Ravi I.; Berg, Anders H.] Harvard Univ, Sch Med, Boston, MA USA. [Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA 02215 USA. [Karumanchi, S. Ananth] Howard Hughes Med Inst, Boston, MA 02115 USA. [Berg, Anders H.] Beth Israel Deaconess Med Ctr, Dept Pathol, Div Clin Chem, Boston, MA 02215 USA. RP Berg, AH (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave,Dana 576, Boston, MA 02215 USA. EM ahberg@bidmc.harvard.edu FU National Kidney Foundation Young Investigator award; National Institutes of Health [K24 DK094872]; Howard Hughes Medical Institute; American Diabetes Association Junior Faculty Award [1-11-JF22] FX Dr Kalim has received support from the National Kidney Foundation Young Investigator award; Dr Thadhani receives support from National Institutes of Health award K24 DK094872; Dr Karumanchi receives support from the Howard Hughes Medical Institute; and Dr Berg received support from the American Diabetes Association Junior Faculty Award (1-11-JF22). NR 130 TC 19 Z9 20 U1 2 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD NOV PY 2014 VL 64 IS 5 BP 793 EP 803 DI 10.1053/j.ajkd.2014.04.034 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA AS4IM UT WOS:000344237900021 PM 25037561 ER PT J AU Pennock, S Haddock, LJ Mukai, S Kazlauskas, A AF Pennock, Steven Haddock, Luis J. Mukai, Shizuo Kazlauskas, Andrius TI Vascular Endothelial Growth Factor Acts Primarily via Platelet-Derived Growth Factor Receptor alpha to Promote Proliferative Vitreoretinopathy SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID INTACT CAT EYE; RETINAL-DETACHMENT; PDGF RECEPTOR; RISK-FACTORS; IN-VIVO; VEGF-E; CELLS; P53; KINASES; ELECTRORETINOGRAM AB Proliferative vitreoretinopathy (PVR) is a nonneovascular blinding disease and the leading cause for failure in surgical repair of rhegmatogenous retinal detachments. Once formed, PVR is difficult to treat. Hence, there is an acute interest in developing approaches to prevent PVR. Of the many growth factors and cytokines that accumulate in vitreous as PVR develops, neutralizing vascular endothelial growth factor (VEGF) A has recently been found to prevent PVR in at least one animal model. The goal of this study was to test if Food and Drug Administration approved agents could protect the eye from PVR in multiple animal models and to further investigate the underlying mechanisms. Neutralizing VEGF with aflibercept (VEGF Trap-Eye) safely and effectively protected rabbits from PVR in multiple models of disease. Furthermore, aflibercept reduced the bioactivity of both experimental and clinical PVR vitreous. Finally, although VEGF could promote some PVR-associated cellular responses via VEGF receptors expressed on the retinal pigment epithelial cells that drive this disease, VEGF's major contribution to vitreal bioactivity occurred via platelet-derived growth factor receptor a. Thus, VEGF promotes PVR by a noncanonical ability to engage platelet-derived growth factor receptor a. These findings indicate that VEGF contributes to nonangiogenic diseases and that anti VEGF-based therapies may be effective on a wider spectrum of diseases than previously appreciated. C1 [Kazlauskas, Andrius] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. RP Kazlauskas, A (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, 20 Stamford St, Boston, MA 02114 USA. EM andrius_kazlauskas@meei.harvard.edu FU NIH [EY022970]; Mukai Fund of the Massachusetts Eye and Ear Infirmary (Boston) FX Supported by NIH grant EY022970 (A.K.) and the Mukai Fund of the Massachusetts Eye and Ear Infirmary (Boston) (S.M.). NR 59 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 EI 1525-2191 J9 AM J PATHOL JI Am. J. Pathol. PD NOV PY 2014 VL 184 IS 11 BP 3052 EP 3068 DI 10.1016/j.ajpath.2014.07.026 PG 17 WC Pathology SC Pathology GA AS0LS UT WOS:000343969200018 PM 25261788 ER PT J AU Balamurugan, AN Naziruddin, B Lockridge, A Tiwari, M Loganathan, G Takita, M Matsumoto, S Papas, K Trieger, M Rainis, H Kin, T Kay, TW Wease, S Messinger, S Ricordi, C Alejandro, R Markmann, J Kerr-Conti, J Rickels, MR Liu, C Zhang, X Witkowski, P Posselt, A Maffi, P Secchi, A Berney, T O'Connell, PJ Hering, BJ Barton, FB AF Balamurugan, A. N. Naziruddin, B. Lockridge, A. Tiwari, M. Loganathan, G. Takita, M. Matsumoto, S. Papas, K. Trieger, M. Rainis, H. Kin, T. Kay, T. W. Wease, S. Messinger, S. Ricordi, C. Alejandro, R. Markmann, J. Kerr-Conti, J. Rickels, M. R. Liu, C. Zhang, X. Witkowski, P. Posselt, A. Maffi, P. Secchi, A. Berney, T. O'Connell, P. J. Hering, B. J. Barton, F. B. TI Islet Product Characteristics and Factors Related to Successful Human Islet Transplantation From the Collaborative Islet Transplant Registry (CITR) 1999-2010 SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Clinical research; practice; diabetes: type 1; endocrinology; diabetology; health services and outcomes research; islet isolation; islet transplantation; Organ Procurement and Transplantation Network (OPTN); pancreas; simultaneous pancreas-kidney transplantation; registry; registry analysis ID HISTIDINE-TRYPTOPHAN-KETOGLUTARATE; OF-WISCONSIN SOLUTION; ISOLATION-RELATED VARIABLES; PANCREAS PRESERVATION; ISOLATION OUTCOMES; 2-LAYER METHOD; CLINICAL TRANSPLANTATION; COLLAGENASE NB1; GRAFT-SURVIVAL; CULTURE AB The Collaborative Islet Transplant Registry (CITR) collects data on clinical islet isolations and transplants. This retrospective report analyzed 1017 islet isolation procedures performed for 537 recipients of allogeneic clinical islet transplantation in 1999-2010. This study describes changes in donor and islet isolation variables by era and factors associated with quantity and quality of final islet products. Donor body weight and BMI increased significantly over the period (p<0.001). Islet yield measures have improved with time including islet equivalent (IEQ)/particle ratio and IEQs infused. The average dose of islets infused significantly increased in the era of 2007-2010 when compared to 1999-2002 (445.4156.8 vs. 421.3 +/- 155.4x10(3) IEQ; p<0.05). Islet purity and total number of cells significantly improved over the study period (p<0.01 and <0.05, respectively). Otherwise, the quality of clinical islets has remained consistently very high through this period, and differs substantially from nonclinical islets. In multivariate analysis of all recipient, donor and islet factors, and medical management factors, the only islet product characteristic that correlated with clinical outcomes was total IEQs infused. This analysis shows improvements in both quantity and some quality criteria of clinical islets produced over 1999-2010, and these parallel improvements in clinical outcomes over the same period. Product criteria from clinical grade allogeneic human islets exhibit consistently superior-quality characteristics and significantly increasing islet equivalent yield, paralleling improving success rates of islet transplantation for type I diabetes. C1 [Balamurugan, A. N.; Lockridge, A.; Tiwari, M.; Loganathan, G.; Hering, B. J.] Univ Minnesota, Dept Surg, Schulze Diabet Inst, Minneapolis, MN 55455 USA. [Naziruddin, B.; Takita, M.] Baylor Annette C & Harold C Simmons Transplant In, Dallas, TX USA. [Matsumoto, S.] Otsuka Pharmaceut Factory Inc, Ctr Res & Dev, Tokushima, Japan. [Papas, K.] Univ Arizona, Inst Cellular Transplantat, Tucson, AZ USA. [Trieger, M.; Rainis, H.; Wease, S.; Barton, F. B.] EMMES Corp, Rockville, MD USA. [Kin, T.] Univ Alberta, Clin Islet Lab, Edmonton, AB, Canada. [Kay, T. W.] St Vincents Hosp, Melbourne, Vic, Australia. [Messinger, S.] Univ Miami, Dept Publ Hlth Serv, Miami, FL USA. [Ricordi, C.; Alejandro, R.] Univ Miami, Diabet Res Inst, Miami, FL USA. [Markmann, J.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Kerr-Conti, J.] Lille Univ Hosp, Lille, France. [Rickels, M. R.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Liu, C.] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. [Zhang, X.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Witkowski, P.] Univ Chicago, Dept Surg, Chicago, IL 60637 USA. [Posselt, A.] Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. [Maffi, P.; Secchi, A.] San Raffaele Univ, Vita Salute, Milan, Italy. [Berney, T.] Univ Hosp Geneva, Dept Surg, Geneva, Switzerland. [O'Connell, P. J.] Univ Sydney, Westmead Hosp, Natl Pancreas Transplant Unit, Sydney, NSW 2006, Australia. RP Balamurugan, AN (reprint author), Univ Louisville, Dept Surg, Cardiovasc Innovat Inst, Islet Cell Lab, Louisville, KY 40292 USA. EM isletologist@hotmail.com; fbarton@emmes.com RI Loganathan, Gopalakrishnan/D-8762-2014; OI Ricordi, Camillo/0000-0001-8092-7153 FU NIDDK; National Institutes of Health; JDRF International FX The CITR is funded by the NIDDK, National Institutes of Health and by a supplemental grant from the JDRF International. Additional data were made available through cooperative agreements with the U. S. United Network for Organ Sharing (UNOS), Alexandria, Virginia, the Administrative and Bioinformatics Coordinating Center of the City of Hope, Duarte, California (1999-2009) and the NIDDK-sponsored CIT (www.citisletstudy.org), coordinated by the University of Iowa Clinical Trials and Data Management Center (2008-present). NR 58 TC 25 Z9 25 U1 3 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1600-6135 EI 1600-6143 J9 AM J TRANSPLANT JI Am. J. Transplant. PD NOV PY 2014 VL 14 IS 11 BP 2595 EP 2606 DI 10.1111/ajt.12872 PG 12 WC Surgery; Transplantation SC Surgery; Transplantation GA AS3LH UT WOS:000344178800020 PM 25278159 ER PT J AU Rathmell, JP AF Rathmell, James P. TI The Proper Role for Epidural Injection of Corticosteroids SO ANESTHESIOLOGY LA English DT Editorial Material ID PAIN C1 [Rathmell, James P.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Div Pain Med, Boston, MA 02114 USA. [Rathmell, James P.] Harvard Univ, Sch Med, Boston, MA USA. RP Rathmell, JP (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Div Pain Med, Boston, MA 02114 USA. EM rathmell.james@mgh.harvard.edu NR 9 TC 2 Z9 2 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD NOV PY 2014 VL 121 IS 5 BP 919 EP 921 DI 10.1097/ALN.0000000000000439 PG 3 WC Anesthesiology SC Anesthesiology GA AS6JA UT WOS:000344368700005 PM 25335170 ER PT J AU Sasaki, N Meyer, MJ Malviya, SA Stanislaus, AB MacDonald, T Doran, ME Igumenshcheva, A Hoang, AH Eikermann, M AF Sasaki, Nobuo Meyer, Matthew J. Malviya, Sanjana A. Stanislaus, Anne B. MacDonald, Teresa Doran, Mary E. Igumenshcheva, Arina Hoang, Alan H. Eikermann, Matthias TI Effects of Neostigmine Reversal of Nondepolarizing Neuromuscular Blocking Agents on Postoperative Respiratory Outcomes A Prospective Study SO ANESTHESIOLOGY LA English DT Article ID NEGATIVE PHARYNGEAL PRESSURE; GENIOGLOSSUS MUSCLE-ACTIVITY; PARTIALLY PARALYZED HUMANS; POSTANESTHESIA CARE-UNIT; ACETYLCHOLINE-RECEPTOR; AIRWAY COLLAPSIBILITY; BLOCKADE; COMPLICATIONS; EDROPHONIUM; ATRACURIUM AB Background: We tested the hypothesis that neostigmine reversal of neuromuscular blockade reduced the incidence of signs and symptoms of postoperative respiratory failure. Methods: We enrolled 3,000 patients in this prospective, observer-blinded, observational study. We documented the intraoperative use of neuromuscular blocking agents and neostigmine. At postanesthesia care unit admission, we measured train-of-four ratio and documented the ratio of peripheral oxygen saturation to fraction of inspired oxygen (S/F). The primary outcome was oxygenation at postanesthesia care unit admission (S/F). Secondary outcomes included the incidence of postoperative atelectasis and postoperative hospital length of stay. Post hoc, we defined high-dose neostigmine as more than 60 g/kg and unwarranted use of neostigmine as neostigmine administration in the absence of appropriate neuromuscular transmission monitoring. Results: Neostigmine reversal did not improve S/F at postanesthesia care unit admission (164 [95% CI, 162 to 164] vs. 164 [161 to 164]) and was associated with an increased incidence of atelectasis (8.8% vs. 4.5%; odds ratio, 1.67 [1.07 to 2.59]). High-dose neostigmine was associated with longer time to postanesthesia care unit discharge readiness (176 min [165 to 188] vs. 157 min [153 to 160]) and longer postoperative hospital length of stay (2.9 days [2.7 to 3.2] vs. 2.8 days [2.8 to 2.9]). Unwarranted use of neostigmine (n = 492) was an independent predictor of pulmonary edema (odds ratio, 1.91 [1.21 to 3.00]) and reintubation (odds ratio, 3.68 [1.10 to 12.4]). Conclusions: Neostigmine reversal did not affect oxygenation but was associated with increased atelectasis. High-dose neostigmine or unwarranted use of neostigmine may translate to increased postoperative respiratory morbidity. C1 [Sasaki, Nobuo] Showa Gen Hosp, Dept Emergency & Crit Care Med, Tokyo, Japan. [Meyer, Matthew J.; Eikermann, Matthias] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Malviya, Sanjana A.; Stanislaus, Anne B.; Igumenshcheva, Arina; Hoang, Alan H.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02115 USA. [Igumenshcheva, Arina] Massachusetts Gen Hosp, MGH Anesthesia Res Grants, BWH Dept Prevent Med, Boston, MA 02115 USA. [MacDonald, Teresa; Doran, Mary E.] Massachusetts Gen Hosp, Boston, MA 02115 USA. [Eikermann, Matthias] Univ Klinikum Essen, Klin Anaesthesie & Intens Med, Essen, Germany. RP Meyer, MJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02115 USA. EM mjmeyer@mgh.harvard.edu FU Schering-Plough Research Institute, Kenilworth, New Jersey, a Division of Schering Corporation [39442] FX An investigator-initiated grant (IISP# 39442) was provided by Schering-Plough Research Institute, Kenilworth, New Jersey, a Division of Schering Corporation, to the Massachusetts General Hospital. NR 41 TC 32 Z9 32 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD NOV PY 2014 VL 121 IS 5 BP 959 EP 968 DI 10.1097/ALN.0000000000000440 PG 10 WC Anesthesiology SC Anesthesiology GA AS6JA UT WOS:000344368700011 PM 25225821 ER PT J AU Akeju, O Pavone, KJ Westover, MB Vazquez, R Prerau, MJ Harrell, PG Hartnack, KE Rhee, J Sampson, AL Habeeb, K Lei, G Pierce, ET Walsh, JL Brown, EN Purdon, PL AF Akeju, Oluwaseun Pavone, Kara J. Westover, M. Brandon Vazquez, Rafael Prerau, Michael J. Harrell, Priscilla G. Hartnack, Katharine E. Rhee, James Sampson, Aaron L. Habeeb, Kathleen Lei, Gao Pierce, Eric T. Walsh, John L. Brown, Emery N. Purdon, Patrick L. TI A Comparison of Propofol- and Dexmedetomidine-induced Electroencephalogram Dynamics Using Spectral and Coherence Analysis SO ANESTHESIOLOGY LA English DT Article ID GENERAL-ANESTHESIA; THALAMOCORTICAL MECHANISMS; INDUCED UNCONSCIOUSNESS; BEHAVIORAL-EXPERIMENTS; BISPECTRAL INDEX; SLEEP; CONSCIOUSNESS; EEG; SEDATION; AROUSAL AB Background: Electroencephalogram patterns observed during sedation with dexmedetomidine appear similar to those observed during general anesthesia with propofol. This is evident with the occurrence of slow (0.1 to 1 Hz), delta (1 to 4 Hz), propofol-induced alpha (8 to 12 Hz), and dexmedetomidine-induced spindle (12 to 16 Hz) oscillations. However, these drugs have different molecular mechanisms and behavioral properties and are likely accompanied by distinguishing neural circuit dynamics. Methods: The authors measured 64-channel electroencephalogram under dexmedetomidine (n = 9) and propofol (n = 8) in healthy volunteers, 18 to 36 yr of age. The authors administered dexmedetomidine with a 1-mu g/kg loading bolus over 10 min, followed by a 0.7 mu g kg(-1) h(-1) infusion. For propofol, the authors used a computer-controlled infusion to target the effect-site concentration gradually from 0 to 5 g/ml. Volunteers listened to auditory stimuli and responded by button press to determine unconsciousness. The authors analyzed the electroencephalogram using multitaper spectral and coherence analysis. Results: Dexmedetomidine was characterized by spindles with maximum power and coherence at approximately 13 Hz (mean SD; power, -10.8 +/- 3.6 dB; coherence, 0.8 +/- 0.08), whereas propofol was characterized with frontal alpha oscillations with peak frequency at approximately 11 Hz (power, 1.1 +/- 4.5 dB; coherence, 0.9 +/- 0.05). Notably, slow oscillation power during a general anesthetic state under propofol (power, 13.2 +/- 2.4 dB) was much larger than during sedative states under both propofol (power, -2.5 +/- 3.5 dB) and dexmedetomidine (power, -0.4 +/- 3.1 dB). Conclusion: The results indicate that dexmedetomidine and propofol place patients into different brain states and suggest that propofol enables a deeper state of unconsciousness by inducing large-amplitude slow oscillations that produce prolonged states of neuronal silence. C1 [Akeju, Oluwaseun; Pavone, Kara J.; Vazquez, Rafael; Prerau, Michael J.; Harrell, Priscilla G.; Hartnack, Katharine E.; Rhee, James; Sampson, Aaron L.; Lei, Gao; Pierce, Eric T.; Walsh, John L.; Brown, Emery N.; Purdon, Patrick L.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Westover, M. Brandon] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Habeeb, Kathleen] Massachusetts Gen Hosp, Clin Res Ctr, Boston, MA 02114 USA. [Akeju, Oluwaseun; Westover, M. Brandon; Vazquez, Rafael; Prerau, Michael J.; Harrell, Priscilla G.; Rhee, James; Lei, Gao; Pierce, Eric T.; Walsh, John L.; Brown, Emery N.; Purdon, Patrick L.] Harvard Univ, Sch Med, Boston, MA USA. [Brown, Emery N.; Purdon, Patrick L.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Harvard Massachusetts Inst Technol Div Hlth Sci &, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. RP Purdon, PL (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 149 13th St,Rm 4005, Charlestown, MA 02129 USA. EM patrickp@nmr.mgh.harvard.edu OI Gao, Lei/0000-0003-1476-1460 FU National Institutes of Health, Bethesda, Maryland [DP2-OD006454, DP1-OD003646, TR01-GM104948, T32GM007592]; Foundation of Anesthesia Education and Research, Rochester, Minnesota; Massachusetts General Hospital Faculty Development Award, Boston, Massachusetts; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts FX Supported by grant numbers DP2-OD006454 (to Dr. Purdon), DP1-OD003646 and TR01-GM104948 (to Dr. Brown), and T32GM007592 (to Drs. Akeju and Rhee) from the National Institutes of Health, Bethesda, Maryland; Foundation of Anesthesia Education and Research, Rochester, Minnesota (to Dr. Akeju); Massachusetts General Hospital Faculty Development Award, Boston, Massachusetts (to Dr. Akeju); and funds from the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts. NR 37 TC 21 Z9 21 U1 1 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD NOV PY 2014 VL 121 IS 5 BP 978 EP 989 DI 10.1097/ALN.0000000000000419 PG 12 WC Anesthesiology SC Anesthesiology GA AS6JA UT WOS:000344368700013 PM 25187999 ER PT J AU Akeju, O Westover, MB Pavone, KJ Sampson, AL Hartnack, KE Brown, EN Purdon, PL AF Akeju, Oluwaseun Westover, M. Brandon Pavone, Kara J. Sampson, Aaron L. Hartnack, Katharine E. Brown, Emery N. Purdon, Patrick L. TI Effects of Sevoflurane and Propofol on Frontal Electroencephalogram Power and Coherence SO ANESTHESIOLOGY LA English DT Article ID INDUCED ALPHA-RHYTHM; GENERAL-ANESTHESIA; INDUCED UNCONSCIOUSNESS; INHALED ANESTHETICS; CALCIUM CURRENTS; CONSCIOUSNESS; MECHANISMS; ISOFLURANE; NEURONS; SLEEP AB Background: The neural mechanisms of anesthetic vapors have not been studied in depth. However, modeling and experimental studies on the intravenous anesthetic propofol indicate that potentiation of -aminobutyric acid receptors leads to a state of thalamocortical synchrony, observed as coherent frontal alpha oscillations, associated with unconsciousness. Sevoflurane, an ether derivative, also potentiates -aminobutyric acid receptors. However, in humans, sevoflurane-induced coherent frontal alpha oscillations have not been well detailed. Methods: To study the electroencephalogram dynamics induced by sevoflurane, the authors identified age- and sex-matched patients in which sevoflurane (n = 30) or propofol (n = 30) was used as the sole agent for maintenance of general anesthesia during routine surgery. The authors compared the electroencephalogram signatures of sevoflurane with that of propofol using time-varying spectral and coherence methods. Results: Sevoflurane general anesthesia is characterized by alpha oscillations with maximum power and coherence at approximately 10 Hz, (mean SD; peak power, 4.3 +/- 3.5 dB; peak coherence, 0.73 +/- 0.1). These alpha oscillations are similar to those observed during propofol general anesthesia, which also has maximum power and coherence at approximately 10 Hz (peak power, 2.1 +/- 4.3 dB; peak coherence, 0.71 +/- 0.1). However, sevoflurane also exhibited a distinct theta coherence signature (peak frequency, 4.9 +/- 0.6 Hz; peak coherence, 0.58 +/- 0.1). Slow oscillations were observed in both cases, with no significant difference in power or coherence. Conclusions: The study results indicate that sevoflurane, like propofol, induces coherent frontal alpha oscillations and slow oscillations in humans to sustain the anesthesia-induced unconscious state. These results suggest a shared molecular and systems-level mechanism for the unconscious state induced by these drugs. C1 [Akeju, Oluwaseun; Pavone, Kara J.; Sampson, Aaron L.; Hartnack, Katharine E.; Brown, Emery N.; Purdon, Patrick L.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Westover, M. Brandon] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Akeju, Oluwaseun; Brown, Emery N.; Purdon, Patrick L.] Harvard Univ, Sch Med, Boston, MA USA. [Westover, M. Brandon; Brown, Emery N.; Purdon, Patrick L.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Harvard Massachusetts Inst Technol Div Hlth Sci &, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. RP Purdon, PL (reprint author), Massachusetts Gen Hosp, 149 13th St,Rm 4005, Charlestown, MA 02129 USA. EM patrickp@nmr.mgh.harvard.edu FU National Institutes of Health, Bethesda, Maryland [DP2-OD006454, DP1-OD003646, TR01-GM104948, T32GM007592]; Foundation of Anesthesia Education and Research, Rochester, Minnesota; Massachusetts General Hospital Faculty Development Award, Boston, Massachusetts; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts FX Supported by grant numbers DP2-OD006454 (to Dr. Purdon), DP1-OD003646 and TR01-GM104948 (to Dr. Brown), and T32GM007592 (to Dr. Akeju) from the National Institutes of Health, Bethesda, Maryland; Foundation of Anesthesia Education and Research, Rochester, Minnesota (to Dr. Akeju); Massachusetts General Hospital Faculty Development Award, Boston, Massachusetts (to Dr. Akeju); and funds from the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts. NR 32 TC 21 Z9 21 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD NOV PY 2014 VL 121 IS 5 BP 990 EP 998 DI 10.1097/ALN.0000000000000436 PG 9 WC Anesthesiology SC Anesthesiology GA AS6JA UT WOS:000344368700014 PM 25233374 ER PT J AU Cohen, SP Hayek, S Semenov, Y Pasquina, PF White, RL Veizi, E Huang, JHY Kurihara, C Zhao, ZR Guthmiller, KB Griffith, SR Verdun, AV Giampetro, DM Vorobeychik, Y AF Cohen, Steven P. Hayek, Salim Semenov, Yevgeny Pasquina, Paul F. White, Ronald L. Veizi, Elias Huang, Julie H. Y. Kurihara, Connie Zhao, Zirong Guthmiller, Kevin B. Griffith, Scott R. Verdun, Aubrey V. Giampetro, David M. Vorobeychik, Yakov TI Epidural Steroid Injections, Conservative Treatment, or Combination Treatment for Cervical Radicular Pain A Multicenter, Randomized, Comparative-effectiveness Study SO ANESTHESIOLOGY LA English DT Article ID LOW-BACK-PAIN; LUMBAR SPINAL STENOSIS; NEUROPATHIC PAIN; TRANSFORAMINAL INJECTION; CONTROLLED-TRIAL; DOUBLE-BLIND; CORTICOSTEROID INJECTIONS; CHRONIC RADICULOPATHY; DISK HERNIATION; ACUTE SCIATICA AB Background: Cervical radicular pain is a major cause of disability. No studies have been published comparing different types of nonsurgical therapy. Methods: A comparative-effectiveness study was performed in 169 patients with cervical radicular pain less than 4 yr in duration. Participants received nortriptyline and/or gabapentin plus physical therapies, up to three cervical epidural steroid injections (ESI) or combination treatment over 6 months. The primary outcome measure was average arm pain on a 0 to 10 scale at 1 month. Results: One-month arm pain scores were 3.5 (95% CI, 2.8 to 4.2) in the combination group, 4.2 (CI, 2.8 to 4.2) in ESI patients, and 4.3 (CI, 2.8 to 4.2) in individuals treated conservatively (P = 0.26). Combination group patients experienced a mean reduction of -3.1 (95% CI, -3.8 to -2.3) in average arm pain at 1 month versus -1.8 (CI, -2.5 to -1.2) in the conservative group and -2.0 (CI, -2.7 to -1.3) in ESI patients (P = 0.035). For neck pain, a mean reduction of -2.2 (95% CI, -3.0 to -1.5) was noted in combination patients versus -1.2 (CI, -1.9 to -0.5) in conservative group patients and -1.1 (CI, -1.8 to -0.4) in those who received ESI; P = 0.064). Three-month posttreatment, 56.9% of patients treated with combination therapy experienced a positive outcome versus 26.8% in the conservative group and 36.7% in ESI patients (P = 0.006). Conclusions: For the primary outcome measure, no significant differences were found between treatments, although combination therapy provided better improvement than stand-alone treatment on some measures. Whereas these results suggest an interdisciplinary approach to neck pain may improve outcomes, confirmatory studies are needed. C1 [Cohen, Steven P.] Johns Hopkins Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21029 USA. [Cohen, Steven P.] Johns Hopkins Sch Med, Dept Phys Med & Rehabil, Baltimore, MD 21029 USA. [Cohen, Steven P.] Uniformed Serv Univ Hlth Sci, Dept Anesthesiol, Bethesda, MD 20814 USA. [Hayek, Salim] Univ Hosp Cleveland, Dept Anesthesiol, Case Western Reserve Sch Med, Cleveland, OH 44106 USA. [Semenov, Yevgeny] Harvard Univ, Sch Med, Dept Anesthesia, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Pasquina, Paul F.] Uniformed Serv Univ Hlth Sci, Dept Phys Med & Rehabil, Bethesda, MD 20814 USA. [White, Ronald L.] Reg Med Ctr, Dept Surg, Pain Treatment Ctr, Landstuhl, Germany. [Veizi, Elias] Case Western Reserve Univ, Dept Anesthesiol, Louis Stokes Cleveland VA Med Ctr, Cleveland, OH 44106 USA. [Huang, Julie H. Y.] Weill Cornell Med Univ, Mem Sloan Kettering Canc Ctr, Dept Anesthesiol, New York, NY USA. [Kurihara, Connie; Griffith, Scott R.; Verdun, Aubrey V.] Walter Reed Natl Mil Med Ctr, Dept Surg, Anesthesia Serv, Bethesda, MD USA. [Zhao, Zirong] Dist Columbia VA Hosp, Dept Internal Med, Washington, DC USA. [Zhao, Zirong] Dist Columbia VA Hosp, Dept Neurol, Washington, DC USA. [Guthmiller, Kevin B.] San Antonio Mil Med Ctr, Dept Anesthesiol, Pain Treatment Ctr, San Antonio, TX USA. [Griffith, Scott R.; Verdun, Aubrey V.] Uniformed Serv Univ Hlth Sci, Dept Anesthesiol, Bethesda, MD 20814 USA. [Giampetro, David M.; Vorobeychik, Yakov] Penn State Hershey Med Ctr, Dept Anesthesiol, Hershey, PA USA. [Giampetro, David M.; Vorobeychik, Yakov] Penn State Hershey Med Ctr, Dept Neurol, Hershey, PA USA. RP Cohen, SP (reprint author), Johns Hopkins Sch Med, 550 North Broadway,Suite 301, Baltimore, MD 21029 USA. EM scohen40@jhmi.edu FU Congressional Grant from the Center for Rehabilitation Sciences Research, Uniformed Services University of the Health Sciences, Bethesda, Maryland, SAP Grant [111726] FX Funded in part by a Congressional Grant from the Center for Rehabilitation Sciences Research, Uniformed Services University of the Health Sciences, Bethesda, Maryland, SAP Grant No. 111726. The role of the funding source was only provisions to pay research personnel. NR 64 TC 29 Z9 29 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD NOV PY 2014 VL 121 IS 5 BP 1045 EP 1055 DI 10.1097/ALN.0000000000000409 PG 11 WC Anesthesiology SC Anesthesiology GA AS6JA UT WOS:000344368700020 PM 25335172 ER PT J AU Baer, L Ball, S Sparks, JD Raskin, J Dube, S Ferguson, M Fava, M AF Baer, Lee Ball, Susan Sparks, Jon David Raskin, Joel Dube, Sanjay Ferguson, Margaret Fava, Maurizio TI Further evidence for the reliability and validity of the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) SO ANNALS OF CLINICAL PSYCHIATRY LA English DT Article ID MAJOR DEPRESSIVE DISORDER; REUPTAKE INHIBITOR TREATMENT; RATING-SCALE; DOUBLE-BLIND; RESIDUAL SYMPTOMS; ANXIETY DISORDER; PLACEBO; OUTCOMES; FATIGUE; AUGMENTATION AB BACKGROUND: The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) was developed to assess clinically relevant cognitive and physical symptoms associated with depression that are not adequately assessed by traditional measures. Although the CPFQ has been shown previously to be a reliable and valid measure, the purpose of the present study was to provide additional evidence using larger samples from 4 independent clinical trials that were designed to test the efficacy and safety of different antidepressants. METHODS: The psychometric analyses were based on data from 4 independent clinical trials that were designed to test the safety and efficacy of different antidepressants. Reliability of the items and of the overall questionnaire was evaluated with principal components analysis, whereas validity was assessed by associations of the questionnaire scores with convergent and divergent external criteria. RESULTS: Overall, the results have replicated previous findings that the CPFQ has good internal reliability. Validation also is strengthened by the demonstration of predictive differences among known groups as well as a sensitivity to change with antidepressant treatment. CONCLUSIONS: Results support the use of the CPFQ as a valuable instrument for the detection of clinically relevant symptoms that are not captured by typical measures of depression used for the assessment of treatment outcomes. C1 [Baer, Lee; Fava, Maurizio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Ball, Susan; Sparks, Jon David; Raskin, Joel; Dube, Sanjay; Ferguson, Margaret] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Ball, Susan] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Dube, Sanjay] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Pittsburgh, PA USA. [Dube, Sanjay] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Baer, L (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Wang Ambulatory Care Ctr, Room 812 15 Parkman St, Boston, MA 02114 USA. EM baer.lee@mgh.harvard.edu FU Eli Lilly and Company FX We thank Dr. Rodney Moore (inVentiv Health Clinical, funded by Eli Lilly and Company) for his assistance in drafting the manuscript. NR 36 TC 4 Z9 4 U1 1 U2 2 PU QUADRANT HEALTHCOM INC PI PARSIPPANY PA 7 CENTURY DRIVE, STE 302, PARSIPPANY, NJ 07054-4603 USA SN 1040-1237 EI 1547-3325 J9 ANN CLIN PSYCHIATRY JI Ann. Clin. Psychiatry PD NOV PY 2014 VL 26 IS 4 BP 270 EP 280 PG 11 WC Psychiatry SC Psychiatry GA AS8QT UT WOS:000344514100005 PM 25401714 ER PT J AU Caceres, SM Malcolm, KC Taylor-Cousar, JL Nichols, DP Saavedra, MT Bratton, DL Moskowitz, SM Burns, JL Nick, JA AF Caceres, Silvia M. Malcolm, Kenneth C. Taylor-Cousar, Jennifer L. Nichols, David P. Saavedra, Milene T. Bratton, Donna L. Moskowitz, Samuel M. Burns, Jane L. Nick, Jerry A. TI Enhanced In Vitro Formation and Antibiotic Resistance of Nonattached Pseudomonas aeruginosa Aggregates through Incorporation of Neutrophil Products SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID CYSTIC-FIBROSIS PATIENTS; BACTERIAL BIOFILMS; INHALED TOBRAMYCIN; GENE-EXPRESSION; F-ACTIN; SPUTUM; INFECTION; DNA; INFLAMMATION; AZITHROMYCIN AB Pseudomonas aeruginosa is a major pathogen in cystic fibrosis (CF) lung disease. Children with CF are routinely exposed to P. aeruginosa from the natural environment, and by adulthood, 80% of patients are chronically infected. P. aeruginosa in the CF airway exhibits a unique biofilm-like structure, where it grows in small clusters or aggregates of bacteria in association with abundant polymers of neutrophil-derived components F-actin and DNA, among other components. These aggregates differ substantially in size and appearance compared to surface-attached in vitro biofilm models classically utilized for studies but are believed to share properties of surface-attached biofilms, including antibiotic resistance. However, little is known about the formation and function of surface-independent modes of biofilm growth, how they might be eradicated, and quorum sensing communication. To address these issues, we developed a novel in vitro model of P. aeruginosa aggregates incorporating human neutrophil-derived products. Aggregates grown in vitro and those found in CF patients' sputum samples were morphologically similar; viable bacteria were distributed in small pockets throughout the aggregate. The lasA quorum sensing gene was differentially expressed in the presence of neutrophil products. Importantly, aggregates formed in the presence of neutrophils acquired resistance to tobramycin, which was lost when the aggregates were dispersed with DNase, and antagonism of tobramycin and azithromycin was observed. This novel yet simple in vitro system advances our ability to model infection of the CF airway and will be an important tool to study virulence and test alternative eradication strategies against P. aeruginosa. C1 [Caceres, Silvia M.; Malcolm, Kenneth C.; Taylor-Cousar, Jennifer L.; Nichols, David P.; Saavedra, Milene T.; Nick, Jerry A.] Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. [Nichols, David P.; Bratton, Donna L.] Natl Jewish Hlth, Dept Pediat, Denver, CO USA. [Malcolm, Kenneth C.; Taylor-Cousar, Jennifer L.; Nichols, David P.; Saavedra, Milene T.; Nick, Jerry A.] Univ Colorado, Dept Med, Aurora, CO USA. [Moskowitz, Samuel M.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Moskowitz, Samuel M.] Harvard Univ, Sch Med, Boston, MA USA. [Burns, Jane L.] Univ Washington, Sch Med, Dept Pediat, Div Pediat Infect Dis,Seattle Childrens Hosp, Seattle, WA 98195 USA. RP Malcolm, KC (reprint author), Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. EM malcolmk@njhealth.org FU Investigator Support Trial grant from Genentech; Rebecca Runyon Bryan Chair for Cystic Fibrosis; NIH [HL34303] FX Support for this work was provided by an Investigator Support Trial grant from Genentech and the Rebecca Runyon Bryan Chair for Cystic Fibrosis (J.A.N.) and NIH HL34303 (D. L. B.). NR 61 TC 6 Z9 6 U1 7 U2 14 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD NOV PY 2014 VL 58 IS 11 BP 6851 EP 6860 DI 10.1128/AAC.03514-14 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA AS3EF UT WOS:000344158600061 PM 25182651 ER PT J AU Fan, KH Jiang, JB Wang, ZR Fan, RC Yin, W Sun, YG Li, HQ AF Fan, Kuohai Jiang, Junbing Wang, Zhirui Fan, Ruicheng Yin, Wei Sun, Yaogui Li, Hongquan TI Expression and Purification of Soluble Porcine Cystatin 11 in Pichia pastoris SO APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY LA English DT Article DE Antimicrobial activity; Pichia pastoris; Expression; Purification; Porcine CST11 ID ANTIMICROBIAL PEPTIDES AB Cystatin 11 (CST11) belongs to the cystatin type 2 family of cysteine protease inhibitors and exhibits antimicrobial activity in vitro. In this study, we describe the expression and purification of recombinant porcine CST11 in the Pichia pastoris system. We then assess its antimicrobial activity against Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, and Bacillus subtilis by liquid growth inhibition assay. Kinetic studies indicate that the recombinant porcine CST11 has high potency against E. coli and S. aureus. Scanning electronic microscope analysis showed that CST11 might be targeting the bacterial membrane and, thus, could potentially be developed as a therapeutic agent for inhibiting microbe infection without the risk of antibiotic resistance. C1 [Fan, Kuohai; Jiang, Junbing; Fan, Ruicheng; Yin, Wei; Sun, Yaogui; Li, Hongquan] Shanxi Agr Univ, Coll Anim Sci & Vet Med, Taigu 030801, Shanxi, Peoples R China. [Wang, Zhirui] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. [Wang, Zhirui] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Zhirui] MGH DF HCC Recombinant Prot Express & Purificat C, Boston, MA USA. RP Li, HQ (reprint author), Shanxi Agr Univ, Coll Anim Sci & Vet Med, Taigu 030801, Shanxi, Peoples R China. EM livets@163.com FU Key Scientific and Technological Project of Shanxi Province [20100312016] FX This research was sponsored by the Key Scientific and Technological Project of Shanxi Province (Grant No. 20100312016). These experiments comply with the current laws of China. NR 13 TC 1 Z9 2 U1 1 U2 11 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0273-2289 EI 1559-0291 J9 APPL BIOCHEM BIOTECH JI Appl. Biochem. Biotechnol. PD NOV PY 2014 VL 174 IS 5 BP 1959 EP 1968 DI 10.1007/s12010-014-1148-z PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA AS5XK UT WOS:000344339700021 PM 25161037 ER PT J AU Tsao, CW Pencina, KM Massaro, JM Benjamin, EJ Levy, D Vasan, RS Hoffmann, U O'Donnell, CJ Mitchell, GF AF Tsao, Connie W. Pencina, Karol M. Massaro, Joseph M. Benjamin, Emelia J. Levy, Daniel Vasan, Ramachandran S. Hoffmann, Udo O'Donnell, Christopher J. Mitchell, Gary F. TI Cross-Sectional Relations of Arterial Stiffness, Pressure Pulsatility, Wave Reflection, and Arterial Calcification SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE hemodynamics; vascular calcification; vascular stiffness ID ISOLATED SYSTOLIC HYPERTENSION; CORONARY-HEART-DISEASE; AORTIC STIFFNESS; CARDIOVASCULAR EVENTS; OLDER-ADULTS; ATHEROSCLEROSIS; ROTTERDAM; CALCIUM; AGE; ASSOCIATION AB Objective Arterial hemodynamics and vascular calcification are associated with increased risk for cardiovascular disease, but their inter-relations remain unclear. We sought to examine the associations of arterial stiffness, pressure pulsatility, and wave reflection with arterial calcification in individuals free of prevalent cardiovascular disease. Approach and Results Framingham Heart Study Third Generation and Offspring Cohort participants free of cardiovascular disease underwent applanation tonometry to measure arterial stiffness, pressure pulsatility, and wave reflection, including carotid-femoral pulse wave velocity, central pulse pressure, forward wave amplitude, and augmentation index. Participants in each cohort (n=1905, 456 years and n=1015, 65 +/- 9 years, respectively) underwent multidetector computed tomography to assess the presence and quantity of thoracic aortic calcification, abdominal aortic calcification, and coronary artery calcification. In multivariable-adjusted models, both higher carotid-femoral pulse wave velocity and central pulse pressure were associated with greater thoracic aortic calcification and abdominal aortic calcification, whereas higher augmentation index was associated with abdominal aortic calcification. Among the tonometry measures, carotid-femoral pulse wave velocity was the strongest correlate of all calcification measures in multivariable-adjusted models (odds ratio per SD for thoracic aortic calcification, 2.69 [95% confidence interval, 2.17-3.35]; abdominal aortic calcification, 1.47 [95% confidence interval, 1.26-1.73]; and coronary artery calcification, 1.48 [95% confidence interval, 1.28-1.72]; all P<0.001, respectively). We observed stronger relations of carotid-femoral pulse wave velocity, central pulse pressure, and forward wave amplitude with nearly all continuous calcification measures in the younger Third Generation Cohort as compared with the Offspring Cohort. Conclusions In community-dwelling individuals without prevalent cardiovascular disease, abnormal central arterial hemodynamics were positively associated with vascular calcification and were observed at younger ages than previously recognized. The mechanisms of these associations may be bidirectional and deserve further study. C1 [Tsao, Connie W.] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Dept Med, Boston, MA 02215 USA. [Pencina, Karol M.; Massaro, Joseph M.] Boston Univ, Sch Med, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02215 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Med, Sect Cardiol & Preventat Med, Boston, MA 02215 USA. [Levy, Daniel] NHLBI, Bethesda, MD 20892 USA. [Tsao, Connie W.; Benjamin, Emelia J.; Levy, Daniel; Vasan, Ramachandran S.; O'Donnell, Christopher J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Tsao, Connie W.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Norwood, MA USA. RP Tsao, CW (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc, 330 Brookline Ave,RW-453, Boston, MA 02215 USA. EM ctsao1@bidmc.harvard.edu OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute [N01-HC-25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, HL107385]; National Institutes of Health [K23 HL118529]; American Heart Association [13SDG14250015]; Harvard Medical School Fellowship FX The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute (N01-HC-25195, HL076784, AG028321, HL070100, HL060040, HL080124, HL071039, HL077447, and HL107385). Dr Tsao is supported by National Institutes of Health K23 HL118529, the American Heart Association (13SDG14250015), and the Harvard Medical School Fellowship. NR 29 TC 17 Z9 18 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 EI 1524-4636 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD NOV PY 2014 VL 34 IS 11 BP 2495 EP 2500 DI 10.1161/ATVBAHA.114.303916 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AS1QX UT WOS:000344056400018 PM 25169933 ER PT J AU Baker, JF Von Feldt, J Mostoufi-Moab, S Noaiseh, G Taratuta, E Kim, W Leonard, MB AF Baker, Joshua F. Von Feldt, Joan Mostoufi-Moab, Sogol Noaiseh, Ghaith Taratuta, Elena Kim, Woojin Leonard, Mary B. TI Deficits in Muscle Mass, Muscle Density, and Modified Associations With Fat in Rheumatoid Arthritis SO ARTHRITIS CARE & RESEARCH LA English DT Article ID CHRONIC KIDNEY-DISEASE; METABOLIC RISK-FACTORS; BODY-COMPOSITION; BONE-STRUCTURE; ADIPOSITY; CACHEXIA; ADIPONECTIN; CHILDREN; OBESITY; PATHOPHYSIOLOGY AB Objective. To quantify muscle outcomes, independent of fat mass, in rheumatoid arthritis (RA) patients compared to healthy controls. Methods. Quantitative computed tomography scans measured calf muscle and fat cross-sectional area (CSA) and muscle density (an index of intramuscular adipose tissue), and isometric dynamometry was used to measure ankle muscle strength in 50 participants with RA ages 18-70 years and 500 healthy controls. Multivariable linear regression models assessed muscle deficits in RA after adjusting for group differences in adiposity and assessing for an altered muscle-fat association. Associations between RA disease characteristics and fat-adjusted muscle outcomes were also assessed. Results. Compared to controls, RA subjects had significantly greater body mass index (BMI) and fat area, and lower muscle area, muscle density, and muscle strength (P < 0.001 for all). Strength deficits were eliminated with adjustment for the smaller muscle area. The magnitude of muscle deficits, relative to controls, was significantly greater (P < 0.03 for interaction) in participants with lower fat area and BMI. Among those in the lower tertiles of adiposity, RA subjects demonstrated more significant deficits compared to controls with similar adiposity. In contrast, among those in the highest tertile for adiposity, RA was not associated with muscle deficits. Among RA, greater Sharp/van der Heijde scores were associated with lower muscle CSA and muscle density. Greater disease activity and disability were associated with low muscle density. Conclusion. Deficits in muscle area and muscle density are present in RA patients compared to controls and are most pronounced in subjects with low fat mass. Greater joint destruction is associated with greater muscle deficits. C1 [Baker, Joshua F.; Von Feldt, Joan] Univ Penn, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Baker, Joshua F.; Von Feldt, Joan; Mostoufi-Moab, Sogol; Taratuta, Elena; Kim, Woojin; Leonard, Mary B.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Mostoufi-Moab, Sogol; Leonard, Mary B.] Univ Penn, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Noaiseh, Ghaith] Univ Pittsburgh, Pittsburgh, PA USA. RP Baker, JF (reprint author), Hosp Univ Penn, Dept Med, Div Rheumatol, 8 Penn Tower Bldg,34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM bakerjo@uphs.upenn.edu FU University of Pennsylvania Clinical and Translational Research Center [UL1-RR024134] FX Supported by the University of Pennsylvania Clinical and Translational Research Center (UL1-RR024134). NR 35 TC 11 Z9 11 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD NOV PY 2014 VL 66 IS 11 BP 1612 EP 1618 DI 10.1002/acr.22328 PG 7 WC Rheumatology SC Rheumatology GA AS5UF UT WOS:000344334200003 PM 24664868 ER PT J AU Kerr, G Aujero, M Richards, J Sayles, H Davis, L Cannon, G Caplan, L Michaud, K Mikuls, T AF Kerr, Gail Aujero, Mireille Richards, John Sayles, Harlan Davis, Lisa Cannon, Grant Caplan, Liron Michaud, Kaleb Mikuls, Ted TI Associations of Hydroxychloroquine Use With Lipid Profiles in Rheumatoid Arthritis: Pharmacologic Implications SO ARTHRITIS CARE & RESEARCH LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; MODIFYING ANTIRHEUMATIC DRUGS; RISK-FACTORS; CARDIOVASCULAR RISK; DISEASE-ACTIVITY; VETERANS; ATHEROSCLEROSIS; METHOTREXATE; MANAGEMENT; THERAPY AB Objective. To evaluate the association of hydroxychloroquine (HCQ) use with lipid profiles in a Veterans Affairs Rheumatoid Arthritis (VARA) cohort. Methods. Lipid profiles in HCQ users were compared with HCQ nonusers, adjusting for potential confounders (age, sex, race, disease activity, prednisone, disease-modifying antirheumatic drugs, diabetes mellitus, and statin use). Applying current National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines for reduction of cardiovascular disease (CVD) events risk, the frequency of target lipid profiles with HCQ status was evaluated. Varied periods of HCQ exposure were compared to ascertain pharmacologic associations with lipid values. CVDs were compared between HCQ users and nonusers. Results. In an elderly, predominantly male VARA cohort, 1,011 patients had lipid profiles; 787 patients (77.8%) were white. Statin use was recorded in 11.6% of patients, diabetes mellitus in 33.5%, and CVD in 31.2%. HCQ users (n = 150) were older, had longer rheumatoid arthritis (RA) disease duration, and had lower disease activity. Optimum lipid profiles, including total cholesterol: high-density lipoprotein (HDL) and HDL: low-density lipoprotein ratios (P <= 0.001), were more frequent in HCQ users, with the exception of HDL (P = 0.165), and persisted in multivariate analyses. Similarly, more HCQ users had NCEP-ATP III target levels. Varied periods of HCQ exposure suggested lipid changes to occur early, but lost within a year of drug discontinuation. HCQ users had less prevalent CVD. Conclusion. In RA patients, HCQ use of at least 3 months' duration was associated with better lipid profiles irrespective of disease activity or statin use. Given the increased CVD risks in RA and the relative low cost and toxicity of HCQ, continued use, regardless of treatment regimen, should be considered. C1 [Kerr, Gail] Georgetown Univ, Washington DC Vet Affairs Med Ctr, Washington, DC USA. [Kerr, Gail] Howard Univ Hosp, Washington, DC USA. [Aujero, Mireille; Richards, John] Washington DC Vet Affairs Med Ctr, Washington, DC USA. [Richards, John] Georgetown Univ, Washington, DC USA. [Sayles, Harlan; Michaud, Kaleb; Mikuls, Ted] Univ Nebraska Med Ctr, Nebraska Arthrit Outcomes Res Ctr, Omaha, NE USA. [Davis, Lisa; Caplan, Liron] Denver Vet Affairs Med Ctr, Denver, CO USA. [Davis, Lisa; Caplan, Liron] Univ Colorado, Denver, CO 80202 USA. [Cannon, Grant] George Whalen Vet Affairs Med Ctr, Salt Lake City, UT USA. [Mikuls, Ted] Univ Nebraska Med Ctr, Omaha Vet Affairs Med Ctr, Omaha, NE USA. RP Kerr, G (reprint author), Vet Affairs Med Ctr, Rheumatol Sect 151K, 50 Irving St NW, Washington, DC 20422 USA. EM gail.kerr@va.gov FU Nebraska Arthritis Outcomes Research Center at the University of Nebraska Medical Center; Veterans Affairs Health Services Research and Development Program of the Veterans Health Administration; Abbott Laboratories; Amgen; Bristol-Myers Squibb; Veterans Health Administration (Veterans Affairs Merit award); Veterans Affairs Health Services Research and Development Program Career Development Award [CDA 07-221] FX The Veterans Affairs Rheumatoid Arthritis Registry was supported by the Nebraska Arthritis Outcomes Research Center at the University of Nebraska Medical Center, the Veterans Affairs Health Services Research and Development Program of the Veterans Health Administration, and unrestricted grants from Abbott Laboratories, Amgen, and Bristol-Myers Squibb. Dr. Mikuls' work was supported by the Veterans Health Administration (Veterans Affairs Merit award) and a Veterans Affairs Health Services Research and Development Program Career Development Award (CDA 07-221). NR 45 TC 13 Z9 13 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD NOV PY 2014 VL 66 IS 11 BP 1619 EP 1626 DI 10.1002/acr.22341 PG 8 WC Rheumatology SC Rheumatology GA AS5UF UT WOS:000344334200004 PM 24692402 ER PT J AU Nagaraja, V Hays, RD Khanna, PP Spiegel, BMR Chang, L Melmed, GY Bolus, R Khanna, D AF Nagaraja, Vivek Hays, Ron D. Khanna, Puja P. Spiegel, Brennan M. R. Chang, Lin Melmed, Gil Y. Bolus, Roger Khanna, Dinesh TI Construct Validity of the Patient-Reported Outcomes Measurement Information System Gastrointestinal Symptom Scales in Systemic Sclerosis SO ARTHRITIS CARE & RESEARCH LA English DT Article ID QUALITY-OF-LIFE; TRACT INSTRUMENT; GASTROESOPHAGEAL-REFLUX; PHYSICAL FUNCTION; SCLERODERMA; PROMIS; VALIDATION; MANIFESTATIONS; INVOLVEMENT; MOTILITY AB Objective. Gastrointestinal (GI) involvement is common in patients with systemic sclerosis (SSc; scleroderma). The Patient-Reported Outcomes Measurement Information System (PROMIS) GI symptom item bank captures upper and lower GI symptoms (reflux, disrupted swallowing, nausea/vomiting, belly pain, gas/bloating/flatulence, diarrhea, constipation, and fecal incontinence). The objective of this study was to evaluate the construct validity of the PROMIS GI bank in SSc. Methods. A total of 167 patients with SSc were administered the PROMIS GI bank and the University of California, Los Angeles, Scleroderma Clinical Trials Consortium Gastrointestinal Scale (GIT 2.0) instrument. GIT 2.0 is a multi-item instrument that measures SSc-associated GI symptoms. Product-moment correlations and a multitrait-multimethod analysis of the PROMIS GI scales with the GIT 2.0 symptom scales were used to evaluate convergent and discriminant validity. Results. Patients with SSc GI involvement had PROMIS GI scale scores 0.2-0.7 SD worse than the US general population. Correlations among scales measuring the same domains for the PROMIS GI and GIT 2.0 measures were large, ranging from 0.61 to 0.87 (average r = 0.77). The average correlation between different symptom scales was 0.22, supporting discriminant validity. Conclusion. This study provides support for the construct validity of the PROMIS GI scales in SSc. Future research is needed to assess the responsiveness to change of these scales in patients with SSc. C1 [Nagaraja, Vivek; Khanna, Puja P.; Khanna, Dinesh] Univ Michigan, Ann Arbor, MI 48109 USA. [Hays, Ron D.] RAND Corp, Santa Monica, CA USA. [Hays, Ron D.; Bolus, Roger] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Spiegel, Brennan M. R.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. [Spiegel, Brennan M. R.; Bolus, Roger] VA Ctr Outcomes Res & Educ, Los Angeles, CA USA. [Chang, Lin] Univ Calif Los Angeles, David Geffen Sch Med, Gail & Gerald Oppenheimer Family Ctr Neurobiol St, Los Angeles, CA 90095 USA. [Melmed, Gil Y.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RP Khanna, D (reprint author), Univ Michigan Scleroderma Program, Div Rheumatol, Dept Internal Med, 300 North Ingalls St,Suite 7C27,SPC 5422, Ann Arbor, MI 48109 USA. EM khannad@med.umich.edu FU NIH Common Fund Initiative (Northwestern University) [U54-AR-057951, U01-AR-052177, U54-AR057943]; American Institutes for Research [U54-AR-057926]; State University of New York, Stony Brook [U01-AR-057948, U01-AR-052170]; University of Washington, Seattle [U01-AR-057954, U01-AR-052171]; University of North Carolina, Chapel Hill [U01-AR-052181]; Children's Hospital of Philadelphia [U01-AR-057956]; Stanford University [U01-AR-052158]; Boston University [U01-AR-057929]; University of California, Los Angeles [U01-AR-057936]; University of Pittsburgh [U01-AR-052155]; Georgetown University [U01-AR-057971]; Children's Hospital Medical Center, Cincinnati [U01-AR-057940]; University of Maryland, Baltimore [U01-AR-057967]; Duke University [U01-AR-052186]; NIH/National Institute on Aging [P30-AG-028748, P30-AG-021684]; National Center on Minority Health and Health Disparities [2P20-MD-000182]; NIH/National Institute for Arthritis and Musculoskeletal and Skin Disease [K24-AR-063120-02] FX PROMIS was funded with cooperative agreements from the NIH Common Fund Initiative (Northwestern University, grants U54-AR-057951, U01-AR-052177, and U54-AR057943; American Institutes for Research, grant U54-AR-057926; State University of New York, Stony Brook, grants U01-AR-057948 and U01-AR-052170; University of Washington, Seattle, grants U01-AR-057954 and U01-AR-052171; University of North Carolina, Chapel Hill, grant U01-AR-052181; Children's Hospital of Philadelphia, grant U01-AR-057956; Stanford University, grant U01-AR-052158; Boston University, grant U01-AR-057929; University of California, Los Angeles, grant U01-AR-057936; University of Pittsburgh, grant U01-AR-052155; Georgetown University, grant U01-AR-057971; Children's Hospital Medical Center, Cincinnati, grant U01-AR-057940; University of Maryland, Baltimore, grant U01-AR-057967; and Duke University, grant U01-AR-052186). See Appendix A for principal investigators and NIH science officers.; Dr. Hays's work was supported by the NIH/National Institute on Aging (grants P30-AG-028748 and P30-AG-021684) and the National Center on Minority Health and Health Disparities (grant 2P20-MD-000182). Dr. Dinesh Khanna's work was supported by the NIH/National Institute for Arthritis and Musculoskeletal and Skin Disease (grant K24-AR-063120-02). NR 31 TC 6 Z9 6 U1 13 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD NOV PY 2014 VL 66 IS 11 BP 1725 EP 1730 DI 10.1002/acr.22337 PG 6 WC Rheumatology SC Rheumatology GA AS5UF UT WOS:000344334200017 PM 24692332 ER PT J AU Miloslavsky, EM Specks, U Merkel, PA Seo, P Spiera, R Langford, CA Hoffman, GS Kallenberg, CGM Clair, EWS Tchao, NK Viviano, L Ding, L Ikle, D Villarreal, M Jepson, B Brunetta, P Allen, NB Fervenza, FC Geetha, D Keogh, K Kissin, EY Monach, PA Peikert, T Stegeman, C Ytterberg, SR Stone, JH AF Miloslavsky, E. M. Specks, U. Merkel, P. A. Seo, P. Spiera, R. Langford, C. A. Hoffman, G. S. Kallenberg, C. G. M. Clair, E. W. St. Tchao, N. K. Viviano, L. Ding, L. Ikle, D. Villarreal, M. Jepson, B. Brunetta, P. Allen, N. B. Fervenza, F. C. Geetha, D. Keogh, K. Kissin, E. Y. Monach, P. A. Peikert, T. Stegeman, C. Ytterberg, S. R. Stone, J. H. CA Rituximab ANCA-Associated Vasculit TI Rituximab for the Treatment of Relapses in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; ACTIVE RHEUMATOID-ARTHRITIS; ANCA-ASSOCIATED VASCULITIS; REMISSION-INDUCTION; WEGENERS-GRANULOMATOSIS; MAINTENANCE THERAPY; RANDOMIZED-TRIAL; RISK-FACTORS; CYCLOPHOSPHAMIDE; EFFICACY AB Objective. Disease relapses are frequent in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. Methods. The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After remission was achieved, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a pre-specified protocol. Investigators remained blinded with regard to the original treatment assignment. Results. Twenty-six patients received RTX for disease relapse after remission had initially been achieved with their originally assigned treatment. Fifteen of these patients were initially randomized to receive RTX and 11 to receive CYC/AZA. Thirteen (87%) of the patients originally assigned to receive RTX and 10 (91%) originally assigned to receive CYC/AZA achieved remission again with open-label RTX (an overall percentage of 88%). In half of the patients treated with open-label RTX, prednisone could be discontinued entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events per patient-year versus 11.8 adverse events per patient-year). Conclusion. Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment. C1 [Miloslavsky, E. M.; Stone, J. H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Specks, U.; Fervenza, F. C.; Keogh, K.; Peikert, T.; Ytterberg, S. R.] Mayo Clin, Rochester, MN USA. [Merkel, P. A.] Univ Penn, Philadelphia, PA 19104 USA. [Seo, P.; Geetha, D.] Johns Hopkins Univ, Baltimore, MD USA. [Spiera, R.] Hosp Special Surg, New York, NY 10021 USA. [Langford, C. A.; Hoffman, G. S.] Cleveland Clin, Cleveland, OH 44106 USA. [Kallenberg, C. G. M.; Stegeman, C.] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Kallenberg, C. G. M.; Stegeman, C.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Clair, E. W. St.; Allen, N. B.] Duke Univ, Med Ctr, Durham, NC USA. [Tchao, N. K.] Immune Tolerance Network, San Francisco, CA USA. [Ding, L.] NIAID, NIH, Bethesda, MD 20892 USA. [Ikle, D.; Villarreal, M.; Jepson, B.] Rho, Chapel Hill, NC USA. [Brunetta, P.] Genentech Inc, San Francisco, CA 94080 USA. [Kissin, E. Y.; Monach, P. A.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Rheumatol Unit, Yawkey 2C,55 Fruit St, Boston, MA 02114 USA. EM jhstone@mgh.harvard.edu FU NIH [N01-AI-15416, 1 UL1-RR-024150-01, UL1-RR-025005, K23-AR-052820, K24-AR-049185, UL1-RR-025771, M01-RR-00533, K24-AR-02224]; National Institute of Allergy and Infectious Diseases, NIH; Juvenile Diabetes Research Foundation; Genentech (Clinical Immunology Fellowship); Arthritis Foundation FX The Rituximab in ANCA-Associated Vasculitis (RAVE) trial 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 San Francisco 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 medication and partial funding for the RAVE trial. At the Mayo Clinic, Johns Hopkins University, and Boston University School of Medicine, the RAVE trial was supported by the NIH (Mayo Clinic: National Center for Research Resources Clinical and Translational Science award 1 UL1-RR-024150-01; Johns Hopkins University: National Center for Research Resources Clinical and Translational Science award 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 Clinical and Translational Science award UL1-RR-025771, grant M01-RR-00533, and career development award K24-AR-02224 to Dr. Merkel). Dr. Miloslavsky's work was supported by Genentech (Clinical Immunology Fellowship 2012-2013). Dr. Monach's work was supported by the Arthritis Foundation (Arthritis Investigator Award). NR 24 TC 22 Z9 22 U1 0 U2 4 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 NOV PY 2014 VL 66 IS 11 BP 3151 EP 3159 DI 10.1002/art.38788 PG 9 WC Rheumatology SC Rheumatology GA AS6BI UT WOS:000344349500025 PM 25047592 ER PT J AU Baker, JF Smolen, JS Aletaha, D Shults, J Conaghan, PG Emery, P Baker, DG Ostergaard, M AF Baker, Joshua F. Smolen, Josef S. Aletaha, Daniel Shults, Justine Conaghan, Philip G. Emery, Paul Baker, Daniel G. Ostergaard, Mikkel TI Is the modified Disease Activity Score superior to the Disease Activity Score in early arthritis and rheumatoid arthritis? Comment on the article by Baker et al Reply SO ARTHRITIS & RHEUMATOLOGY LA English DT Letter ID JOINT DAMAGE C1 [Baker, Joshua F.] Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Baker, Joshua F.; Shults, Justine] Univ Penn, Philadelphia, PA 19104 USA. [Smolen, Josef S.; Aletaha, Daniel] Med Univ Vienna, Vienna, Austria. [Conaghan, Philip G.; Emery, Paul] Univ Leeds, Leeds Inst Rheumat & Musculoskeletal Med, Leeds, W Yorkshire, England. [Conaghan, Philip G.; Emery, Paul] NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds, W Yorkshire, England. [Baker, Daniel G.] Janssen Res & Dev LLC, Spring House, PA USA. [Ostergaard, Mikkel] Glostrup Cty Hosp, Copenhagen, Denmark. [Ostergaard, Mikkel] Univ Copenhagen, Copenhagen, Denmark. RP Baker, JF (reprint author), Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2014 VL 66 IS 11 BP 3245 EP 3246 DI 10.1002/art.38810 PG 3 WC Rheumatology SC Rheumatology GA AS6BI UT WOS:000344349500037 PM 25132673 ER PT J AU Khosroshahi, A Cheryk, LA Bloch, DB Stone, JH AF Khosroshahi, Arezou Cheryk, Lynn A. Bloch, Donald B. Stone, John H. TI The prozone effect in serum assays for IgG4: comment on the article by Khosroshahi et al Reply SO ARTHRITIS & RHEUMATOLOGY LA English DT Letter C1 [Khosroshahi, Arezou] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Cheryk, Lynn A.] Mayo Clin Labs, Andover, MA USA. [Bloch, Donald B.; Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Khosroshahi, A (reprint author), Emory Univ, Sch Med, Atlanta, GA 30322 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 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 NOV PY 2014 VL 66 IS 11 BP 3247 EP 3248 DI 10.1002/art.38751 PG 3 WC Rheumatology SC Rheumatology GA AS6BI UT WOS:000344349500039 PM 24965491 ER PT J AU Zhao, SD Parmigiani, G Huttenhower, C Waldron, L AF Zhao, Sihai Dave Parmigiani, Giovanni Huttenhower, Curtis Waldron, Levi TI Mas-o-menos: a simple sign averaging method for discrimination in genomic data analysis SO BIOINFORMATICS LA English DT Article ID GENE-EXPRESSION PROFILE; NEGATIVE BREAST-CANCER; OVARIAN-CANCER; BLADDER-CANCER; MOLECULAR SUBTYPES; LINEAR-MODELS; ESTIMATING COEFFICIENTS; UROTHELIAL CARCINOMA; PROGNOSTIC SIGNATURE; NO NEVERMIND AB Motivation: The successful translation of genomic signatures into clinical settings relies on good discrimination between patient sub-groups. Many sophisticated algorithms have been proposed in the statistics and machine learning literature, but in practice simpler algorithms are often used. However, few simple algorithms have been formally described or systematically investigated. Results: We give a precise definition of a popular simple method we refer to as mas-o-menos, which calculates prognostic scores for discrimination by summing standardized predictors, weighted by the signs of their marginal associations with the outcome. We study its behavior theoretically, in simulations and in an extensive analysis of 27 independent gene expression studies of bladder, breast and ovarian cancer, altogether totaling 3833 patients with survival outcomes. We find that despite its simplicity, mas-o-menos can achieve good discrimination performance. It performs no worse, and sometimes better, than popular and much more CPU-intensive methods for discrimination, including lasso and ridge regression. C1 [Zhao, Sihai Dave] Univ Illinois, Dept Stat, Champaign, IL 61820 USA. [Parmigiani, Giovanni; Huttenhower, Curtis] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Parmigiani, Giovanni] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Waldron, Levi] CUNY Hunter Coll, Sch Publ Hlth, New York, NY 10035 USA. RP Zhao, SD (reprint author), Univ Illinois, Dept Stat, Champaign, IL 61820 USA. OI Waldron, Levi/0000-0003-2725-0694 FU National Cancer Institute at the National Institutes of Health [1RC4CA156551-01, 5P30 CA006516-46]; National Science Foundation [CAREER DBI-1053486] FX This work was funded by the National Cancer Institute at the National Institutes of Health (1RC4CA156551-01 and 5P30 CA006516-46 to G.P.) and by the National Science Foundation (CAREER DBI-1053486 to C.H.). NR 65 TC 2 Z9 2 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD NOV 1 PY 2014 VL 30 IS 21 BP 3062 EP 3069 DI 10.1093/bioinformatics/btu488 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA AT0SG UT WOS:000344644600010 PM 25061068 ER PT J AU Lindqvist, D Wolkowitz, OM Mellon, S Yehuda, R Flory, JD Henn-Haase, C Bierer, LM Abu-Amara, D Coy, M Neylan, TC Makotkine, L Reus, VI Yan, X Taylor, NM Marmar, CR Dhabhar, FS AF Lindqvist, Daniel Wolkowitz, Owen M. Mellon, Synthia Yehuda, Rachel Flory, Janine D. Henn-Haase, Clare Bierer, Linda M. Abu-Amara, Duna Coy, Michelle Neylan, Thomas C. Makotkine, Louri Reus, Victor I. Yan, Xiaodan Taylor, Nicole M. Marmar, Charles R. Dhabhar, Firdaus S. TI Proinflammatory milieu in combat-related PTSD is independent of depression and early life stress SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE Post-traumatic stress disorder (PTSD); Inflammation; Cytokines; Depression; Early life trauma; Combat ID C-REACTIVE PROTEIN; MAJOR DEPRESSION; GLUCOCORTICOID SENSITIVITY; MYOCARDIAL-INFARCTION; SERUM INTERLEUKIN-6; DISORDER; IMMUNE; INFLAMMATION; RISK; SYMPTOMS AB Background: Chronic inflammation may be involved in combat-related post-traumatic stress disorder (PTSD) and may help explain comorbid physical diseases. However, the extent to which combat exposure per se, depression, or early life trauma, all of which are associated with combat PTSD, may confound the relationship between PTSD and inflammation is unclear. Methods: We quantified interleukin (IL)-6, IL-1 beta, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and C-reactive protein (CRP) in 51 combat-exposed males with PTSD and 51 combat-exposed males without PTSD, and assessed PTSD and depression severity as well as history of early life trauma. To decrease the possibility of Type I errors, we summed standardized scores of IL-1 beta, IL-6, TNF alpha, IFN gamma and CRP into a total "pro-inflammatory score". PTSD symptom severity was assessed with the Clinician Administered PTSD Scale (CAPS) rating scale. Results: Subjects with PTSD had significantly higher pro-inflammatory scores compared to combat-exposed subjects without PTSD (p = 0.006), and even after controlling for early life trauma, depression diagnosis and severity, body mass index, ethnicity, education, asthma/allergies, time since combat and the use of possibly confounding medications (p = 0.002). Within the PTSD group, the pro-inflammatory score was not significantly correlated with depressive symptom severity, CAPS total score, or with the number of early life traumas. Conclusions: Combat-related PTSD in males is associated with higher levels of pro-inflammatory cytokines, even after accounting for depression and early life trauma. These results, from one of the largest studies of inflammatory cytokines in PTSD to date, suggest that immune activation may be a core element of PTSD pathophysiology more so than a signature of combat exposure alone. (C) 2014 Published by Elsevier Inc. C1 [Lindqvist, Daniel; Wolkowitz, Owen M.; Coy, Michelle; Neylan, Thomas C.; Reus, Victor I.] Univ Calif San Francisco, Dept Psychiat, Sch Med, San Francisco, CA 94143 USA. [Lindqvist, Daniel] Lund Univ, Dept Clin Sci, Sect Psychiat, Lund, Sweden. [Mellon, Synthia] Univ Calif San Francisco, Sch Med, Dept OB GYN & Reprod Sci, San Francisco, CA 94143 USA. [Yehuda, Rachel; Flory, Janine D.; Bierer, Linda M.; Makotkine, Louri] James J Peters Vet Adm Med Ctr, MSSM, Dept Psychiat, New York, NY USA. [Henn-Haase, Clare; Abu-Amara, Duna; Yan, Xiaodan; Marmar, Charles R.] NYU, Dept Psychiat, Steven & Alexandra Cohen Vet Ctr Posttraumat Stre, New York, NY 10003 USA. [Taylor, Nicole M.; Dhabhar, Firdaus S.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. RP Wolkowitz, OM (reprint author), Univ Calif San Francisco, Dept Psychiat, Sch Med, 401 Parnassus Ave, San Francisco, CA 94143 USA. EM Owen.Wolkowitz@ucsf.edu; Charles.Marmar@nyumc.org RI reus, victor/I-7923-2015 OI reus, victor/0000-0002-8193-5697 FU U.S. Department of Defense [W81XWH-11-2-0223, W81XWH-10-1-0021]; Mental Illness Research, Education and Clinical Center (MIRECC); Swedish Society of Medicine; Sjobring Foundation; OM Persson Foundation; province of Scania (Sweden) FX This study was supported by the following grants: U.S. Department of Defense, W81XWH-11-2-0223 (PI: Charles Marmar); U.S. Department of Defense, W81XWH-10-1-0021 (PI: Owen M. Wolkowitz); The Mental Illness Research, Education and Clinical Center (MIRECC). Daniel Lindqvist received postdoc grants from the Swedish Society of Medicine; the Sjobring Foundation; the OM Persson Foundation and the province of Scania (Sweden) state grants (ALF). The authors declare no conflict of interest. NR 71 TC 32 Z9 32 U1 9 U2 21 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 EI 1090-2139 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD NOV PY 2014 VL 42 BP 81 EP 88 DI 10.1016/j.bbi.2014.06.003 PG 8 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA AS7IK UT WOS:000344429900012 PM 24929195 ER PT J AU Narla, A Payne, EM Abayasekara, N Hurst, SN Raiser, DM Look, AT Berliner, N Ebert, BL Khanna-Gupta, A AF Narla, Anupama Payne, Elspeth M. Abayasekara, Nirmalee Hurst, Slater N. Raiser, David M. Look, A. Thomas Berliner, Nancy Ebert, Benjamin L. Khanna-Gupta, Arati TI L-Leucine improves the anaemia in models of Diamond Blackfan anaemia and the 5q-syndrome in a TP53-independent way SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE diamond-blackfan anaemia; leucine; haematopoiesis; TP53 ID MTOR PATHWAY; ZEBRAFISH; RIBOSOMOPATHIES AB Haploinsufficiency of ribosomal proteins (RPs) and upregulation of the tumour suppressor TP53 have been shown to be the common basis for the anaemia observed in Diamond Blackfan anaemia and 5q- myelodysplastic syndrome. We previously demonstrated that treatment with L-Leucine resulted in a marked improvement in anaemia in disease models. To determine if the L-Leucine effect was Tp53-dependent, we used antisense MOs to rps19 and rps14 in zebrafish; expression of tp53 and its downstream target cdkn1a remained elevated following L-leucine treatment. We confirmed this observation in human CD34+ cells. L-Leucine thus alleviates anaemia in RP-deficient cells in a TP53-independent manner. C1 [Narla, Anupama] Stanford Univ, Sch Med, Lucile Packard Childrens Hosp, Div Pediat Hematol Oncol, Stanford, CA 94305 USA. [Narla, Anupama; Abayasekara, Nirmalee; Hurst, Slater N.; Raiser, David M.; Berliner, Nancy; Ebert, Benjamin L.; Khanna-Gupta, Arati] Harvard Univ, Brigham & Womens Hosp, Div Hematol, Sch Med, Boston, MA 02115 USA. [Payne, Elspeth M.] UCL, London, England. [Payne, Elspeth M.] Univ Coll London Hosp, Natl Inst Hlth Res, Biomed Res Ctr, London, England. [Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Khanna-Gupta, A (reprint author), Brigham & Womens Hosp, Div Hematol, Karp Res Bldg,5th Floor,Room 5117, Boston, MA 02115 USA. EM akhanna-gupta@partners.org RI Zebrafish, UCL/A-3125-2009 FU National Institutes of Health [K08 DK090145-01A1]; American Society of Hematology; Leukaemia and Lymphoma Research UK (GSK); Tomasso Family Hematology Fund FX The authors would like to thank Marie McConkey and Hong Sun for technical assistance. This work was funded by the National Institutes of Health (K08 DK090145-01A1) and the American Society of Hematology (Scholar Award) to A.N, Leukaemia and Lymphoma Research UK (GSK Greg Harper fellowship) to E. M. P, and by the Tomasso Family Hematology Fund to AK-G. NR 15 TC 11 Z9 11 U1 0 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 NOV PY 2014 VL 167 IS 4 BP 524 EP 528 DI 10.1111/bjh.13069 PG 5 WC Hematology SC Hematology GA AS6CA UT WOS:000344351200011 PM 25098371 ER PT J AU Recklitis, CJ Zhou, ES Zwemer, EK Hu, JC Kantoff, PW AF Recklitis, Christopher J. Zhou, Eric S. Zwemer, Eric K. Hu, Jim C. Kantoff, Philip W. TI Suicidal Ideation in Prostate Cancer Survivors: Understanding the Role of Physical and Psychological Health Outcomes SO CANCER LA English DT Article DE suicide ideation; prostate cancer; physical well-being; emotional well-being; depression ID REPLICATION NCS-R; QUALITY-OF-LIFE; RADICAL PROSTATECTOMY; CHILDHOOD-CANCER; ADULT SURVIVORS; RISK-FACTORS; POPULATION; DEPRESSION; THOUGHTS; VALIDATION AB BACKGROUNDEpidemiological studies have shown prostate cancer (PC) survivors are at an increased risk of suicide compared with the general population, but to the authors' knowledge very little is known regarding what factors are associated with this increased risk. The current study examined the prevalence of suicidal ideation (SI) and its association with cancer treatment and posttreatment physical and emotional health in a cohort of long-term PC survivors. METHODSA total of 693 PC survivors (3-8 years after diagnosis) completed a mailed survey on physical and psychological functioning, including cancer treatments, the Short Form-12 (SF-12), the Expanded Prostate Cancer Index Composite Instrument (EPIC-26), a depression rating scale, and 8 items regarding recent suicidal thoughts and behaviors. RESULTSA total of 86 PC survivors (12.4%) endorsed SI, with 10 individuals (1.4%) reporting serious SI. Serious SI was more common in this sample compared with age-adjusted and sex-adjusted normative data. SI was not associated with most demographic variables, or with PC stage or treatments. However, SI was found to be significantly associated with employment status, poor physical and emotional functioning, greater symptom burden on the EPIC-26, higher frequency of significant pain, and clinically significant depression (P<.01). In an adjusted logistic model, poor physical and emotional function, including disability status and pain, were found to be associated with SI (P<.05), even after adjusting for depression. CONCLUSIONSA significant percentage of PC survivors report recent SI, which is associated with both physical and psychological dysfunction, but not PC treatments. The results of the current study help to explain the increased risk of suicide previously reported in PC survivors and have important implications for identifying and treating those survivors at greatest risk of suicidality. Cancer 2014;120:3393-3400. (c) 2014 American Cancer Society. C1 [Recklitis, Christopher J.; Zhou, Eric S.; Kantoff, Philip W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Perini Family Survivors Ctr, Boston, MA 02115 USA. [Zwemer, Eric K.] Boston Childrens Hosp, Dept Med, Boston, MA USA. [Hu, Jim C.] Univ Calif Los Angeles, Dept Urol, Los Angeles, CA USA. RP Recklitis, CJ (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM christopher_recklitis@dfci.harvard.edu FU American Foundation for Suicide Prevention [PRG-1-10-156] FX Supported by the American Foundation for Suicide Prevention (PRG-1-10-156). NR 47 TC 10 Z9 10 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD NOV 1 PY 2014 VL 120 IS 21 BP 3393 EP 3400 DI 10.1002/cncr.28880 PG 8 WC Oncology SC Oncology GA AS3FZ UT WOS:000344164100020 PM 24962506 ER PT J AU Gareen, IF Duan, FH Greco, EM Snyder, BS Boiselle, PM Park, ER Fryback, D Gatsonis, C AF Gareen, Ilana F. Duan, Fenghai Greco, Erin M. Snyder, Bradley S. Boiselle, Phillip M. Park, Elyse R. Fryback, Dennis Gatsonis, Constantine TI Impact of Lung Cancer Screening Results on Participant Health-Related Quality of Life and State Anxiety in the National Lung Screening Trial SO CANCER LA English DT Article DE quality of life; anxiety; lung cancer; screening; clinical trials ID RISK PERCEPTIONS; SOCIOECONOMIC-STATUS; PROSTATE-CANCER; GUIDELINES; MANAGEMENT; SOCIETY; SF-36; AGE AB BACKGROUNDLow-dose computed tomography (LDCT) lung screening has been associated with a 20% reduction in lung cancer mortality. A major barrier to the adoption of lung screening is the potential negative psychological impact of a false-positive (FP) screen, occurring in 20% to 50% of those screened. The objective of this study was to assess the impact of abnormal findings on health-related quality of life (HRQoL) and anxiety in the American College of Radiology (ACRIN)/National Lung Screening Trial (NLST). METHODSThe NLST was a randomized screening trial comparing LDCT with chest X-ray screening (CXR). This study was part of the original protocol. A total of 2812 participants at 16 of 23 ACRIN sites who had baseline HRQoL assessments were asked to complete the Short Form-36 and the State Trait Anxiety Inventory (form Y-1) questionnaires to assess short-term (1 month) and long-term (6 months) effects of screening. FP were lung cancer-free at 1 year, and true-positives (TP) were not. RESULTSOf the total participants, 1024 (36.4%) participants were FP, 63 (2.2%) were TP, 344 (12.2%) had significant incidental findings (SIFs), and 1381 (49.1%) had negative screens. Participants had been randomized to LDCT (n=1947) and CXR (n=865). Short-term and long-term HRQoL and state anxiety did not differ across participants with FP, SIF, or negative screens. Short-term and long-term HRQoL were lower and anxiety was higher for TP participants compared to participants with FP, SIF, and negative screens. CONCLUSIONSIn a large multicenter lung screening trial, participants receiving a false-positive or SIF screen result experienced no significant difference in HRQoL or state anxiety at 1 or at 6 months after screening relative to those receiving a negative result. Cancer 2014;120:3401-3409. (c) 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-No Derivs 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 [Gareen, Ilana F.; Duan, Fenghai; Greco, Erin M.; Snyder, Bradley S.; Gatsonis, Constantine] Brown Univ, Ctr Stat Sci, Sch Publ Hlth, Providence, RI 02912 USA. [Gareen, Ilana F.] Brown Univ, Dept Epidemiol, Sch Publ Hlth, Providence, RI 02912 USA. [Duan, Fenghai; Gatsonis, Constantine] Brown Univ, Sch Publ Hlth, Dept Biostat, Providence, RI 02912 USA. [Boiselle, Phillip M.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Boiselle, Phillip M.] Harvard Univ, Sch Med, Boston, MA USA. [Park, Elyse R.] Harvard Univ, Sch Med, Mongan Inst Hlth Policy, Boston, MA USA. [Park, Elyse R.] Harvard Univ, Sch Med, Dept Med, Tobacco Res & Treatment Ctr,Massachusetts Gen Hos, Boston, MA USA. [Park, Elyse R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Fryback, Dennis] Univ Wisconsin Madison, Madison, WI USA. RP Gareen, IF (reprint author), Brown Univ, Ctr Stat Sci, Box G-S121-7, Providence, RI 02912 USA. EM igareen@stat.brown.edu RI Gareen, Ilana/I-2816-2014 OI Gareen, Ilana/0000-0002-0457-5595 FU Cancer Imaging Program [U01-CA-80098, CA 79778] FX This study was supported through grants U01-CA-80098 and CA 79778 under a cooperative agreement with the Cancer Imaging Program. NR 35 TC 28 Z9 28 U1 3 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD NOV 1 PY 2014 VL 120 IS 21 BP 3401 EP 3409 DI 10.1002/cncr.28833 PG 9 WC Oncology SC Oncology GA AS3FZ UT WOS:000344164100021 PM 25065710 ER PT J AU Beumer, JH Owzar, K Lewis, LD Jiang, C Holleran, JL Christner, SM Blum, W Devine, S Kolitz, JE Linker, C Vij, R Alyea, EP Larson, RA Ratain, MJ Egorin, MJ AF Beumer, Jan H. Owzar, Kouros Lewis, Lionel D. Jiang, Chen Holleran, Julianne L. Christner, Susan M. Blum, William Devine, Steven Kolitz, Jonathan E. Linker, Charles Vij, Ravi Alyea, Edwin P. Larson, Richard A. Ratain, Mark J. Egorin, Merrill J. TI Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; an alliance study (CALGB 10503, 19808, and 100103) SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Busulfan; Bone marrow transplant; Elderly; Pharmacokinetics ID BONE-MARROW-TRANSPLANTATION; HIGH-DOSE BUSULFAN; DAILY IV BUSULFAN; INTRAVENOUS BUSULFAN; BODY-WEIGHT; VENOOCCLUSIVE DISEASE; CONDITIONING THERAPY; SYSTEMIC EXPOSURE; OLDER PATIENTS; CHILDREN AB Older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome have often been excluded from myeloablative-conditioning regimens containing busulfan because of non-disease-related morbidity and mortality. We hypothesized that busulfan clearance (BuCL) in older patients (> 60 years) would be reduced compared to that in younger patients, potentially explaining observed differences in busulfan tolerability. AML patients in three CALGB hematopoietic cell transplantation studies were treated with a conditioning regimen using IV busulfan, dosed at 0.8 mg/kg. Plasma busulfan concentrations were determined by LC-MS and analyzed by non-compartmental methods. BuCL was normalized to actual (ABW), ideal (IBW), or corrected (CBW) body weight (kg). Differences in BuCL between age groups were examined using the Wilcoxon rank sum test. One hundred and eighty-five patients were accrued; 174 provided useable pharmacokinetic data. Twenty-nine patients a parts per thousand yen60 years old (median 66; range 60-74) had a significantly higher BuCL versus those < 60 years old (median 50; range 18-60): BuCL 236 versus 168 mL/min, p = 0.0002; BuCL/ABW 3.0 versus 2.1 mL/min/kg, p = 0.0001; BuCL/IBW 3.8 versus 2.6 mL/min/kg, p = 0.0035; BuCL/CBW 3.4 versus 2.6 mL/min/kg, p = 0.0005. Inter-patient variability in clearance (CV %) was up to 48 % in both age groups. Phenytoin administration, a potential confounder, did not affect BuCL, regardless of weight normalization (p > 0.34). Contrary to our hypothesis, BuCL was significantly higher in older patients compared to younger patients in these studies and does not explain the previously reported increase in busulfan toxicity observed in older patients. C1 [Beumer, Jan H.] Univ Pittsburgh, Dept Pharmaceut Sci, Sch Pharm, Pittsburgh, PA 15213 USA. [Beumer, Jan H.; Holleran, Julianne L.; Christner, Susan M.; Egorin, Merrill J.] Univ Pittsburgh, Canc Therapeut Program, Inst Canc, Pittsburgh, PA 15213 USA. [Beumer, Jan H.] Univ Pittsburgh, Inst Canc, Melanoma Program, Pittsburgh, PA 15213 USA. [Beumer, Jan H.] Univ Pittsburgh, Ctr Canc, Pittsburgh, PA 15213 USA. [Owzar, Kouros; Jiang, Chen] Duke Univ, Med Ctr, Alliance Stat & Data Ctr, Durham, NC USA. [Lewis, Lionel D.] Geisel Sch Med Dartmouth, Dartmouth Hitchcock Med Ctr, Norris Cotton Canc Ctr, Hanover, NH 03756 USA. [Blum, William; Devine, Steven] Ohio State Univ, James Canc Hosp, Div Hematol, Columbus, OH 43210 USA. [Kolitz, Jonathan E.] Hofstra North Shore LIJ Sch Med, Lake Success, NY 11042 USA. [Linker, Charles] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Vij, Ravi] St Louis Univ, Sch Med, St Louis, MO 63110 USA. [Alyea, Edwin P.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Alyea, Edwin P.] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Alyea, Edwin P.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Larson, Richard A.; Ratain, Mark J.] Univ Chicago, Chicago, IL 60637 USA. [Egorin, Merrill J.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Sch Med, Pittsburgh, PA 15213 USA. [Egorin, Merrill J.] Univ Pittsburgh, Div Hematol Oncol, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. RP Beumer, JH (reprint author), Univ Pittsburgh, Ctr Canc, Hillman Res Pavilion,Room G27E,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM beumerj@gmail.com; kouros.owzar@duke.edu; Lionel.D.Lewis@dartmouth.edu; chen.jiang@duke.edu; HollJL@UPMC.EDU; christners@upmc.edu; William.Blum@osumc.edu; Steven.Devine@osumc.edu; kolitz@nshs.edu; chas.linker@gmail.com; rvij@dom.wustl.edu; Edwin_Alyea@dfci.harvard.edu; rlarson@medicine.bsd.uchicago.edu; mratain@medicine.bsd.uchicago.edu OI Larson, Richard/0000-0001-9168-3203; Beumer, Jan/0000-0002-8978-9401 FU National Cancer Institute [CA31946, CA33601]; Christiana Care Health Services, Inc. CCOP, Wilmington, DE [CA45418]; Dana-Farber Cancer Institute, Boston, MA [CA32291]; Monter Cancer Center of North Shore-LIJ Health Systems, Lake Success, NY [CA35279]; Massachusetts General Hospital, Boston, MA [CA32291]; Mount Sinai Medical Center, Miami, FL [CA45564]; The Ohio State University Medical Center, Columbus, OH [CA77658]; Rhode Island Hospital, Providence, RI [CA08025]; Roswell Park Cancer Institute, Buffalo, NY [CA59518]; University of California at San Francisco, San Francisco, CA [CA60138]; University of Chicago, Chicago, IL [CA41287]; University of Maryland Greenebaum Cancer Center, Baltimore, MD [CA31983]; University of Massachusetts Medical School, Worcester, MA [CA37135]; University of Minnesota, Minneapolis, MN [CA16450]; University of Nebraska Medical Center, Omaha, NE [CA77298]; University of North Carolina at Chapel Hill, Chapel Hill, NC [CA47559]; University of Vermont, Burlington, VT [CA77406]; Wake Forest University School of Medicine, Winston-Salem, NC [CA03927]; Washington University School of Medicine, St. Louis, MO [CA77440]; Weill Medical College of Cornell University, New York, NY [CA07968]; Western Pennsylvania Cancer Institute, Pittsburgh, PA [CA31946]; Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, NH [CA04326]; Walter Reed Army Medical Center, Washington, DC [CA26806]; [P30CA047904] FX We thank the University of Pittsburgh Cancer Institute Hematology/Oncology Writing Group for constructive suggestions regarding the manuscript. This project used the UPCI Clinical Pharmacology Analytical Facility (CPAF) and was supported in part by award P30CA047904 (Jan H. Beumer). (Alliance) was supported, in part, by grants from the National Cancer Institute (CA31946) to the Alliance for Clinical Trials in Oncology (Monica M. Bertagnolli, M. D., Chair) and to the Alliance Statistics and Data Center (Daniel J. Sargent, Ph.D., CA33601). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. The following institutions participated in this study: Christiana Care Health Services, Inc. CCOP, Wilmington, DE, Stephen Grubbs, M.D., supported by CA45418; Dana-Farber Cancer Institute, Boston, MA, Harold J. Burstein, M. D., Ph.D., supported by CA32291; Monter Cancer Center of North Shore-LIJ Health Systems, Lake Success, NY, Daniel Budman, MD, supported by CA35279; Massachusetts General Hospital, Boston, MA, Jeffrey W. Clark, M. D., supported by CA32291; Mount Sinai Medical Center, Miami, FL, Michael A. Schwartz, M. D., supported by CA45564; The Ohio State University Medical Center, Columbus, OH, Clara D. Bloomfield, M. D., supported by CA77658; Rhode Island Hospital, Providence, RI, William Sikov, M. D., supported by CA08025; Roswell Park Cancer Institute, Buffalo, NY, Ellis Levine, M. D., supported by CA59518; University of California at San Francisco, San Francisco, CA, Charles J. Ryan, M. D., supported by CA60138; University of Chicago, Chicago, IL, Hedy L. Kindler, M. D., supported by CA41287; University of Maryland Greenebaum Cancer Center, Baltimore, MD, Martin Edelman, M. D., supported by CA31983; University of Massachusetts Medical School, Worcester, MA, William V. Walsh, M. D., supported by CA37135; University of Minnesota, Minneapolis, MN, Bruce A. Peterson, M. D., supported by CA16450; University of Nebraska Medical Center, Omaha, NE, Apar Ganti, M. D., supported by CA77298; University of North Carolina at Chapel Hill, Chapel Hill, NC, Thomas C. Shea, M. D., supported by CA47559; University of Vermont, Burlington, VT, Steven M. Grunberg, M. D., supported by CA77406; Wake Forest University School of Medicine, Winston-Salem, NC, David D. Hurd, M. D., supported by CA03927; Washington University School of Medicine, St. Louis, MO, Nancy Bartlett, M. D., supported by CA77440; Weill Medical College of Cornell University, New York, NY, John Leonard, M. D., supported by CA07968; Western Pennsylvania Cancer Institute, Pittsburgh, PA, John Lister, M. D., supported by CA31946; Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, NH, Konstantin Dragnev, M. D., supported by CA04326; Walter Reed Army Medical Center, Washington, DC, David C. Van Echo, M. D., supported by CA26806. NR 61 TC 4 Z9 4 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD NOV PY 2014 VL 74 IS 5 BP 927 EP 938 DI 10.1007/s00280-014-2571-0 PG 12 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA AS5QF UT WOS:000344324200005 PM 25163570 ER PT J AU Yonetsu, T Suh, W Abtahian, F Kato, K Vergallo, R Kim, SJ Jia, HB McNulty, I Lee, H Jang, IK AF Yonetsu, Taishi Suh, William Abtahian, Farhad Kato, Koji Vergallo, Rocco Kim, Soo-Joong Jia, Haibo McNulty, Iris Lee, Hang Jang, Ik-Kyung TI Comparison of Near-Infrared Spectroscopy and Optical Coherence Tomography for Detection of Lipid SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE optical coherence tomography; spectroscopy; atherosclerosis; plaque ID CORONARY PLAQUES; INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC PLAQUES; FIBROUS CAP; MORPHOLOGY; THERAPY; IMPACT; IVUS AB ObjectivesTo compare intracoronary near-infrared spectroscopy (NIRS) and optical coherence tomography (OCT) for the detection of lipid, to identify NIRS signals to differentiate superficial lipid, and to characterize the plaque with yellow block (YB) chemograms on NIRS. BackgroundIntracoronary NIRS has been developed to detect lipid core plaque (LCP). MethodsWe investigated a total of 17 patients who underwent both OCT and NIRS. NIRS analysis included plaque lipid core burden index (LCBI), LCP length, and the presence of YB on the block chemogram. OCT analysis included maximum lipid arc (LA), the length of lipid (LL), lipid index, and the thinnest fibrous cap thickness (FCT). ResultsTwenty-five plaques with >40% plaque burden were analyzed. LCP, showing LCBI>0, was observed in 20 plaques (80%) and YB was detected in seven plaques (28%). Plaque LCBI showed modest correlations with maximum LA and lipid index by OCT (r(2)=0.319, P=0.003 and r(2)=0. 404, P=0.001, respectively). Lipid length showed a significant correlation between NIRS and OCT measurements (r(2)=0.581, P<0.001). There was no significant difference in NIRS parameters between superficial and deep lipid. Plaques with YB compared with those without YB showed a larger LA, longer LL, and thinner FCT (18529 degrees vs. 105 +/- 76 degrees, P=0.014; 8.5 +/- 3.3 mm vs. 3.3 +/- 2.7 mm, P=0.001; 112 +/- 42 vs. 166 +/- 61 mu m, P=0.033). ConclusionsNIRS and OCT parameters showed modest linear correlations in the measurement of lipid. The accurate depth of lipid in the vessel wall could not be identified by quantitative NIRS parameters. YB chemograms represented more vulnerable features on OCT. (c) 2013 Wiley Periodicals, Inc. C1 [Yonetsu, Taishi; Abtahian, Farhad; Kato, Koji; Vergallo, Rocco; Kim, Soo-Joong; Jia, Haibo; McNulty, Iris; Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Suh, William] Ronald Reagan UCLA Med Ctr, Los Angeles, CA USA. [Kim, Soo-Joong] Kyung Hee Univ, Coll Med, Div Cardiol, Seoul, South Korea. [Jia, Haibo] Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, Harbin, Peoples R China. [Lee, Hang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Biostat, Boston, MA USA. RP Jang, IK (reprint author), Brigham & Womens Hosp, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02115 USA. EM ijang@partners.org FU LightLab Imaging/St. Jude Medical; "Enrico ed Enrica Sovena" Foundation; InfraReDex FX Grant sponsor: LightLab Imaging/St. Jude Medical (to I.K.J.), The "Enrico ed Enrica Sovena" Foundation (to R.V.), and InfraReDex. NR 16 TC 7 Z9 7 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1522-1946 EI 1522-726X J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD NOV 1 PY 2014 VL 84 IS 5 BP 710 EP 717 DI 10.1002/ccd.25084 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AS0MS UT WOS:000343971700005 PM 23785015 ER PT J AU Papakostas, TD Jakobiec, FA Mantagos, J Rashid, A Fay, A Vavvas, DG AF Papakostas, Thanos D. Jakobiec, Frederick A. Mantagos, Jason Rashid, Alia Fay, Aaron Vavvas, Demetrios G. TI Idiopathic dacryoadenitis mimicking a primary intraocular tumour in a young girl SO CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Letter ID INFLAMMATORY ORBITAL PSEUDOTUMOR; LACRIMAL GLAND; CHILDHOOD C1 [Papakostas, Thanos D.; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, Boston, MA 02115 USA. [Fay, Aaron] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Oculoplast Serv,Dept Ophthalmol, Boston, MA USA. [Jakobiec, Frederick A.; Rashid, Alia] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, David G Cogan Lab Ophthalm Pathol, Boston, MA USA. [Mantagos, Jason] Harvard Univ, Childrens Hosp, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. RP Papakostas, TD (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, Boston, MA 02115 USA. OI Vavvas, Demetrios/0000-0002-8622-6478 NR 6 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1442-6404 EI 1442-9071 J9 CLIN EXP OPHTHALMOL JI Clin. Exp. Ophthalmol. PD NOV PY 2014 VL 42 IS 8 BP 785 EP 788 PG 4 WC Ophthalmology SC Ophthalmology GA AS6MB UT WOS:000344376500011 PM 24533840 ER PT J AU Shores, MM Arnold, AM Biggs, ML Longstreth, WT Smith, NL Kizer, JR Cappola, AR Hirsch, CH Marck, BT Matsumoto, AM AF Shores, Molly M. Arnold, Alice M. Biggs, Mary L. Longstreth, W. T., Jr. Smith, Nicholas L. Kizer, Jorge R. Cappola, Anne R. Hirsch, Calvin H. Marck, Brett T. Matsumoto, Alvin M. TI Testosterone and dihydrotestosterone and incident ischaemic stroke in men in the Cardiovascular Health Study SO CLINICAL ENDOCRINOLOGY LA English DT Article ID HORMONE-BINDING GLOBULIN; SYMPTOMATIC ANDROGEN DEFICIENCY; OLDER MEN; ELDERLY-MEN; SERUM TESTOSTERONE; METABOLIC SYNDROME; ARTERIAL STIFFNESS; MASS-SPECTROMETRY; ESTRADIOL LEVELS; ALL-CAUSE AB ObjectiveIschaemic stroke is a major cause of morbidity and mortality in elderly men. Our main objective was to examine whether testosterone (T) or dihydrotestosterone (DHT) was associated with incident ischaemic stroke in elderly men. DesignCohort study. ParticipantsElderly men in the Cardiovascular Health Study who had no history of stroke, heart disease or prostate cancer as of 1994 and were followed until December 2010. MeasurementsAdjudicated ischaemic stroke. ResultsAmong 1032 men (mean age 76, range 66-97), followed for a median of 10years, 114 had an incident ischaemic stroke. Total T and free T were not significantly associated with stroke risk, while DHT had a nonlinear association with incident stroke (P=0006) in analyses adjusted for stroke risk factors. The lowest risk of stroke was at DHT levels of 50-75ng/dl, with greater risk of stroke at DHT levels above 75ng/dl or below 50ng/dl. Results were unchanged when SHBG was added to the model. Calculated free DHT had an inverse linear association with incident ischaemic stroke with HR 077 (95% CI, 061, 098) per standard deviation in analyses adjusted for stroke risk factors. ConclusionsDihydrotestosterone had a nonlinear association with stroke risk in which there was an optimal DHT level associated with the lowest stroke risk. Further studies are needed to confirm these results and to clarify whether there is an optimal androgen range associated with the least risk of adverse outcomes in elderly men. C1 [Shores, Molly M.; Smith, Nicholas L.; Marck, Brett T.; Matsumoto, Alvin M.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Shores, Molly M.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Arnold, Alice M.; Biggs, Mary L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Longstreth, W. T., Jr.; Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Kizer, Jorge R.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Cappola, Anne R.] Univ Penn, Dept Internal Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Hirsch, Calvin H.] Univ Calif Davis, Dept Internal Med, Davis, CA 95616 USA. [Marck, Brett T.; Matsumoto, Alvin M.] VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA 98108 USA. [Matsumoto, Alvin M.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA USA. RP Shores, MM (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,S-116A, Seattle, WA 98108 USA. EM molly.shores@va.gov FU VA Research Service; VA Epidemiology Research and Information Center (ERIC); VA Geriatric Research and Information Center (GRECC); National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201200036C, N01-HC-85239, N01 HC-55222, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85086, HL080295]; National Institute on Aging (NIA) [AG-023629]; [1R01HL091952] FX This project was supported by the VA Research Service, the VA Epidemiology Research and Information Center (ERIC), and the VA Geriatric Research and Information Center (GRECC) and by 1R01HL091952. This research was supported by contracts HHSN268201200036C, N01-HC-85239, N01 HC-55222, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85086 and Grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by AG-023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org. NR 47 TC 12 Z9 12 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD NOV PY 2014 VL 81 IS 5 BP 746 EP 753 DI 10.1111/cen.12452 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS3KR UT WOS:000344176900015 PM 24645738 ER PT J AU Weisbord, SD AF Weisbord, Steven D. TI AKI and Medical Care after Coronary Angiography: Renalism Revisited SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID CHRONIC KIDNEY-DISEASE; MYOCARDIAL-INFARCTION; MORTALITY; INTERVENTION; DECLINE; RISK C1 [Weisbord, Steven D.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Med Serv Line, Renal Sect, Pittsburgh, PA 15240 USA. [Weisbord, Steven D.] Univ Pittsburgh, Sch Med, Dept Med, Renal Electrolyte Div, Pittsburgh, PA 15213 USA. RP Weisbord, SD (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Med Serv Line, Renal Sect, 7E 111F U,Room 120, Pittsburgh, PA 15240 USA. EM weisbordsd@upmc.edu NR 12 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD NOV PY 2014 VL 9 IS 11 BP 1823 EP 1825 DI 10.2215/CJN.09430914 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA AS7OY UT WOS:000344446200001 PM 25318756 ER PT J AU Pendergraft, WF Herlitz, LC Thornley-Brown, D Rosner, M Niles, JL AF Pendergraft, William F., III Herlitz, Leal C. Thornley-Brown, Denyse Rosner, Mitchell Niles, John L. TI Nephrotoxic Effects of Common and Emerging Drugs of Abuse SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Review ID ANDROGENIC STEROID USE; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; COCAINE USE; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; CANNABINOID RECEPTORS; RENAL-DISEASE; GLOBAL BURDEN; ECSTASY MDMA; CASE SERIES; KIDNEY AB The kidneys can be injured in diverse ways by many drugs, both legal and illegal. Novel associations and descriptions of nephrotoxic effects of common and emerging drugs of abuse have appeared over the past several years. Anabolic androgenic steroids, illicitly used by athletes and others for decades to increase muscle mass and decrease body fat, are emerging as podocyte toxins given recent descriptions of severe forms of FSGS in long-term abusers. Synthetic cannabinoids, a new group of compounds with marijuana-like effects, recently became popular as recreational drugs and have been associated with an atypical form of AKI. 3,4-Methylenedioxymethamphetamine, commonly known as ecstasy, is a widely used synthetic recreational drug with mood-enhancing properties and a constellation of toxicities that can result in death. These toxic effects include hyperthermia, hypotonic hyponatremia due to its arginine vasopressin secretagogue like effects, rhabdomyolysis, and cardiovascular collapse. Cocaine, a serotonin-norepinephrine-dopamine reuptake inhibitor that serves as an illegal stimulant, appetite suppressant, and anesthetic, also causes vasoconstriction and rhabdomyolysis. Recent adulteration of much of the world's supply of cocaine with levamisole, an antihelminthic agent with attributes similar to but distinct from those of cocaine, appears to have spawned a new type of ANCA-associated systemic vasculitis. This review discusses the nephrotoxic effects of these common and emerging drugs of abuse, of which both community and health care providers should become aware given their widespread abuse. Future investigation into pathogenetic mechanisms associated with these drugs is critical and may provide a window into ways to lessen and even prevent the nephrotoxic effects of these drugs of abuse and perhaps allow a deeper understanding of the nephrotoxicities themselves. C1 [Pendergraft, William F., III] Univ N Carolina, Dept Med, Div Nephrol & Hypertens, UNC Kidney Ctr, Chapel Hill, NC USA. [Pendergraft, William F., III; Niles, John L.] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Pendergraft, William F., III; Niles, John L.] Massachusetts Gen Hosp, Div Nephrol, Vasculitis & Glomerulonephritis Clin, Boston, MA 02114 USA. [Herlitz, Leal C.] Columbia Univ, Ctr Med, Dept Pathol & Cell Biol, Div Renal Pathol, New York, NY USA. [Thornley-Brown, Denyse] Univ Alabama Birmingham, Dept Internal Med, Div Nephrol, Birmingham, AL USA. [Rosner, Mitchell] Univ Virginia Hlth Syst, Dept Med, Div Nephrol, Charlottesville, VA USA. RP Niles, JL (reprint author), Massachusetts Gen Hosp, Dept Med, Div Nephrol, 151 Merrimac St,Floor 3, Boston, MA 02114 USA. EM jlniles@partners.org FU National Institute of Diabetes and Digestive and Kidney Diseases [1-F32-DK097891-02] FX W.F.P. is supported in part by National Institute of Diabetes and Digestive and Kidney Diseases grant no. 1-F32-DK097891-02. NR 92 TC 12 Z9 12 U1 3 U2 15 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 EI 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD NOV PY 2014 VL 9 IS 11 BP 1996 EP 2005 DI 10.2215/CJN.00360114 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA AS7OY UT WOS:000344446200026 PM 25035273 ER PT J AU Fay, AP Elfiky, A Telo, GH Mckay, RR Kaymakcalan, M Nguyen, PL Vaidya, A Ruan, DT Bellmunt, J Choueiri, TK AF Fay, Andre P. Elfiky, Aymen Telo, Gabriela H. Mckay, Rana R. Kaymakcalan, Marina Nguyen, Paul L. Vaidya, Anand Ruan, Daniel T. Bellmunt, Joaquim Choueiri, Toni K. TI Adrenocortical carcinoma: The management of metastatic disease SO CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY LA English DT Review DE Adrenocortical carcinoma; Therapeutics; Targeted therapies; Metastatic disease ID ADRENAL-CORTICAL CARCINOMA; LONG-TERM SURVIVAL; ERLOTINIB PLUS GEMCITABINE; PHASE-II; RADIATION-THERAPY; ADJUVANT MITOTANE; RADIOFREQUENCY ABLATION; SURGICAL RESECTION; SIGNALING PATHWAY; MTOR INHIBITORS AB Adrenocortical cancer is a rare malignancy. While surgery is the cornerstone of the management of localized disease, metastatic disease is hard to treat. Cytotoxic chemotherapy and mitotane have been utilized with a variable degree of benefit and few long-term responses. A growing understanding of the molecular pathogenesis of this malignancy as well as multidisciplinary and multi-institutional collaborative efforts will result in better defined targets and subsequently, effective novel therapies. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Fay, Andre P.; Elfiky, Aymen; Mckay, Rana R.; Kaymakcalan, Marina; Nguyen, Paul L.; Ruan, Daniel T.; Bellmunt, Joaquim; Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Elfiky, Aymen; Nguyen, Paul L.; Vaidya, Anand; Ruan, Daniel T.; Bellmunt, Joaquim; Choueiri, Toni K.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Elfiky, Aymen; Nguyen, Paul L.; Vaidya, Anand; Ruan, Daniel T.; Bellmunt, Joaquim; Choueiri, Toni K.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Telo, Gabriela H.] Joslin Diabet Ctr, Boston, MA 02215 USA. RP Choueiri, TK (reprint author), Dana Farber Canc Inst, 450 Brookline Ave DANA 1230, Boston, MA 02215 USA. EM Andre_Fay@dfci.harvard.edu; toni_choueiri@dfci.harvard.edu FU CAPES-CNPq - Brazil FX Andre P. Fay receives a scholarship from CAPES-CNPq - Brazil. NR 97 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1040-8428 EI 1879-0461 J9 CRIT REV ONCOL HEMAT JI Crit. Rev. Oncol./Hematol. PD NOV PY 2014 VL 92 IS 2 BP 123 EP 132 DI 10.1016/j.critrevonc.2014.05.009 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA AS8QW UT WOS:000344514300005 PM 24958272 ER PT J AU Sabbatino, F Fusciello, C Somma, D Pacelli, R Poudel, R Pepin, D Leonardi, A Carlomagno, C Scarpati, GD Ferrone, S Pepe, S AF Sabbatino, Francesco Fusciello, Celeste Somma, Domenico Pacelli, Roberto Poudel, Ravin Pepin, David Leonardi, Antonio Carlomagno, Chiara Scarpati, Giuseppina Della Vittoria Ferrone, Soldano Pepe, Stefano TI Effect of p53 Activity on the Sensitivity of Human Glioblastoma Cells to PARP-1 Inhibitor in Combination with Topoisomerase I Inhibitor or Radiation SO CYTOMETRY PART A LA English DT Article DE p53; glioblastoma; PARP inhibitor; radiotherapy; topotecan; combinatorial strategy ID PHOSPHORYLATED HISTONE H2AX; ADP-RIBOSE POLYMERASE; DOUBLE-STRAND BREAKS; POLY(ADP-RIBOSE) POLYMERASE; CANCER-THERAPY; PHASE-II; MULTIFORME; TOPOTECAN; EXPRESSION; APOPTOSIS AB Poly (ADP-Ribose) polymerase-1 (PARP-1) is involved in the DNA repairing system by sensing and signaling the presence of DNA damage. Inhibition of PARP-1 is tested in combination with DNA damaging agents such as topoisomerase I inhibitors or ionizing radiations (RT) for the treatment of glioblastoma (GBM). Disruption of p53, widely prevalent in GBMs, plays a major role in DNA repairing system. The current study investigates whether p53 activity has an effect on the sensitivity of human GBM cells to PARP-1 inhibitors in combination with topoisomerase I inhibitor topotecan (TPT) and/or RT. Human GBM cell lines carrying a different functional status of p53 were treated with PARP-1 inhibitor NU1025, in combination with TPT and/or RT. Cytotoxic effects were examined by analyzing the antiproliferative activity, the cell cycle perturbations, and the DNA damage induced by combined treatments. PARP inhibition enhanced the antiproliferative activity, the cell cycle perturbations and the DNA damage induced by both TPT or RT in GBM cells. These effects were influenced by the p53 activity: cells carrying an active p53 were more sensitive to the combination of PARP inhibitor and RT, while cells carrying an inactive p53 displayed a higher sensitivity to the combination of PARP inhibitor and TPT. Our study suggests that p53 activity influences the differential sensitivity of GBM cells to combined treatments of TPT, RT, and PARP inhibitors. (c) 2014 International Society for Advancement of Cytometry C1 [Sabbatino, Francesco; Fusciello, Celeste; Carlomagno, Chiara] Univ Naples Federico II, Dept Clin Med & Surg, I-80131 Naples, Italy. [Sabbatino, Francesco; Poudel, Ravin; Pepin, David; Ferrone, Soldano] Harvard Univ, Massachusetts Gen Hosp, Dept Surg, Sch Med, Boston, MA 02114 USA. [Somma, Domenico; Leonardi, Antonio] Univ Naples Federico II, Dept Mol Med Med Biotechnol, I-80131 Naples, Italy. [Pacelli, Roberto] Univ Naples Federico II, Dept Biomed Adv Sci, I-80131 Naples, Italy. [Pacelli, Roberto] Inst Biostruct & Bioimaging CNR, I-80131 Naples, Italy. [Scarpati, Giuseppina Della Vittoria] Univ Naples Federico II, Dept Diagnost Imaging & Radiat Oncol, I-80131 Naples, Italy. [Pepe, Stefano] Univ Salerno, Fac Pharm & Med, Dept Med, I-84131 Salerno, Italy. RP Sabbatino, F (reprint author), Massachusetts Gen Hosp, Dept Surg, 55 Fruit St, Boston, MA 02114 USA. EM fsabbatino@partners.org RI Sabbatino, Francesco/F-4992-2014; OI LEONARDI, Antonio/0000-0001-8636-9623; Sabbatino, Francesco/0000-0001-6431-8278; Poudel, Ravin/0000-0003-2622-3889 FU F.A.R.O. (Finanziamenti per l'avvio di ricerche originali); Polo delle Scienze e delle Tecnologie per la Vita [0086257]; National Cancer Institute PHS grants [RO1CA138188]; Fondazione Umberto Veronesi Post Doctoral Fellowship FX Grant sponsor: F.A.R.O. (Finanziamenti per l'avvio di ricerche originali); Grant sponsor: Polo delle Scienze e delle Tecnologie per la Vita, Grant number: 0086257; Grant sponsor: National Cancer Institute PHS grants, Grant number: RO1CA138188; Grant sponsor: Fondazione Umberto Veronesi Post Doctoral Fellowship NR 44 TC 5 Z9 5 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD NOV PY 2014 VL 85A IS 11 BP 953 EP 961 DI 10.1002/cyto.a.22563 PG 9 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AS3GT UT WOS:000344166300008 PM 25182801 ER PT J AU Choi, JH Choi, SS Kim, ES Jedrychowski, MP Yang, YR Jang, HJ Suh, PG Banks, AS Gygi, SP Spiegelman, BM AF Choi, Jang Hyun Choi, Sun-Sil Kim, Eun Sun Jedrychowski, Mark P. Yang, Yong Ryoul Jang, Hyun-Jun Suh, Pann-Ghill Banks, Alexander S. Gygi, Steven P. Spiegelman, Bruce M. TI Thrap3 docks on phosphoserine 273 of PPAR gamma and controls diabetic gene programming SO GENES & DEVELOPMENT LA English DT Article DE PPAR gamma; phosphorylation; Thrap3 interaction; gene reprogramming; energy homeostasis ID ACTIVATED RECEPTOR-GAMMA; INSULIN-RESISTANCE; THYROID-HORMONE; ADIPOSE-TISSUE; NUCLEAR RECEPTORS; COACTIVATOR COMPLEX; RETINOIC ACID; CO-REPRESSOR; OBESITY; LIGAND AB Phosphorylation of peroxisome proliferator-activated receptor gamma (PPAR gamma) at Ser273 by cyclin-dependent kinase 5 (CDK5) in adipose tissue stimulates insulin resistance, but the underlying molecular mechanisms are unclear. We show here that Thrap3 (thyroid hormone receptor-associated protein 3) can directly interact with PPAR gamma when it is phosphorylated at Ser273, and this interaction controls the diabetic gene programming mediated by the phosphorylation of PPAR gamma. Knockdown of Thrap3 restores most of the genes dysregulated by CDK5 action on PPAR gamma in cultured adipocytes. Importantly, reduced expression of Thrap3 in fat tissue by antisense oligonucleotides (ASOs) regulates a specific set of genes, including the key adipokines adiponectin and adipsin, and effectively improves hyperglycemia and insulin resistance in high-fat-fed mice without affecting body weight. These data indicate that Thrap3 plays a crucial role in controlling diabetic gene programming and may provide opportunities for the development of new therapeutics for obesity and type 2 diabetes. C1 [Choi, Jang Hyun; Choi, Sun-Sil; Kim, Eun Sun; Yang, Yong Ryoul; Jang, Hyun-Jun; Suh, Pann-Ghill] Ulsan Natl Inst Sci & Technol, Dept Biol Sci, Ulsan 689798, South Korea. [Jedrychowski, Mark P.; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Banks, Alexander S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM janghchoi@unist.ac.kr; bruce_spiegelman@dfci.harvard.edu RI Choi, Jang Hyun/B-3055-2012; Banks, Alexander/B-4832-2012 OI Banks, Alexander/0000-0003-1787-6925 FU National Research Foundation of Korea (NRF) - Ministry of Education, Science, and Technology [NRF-2012R1A1A1015407]; NRF - Korean government (Ministry of Science, ICT [Information and Communications Technology], and Future Planning [MSIP]) [2010-0028684]; National Institutes of Health (NIH) [K01DK093638]; NIH [DK031405] FX We are grateful for technical assistance from the In Vivo Research Center at Ulsan National Institute of Science and Technology. This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by Ministry of Education, Science, and Technology grant NRF-2012R1A1A1015407 (to J.H.C., S.-S.C., and E.S.K.). Y.R.Y., H.-J.J, and P.-G.S. were supported by the NRF grant funded by the Korean government (Ministry of Science, ICT [Information and Communications Technology], and Future Planning [MSIP]) (no. 2010-0028684). A.S.B. is supported by National Institutes of Health (NIH) K01DK093638, and B.M.S. is supported by NIH DK031405. NR 48 TC 12 Z9 12 U1 0 U2 7 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD NOV 1 PY 2014 VL 28 IS 21 BP 2361 EP 2369 DI 10.1101/gad.249367.114 PG 9 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA AS7OZ UT WOS:000344446300003 PM 25316675 ER PT J AU Willems, T Gymrek, M Highnam, G Mittelman, D Erlich, Y AF Willems, Thomas Gymrek, Melissa Highnam, Gareth Mittelman, David Erlich, Yaniv CA 1000 Genomes Project Consortium TI The landscape of human STR variation SO GENOME RESEARCH LA English DT Article ID MULTILOCUS GENOTYPE DATA; DINUCLEOTIDE REPEAT; TANDEM REPEATS; HUMAN GENOME; MICROSATELLITE VARIABILITY; LINKAGE DISEQUILIBRIUM; ALLELE FREQUENCIES; FUNCTIONAL IMPACT; PERSONAL GENOMES; MUTATION-RATES AB Short tandem repeats are among the most polymorphic loci in the human genome. These loci play a role in the etiology of a range of genetic diseases and have been frequently utilized in forensics, population genetics, and genetic genealogy. Despite this plethora of applications, little is known about the variation of most STRs in the human population. Here, we report the largest-scale analysis of human STR variation to date. We collected information for nearly 700,000 STR loci across more than 1000 individuals in Phase 1 of the 1000 Genomes Project. Extensive quality controls show that reliable allelic spectra can be obtained for close to 90% of the STR loci in the genome. We utilize this call set to analyze determinants of STR variation, assess the human reference genome's representation of STR alleles, find STR loci with common loss-of-function alleles, and obtain initial estimates of the linkage disequilibrium between STRs and common SNPs. Overall, these analyses further elucidate the scale of genetic variation beyond classical point mutations. C1 [Willems, Thomas; Gymrek, Melissa; 1000 Genomes Project Consortium] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Willems, Thomas] MIT, Computat & Syst Biol Program, Cambridge, MA 02139 USA. [Gymrek, Melissa] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Gymrek, Melissa] Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Gymrek, Melissa] Massachusetts Gen Hosp, Dept Mol Biol & Diabet Unit, Boston, MA 02114 USA. [Highnam, Gareth; Mittelman, David] Virginia Tech, Virginia Bioinformat Inst, Blacksburg, VA 24061 USA. [Highnam, Gareth; Mittelman, David] Virginia Tech, Dept Biol Sci, Blacksburg, VA 24061 USA. [Mittelman, David] Gene Gene Ltd, Houston, TX 77008 USA. RP Erlich, Y (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM yaniv@wi.mit.edu OI /0000-0002-6086-3903 FU National Defense Science and Engineering Graduate Fellowship; Burroughs Wellcome Fund; AWS Education Grant award FX M.G. is supported by a National Defense Science and Engineering Graduate Fellowship. Y.E. is an Andria and Paul Heafy Family Fellow and holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. This study was funded by a gift from Cathy and Jim Stone and an AWS Education Grant award. We thank Chris Tyler-Smith, Wei Wei, Qasim Ayub, and Yali Xue for providing the results of the Y-STR panel for the 1000 Genomes Project individuals and the 1000 Genomes Project Consortium members for useful discussions. Y.E. dedicates this manuscript to Lia Erlich, who was born during the last revision of this work. NR 69 TC 20 Z9 21 U1 4 U2 25 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 EI 1549-5469 J9 GENOME RES JI Genome Res. PD NOV PY 2014 VL 24 IS 11 BP 1894 EP 1904 DI 10.1101/gr.177774.114 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA AS7NG UT WOS:000344442000016 PM 25135957 ER PT J AU Caska, CM Smith, TW Renshaw, KD Allen, SN Uchino, BN Birmingham, W Carlisle, M AF Caska, Catherine M. Smith, Timothy W. Renshaw, Keith D. Allen, Steven N. Uchino, Bert N. Birmingham, Wendy Carlisle, McKenzie TI Posttraumatic stress disorder and responses to couple conflict: Implications for cardiovascular risk SO HEALTH PSYCHOLOGY LA English DT Article DE medically unexplained symptoms; parental divorce; parental death; adolescence ID CORONARY-HEART-DISEASE; ANGER; VETERANS; PTSD; QUESTIONNAIRE; METAANALYSIS; REACTIVITY; HOSTILITY; DIAGNOSES; QUALITY AB Objective: Functional somatic symptoms (FSSs) are physical symptoms that cannot be (fully) explained by organic pathology. FSSs are very common among children and adolescents, yet their etiology is largely unknown. We hypothesize that (a) the experience of family disruption due to parental divorce or parental death increases FSSs in adolescents; (b) symptoms of depression and anxiety contribute to the relationship between family disruption and FSSs; (c) girls are more vulnerable to these effects than boys. Method: Data were obtained from the prospective population cohort of Dutch adolescents of the Tracking Adolescents' Individual Lives Survey (N = 2,230), aged 10 to 12 years at baseline. FSSs were assessed using the Somatic Complaints subscale of the Youth Self-Report. Parental divorce and parental death were assessed with self-reports. Both outcome and predictors were assessed during 3 assessment waves over the course of 5 years. Linear mixed models were used to investigate associations between both types of family disruption and FSSs. Results: An interaction with age was found for parental divorce (B = 0.01, p =.02) and parental death (B = 0.03, p =.04), indicating that the influence of family disruption on FSSs increases during adolescence. This relationship seems to be partly explained by symptoms of depression and anxiety. No gender differences were found with regard to the effects of family disruption on FSSs. Conclusions: Family disruption is associated with an increased level of FSSs in late adolescence in both genders. This relationship is partly explained by symptoms of depression and/or anxiety. C1 [Caska, Catherine M.; Smith, Timothy W.; Uchino, Bert N.; Birmingham, Wendy; Carlisle, McKenzie] Univ Utah, Dept Psychol, Salt Lake City, UT 84112 USA. [Renshaw, Keith D.] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Allen, Steven N.] VA Salt Lake City Hlth Care Team, PTSD Clin Team, Salt Lake City, UT USA. RP Caska, CM (reprint author), VA Puget Sound Hlth Care Syst, Seattle Div, 1660 S Columbian Way 116MHC, Seattle, WA 98108 USA. EM cmcaska@gmail.com FU National Institute of Mental Health [1F31MH091915-01A1] FX The research reported in this article was supported in part by National Institute of Mental Health Grant 1F31MH091915-01A1 and is based on the doctoral dissertation of Catherine M. Caska. We thank everyone who assisted in this investigation, especially Courtney Smith, the Utah National Guard, and the Salt Lake City VA's PTSD Clinical Team. NR 42 TC 7 Z9 7 U1 5 U2 16 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD NOV PY 2014 VL 33 IS 11 BP 1273 EP 1280 DI 10.1037/hea0000133 PG 8 WC Psychology, Clinical; Psychology SC Psychology GA AS1BC UT WOS:000344010300001 PM 25110851 ER PT J AU Nillni, YI Gradus, JL Gutner, CA Luciano, MT Shipherd, JC Street, AE AF Nillni, Yael I. Gradus, Jaimie L. Gutner, Cassidy A. Luciano, Matthew T. Shipherd, Jillian C. Street, Amy E. TI Deployment Stressors and Physical Health Among OEF/OIF Veterans: The Role of PTSD SO HEALTH PSYCHOLOGY LA English DT Article DE harassment; trauma; posttraumatic stress disorder; physical health; veteran ID SEXUAL-HARASSMENT; PERCEIVED HEALTH; MILITARY SERVICE; SOMATIC SYMPTOMS; WAR VETERANS; CHRONIC PAIN; DISORDER; EXPOSURE; ASSAULT; TRAUMA AB Objective: There is a large body of literature documenting the relationship between traumatic stress and deleterious physical health outcomes. Although posttraumatic stress disorder (PTSD) symptoms have been proposed to explain this relationship, previous research has produced inconsistent results when moderating variables such as gender or type of traumatic stressor are considered. Within a large sample of Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) Veterans, the current study examined if deployment stressors (i. e., combat stress, harassment stress) contributed unique variance to the prediction of physical health symptoms (i.e., pain, nonpain) beyond the effects of PTSD symptoms. Methods: A total of 2,332 OEF/OIF Veterans, with equal representation of women and men, completed a series of self-report measures assessing deployment stressors, PTSD symptoms, and physical health symptoms. Results: Results revealed that harassment, but not combat stress, added unique variance in the prediction of pain and nonpain symptoms after accounting for PTSD symptoms. Conclusions: This study extends the existing literature by demonstrating the unique influence of harassment stress on physical health outcomes. Specifically, the relationship between combat stress and physical health symptoms appears to be explained mainly by an individual's experience of PTSD symptoms, whereas the relationship between harassment stress and physical health symptoms is not fully explained by PTSD symptoms, suggesting that other variables may be involved in the pathway from harassment stress to physical health symptoms. C1 [Nillni, Yael I.; Gradus, Jaimie L.; Gutner, Cassidy A.; Luciano, Matthew T.; Shipherd, Jillian C.; Street, Amy E.] Vet Affairs Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA 02130 USA. [Nillni, Yael I.; Gradus, Jaimie L.; Gutner, Cassidy A.; Shipherd, Jillian C.; Street, Amy E.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. RP Nillni, YI (reprint author), Vet Affairs Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, 150 South Huntington Ave,116B-3, Boston, MA 02130 USA. EM yael.nillni@va.gov OI Gradus, Jaimie/0000-0003-1459-5327 NR 38 TC 2 Z9 2 U1 2 U2 12 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD NOV PY 2014 VL 33 IS 11 BP 1281 EP 1287 DI 10.1037/hea0000084 PG 7 WC Psychology, Clinical; Psychology SC Psychology GA AS1BC UT WOS:000344010300002 PM 25020154 ER PT J AU El-Serag, HB Kanwal, F AF El-Serag, Hashem B. Kanwal, Fasiha TI Epidemiology of Hepatocellular Carcinoma in the United States: Where Are We? Where Do We Go? SO HEPATOLOGY LA English DT Review ID CHRONIC HEPATITIS-B; C VIRUS-INFECTION; ADVANCED LIVER-DISEASE; RISK-FACTORS; ANTIVIRAL THERAPY; REDUCES RISK; METAANALYSIS; CANCER; CIRRHOSIS; PROGRESSION C1 [El-Serag, Hashem B.; Kanwal, Fasiha] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Sect Gastroenterol & Hepatol, Houston, TX 77030 USA. [El-Serag, Hashem B.; Kanwal, Fasiha] Houston VA HSR&D Ctr Excellence Houston, Houston, TX USA. RP El-Serag, HB (reprint author), Michael E DeBakey VA Med Ctr, 2002 Holcombe Blvd 152, Houston, TX 77030 USA. EM hasheme@bcm.edu FU Houston VA HSR&D Center of Excellence [HFP90-020]; Texas Digestive Disease Center NIH [DK58338]; National Institute of Diabetes and Digestive and Kidney Diseases [K24-04-107] FX This work is funded, in part, by the Houston VA HSR&D Center of Excellence (HFP90-020) and the Texas Digestive Disease Center NIH DK58338. Dr. El-Serag is also supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K24-04-107). NR 58 TC 79 Z9 81 U1 3 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD NOV PY 2014 VL 60 IS 5 BP 1767 EP 1775 DI 10.1002/hep.27222 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6CM UT WOS:000344352400033 PM 24839253 ER PT J AU Hato, T Goyal, L Greten, TF Duda, DG Zhu, AX AF Hato, Tai Goyal, Lipika Greten, Tim F. Duda, Dan G. Zhu, Andrew X. TI Immune Checkpoint Blockade in Hepatocellular Carcinoma: Current Progress and Future Directions SO HEPATOLOGY LA English DT Review ID REGULATORY T-CELLS; PERCUTANEOUS ETHANOL INJECTION; SUPPRESSOR-CELLS; POSTOPERATIVE RECURRENCE; CTLA-4 BLOCKADE; LIVER; RESPONSES; PD-1; RECEPTOR; MOLECULES AB Immune checkpoint blockade has recently emerged as a promising therapeutic approach for various malignancies including hepatocellular carcinoma (HCC). Preclinical and clinical studies have shown the potential benefit of modulating the immunogenicity of HCC. In addition, recent advances in tumor immunology have broadened our understanding of the complex mechanism of immune evasion. In this review we summarize the current knowledge on HCC immunology and discuss the potential of immune checkpoint blockade as a novel HCC therapy from the basic, translational, and clinical perspectives. C1 [Hato, Tai; Duda, Dan G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. [Goyal, Lipika; Zhu, Andrew X.] Massachusetts Gen Hosp, Ctr Canc, Dept Med, Boston, MA 02114 USA. [Greten, Tim F.] NCI, Gastrointestinal Malignancy Sect, Thorac & Gastrointestinal Oncol Branch, Bethesda, MD 20892 USA. RP Duda, DG (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. EM GDUDA@PARTNERS.ORG; AZHU@PARTNERS.ORG RI Greten, Tim/B-3127-2015 OI Greten, Tim/0000-0002-0806-2535 FU National Institutes of Health [P01-CA080124, R01-CA159258, R21-CA139168]; National Cancer Institute/Proton Beam Federal Share Program award; American Cancer Society [120733-RSG-11-073-01-TBG]; Astellas Foundation for Research on Metabolic Disorders, Japan FX Supported by National Institutes of Health grants P01-CA080124, R01-CA159258, and R21-CA139168, a National Cancer Institute/Proton Beam Federal Share Program award, and the American Cancer Society grant 120733-RSG-11-073-01-TBG (to D. G. D.); and a Postdoctoral Fellowship from Astellas Foundation for Research on Metabolic Disorders, Japan (to T.H.). NR 62 TC 23 Z9 26 U1 3 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 EI 1527-3350 J9 HEPATOLOGY JI Hepatology PD NOV PY 2014 VL 60 IS 5 BP 1776 EP 1782 DI 10.1002/hep.27246 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6CM UT WOS:000344352400034 PM 24912948 ER PT J AU Dutta, P Nahrendorf, M AF Dutta, Partha Nahrendorf, Matthias TI Regulation and consequences of monocytosis SO IMMUNOLOGICAL REVIEWS LA English DT Review DE monocytes; macrophages; stem cells; spleen ID HEMATOPOIETIC STEM-CELLS; ACUTE MYOCARDIAL-INFARCTION; BINDING CASSETTE TRANSPORTERS; PROGENITOR CELLS; DENDRITIC CELLS; ATHEROSCLEROTIC LESIONS; INSULIN-RESISTANCE; ADIPOSE-TISSUE; IN-VIVO; ACCELERATES ATHEROSCLEROSIS AB Monocytes are part of the vertebrate innate immune system. Blood monocytes are produced by bone marrow and splenic progenitors that derive from hematopoietic stem cells (HSCs). In cardiovascular disease, such as atherosclerosis and myocardial infarction, HSCs proliferate at higher levels that in turn increase production of hematopoietic cells, including monocytes. Once produced in hematopoietic niches, monocytes intravasate blood vessels, circulate, and migrate to sites of inflammation. Monocyte recruitment to atherosclerotic plaque and the ischemic heart depends on various chemokines, such as CCL2, CX(3)CL1, and CCL5. Once in tissue, monocytes can differentiate into macrophages and dendritic cells. Macrophages are end effector cells that regulate the steady state and tissue healing, but they can also promote disease. At sites of inflammation, monocytes and macrophages produce inflammatory cytokines, which can exacerbate disease progression. Macrophages can also phagocytose tissue debris and produce pro-healing cytokines. Additionally, macrophages are antigen-presenting cells and can prime T cells. The tissue environment, including cytokines and types of inflammation, instructs macrophage specialization. Understanding monocytosis and its consequences in disease will reveal new therapeutic opportunities without compromising steady state functions. C1 [Dutta, Partha; Nahrendorf, Matthias] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Dutta, Partha; Nahrendorf, Matthias] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Dutta, P (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM pdutta1@partners.org FU National Institute of Health [R01-HL096576, R01HL117829, R01HL114477, K99-HL121076] FX This work was funded in part by grants from the National Institute of Health R01-HL096576, R01HL117829, R01HL114477 (M. N.); K99-HL121076 (P. D.). The authors have no conflicts of interest to declare. NR 114 TC 7 Z9 8 U1 2 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 EI 1600-065X J9 IMMUNOL REV JI Immunol. Rev. PD NOV PY 2014 VL 262 IS 1 SI SI BP 167 EP 178 DI 10.1111/imr.12219 PG 12 WC Immunology SC Immunology GA AS0WX UT WOS:000343997600012 PM 25319334 ER PT J AU Low, D Mino-Kenudson, M Mizoguchi, E AF Low, Daren Mino-Kenudson, Mari Mizoguchi, Emiko TI Recent Advancement in Understanding Colitis-associated Tumorigenesis SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE inflammatory bowel disease; epithelial dysplasia; guts microbiome ID INFLAMMATORY-BOWEL-DISEASE; DEXTRAN SULFATE SODIUM; INTESTINAL EPITHELIAL-CELLS; BETA-CATENIN ACTIVATION; ULCERATIVE-COLITIS; COLORECTAL-CANCER; SUPPRESSOR-CELLS; OXIDATIVE STRESS; TUMOR-GROWTH; COLON-CANCER AB Chronic inflammation predisposes patients with inflammatory bowel disease to the risk of developing colitis-associated cancer (CAC). Growing evidence strongly suggests that CAC development is multifactorial and is attributed to concurrent, dynamic dysregulations in host immunity, enteric microbiota, and epithelial restitution during the course of chronic inflammation. This article discusses the recent advances in understanding the different forms of CAC that may develop in patients with inflammatory bowel disease and animal models, as well as molecular alterations and other processes that orchestrate the development of CAC. C1 [Low, Daren; Mizoguchi, Emiko] Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mizoguchi, Emiko] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Mizoguchi, E (reprint author), Massachusetts Gen Hosp, GRJ 825D,55 Fruit St, Boston, MA 02114 USA. EM emizoguchi@mgh.harvard.edu FU National Institutes of Health [DK 80070, DK74454, DK64289]; Eli and Edythe L. Broad Medical Foundation; American Gastroenterological Association Foundation; Singapore A*STAR International Fellowship; National Cancer Institute [P50 CA127003, R01 CA169086] FX Supported by National Institutes of Health (DK 80070, DK74454, and DK64289) and grants from the Eli and Edythe L. Broad Medical Foundation and American Gastroenterological Association Foundation to E. Mizoguchi. D. Low was awarded the Singapore A*STAR International Fellowship. M. Mino-Kenudson was supported by National Cancer Institute grants P50 CA127003 and R01 CA169086. NR 82 TC 4 Z9 5 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD NOV PY 2014 VL 20 IS 11 BP 2115 EP 2123 DI 10.1097/MIB.0000000000000094 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS5YI UT WOS:000344342000027 PM 25337866 ER PT J AU Zhang, Z Adappa, ND Doghramji, LJ Chiu, AG Lautenbach, E Cohen, NA Palmer, JN AF Zhang, Zi Adappa, Nithin D. Doghramji, Laurel J. Chiu, Alexander G. Lautenbach, Ebbing Cohen, Noam A. Palmer, James N. TI Quality of life improvement from sinus surgery in chronic rhinosinusitis patients with asthma and nasal polyps SO INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY LA English DT Article DE chronic rhinosinusitis; quality of life; asthma; nasal polyps; functional endoscopic sinus surgery ID EUROPEAN POSITION PAPER; OUTCOMES; BACTERIA; ALLERGY; LONG; CARE AB BackgroundIt is unclear whether chronic rhinosinusitis (CRS) patients with both nasal polyps and asthma have different quality of life (QOL) improvement after functional endoscopic sinus surgery (FESS). We aimed to determine whether CRS patients with asthma and nasal polyps had a greater QOL improvement after FESS compared to patients without asthma or polyps. MethodsThis retrospective analysis included adult CRS patients who underwent FESS between 2007 and 2011. QOL was measured using the 22-item Sino-Nasal Outcome Test (SNOT-22). Variables collected included baseline demographics, clinical factors, SNOT-22 scores before FESS, and 1 month, 3 months, and 6 months post-FESS. Groups tested were asthma alone, polyps alone, asthma and polyps, and no asthma or polyps. Linear mixed-effects regression model was performed to calculate -coefficients, which represent the adjusted mean QOL differences. ResultsAmong the 376 patients included, 40.16% had both asthma and polyps (n = 151), 14.36% had asthma alone (n = 54), 19.45% had polyps alone (n = 75), and 25.53% had no asthma or polyps (n = 96). After adjusting for all factors, there were significantly more QOL improvements in patients with both asthma and nasal polyps from baseline to 1-month (-coefficient = -10.05; 95% CI, -15.86 to -4.23; p = 0.001) and 3-month follow-up (-coefficient = -8.27; 95% CI, -14.98 to -1.56; p = 0.016), and patients with asthma alone from baseline to 6-month follow-up (-coefficient = -8.78; 95% CI, -17.45 to -0.11; p = 0.047), when compared to patients without asthma or nasal polyps. ConclusionCRS patients with both asthma and nasal polyps or asthma alone experience a larger QOL benefit from FESS immediately after FESS compared to CRS patients without asthma or polyps. C1 [Zhang, Zi; Lautenbach, Ebbing] Univ Penn, Ctr Clin Epidemiol & Biostat, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Adappa, Nithin D.; Doghramji, Laurel J.; Cohen, Noam A.; Palmer, James N.] Univ Penn, Dept Otorhinolaryngol Head & Neck Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. [Chiu, Alexander G.] Univ Arizona, Dept Surg, Tucson, AZ USA. [Lautenbach, Ebbing] Univ Penn, Perelman Sch Med, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Cohen, Noam A.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Zhang, Z (reprint author), 8th Floor,Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM zizhang@mail.med.upenn.edu OI Cohen, Noam/0000-0002-9462-3932 FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health [K24 AI080942/AI/NIAID NIH HHS/United States] FX National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (K24 AI080942/AI/NIAID NIH HHS/United States to E. L.). NR 27 TC 13 Z9 13 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2042-6976 EI 2042-6984 J9 INT FORUM ALLERGY RH JI Int. Forum Allergy Rhinol. PD NOV PY 2014 VL 4 IS 11 BP 885 EP 892 DI 10.1002/alr.21406 PG 8 WC Otorhinolaryngology SC Otorhinolaryngology GA AS6GE UT WOS:000344361600005 PM 25256422 ER PT J AU Gerbasi, ME Richards, LK Thomas, JJ Agnew-Blais, JC Thompson-Brenner, H Gilman, SE Becker, AE AF Gerbasi, Margaret E. Richards, Lauren K. Thomas, Jennifer J. Agnew-Blais, Jessica C. Thompson-Brenner, Heather Gilman, Stephen E. Becker, Anne E. TI Globalization and Eating Disorder Risk: Peer Influence, Perceived Social Norms, and Adolescent Disordered Eating in Fiji SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE peer influence; social norms; adolescent; cultural; Fiji; globalization ID WEIGHT-CONTROL BEHAVIORS; GLOBAL MENTAL-HEALTH; QUESTIONNAIRE EDE-Q; BODY-IMAGE CONCERNS; SOCIOCULTURAL INFLUENCES; BULIMIC SYMPTOMS; FIELD EXPERIMENT; GIRLS; MEDIA; WOMEN AB Objective: The increasing global health burden imposed by eating disorders warrants close examination of social exposures associated with globalization that potentially elevate risk during the critical developmental period of adolescence in low-and middle-income countries (LMICs). The study aim was to investigate the association of peer influence and perceived social norms with adolescent eating pathology in Fiji, a LMIC undergoing rapid social change. Method: We measured peer influence on eating concerns (with the Inventory of Peer Influence on Eating Concerns; IPIEC), perceived peer norms associated with disordered eating and body concerns, perceived community cultural norms, and individual cultural orientations in a representative sample of school-going ethnic Fijian adolescent girls (n = 523). We then developed a multivariable linear regression model to examine their relation to eating pathology (measured by the Eating Disorder Examination-Questionnaire; EDE-Q). Results: We found independent and statistically significant associations between both IPIEC scores and our proxy for perceived social norms specific to disordered eating (both p < .001) and EDEQ global scores in a fully adjusted linear regression model. Discussion: Study findings support the possibility that peer influence as well as perceived social norms relevant to disordered eating may elevate risk for disordered eating in Fiji, during the critical developmental period of adolescence. Replication and extension of these research findings in other populations undergoing rapid social transition-and where globalization is also influencing local social norms-may enrich etiologic models and inform strategies to mitigate risk. (C) 2014 Wiley Periodicals, Inc. C1 [Gerbasi, Margaret E.; Becker, Anne E.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA 02115 USA. [Richards, Lauren K.; Thompson-Brenner, Heather] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Thomas, Jennifer J.; Becker, Anne E.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Thomas, Jennifer J.; Becker, Anne E.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Agnew-Blais, Jessica C.; Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gilman, Stephen E.; Becker, Anne E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Becker, AE (reprint author), Harvard Univ, Sch Med, Dept Global Hlth & Social Med, 641 Huntington Ave, Boston, MA 02115 USA. EM anne_becker@hms.harvard.edu RI Agnew-Blais, Jessica/L-9236-2015; Gilman, Stephen/E-7632-2010; OI Agnew-Blais, Jessica/0000-0002-0755-6867; Gilman, Stephen/0000-0002-8331-6419; Gerbasi, Margaret/0000-0003-1786-6962 FU Harvard University; [K23 MH068575]; [K23 MH071641]; [R36MH095395] FX Supported by K23 MH068575 (to A. E. B.), K23 MH071641 (to H. T. B.), and R36MH095395 (to L. R.) and by Harvard University Research Enabling Grant (to A. E. B.). NR 54 TC 1 Z9 1 U1 2 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 EI 1098-108X J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD NOV PY 2014 VL 47 IS 7 SI SI BP 727 EP 737 DI 10.1002/eat.22349 PG 11 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA AS6CO UT WOS:000344352600008 PM 25139374 ER PT J AU Swanson, SA Horton, NJ Crosby, RD Micali, N Sonneville, KR Eddy, K Field, AE AF Swanson, Sonja A. Horton, Nicholas J. Crosby, Ross D. Micali, Nadia Sonneville, Kendrin R. Eddy, Kamryn Field, Alison E. TI A Latent Class Analysis to Empirically Describe Eating Disorders Through Developmental Stages SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE eating disorder; latent class analysis; eating disorder not otherwise specified; purging disorder; binge eating disorder; classification ID COMORBIDITY-SURVEY-REPLICATION; ADOLESCENT GIRLS; PURGING DISORDER; LONGITUDINAL ASSOCIATIONS; DIAGNOSTIC INTERVIEW; ADVERSE OUTCOMES; RISK BEHAVIOR; UNITED-STATES; DRUG-USE; PREVALENCE AB Objectives: The current standards for classifying eating disorders were primarily informed by adult, clinical study populations, while it is unknown whether an empirically based classification system can be supported across preadolescence through young adulthood. Using latent class analyses, we sought to empirically classify disordered eating in females from preadolescence to young adulthood, and assess the association between classes and adverse outcomes. Method: Latent class models were fit using observations from the 9,039 girls participating in the growing up today study, an on-going cohort following participants annually or biennially since 1996 when they were ages 9-14 years. Associations between classes and drug use, binge drinking, and depressive symptoms were assessed using generalized estimating equations. Results: Across age groups, there was evidence of six classes: a large asymptomatic class, a class characterized by shape/weight concerns, a class characterized by overeating without loss of control, and three resembling full and subthreshold binge eating disorder, purging disorder, and bulimia nervosa. Relative prevalences of classes varied across developmental stages, with symptomatic classes increasing in prevalence with increasing age. Symptomatic classes were associated with concurrent and incident drug use, binge drinking, and high depressive symptoms. Discussion: A classification system resembling broader definitions of DSM-5 diagnoses along with two further subclinical symptomatic classes may be a useful framework for studying disordered eating among adolescent and young adult females. (C) 2014 Wiley Periodicals, Inc. Int C1 [Swanson, Sonja A.; Field, Alison E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Horton, Nicholas J.] Amherst Coll, Dept Math & Stat, Amherst, MA 01002 USA. [Crosby, Ross D.] Univ N Dakota, Sch Med & Hlth Sci, Neuropsychiat Res Inst, Fargo, ND USA. [Crosby, Ross D.] Univ N Dakota, Sch Med & Hlth Sci, Dept Clin Neurosci, Fargo, ND USA. [Micali, Nadia] UCL, Behav & Brain Sci Unit, Inst Child Hlth, London, England. [Sonneville, Kendrin R.; Field, Alison E.] Boston Childrens Hosp, Dept Med, Div Adolescent Med, Boston, MA USA. [Sonneville, Kendrin R.; Eddy, Kamryn; Field, Alison E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Eddy, Kamryn] Massachusetts Gen Hosp, Dept Psychiat, Harris Ctr Educ & Advocacy Eating Disorders, Boston, MA 02114 USA. [Field, Alison E.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. RP Swanson, SA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave,Kresge 9th Floor, Boston, MA 02115 USA. EM sswanson@hsph.harvard.edu OI Crosby, Ross/0000-0001-9131-1629 FU National Institutes of Health [MH087786, DK59570, DK46200, HL68041, HD049889] FX Supported by: MH087786, DK59570, DK46200, HL68041, and HD049889 from National Institutes of Health and by National Institutes of Health. NR 31 TC 5 Z9 5 U1 5 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 EI 1098-108X J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD NOV PY 2014 VL 47 IS 7 SI SI BP 762 EP 772 DI 10.1002/eat.22308 PG 11 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA AS6CO UT WOS:000344352600012 PM 24909947 ER PT J AU Slane, JD Klump, KL McGue, M Iacono, WG AF Slane, Jennifer D. Klump, Kelly L. McGue, Matthew Iacono, William G. TI Developmental Trajectories of Disordered Eating from Early Adolescence to Young Adulthood: A Longitudinal Study SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE disordered eating; longitudinal; developmental; growth curve ID RISK-FACTORS; ADVERSE OUTCOMES; NATURAL-HISTORY; BODY-WEIGHT; GIRLS; BEHAVIORS; ATTITUDES; WOMEN; PREADOLESCENT; SYMPTOMS AB Objective: Research examining changes in eating disorder symptoms across adolescence suggests an increase in disordered eating from early to late adolescence. However, relevant studies have largely been cross-sectional in nature and most have not examined the changes in the attitudinal symptoms of eating disorders (e. g., weight concerns). This longitudinal study aimed to address gaps in the available data by examining the developmental trajectories of disordered eating in females from preadolescence into young adulthood. Method: Participants were 745 same-sex female twins from the Minnesota Twin Family Study. Disordered eating was assessed using the Total Score, Body Dissatisfaction subscale, Weight Preoccupation subscale, and a combined Binge Eating and Compensatory Behavior subscale from the Minnesota Eating Behavior Survey assessed at the ages of 11, 14, 18, 21, and 25. Several latent growth models were fit to the data to identify the trajectory that most accurately captures the changes in disordered eating symptoms from 11 to 25 years. Results: The best-fitting models for overall levels of disordered eating, body dissatisfaction, and weight preoccupation showed an increase in from 11 through 25 years. In contrast, bulimic behaviors increased to age of 18 and then stabilized to age of 25. Discussion: The findings expanded upon extant research by investigating longitudinal, symptom specific, within person changes and showing an increase in cognitive symptoms into young adulthood and the stability of disordered eating behaviors past late adolescence. (C) 2014 Wiley Periodicals, Inc. C1 [Slane, Jennifer D.] VA Pittsburgh Healthcare Syst, VISN Mental Illness Res Educ & Clin Ctr MIRECC 4, Pittsburgh, PA USA. [Slane, Jennifer D.] Univ Pittsburgh, Dept Psychiat, Med Ctr, Pittsburgh, PA USA. [Klump, Kelly L.] Michigan State Univ, Dept Psychol, E Lansing, MI 48824 USA. [McGue, Matthew; Iacono, William G.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. RP Slane, JD (reprint author), VA Pittsburgh Healthcare Syst, VISN Mental Illness Res Educ & Clin Ctr 4, Univ Dr, Pittsburgh, PA 15261 USA. EM slane@msu.edu FU National Institute on Alcohol Abuse and Alcoholism [R01 AA009367] FX Supported by R01 AA009367 from National Institute on Alcohol Abuse and Alcoholism. NR 42 TC 3 Z9 4 U1 6 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 EI 1098-108X J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD NOV PY 2014 VL 47 IS 7 SI SI BP 793 EP 801 DI 10.1002/eat.22329 PG 9 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA AS6CO UT WOS:000344352600015 PM 24995824 ER PT J AU Wu, RI Schorge, JO Cin, PD Young, RH Oliva, E AF Wu, Roseann I. Schorge, John O. Cin, Paola D. Young, Robert H. Oliva, Esther TI Mullerian Adenosarcoma of the Uterus With Low-grade Sarcomatous Overgrowth Characterized by Prominent Hydropic Change Resulting in Mimicry of a Smooth Muscle Tumor SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Mullerian adenosarcoma; Low-grade sarcomatous overgrowth; Hydropic change; Sex cord-like; Smooth muscle differentiation ID SEX-CORD TUMORS; ENDOMETRIAL STROMAL TUMORS; CLINICOPATHOLOGIC ANALYSIS; DIFFERENTIATION; UPDATE AB A 28-y-old woman was found to have a large subserosal uterine mass that was excised and interpreted as a "clear cell leiomyoma." Five years later, the tumor recurred as serosal-based ileal and uterine masses; they were treated by partial ileal resection and hysterectomy. All 3 masses were predominantly characterized by conspicuous edema separating bland cells growing in cords and clusters, with scant to moderately conspicuous clear cytoplasm. The edema was indistinguishable from the hydropic change commonly seen in benign smooth muscle tumors and the cords similar to those often present in them. However, the mass from the hysterectomy specimen had a small, grossly recognizable cystic region, which on microscopic examination was a typical low-grade mullerian adenosarcoma. The stroma of the latter ranged from cellular endometrial-type to edematous and hypocellular similar to that dominating the other specimens. The cellular and edematous regions focally had cords and tubules of sex cord-like type confirmed by inhibin and calretinin positivity. Smooth muscle differentiation was also seen as a "starburst" pattern. This case of adenosarcoma is unusual due to its (1) serosal location, (2) overgrowth of stroma, which differed from typical adenosarcoma with sarcomatous overgrowth by its low-grade nature, (3) hydropic change associated with cords and nests of cells with clear cytoplasm, which prompted the initial specimen to be considered an epithelioid leiomyoma, and (4) prominent smooth muscle metaplasia mostly with a "starburst" morphology. All these features have only rarely been documented in prior mullerian adenosarcomas. C1 [Wu, Roseann I.; Young, Robert H.; Oliva, Esther] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Cin, Paola D.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Schorge, John O.] Harvard Univ, Dept Obstet & Gynecol, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Oliva, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 219, Boston, MA 02114 USA. EM eoliva@partners.org NR 18 TC 4 Z9 4 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD NOV PY 2014 VL 33 IS 6 BP 573 EP 580 DI 10.1097/PGP.0000000000000100 PG 8 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA AS2QC UT WOS:000344123500005 PM 25272296 ER PT J AU Clark, RM Lynch, MP Kolp, R Zukerberg, LR Growdon, WB Rueda, BR AF Clark, Rachel M. Lynch, Maureen P. Kolp, Rebecca Zukerberg, Lawrence R. Growdon, Whitfield B. Rueda, Bo R. TI The N-methyl-D-aspartate Receptor, a Precursor to N-methyl-D-aspartate Receptor Encephalitis, is Found in the Squamous Tissue of Ovarian Teratomas SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Ovarian teratoma; NMDA receptor encephalitis; Squamous tissue ID ANTI-NMDAR ENCEPHALITIS; GLUTAMATE-RECEPTOR; ANTIBODIES; SYMPTOMS AB Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is the most common antibody-mediated limbic encephalitis and is associated with underlying ovarian teratoma. Previous studies suggest that expression of NMDAR on teratoma neural tissue initiates an autoimmune response to NMDAR in the brain. As some teratomas of patients with anti-NMDAR encephalitis lack neuronal tissue, we questioned if there could be an alternate mechanism of the disease. We performed immunohistochemical analyses for NMDAR and correlated its expression with histology on 10 control teratomas and 5 teratomas associated with anti-NMDAR encephalitis. Both control and case teratomas expressed NMDAR-bearing neural tissue. All 15 teratomas contained large amounts of NMDAR bearing squamous epithelium; in 2 cases this was the only tissue expressing NMDAR. NMDAR-bearing neural tissue is not the sole source of encephalitis in all patients. Furthermore, we speculate that NMDAR expression by squamous epithelium may contribute to the disease development in some patients. C1 [Clark, Rachel M.; Lynch, Maureen P.; Growdon, Whitfield B.; Rueda, Bo R.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. [Clark, Rachel M.; Growdon, Whitfield B.; Rueda, Bo R.] Massachusetts Gen Hosp, Div Gynecol Oncol, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. [Zukerberg, Lawrence R.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Zukerberg, Lawrence R.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Clark, Rachel M.; Lynch, Maureen P.; Kolp, Rebecca; Growdon, Whitfield B.; Rueda, Bo R.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. RP Rueda, BR (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Vincent Dept Obstet & Gynecol, 55 Fruit St, Boston, MA 02114 USA. EM brueda@partners.org FU Vincent Memorial Research Funds; Advanced Medical Research Foundation FX Supported by the Vincent Memorial Research Funds and The Advanced Medical Research Foundation. NR 15 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 EI 1538-7151 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD NOV PY 2014 VL 33 IS 6 BP 598 EP 606 DI 10.1097/PGP.0000000000000104 PG 9 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA AS2QC UT WOS:000344123500008 PM 25272299 ER PT J AU Kopacz, MS AF Kopacz, Marek S. TI Moral injury - A war trauma affecting current and former military personnel SO INTERNATIONAL JOURNAL OF SOCIAL PSYCHIATRY LA English DT Letter ID EVENTS; COMBAT C1 US Dept Vet Affairs, VISN Ctr Excellence Suicide Prevent 2, Canandaigua, NY 14424 USA. RP Kopacz, MS (reprint author), US Dept Vet Affairs, VISN Ctr Excellence Suicide Prevent 2, 400 Ft Hill Ave, Canandaigua, NY 14424 USA. EM marek.kopacz@va.gov NR 12 TC 1 Z9 1 U1 0 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0020-7640 EI 1741-2854 J9 INT J SOC PSYCHIATR JI Int. J. Soc. Psychiatr. PD NOV PY 2014 VL 60 IS 7 BP 722 EP 723 DI 10.1177/0020764014547063 PG 2 WC Psychiatry SC Psychiatry GA AS4LD UT WOS:000344246500014 PM 25336198 ER PT J AU Cohen, GM Drain, PK Noubary, F Cloete, C Bassett, IV AF Cohen, Gabriel M. Drain, Paul K. Noubary, Farzad Cloete, Christie Bassett, Ingrid V. TI Diagnostic Delays and Clinical Decision Making With Centralized Xpert MTB/RIF Testing in Durban, South Africa SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE tuberculosis; HIV; AIDS; Xpert MTB; RIF assay; diagnostic testing; South Africa ID UNDERMINES POTENTIAL IMPACT; LOW-INCOME COUNTRIES; OF-CARE DIAGNOSIS; PULMONARY TUBERCULOSIS; ANTIRETROVIRAL THERAPY; RIFAMPIN RESISTANCE; MDR-TB; IMPLEMENTATION; SETTINGS; ACCURACY AB Setting:We conducted a retrospective study among HIV-infected adult suspects (18 years) with pulmonary tuberculosis (TB), who underwent Xpert MTB/RIF (Xpert) testing at McCord Hospital and its adjoining HIV clinic in Durban, South Africa.Objective:To determine if Xpert testing performed at a centralized laboratory accelerated time to TB diagnosis.Design:We obtained data on sputum smear microscopy [acid-fast bacilli (AFB)], Xpert, and the rationale for treatment initiation from medical records. The primary outcome was total diagnostic time, defined as time from sputum collection to clinicians' receipt of results. A linear mixed-effect model compared the duration of steps in the diagnostic pathway across testing modalities.Results:Among 403 participants, the median total diagnostic time for AFB and Xpert was 3.3 and 6.4 days, respectively (P < 0.001). When compared with AFB, the median delay for Xpert laboratory processing was 1.4 days (P < 0.001) and result transfer to clinic was 1.7 days (P < 0.001). Among 86 Xpert-positive participants who initiated treatment, 49 (57%) started treatment based on clinical suspicion or AFB-positive results, whereas only 32 (37%) started treatment based on Xpert-positive results.Conclusions:In our setting, Xpert results took twice as long as AFB results to reach clinicians. Replacing AFB with centralized Xpert may delay TB diagnoses in some settings. C1 [Cohen, Gabriel M.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Med, Sch Med, Boston, MA 02215 USA. [Drain, Paul K.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Drain, Paul K.] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Drain, Paul K.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Noubary, Farzad] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. [Noubary, Farzad] Tufts Univ, Tufts Clin & Translat Sci Inst, Boston, MA 02111 USA. [Cloete, Christie] McCord Hosp, Durban, Kwazulu Natal, South Africa. [Bassett, Ingrid V.] Harvard Univ, Sch Med, Ctr AIDS Res, Boston, MA 02215 USA. RP Cohen, GM (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Med, Sch Med, 330 Brookline Ave, Boston, MA 02215 USA. EM gcohen1@bidmc.harvard.edu FU Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University [R24 TW007988]; Harvard Global Health Institute; The Program for AIDS Clinical Research Training [T32 AI007433]; National Institute of Mental Health [R01 MH090326]; NCATS/NIH [UL1TR000011] FX G.C. and P. K. D. were supported by the Fogarty International Clinical Research Scholars and Fellows Program at Vanderbilt University (R24 TW007988). The Centre for the AIDS Programme of Research in South Africa (CAPRISA) in Durban, South Africa, served as the site for G.C.'s clinical research training year. P. K. D. was also supported by the Harvard Global Health Institute and The Program for AIDS Clinical Research Training (T32 AI007433). I. V. B. was supported by the National Institute of Mental Health (R01 MH090326). Access to REDCap was made available through the Vanderbilt Institute for Clinical and Translational Research grant support (UL1TR000011 from NCATS/NIH). NR 35 TC 8 Z9 8 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD NOV 1 PY 2014 VL 67 IS 3 BP E88 EP E93 DI 10.1097/QAI.0000000000000309 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AS6GC UT WOS:000344361400001 PM 25314255 ER PT J AU Gellad, WF Stein, BD Ruder, T Henderson, R Frazee, SG Mehrotra, A Donohue, JM AF Gellad, Walid F. Stein, Bradley D. Ruder, Teague Henderson, Rochelle Frazee, Sharon G. Mehrotra, Ateev Donohue, Julie M. TI Geographic Variation in Receipt of Psychotherapy in Children Receiving Attention-Deficit/Hyperactivity Disorder Medications SO JAMA PEDIATRICS LA English DT Letter ID ADHD C1 [Gellad, Walid F.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Gellad, Walid F.; Stein, Bradley D.; Ruder, Teague; Mehrotra, Ateev] RAND Corp, Pittsburgh, PA 15213 USA. [Gellad, Walid F.] Univ Pittsburgh, Div Gen Med, Pittsburgh, PA USA. [Gellad, Walid F.] Univ Pittsburgh, Ctr Pharmaceut Policy & Prescribing, Pittsburgh, PA USA. [Stein, Bradley D.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Henderson, Rochelle; Frazee, Sharon G.] Express Scripts, St Louis, MO USA. [Mehrotra, Ateev] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Donohue, Julie M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA USA. RP Gellad, WF (reprint author), RAND Corp, 4570 Fifth Ave,Ste 600, Pittsburgh, PA 15213 USA. EM wgellad@rand.org OI Donohue, Julie/0000-0003-2418-6017 NR 6 TC 5 Z9 5 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6203 EI 2168-6211 J9 JAMA PEDIATR JI JAMA Pediatr. PD NOV PY 2014 VL 168 IS 11 BP 1074 EP 1076 DI 10.1001/jamapediatrics.2014.1647 PG 4 WC Pediatrics SC Pediatrics GA AT1NS UT WOS:000344701500024 PM 25243391 ER PT J AU Kwon, YM Fehring, TK Lombardi, AV Barnes, CL Cabanela, ME Jacobs, JJ AF Kwon, Young-Min Fehring, Thomas K. Lombardi, Adolph V. Barnes, C. Lowry Cabanela, Miguel E. Jacobs, Joshua J. TI Risk Stratification Algorithm for Management of Patients with Dual Modular Taper Total Hip Arthroplasty: Consensus Statement of the American Association of Hip and Knee Surgeons, the American Academy of Orthopaedic Surgeons and the Hip Society SO JOURNAL OF ARTHROPLASTY LA English DT Article DE dual taper; taper corrosion; risk stratification ID TISSUE-REACTIONS; CORROSION; NECK; JUNCTION; PROSTHESES; INFECTION; FAILURE; STEM AB Although 'dual taper' modular stems with interchangeable modular necks have the potential to optimize hip biomechanical parameters, there is increasing concern regarding the occurrence of adverse local tissue reactions from mechanically assisted crevice corrosion at the neck-stem taper junction. A systematic treatment approach (risk stratification algorithm) based on the currently available data is recommended to optimize patient management. While specialized tests such as metal ion analysis and MARS MRI are useful modalities in evaluating for adverse tissue reactions, over-reliance on any single investigative tool in the clinical decision-making process should be avoided. There should be a low threshold to perform a systematic evaluation of patients with dual taper stem total hip arthroplasty as early recognition and diagnosis will facilitate the initiation of appropriate treatment. (C) 2014 Elsevier Inc. All rights reserved. C1 [Kwon, Young-Min] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Fehring, Thomas K.] Ortho Carolina Hip & Knee Ctr, Charlotte, NC USA. [Lombardi, Adolph V.] Ohio State Univ, Joint Implant Surg Inc, New Albany, OH USA. [Barnes, C. Lowry] Univ Arkansas Med Sci, Arkansas Special Orthopaed, Little Rock, AR 72205 USA. [Cabanela, Miguel E.] Mayo Clin, Dept Orthopaed Surg, Rochester, MN USA. [Jacobs, Joshua J.] Rush Univ, Med Ctr, Dept Orthopaed Surg, Chicago, IL 60612 USA. RP Kwon, YM (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. OI Jacobs, Joshua/0000-0003-3902-7334 NR 18 TC 20 Z9 20 U1 0 U2 3 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD NOV PY 2014 VL 29 IS 11 BP 2060 EP 2064 DI 10.1016/j.arth.2014.07.029 PG 5 WC Orthopedics SC Orthopedics GA AS4FG UT WOS:000344228000002 PM 25189673 ER PT J AU Gromov, K Greene, ME Sillesen, NH Troelsen, A Malchau, H Huddleston, JI Emerson, R Garcia-Cimbrelo, E Gebuhr, P AF Gromov, Kirill Greene, Meridith E. Sillesen, Nanna H. Troelsen, Anders Malchau, Henrik Huddleston, James I. Emerson, Roger Garcia-Cimbrelo, Eduardo Gebuhr, Peter CA Multictr Writing Comm TI Regional Differences Between US and Europe in Radiological Osteoarthritis and Self Assessed Quality of Life in Patients Undergoing Total Hip Arthroplasty Surgery SO JOURNAL OF ARTHROPLASTY LA English DT Article DE hip arthroplasty; osteoarthritis; regional differences; patient-reported outcome; quality of life ID KNEE REPLACEMENT SURGERY; JOINT REPLACEMENT; SELECTION; PRIORITY; CRITERIA AB Precise indications for THA remain unclear and regional differences might exist in selecting patients for surgery. In this study we investigate radiological OA grade and self-reported quality of life in 909 patients undergoing THA in 16 centers across US and Europe. Patients in US were younger and had higher BMI. More patients with mild Tonnis OA grade underwent surgery in the US compared to Europe. Patients in the US had significantly higher pain VAS and significantly lower SF-36 Physical, while having significantly higher EQ-VAS scores preoperatively. Patient demographics and disease severity according to radiological OA grade and self-reported survey scores vary between the United States and Europe. This knowledge can be used in the interpretation of US and European based studies on outcome following THA. (C) 2014 Elsevier Inc. All rights reserved. C1 [Huddleston, James I.] Stanford Univ, Med Ctr, Dept Orthopaed Surg, Stanford, CA 94305 USA. [Emerson, Roger] Texas Ctr Joint Replacement, Plano, TX USA. [Garcia-Cimbrelo, Eduardo] Hosp La Paz, Dept Orthopaed, Madrid, Spain. [Gebuhr, Peter] Copenhagen Univ Hosp, Dept Orthoped, Copenhagen, Denmark. [Gromov, Kirill; Greene, Meridith E.; Sillesen, Nanna H.; Malchau, Henrik] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Gromov, Kirill; Sillesen, Nanna H.; Troelsen, Anders] Copenhagen Univ Hosp, Dept Orthopaed Surg, Copenhagen, Denmark. RP Gromov, K (reprint author), Copenhagen Univ Hosp, Dept Orthoped, Copenhagen, Denmark. RI Garcia-Alonso, Maria Cristina/K-3779-2014 OI Garcia-Alonso, Maria Cristina/0000-0003-0275-4626 NR 32 TC 2 Z9 2 U1 0 U2 6 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD NOV PY 2014 VL 29 IS 11 BP 2078 EP 2083 DI 10.1016/j.arth.2014.07.006 PG 6 WC Orthopedics SC Orthopedics GA AS4FG UT WOS:000344228000005 PM 25129452 ER PT J AU Stoesz, M Wood, K Clark, W Kwon, YM Freiberg, AA AF Stoesz, Michael Wood, Kristin Clark, Wesley Kwon, Young-Min Freiberg, Andrew A. TI Utility of Noninvasive Transcutaneous Measurement of Postoperative Hemoglobin in Total Joint Arthroplasty Patients SO JOURNAL OF ARTHROPLASTY LA English DT Article DE transcutaneous hemoglobin measurement; postoperative venipuncture; total joint arthroplasty; anemia; cost-effective ID PULSE CO-OXIMETRY; SPINE SURGERY; ACCURACY AB This study prospectively evaluated the clinical utility of a noninvasive transcutaneous device for postoperative hemoglobin measurement in 100 total hip and knee arthroplasty patients. A protocol to measure hemoglobin noninvasively, prior to venipuncture, successfully avoided venipuncture in 73% of patients. In the remaining 27 patients, there were a total of 48 venipunctures performed during the postoperative hospitalization period due to reasons including transcutaneous hemoglobin measurement less than or equal to 9 g/dL (19), inability to obtain a transcutaneous hemoglobin measurement (8), clinical signs of anemia (3), and noncompliance with the study protocol (18). Such screening protocols may provide a convenient and cost-effective alternative to routine venipuncture for identifying patients at risk for blood transfusion after elective joint arthroplasty. (C) 2014 Elsevier Inc. All rights reserved. C1 [Stoesz, Michael; Wood, Kristin; Clark, Wesley; Kwon, Young-Min; Freiberg, Andrew A.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Freiberg, AA (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. NR 16 TC 2 Z9 2 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD NOV PY 2014 VL 29 IS 11 BP 2084 EP 2086 DI 10.1016/j.arth.2014.06.029 PG 3 WC Orthopedics SC Orthopedics GA AS4FG UT WOS:000344228000006 PM 25087726 ER PT J AU Sinha, P Aarnisalo, P Chubb, R Ono, N Fulzele, K Selig, M Saeed, H Chen, M Weinstein, LS Pajevic, PD Kronenberg, HM Wu, JY AF Sinha, Partha Aarnisalo, Piia Chubb, Rhiannon Ono, Noriaki Fulzele, Keertik Selig, Martin Saeed, Hamid Chen, Min Weinstein, Lee S. Pajevic, Paola Divieti Kronenberg, Henry M. Wu, Joy Y. TI Loss of G(s)alpha Early in the Osteoblast Lineage Favors Adipogenic Differentiation of Mesenchymal Progenitors and Committed Osteoblast Precursors SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE OSTEOBLASTS; G(S)A; MESENCHYMAL PROGENITORS; ADIPOCYTES ID HEMATOPOIETIC STEM-CELLS; RECEPTOR-RELATED PROTEIN-5; BONE-MARROW FAT; PARATHYROID-HORMONE; ADIPOCYTE DIFFERENTIATION; PPAR-GAMMA; TARGETED DISRUPTION; ANOREXIA-NERVOSA; TRABECULAR BONE; LEAN PHENOTYPE AB In humans, aging and glucocorticoid treatment are associated with reduced bone mass and increased marrow adiposity, suggesting that the differentiation of osteoblasts and adipocytes may be coordinately regulated. Within the bone marrow, both osteoblasts and adipocytes are derived from mesenchymal progenitor cells, but the mechanisms guiding the commitment of mesenchymal progenitors into osteoblast versus adipocyte lineages are not fully defined. The heterotrimeric G protein subunit G(s) activates protein kinase A signaling downstream of several G protein-coupled receptors including the parathyroid hormone receptor, and plays a crucial role in regulating bone mass. Here, we show that targeted ablation of G(s) in early osteoblast precursors, but not in differentiated osteocytes, results in a dramatic increase in bone marrow adipocytes. Mutant mice have reduced numbers of mesenchymal progenitors overall, with an increase in the proportion of progenitors committed to the adipocyte lineage. Furthermore, cells committed to the osteoblast lineage retain adipogenic potential both in vitro and in vivo. These findings have clinical implications for developing therapeutic approaches to direct the commitment of mesenchymal progenitors into the osteoblast lineage. (c) 2014 American Society for Bone and Mineral Research C1 [Sinha, Partha; Aarnisalo, Piia; Chubb, Rhiannon; Ono, Noriaki; Fulzele, Keertik; Pajevic, Paola Divieti; Kronenberg, Henry M.; Wu, Joy Y.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Aarnisalo, Piia] Univ Helsinki, Dept Clin Chem, SF-00100 Helsinki, Finland. [Aarnisalo, Piia] Univ Helsinki, Cent Hosp, Hosp Dist Helsinki & Uusimaa, Lab Serv HUSLAB, Helsinki, Finland. [Selig, Martin] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Saeed, Hamid; Wu, Joy Y.] Stanford Univ, Sch Med, Div Endocrinol, Stanford, CA 94305 USA. [Chen, Min; Weinstein, Lee S.] NIDDK, Metabol Dis Branch, Bethesda, MD USA. RP Wu, JY (reprint author), Stanford Univ, Sch Med, 300 Pasteur Dr,Room S-025, Stanford, CA 94305 USA. EM jywu1@stanford.edu FU MGH Executive Committee on Research; Harvard Stem Cell Institute; National Institutes of Health [AR054741, AR059942]; Ruth Kirschstein NRSA [DK11794, AR060211]; National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program FX This work was supported by the MGH Executive Committee on Research (JYW), the Harvard Stem Cell Institute (JYW), and National Institutes of Health grants AR054741 and AR059942 to JYW; Ruth Kirschstein NRSA to PS; DK11794 to HMK; AR060211 to PDP; and by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program (MC and LSW). NR 86 TC 8 Z9 8 U1 0 U2 4 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 NOV PY 2014 VL 29 IS 11 BP 2414 EP 2426 DI 10.1002/jbmr.2270 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS4DF UT WOS:000344222800011 PM 24806274 ER PT J AU Wu, CJ AF Wu, Catherine J. TI Shifting ecologies of malignant and nonmalignant cells following BRAF inhibition SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; CANCER; MUTATIONS; EVOLUTION AB Clinical vignette: A 49-year-old-man with stage IV BRAF(V600E)-driven melanoma was initiated on twice-daily 960 mg of vemurafenib for treatment of progressive and recurrent subcutaneous metastatic disease of the left lower extremity. The patient's melanoma responded well to targeted BRAF inhibition. At treatment onset, hematologic parameters were all within normal limits; however, within three months of initiating therapy, wbc were found to be elevated (to 20 K) with sustained lymphocytosis of mature phenotype. lmmunophenotypic analysis was consistent with chronic lymphocytic leukemia (CLL), and FISH results revealed presence of the CLL-associated deletion in chromosome 13q14 as well as in 2p33. Vemurafenib was withdrawn after approximately one year of therapy, and subsequently, his peripheral lymphocytosis resolved and CLL regressed. Nevertheless, a monoclonal B cell population persisted even 732 days after discontinuation of vemurafenib. C1 [Wu, Catherine J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Wu, Catherine J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wu, Catherine J.] Broad Inst, Cambridge, MA USA. RP Wu, CJ (reprint author), Dana Farber Canc Inst, Rm 540B,44 Binney St, Boston, MA 02115 USA. EM cwu@partners.org FU Blavatnik Family Foundation; American Association for Cancer Research (AACR); Leukemia and Lymphoma Society; National Cancer Institute (NCI) [1R01CA182461-01, 1R01CA184922-01] FX C.J. Wu acknowledges support from the Blavatnik Family Foundation, American Association for Cancer Research (AACR) (SU2C Innovative Research Grant), the Leukemia and Lymphoma Society (Scholar Award, Quest for Cures Award), and the National Cancer Institute (NCI) (1R01CA182461-01, 1R01CA184922-01). NR 15 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2014 VL 124 IS 11 BP 4681 EP 4683 DI 10.1172/JCI78783 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AS3UK UT WOS:000344203300004 PM 25329690 ER PT J AU Yuen, M Sandaradura, SA Dowling, JJ Kostyukova, AS Moroz, N Quinlan, KG Lehtokari, VL Ravenscroft, G Todd, EJ Ceyhan-Birsoy, O Gokhin, DS Maluenda, J Lek, M Nolent, F Pappas, CT Novak, SM D'Amico, A Malfatti, E Thomas, BP Gabriel, SB Gupta, N Daly, MJ Ilkovski, B Houweling, PJ Davidson, AE Swanson, LC Brownstein, CA Gupta, VA Medne, L Shannon, P Martin, N Bick, DP Flisberg, A Holmberg, E Van den Bergh, P Lapunzina, P Waddell, LB Sioboda, DD Bertini, E Chitayat, D Telfer, WR Laquerriere, A Gregorio, CC Ottenheijm, CAC Bonnemann, CG Pelin, K Beggs, AH Hayashi, YK Romero, NB Laing, NG Nishino, I Wallgren-Pettersson, C Melki, J Fowler, VM MacArthur, DG North, KN Clarke, NF AF Yuen, Michaele Sandaradura, Sarah A. Dowling, James J. Kostyukova, Alla S. Moroz, Natalia Quinlan, Kate G. Lehtokari, Vilma-Lotta Ravenscroft, Gianina Todd, Emily J. Ceyhan-Birsoy, Ozge Gokhin, David S. Maluenda, Jerome Lek, Monkol Nolent, Flora Pappas, Christopher T. Novak, Stefanie M. D'Amico, Adele Malfatti, Edoardo Thomas, Brett P. Gabriel, Stacey B. Gupta, Namrata Daly, Mark J. Ilkovski, Biljana Houweling, Peter J. Davidson, Ann E. Swanson, Lindsay C. Brownstein, Catherine A. Gupta, Vandana A. Medne, Livija Shannon, Patrick Martin, Nicole Bick, David P. Flisberg, Anders Holmberg, Eva Van den Bergh, Peter Lapunzina, Pablo Waddell, Leigh B. Sioboda, Darcee D. Bertini, Enrico Chitayat, David Telfer, William R. Laquerriere, Annie Gregorio, Carol C. Ottenheijm, Coen A. C. Boennemann, Carsten G. Pelin, Katarina Beggs, Alan H. Hayashi, Yukiko K. Romero, Norma B. Laing, Nigel G. Nishino, Ichizo Wallgren-Pettersson, Carina Melki, Judith Fowler, Velia M. MacArthur, Daniel G. North, Kathryn N. Clarke, Nigel F. TI Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MUSCLE ALPHA-TROPOMYOSIN; SKELETAL-MUSCLE; POINTED-END; N-TERMINUS; ACTIN; TROPOMODULIN; MUTATIONS; LENGTH; POLYMERIZATION; DEFICIENCY AB Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of Imod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle. C1 [Yuen, Michaele; Sandaradura, Sarah A.; Quinlan, Kate G.; Ilkovski, Biljana; Houweling, Peter J.; Waddell, Leigh B.; North, Kathryn N.; Clarke, Nigel F.] Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW, Australia. [Yuen, Michaele; Sandaradura, Sarah A.; Quinlan, Kate G.; Houweling, Peter J.; Waddell, Leigh B.; Clarke, Nigel F.] Univ Sydney, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia. [Dowling, James J.; Davidson, Ann E.; Telfer, William R.] Univ Michigan, Med Ctr, Dept Pediat, Ann Arbor, MI 48109 USA. [Dowling, James J.; Davidson, Ann E.; Telfer, William R.] Univ Michigan, Med Ctr, Dept Neurol, Ann Arbor, MI 48109 USA. [Dowling, James J.; Davidson, Ann E.] Hosp Sick Children, Div Neurol, Toronto, ON M5G 1X8, Canada. [Dowling, James J.; Davidson, Ann E.] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada. [Kostyukova, Alla S.; Moroz, Natalia] Washington State Univ, Gene & Linda Voiland Sch Chem Engn & Bioengn, Pullman, WA 99164 USA. [Lehtokari, Vilma-Lotta; Wallgren-Pettersson, Carina] Univ Helsinki, Folkhalsan Inst Genet, Haartman Inst, Helsinki, Finland. [Lehtokari, Vilma-Lotta; Wallgren-Pettersson, Carina] Univ Helsinki, Haartman Inst, Dept Med Genet, Helsinki, Finland. [Ravenscroft, Gianina; Todd, Emily J.; Laing, Nigel G.] Univ Western Australia, Western Australia Inst Med Res, Nedlands, WA 6009, Australia. [Ravenscroft, Gianina; Todd, Emily J.; Laing, Nigel G.] Univ Western Australia, Med Res Ctr, Nedlands, WA 6009, Australia. [Ceyhan-Birsoy, Ozge; Swanson, Lindsay C.; Brownstein, Catherine A.; Gupta, Vandana A.; Beggs, Alan H.] Harvard Univ, Boston Childrens Hosp, Sch Med, Div Genet & Genom,Manton Ctr Orphan Dis Res, Boston, MA USA. [Gokhin, David S.; Fowler, Velia M.] Scripps Res Inst, Dept Cell & Mol Biol, La Jolla, CA 92037 USA. [Maluenda, Jerome; Nolent, Flora; Melki, Judith] INSERM, Unite Mixte Rech 788, F-94275 Le Kremlin Bicetre, France. [Maluenda, Jerome; Nolent, Flora; Melki, Judith] Univ Paris, Le Kremlin Bicetre, France. [Lek, Monkol; Thomas, Brett P.; Daly, Mark J.; MacArthur, Daniel G.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Lek, Monkol; Thomas, Brett P.; Gabriel, Stacey B.; Gupta, Namrata; Daly, Mark J.; MacArthur, Daniel G.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Pappas, Christopher T.; Novak, Stefanie M.; Gregorio, Carol C.] Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ USA. [D'Amico, Adele; Bertini, Enrico] Bambino Gesu Pediat Hosp, Lab Mol Med Neuromuscular & Neurodegenerat Dis, Rome, Italy. [Malfatti, Edoardo; Romero, Norma B.] Grp Hosp Univ La Pitie Salpetriere, Inst Myol, Neuromuscular Morphol Unit, Paris, France. [Houweling, Peter J.; North, Kathryn N.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Medne, Livija] Childrens Hosp Philadelphia, Div Human Genet & Neurol, Philadelphia, PA 19104 USA. [Shannon, Patrick] Mt Sinai Hosp, Dept Pathol & Lab Med, Toronto, ON M5G 1X5, Canada. [Martin, Nicole; Chitayat, David] Univ Toronto, Mt Sinai Hosp, Dept Obstet & Gynaecol, Prenatal Diag & Med Genet Program, Toronto, ON M5G 1X5, Canada. [Bick, David P.] Med Coll Wisconsin, Dept Pediat, Genet Sect, Milwaukee, WI 53226 USA. [Bick, David P.] Med Coll Wisconsin, Ctr Mol Genet, Milwaukee, WI 53226 USA. [Flisberg, Anders] Sahlgrens Univ Hosp, Dept Neonatol, Gothenburg, Sweden. [Holmberg, Eva] Sahlgrens Univ Hosp, Dept Clin Genet, Gothenburg, Sweden. [Van den Bergh, Peter] St Luc Univ Hosp, Neuromuscular Reference Ctr, Brussels, Belgium. [Lapunzina, Pablo] Hosp Univ La Paz, Inst Invest Sanitaria, Inst Genet Med & Mol, Madrid, Spain. [Lapunzina, Pablo] Univ Autonoma Madrid, Madrid, Spain. [Lapunzina, Pablo] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras, Madrid, Spain. [Sioboda, Darcee D.] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. [Chitayat, David] Univ Toronto, Hosp Sick Children, Dept Paediat, Div Clin & Med Genet, Toronto, ON M5G 1X8, Canada. [Laquerriere, Annie] Univ Rouen, Pathol Lab, Rouen, France. [Laquerriere, Annie] Univ Rouen, NeoVasc Reg INSERM Team ERI28, Rouen, France. [Ottenheijm, Coen A. C.] Vrije Univ Amsterdam, Med Ctr, Inst Cardiovasc Res, Dept Physiol, Amsterdam, Netherlands. [Boennemann, Carsten G.] NINDS, Neuromuscular & Neurogenet Disorders Childhood Se, NIH, Bethesda, MD 20892 USA. [Pelin, Katarina] Univ Helsinki, Dept Biosci, Helsinki, Finland. [Hayashi, Yukiko K.] Tokyo Med Univ, Dept Neurophysiol, Tokyo 1608402, Japan. [Hayashi, Yukiko K.; Nishino, Ichizo] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Neuromuscular Res, Tokyo, Japan. [Melki, Judith] Ctr Hosp Sud Francilien, Unite Genet Med, Corbel Essonnes, France. [North, Kathryn N.] Univ Melbourne, Dept Paediat, Melbourne, Vic 3010, Australia. RP North, KN (reprint author), Royal Childrens Hosp, Murdoch Childrens Res Inst, Flemington Rd, Parkville, Vic 3052, Australia. EM kathryn.north@mcri.edu.au RI North, Kathryn/K-6476-2012; Houweling, Peter/B-4157-2016; d'amico, adele/J-9203-2016 OI North, Kathryn/0000-0003-0841-8009; Houweling, Peter/0000-0001-6132-2554; Pelin, Katarina/0000-0002-7040-7266; d'amico, adele/0000-0003-2438-2624 FU National Health and Medical Research Council of Australia [1022707, 1031893, 1035828, 1035955, 0511981, 1002147, 1075451]; Association Francaise contre les Myopathies [15734, DAJ1891]; National Hospital Clinical Research Program [A0M10181]; National Institute of Child Health and Development of the NIH [R01 HD 075802]; Muscular Dystrophy Association (USA) [MDA201302]; AUism Charitable Foundation; National Institute on Aging [AG000114]; University of Sydney Australian Postgraduate Award; International Postgraduate Research Scholarship; University of Western Australia Postgraduate Award; Dubai-Harvard Foundation for Medical Research postdoctoral fellowship; Schlumberger Foundation Faculty; Italian Ministry of Health Ricerca finalizzata [GR-2010-2310981]; NIH [GM081688, K01 AR062601]; Muscular Dystrophy Association (USA); National Human Genome Research Institute of the NIH [U54 HG003067] FX This work was funded by the National Health and Medical Research Council of Australia (1022707 and 1031893 to N.F. Clarke, K.N. North, and N.G. Laing; 1035828 to N.F. Clarke; 1035955 to G. Ravenscroft; 0511981 to K.G. Quinlan; 1002147 to N.G. Laing; and 1075451 to S.A. Sandaradura), the Association Francaise contre les Myopathies (15734 to G. Ravenscroft and N.G. Laing; DAJ1891 to J. Melki), the National Hospital Clinical Research Program (A0M10181 to J. Melki), the National Institute of Child Health and Development of the NIH (R01 HD 075802 to A.H. Beggs), the Muscular Dystrophy Association (USA) (MDA201302 to A.H. Beggs), the AUism Charitable Foundation (to A.H. Beggs), and the National Institute on Aging (AG000114 to D.D. Sloboda). M. Kreissl is supported by a University of Sydney Australian Postgraduate Award and an International Postgraduate Research Scholarship. E.J. Todd is supported by a University of Western Australia Postgraduate Award. O. Ceyhan-Birsoy is supported by a Dubai-Harvard Foundation for Medical Research postdoctoral fellowship and Schlumberger Foundation Faculty for the Future grant. A. D'Amico and E. Bertini are supported by the Italian Ministry of Health Ricerca finalizzata (GR-2010-2310981). A.S. Kostyukova is supported by NIH grant GM081688, and V.A. Gupta is supported by NIH grant K01 AR062601. D.S. Gokhin is supported by a Development Grant from the Muscular Dystrophy Association (USA). Exome sequencing was supported by grants from the National Human Genome Research Institute of the NIH (Medical Sequencing Program grant U54 HG003067 to the Broad Institute principal investigator, Lander) and by the Gene Partnership Project of Boston Children's Hospital. The authors would like to thank the study patients and their families, without whose participation this work would not have been possible. We thank F. Muntoni (Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital for Children), C. Lacroix, (Service de Neuropathologie, CHU Bicetre), V. Zupan-Simunek (Service de Neonatologie, Hopital Antoine Beclere), A. Kan and N. Graf (The Children's Hospital at Westmead), and F. Fattori (Bambino Gesu Children's Hospital) for contribution and/or analysis of patient samples; S. Brammah(Concord Hospital) for provision of EM control images; T. Peduto (The Children's Hospital at Westmead) for assistance with analysis of muscle MRI; D.M. Margulies (Boston Children's Hospital) for support of WES through The Gene Partnership; and T. Yu and P. Park (Boston Children's Hospital) for WES pipeline development. We thank S.V. Brooks (University of Michigan) for assistance with experimental work and R. Dominguez (University of Pennsylvania) for providing reagents. NR 37 TC 35 Z9 38 U1 1 U2 8 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2014 VL 124 IS 11 BP 4693 EP 4708 DI 10.1172/JCI75199 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AS3UK UT WOS:000344203300008 PM 25250574 ER PT J AU McCormick, JA Yang, CL Zhang, C Davidge, B Blankenstein, KI Terker, AS Yarbrough, B Meermeier, NP Park, HJ McCully, B West, M Borschewski, A Himmerkus, N Bleich, M Bachmann, S Mutig, K Argaiz, ER Gamba, G Singer, JD Ellison, DH AF McCormick, James A. Yang, Chao-Ling Zhang, Chong Davidge, Brittney Blankenstein, Katharina I. Terker, Andrew S. Yarbrough, Bethzaida Meermeier, Nicholas P. Park, Hae J. McCully, Belinda West, Mark Borschewski, Aljona Himmerkus, Nina Bleich, Markus Bachmann, Sebastian Mutig, Kerim Argaiz, Eduardo R. Gamba, Gerardo Singer, Jeffrey D. Ellison, David H. TI Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3 SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NA-CL COTRANSPORTER; PSEUDOHYPOALDOSTERONISM TYPE-II; SODIUM-CHLORIDE COTRANSPORTER; DISEASE-CAUSING MUTATIONS; BLOOD-PRESSURE; CYCLIN-E; DISTAL NEPHRON; UBIQUITINATION; DEGRADATION; EXPRESSION AB Familial hyperkalemic hypertension (FHHt) is a monogenic disease resulting from mutations in genes encoding WNK kinases, the ubiquitin scaffold protein cullin 3 (CUL3), or the substrate adaptor kelch-like 3 (KLHL3). Disease-associated CUL3 mutations abrogate WNK kinase degradation in cells, but it is not clear how mutant forms of CUL3 promote WNK stability. Here, we demonstrated that an FHHt-causing CUL3 mutant (CUL3 Delta 403-459) not only retains the ability to bind and ubiquitylate WNK kinases and KLHL3 in cells, but is also more heavily neddylated and activated than WT CUL3. In cells, activated CUL3 Delta 403-459 depleted KLHL3, preventing WNK degradation, despite increased CUL3-mediated WNK ubiquitylation; therefore, CUL3 loss in kidney should phenocopy FHHt in murine models. As predicted, nephron-specific deletion of Cul3 in mice did increase WNK kinase levels and the abundance of phosphorylated Na-Cl cotransporter (NCC). Over time, however, Cul3 deletion caused renal dysfunction, including hypochloremic alkalosis, diabetes insipidus, and salt-sensitive hypotension, with depletion of sodium potassium chloride cotransporter 2 and aquaporin 2. Moreover, these animals exhibited renal inflammation, fibrosis, and increased cyclin E. These results indicate that FHHt-associated CUL3 Delta 403-459 targets KLHL3 for degradation, thereby preventing WNK degradation, whereas general loss of CUL3 activity - while also impairing WNK degradation - has widespread toxic effects in the kidney. C1 [McCormick, James A.; Yang, Chao-Ling; Zhang, Chong; Terker, Andrew S.; Yarbrough, Bethzaida; Meermeier, Nicholas P.; Park, Hae J.; Ellison, David H.] Oregon Hlth & Sci Univ, Div Nephrol & Hypertens, Dept Med, Portland, OR 97239 USA. [Zhang, Chong] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Dept Nephrol, Shanghai 200030, Peoples R China. [Davidge, Brittney; West, Mark; Singer, Jeffrey D.] Portland State Univ, Dept Biol, Portland, OR 97207 USA. [Blankenstein, Katharina I.; Borschewski, Aljona; Bachmann, Sebastian; Mutig, Kerim; Ellison, David H.] Charite, Inst Vegetat Anat, Campus Charite Mitte, D-13353 Berlin, Germany. [McCully, Belinda] Oregon Hlth & Sci Univ, Dept Surg, Div Trauma Crit Care & Acute Care Surg, Portland, OR 97239 USA. [Himmerkus, Nina; Bleich, Markus] Univ Kiel, Inst Physiol, Kiel, Germany. [Argaiz, Eduardo R.; Gamba, Gerardo] Univ Nacl Autonoma Mexico, Mol Physiol Unit, Inst Invest Biomed, Mexico City 04510, DF, Mexico. [Argaiz, Eduardo R.; Gamba, Gerardo] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City, DF, Mexico. [Ellison, David H.] Portland VA Med Ctr, Portland, OR USA. RP Ellison, DH (reprint author), Oregon Hlth & Sci Univ, Div Nephrol & Hypertens, CH12R,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM jsinger@pdx.edu; ellisond@ohsu.edu OI Terker, Andrew/0000-0003-1498-9043; Bleich, Markus/0000-0002-1745-2295 FU NIH [R01 DK5149 6, K01 DK076617, R01 DK098141, R01 GM082940]; Department of Veterans Affairs [1I01BX002228-01A1]; Shanghai Municipal Education Commission; Shanghai Jiao Tong University K.C. Wong Medical Fellowship Fund; Conacyt; Europeans Union; American Heart Association [13PRE14090030] FX This work was supported by NIH grants R01 DK5149 6 (to D.H. Ellison), K01 DK076617 and R01 DK098141 (to J.A. McCormick), and R01 GM082940 (to J.D. Singer) as well as by Merit Review grant 1I01BX002228-01A1 from the Department of Veterans Affairs (to D.H. Ellison). C. Zhang was supported by the Shanghai Municipal Education Commission and a Shanghai Jiao Tong University K.C. Wong Medical Fellowship Fund. E.R. Argaiz was supported by a scholarship from Conacyt and is a graduate student in the biomedical science PhD program of Universidad Nacional Autonoma de Mexico. D.H. Ellison received a Marie Curie Fellowship from the Europeans Union during part of these studies. A.S. Terker is supported by a Predoctoral Fellowship from the American Heart Association (13PRE14090030). The authors appreciate the interpretation of the renal morphology and advice provided by Megan Troxell, and the helpful discussions with Juliette Hadchouel. NR 40 TC 34 Z9 36 U1 0 U2 7 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2014 VL 124 IS 11 BP 4723 EP 4736 DI 10.1172/JCI76126 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AS3UK UT WOS:000344203300010 PM 25250572 ER PT J AU Dubovsky, JA Flynn, R Du, J Harrington, BK Zhong, YM Kaffenberger, B Yang, C Towns, WH Lehman, A Johnson, AJ Muthusamy, N Devine, SM Jaglowski, S Serody, JS Murphy, WJ Munn, DH Luznik, L Hill, GR Wong, HK MacDonald, KKP Maillard, I Koreth, J Elias, L Cutler, C Soiffer, RJ Antin, JH Ritz, J Panoskaltsis-Mortari, A Byrd, JC Blazar, BR AF Dubovsky, Jason A. Flynn, Ryan Du, Jing Harrington, Bonnie K. Zhong, Yiming Kaffenberger, Benjamin Yang, Carrie Towns, William H. Lehman, Amy Johnson, Amy J. Muthusamy, Natarajan Devine, Steven M. Jaglowski, Samantha Serody, Jonathan S. Murphy, William J. Munn, David H. Luznik, Leo Hill, Geoffrey R. Wong, Henry K. MacDonald, Kelli K. P. Maillard, Ivan Koreth, John Elias, Laurence Cutler, Corey Soiffer, Robert J. Antin, Joseph H. Ritz, Jerome Panoskaltsis-Mortari, Angela Byrd, John C. Blazar, Bruce R. TI Ibrutinib treatment ameliorates murine chronic graft-versus-host disease SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CD4(+) T-CELLS; CHRONIC LYMPHOCYTIC-LEUKEMIA; BRUTONS TYROSINE KINASE; BRONCHIOLITIS OBLITERANS; BONE-MARROW; EXTRACORPOREAL PHOTOPHERESIS; THERAPEUTIC TARGET; MICE LACKING; CHRONIC GVHD; ITK AB Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4(+) T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell-mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials. C1 [Dubovsky, Jason A.; Zhong, Yiming; Kaffenberger, Benjamin; Yang, Carrie; Towns, William H.; Lehman, Amy; Johnson, Amy J.; Muthusamy, Natarajan; Devine, Steven M.; Jaglowski, Samantha; Wong, Henry K.; Byrd, John C.] Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA. [Flynn, Ryan; Du, Jing; Panoskaltsis-Mortari, Angela; Blazar, Bruce R.] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN 55455 USA. [Flynn, Ryan; Du, Jing; Panoskaltsis-Mortari, Angela; Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [Harrington, Bonnie K.] Ohio State Univ, Coll Vet Med Vet & Comparat Med, Columbus, OH 43210 USA. [Serody, Jonathan S.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA. [Murphy, William J.] Univ Calif Davis, Ctr Canc, Dept Dermatol, Sacramento, CA 95817 USA. [Murphy, William J.] Sch Med, Sacramento, CA 95816 USA. [Munn, David H.] Med Coll Georgia, Sch Med, Dept Pediat, Augusta, GA 30912 USA. [Luznik, Leo] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Luznik, Leo] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Hill, Geoffrey R.; MacDonald, Kelli K. P.] Med Res Berghofer Med Res Inst, Queensland Inst, Brisbane, Qld, Australia. [Maillard, Ivan] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Koreth, John; Cutler, Corey; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Elias, Laurence] Pharmacyclics Inc, Sunnyvale, CA USA. RP Blazar, BR (reprint author), Univ Minnesota, MMC 109, Minneapolis, MN 55455 USA. EM blaza001@umn.edu RI Hill, Geoffrey/O-2630-2016; MacDonald, Kelli/O-2722-2016; Jaglowski, Samantha/E-3304-2011; OI Ritz, Jerome/0000-0001-5526-4669; Hill, Geoffrey/0000-0003-2994-0429; MacDonald, Kelli/0000-0003-3451-4221; Serody, Jonathan/0000-0003-4568-1092; Harrington, Bonnie/0000-0003-2658-6188 FU NIH [P01 AI056299, P01 CA142106, R01 HL56067, R01 AI34495, T32 AI1007313]; National Cancer Institute [P01 CA095426, K12 CA133250-05, P50 CA140158, T32 CA009338-33-03]; American Cancer Society [125039-PF-13-246-01-LIB]; Leukemia & Lymphoma Society; American Society of Hematology; Harry Mangurian Foundation; D. Warren Brown Family Foundation; Jock and Bunny Adams Research and Education Endowment FX The authors gratefully acknowledge Leslie J. Berg for providing critical reagents as well as Jessica MacMurray for experimental assistance. This work was supported by grants from the NIH (P01 AI056299, P01 CA142106, R01 HL56067, and R01 AI34495 to B.R. Blazar; T32 AI1007313 to R. Flynn). In addition, support was provided by National Cancer Institute grants (P01 CA095426, K12 CA133250-05, and P50 CA140158 to J.C. Byrd; T32 CA009338-33-03 to J.A. Dubovsky), as well as grants from the American Cancer Society (125039-PF-13-246-01-LIB to J.A. Dubovsky), the Leukemia & Lymphoma Society, the American Society of Hematology, Mr. and Mrs. Michael Thomas, the Harry Mangurian Foundation, the D. Warren Brown Family Foundation, and the Jock and Bunny Adams Research and Education Endowment (to J.H. Antin). NR 61 TC 36 Z9 36 U1 1 U2 14 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2014 VL 124 IS 11 BP 4867 EP 4876 DI 10.1172/JCI75328 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AS3UK UT WOS:000344203300022 PM 25271622 ER PT J AU Wegiel, B Larsen, R Gallo, D Chin, BY Harris, C Mannam, P Kaczmarek, E Lee, PJ Zuckerbraun, BS Flavell, R Soares, MP Otterbein, LE AF Wegiel, Barbara Larsen, Rasmus Gallo, David Chin, Beek Yoke Harris, Clair Mannam, Praveen Kaczmarek, Elzbieta Lee, Patty J. Zuckerbraun, Brian S. Flavell, Richard Soares, Miguel P. Otterbein, Leo E. TI Macrophages sense and kill bacteria through carbon monoxide-dependent inflammasome activation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID INNATE IMMUNE RECOGNITION; HEME OXYGENASE-1; NALP3 INFLAMMASOME; NLRP3 INFLAMMASOME; ESCHERICHIA-COLI; CELL-DEATH; EXPRESSION; RECEPTOR; IL-1-BETA; CASPASE-1 AB Microbial clearance by eukaryotes relies on complex and coordinated processes that remain poorly understood. The gasotransmitter carbon monoxide (CO) is generated by the stress-responsive enzyme heme oxygenase-1 (HO-1, encoded by Hmox1), which is highly induced in macrophages in response to bacterial infection. HO-1 deficiency results in inadequate pathogen clearance, exaggerated tissue damage, and increased mortality. Here, we determined that macrophage-generated CO promotes ATP production and release by bacteria, which then activates the Nacht, LRR, and PYD domains-containing protein 3 (NALP3) inflammasome, intensifying bacterial killing. Bacterial killing defects in HO-1-deficient murine macrophages were restored by administration of CO. Moreover, increased CO levels enhanced the bacterial clearance capacity of human macrophages and WT murine macrophages. CO-dependent bacterial clearance required the NALP3 inflammasome, as CO did not increase bacterial killing in macrophages isolated from NALP3-deficient or caspase-1-deficient mice. IL-1 beta cleavage and secretion were impaired in HO-1-deficient macrophages, and CO-dependent processing of IL-1 beta required the presence of bacteria-derived ATR We found that bacteria remained viable to generate and release ATP in response to CO. The ATP then bound to macrophage nucleotide P2 receptors, resulting in activation of the NALP3/IL-1 beta inflammasome to amplify bacterial phagocytosis by macrophages. Taken together, our results indicate that macrophage-derived CO permits efficient and coordinated regulation of the host innate response to invading microbes. C1 [Wegiel, Barbara; Gallo, David; Chin, Beek Yoke; Harris, Clair; Otterbein, Leo E.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Transplant Inst,Dept Surg, Boston, MA 02215 USA. [Larsen, Rasmus; Soares, Miguel P.] Inst Gulbenkian Ciencias, Oeiras, Portugal. [Mannam, Praveen; Lee, Patty J.; Flavell, Richard] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. [Kaczmarek, Elzbieta] Harvard Univ, Sch Med, BIDMC, Ctr Vasc Biol,Dept Surg, Boston, MA 02215 USA. [Zuckerbraun, Brian S.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Flavell, Richard] Howard Hughes Med Inst, New Haven, CT 06510 USA. RP Otterbein, LE (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Transplant Inst,Ctr Life Sci, 3 Blackfan Circle, Boston, MA 02215 USA. EM lotterbe@bidmc.harvard.edu OI Soares, Miguel/0000-0002-9314-4833; Flavell, Richard/0000-0003-4461-0778 FU NIH [HL-071797, HL-076167, R21CA169904-01, HL-106227]; American Heart Association [10SDG2640091]; Julie Henry Fund at the Transplant Center of the BIDMC; Fundacao para a Ciencia e Tecnologia (Portugal) [SFRH/BPD/25436/2005, PTDC/BI0/70815/2006, PTDC/BIA-B CM/101311/2008, PTDC/SAU-FCF/100762/2008]; European Community [LSH-2005-1.2.5-1, ERC-2011-AdG, 294709 - DAMAGECONTROL] FX This work was largely supported by NIH grants HL-071797 and HL-076167 (to L.E. Otterbein) and American Heart Association grants 10SDG2640091 and NIH R21CA169904-01 (to B. Wegiel). We thank Bryan Davis (MIT/Harvard Medical School) and Bernard Strauss (MIT) for providing mutant strains from the Keio E. coli knockout library. We are grateful to D. Nakatsu for providing QC-15. We thank the Julie Henry Fund at the Transplant Center of the BIDMC for their support. L.E. Otterbein holds an honorary visiting professorship at Aston University (Birmingham, United Kingdom). This work was supported by Fundacao para a Ciencia e Tecnologia (Portugal) grants SFRH/BPD/25436/2005 and PTDC/BI0/70815/2006 (to R. Larsen) and PTDC/BIA-B CM/101311/2008 and PTDC/SAU-FCF/100762/2008 (to M.P. Soares), the European Community, 6th Framework grant LSH-2005-1.2.5-1 and ERC-2011-AdG, 294709 - DAMAGECONTROL (to M.P. Soares), and in part by NIH grant HL-106227 (to E. Kaczmarek). R. Flavell is an investigator of the Howard Hughes Medical Institute. NR 72 TC 43 Z9 44 U1 5 U2 20 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD NOV PY 2014 VL 124 IS 11 BP 4926 EP 4940 DI 10.1172/JCI72853 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AS3UK UT WOS:000344203300028 PM 25295542 ER PT J AU Freireich, EJ Wiernik, PH Steensma, DP AF Freireich, Emil J. Wiernik, Peter H. Steensma, David P. TI The Leukemias: A Half-Century of Discovery SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; TRANS-RETINOIC ACID; NORTH-AMERICAN INTERGROUP; ABL TYROSINE KINASE; CHRONIC MYELOGENOUS LEUKEMIA; MINIMAL RESIDUAL DISEASE; LOW-DOSE CYTARABINE C1 [Freireich, Emil J.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Wiernik, Peter H.] Canc Res Fdn New York, New York, NY USA. [Steensma, David P.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Freireich, EJ (reprint author), Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. FU NCI NIH HHS [P30 CA016672] NR 105 TC 13 Z9 13 U1 1 U2 8 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2014 VL 32 IS 31 BP 3463 EP + DI 10.1200/JCO.2014.57.1034 PG 8 WC Oncology SC Oncology GA AS6MY UT WOS:000344378700002 PM 25185093 ER PT J AU Bardia, A Haber, DA AF Bardia, Aditya Haber, Daniel A. TI Solidifying Liquid Biopsies: Can Circulating Tumor Cell Monitoring Guide Treatment Selection in Breast Cancer? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID PROSTATE-CANCER; PROGRESSION; SURVIVAL; MARKERS; TRIAL; BLOOD C1 [Bardia, Aditya] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Bardia, A (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. FU NCI NIH HHS [R01 CA129933] NR 19 TC 4 Z9 4 U1 0 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2014 VL 32 IS 31 BP 3470 EP + DI 10.1200/JCO.2014.57.1505 PG 4 WC Oncology SC Oncology GA AS6MY UT WOS:000344378700003 PM 25024075 ER PT J AU Smerage, JB Barlow, WE Hortobagyi, GN Winer, EP Leyland-Jones, B Srkalovic, G Tejwani, S Schott, AF O'Rourke, MA Lew, DL Doyle, GV Gralow, JR Livingston, RB Hayes, DF AF Smerage, Jeffrey B. Barlow, William E. Hortobagyi, Gabriel N. Winer, Eric P. Leyland-Jones, Brian Srkalovic, Gordan Tejwani, Sheela Schott, Anne F. O'Rourke, Mark A. Lew, Danika L. Doyle, Gerald V. Gralow, Julie R. Livingston, Robert B. Hayes, Daniel F. TI Circulating Tumor Cells and Response to Chemotherapy in Metastatic Breast Cancer: SWOG S0500 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SURVIVAL; SINGLE; BLOOD AB Purpose Increased circulating tumor cells (CTCs; five or more CTCs per 7.5 mL of whole blood) are associated with poor prognosis in metastatic breast cancer (MBC). A randomized trial of patients with persistent increase in CTCs tested whether changing chemotherapy after one cycle of first-line chemotherapy would improve the primary outcome of overall survival (OS). Patients and Methods Patients with MBC who did not have increased CTCs at baseline remained on initial therapy until progression (arm A). Patients with initially increased CTCs that decreased after 21 days of therapy remained on initial therapy (arm B). Patients with persistently increased CTCs after 21 days of therapy were randomly assigned to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2). Results Of 595 eligible and evaluable patients, 276 (46%) did not have increased CTCs (arm A). Of those with initially increased CTCs, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomly assigned to arm C1 or C2. No difference in median OS was observed between arm C1 and C2 (10.7 and 12.5 months, respectively; P = .98). CTCs were strongly prognostic. Median OS for arms A, B, and C (C1 and C2 combined) were 35 months, 23 months, and 13 months, respectively (P < .001). Conclusion This study confirms the prognostic significance of CTCs in patients with MBC receiving first-line chemotherapy. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging OS. For this population, there is a need for more effective treatment than standard chemotherapy. (C) 2014 by American Society of Clinical Oncology C1 [Smerage, Jeffrey B.; Schott, Anne F.; Hayes, Daniel F.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Srkalovic, Gordan] Sparrow Reg Canc Ctr, Lansing, MI USA. [Tejwani, Sheela] Henry Ford Hosp, Detroit, MI 48202 USA. [Barlow, William E.; Lew, Danika L.] SWOG Stat Ctr, Seattle, WA USA. [Gralow, Julie R.] Seattle Canc Care Alliance, Seattle, WA USA. [Hortobagyi, Gabriel N.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Winer, Eric P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Leyland-Jones, Brian] Avera Canc Inst, Sioux Falls, SD USA. [O'Rourke, Mark A.] Greenville Hlth Syst, Inst Canc, Greenville Community Clin Oncol Program, Greenville, SC USA. [Doyle, Gerald V.] Immunicon, Huntingdon Valley, PA USA. [Livingston, Robert B.] Univ Arizona, Ctr Canc, Tucson, AZ USA. RP Hayes, DF (reprint author), Univ Michigan, Ctr Comprehens Canc, 1500 E Med Ctr Dr,6312 CCC, Ann Arbor, MI 48109 USA. EM hayesdf@umich.edu FU Public Health Service Cooperative Agreement Grants from the National Cancer Institute [CA32102, CA38926, CA 63848, CA27057, CA67663, CA58416, CA22433, CA 95860, CA04919, CA16385, CA 63844, CA45808, CA20319, CA58882, CA35192, CA14028, CA45807, CA74647, CA37981, CA46441, CA42777, CA35178]; Department of Health and Human Services; Immunicon and Veridex; [CA86780]; [CA58861]; [CA67575]; [CA45560]; [CA12644]; [CA45377]; [CA35281]; [CA35431]; [CA76447]; [CA46368]; [CA73590]; [CA105409]; [CA46113]; [CA48723]; [CA31946]; [CA21115]; [CA35103] FX Supported in part by Public Health Service Cooperative Agreement Grants No. CA32102, CA38926, CA 63848, CA27057, CA67663, CA58416, CA22433, CA 95860, CA04919, CA16385, CA 63844, CA45808, CA20319, CA58882, CA35192, CA14028, CA45807, CA74647, CA37981, CA46441, CA42777, CA35178, CA86780, CA58861, CA67575, CA45560, CA12644, CA45377, CA35281, CA35431, CA76447, CA46368, CA73590, CA105409, CA46113, CA48723, CA31946, CA21115, and CA35103 from the National Cancer Institute, Department of Health and Human Services, and by Immunicon and Veridex. Circulating tumor cell assays were performed by Janssen Diagnostics at no charge to the clinical sponsor (SWOG). NR 12 TC 133 Z9 140 U1 2 U2 16 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2014 VL 32 IS 31 BP 3483 EP + DI 10.1200/JCO.2014.56.2561 PG 8 WC Oncology SC Oncology GA AS6MY UT WOS:000344378700007 PM 24888818 ER PT J AU Wright, AA Hatfield, LA Earle, CC Keating, NL AF Wright, Alexi A. Hatfield, Laura A. Earle, Craig C. Keating, Nancy L. TI End-of-Life Care for Older Patients With Ovarian Cancer Is Intensive Despite High Rates of Hospice Use SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MEDICARE BENEFICIARIES; MENTAL-HEALTH; QUALITY; DEATH; AGGRESSIVENESS; SURVIVAL; TRENDS; ASSOCIATIONS; DISCUSSIONS; TRANSITIONS AB Purpose To date, few studies have examined end-of-life care for patients with ovarian cancer. One study documented increased hospice use among older patients with ovarian cancer from 2000 to 2005. We sought to determine whether increased hospice use was associated with less-intensive end-of-life medical care. Patients and Methods We identified 6,956 individuals age >= 66 years living in SEER areas who were enrolled in fee-for-service Medicare, diagnosed with epithelial ovarian cancer between 1997 and 2007, and died as a result of ovarian cancer by December 2007. We examined changes in medical care during patients' last month of life over time. Results Between 1997 and 2007, hospice use increased significantly, and terminal hospitalizations decreased (both P < .001). However, during this time, we also observed statistically significant increases in intensive care unit admissions, hospitalizations, repeated emergency department visits, and health care transitions (all P <= .01). In addition, the proportion of patients referred to hospice from inpatient settings rose over time (P = .001). Inpatients referred to hospice were more likely to enroll in hospice within 3 days of death than outpatients (adjusted odds ratio, 1.36; 95% CI, 1.12 to 1.66). Conclusion Older women with ovarian cancer were more likely to receive hospice services near death and less likely to die in a hospital in 2007 compared with earlier years. Despite this, use of hospital-based services increased over time, and patients underwent more transitions among health care settings near death, suggesting that the increasing use of hospice did not offset intensive end-of-life care. (C) 2014 by American Society of Clinical Oncology C1 [Wright, Alexi A.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Wright, Alexi A.; Hatfield, Laura A.; Keating, Nancy L.] Harvard Univ, Sch Med, Boston, MA USA. [Keating, Nancy L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Earle, Craig C.] Canc Care Ontario, Toronto, ON, Canada. [Earle, Craig C.] Ontario Inst Canc Res, Toronto, ON, Canada. RP Wright, AA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM alexi_wright@dfci.harvard.edu FU National Cancer Institute (NCI) [1K07 CA166210]; American Cancer Society, a Conquer Cancer Foundation of the American Society for Clinical Oncology Career Development Award [MRSG-13-013]; National Palliative Care Research Center Junior Faculty Career Development Award; Gloria Spivak Faculty Advancement Fund; NCI [1R01 CA164021] FX Supported in part by Grant No. 1K07 CA166210 from the National Cancer Institute (NCI), Grant No. MRSG-13-013 from the American Cancer Society, a Conquer Cancer Foundation of the American Society for Clinical Oncology Career Development Award, the National Palliative Care Research Center Junior Faculty Career Development Award, and the Gloria Spivak Faculty Advancement Fund (A.A.W.) and by Research Grant No. 1R01 CA164021 from the NCI (N.L.K.). NR 36 TC 16 Z9 16 U1 4 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2014 VL 32 IS 31 BP 3534 EP + DI 10.1200/JCO.2014.55.5383 PG 7 WC Oncology SC Oncology GA AS6MY UT WOS:000344378700014 PM 25287831 ER PT J AU Ganz, PA Petersen, L Castellon, SA Bower, JE Silverman, DHS Cole, SW Irwin, MR Belin, TR AF Ganz, Patricia A. Petersen, Laura Castellon, Steven A. Bower, Julienne E. Silverman, Daniel H. S. Cole, Steven W. Irwin, Michael R. Belin, Thomas R. TI Cognitive Function After the Initiation of Adjuvant Endocrine Therapy in Early-Stage Breast Cancer: An Observational Cohort Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID STANDARD-DOSE CHEMOTHERAPY; HEALTH SURVEY SF-36; HORMONAL-THERAPY; WOMEN; MEMORY; TAMOXIFEN; ESTROGEN; DYSFUNCTION; IMPAIRMENT; BRAIN AB Purpose This report examines cognitive complaints and neuropsychological (NP) testing outcomes in patients with early-stage breast cancer after the initiation of endocrine therapy (ET) to determine whether this therapy plays any role in post-treatment cognitive complaints. Patients and Methods One hundred seventy-three participants from the Mind Body Study (MBS) observational cohort provided data from self-report questionnaires and NP testing obtained at enrollment (T1, before initiation of ET), and 6 months later (T2). Bivariate analyses compared demographic and treatment variables, cognitive complaints, depressive symptoms, quality of life, and NP functioning between those who received ET versus not. Multivariable linear regression models examined predictors of cognitive complaints at T2, including selected demographic variables, depressive symptoms, ET use, and other medical variables, along with NP domains that were identified in bivariate analyses. Results Seventy percent of the 173 MBS participants initiated ET, evenly distributed between tamoxifen or aromatase inhibitors. ET-treated participants reported significantly increased language and communication (LC) cognitive complaints at T2 (P = .003), but no significant differences in NP test performance. Multivariable regression on LC at T2 found higher LC complaints significantly associated with T1 LC score (P < .001), ET at T2 (P = .004), interaction between ET and past hormone therapy (HT) (P < .001), and diminished improvement in NP psychomotor function (P = .05). Depressive symptoms were not significant (P = .10). Conclusion Higher LC complaints are significantly associated with ET 6 months after starting treatment and reflect diminished improvements in some NP tests. Past HT is a significant predictor of higher LC complaints after initiation of ET. (C) 2014 by American Society of Clinical Oncology C1 [Ganz, Patricia A.; Belin, Thomas R.] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Los Angeles, CA 90095 USA. [Ganz, Patricia A.; Petersen, Laura] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Ganz, Patricia A.; Silverman, Daniel H. S.; Cole, Steven W.; Irwin, Michael R.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Castellon, Steven A.] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. [Castellon, Steven A.; Bower, Julienne E.] Univ Calif Los Angeles, Los Angeles, CA 90095 USA. [Bower, Julienne E.; Cole, Steven W.; Irwin, Michael R.] Univ Calif Los Angeles, Semel Inst, Cousins Ctr Psychoneuroimmunol, Los Angeles, CA 90095 USA. RP Ganz, PA (reprint author), Univ Calif Los Angeles, Div Canc Prevent & Control Res, Jonsson Comprehens Canc Ctr, A2-125 CHS,Box 956900, Los Angeles, CA 90095 USA. EM pganz@mednet.ucla.edu RI Irwin, Michael/H-4870-2013 OI Irwin, Michael/0000-0002-1502-8431 FU National Cancer Institute [R01-CA109650]; Breast Cancer Research Foundation [R01-AG034588, R01-AG026364, R01-CA119159, R01-HL079955, R01-HL095799, P30-AG028748, UL RR 033176]; Cousins Center for Psychoneuroimmunology FX Supported by funding from the National Cancer Institute Grant No. R01-CA109650 and the Breast Cancer Research Foundation (P.A.G.), Grants No. R01-AG034588, R01-AG026364, R01-CA119159, R01-HL079955, R01-HL095799, P30-AG028748, UL RR 033176 (M.R.I.), and the Cousins Center for Psychoneuroimmunology (M.R.I.). NR 48 TC 25 Z9 25 U1 1 U2 11 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2014 VL 32 IS 31 BP 3559 EP + DI 10.1200/JCO.2014.56.1662 PG 16 WC Oncology SC Oncology GA AS6MY UT WOS:000344378700018 PM 25267747 ER PT J AU Ligibel, JA Alfano, CM Courneya, KS Demark-Wahnefried, W Burger, RA Chlebowski, RT Fabian, CJ Gucalp, A Hershman, DL Hudson, MM Jones, LW Kakarala, M Ness, KK Merrill, JK Wollins, DS Hudis, CA AF Ligibel, Jennifer A. Alfano, Catherine M. Courneya, Kerry S. Demark-Wahnefried, Wendy Burger, Robert A. Chlebowski, Rowan T. Fabian, Carol J. Gucalp, Ayca Hershman, Dawn L. Hudson, Melissa M. Jones, Lee W. Kakarala, Madhuri Ness, Kirsten K. Merrill, Janette K. Wollins, Dana S. Hudis, Clifford A. TI American Society of Clinical Oncology Position Statement on Obesity and Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BODY-MASS INDEX; LONG-TERM EFFECTIVENESS; BREAST-CANCER; WEIGHT-LOSS; PHYSICAL-ACTIVITY; HEALTH BEHAVIORS; LIFE-STYLE; POSTMENOPAUSAL WOMEN; TEACHABLE MOMENT; RANDOMIZED-TRIAL AB Rates of obesity have increased significantly over the last three decades in the United States and globally. In addition to contributing to heart disease and diabetes, obesity is a major unrecognized risk factor for cancer. Obesity is associated with worsened prognosis after cancer diagnosis and also negatively affects the delivery of systemic therapy, contributes to morbidity of cancer treatment, and may raise the risk of second malignancies and comorbidities. Research shows that the time after a cancer diagnosis can serve as a teachable moment to motivate individuals to adopt risk-reducing behaviors. For this reason, the oncology care team-the providers with whom a patient has the closest relationships in the critical period after a cancer diagnosis-is in a unique position to help patients lose weight and make other healthy lifestyle changes. The American Society of Clinical Oncology is committed to reducing the impact of obesity on cancer and has established a multipronged initiative to accomplish this goal by 1) increasing education and awareness of the evidence linking obesity and cancer; 2) providing tools and resources to help oncology providers address obesity with their patients; 3) building and fostering a robust research agenda to better understand the pathophysiology of energy balance alterations, evaluate the impact of behavior change on cancer outcomes, and determine the best methods to help cancer survivors make effective and useful changes in lifestyle behaviors; and 4) advocating for policy and systems change to address societal factors contributing to obesity and improve access to weight management services for patients with cancer. (C) 2014 by American Society of Clinical Oncology C1 [Ligibel, Jennifer A.] Dana Farber Canc Inst, Boston, MA 02155 USA. [Alfano, Catherine M.] NCI, Bethesda, MD 20892 USA. [Courneya, Kerry S.] Univ Alberta, Edmonton, AB, Canada. [Demark-Wahnefried, Wendy] Univ Alabama Birmingham, Birmingham, AL USA. [Burger, Robert A.] Univ Penn, Philadelphia, PA 19104 USA. [Chlebowski, Rowan T.] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [Fabian, Carol J.] Univ Kansas, Med Ctr, Westwood, KS USA. [Gucalp, Ayca; Jones, Lee W.; Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Hershman, Dawn L.] Columbia Univ, Med Ctr, New York, NY USA. [Hudson, Melissa M.; Ness, Kirsten K.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Kakarala, Madhuri] Van Andel Inst, Grand Rapids, MI USA. [Merrill, Janette K.; Wollins, Dana S.] Amer Soc Clin Oncol, Alexandria, VA USA. RP Ligibel, JA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02155 USA. EM jligibel@partners.org NR 48 TC 79 Z9 79 U1 0 U2 10 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2014 VL 32 IS 31 BP 3568 EP + DI 10.1200/JCO.2014.58.4680 PG 8 WC Oncology SC Oncology GA AS6MY UT WOS:000344378700019 PM 25273035 ER PT J AU Azzoli, CG Engelman, J Fidias, P Gainor, JF Heist, RS Lamont, EB Lennes, IT Rosovsky, RP Sequist, LV Shaw, AT Temel, JS AF Azzoli, Christopher G. Engelman, Jeffrey Fidias, Panos Gainor, Justin F. Heist, Rebecca S. Lamont, Elizabeth B. Lennes, Inga T. Rosovsky, Rachel P. Sequist, Lecia V. Shaw, Alice Tsang Temel, Jennifer S. TI Genotyping Lung Cancer Is an Investment in the Future SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID CRIZOTINIB; EGFR C1 [Azzoli, Christopher G.; Engelman, Jeffrey; Fidias, Panos; Gainor, Justin F.; Heist, Rebecca S.; Lamont, Elizabeth B.; Lennes, Inga T.; Rosovsky, Rachel P.; Sequist, Lecia V.; Shaw, Alice Tsang; Temel, Jennifer S.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Azzoli, CG (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 10 TC 2 Z9 2 U1 1 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2014 VL 32 IS 31 BP 3576 EP + DI 10.1200/JCO.2014.56.6430 PG 3 WC Oncology SC Oncology GA AS6MY UT WOS:000344378700022 PM 25199750 ER PT J AU Beca, F Andre, R Martins, DS Bilhim, T Martins, D Schmitt, F AF Beca, Francisco Andre, Rosario Martins, Duarte Saraiva Bilhim, Tiago Martins, Diana Schmitt, Fernando TI p-mTOR expression is associated with better prognosis in luminal breast carcinoma SO JOURNAL OF CLINICAL PATHOLOGY LA English DT Article ID RENAL-CELL CARCINOMA; CANCER; THERAPY; RECOMMENDATIONS; ACTIVATION; PATHWAY; GROWTH; PTEN AB Aims Despite considerable interest in the PI3K/AKT/mTOR pathway in breast carcinomas (BC), published data reports contradictory results regarding the association of phosphorylated mammalian target of Rapamycin (p-mTOR) expression with clinico-pathological features and prognosis in BC. Here, we evaluate the main clinico-pathological associations with p-mTOR expression in BC, with focus on the different molecular subtypes. Methods In this retrospective study, 331 BC patients were included in final analysis. Outcome measures included disease-free survival (DFS) and overall survival (OS) times. Baseline data and outcome measures were compared between immunohistochemical p-mTOR expressing and non-expressing BCs. Subgroup analysis was performed to assess the effect of p-mTOR expression in the outcome for each BC molecular subtype. Results 43.8% of the tumours were positive for p-mTOR, with a significant correlation between p-mTOR expression with smaller (<2 cm) (p=0.021) and lower-grade tumours (p<0.001). Expression of p-mTOR was also associated with longer DFS (HR of 0.32, p<0.001) and OS (HR of 0.20, p<0.001). In a multivariable analysis, the HR remained significant with minimal change (HR=0.26, p=0.002 for OS; HR=0.40, p=0.002 for DFS). In subgroup analysis, luminal p-mTOR-expressing tumours demonstrated longer DFS and OS (HR 0.33, p=0.003; HR 0.20, p=0.003, respectively) independently of size, grade, lymph node status and Her-2 overexpression. Conclusions p-mTOR expression is associated with smaller, lower-grade and with luminal BC. In multivariable analysis, p-mTOR expression was associated with longer DFS and OS, independently of the size, grade and lymph node status, especially in luminal BCs. C1 [Beca, Francisco] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Beca, Francisco; Martins, Diana; Schmitt, Fernando] Univ Porto, IPATIMUP Inst Mol Pathol & Immunol, P-4100 Oporto, Portugal. [Beca, Francisco] Univ Porto, Fac Med, Dept Pathol & Oncol, P-4100 Oporto, Portugal. [Andre, Rosario] Champalimaud Fdn, Champalimaud Clin Ctr, Lisbon, Portugal. [Andre, Rosario] Univ Nova Lisboa, Fac Ciencias Med, Dept Genet Oncol & Human Toxicol, P-1200 Lisbon, Portugal. [Martins, Duarte Saraiva] Ctr Hosp Lisboa Ocidental, Hosp Santa Cruz, Dept Pediat Cardiol, Lisbon, Portugal. [Bilhim, Tiago] Univ Nova Lisboa, Fac Ciencias Med, Dept Radiol, P-1200 Lisbon, Portugal. [Bilhim, Tiago] Ctr Hosp Lisboa Cent, Hosp Sao Jose, Lisbon, Portugal. [Schmitt, Fernando] Univ Toronto, Fac Med, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Schmitt, Fernando] Univ Hlth Network, Dept Pathol, Toronto, ON, Canada. RP Schmitt, F (reprint author), Univ Toronto, Toronto Gen Hosp, Univ Hlth Network, Fac Med,Dept Lab Med & Pathobiol, 200 Elizabeth St,11E-215B, Toronto, ON M5G 2C4, Canada. EM fernando.schmitt@ipatimup.pt RI Faculdade de Ciencias Medicas, Nova Medical School/K-6209-2013 OI Beca, Francisco/0000-0002-4409-012X; FU Portuguese National Funds through Fundacao para a Ciencia e Tecnologia (FCT) [FCT: HMSP-ICJ/0006/2012]; FCT FX This work was partially supported by Portuguese National Funds through Fundacao para a Ciencia e Tecnologia (FCT) regarding project's reference FCT: HMSP-ICJ/0006/2012 in the framework of Harvard Medical School-Portugal Program. IPATIMUP is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by FCT. NR 26 TC 4 Z9 7 U1 1 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0021-9746 EI 1472-4146 J9 J CLIN PATHOL JI J. Clin. Pathol. PD NOV PY 2014 VL 67 IS 11 BP 961 EP 967 DI 10.1136/jclinpath-2014-202320 PG 7 WC Pathology SC Pathology GA AS1UP UT WOS:000344067700006 PM 25053543 ER PT J AU Shimizu, T Takebayashi, T Sato, Y Niizeki, H Aoyama, Y Kitajima, Y Iwatsuki, K Hashimoto, T Yamagami, J Werth, VP Amagai, M Tanikawa, A AF Shimizu, Tomoko Takebayashi, Toru Sato, Yuji Niizeki, Hironori Aoyama, Yumi Kitajima, Yasuo Iwatsuki, Keiji Hashimoto, Takashi Yamagami, Jun Werth, Victoria P. Amagai, Masayuki Tanikawa, Akiko TI Grading criteria for disease severity by pemphigus disease area index SO JOURNAL OF DERMATOLOGY LA English DT Article DE clinical trial; Japanese pemphigus disease severity score; outcome instrument; pemphigus; pemphigus disease area index; severity index ID DISORDER INTENSITY SCORE AB Pemphigus is a group of autoimmune blistering diseases that affect the skin and mucous membranes. A reliable and accurate disease severity tool to assess pemphigus severity is crucial for managing pemphigus and for clinical trials. The purpose of this study was to compare the pemphigus disease area index activity score (PDAI), the Japanese pemphigus disease severity score (JPDSS) and the physician's subjective impression, and also to find appropriate severity grading cut-offs for the PDAI. We also evaluated the correlation between PDAI activity score and the JPDSS. Thirty-seven pemphigus patients and 110 assessments were analyzed in this study. The optimal points of pemphigus disease severity score in PDAI were: mild (0-8), moderate (9-24) and severe (25). In mild or moderate cases, the JPDSS was well correlated with the PDAI, but in severe cases the JPDSS reached a plateau at a PDAI score of approximately 30. The PDAI evaluates disease severity more accurately than the JPDSS, particularly in severe cases. The PDAI is not only a useful tool to measure the extent of cutaneous lesions, but also an excellent scoring system for evaluating pemphigus disease severity. C1 [Shimizu, Tomoko; Yamagami, Jun; Amagai, Masayuki; Tanikawa, Akiko] Keio Univ, Sch Med, Dept Dermatol, Tokyo 1608582, Japan. [Takebayashi, Toru] Keio Univ, Sch Med, Dept Prevent Med & Publ Hlth, Tokyo 1608582, Japan. [Sato, Yuji] Keio Univ, Sch Med, Clin Res Ctr, Tokyo 1608582, Japan. [Niizeki, Hironori] Natl Ctr Child Hlth & Dev, Dept Dermatol, Tokyo, Japan. [Niizeki, Hironori] Nara Med Univ, Sch Med, Nara, Japan. [Aoyama, Yumi; Iwatsuki, Keiji] Okayama Univ Hosp, Okayama, Japan. [Kitajima, Yasuo] Kizawa Mem Hosp, Gifu, Japan. [Hashimoto, Takashi] Kurume Univ, Sch Med, Fukuoka, Japan. [Werth, Victoria P.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Werth, Victoria P.] Univ Penn, Philadelphia, PA 19104 USA. RP Tanikawa, A (reprint author), Keio Univ, Sch Med, Dept Dermatol, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan. EM tanikawa@z3.keio.jp RI Takebayashi, Toru/K-7526-2013; Amagai, Masayuki/K-5325-2013 OI Takebayashi, Toru/0000-0002-8268-8026; Amagai, Masayuki/0000-0003-3314-7052 FU Ministry of Health, Labor and Welfare of Japan [H23-028] FX This work was supported by the Research on Measures for Intractable Diseases Project: matching fund subsidy (H23-028) from the Ministry of Health, Labor and Welfare of Japan. NR 10 TC 4 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0385-2407 EI 1346-8138 J9 J DERMATOL JI J. Dermatol. PD NOV PY 2014 VL 41 IS 11 BP 969 EP 973 DI 10.1111/1346-8138.12649 PG 5 WC Dermatology SC Dermatology GA AS5XN UT WOS:000344340000004 PM 25346300 ER PT J AU Hayashi, M Tanemura, A Matsuda, K Hosokawa, K Izumi, M Ohara, K Mihm, MC Katayama, I AF Hayashi, Misa Tanemura, Atsushi Matsuda, Ken Hosokawa, Ko Izumi, Miki Ohara, Kuniaki Mihm, Martin C. Katayama, Ichiro TI Pigmented epithelioid melanocytoma with lymph node metastasis in a patient with uncontrolled atopic dermatitis SO JOURNAL OF DERMATOLOGY LA English DT Letter ID BLUE NEVUS; MELANOMA C1 [Hayashi, Misa; Tanemura, Atsushi; Katayama, Ichiro] Osaka Univ, Grad Sch Med, Dept Dermatol Integrated Med, Suita, Osaka 5650871, Japan. [Matsuda, Ken; Hosokawa, Ko] Osaka Univ, Grad Sch Med, Dept Plast Surg, Suita, Osaka 5650871, Japan. [Izumi, Miki] Tokyo Med Univ, Dept Med Educ, Tokyo 1608402, Japan. [Ohara, Kuniaki] Toranomon Gen Hosp, Dept Dermatol, Tokyo, Japan. [Mihm, Martin C.] Massachusetts Gen Hosp, Div Dermatopathol, Boston, MA 02114 USA. [Mihm, Martin C.] Harvard Univ, Sch Med, Boston, MA USA. RP Tanemura, A (reprint author), Osaka Univ, Grad Sch Med, Dept Dermatol Integrated Med, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. EM tanemura@derma.med.osaka-u.ac.jp NR 5 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0385-2407 EI 1346-8138 J9 J DERMATOL JI J. Dermatol. PD NOV PY 2014 VL 41 IS 11 BP 1023 EP 1025 DI 10.1111/1346-8138.12631 PG 3 WC Dermatology SC Dermatology GA AS5XN UT WOS:000344340000021 PM 25294720 ER PT J AU Mackesy, DZ Goalstone, ML AF Mackesy, Daniel Z. Goalstone, Marc L. TI Extracellular signal-regulated kinase-5: Novel mediator of insulin and tumor necrosis factor alpha-stimulated vascular cell adhesion molecule-1 expression in vascular cells SO JOURNAL OF DIABETES LA English DT Article DE extracellular signal-regulated kinase-5; hyperinsulinemia; tumor necrosis factor alpha; type-2 diabetes mellitus; vascular cell adhesion molecule-1 ID ENDOTHELIAL DYSFUNCTION; PROTEIN-KINASE; ERK5; ATHEROSCLEROSIS; MECHANISM; PATHWAY; MIGRATION; SURVIVAL; GROWTH; TISSUE AB Background: Atherosclerosis may be stimulated by the increased presence of insulin and tumor necrosis-factor-alpha (TNF alpha) with subsequent expression of vascular cell adhesion molecule-1 (VCAM-1). We hypothesized that extracellular signal-regulated kinase-5 (ERK5) plays an important role in insulin and TNF alpha-stimulated total and cell surface VCAM-1 expression. Methods: Rat aorta vascular endothelial cells were first transfected with either no inhibitory RNA, inactive (scrambled) inhibitory ERK5 RNA (scERK5) or active inhibitory ERK5 RNA (siERK5) and then treated with either (i) no analog; (ii) insulin (1 nM), or TNF alpha (1 ng/mL) alone, or (iii) insulin plus TNFa for 6 h. Thereafter either total VCAM-1 protein or surface VCAM-1 protein was determined. Results: Genetic inhibition of ERK5 decreased TNF alpha-stimulated total VCAM-1 expression by 57% and surface expression by 27%. In contrast, genetic inhibition of ERK5 did not significantly decrease insulin-stimulated total or surface VCAM-1 expression. Interestingly, genetic inhibition of ERK5 did not significantly decrease insulin plus TNFa-stimulated total VCAM-1 expression, but significantly (P < 0.05) decreased insulin plus TNFa-stimulated surface VCAM-1 expression 41%. Conclusions: We report here that ERK5 plays a minor role in insulin-stimulation of VCAM-1, but plays a significant role in TNF alpha-stimulation of both total and cell surface VCAM-1 protein expression. Taken together, these results demonstrate that not only does ERK5 have differential mediation of insulin and TNF alpha-stimulated VCAM-1 expression, but also has differential regulation of insulin plus TNF alpha-stimulated total and surface VCAM-1 expression, suggesting that other intermediates of the insulin and TNF alpha intracellular pathways are contributing to atherogenesis. C1 [Mackesy, Daniel Z.; Goalstone, Marc L.] Eastern Colorado Hlth Care Syst, Res Dept, Denver, CO USA. [Goalstone, Marc L.] Univ Colorado, Sch Med, Dept Endocrinol, Denver, CO USA. RP Goalstone, ML (reprint author), Denver VA Med Ctr, 1055 Clermont St,MS 151, Denver, CO 80220 USA. EM marc.goalstone@va.gov FU Research Service of the Department of Veterans Affairs; VA Career Development Award FX This work was supported by the Research Service of the Department of Veterans Affairs (to M.L.G.), in which Dr Goalstone is a recipient of a VA Career Development Award. We would also like to acknowledge the assistance of Harsh Pratap (Flow Cytometry technician for the Mucosal and Vaccine Research Colorado) of the Eastern Colorado Health Care Service (Denver VAMC). NR 30 TC 6 Z9 7 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1753-0393 EI 1753-0407 J9 J DIABETES JI J. Diabetes PD NOV PY 2014 VL 6 IS 6 BP 595 EP 602 DI 10.1111/1753-0407.12132 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS6BS UT WOS:000344350500016 PM 24460840 ER PT J AU Richards, KA Negron, E Cohn, JA Steinberg, Z Eggener, SE Shalhav, AL AF Richards, Kyle A. Negron, Edris Cohn, Joshua A. Steinberg, Zoe Eggener, Scott E. Shalhav, Arieh L. TI The Impact of Body Mass Index on Renal Functional Outcomes Following Minimally Invasive Partial Nephrectomy SO JOURNAL OF ENDOUROLOGY LA English DT Article ID LAPAROSCOPIC PARTIAL NEPHRECTOMY; CHRONIC KIDNEY-DISEASE; INTRAABDOMINAL FAT; OBESITY; CANCER; PREDICTORS; EQUATION AB Objective: To assess the impact of body mass index (BMI) on perioperative and renal functional outcomes in patients undergoing minimally invasive partial nephrectomy (MIPN). Materials and Methods: In our IRB-approved, prospectively maintained clinical database, we identified 1206 patients who underwent kidney surgery from 2002 to 2013. Estimated glomerular filtration rate (eGFR) was obtained at baseline and each follow-up visit. From this group, patients who underwent MIPN with more than 12 months of follow-up were selected. Patients were separated into 4 cohorts based on BMI: normal weight (<25kg/m(2)), preobese (25-30kg/m(2)), obese class 1 (30-35kg/m(2)), and obese class >= 2 (>35kg/m(2)). Change in eGFR was compared across demographic and clinical variables through linear and logistic regression models. Results: A total of 235 patients met inclusion criteria with median follow-up of 29 months (interquartile range [IQR] 19, 45). There were no differences in demographic, perioperative, or pathologic features between BMI groups. While controlling for gender, race, Charlson comorbidity score, tumor size, and ischemia time, obese class 1 (odds ratio [OR] 4.68, p=0.019), obese class >= 2 (OR 4.27, p=0.033), and age (OR 1.06, p=0.014) were associated with increased risk of CKD stage >= 3; however, higher baseline eGFR (OR 0.91, p<0.001) was associated with a reduced risk of CKD stage >= 3. While controlling for the same variables, increasing BMI was associated with a significant absolute reduction in eGFR at 1 year (0.38mL/minute/1.73m(2) reduction in GFR per 1kg/m(2) increase in BMI, p=0.009). Conclusions: MIPN is technically feasible in obese patients with similar perioperative outcomes to nonobese patients. BMI is an independent risk factor for worsening kidney function following MIPN. C1 [Richards, Kyle A.; Negron, Edris; Cohn, Joshua A.; Steinberg, Zoe; Eggener, Scott E.; Shalhav, Arieh L.] Univ Chicago, Med Ctr, Dept Surg, Urol Sect, Chicago, IL 60637 USA. [Richards, Kyle A.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Urol, Madison, WI 53705 USA. [Richards, Kyle A.] William S Middleton Mem Vet Adm Med Ctr, Dept Surg, Madison, WI USA. RP Richards, KA (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Third Floor,1685 Highland Ave, Madison, WI 53705 USA. EM richardsk@urology.wisc.edu OI Richards, Kyle/0000-0001-8773-6413; Cohn, Joshua/0000-0002-4953-3321 FU NCATS NIH HHS [UL1 TR000430] NR 26 TC 0 Z9 0 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0892-7790 EI 1557-900X J9 J ENDOUROL JI J. Endourol. PD NOV 1 PY 2014 VL 28 IS 11 BP 1338 EP 1344 DI 10.1089/end.2014.0360 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AS0PM UT WOS:000343979900016 PM 24935823 ER PT J AU Perissinotto, CM Covinsky, KE AF Perissinotto, Carla M. Covinsky, Kenneth E. TI Living Alone, Socially Isolated or Lonely-What are We Measuring? SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material DE aging; loneliness; social isolation; geriatrics ID OLDER-ADULTS; LONELINESS; HEALTH; INTERVENTIONS; VALIDITY; PEOPLE C1 [Perissinotto, Carla M.; Covinsky, Kenneth E.] Univ Calif San Francisco, Div Geriatr, Dept Med, San Francisco, CA 94143 USA. [Covinsky, Kenneth E.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Perissinotto, CM (reprint author), Univ Calif San Francisco, Div Geriatr, Dept Med, 3333 Calif St,Suite 380, San Francisco, CA 94143 USA. EM carla.perissinotto@ucsf.edu NR 13 TC 1 Z9 1 U1 2 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2014 VL 29 IS 11 BP 1429 EP 1431 DI 10.1007/s11606-014-2977-8 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AS1ZC UT WOS:000344077900003 PM 25092012 ER PT J AU Piller, LB Simpson, LM Baraniuk, S Habib, GB Rahman, M Basile, JN Dart, RA Ellsworth, AJ Fendley, H Probstfield, JL Whelton, PK Davis, BR AF Piller, Linda B. Simpson, Lara M. Baraniuk, Sarah Habib, Gabriel B. Rahman, Mahboob Basile, Jan N. Dart, Richard A. Ellsworth, Allan J. Fendley, Herbert Probstfield, Jeffrey L. Whelton, Paul K. Davis, Barry R. CA ALLHAT Collaborative Res Grp TI Characteristics and Long-Term Follow-Up of Participants with Peripheral Arterial Disease During ALLHAT SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE cardiovascular disease; hypertension; clinical trials ID LIPID-LOWERING TREATMENT; HEART-ATTACK TRIAL; NUTRITION EXAMINATION SURVEY; JOINT NATIONAL COMMITTEE; HIGH BLOOD-PRESSURE; INTERMITTENT CLAUDICATION; LOWER-EXTREMITY; HYPERTENSION; MANAGEMENT; PREVALENCE AB Hypertension is a major risk factor for peripheral artery disease (PAD). Little is known about relative efficacy of antihypertensive treatments for preventing PAD. To compare, by randomized treatment groups, hospitalized or revascularized PAD rates and subsequent morbidity and mortality among participants in the Antihypertensive and Lipid-Lower Treatment to Prevent Heart Attack Trial (ALLHAT). Randomized, double-blind, active-control trial in high-risk hypertensive participants. Eight hundred thirty participants with specified secondary outcome of lower extremity PAD events during the randomized phase of ALLHAT. In-trial PAD events were reported during ALLHAT (1994-2002). Post-trial mortality data through 2006 were obtained from administrative databases. Mean follow-up was 8.8 years. Baseline characteristics and intermediate outcomes in three treatment groups, using the Kaplan-Meier method to calculate cumulative event rates and post-PAD mortality rates, Cox proportional hazards regression model for hazard ratios and 95 % confidence intervals, and multivariate Cox regression models to examine risk differences among treatment groups. Following adjustment for baseline characteristics, neither participants assigned to the calcium-channel antagonist amlodipine nor to the ACE-inhibitor lisinopril showed a difference in risk of clinically advanced PAD compared with those in the chlorthalidone arm (HR, 0.86; 95 % CI, 0.72-1.03 and HR, 0.98; 95 % CI, 0.83-1.17, respectively). Of the 830 participants with in-trial PAD events, 63 % died compared to 34 % of those without PAD; there were no significant treatment group differences for subsequent nonfatal myocardial infarction, coronary revascularizations, strokes, heart failure, or mortality. Neither amlodipine nor lisinopril showed superiority over chlorthalidone in reducing clinically advanced PAD risk. These findings reinforce the compelling need for comparative outcome trials examining treatment of PAD in high-risk hypertensive patients. Once PAD develops, cardiovascular event and mortality risk is high, regardless of type of antihypertensive treatment. C1 [Piller, Linda B.; Simpson, Lara M.; Baraniuk, Sarah; Davis, Barry R.] Univ Texas Sch Publ Hlth, Houston, TX 77030 USA. [Habib, Gabriel B.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Rahman, Mahboob] Case Western Reserve Univ, Louis Stokes Cleveland VA Med Ctr, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Basile, Jan N.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Dart, Richard A.] Marshfield Clin Res Fdn, Marshfield, WI USA. [Ellsworth, Allan J.] Univ Washington, Seattle, WA 98195 USA. [Fendley, Herbert] AHEC Family Practice Ctr, Pine Bluff, AR USA. [Probstfield, Jeffrey L.] Univ Washington, Sch Med, Div Cardiol, Seattle, WA USA. [Whelton, Paul K.] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. RP Piller, LB (reprint author), Univ Texas Sch Publ Hlth, 1200 Herman Pressler St,W-906, Houston, TX 77030 USA. EM Linda.b.piller@uth.tmc.edu FU National Heart, Lung, and Blood Institute [NO1-HC-35130, HHSN268201100036C]; Pfizer, Inc. FX This research was supported by contracts NO1-HC-35130 and HHSN268201100036C from the National Heart, Lung, and Blood Institute. The ALLHAT investigators acknowledge contributions of study medications supplied by Pfizer, Inc. (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin) and financial support provided by Pfizer, Inc. NR 33 TC 4 Z9 5 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2014 VL 29 IS 11 BP 1475 EP 1483 DI 10.1007/s11606-014-2947-1 PG 9 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AS1ZC UT WOS:000344077900014 PM 25002161 ER PT J AU Richter, JM AF Richter, James M. TI Capsule Commentary on Tang et al., Evaluation of a Primary Care-Based Post-Discharge Phone Call Program: Keeping the Primary Care Practice at the Center of Post-Hospitalization Care Transition SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material C1 [Richter, James M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Richter, James M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Richter, JM (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM jrichter@partners.org NR 4 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2014 VL 29 IS 11 BP 1532 EP 1532 DI 10.1007/s11606-014-2957-z PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AS1ZC UT WOS:000344077900027 PM 25183472 ER PT J AU Jena, AB Stevens, W McWilliams, JM AF Jena, Anupam B. Stevens, Warren McWilliams, J. Michael TI Turning Evidence into Practice Under Payment Reform: The New Frontier of Translational Science SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE health care reform; health care quality; cost effectiveness ID PHYSICIANS; CARE AB Momentum is building to replace the current fee-for-service payment system with value-based reimbursement models that aim to deliver high quality care at lower costs. Although the goals of payment and delivery system reforms to improve quality and reduce costs are clear, the actual path by which provider groups can achieve these goals is not well understood, in large part because the role of identifying and discouraging the use of low-value, high-cost services and encouraging the use of high-value, low-cost services has traditionally fallen to health plans, not provider groups. The shifting focus towards provider accountability for costs and quality promises to expand the role of provider organizations from mainly delivering care to both delivering and prioritizing it based on costs and quality. We discuss how progress on two important but challenging fronts will be needed for provider groups to successfully translate evidence into value. First, robust evidence on the costs and benefits of treatments will need to be developed and made easily accessible to provider groups. Second, provider groups will need to translate that evidence into systems that support cost-effective clinical decisions. C1 [Jena, Anupam B.; McWilliams, J. Michael] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Jena, Anupam B.] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Stevens, Warren] Precis Hlth Econ, Los Angeles, CA USA. [McWilliams, J. Michael] Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, Boston, MA 02115 USA. RP Jena, AB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM jena@hcp.med.harvard.edu FU Office of the Director, National Institutes of Health (NIH Early Independence Award) [1DP5OD017897-01]; Doris Duke Charitable Foundation (Clinical Scientist Development Award) [2010053]; Beeson Career Development Award Program (National Institute on Aging) [K08 AG038354]; Beeson Career Development Award Program (American Federation for Aging Research); National Institute on Aging [P01 AG032952]; Abbott Laboratories FX Dr. Jena reports receipt of an award from the Office of the Director, National Institutes of Health (NIH Early Independence Award, 1DP5OD017897-01). Dr. McWilliams is supported by grants from the Doris Duke Charitable Foundation (Clinical Scientist Development Award #2010053), Beeson Career Development Award Program (National Institute on Aging K08 AG038354 and the American Federation for Aging Research), and National Institute on Aging (P01 AG032952). Support for this research was provided by Abbott Laboratories. NR 15 TC 0 Z9 0 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2014 VL 29 IS 11 BP 1542 EP 1545 DI 10.1007/s11606-014-2979-6 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AS1ZC UT WOS:000344077900030 PM 25092013 ER PT J AU Doring, ACD Hageman, MGJS Mulder, FJ Guitton, TG Ring, D AF Doering, Anne-Carolin D. Hageman, Michiel G. J. S. Mulder, Frans J. Guitton, Thierry G. Ring, David CA Sci Variation Grp TI Trigger Finger: Assessment of Surgeon and Patient Preferences and Priorities for Decision Making SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Shared decision making; assessment of needs; trigger finger; decision aids ID SUPPORT FRAMEWORK; AIDS; INSTRUMENTS; QUALITY; VIEWS AB Purpose To test the null hypothesis that there are no differences in the priorities and preferences of patients with idiopathic trigger finger (TF) and hand surgeons. Methods One hundred five hand surgeons of the Science of Variation Group and 84 patients with TF completed a survey about their priorities and preferences in decision making regarding the management of TF. The questionnaire was structured according the Ottawa Decision Support Framework for the development of a decision aid. Results Patients desired orthotics more and surgery less than physicians. Patients and physicians disagreed on the main advantage of several treatment options for TFs and on disadvantages of the treatment options. Patients preferred to decide for themselves after receiving advice, whereas physicians preferred a shared decision. Patients preferred booklets, and physicians opted for Internet and video decision aids. Conclusions Comparing patients and hand surgeons, there were some differences in treatment preferences and perceived advantages and disadvantages regarding idiopathic TF differences that might be addressed by a decision aid. Copyright (C) 2014 by the American Society for Surgery of the Hand. All rights reserved. C1 [Doering, Anne-Carolin D.; Hageman, Michiel G. J. S.; Mulder, Frans J.; Guitton, Thierry G.; Ring, David; Sci Variation Grp] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Yawkey Ctr, Orthopaed Hand Serv, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org RI Fernandes, C/F-9839-2012; OI Fernandes, C/0000-0003-0146-6091; Kennedy, Stephen/0000-0001-8177-4988; Guitton, Thierry/0000-0002-2599-1985; Ring, David/0000-0002-6506-4879; Bainbridge, Lionel/0000-0001-7987-2845 FU Marti-Keunig Eckhart Stichting; Anna Foundation FX M.G.H. is supported by Dutch research grants from Marti-Keunig Eckhart Stichting and Anna Foundation. NR 23 TC 7 Z9 7 U1 2 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 EI 1531-6564 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD NOV PY 2014 VL 39 IS 11 BP 2208 EP 2213 DI 10.1016/j.jhsa.2014.08.010 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AS5KU UT WOS:000344310700010 PM 25283491 ER PT J AU Kitay, A Mudgal, C AF Kitay, Alison Mudgal, Chaitanya TI Volar Carpal Subluxation Following Lunate Facet Fracture SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Editorial Material ID DISTAL RADIUS FRACTURES; FIXATION C1 [Kitay, Alison; Mudgal, Chaitanya] Massachusetts Gen Hosp, Dept Hand & Upper Extrem Surg, Boston, MA 02114 USA. RP Kitay, A (reprint author), Brigham & Womens Hosp, Dept Hand & Upper Extrem Surg, 75 Francis St, Boston, MA 02115 USA. EM Alison.kitay@gmail.com NR 9 TC 2 Z9 2 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 EI 1531-6564 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD NOV PY 2014 VL 39 IS 11 BP 2335 EP 2341 DI 10.1016/j.jhsa.2014.04.027 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AS5KU UT WOS:000344310700035 PM 24908555 ER PT J AU Ring, D AF Ring, D. TI The future of hand surgery SO JOURNAL OF HAND SURGERY-EUROPEAN VOLUME LA English DT Editorial Material ID TUNNEL-SYNDROME C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM dring@mgh.harvard.edu NR 13 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1753-1934 EI 2043-6289 J9 J HAND SURG-EUR VOL JI J. Hand Surg.-Eur. Vol. PD NOV PY 2014 VL 39 IS 9 BP 1016 EP 1017 DI 10.1177/1753193414535886 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AS4LM UT WOS:000344247500022 PM 25336675 ER PT J AU Dinter, J Gourdain, P Lai, NY Duong, E Bracho-Sanchez, E Rucevic, M Liebesny, PH Xu, Y Shimada, M Ghebremichael, M Kavanagh, DG Le Gall, S AF Dinter, Jens Gourdain, Pauline Lai, Nicole Y. Ellen Duong Bracho-Sanchez, Edith Rucevic, Marijana Liebesny, Paul H. Xu, Yang Shimada, Mariko Ghebremichael, Musie Kavanagh, Daniel G. Le Gall, Sylvie TI Different Antigen-Processing Activities in Dendritic Cells, Macrophages, and Monocytes Lead to Uneven Production of HIV Epitopes and Affect CTL Recognition SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MHC CLASS-I; CD8(+) T-CELLS; IMMUNODEFICIENCY-VIRUS TYPE-1; CROSS-PRESENTATION; LEUCINE AMINOPEPTIDASE; IMMUNE ESCAPE; GAG PROTEIN; ENDOPLASMIC-RETICULUM; THIMET OLIGOPEPTIDASE; PROTEASOME REGULATOR AB Dendritic cells (DCs), macrophages (MPs), and monocytes are permissive to HIV. Whether they similarly process and present HIV epitopes to HIV-specific CD8 T cells is unknown despite the critical role of peptide processing and presentation for recognition and clearance of infected cells. Cytosolic peptidases degrade endogenous proteins originating from self or pathogens, exogenous Ags preprocessed in endolysosomes, thus shaping the peptidome available for endoplasmic reticulum translocation, trimming, and MHC-I presentation. In this study, we compared the capacity of DCs, MPs, and monocyte cytosolic extracts to produce epitope precursors and epitopes. We showed differences in the proteolytic activities and expression levels of cytosolic proteases between monocyte-derived DCs and MPs and upon maturation with LPS, R848, and CL097, with mature MPs having the highest activities. Using cytosol as a source of proteases to degrade epitope-containing HIV peptides, we showed by mass spectrometry that the degradation patterns of long peptides and the kinetics and amount of antigenic peptides produced differed among DCs, MPs, and monocytes. Additionally, variable intracellular stability of HIV peptides prior to loading onto MHC may accentuate the differences in epitope availability for presentation by MHC-I between these subsets. Differences in peptide degradation led to 2- to 25-fold differences in the CTL responses elicited by the degradation peptides generated in DCs, MPs, and monocytes. Differences in Ag-processing activities between these subsets might lead to variations in the timing and efficiency of recognition of HIV-infected cells by CTLs and contribute to the unequal capacity of HIV-specific CTLs to control viral load. C1 [Le Gall, Sylvie] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ragon Inst MGH,MIT, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02139 USA. RP Le Gall, S (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ragon Inst MGH,MIT, 400 Technol Sq, Cambridge, MA 02139 USA. EM sylvie_legall@hms.harvard.edu FU National Institute of Allergy and Infectious Diseases [AI084753, AI084106]; Ernst Schering Foundation FX This work was supported by National Institute of Allergy and Infectious Diseases Grants AI084753 and AI084106 (to S.L.G.). J.D. is supported in part by a Ph.D. training fellowship from the Ernst Schering Foundation. NR 81 TC 7 Z9 7 U1 0 U2 10 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2014 VL 193 IS 9 BP 4322 EP 4334 DI 10.4049/jimmunol.1400491 PG 13 WC Immunology SC Immunology GA AS1ZS UT WOS:000344079500008 PM 25230751 ER PT J AU Collins, E Gu, F Qi, MS Molano, I Ruiz, P Sun, LY Gilkeson, GS AF Collins, Erin Gu, Fei Qi, Maosong Molano, Ivan Ruiz, Phillip Sun, Lingyun Gilkeson, Gary S. TI Differential Efficacy of Human Mesenchymal Stem Cells Based on Source of Origin SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; STROMAL CELLS; MEDIATED IMMUNOSUPPRESSION; INTERFERON-GAMMA; NITRIC-OXIDE; T-CELLS; TRANSPLANTATION; MICE; NEPHRITIS; SUPPRESSION AB Mesenchymal stem cells (MSCs) are useful in tissue repair but also possess immunomodulatory properties. Murine and uncontrolled human trials suggest efficacy of MSCs in treating lupus. Autologous cells are preferable; however, recent studies suggest that lupus-derived MSCs lack efficacy in treating disease. Thus, the optimum derivation of MSCs for use in lupus is unknown. It is also unknown which in vitro assays of MSC function predict in vivo efficacy. The objectives for this study were to provide insight into the optimum source of MSCs and to identify in vitro assays that predict in vivo efficacy. We derived MSCs from four umbilical cords, four healthy bone marrows (BMs), and four lupus BMs. In diseased MRL/lpr mice, MSCs from healthy BM and umbilical cords significantly decreased renal disease, whereas lupus BM MSCs only delayed disease. Current in vitro assays did not differentiate efficacy of the different MSCs. However, differences in MSC efficacy were observed in B cell proliferation assays. Our results suggest that autologous MSCs from lupus patients are not effective in treating disease. Furthermore, standard in vitro assays for MSC licensing are not predictive of in vivo efficacy, whereas inhibiting B cell proliferation appears to differentiate effective MSCs from ineffective MSCs. C1 [Collins, Erin; Gu, Fei; Qi, Maosong; Molano, Ivan; Gilkeson, Gary S.] Med Univ S Carolina, Dept Med, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Gu, Fei; Sun, Lingyun] Nanjing Univ, Affiliated Hosp, Sch Med, Dept Rheumatol & Immunol,Nanjing Drum Tower Hosp, Nanjing 210008, Jiangsu, Peoples R China. [Ruiz, Phillip] Univ Miami, Sch Med, Dept Pathol, Miami, FL 33136 USA. [Gilkeson, Gary S.] Ralph H Johnson Vet Affairs Med Ctr, Med Res Serv, Charleston, SC 29403 USA. RP Collins, E (reprint author), Med Univ S Carolina, Dept Med, 96 Jonathan Lucas St,Suite 912, Charleston, SC 29425 USA. EM collinel@musc.edu FU Lupus Foundation; National Institutes of Health [National Center for Research Resources] [UL1 RR029882]; National Institutes of Health [National Center for Advancing Translational Sciences] [UL1 TR000062]; Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center FX This work was supported by grants from the Lupus Foundation; the National Institutes of Health (UL1 RR029882 [National Center for Research Resources] and UL1 TR000062 [National Center for Advancing Translational Sciences]); and the Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center. NR 41 TC 6 Z9 8 U1 0 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2014 VL 193 IS 9 BP 4381 EP 4390 DI 10.4049/jimmunol.1401636 PG 10 WC Immunology SC Immunology GA AS1ZS UT WOS:000344079500013 PM 25274529 ER PT J AU Wen, ZM Fan, LY Li, YH Zou, Z Scott, MJ Xiao, GZ Li, S Billiar, TR Wilson, MA Shi, XY Fan, J AF Wen, Zongmei Fan, Liyan Li, Yuehua Zou, Zui Scott, Melanie J. Xiao, Guozhi Li, Song Billiar, Timothy R. Wilson, Mark A. Shi, Xueyin Fan, Jie TI Neutrophils Counteract Autophagy-Mediated Anti-Inflammatory Mechanisms in Alveolar Macrophage: Role in Posthemorrhagic Shock Acute Lung Inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; TLR2 UP-REGULATION; HEMORRHAGIC-SHOCK; NADPH OXIDASE; NLRP3 INFLAMMASOME; ENDOTHELIAL-CELLS; SIGNALING PATHWAYS; NAD(P)H OXIDASE; FAMILY-MEMBER; ORGAN INJURY AB Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome after hemorrhagic shock (HS) resulting from major surgery and trauma. The increased susceptibility in HS patients to the development of ALI suggests not yet fully elucidated mechanisms that enhance proinflammatory responses and/or suppress anti-inflammatory responses in the lung. Alveolar macrophages (AM phi) are at the center of the pathogenesis of ALI after HS. We have previously reported that HS-activated polymorphonuclear neutrophils (PMNs) interact with macrophages to influence inflammation progress. In this study, we explore a novel function of PMNs regulating AM phi anti-inflammatory mechanisms involving autophagy. Using a mouse "two-hit" model of HS/resuscitation followed by intratracheal injection of muramyl dipeptide, we demonstrate that HS initiates high mobility group box 1/TLR4 signaling, which upregulates NOD2 expression in AM phi and sensitizes them to subsequent NOD2 ligand muramyl dipeptide to augment lung inflammation. In addition, upregulated NOD2 signaling induces autophagy in AM phi, which negatively regulates lung inflammation through feedback suppression of NOD2-RIP2 signaling and inflammasome activation. Importantly, we further demonstrate that HS-activated PMNs that migrate in alveoli counteract the anti-inflammatory effect of autophagy in AM phi, possibly through NAD(P)H oxidase-mediated signaling to enhance I-kappa B kinase gamma phosphorylation, NF-kappa B activation, and nucleotide-binding oligomerization domain protein 3 inflammasome activation, and therefore augment post-HS lung inflammation. These findings explore a previously unidentified complexity in the mechanisms of ALI, which involves cell-cell interaction and receptor cross talk. C1 [Wen, Zongmei; Zou, Zui; Shi, Xueyin] Second Mil Med Univ, Changzheng Hosp, Dept Anesthesiol, Shanghai 200003, Peoples R China. [Wen, Zongmei] Tongji Univ, Sch Med, Dept Anesthesiol, Shanghai Pulm Hosp, Shanghai 200433, Peoples R China. [Wen, Zongmei; Li, Yuehua; Scott, Melanie J.; Billiar, Timothy R.; Wilson, Mark A.; Fan, Jie] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA. [Fan, Liyan] Univ Pittsburgh, Sch Arts & Sci, Dept Biol Sci, Pittsburgh, PA 15213 USA. [Xiao, Guozhi] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA. [Li, Song] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Ctr Pharmacogenet, Pittsburgh, PA 15261 USA. [Billiar, Timothy R.; Fan, Jie] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15219 USA. [Wilson, Mark A.; Fan, Jie] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. RP Fan, J (reprint author), Univ Pittsburgh, Sch Med, Dept Surg, 3500 Terrace St, Pittsburgh, PA 15213 USA. EM shixueyin1128@163.com; jif7@pitt.edu FU National Institutes of Health [R01-HL-079669, P50-GM-53789]; U.S. Department Veterans' Affairs merit award; 12th Five-Year Plan of the People's Liberation Army Key Project Grant [BWS12J027]; Natural Science Foundation of China [81372013, 81400052]; Project of Shanghai Leading Talent; Shanghai Pujiang Program [14PJD030] FX This work was supported by National Institutes of Health Grants R01-HL-079669 (to J.F. and M.A.W.) and P50-GM-53789 (to T.R.B. and J.F.), a U.S. Department Veterans' Affairs merit award (to J.F.), 12th Five-Year Plan of the People's Liberation Army Key Project Grant BWS12J027 (to X.S.), Natural Science Foundation of China Grant 81372013 (to X.S.), the Project of Shanghai Leading Talent (to X.S.), Natural Science Foundation of China Grant 81400052 (to Z.W.), and Shanghai Pujiang Program 14PJD030 (to Z.W.). NR 64 TC 10 Z9 10 U1 0 U2 10 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD NOV 1 PY 2014 VL 193 IS 9 BP 4623 EP 4633 DI 10.4049/jimmunol.1400899 PG 11 WC Immunology SC Immunology GA AS1ZS UT WOS:000344079500036 PM 25267975 ER PT J AU Alkozei, A McMahon, E Lahav, A AF Alkozei, Anna McMahon, Erin Lahav, Amir TI Stress levels and depressive symptoms in NICU mothers in the early postpartum period SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Maternal stress; neonatal; preterm ID INTENSIVE-CARE-UNIT; PRETERM BIRTH; PSYCHOLOGICAL DISTRESS; POSTNATAL-DEPRESSION; PARENTAL STRESS; MATERNAL STRESS; RISK; INFANTS; SCALE; DISCHARGE AB Objective: This study examined whether particular maternal and infant factors can identify mothers at risk for increased stress upon admission to the neonatal intensive care unit (NICU). Methods: Eighty-five mothers of preterm infants (25-34 weeks gestation) were assessed using the Parental Stressor Scale (PSS: NICU) and the Edinburgh Postnatal Depression Scale (EPDS) within 3.24 +/- 1.58 d postpartum. Hierarchical linear regression models were used to determine the extent to which maternal stress is influenced by individual factors. Results: Fifty-two percent of mothers experienced increased stress (PSS: NICU score >= 3) and 38% had significant depressive symptoms (EPDS score >= 10). Stress related to alterations in parental role was the most significant source of stress among NICU mothers. Distance from the hospital and married marital status were significant predictors for stress related to alterations in parental role (p = 0.003) and NICU sights and sounds (p = 0.01), respectively. Higher stress levels were associated with higher depressive scores (p = 0.001). Maternal mental health factors, demographic factors, pregnancy factors and infant characteristics were not associated with increased stress. Conclusion: Elevated stress levels and depressive symptoms are already present in mothers of preterm infants upon NICU admission. Being married or living long distance from the hospital is associated with higher stress. Future work is needed to develop effective interventions for alleviating stress in NICU mothers and preventing its potential development into postnatal depression. C1 [Alkozei, Anna; McMahon, Erin; Lahav, Amir] Harvard Univ, Brigham & Womens Hosp, Dept Pediat & Newborn Med, Sch Med, Boston, MA 02115 USA. [Lahav, Amir] MassGen Hosp Children, Dept Pediat, Boston, MA USA. RP Lahav, A (reprint author), Brigham & Womens Hosp, Dept Pediat & Newborn Med, 75 Francis St, Boston, MA 02115 USA. EM amir_lahav@hms.harvard.edu FU Charles H. Hood Foundation; Peter and Elizabeth C. Tower Foundation; Jackson L. Graves Foundation; Little Giraffe Foundation; Nexxspan Healthcare FX This work was supported, in part, by the Charles H. Hood Foundation, Peter and Elizabeth C. Tower Foundation, Jackson L. Graves Foundation, Little Giraffe Foundation and Nexxspan Healthcare. NR 31 TC 8 Z9 8 U1 3 U2 17 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 EI 1476-4954 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD NOV PY 2014 VL 27 IS 17 BP 1738 EP 1743 DI 10.3109/14767058.2014.942626 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AS2AE UT WOS:000344080600004 PM 25005861 ER PT J AU Rajakesari, S Arvold, ND Jimenez, RB Christianson, LW Horvath, MC Claus, EB Golby, AJ Johnson, MD Dunn, IF Lee, EQ Lin, NU Friesen, S Mannarino, EG Wagar, M Hacker, FL Weiss, SE Alexander, BM AF Rajakesari, Selvan Arvold, Nils D. Jimenez, Rachel B. Christianson, Laura W. Horvath, Margaret C. Claus, Elizabeth B. Golby, Alexandra J. Johnson, Mark D. Dunn, Ian F. Lee, Eudocia Q. Lin, Nancy U. Friesen, Scott Mannarino, Edward G. Wagar, Matthew Hacker, Fred L. Weiss, Stephanie E. Alexander, Brian M. TI Local control after fractionated stereotactic radiation therapy for brain metastases SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article; Proceedings Paper CT 55th Annual Meeting of the American-Society-for-Radiation-Oncology CY SEP 22-25, 2013 CL Atlanta, GA SP Amer Soc Radiat Oncol DE Brain metastases; Stereotactic radiosurgery; Stereotactic radiotherapy; Hypofractionated ID GAMMA-KNIFE RADIOSURGERY; STEM METASTASES; CEREBRAL METASTASES; SURGICAL RESECTION; CLINICAL ARTICLE; RADIOTHERAPY; CANCER; TRIAL; TOXICITY; IRRADIATION AB Stereotactic radiosurgery (SRS) is frequently used in the management of brain metastases, but concerns over potential toxicity limit applications for larger lesions or those in eloquent areas. Fractionated stereotactic radiation therapy (SRT) is often substituted for SRS in these cases. We retrospectively analyzed the efficacy and toxicity outcomes of patients who received SRT at our institution. Seventy patients with brain metastases treated with SRT from 2006-2012 were analyzed. The rates of local and distant intracranial progression, overall survival, acute toxicity, and radionecrosis were determined. The SRT regimen was 25 Gy in 5 fractions among 87 % of patients. The most common tumor histologies were non-small cell lung cancer (37 %), breast cancer (20 %) and melanoma (20 %), and the median tumor diameter was 1.7 cm (range 0.4-6.4 cm). Median survival after SRT was 10.7 months. Median time to local progression was 17 months, with a local control rate of 68 % at 6 months and 56 % at 1 year. Acute toxicity was seen in 11 patients (16 %), mostly grade 1 or 2 with the most common symptom being mild headache. Symptomatic radiation-induced treatment change was seen on follow-up MRIs in three patients (4.3 %). SRT appears to be a safe and reasonably effective technique to treat brain metastases deemed less suitable for SRS, though dose intensification strategies may further improve local control. C1 [Rajakesari, Selvan; Arvold, Nils D.; Christianson, Laura W.; Horvath, Margaret C.; Friesen, Scott; Mannarino, Edward G.; Wagar, Matthew; Hacker, Fred L.; Alexander, Brian M.] Harvard Univ, Sch Med, Dept Radiat Oncol, Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02163 USA. [Jimenez, Rachel B.] Harvard Radiat Oncol Program, Boston, MA USA. [Claus, Elizabeth B.; Golby, Alexandra J.; Johnson, Mark D.; Dunn, Ian F.] Harvard Univ, Sch Med, Dept Neurosurg, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Claus, Elizabeth B.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Lee, Eudocia Q.] Harvard Univ, Sch Med, Ctr Neurooncol, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Lin, Nancy U.] Harvard Univ, Sch Med, Dept Med, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Weiss, Stephanie E.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. RP Alexander, BM (reprint author), Harvard Univ, Sch Med, Dept Radiat Oncol, Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02163 USA. EM bmalexander@lroc.harvard.edu NR 42 TC 8 Z9 8 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD NOV PY 2014 VL 120 IS 2 BP 339 EP 346 DI 10.1007/s11060-014-1556-5 PG 8 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AS3JD UT WOS:000344172600013 PM 25059451 ER PT J AU D'Ambrosio, AL Barker, FG AF D'Ambrosio, Anthony L. Barker, Fred G., II TI AANS/CNS Section on Tumors (vol 119, pg 449, 2014) SO JOURNAL OF NEURO-ONCOLOGY LA English DT Correction C1 [D'Ambrosio, Anthony L.] Neurosurg New Jersey, Ridgewood, NJ 07450 USA. [Barker, Fred G., II] Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02114 USA. [Barker, Fred G., II] Harvard Univ, Sch Med, Dept Surg Neurosurg, Boston, MA USA. RP D'Ambrosio, AL (reprint author), Neurosurg New Jersey, 1200 East Ridgewood Ave, Ridgewood, NJ 07450 USA. EM dambrosio@neurosurgerynj.com; barker@helix.mgh.harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD NOV PY 2014 VL 120 IS 2 BP 449 EP 449 DI 10.1007/s11060-014-1615-y PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AS3JD UT WOS:000344172600026 ER PT J AU Donovan, WD Leslie-Mazwi, TM Silva, E Woo, HH Nicola, GN Barr, RM Bello, JA Tu, R Hirsch, JA AF Donovan, William D. Leslie-Mazwi, Thabele M. Silva, Ezequiel, III Woo, Henry H. Nicola, Gregory N. Barr, Robert M. Bello, Jacqueline A. Tu, Raymond Hirsch, Joshua A. TI Diagnostic carotid and cerebral angiography: a historical summary of the evolving changes in coding and reimbursement in a complex procedure family SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Review ID RUC AB Carotid and cerebral angiography have been a mainstay of neurointerventional and neuroradiologic practice for years. Centers for Medicare and Medicaid Services (CMS) and Relative Value Scale Update Committee (RUC) initiatives have compelled the professional societies to bundle component codes under threat of unilateral CMS revision and revaluation. Code bundling usually results in a decrease in the professional Relative Value Unit (RVU) valuation, and thus the MD reimbursement. The year 2013 saw a dramatic revision to the Current Procedural Terminology (CPT) code set that defines carotid and cerebral procedures. This paper reviews the process that led to that code set being revised and estimates the impact on professional reimbursement. We show the current and previous carotid angiography CPT codes and use clinical examples to assess professional RVU valuation before and after code revision. C1 [Donovan, William D.] William W Backus Hosp, Norwich, CT USA. [Leslie-Mazwi, Thabele M.; Hirsch, Joshua A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroendovasc Program, Boston, MA 02114 USA. [Silva, Ezequiel, III] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, South Texas Radiol Grp, San Antonio, TX 78229 USA. [Woo, Henry H.] SUNY Stony Brook, Med Ctr, Cerebrovasc Ctr, Dept Neurol Surg & Radiol, Stony Brook, NY 11794 USA. [Nicola, Gregory N.] Hackensack Univ, Med Ctr, Dept Radiol, Hackensack, NJ USA. [Barr, Robert M.] Mecklenburg Radiol Associates PA, Charlotte, NC USA. [Bello, Jacqueline A.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Tu, Raymond] George Washington Univ, Dept Progress Radiol, Falls Church, VA USA. RP Hirsch, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroendovasc Program, Boston, MA 02114 USA. EM hirsch@snisonline.org NR 6 TC 7 Z9 7 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD NOV PY 2014 VL 6 IS 9 BP 712 EP 717 DI 10.1136/neurintsurg-2014-011416 PG 6 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA AS2HJ UT WOS:000344100200020 PM 25179635 ER PT J AU Hirsch, JA Barr, RM McGinty, G Nicola, GN Schaefer, PW Silva, E Manchikanti, L AF Hirsch, Joshua A. Barr, Robert M. McGinty, Geraldine Nicola, Gregory N. Schaefer, Pamela W. Silva, Ezequiel, III Manchikanti, Laxmaiah TI Affordable care 2014: a tale of two boards SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Review ID OUTCOMES RESEARCH-INSTITUTE; EVOLUTION; IMPACT; ACT AB The Patient Protection and Affordable Care Act (ACA) became law on 23 March 2010. As part of the law, two independent boards were established. The Patient-Centered Outcomes Research Institute embodies national aspirations for employing comparative effectiveness research in healthcare decision-making, and the Independent Payment Advisory Board is focused on the need for a group of impartial experts to establish anticipatable growth rates for Medicare. Approximately 4 years after the bill was passed into law, these independent boards are at very different points in their life cycles. This article provides a status update. C1 [Hirsch, Joshua A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroendovasc Program, Boston, MA 02114 USA. [Barr, Robert M.] Mecklenburg Radiol Associates PA, Charlotte, NC USA. [McGinty, Geraldine] Weill Cornell Med Coll, Dept Radiol, New York, NY USA. [Nicola, Gregory N.] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Schaefer, Pamela W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Silva, Ezequiel, III] Univ Texas Hlth Sci Ctr San Antonio, South Texas Radiol Grp, San Antonio, TX 78229 USA. [Silva, Ezequiel, III] South Texas Radiol Grp, San Antonio, TX USA. [Silva, Ezequiel, III] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, San Antonio, TX 78229 USA. [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Manchikanti, Laxmaiah] Univ Louisville, Dept Anesthesiol & Perioperat Med, Louisville, KY 40292 USA. RP Hirsch, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroendovasc Program, Boston, MA 02114 USA. EM Hirsch@snisonline.org OI McGinty, Geraldine/0000-0001-6111-2514 NR 12 TC 3 Z9 3 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 EI 1759-8486 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD NOV PY 2014 VL 6 IS 9 BP 718 EP 720 DI 10.1136/neurintsurg-2014-011322 PG 3 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA AS2HJ UT WOS:000344100200021 PM 24962452 ER PT J AU Izquierdo-Garcia, D Hansen, AE Forster, S Benoit, D Schachoff, S Furst, S Chen, KT Chonde, DB Catana, C AF Izquierdo-Garcia, David Hansen, Adam E. Foerster, Stefan Benoit, Didier Schachoff, Sylvia Fuerst, Sebastian Chen, Kevin T. Chonde, Daniel B. Catana, Ciprian TI An SPM8-Based Approach for Attenuation Correction Combining Segmentation and Nonrigid Template Formation: Application to Simultaneous PET/MR Brain Imaging SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE integrated PET/MRI; attenuation correction; segmentation; template ID ULTRASHORT ECHO TIME; OF-FLIGHT PET; CT IMAGES; MR; REGISTRATION; RECONSTRUCTION; SEQUENCES; EMISSION; SCANNER; ATLAS AB We present an approach for head MR-based attenuation correction (AC) based on the Statistical Parametric Mapping 8 (SPM8) software, which combines segmentation- and atlas-based features to provide a robust technique to generate attenuation maps (mu maps) from MR data in integrated PET/MR scanners. Methods: Coregistered anatomic MR and CT images of 15 glioblastoma subjects were used to generate the templates. The MR images from these subjects were first segmented into 6 tissue classes (gray matter, white matter, cerebrospinal fluid, bone, soft tissue, and air), which were then nonrigidly coregistered using a diffeomorphic approach. A similar procedure was used to coregister the anatomic MR data for a new subject to the template. Finally, the CT-like images obtained by applying the inverse transformations were converted to linear attenuation coefficients to be used for AC of PET data. The method was validated on 16 new subjects with brain tumors (n = 12) or mild cognitive impairment (n = 4) who underwent CT and PET/MR scans. The p maps and corresponding reconstructed PET images were compared with those obtained using the gold standard CT-based approach and the Dixon-based method available on the Biograph mMR scanner. Relative change (RC) images were generated in each case, and voxel- and regionof-interest based analyses were performed. Results: The leave-one-out cross-validation analysis of the data from the 15 atlas-generation subjects showed small errors in brain linear attenuation coefficients (RC, 1.38% +/- 4.52%) compared with the gold standard. Similar results (RC, 1.86% +/- 4.06%) were obtained from the analysis of the atlas-validation datasets. The voxel- and region-of-interest based analysis of the corresponding reconstructed PET images revealed quantification errors of 3.87% +/- 5.0% and 2.74% +/- 2.28%, respectively. The Dixon-based method performed substantially worse (the mean RC values were 13.0% +/- 10.25% and 9.38% +/- 4.97%, respectively). Areas closer to the skull showed the largest improvement. Conclusion: We have presented an SPM8-based approach for deriving the head p map from MR data to be used for PET AC in integrated PET/MR scanners. Its implementation is straightforward and requires only the morphologic data acquired with a single MR sequence. The method is accurate and robust, combining the strengths of both segmentation- and atlas-based approaches while minimizing their drawbacks. C1 [Izquierdo-Garcia, David; Chen, Kevin T.; Chonde, Daniel B.; Catana, Ciprian] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Izquierdo-Garcia, David; Chen, Kevin T.; Chonde, Daniel B.; Catana, Ciprian] Harvard Univ, Sch Med, Charlestown, MA USA. [Hansen, Adam E.; Benoit, Didier] Copenhagen Univ Hosp, Dept Clin Physiol Nucl Med & PET, Rigshosp, Copenhagen, Denmark. [Foerster, Stefan; Schachoff, Sylvia; Fuerst, Sebastian] Tech Univ Munich, Dept Nucl Med, D-80290 Munich, Germany. [Chen, Kevin T.; Chonde, Daniel B.] MIT, Dept Hlth Sci & Technol, Cambridge, MA 02139 USA. [Chonde, Daniel B.] Harvard Univ, Program Biophys, Cambridge, MA 02138 USA. RP Catana, C (reprint author), Athinoula A Martinos Ctr Biomed Imaging, 149,13th St,Room 1116, Charlestown, MA 02129 USA. EM ccatana@nmr.mgh.harvard.edu RI Hansen, Adam/G-7735-2011 FU NIH [R01CA137254, 1R01EB014894] FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. Funding for this work was provided by NIH grants R01CA137254 and 1R01EB014894. No other potential conflict of interest relevant to this article was reported. NR 31 TC 36 Z9 36 U1 0 U2 14 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD NOV PY 2014 VL 55 IS 11 BP 1825 EP 1830 DI 10.2967/jnumed.113.136341 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AS3XT UT WOS:000344209200013 PM 25278515 ER PT J AU de Prost, N Feng, Y Wellman, T Tucci, MR Costa, EL Musch, G Winkler, T Harris, RS Venegas, JG Chao, W Melo, MFV AF de Prost, Nicolas Feng, Yan Wellman, Tyler Tucci, Mauro R. Costa, Eduardo L. Musch, Guido Winkler, Tilo Harris, R. Scott Venegas, Jose G. Chao, Wei Melo, Marcos F. Vidal TI F-18-FDG Kinetics Parameters Depend on the Mechanism of Injury in Early Experimental Acute Respiratory Distress Syndrome SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE respiratory distress syndrome; adult; endotoxemia; pulmonary edema; positron emission tomography; fluorodeoxyglucose F18 ID INDUCED LUNG INJURY; REGIONAL VENTILATION; METABOLIC-ACTIVITY; PET; INFLAMMATION; ENDOTOXIN; SHEEP; RABBITS; MODEL AB PET with F-18-FDG allows for noninvasive assessment of regional lung metabolism reflective of neutrophilic inflammation. This study aimed at determining during early acute lung injury whether local F-18-FDG phosphorylation rate and volume of distribution were sensitive to the initial regional inflammatory response and whether they depended on the mechanism of injury: endotoxemia and surfactant depletion. Methods: Twelve sheep underwent homogeneous unilateral surfactant depletion (alveolar lavage) and were mechanically ventilated for 4 h (positive end-expiratory pressure, 10 cm H2O; plateau pressure, 30 cm H2O) while receiving intravenous endotoxin (lipopolysaccharide-positive [LPS+] group; n = 6) or not (lipopolysaccharide-negative group; n = 6). F-18-FDG PET emission scans were then acquired. F-18-FDG phosphorylation rate and distribution volume were calculated with a 4-compartment model. Lung tissue expression of inflammatory cytokines was measured using real-time quantitative reverse transcription polymerase chain reaction. Results: F-18-FDG uptake increased in LPS+ (P = 0.012) and in surfactant-depleted sheep (P < 0.001). These increases were topographically heterogeneous, predominantly in dependent lung regions, and without interaction between alveolar lavage and LPS. The increase of F-18-FDG uptake in the LPS+ group was related both to increases in the F-18-FDG phosphorylation rate (P < 0.05) and to distribution volume (P < 0.01). F-18-FDG distribution volume increased with infiltrating neutrophils (P < 0.001) and phosphorylation rate with the regional expression of IL-1 beta (P = 0.026), IL-8 (P = 0.011), and IL-10 (P = 0.023). Conclusion: Noninvasive F-18-FDG PET-derived parameters represent histologic and gene expression markers of early lung injury. Pulmonary metabolism assessed with F-18-FDG PET depends on the mechanism of injury and appears to be additive for endotoxemia and surfactant depletion. F-18-FDG PET may be a valuable imaging biomarker of early lung injury. C1 [de Prost, Nicolas; Feng, Yan; Wellman, Tyler; Tucci, Mauro R.; Costa, Eduardo L.; Musch, Guido; Winkler, Tilo; Venegas, Jose G.; Chao, Wei; Melo, Marcos F. Vidal] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [de Prost, Nicolas] Hop Henri Mondor, AP HP, Med Intens Care Unit, F-94010 Creteil, France. [Wellman, Tyler] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Tucci, Mauro R.; Costa, Eduardo L.] Univ Sao Paulo, Heart Inst Incor, Cardiopulm Dept, Div Pulm, Sao Paulo, Brazil. [Harris, R. Scott] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Pulm & Crit Care Unit, Boston, MA USA. RP de Prost, N (reprint author), Hop Henri Mondor, AP HP, Serv Reanimat Med, F-94010 Creteil, France. EM nicolas.de-prost@hmn.aphp.fr RI Winkler, Tilo/B-5337-2009; OI Winkler, Tilo/0000-0002-7276-5550; de Prost, Nicolas/0000-0002-4833-4320 FU NIH [HL 5R01HL086827, 1R01HL121228]; [5R01HL094639] FX The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. This work was supported by NIH grant HL 5R01HL086827 and 1R01HL121228. GM was supported by 5R01HL094639. No other potential conflict of interest relevant to this article was reported. NR 28 TC 8 Z9 8 U1 1 U2 3 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 EI 1535-5667 J9 J NUCL MED JI J. Nucl. Med. PD NOV PY 2014 VL 55 IS 11 BP 1871 EP 1877 DI 10.2967/jnumed.114.140962 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AS3XT UT WOS:000344209200019 PM 25286924 ER PT J AU Way, D Smucker, WD AF Way, Deborah Smucker, William D. TI A Reflection on "Death as Harm" SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Letter ID CARE C1 [Way, Deborah] Philadelphia Vet Affairs Med Ctr, Palliat Care Serv, Philadelphia, PA USA. [Smucker, William D.] Summa Hlth Syst, Family Med Ctr Akron, Akron, OH 44304 USA. RP Smucker, WD (reprint author), Summa Hlth Syst, Family Med Ctr Akron, Akron, OH 44304 USA. EM Smuckerw@summahealth.org NR 3 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD NOV 1 PY 2014 VL 17 IS 11 BP 1196 EP 1196 DI 10.1089/jpm.2014.0289 PG 1 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AS9XX UT WOS:000344592800002 PM 25302418 ER PT J AU Moghanaki, D Cheuk, AV Fosmire, H Anscher, MS Lutz, ST Hagan, MP Dawson, GA AF Moghanaki, Drew Cheuk, Alice V. Fosmire, Helen Anscher, Mitchell S. Lutz, Stephen T. Hagan, Michael P. Dawson, George A. CA US Vet Healthcare Adm Natl TI Availability of Single-Fraction Palliative Radiotherapy for Cancer Patients Receiving End-of-Life Care within the Veterans Healthcare Administration SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID BONE METASTASES; HOSPICE; DELIVERY; ONCOLOGY; SYSTEM AB Background: Surveys demonstrate <20% of radiation oncologists in the United States offer single-fraction palliative radiotherapy (RT) even though it is an acceptable standard of care. A study was conducted to investigate whether this held true for those practicing within the Veterans Healthcare Administration (VHA). Methods: All radiation oncologists currently practicing at VHA medical centers were surveyed. Comparisons and associations of responses were evaluated by Fisher's exact test. Results: The response rate was 90%. Half were full-time employees of the VHA, and the majority (70%) had thoroughly read guidelines on palliative RT for bone metastases recently published by either the American College of Radiology (ACR, 2009, 2012) or the American Society of Radiation Oncology (ASTRO, 2011). Single-fraction palliative RT for bone metastases had been prescribed by 76% of respondents, and 93% had prescribed a short course of <= 6 fractions. Respondents were less likely to have prescribed a single fraction for patients who had survival estimates of either >6 months or >12 months (66% versus 37%, p<0.0001).Those not offering single-fraction palliative RT (24%) were more likely to be >10 years out of training (37% versus 10%, p=0.01), and to have worked in a private practice setting at some point in their career (36% versus 12%, p=0.03). Conclusions: A majority of radiation oncologists within the VHA offer single-fraction therapy to their patients. These data ensure access to palliative RT is not limited within this health care system by a preference for prolonged treatment courses that may discourage patients and clinicians from seeking this care. C1 [Moghanaki, Drew] Hunter Holmes McGuire Vet Affairs Med Ctr, Richmond, VA 23249 USA. [Moghanaki, Drew; Anscher, Mitchell S.; Hagan, Michael P.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA USA. [Cheuk, Alice V.; Dawson, George A.] James J Peters Vet Affairs Med Ctr, New York, NY USA. [Cheuk, Alice V.; Dawson, George A.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Fosmire, Helen] Richard L Roudebush Vet Affairs Med Ctr, Indianapolis, IN 46202 USA. [Lutz, Stephen T.] Blanchard Valley Reg Hlth Ctr, Findlay, OH USA. [Hagan, Michael P.] US Dept Vet Affairs, Natl Radiat Oncol Program, Richmond, VA USA. [Dawson, George A.] Vet Affairs New Jersey Healthcare Syst, E Orange, NJ USA. RP Moghanaki, D (reprint author), Hunter Holmes McGuire Vet Affairs Med Ctr, Dept Radiat Oncol, 1201 Broad Rock Blvd, Richmond, VA 23249 USA. EM drew.moghanaki@va.gov OI Anscher, Mitchell/0000-0003-4480-111X NR 22 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD NOV 1 PY 2014 VL 17 IS 11 BP 1221 EP 1225 DI 10.1089/jpm.2014.0041 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AS9XX UT WOS:000344592800008 PM 25188468 ER PT J AU Back, AL Park, ER Greer, JA Jackson, VA Jacobsen, JC Gallagher, ER Temel, JS AF Back, Anthony L. Park, Elyse R. Greer, Joseph A. Jackson, Vicki A. Jacobsen, Juliet C. Gallagher, Emily R. Temel, Jennifer S. TI Clinician Roles in Early Integrated Palliative Care for Patients with Advanced Cancer: A Qualitative Study SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID CELL LUNG-CANCER; CONSULT SERVICE; ONCOLOGY; OUTCOMES AB Background: Early palliative care provides better quality of life, increased prognostic awareness, and even improved survival for patients with advanced cancer but how the integrated care model achieves these outcomes has not been completely explained. Methods: To better understand the clinical approach to early outpatient care from the clinicians' perspective, we conducted focus groups with the palliative care clinicians who had participated in a randomized trial of early palliative care for metastatic lung cancer. Results: Clinicians described their role in providing early palliative care as having three distinct roles in the outpatient setting: (1) managing symptoms to improve functional status and as a bridge to other issues; (2) engaging patients in emotional work to facilitate coping, accepting, and planning; and (3) interpreting the oncologist for the patient and the patient for the oncologist. Conclusions: These data lay the foundation for developing training programs for clinicians in early integrated palliative care. C1 [Back, Anthony L.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Park, Elyse R.; Greer, Joseph A.; Jackson, Vicki A.; Jacobsen, Juliet C.; Gallagher, Emily R.; Temel, Jennifer S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Back, AL (reprint author), Seattle Canc Care Alliance, 825 Eastlake Ave E, Seattle, WA 98102 USA. EM tonyback@uw.edu FU National Institutes of Nursing Research [R01NR012735] FX Funding received from the National Institutes of Nursing Research R01NR012735. NR 17 TC 12 Z9 12 U1 1 U2 11 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD NOV 1 PY 2014 VL 17 IS 11 BP 1244 EP 1248 DI 10.1089/jpm.2014.0146 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AS9XX UT WOS:000344592800012 PM 25390467 ER PT J AU Potosek, J Curry, M Buss, M Chittenden, E AF Potosek, Jamie Curry, Michael Buss, Mary Chittenden, Eva TI Integration of Palliative Care in End-Stage Liver Disease and Liver Transplantation SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Review ID QUALITY-OF-LIFE; ADVANCED HEART-FAILURE; UNITED-STATES; HEPATIC-ENCEPHALOPATHY; DOSAGE ADJUSTMENT; ADVANCED LUNG; WAITING-LIST; CIRRHOSIS; HOSPICE; SURVIVAL AB Background: Patients with end-stage liver disease (ESLD) have a life-limiting illness that causes multiple distressing symptoms and negatively affects quality of life (QOL). This population traditionally has not had much attention within the palliative care community. Discussion: This article provides an evidence-based review of palliative care issues that patients with ESLD and those awaiting liver transplant face, including approaches to prognosis, symptom management, advance care planning, and end-of-life care. Conclusion: Tremendous opportunity exists to integrate palliative medicine into the care of these patients. C1 [Potosek, Jamie] Providence Reg Canc Ctr, Dept Hematol Oncol, Lacey, WA USA. [Buss, Mary] Beth Israel Deaconess Med Ctr, Dept Hematol Oncol, Boston, MA 02215 USA. [Curry, Michael] Beth Israel Deaconess Med Ctr, Dept Gastroenterol, Boston, MA 02215 USA. [Chittenden, Eva] Massachusetts Gen Hosp, Dept Med, Div Palliat Care, Boston, MA 02114 USA. RP Potosek, J (reprint author), Providence Reg Canc Ctr Syst Lacey, Dept Hematol Oncol, 4525 Third Ave SE,Suite 200, Lacey, WA 98503 USA. EM jamie.potosek@providence.org NR 72 TC 5 Z9 5 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD NOV 1 PY 2014 VL 17 IS 11 BP 1271 EP 1277 DI 10.1089/jpm.2013.0167 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AS9XX UT WOS:000344592800017 PM 25390468 ER PT J AU Lakdawalla, DN Mascarenhas, M Jena, AB Vanderpuye-Orgle, J LaVallee, C Linthicum, MT Snider, JT AF Lakdawalla, Darius N. Mascarenhas, Maria Jena, Anupam B. Vanderpuye-Orgle, Jacqueline LaVallee, Chris Linthicum, Mark T. Snider, Julia Thornton TI Impact of Oral Nutrition Supplements on Hospital Outcomes in Pediatric Patients SO JOURNAL OF PARENTERAL AND ENTERAL NUTRITION LA English DT Article DE pediatrics; life cycle; CAM; outcomes research; quality; nutrition support practice ID RANDOMIZED CONTROLLED-TRIAL; CONGENITAL HEART-DISEASE; PLACEBO-CONTROLLED TRIAL; LENGTH-OF-STAY; INSTRUMENTAL VARIABLES; CYSTIC-FIBROSIS; 3-MONTH INTERVENTION; PARENTERAL-NUTRITION; ACUTE ILLNESS; MALNUTRITION AB Background: Nutrition deficiency is common among hospitalized children. Although oral nutrition supplements (ONS) may improve malnutrition in this population, the benefits and healthcare costs associated with their use have not yet been fully explored. The objective of this study was to assess the effect of ONS use on inpatient length of stay (LOS) and episode cost in hospitalized children. Materials and Methods: Retrospective analysis of 557,348 hospitalizations of children aged 2-8 years in the Premier Research Database. The effect of ONS use on LOS and episode cost in a propensity score- matched sample was estimated in analyses with and without the use of instrumental variables (IVs) to reduce confounding from unobserved variables. Results: ONS were prescribed in 6066 of 557,348 inpatient episodes (1.09%). In IV analysis, using a matched sample of 11,031 episodes, hospitalizations with ONS use had 14.8% shorter LOS (6.4 vs 7.5 days; 1.1 days [95% CI, 0.2-2.4]). Hospitalizations with ONS use had 9.7% lower cost ($16,552 vs $18,320; $1768 [95% CI, $1924-$1612]). Conclusions: ONS use was associated with lower LOS and episode cost among pediatric inpatients. ONS use in hospitalized pediatric patients may provide a cost-effective, evidence-based approach to improving pediatric hospital care. C1 [Lakdawalla, Darius N.] Univ So Calif, Schaeffer Ctr Hlth Policy & Econ, Los Angeles, CA 90089 USA. [Mascarenhas, Maria] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Jena, Anupam B.] Harvard Univ, Sch Med, Boston, MA USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Vanderpuye-Orgle, Jacqueline; LaVallee, Chris; Linthicum, Mark T.; Snider, Julia Thornton] Precis Hlth Econ, Los Angeles, CA USA. RP Lakdawalla, DN (reprint author), Univ So Calif, Schaeffer Ctr Hlth Policy & Econ, 635 Downey Way,VPD 210-F, Los Angeles, CA 90089 USA. EM dlakdawa@usc.edu OI Lakdawalla, Darius/0000-0001-5934-8042 FU Abbott Nutrition FX Financial disclosure: Financial support for the publication of the supplement in which this article appears was provided by Abbott Nutrition. NR 62 TC 7 Z9 7 U1 3 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0148-6071 EI 1941-2444 J9 JPEN-PARENTER ENTER JI J. Parenter. Enter. Nutr. PD NOV PY 2014 VL 38 SU 2 BP 42S EP 49S DI 10.1177/0148607114549769 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AS5MF UT WOS:000344314200004 PM 25233942 ER PT J AU Hamdy, O Ernst, FR Baumer, D Mustad, V Partridge, J Hegazi, R AF Hamdy, Osama Ernst, Frank R. Baumer, Dorothy Mustad, Vikkie Partridge, Jamie Hegazi, Refaat TI Differences in Resource Utilization Between Patients With Diabetes Receiving Glycemia-Targeted Specialized Nutrition vs Standard Nutrition Formulas in US Hospitals SO JOURNAL OF PARENTERAL AND ENTERAL NUTRITION LA English DT Article DE diabetes; nutrition; inpatient; length of stay; costs ID CRITICALLY-ILL PATIENTS; PROPENSITY SCORE; ENTERAL FORMULA; BIAS AB Objectives: The purpose of the study was to compare patient outcomes and costs for patients with diabetes mellitus (DM) receiving glycemia-targeted specialized nutrition (GTSN) with similar patients receiving standard nutrition (STDN) formulas during acute care hospitalizations. Research Design and Methods: The study was designed as a retrospective analysis over a 10-year period (2000-2009) of clinical and cost data from 125,000 hospital inpatient episodes in the Premier Research Database. Patients received either GTSN or STDN, by tube or orally, as a component of comprehensive care for hyperglycemia in patients with DM. To adjust for potential cohort imbalances, GTSN patients were matched with STDN patients on the basis of propensity scores, adjusting for many characteristics, including age, sex, race, All Patient Refined Diagnosis-Related Group (APR-DRG) illness severity, APR-DRG mortality risk, and comorbidities. Results: Tube-fed patients with DM who were provided GTSN had a 0.88-day (95% confidence interval [CI], 0.73-1.02) shorter length of hospital stay (LOS) on average compared with those patients provided STDN. Orally fed patients with DM who were provided GTSN had a 0.17-day (95% CI, 0.14-0.21) shorter LOS than did those patients provided STDN. The shorter LOS associated with GTSN contributed to a cost savings of $2586 for tube-fed patients and $1356 for orally fed patients. Conclusions: The use of GTSN feeding formulas for patients with DM in acute care hospital settings was associated with reduced LOS and inpatient hospital episode cost in comparison to STDN. C1 [Hamdy, Osama] Joslin Diabet Ctr, Boston, MA 02215 USA. [Ernst, Frank R.; Baumer, Dorothy] Premier Healthcare Alliance, Charlotte, NC USA. [Mustad, Vikkie; Partridge, Jamie; Hegazi, Refaat] Abbott Nutr, Res & Dev, Columbus, OH 43219 USA. [Hegazi, Refaat] E Carolina Univ, Brody Sch Med, Dept Internal Med, Greenville, NC 27858 USA. RP Hegazi, R (reprint author), Abbott Nutr, 3300 Stelzer Rd, Columbus, OH 43219 USA. EM Refaat.Hegazi@abbott.com FU Abbott Nutrition FX Financial disclosure: Financial support for the publication of the supplement in which this article appears was provided by Abbott Nutrition. NR 13 TC 6 Z9 6 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0148-6071 EI 1941-2444 J9 JPEN-PARENTER ENTER JI J. Parenter. Enter. Nutr. PD NOV PY 2014 VL 38 SU 2 BP 86S EP 91S DI 10.1177/0148607114550315 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AS5MF UT WOS:000344314200010 PM 25227669 ER PT J AU Ananthakrishnan, AN AF Ananthakrishnan, Ashwin N. TI Does Vitamin D Deficiency Inhibit Anti-Tumor Necrosis Factor Therapy in Patients With Irritable Bowel Disease or Does It Simply Result From More Severe Disease? Reply SO JOURNAL OF PARENTERAL AND ENTERAL NUTRITION LA English DT Letter ID CROHNS-DISEASE; REDUCED RISK C1 [Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ananthakrishnan, Ashwin N.] Harvard Univ, Sch Med, Boston, MA USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 4 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0148-6071 EI 1941-2444 J9 JPEN-PARENTER ENTER JI J. Parenter. Enter. Nutr. PD NOV PY 2014 VL 38 IS 8 BP 925 EP 925 DI 10.1177/0148607114533349 PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AS5MI UT WOS:000344314500003 PM 25342587 ER PT J AU Legault, G Kieran, MW Scott, RM Chordas, C Milla, SS Karajannis, MA AF Legault, Genevieve Kieran, Mark W. Scott, Robert Michael Chordas, Christine Milla, Sarah S. Karajannis, Matthias A. TI Recurrent Ascites in a Patient With Low-grade Astrocytoma and Ventriculo-Peritoneal Shunt Treated With the Multikinase Inhibitor Sorafenib SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE pediatric low-grade astrocytoma; ascites; sorafenib; toxicity ID OVARIAN-CANCER; PHASE-II; TUMOR; HYDROCEPHALUS; CARCINOMA; GROWTH; GLIOMA AB This report describes a 6-year-old boy with disseminated low-grade astrocytoma and ventriculo-peritoneal shunt, who developed recurrent ascites while receiving sorafenib on a clinical trial. Laboratory analysis of the peritoneal fluid showed no elevation of protein content and no evidence of underlying infection or tumor dissemination. This report highlights ascites as a previously unrecognized adverse reaction to sorafenib in a patient with a ventriculo-peritoneal shunt. We conclude that such patients should be closely monitored for this complication when treated with sorafenib. C1 [Legault, Genevieve; Karajannis, Matthias A.] NYU Langone Med Ctr, Dept Pediat, New York, NY USA. [Milla, Sarah S.] NYU Langone Med Ctr, Dept Radiol, New York, NY USA. [Kieran, Mark W.] Boston Childrens Hosp, Dept Pediat Oncol, Boston, MA USA. [Scott, Robert Michael] Boston Childrens Hosp, Dept Neurosurg, Boston, MA USA. [Kieran, Mark W.; Chordas, Christine] Dana Farber Canc Inst, Dept Pediat Neurooncol, Boston, MA 02115 USA. RP Karajannis, MA (reprint author), Hassenfeld Childrens Ctr Canc & Blood Disorders, NYU Langone Med Ctr, 160 East 32nd St,2nd Floor, New York, NY 10016 USA. EM matthias.karajannis@nyumc.org FU Pediatric Low-Grade Astrocytoma Foundation; Making Headway Foundation; Bayer HealthCare Pharmaceuticals FX The phase II clinical trial with sorafenib for children and young adults with recurrent or progressive low-grade astrocytomas (ClinicalTrials.gov identifier NCT01338857) was supported by the Pediatric Low-Grade Astrocytoma Foundation, Making Headway Foundation and Bayer HealthCare Pharmaceuticals. NR 19 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 EI 1536-3678 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD NOV PY 2014 VL 36 IS 8 BP E533 EP E535 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AS4DX UT WOS:000344224500013 PM 24351969 ER PT J AU Yager, PH Clark, ME Dapul, HR Murphy, S Zheng, H Noviski, N AF Yager, Phoebe H. Clark, Maureen E. Dapul, Heda R. Murphy, Sarah Zheng, Hui Noviski, Natan TI Reliability of Circulatory and Neurologic Examination by Telemedicine in a Pediatric Intensive Care Unit SO JOURNAL OF PEDIATRICS LA English DT Article AB Objective To test the hypothesis that telemedicine can reliably be used for many aspects of circulatory and neurologic examinations of children admitted to a pediatric intensive care unit (PICU). Study design A prospective, randomized study in a 14-bed PICU in a tertiary care, academic-affiliated institution. Eligible patients were >2 months or <19 years of age, not involved in a concurrent study, had parents/guardian able to sign an informed consent form, were not at end-of-life, and had an attending who not only deemed them medically stable, but also felt that the study would not interrupt their care. Other than the Principal Investigator, 6 pediatric intensivists and 7 pediatric critical care fellows were eligible study providers. Two physician providers were randomly assigned to perform circulatory and neurologic examinations according to the American Heart Association/Pediatric Advanced Life Support guidelines in-person and via telemedicine. Findings were recorded on a standardized data collection form and compared. Results One hundred ten data collection forms were completed. For many aspects of the circulatory and neurologic examinations, outcomes showed substantial to perfect agreement between the in-person and telemedical care providers (kappa = 0.64-1.00). However, assessments of muscle tone had a kappa = 0.23, with a kappa = 0.37 for skin color. Conclusions Telemedicine can reliably identify normal and abnormal findings of many aspects of circulatory and neurologic examinations in PICU patients. This finding opens the door to further studies on the use of telemedicine across other disciplines. C1 [Yager, Phoebe H.; Clark, Maureen E.; Murphy, Sarah; Zheng, Hui; Noviski, Natan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dapul, Heda R.] Maimonides Hosp, Brooklyn, NY 11219 USA. RP Noviski, N (reprint author), Massachusetts Gen Hosp, Dept Pediat, 175 Cambridge St, Boston, MA 02114 USA. EM nnoviski@partners.org NR 19 TC 0 Z9 0 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD NOV PY 2014 VL 165 IS 5 BP 962 EP U403 DI 10.1016/j.jpeds.2014.07.002 PG 10 WC Pediatrics SC Pediatrics GA AS4HP UT WOS:000344235000019 PM 25112695 ER PT J AU Langdon, KJ Leventhal, AM AF Langdon, Kirsten J. Leventhal, Adam M. TI Posttraumatic stress symptoms and tobacco abstinence effects in a non-clinical sample: Evaluating the mediating role of negative affect reduction smoking expectancies SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE Posttraumatic stress; cigarette smoking; nicotine withdrawal; negative affect; abstinence ID RECRUITED DAILY SMOKERS; LAPSE BEHAVIOR; NICOTINE DEPENDENCE; RESIST SMOKING; DISORDER; PTSD; VETERANS; WITHDRAWAL; DEPRESSION; TRAUMA AB The relation between posttraumatic stress symptoms and smoking is well documented but poorly understood. The present investigation sought to evaluate the impact of posttraumatic stress symptoms on subjective and behavioral tobacco abstinence effects both directly and indirectly through negative affect reduction smoking outcome expectancies. Participants included 275 (68.7% male; M-age=43.9, 10+ cig/day) adult non-treatment seeking smokers, who attended two counterbalanced laboratory sessions (16 h of smoking deprivation vs ad libitum smoking), during which they completed self-report measures of withdrawal symptoms and mood followed by a smoking lapse task in which they could earn money for delaying smoking and purchase cigarettes to smoke. Results supported a mediational pathway whereby higher baseline symptoms of posttraumatic stress predicted greater endorsement of expectancies that smoking will effectively reduce negative affect, which in turn predicted greater abstinence-provoked exacerbations in nicotine withdrawal symptoms and negative affect. Posttraumatic stress symptoms also predicted number of cigarettes purchased independent of negative affect reduction expectancies, but did not predict delaying smoking for money. Findings highlight tobacco abstinence effects as a putative mechanism underlying posttraumatic stress disorder (PTSD)-smoking comorbidity, indicate an important mediating role of beliefs for smoking-induced negative affect reduction, and shed light on integrated treatment approaches for these two conditions. C1 [Langdon, Kirsten J.] VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA 02130 USA. [Langdon, Kirsten J.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Leventhal, Adam M.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. RP Langdon, KJ (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, Womens Hlth Sci Div, 150 South Huntington Ave 116B-3, Boston, MA 02130 USA. EM kirsten.langdon@va.gov FU National Research Service Award (NRSA) by National Institute on Drug Abuse [F31DA026634]; National Institute of Health [R01DA026831, K08DA025041] FX This project was supported by a National Research Service Award (NRSA) F31DA026634 awarded to KJ Langdon by the National Institute on Drug Abuse. This work was also supported by grants R01DA026831 and K08DA025041 awarded to AM Leventhal by the National Institute of Health. NR 55 TC 1 Z9 1 U1 1 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 EI 1461-7285 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD NOV PY 2014 VL 28 IS 11 BP 1009 EP 1017 DI 10.1177/0269881114546708 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AS0OG UT WOS:000343976600005 PM 25142407 ER PT J AU Tomar, R Mudumana, SP Pathak, N Hukriede, NA Drummond, IA AF Tomar, Ritu Mudumana, Sudha P. Pathak, Narendra Hukriede, Neil A. Drummond, Iain A. TI osr1 Is Required for Podocyte Development Downstream of wt1a SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CONGENITAL NEPHROTIC SYNDROME; ZEBRAFISH PRONEPHROS; KIDNEY DEVELOPMENT; INTERMEDIATE MESODERM; EXPRESSION ANALYSIS; HOMEOBOX GENE; NEPHRIN GENE; MICE LACKING; CELL FATE; DIFFERENTIATION AB Odd-skipped related 1 (Osr1) encodes a zinc finger transcription factor required for kidney development. Osr1 deficiency in mice results in metanephric kidney agenesis, whereas knockdown or mutation studies in zebrafish revealed that pronephric nephrons require osr1 for proximal tubule and podocyte development. osr1-deficient pronephric podocyte progenitors express the Wilms' tumor suppressor wt1a but do not undergo glomerular morphogenesis or express the foot process junctional markers nephrin and podocin. The function of osr1 in podocyte differentiation remains unclear, however. Here, we found by double fluorescence in situ hybridization that podocyte progenitors coexpress osr1 and wt1a. Knockdown of wt1a disrupted podocyte differentiation and prevented expression of osr1. Blocking retinoic acid signaling, which regulates wt1a, also prevented osr1 expression in podocyte progenitors. Furthermore, unlike the osr1-deficient proximal tubule phenotype, which can be rescued by manipulation of endoderm development, podocyte differentiation was not affected by altered endoderm development, as assessed by nephrin and podocin expression in double osr1/sox32-deficient embryos. These results suggest a different, possibly cell- autonomous requirement for osr1 in podocyte differentiation downstream of wt1a. Indeed, osr1-deficient embryos did not exhibit podocyte progenitor expression of the transcription factor Ihx1a, and forced expression of activated forms of the Ihx1a gene product rescued nephrin expression in osrl-deficient podocytes. Our results place osr1 in a framework of transcriptional regulators that control the expression of podocin and nephrin and thereby mediate podocyte differentiation. C1 [Tomar, Ritu; Mudumana, Sudha P.; Pathak, Narendra; Drummond, Iain A.] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA 02129 USA. [Hukriede, Neil A.] Univ Pittsburgh, Dept Dev Biol, Pittsburgh, PA USA. [Drummond, Iain A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Drummond, IA (reprint author), Massachusetts Gen Hosp, Div Nephrol, 149 13th St,Room 149-8000, Charlestown, MA 02129 USA. EM idrummond@mgh.harvard.edu FU National Institutes of Health [R01-DK071041, 2R01-DK069403, K01-DK078741]; American Heart Association [0625923T] FX The authors acknowledge the support of the Massachusetts General Hospital fish facility staff and technical support from Ms. Yan Liu. This work was supported by the National Institutes of Health grant R01-DK071041 to I.A.D., 2R01-DK069403 to N.A.H., K01-DK078741 to N.P., and the American Heart Association postdoctoral fellowship 0625923T to S.P.M. NR 46 TC 3 Z9 3 U1 1 U2 3 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD NOV PY 2014 VL 25 IS 11 BP 2539 EP 2545 DI 10.1681/ASN.2013121327 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AS1KO UT WOS:000344040300017 PM 24722440 ER PT J AU Chan, KE Thadhani, RI Maddux, FW AF Chan, Kevin E. Thadhani, Ravi I. Maddux, Franklin W. TI Adherence Barriers to Chronic Dialysis in the United States SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID STAGE RENAL-DISEASE; HEMODIALYSIS; DEPRESSION; MORTALITY; HOSPITALIZATION; ASSOCIATIONS; NONADHERENCE; DOPPS; CARE AB Hemodialysis patients often do not attend their scheduled treatment session. We investigated factors associated with missed appointments and whether such nonadherence poses significant harm to patients and increases overall health care utilization in an observational analysis of 44 million hemodialysis treatments for 182,536 patients with ESRD in the United States. We assessed the risk of hospitalization, emergency room visit, or intensive-coronary care unit (ICU-CCU) admission in the 2 days after a missed treatment relative to the risk for patients who received hemodialysis. Over the 5-year study period, the average missed treatment rate was 7.1 days per patient-year. In covariate adjusted logistic regression, the risk of hospitalization (odds ratio [OR], 3.98; 95% confidence interval [95% CI], 3.93 to 4.04), emergency room visit (OR, 2.00; 95% CI, 1.87 to 2.14), or ICU-CCU admission (OR, 3.89; 95% Cl, 3.81 to 3.96) increased significantly after a missed treatment. Overall, 0.9 missed treatment days per year associated with suboptimal transportation to dialysis, inclement weather, holidays, psychiatric illness, pain, and gastrointestinal upset. These barriers also associated with excess hospitalization (5.6 more events per patient-year), emergency room visits (1.1 more visits), and ICU-CCU admissions (0.8 more admissions). In conclusion, poor adherence to hemodialysis treatments may be a substantial roadblock to achieving better patient outcomes. Addressing systemic and patient barriers that impede access to hemodialysis care may decrease missed appointments and reduce patient morbidity. C1 [Chan, Kevin E.; Maddux, Franklin W.] Fresenius Med Care North Amer, Div Clin Res, Waltham, MA 02451 USA. [Chan, Kevin E.; Thadhani, Ravi I.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. RP Chan, KE (reprint author), Fresenius Med Care North Amer, Div Clin Res, 920 Winter St, Waltham, MA 02451 USA. EM kevin.chan@fmc-na.com FU Fresenius Medical Care North America FX K.E.C. and F.W.M. receive salary support from Fresenius Medical Care North America. R.I.T. is a consultant to Fresenius Medical Care North America. The Management Board of Fresenius Medical Care had no role in the design and conduct of this study. NR 14 TC 5 Z9 5 U1 1 U2 10 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD NOV PY 2014 VL 25 IS 11 BP 2642 EP 2648 DI 10.1681/ASN.2013111160 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AS1KO UT WOS:000344040300027 PM 24762400 ER PT J AU Blackhall, F Kim, DW Besse, B Nokihara, H Han, JY Wilner, KD Reisman, A Iyer, S Hirsh, V Shaw, AT AF Blackhall, Fiona Kim, Dong-Wan Besse, Benjamin Nokihara, Hiroshi Han, Ji-Youn Wilner, Keith D. Reisman, Arlene Iyer, Shrividya Hirsh, Vera Shaw, Alice T. TI Patient-Reported Outcomes and Quality of Life in PROFILE 1007: A Randomized Trial of Crizotinib Compared with Chemotherapy in Previously Treated Patients with ALK-Positive Advanced Non-Small-Cell Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Patient-reported outcomes; Quality of life; Crizotinib; Non-small-cell lung cancer ID CLINICAL-TRIALS; PHASE-III; SYMPTOM; ERLOTINIB; ADENOCARCINOMA; GEFITINIB; DISTRESS; AFATINIB; FATIGUE; QLQ-C30 AB Introduction: The main objective of the current post hoc analysis was to compare patient-reported outcomes between crizotinib (N = 172) and chemotherapy subgroups (pemetrexed [N = 99] and docetaxel [N = 72]) in previously treated patients with advanced ALK-positive non-small-cell lung cancer, in PROFILE 1007 study (Pfizer; NCT0093283). Methods: Patient-reported outcomes were assessed at baseline, day 1 of each cycle, and end of treatment. General health status was measured using the EuroQol-5D visual analog scale and health utility index scores were assessed using the EuroQol-5D descriptive system. Functioning, lung cancer symptoms, and global quality of life (QOL) were assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and the QLQ-LC13 lung cancer module. Repeated measures mixed-effects analyses compared overall scores and change from baseline scores, controlling for baseline scores. Results: The overall mean EQ-5D health utility index scores (95% CI) on treatment were significantly greater (p < 0.05) for crizotinib (0.82 [0.79-0.85]) than for chemotherapy (0.73 [0.70-0.77]; 0.74 [0.70-0.79] for pemetrexed and 0.66 [0.58-0.74] for docetaxel). A significantly greater improvement from baseline was observed with crizotinib versus pemetrexed and versus docetaxel treatment groups for general health status, physical functioning, global QOL, dyspnea, fatigue, and pain. Improvement rates for fatigue, cough, pain, dyspnea, and global QOL were significantly greater on crizotinib compared with pemetrexed and docetaxel, respectively. Worsening rates for diarrhea and constipation were higher with crizotinib. Conclusion: The benefits of crizotinib in improving symptoms and QOL are demonstrated regardless of whether the comparator is pemetrexed or docetaxel. C1 [Blackhall, Fiona] Univ Manchester, Inst Canc Sci, Dept Med Oncol, Manchester, Lancs, England. [Blackhall, Fiona] Christie Hosp NHS Fdn Trust, Manchester M20 4BX, Lancs, England. [Kim, Dong-Wan] Seoul Natl Univ Hosp, Dept Internal Med, Seoul 110744, South Korea. [Besse, Benjamin] Inst Gustave Roussy, Dept Thorac Oncol, Villejuif, France. [Nokihara, Hiroshi] Natl Canc Ctr, Tokyo, Japan. [Han, Ji-Youn] Natl Canc Ctr, Ctr Lung Canc, Div Translat & Clin Res, Goyang, South Korea. [Wilner, Keith D.] Pfizer Oncol, Clin Dev, La Jolla, CA USA. [Reisman, Arlene] Pfizer Global Innovat Pharma Business, Biostat, New York, NY USA. [Iyer, Shrividya] Pfizer Oncol, Global Outcomes & Evidence, New York, NY USA. [Hirsh, Vera] McGill Univ, Ctr Hlth, Dept Oncol, Montreal, PQ, Canada. [Shaw, Alice T.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Blackhall, F (reprint author), Christie Hosp NHS Fdn Trust, Dept Med Oncol, Wilmslow Rd, Manchester M20 4BX, Lancs, England. EM Fiona.Blackhall@chris-tie.nhs.ukx RI Blackhall, Fiona/N-2186-2015 OI Blackhall, Fiona/0000-0001-8716-3395 FU Pfizer, Inc. FX Editorial support was provided by Roger Wild at ACUMED (Tytherington, UK) with funding from Pfizer, Inc. Programming support was provided by Pfizer, Inc. NR 27 TC 8 Z9 8 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD NOV PY 2014 VL 9 IS 11 BP 1625 EP 1633 DI 10.1097/JTO.0000000000000318 PG 9 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AS6IT UT WOS:000344368100010 PM 25436797 ER PT J AU Awad, MM Lax, TP Slawski, BR Shaw, AT AF Awad, Mark M. Lax, Timothy P. Slawski, Benjamin R. Shaw, Alice T. TI Successful Desensitization of Two Patients with ALK-Positive Lung Cancer and Hypersensitivity to Crizotinib SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Anaplastic lymphoma kinase; Crizotinib; Hypersensitivity; Desensitization ID CHEMOTHERAPY; EML4-ALK; GENE AB The tyrosine kinase inhibitor crizotinib is an effective therapy for patients with cancers harboring rearrangements of the anaplastic lymphoma kinase (ALK) gene. Here, we describe two patients with advanced ALK-positive lung cancer who developed hypersensitivity to crizotinib, requiring temporary discontinuation of the drug. Both patients were treated with a rapid oral desensitization protocol allowing them to resume crizotinib without further signs or symptoms of hypersensitivity. C1 [Awad, Mark M.; Shaw, Alice T.] Massachusetts Gen Hosp, Dept Med, Div Med Oncol, Boston, MA 02114 USA. [Lax, Timothy P.; Slawski, Benjamin R.] Massachusetts Gen Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Shaw, AT (reprint author), Massachusetts Gen Hosp, Dept Med, Div Med Oncol, Ctr Canc, Yawkey 7B,32 Fruit St, Boston, MA 02114 USA. EM ashaw1@mgh.harvard.edu FU Pfizer; Ariad; Chugai; Novartis; Genentech; Ignyta; Roche; Bristol-Myers Squibb FX Dr. Shaw has served as a paid consultant for Pfizer, Ariad, Chugai, Novartis, Genentech, and Ignyta. Dr. Shaw has also received institutional research funding from Pfizer, Ariad, Novartis, Roche, and Bristol-Myers Squibb. All other authors declare no conflict of interest. NR 11 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 EI 1556-1380 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD NOV PY 2014 VL 9 IS 11 BP 1726 EP 1728 DI 10.1097/JTO.0000000000000350 PG 3 WC Oncology; Respiratory System SC Oncology; Respiratory System GA AS6IT UT WOS:000344368100026 PM 25436807 ER PT J AU Herr, MW Bonanno, A Montalbano, LA Deschler, DG Emerick, KS AF Herr, Marc W. Bonanno, Andrea Montalbano, Lisa A. Deschler, Daniel G. Emerick, Kevin S. TI Shoulder Function Following Reconstruction With the Supraclavicular Artery Island Flap SO LARYNGOSCOPE LA English DT Article DE Head and neck; reconstructive surgery; flaps ID SELECTIVE NECK DISSECTION; MAJOR MYOCUTANEOUS FLAP; DONOR-SITE; HEAD; COMPLICATIONS; NERVE; EXPERIENCE; MORBIDITY AB Objectives/HypothesisThe supraclavicular artery island flap (SCAIF) is a pedicled fasciocutaneous flap used for head and neck reconstruction. In recent years, its use has significantly increased as a result of several advantageous characteristics, including pliability, an excellent color and texture match, ability to reconstruct a variety of skin and aerodigestive tract defects, and short harvest times. Clinical experience suggests that donor site complications are relatively infrequent and typically self-limiting, and there have been no documented cases of prolonged or permanent shoulder dysfunction. However, formal studies have not been performed to assess this outcome. The goal of this study was to evaluate the effects of SCAIF flap harvest on postoperative shoulder strength and flexibility. Study DesignProspective cohort pilot study. MethodsData was gathered prospectively during routine follow-up and surveillance. The Penn Shoulder Score and Constant Shoulder Scale were used to measure subjective and objective outcomes. Physical therapists performed testing for strength and flexibility. ResultsTen patients were evaluated from January to July, 2013. Subjective self-reporting of shoulder function and satisfaction was good to excellent in most patients. The majority of patients demonstrated limitations in range of motion for one or more shoulder movements. Muscle strength was preserved postoperatively. ConclusionHarvest of the SCAIF appears to have limited postoperative morbidity. Postoperative shoulder strength and function appears to be very good; however, some limitation of range of motion was observed. Level of Evidence4 Laryngoscope, 124:2478-2483, 2014 C1 [Herr, Marc W.; Deschler, Daniel G.; Emerick, Kevin S.] Massachusetts Eye & Ear Infirm, Div Head & Neck Surg Oncol & Reconstruct, Boston, MA 02114 USA. [Herr, Marc W.; Deschler, Daniel G.; Emerick, Kevin S.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Bonanno, Andrea; Montalbano, Lisa A.] Massachusetts Gen Hosp, Dept Phys Therapy, Boston, MA 02114 USA. RP Herr, MW (reprint author), Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. EM marc.w.herr@gmail.com NR 38 TC 4 Z9 5 U1 2 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD NOV PY 2014 VL 124 IS 11 BP 2478 EP 2483 DI 10.1002/lary.24761 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA AS6OH UT WOS:000344382100017 PM 24913956 ER PT J AU Chen, MH Blackington, LH Zhou, J Chu, TF Gauvreau, K Marcus, KJ Fisher, DC Diller, LR Ng, AK AF Chen, Ming Hui Blackington, Lauren H. Zhou, Jing Chu, Tammy F. Gauvreau, Kimberlee Marcus, Karen J. Fisher, David C. Diller, Lisa R. Ng, Andrea K. TI Blood pressure is associated with occult cardiovascular disease in prospectively studied Hodgkin lymphoma survivors after chest radiation SO LEUKEMIA & LYMPHOMA LA English DT Article DE Blood pressure; radiation; Hodgkin lymphoma; cardiovascular risk factors; hs-CRP ID CHILDHOOD-CANCER SURVIVOR; CORONARY-ARTERY-DISEASE; MEDIASTINAL IRRADIATION; CARDIAC MORBIDITY; 5-YEAR SURVIVORS; ADULT SURVIVORS; RISK; MORTALITY; RECOMMENDATIONS; INFLAMMATION AB The objectives of this study were to prospectively screen a cohort of asymptomatic long-term survivors of Hodgkin lymphoma (HL) treated with chest irradiation for occult cardiovascular disease (CVD), and correlate screen-detected disease with prospectively measured cardiovascular risk factors (CRFs). A total of 182 HL survivors treated with chest irradiation (median follow-up time 14.8 years) were enrolled and underwent prospective CRF measurement and resting and stress echocardiography to assess coronary artery disease (CAD)/valve disease and left ventricular systolic dysfunction (LVSD). Forty-seven (26%) patients had occult CAD/valve disease and/or LVSD. LVSD was not correlated with CRFs. Controlling for treatment factors, hypertension (odds ratio [OR] = 3.0) and elevated high-sensitivity C-reactive protein (hs-CRP) (OR = 2.7) increased the likelihood of occult CAD/valve disease. Risk of CAD/valve disease rose exponentially with increasing blood pressure (BP) values, even in the normal range. Our findings suggest that BP screening may be useful in determining those survivors at greatest risk for occult CVD. C1 [Chen, Ming Hui; Blackington, Lauren H.; Zhou, Jing; Chu, Tammy F.; Gauvreau, Kimberlee] Boston Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Chen, Ming Hui] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Ng, Andrea K.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Chen, Ming Hui; Gauvreau, Kimberlee; Marcus, Karen J.; Fisher, David C.; Diller, Lisa R.; Ng, Andrea K.] Harvard Univ, Sch Med, Boston, MA USA. [Marcus, Karen J.; Diller, Lisa R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Fisher, David C.] Dana Farber Canc Inst, Dept Hematol Oncol, Boston, MA 02115 USA. RP Chen, MH (reprint author), Boston Childrens Hosp, Dept Cardiol, 300 Longwood Ave, Boston, MA 02115 USA. EM minghui.chen@cardio.chboston.org FU Translational Fund for Research in Cardiology and Oncology, Department of Cardiology, Boston Children's Hospital; Swim-Across-America Foundation FX We gratefully acknowledge the staff of the Perini Survivors Clinic and Adult Survivorship Clinic at Dana-Farber Cancer Institute, in particular Richard Boyajian, NP, for their assistance with patient recruitment. Support from the Translational Fund for Research in Cardiology and Oncology, Department of Cardiology, Boston Children's Hospital and the Swim-Across-America Foundation helped to make this study possible. We appreciate the invaluable contribution of our research assistants, Molly Cook, Elizabeth Abernathey and Siri Kirin Khalsa, in data collection and preparation of this manuscript. Furthermore, we are grateful to our patients with HL whose participation and dedication inspired us. Finally, we acknowledge Dr. Peter M.Mauch's valuable input in the conduction of this study, and for all the patients with HL he has treated and followed over the years that allow the study of late effects in these long-term survivors. NR 28 TC 2 Z9 2 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD NOV PY 2014 VL 55 IS 11 BP 2477 EP 2483 DI 10.3109/10428194.2013.879716 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA AS5XD UT WOS:000344339000011 PM 24397615 ER PT J AU Garcia-Albeniz, X Logan, RW Schrag, D Hernan, MA AF Garcia-Albeniz, Xabier Logan, Roger W. Schrag, Deborah Hernan, Miguel A. TI Evaluation of the Duplication of Staging CT Scans for Localized Colon Cancer in a Medicare Population SO MEDICAL CARE LA English DT Article DE colon cancer; CAT scan; SEER-Medicare; staging; prognosis ID COMBINED ANTIRETROVIRAL THERAPY; HEALTH-CARE; FOLLOW-UP; DIAGNOSIS; COUNTRIES; MORTALITY AB Background: To quantify and characterize duplicated tests performed during the staging of localized colon cancer in the Medicare population. Methods: We used the SEER-Medicare linked database to select patients diagnosed with localized colon cancer between the years 1996 and 2009. We considered a patient as adequately staged after having received a colonoscopy, an abdominal computed tomography (CT) scan, and a pelvic CT scan. Abdominal and pelvic CT scans performed between complete staging and first cancer-directed treatment, if not ordered due to an acute condition, were considered duplicates. We characterized the institutions providing the tests and evaluated the association with survival using a weighted pooled logistic regression adjusted by baseline and time-varying confounders. Results: Of 36,291 patients with a complete staging, 2680 (7.4%) had at least 1 duplicated test. Patients receiving a duplicate had a higher comorbidity score, were more symptomatic, and had more visits to the emergency department and clinical evaluations. They also were treated with surgery less frequently and had worse survival (hazard ratio 1.22, 95% confidence interval, 1.16-1.28). The type of institution involved in the staging (nonprofit/government centers, proprietary centers, free-standing facilities) was not associated with receiving duplicated tests. Conclusions: We found a low frequency of duplicated abdominal or pelvic CT scans in the staging of colon cancer in the Medicare population. C1 [Garcia-Albeniz, Xabier; Logan, Roger W.; Hernan, Miguel A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hernan, Miguel A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Hernan, Miguel A.] Harvard Mit Div Hlth Sci & Technol, Boston, MA USA. RP Garcia-Albeniz, X (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM xabi@post.harvard.edu FU NIH [P01-CA134294]; ASISA Fellowship; National Cancer Institute's Surveillance, Epidemiology and End Results Program [N01-PC-35136, N01-PC-35139, N02-PC-15105]; Centers for Disease Control and Prevention's National Program of Cancer Registries [U55/CCR921930-02] FX Partly funded by NIH grant P01-CA134294. X.G.-A. is a recipient of an "ASISA Fellowship." The collection of the California 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 under contract N01-PC-35136 awarded to the Northern California Cancer Center, contract N01-PC-35139 awarded to the University of Southern California, and contract N02-PC-15105 awarded to the Public Health Institute; and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement #U55/CCR921930-02 awarded to the Public Health Institute. NR 22 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD NOV PY 2014 VL 52 IS 11 BP 963 EP 968 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AR9XL UT WOS:000343930300005 PM 25226545 ER PT J AU Quinones, AR Ramsey, K Newsom, JT Dorr, DA AF Quinones, Ana R. Ramsey, Katrina Newsom, Jason T. Dorr, David A. TI Racial and Ethnic Differences in Clinical Outcome Trajectories for Care Managed Patients SO MEDICAL CARE LA English DT Article DE racial/ethnic differences; complex care patients; multimorbidity; hemoglobin A1c; blood pressure; multilevel modeling ID RANDOMIZED CONTROLLED-TRIAL; HEALTH-CARE; MEXICAN-AMERICANS; MULTIMORBIDITY; QUALITY; HOSPITALIZATION; CONSEQUENCES; PREVALENCE; DISEASES; SENIORS AB Background: Care management has demonstrated improvements in quality of care for patients with complex care needs. The extent to which these interventions benefit race/ethnic minority populations is unclear. Objectives: To characterize race/ethnic differences in the longitudinal control of clinical outcomes for patients with complex care needs enrolled in Care Management Plus, a health information technology-enabled care coordination intervention. Research Design: Multilevel models of repeated observations from clinical encounters before and after program enrollment for 6 Oregon and California primary care clinics. Subjects: A total of 18,675 clinic patients were examined. We estimated multilevel models for 1481 and 5320 care-managed individuals with repeated hemoglobin A1c and blood pressure measurements, respectively. Measures: Primary outcomes were changes over time for 2 clinical markers of health status for complex care patients: (1) hemoglobin A1c for patients with diabetes; and (2) mid-blood pressure (BP) (average systolic and diastolic blood pressure). Results: We found significant reductions in A1c for patients with previously uncontrolled A1c (preperiod slope, b = 1.03 [0.83, 1.24]; postperiod slope, b = -0.63 [-0.91, -0.35]). For mid-BP we found increasing unconditional preperiod trajectories (b = 3.52 [2.39, 4.64]) and decreasing postperiod trajectories (b= -5.21 [-5.70, -4.72]). We also found the trajectories of A1c and mid-BP were not statistically different for black, Latino, and white patients. Conclusions: These analyses demonstrate some promising results for intermediate clinical outcomes for underrepresented patients with complex chronic care needs. It remains to be seen whether these health care system delivery redesigns yield long-term benefits for patients, such as improvements in function and quality of life. C1 [Quinones, Ana R.; Ramsey, Katrina] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA. [Quinones, Ana R.] Portland VA Med Ctr, Portland, OR USA. [Newsom, Jason T.] Portland State Univ, Sch Community Hlth, Portland, OR 97207 USA. [Newsom, Jason T.] Portland State Univ, Inst Aging, Portland, OR 97207 USA. [Dorr, David A.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. RP Quinones, AR (reprint author), Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM quinones@ohsu.edu FU Medical Research Foundation of Oregon [MRF-1217]; American Diabetes Association [ADA 7-13-CD-08]; Programs to Increase Diversity among Individuals Engaged in Health Related-Research [NIH/NHLBI R25HL105430] FX Supported by the Medical Research Foundation of Oregon (MRF-1217, Quinones PI) and the American Diabetes Association (ADA 7-13-CD-08, Quinones PI). A.R.Q. was also supported by the Programs to Increase Diversity among Individuals Engaged in Health Related-Research (NIH/NHLBI R25HL105430). The views expressed in this article are those of the authors and do not necessarily represent the views of the Medical Research Foundation, the National Institutes of Health, or the American Diabetes Association. NR 33 TC 1 Z9 1 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 EI 1537-1948 J9 MED CARE JI Med. Care PD NOV PY 2014 VL 52 IS 11 BP 998 EP 1005 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AR9XL UT WOS:000343930300010 PM 25304019 ER PT J AU Pozdnyakova, O Wu, KD Patki, A Rodig, SJ Thiele, J Hasserjian, RP AF Pozdnyakova, Olga Wu, Kaida Patki, Abhay Rodig, Scott J. Thiele, Juergen Hasserjian, Robert P. TI High concordance in grading reticulin fibrosis and cellularity in patients with myeloproliferative neoplasms SO MODERN PATHOLOGY LA English DT Article DE anti-JAK2 therapy; bone marrow; collagen deposition; hematopoietic cellularity; inter-rater agreement; reticulin fibrosis ID CHRONIC IDIOPATHIC MYELOFIBROSIS; BONE-MARROW FIBROSIS; INTERNATIONAL WORKING GROUP; REVISED RESPONSE CRITERIA; PLACEBO-CONTROLLED TRIAL; ESSENTIAL THROMBOCYTHEMIA; POLYCYTHEMIA-VERA; EUROPEAN CONSENSUS; FOLLOW-UP; IWG-MRT AB The myeloproliferative neoplasms primary myelofibrosis, polycythemia vera, and, rarely, essential thrombocythemia are characterized by variable degrees of bone marrow fibrosis, either at presentation or upon progression. The increasing use of emerging therapies that may alter disease biology and morphology demands accurate and reproducible assessment of fibrosis grade. To assess concordance of hematopoietic cellularity and fibrosis grading, three hematopathologists independently evaluated a total of 728 bone marrow biopsies from 261 patients with myeloproliferative neoplasms on three clinical trials using fedratinib (SAR302503), a JAK2 inhibitor, including 249 taken at baseline and 479 on therapy. Concordance between the pathologists was evaluated by Pearson correlation coefficient (cellularity) and unweighted kappa statistic (fibrosis grade). There was high correlation of cellularity assessment (r = 0.92) and fibrosis grading (kappa = 0.83) between the three pathologists. Concordance with World Health Organization (WHO) grade 3 samples was higher compared with grades 0, 1, and 2. Concordance of fibrosis grading in pretreatment samples was superior to that of post-treatment samples (kappa = 0.83 and 0.79, respectively, P = 0.023). Our analysis suggests that the updated 2008 WHO reticulin fibrosis grading system is highly reproducible, even in patients undergoing JAK2 inhibitor therapy. This system is practically applicable to establish baseline fibrosis grade as well as changes in fibrosis in subsequent samples on therapy. C1 [Pozdnyakova, Olga; Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Wu, Kaida; Patki, Abhay] Sanofi Oncol, Cambridge, MA USA. [Thiele, Juergen] Univ Cologne, D-50931 Cologne, Germany. [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Hasserjian, RP (reprint author), Massachusetts Gen Hosp, Dept Pathol, WRN244,55 Fruit St, Boston, MA 02114 USA. EM rhasserjian@partners.org NR 51 TC 10 Z9 10 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 EI 1530-0285 J9 MODERN PATHOL JI Mod. Pathol. PD NOV PY 2014 VL 27 IS 11 BP 1447 EP 1454 DI 10.1038/modpathol.2014.69 PG 8 WC Pathology SC Pathology GA AS7HW UT WOS:000344428500003 PM 24762543 ER PT J AU Wood, AR Esko, T Yang, J Vedantam, S Pers, TH Gustafsson, S Chun, AY Estrada, K Luan, J Kutalik, Z Amin, N Buchkovich, ML Croteau-Chonka, DC Day, FR Duan, Y Fall, T Fehrmann, R Ferreira, T Jackson, AU Karjalainen, J Lo, KS Locke, AE Magi, R Mihailov, E Porcu, E Randall, JC Scherag, A Vinkhuyzen, AAE Westra, HJ Winkler, TW Workalemahu, T Zhao, JH Absher, D Albrecht, E Anderson, D Baron, J Beekman, M Demirkan, A Ehret, GB Feenstra, B Feitosa, MF Fischer, K Fraser, RM Goel, A Gong, J Justice, AE Kanoni, S Kleber, ME Kristiansson, K Lim, U Lotay, V Lui, JC Mangino, M Leach, IM Medina-Gomez, C Nalls, MA Nyholt, DR Palmer, CD Pasko, D Pechlivanis, S Prokopenko, I Ried, JS Ripke, S Shungin, D Stancakova, A Strawbridge, RJ Sung, YJ Tanaka, T Teumer, A Trompet, S van der Laan, SW van Setten, J Van Vliet-Ostaptchouk, JV Wang, ZM Yengo, L Zhang, WH Afzal, U Arnlov, J Arscott, GM Bandinelli, S Barrett, A Bellis, C Bennett, AJ Berne, C Bluher, M Bolton, JL Bottcher, Y Boyd, HA Bruinenberg, M Buckley, BM Buyske, S Caspersen, IH Chines, PS Clarke, R Claudi-Boehm, S Cooper, M Daw, EW De Jong, PA Deelen, J Delgado, G Denny, JC Dhonukshe-Rutten, R Dimitriou, M Doney, ASF Dorr, M Eklund, N Eury, E Folkersen, L Garcia, ME Geller, F Giedraitis, V Go, AS Grallert, H Grammer, TB Grassler, J Gronberg, H de Groot, LCPGM Groves, CJ Haessler, J Hall, P Haller, T Hallmans, G Hannemann, A Hartman, CA Hassinen, M Hayward, C Heard-Costa, NL Helmer, Q Hemani, G Henders, AK Hillege, HL Hlatky, MA Hoffmann, W Hoffmann, P Holmen, O Houwing-Duistermaat, JJ Illig, T Isaacs, A James, AL Jeff, J Johansen, B Johansson, A Jolley, J Juliusdottir, T Junttila, J Kho, AN Kinnunen, L Klopp, N Kocher, T Kratzer, W Lichtner, P Lind, L Lindstrom, J Lobbens, S Lorentzon, M Lu, YC Lyssenko, V Magnusson, PKE Mahajan, A Maillard, M McArdle, WL McKenzie, CA McLachlan, S McLaren, PJ Menni, C Merger, S Milani, L Moayyeri, A Monda, KL Morken, MA Muller, G Muller-Nurasyid, M Musk, AW Narisu, N Nauck, M Nolte, IM Nothen, MM Oozageer, L Pilz, S Rayner, NW Renstrom, F Robertson, NR Rose, LM Roussel, R Sanna, S Scharnagl, H Scholtens, S Schumacher, FR Schunkert, H Scott, RA Sehmi, J Seufferlein, T Shin, JX Silventoinen, K Smit, JH Smith, AV Smolonska, J Stanton, AV Stirrups, K Stott, DJ Stringham, HM Sundstrom, J Swertz, MA Syvanen, AC Tayo, BO Thorleifsson, G Tyrer, JP van Dijk, S van Schoor, NM van der Velde, N van Heemst, D van Oort, FVA Vermeulen, SH Verweij, N Vonk, JM Waite, LL Waldenberger, M Wennauer, R Wilkens, LR Willenborg, C Wilsgaard, T Wojczynski, MK Wong, A Wright, AF Zhang, QY Arveiler, D Bakker, SJL Beilby, J Bergman, RN Bergmann, S Biffar, R Blangero, J Boomsma, DI Bornstein, SR Bovet, P Brambilla, P Brown, MJ Campbell, H Caulfield, MJ Chakravarti, A Collins, R Collins, FS Crawford, DC Cupples, LA Danesh, J de Faire, U den Ruijter, HM Erbel, R Erdmann, J Eriksson, JG Farrall, M Ferrannini, E Ferrieres, J Ford, I Forouhi, NG Forrester, T Gansevoort, RT Gejman, PV Gieger, C Golay, A Gottesman, O Gudnason, V Gyllensten, U Haas, DW Hall, AS Harris, TB Hattersley, AT Heath, AC Hengstenberg, C Hicks, AA Hindorff, LA Hingorani, AD Hofman, A Hovingh, GK Humphries, SE Hunt, SC Hypponen, E Jacobs, KB Jarvelin, MR Jousilahti, P Jula, AM Kaprio, J Kastelein, JJP Kayser, M Kee, F Keinanen-Kiukaanniemi, SM Kiemeney, LA Kooner, JS Kooperberg, C Koskinen, S Kovacs, P Kraja, AT Kumari, M Kuusisto, J Lakka, TA Langenberg, C Le Marchand, L Lehtimaki, T Lupoli, S Madden, PAF Mannisto, S Manunta, P Marette, A Matise, TC McKnight, B Meitinger, T Moll, FL Montgomery, GW Morris, AD Morris, AP Murray, JC Nelis, M Ohlsson, C Oldehinkel, AJ Ong, KK Ouwehand, WH Pasterkamp, G Peters, A Pramstaller, PP Price, JF Qi, L Raitakari, OT Rankinen, T Rao, DC Rice, TK Ritchie, M Rudan, I Salomaa, V Samani, NJ Saramies, J Sarzynski, MA Schwarz, PEH Sebert, S Sever, P Shuldiner, AR Sinisalo, J Steinthorsdottir, V Stolk, RP Tardif, JC Tonjes, A Tremblay, A Tremoli, E Virtamo, J Vohl, MC Amouyel, P Asselbergs, FW Assimes, TL Bochud, M Boehm, BO Boerwinkle, E Bottinger, EP Bouchard, C Cauchi, S Chambers, JC Chanock, SJ Cooper, RS de Bakker, PIW Dedoussis, G Ferrucci, L Franks, PW Froguel, P Groop, LC Haiman, CA Hamsten, A Hayes, MG Hui, J Hunter, DJ Hveem, K Jukema, JW Kaplan, RC Kivimaki, M Kuh, D Laakso, M Liu, YM Martin, NG Marz, W Melbye, M Moebus, S Munroe, PB Njolstad, I Oostra, BA Palmer, CNA Pedersen, NL Perola, M Perusse, L Peters, U Powell, JE Power, C Quertermous, T Rauramaa, R Reinmaa, E Ridker, PM Rivadeneira, F Rotter, JI Saaristo, TE Saleheen, D Schlessinger, D Slagboom, PE Snieder, H Spector, TD Strauch, K Stumvoll, M Tuomilehto, J Uusitupa, M van der Harst, P Volzke, H Walker, M Wareham, NJ Watkins, H Wichmann, HE Wilson, JF Zanen, P Deloukas, P Heid, IM Lindgren, CM Mohlke, KL Speliotes, EK Thorsteinsdottir, U Barroso, I Fox, CS North, KE Strachan, DP Beckmann, JS Berndt, SI Boehnke, M Borecki, IB McCarthy, MI Metspalu, A Stefansson, K Uitterlinden, AG van Duijn, CM Franke, L Willer, CJ Price, AL Lettre, G Loos, RJF Weedon, MN Ingelsson, E O'Connell, JR Abecasis, GR Chasman, DI Goddard, ME Visscher, PM Hirschhorn, JN Frayling, TM AF Wood, Andrew R. Esko, Tonu Yang, Jian Vedantam, Sailaja Pers, Tune H. Gustafsson, Stefan Chun, Audrey Y. Estrada, Karol Luan, Jian'an Kutalik, Zoltan Amin, Najaf Buchkovich, Martin L. Croteau-Chonka, Damien C. Day, Felix R. Duan, Yanan Fall, Tove Fehrmann, Rudolf Ferreira, Teresa Jackson, Anne U. Karjalainen, Juha Lo, Ken Sin Locke, Adam E. Maegi, Reedik Mihailov, Evelin Porcu, Eleonora Randall, Joshua C. Scherag, Andre Vinkhuyzen, Anna A. E. Westra, Harm-Jan Winkler, Thomas W. Workalemahu, Tsegaselassie Zhao, Jing Hua Absher, Devin Albrecht, Eva Anderson, Denise Baron, Jeffrey Beekman, Marian Demirkan, Ayse Ehret, Georg B. Feenstra, Bjarke Feitosa, Mary F. Fischer, Krista Fraser, Ross M. Goel, Anuj Gong, Jian Justice, Anne E. Kanoni, Stavroula Kleber, Marcus E. Kristiansson, Kati Lim, Unhee Lotay, Vaneet Lui, Julian C. Mangino, Massimo Leach, Irene Mateo Medina-Gomez, Carolina Nalls, Michael A. Nyholt, Dale R. Palmer, Cameron D. Pasko, Dorota Pechlivanis, Sonali Prokopenko, Inga Ried, Janina S. Ripke, Stephan Shungin, Dmitry Stancakova, Alena Strawbridge, Rona J. Sung, Yun Ju Tanaka, Toshiko Teumer, Alexander Trompet, Stella van der Laan, Sander W. van Setten, Jessica Van Vliet-Ostaptchouk, Jana V. Wang, Zhaoming Yengo, Loic Zhang, Weihua Afzal, Uzma Arnloev, Johan Arscott, Gillian M. Bandinelli, Stefania Barrett, Amy Bellis, Claire Bennett, Amanda J. Berne, Christian Blueher, Matthias Bolton, Jennifer L. Boettcher, Yvonne Boyd, Heather A. Bruinenberg, Marcel Buckley, Brendan M. Buyske, Steven Caspersen, Ida H. Chines, Peter S. Clarke, Robert Claudi-Boehm, Simone Cooper, Matthew Daw, E. Warwick De Jong, Pim A. Deelen, Joris Delgado, Graciela Denny, Josh C. Dhonukshe-Rutten, Rosalie Dimitriou, Maria Doney, Alex S. F. Doerr, Marcus Eklund, Niina Eury, Elodie Folkersen, Lasse Garcia, Melissa E. Geller, Frank Giedraitis, Vilmantas Go, Alan S. Grallert, Harald Grammer, Tanja B. Graessler, Juergen Groenberg, Henrik de Groot, Lisette C. P. G. M. Groves, Christopher J. Haessler, Jeffrey Hall, Per Haller, Toomas Hallmans, Goran Hannemann, Anke Hartman, Catharina A. Hassinen, Maija Hayward, Caroline Heard-Costa, Nancy L. Helmer, Quinta Hemani, Gibran Henders, Anjali K. Hillege, Hans L. Hlatky, Mark A. Hoffmann, Wolfgang Hoffmann, Per Holmen, Oddgeir Houwing-Duistermaat, Jeanine J. Illig, Thomas Isaacs, Aaron James, Alan L. Jeff, Janina Johansen, Bent Johansson, Asa Jolley, Jennifer Juliusdottir, Thorhildur Junttila, Juhani Kho, Abel N. Kinnunen, Leena Klopp, Norman Kocher, Thomas Kratzer, Wolfgang Lichtner, Peter Lind, Lars Lindstroem, Jaana Lobbens, Stephane Lorentzon, Mattias Lu, Yingchang Lyssenko, Valeriya Magnusson, Patrik K. E. Mahajan, Anubha Maillard, Marc McArdle, Wendy L. McKenzie, Colin A. McLachlan, Stela McLaren, Paul J. Menni, Cristina Merger, Sigrun Milani, Lili Moayyeri, Alireza Monda, Keri L. Morken, Mario A. Mueller, Gabriele Mueller-Nurasyid, Martina Musk, Arthur W. Narisu, Narisu Nauck, Matthias Nolte, Ilja M. Noethen, Markus M. Oozageer, Laticia Pilz, Stefan Rayner, Nigel W. Renstrom, Frida Robertson, Neil R. Rose, Lynda M. Roussel, Ronan Sanna, Serena Scharnagl, Hubert Scholtens, Salome Schumacher, Fredrick R. Schunkert, Heribert Scott, Robert A. Sehmi, Joban Seufferlein, Thomas Shin, Jianxin Silventoinen, Karri Smit, Johannes H. Smith, Albert Vernon Smolonska, Joanna Stanton, Alice V. Stirrups, Kathleen Stott, David J. Stringham, Heather M. Sundstrom, Johan Swertz, Morris A. Syvanen, Ann-Christine Tayo, Bamidele O. Thorleifsson, Gudmar Tyrer, Jonathan P. van Dijk, Suzanne van Schoor, Natasja M. van der Velde, Nathalie van Heemst, Diana van Oort, Floor V. A. Vermeulen, Sita H. Verweij, Niek Vonk, Judith M. Waite, Lindsay L. Waldenberger, Melanie Wennauer, Roman Wilkens, Lynne R. Willenborg, Christina Wilsgaard, Tom Wojczynski, Mary K. Wong, Andrew Wright, Alan F. Zhang, Qunyuan Arveiler, Dominique Bakker, Stephan J. L. Beilby, John Bergman, Richard N. Bergmann, Sven Biffar, Reiner Blangero, John Boomsma, Dorret I. Bornstein, Stefan R. Bovet, Pascal Brambilla, Paolo Brown, Morris J. Campbell, Harry Caulfield, Mark J. Chakravarti, Aravinda Collins, Rory Collins, Francis S. Crawford, Dana C. Cupples, L. Adrienne Danesh, John de Faire, Ulf den Ruijter, Hester M. Erbel, Raimund Erdmann, Jeanette Eriksson, Johan G. Farrall, Martin Ferrannini, Ele Ferrieres, Jean Ford, Ian Forouhi, Nita G. Forrester, Terrence Gansevoort, Ron T. Gejman, Pablo V. Gieger, Christian Golay, Alain Gottesman, Omri Gudnason, Vilmundur Gyllensten, Ulf Haas, David W. Hall, Alistair S. Harris, Tamara B. Hattersley, Andrew T. Heath, Andrew C. Hengstenberg, Christian Hicks, Andrew A. Hindorff, Lucia A. Hingorani, Aroon D. Hofman, Albert Hovingh, G. Kees Humphries, Steve E. Hunt, Steven C. Hypponen, Elina Jacobs, Kevin B. Jarvelin, Marjo-Riitta Jousilahti, Pekka Jula, Antti M. Kaprio, Jaakko Kastelein, John J. P. Kayser, Manfred Kee, Frank Keinanen-Kiukaanniemi, Sirkka M. Kiemeney, Lambertus A. Kooner, Jaspal S. Kooperberg, Charles Koskinen, Seppo Kovacs, Peter Kraja, Aldi T. Kumari, Meena Kuusisto, Johanna Lakka, Timo A. Langenberg, Claudia Le Marchand, Loic Lehtimaki, Terho Lupoli, Sara Madden, Pamela A. F. Mannisto, Satu Manunta, Paolo Marette, Andre Matise, Tara C. McKnight, Barbara Meitinger, Thomas Moll, Frans L. Montgomery, Grant W. Morris, Andrew D. Morris, Andrew P. Murray, Jeffrey C. Nelis, Mari Ohlsson, Claes Oldehinkel, Albertine J. Ong, Ken K. Ouwehand, Willem H. Pasterkamp, Gerard Peters, Annette Pramstaller, Peter P. Price, Jackie F. Qi, Lu Raitakari, Olli T. Rankinen, Tuomo Rao, D. C. Rice, Treva K. Ritchie, Marylyn Rudan, Igor Salomaa, Veikko Samani, Nilesh J. Saramies, Jouko Sarzynski, Mark A. Schwarz, Peter E. H. Sebert, Sylvain Sever, Peter Shuldiner, Alan R. Sinisalo, Juha Steinthorsdottir, Valgerdur Stolk, Ronald P. Tardif, Jean-Claude Toenjes, Anke Tremblay, Angelo Tremoli, Elena Virtamo, Jarmo Vohl, Marie-Claude Amouyel, Philippe Asselbergs, Folkert W. Assimes, Themistocles L. Bochud, Murielle Boehm, Bernhard O. Boerwinkle, Eric Bottinger, Erwin P. Bouchard, Claude Cauchi, Stephane Chambers, John C. Chanock, Stephen J. Cooper, Richard S. de Bakker, Paul I. W. Dedoussis, George Ferrucci, Luigi Franks, Paul W. Froguel, Philippe Groop, Leif C. Haiman, Christopher A. Hamsten, Anders Hayes, M. Geoffrey Hui, Jennie Hunter, David J. Hveem, Kristian Jukema, J. Wouter Kaplan, Robert C. Kivimaki, Mika Kuh, Diana Laakso, Markku Liu, Yongmei Martin, Nicholas G. Maerz, Winfried Melbye, Mads Moebus, Susanne Munroe, Patricia B. Njolstad, Inger Oostra, Ben A. Palmer, Colin N. A. Pedersen, Nancy L. Perola, Markus Perusse, Louis Peters, Ulrike Powell, Joseph E. Power, Chris Quertermous, Thomas Rauramaa, Rainer Reinmaa, Eva Ridker, Paul M. Rivadeneira, Fernando Rotter, Jerome I. Saaristo, Timo E. Saleheen, Danish Schlessinger, David Slagboom, P. Eline Snieder, Harold Spector, Tim D. Strauch, Konstantin Stumvoll, Michael Tuomilehto, Jaakko Uusitupa, Matti van der Harst, Pim Voelzke, Henry Walker, Mark Wareham, Nicholas J. Watkins, Hugh Wichmann, H-Erich Wilson, James F. Zanen, Pieter Deloukas, Panos Heid, Iris M. Lindgren, Cecilia M. Mohlke, Karen L. Speliotes, Elizabeth K. Thorsteinsdottir, Unnur Barroso, Ines Fox, Caroline S. North, Kari E. Strachan, David P. Beckmann, Jacques S. Berndt, Sonja I. Boehnke, Michael Borecki, Ingrid B. McCarthy, Mark I. Metspalu, Andres Stefansson, Kari Uitterlinden, Andre G. van Duijn, Cornelia M. Franke, Lude Willer, Cristen J. Price, Alkes L. Lettre, Guillaume Loos, Ruth J. F. Weedon, Michael N. Ingelsson, Erik O'Connell, Jeffrey R. Abecasis, Goncalo R. Chasman, Daniel I. Goddard, Michael E. Visscher, Peter M. Hirschhorn, Joel N. Frayling, Timothy M. CA Elect Med Records & Genom eMERGE C MIGen Consortium PAGE Consortium LifeLines Cohort Study TI Defining the role of common variation in the genomic and biological architecture of adult human height SO NATURE GENETICS LA English DT Article ID GENETIC-VARIATION; COMPLEX TRAITS; HERITABILITY; MUTATIONS; SNPS AB Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated similar to 2,000, similar to 3,700 and similar to 9,500 SNPs explained similar to 21%, similar to 24% and similar to 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants. C1 [Wood, Andrew R.; Pasko, Dorota; Weedon, Michael N.; Frayling, Timothy M.] Univ Exeter, Sch Med, Exeter, Devon, England. [Esko, Tonu; Maegi, Reedik; Mihailov, Evelin; Fischer, Krista; Haller, Toomas; Milani, Lili; Morris, Andrew P.; Nelis, Mari; Perola, Markus; Reinmaa, Eva; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. 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[Albrecht, Eva; Ried, Janina S.; Grallert, Harald; Mueller-Nurasyid, Martina; Gieger, Christian; Strauch, Konstantin] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, Neuherberg, Germany. [Anderson, Denise; Cooper, Matthew] Univ Western Australia, Telethon Inst Child Hlth Res, Ctr Child Hlth Res, Perth, WA 6009, Australia. [Baron, Jeffrey; Lui, Julian C.] US Natl Inst Hlth, Program Dev Endocrinol & Genet, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Growth & Dev, Bethesda, MD USA. [Beekman, Marian; Deelen, Joris; Helmer, Quinta; Houwing-Duistermaat, Jeanine J.; van Heemst, Diana; Slagboom, P. Eline] Leiden Univ, Med Ctr, Netherlands Consortium Hlth Aging, Leiden, Netherlands. [Beekman, Marian; Deelen, Joris; Slagboom, P. Eline] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands. [Demirkan, Ayse] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Ehret, Georg B.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Ehret, Georg B.] Univ Hosp Geneva, Dept Specialties Internal Med, Div Cardiol, Geneva, Switzerland. [Feenstra, Bjarke; Boyd, Heather A.; Geller, Frank; Melbye, Mads] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. [Feitosa, Mary F.; Daw, E. Warwick; Wojczynski, Mary K.; Zhang, Qunyuan; Kraja, Aldi T.; Rao, D. C.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Fraser, Ross M.; Bolton, Jennifer L.; McLachlan, Stela; Campbell, Harry; Price, Jackie F.; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Goel, Anuj; Farrall, Martin; Watkins, Hugh] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England. [Gong, Jian; Haessler, Jeffrey; Kooperberg, Charles; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Justice, Anne E.; Monda, Keri L.; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Kanoni, Stavroula; Deloukas, Panos] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England. [Kleber, Marcus E.; Delgado, Graciela; Grammer, Tanja B.; Maerz, Winfried] Heidelberg Univ, Med Fac Mannheim, Dept Med Nephrol Hypertens Endocrinol Diabet Rheu, Heidelberg, Germany. [Kleber, Marcus E.] Univ Ulm, Med Ctr, Dept Internal Med 2, D-89069 Ulm, Germany. [Kristiansson, Kati; Eklund, Niina; Kinnunen, Leena; Lindstroem, Jaana; Thorleifsson, Gudmar; Jousilahti, Pekka; Jula, Antti M.; Kaprio, Jaakko; Koskinen, Seppo; Mannisto, Satu; Salomaa, Veikko; Virtamo, Jarmo; Perola, Markus; Tuomilehto, Jaakko] Natl Inst Hlth & Welf, Helsinki, Finland. [Lim, Unhee; Wilkens, Lynne R.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Lotay, Vaneet; Jeff, Janina; Lu, Yingchang; Gottesman, Omri; Bottinger, Erwin P.; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA. [Mangino, Massimo; Menni, Cristina; Moayyeri, Alireza; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England. [Leach, Irene Mateo; Hillege, Hans L.; Verweij, Niek; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Medina-Gomez, Carolina; Hofman, Albert; Kayser, Manfred; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijn, Cornelia M.] Netherlands Consortium Hlth Aging, Rotterdam, Netherlands. [Medina-Gomez, Carolina; Rivadeneira, Fernando; Uitterlinden, Andre G.; van Duijn, Cornelia M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Nalls, Michael A.] NIA, Neurogenet Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Nyholt, Dale R.; Henders, Anjali K.; Montgomery, Grant W.; Martin, Nicholas G.] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia. [Prokopenko, Inga; Barrett, Amy; Bennett, Amanda J.; Groves, Christopher J.; Rayner, Nigel W.; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Prokopenko, Inga; Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Ripke, Stephan] Broad Inst & Harvard Univ, Stanley Ctr Psychiat Res, Cambridge, MA 02139 USA. [Shungin, Dmitry; Renstrom, Frida; Franks, Paul W.] Lund Univ, Skane Univ Hosp, Ctr Diabet, Department Clin Sci,Genet & Mol Epidemiol Unit, Malmo, Sweden. [Shungin, Dmitry; Franks, Paul W.] Umea Univ, Dept Publ Hlth & Clin Med, Med Unit, Umea, Sweden. [Shungin, Dmitry] Umea Univ, Dept Odontol, Umea, Sweden. [Stancakova, Alena] Univ Eastern Finland, Dept Med, Kuopio, Finland. [Strawbridge, Rona J.; Folkersen, Lasse; Hamsten, Anders] Karolinska Inst, Ctr Mol Med, Atherosclerosis Res Unit, Dept Med, Stockholm, Sweden. [Sung, Yun Ju; Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA. [Teumer, Alexander] Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Trompet, Stella; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. [Trompet, Stella; van Heemst, Diana] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands. [van der Laan, Sander W.; den Ruijter, Hester M.; Pasterkamp, Gerard] Univ Med Ctr Utrecht, Div Heart & Lungs, Expt Cardiol Lab, Utrecht, Netherlands. [van Setten, Jessica; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Van Vliet-Ostaptchouk, Jana V.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands. [Wang, Zhaoming; Doerr, Marcus; Hoffmann, Wolfgang; Nauck, Matthias; Voelzke, Henry] DZHK Deutsch Zentrum Herz Kreislaufforschung, German Ctr Cardiovasc Res, Greifswald, Germany. [Wang, Zhaoming; Hannemann, Anke; Nauck, Matthias] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Wang, Zhaoming; Jacobs, Kevin B.; Chanock, Stephen J.; Berndt, Sonja I.] US Natl Inst Hlth, NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Wang, Zhaoming; Jacobs, Kevin B.] SAIC Frederick Inc, NCI Frederick, Core Genotyping Facil, Frederick, MD USA. [Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Cauchi, Stephane; Froguel, Philippe] CNRS, UMR 8199, Lille, France. [Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Cauchi, Stephane; Froguel, Philippe] European Genom Inst Diabet, Lille, France. [Yengo, Loic; Eury, Elodie; Lobbens, Stephane; Cauchi, Stephane; Froguel, Philippe] Univ Lille 2, Lille, France. [Zhang, Weihua; Afzal, Uzma; Sehmi, Joban; Jarvelin, Marjo-Riitta; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England. [Arnloev, Johan] Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden. [Arscott, Gillian M.; Beilby, John; Hui, Jennie] PathWest Lab Med Western Australia, Nedlands, WA, Australia. [Bandinelli, Stefania] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy. [Bellis, Claire; Blangero, John] Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA. [Berne, Christian] Uppsala Univ, Dept Med Sci Endocrinol Diabet & Metab, Uppsala, Sweden. [Blueher, Matthias; Boettcher, Yvonne; Kovacs, Peter; Toenjes, Anke; Stumvoll, Michael] Univ Leipzig, Integrated Res & Treatment Ctr IFB Adipos Dis, D-04109 Leipzig, Germany. [Blueher, Matthias; Kovacs, Peter; Toenjes, Anke; Stumvoll, Michael] Univ Leipzig, Dept Med, D-04109 Leipzig, Germany. [Bruinenberg, Marcel] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Buckley, Brendan M.] Univ Coll Cork, Dept Pharm & Therapeut, Cork, Ireland. [Buyske, Steven] Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ USA. [Buyske, Steven; Matise, Tara C.] Rutgers State Univ, Dept Genet, Piscataway, NJ USA. [Caspersen, Ida H.; Johansen, Bent] Norwegian Univ Sci & Technol, Dept Biol, N-7034 Trondheim, Norway. [Chines, Peter S.; Morken, Mario A.; Narisu, Narisu; Collins, Francis S.] US Natl Inst Hlth, NHGRI, Genome Technol Branch, Bethesda, MD USA. [Clarke, Robert; Collins, Rory] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Clin Trial Serv Unit, Oxford, England. [Claudi-Boehm, Simone; Merger, Sigrun; Boehm, Bernhard O.] Univ Ulm, Med Ctr, Div Endocrinol Diabet & Metab, D-89069 Ulm, Germany. [De Jong, Pim A.] Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. [Denny, Josh C.] Vanderbilt Univ, Dept Biomed Informat, Nashville, TN 37235 USA. [Dhonukshe-Rutten, Rosalie; de Groot, Lisette C. P. G. M.] Wageningen Univ, Dept Human Nutr, NL-6700 AP Wageningen, Netherlands. [Dimitriou, Maria; Dedoussis, George] Harokopio Univ, Dept Dietet Nutr, Athens, Greece. [Doney, Alex S. F.; Morris, Andrew D.; Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp, Med Res Inst, Dundee, Scotland. [Doney, Alex S. F.; Morris, Andrew P.; Palmer, Colin N. A.] Univ Dundee, Inst Med Res, Sch Med, Dundee, Scotland. [Doerr, Marcus] Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany. [Eklund, Niina; Kaprio, Jaakko; Groop, Leif C.; Perola, Markus] Univ Helsinki, Inst Mol Med, Helsinki, Finland. [Garcia, Melissa E.; Harris, Tamara B.] US Natl Inst Hlth, Natl Inst Aging, Lab Epidemiol & Populat Sci, Bethesda, MD USA. [Giedraitis, Vilmantas] Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden. [Go, Alan S.] Kaiser Permanente, Div Res, Oakland, CA USA. [Grallert, Harald; Illig, Thomas; Klopp, Norman; Waldenberger, Melanie; Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany. [Grallert, Harald] German Ctr Diabet Res DZD, Neuherberg, Germany. [Graessler, Juergen; Bornstein, Stefan R.; Schwarz, Peter E. H.] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dept Med 3, D-01062 Dresden, Germany. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, Unit Nutr Res, Umea, Sweden. [Hartman, Catharina A.; Oldehinkel, Albertine J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Hassinen, Maija; Rauramaa, Rainer] Kuopio Res Inst Exercise Med, Kuopio, Finland. [Hayward, Caroline; Wright, Alan F.] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Western Gen Hosp, Edinburgh, Midlothian, Scotland. [Heard-Costa, Nancy L.; Cupples, L. Adrienne; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Heard-Costa, Nancy L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Helmer, Quinta; Houwing-Duistermaat, Jeanine J.] Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, Leiden, Netherlands. [Helmer, Quinta] Vrije Univ Amsterdam, Fac Psychol & Educ, Amsterdam, Netherlands. [Hillege, Hans L.; Nolte, Ilja M.; Scholtens, Salome; Smolonska, Joanna; Vonk, Judith M.; Stolk, Ronald P.; Snieder, Harold] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Hlatky, Mark A.; Assimes, Themistocles L.; Melbye, Mads; Quertermous, Thomas] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Hoffmann, Wolfgang; Voelzke, Henry] Univ Med Greifswald, Inst Community Med, Greifswald, Germany. [Hoffmann, Per] Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland. [Hoffmann, Per; Noethen, Markus M.] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Hoffmann, Per; Noethen, Markus M.] Univ Bonn, Inst Human Genet, Bonn, Germany. [Holmen, Oddgeir; Hveem, Kristian] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, N-7034 Trondheim, Norway. [Illig, Thomas; Klopp, Norman] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany. [Isaacs, Aaron; van Duijn, Cornelia M.] Ctr Med Syst Biol, Leiden, Netherlands. [James, Alan L.] Dept Pulm Physiol & Sleep Med, Nedlands, WA, Australia. [James, Alan L.] Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia. [Johansson, Asa; Gyllensten, Ulf] Uppsala Univ, Dept Immunol Genet & Pathol, SciLifeLab, Rudbeck Lab, Uppsala, Sweden. [Jolley, Jennifer; Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge, England. [Jolley, Jennifer; Ouwehand, Willem H.] NHS Blood & Transplant, Cambridge, England. [Junttila, Juhani] Univ Oulu, Dept Med, Oulu, Finland. [Kho, Abel N.; Hayes, M. Geoffrey] Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USA. [Kocher, Thomas] Univ Med Greifswald, Dept Restorat Dent Periodontol & Endodontol, Unit Periodontol, Greifswald, Germany. [Kratzer, Wolfgang; Seufferlein, Thomas] Univ Ulm, Med Ctr, Dept Internal Med 1, D-89069 Ulm, Germany. [Lichtner, Peter] Helmholtz Zentrum MiInchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany. [Lind, Lars; Sundstrom, Johan] Uppsala Univ, Dept Med Sci Cardiovasc Epidemiol, Uppsala, Sweden. [Lorentzon, Mattias; Ohlsson, Claes] Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Gothenburg, Sweden. [Lu, Yingchang; Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Lyssenko, Valeriya] Steno Diabet Ctr AS, Gentofte, Denmark. [Maillard, Marc] Univ Lausanne Hosp CHUV, Dept Med, Serv Nephrol, Lausanne, Switzerland. [McArdle, Wendy L.] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [McKenzie, Colin A.; Forrester, Terrence] Univ W Indies, Res Inst Trop Med, Trop Metab Res Unit, Kingston 7, Jamaica. [McLaren, Paul J.; Ong, Ken K.] Ecole Polytech Fed Lausanne, Global Hlth Inst, Dept Life Sci, Lausanne, Switzerland. [McLaren, Paul J.] Univ Lausanne Hosp, Inst Microbiol, Lausanne, Switzerland. [McLaren, Paul J.] Univ Lausanne, Lausanne, Switzerland. [Monda, Keri L.] Amgen Inc, Ctr Observat Res, Thousand Oaks, CA 91320 USA. [Mueller, Gabriele] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Ctr Evidence Based Healthcare, D-01062 Dresden, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [Mueller-Nurasyid, Martina; Strauch, Konstantin] Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Genet Epidemiol, Neuherberg, Germany. [Mueller-Nurasyid, Martina; Schunkert, Heribert; Hengstenberg, Christian; Meitinger, Thomas; Peters, Annette] DZHK Deutsch Forschungszentrum Herz Kreislauferkr, German Res Ctr Cardiovasc Res, Munich, Germany. [Musk, Arthur W.] Sir Charles Gairdner Hosp, Dept Med Res, Nedlands, WA 6009, Australia. [Pilz, Stefan; van Schoor, Natasja M.] Vrije Univ Amsterdam Med Ctr, Inst Res Extramural Med EMGO, Inst Hlth & Care Res, Dept Epidemiol & Biostat, Amsterdam, Netherlands. [Pilz, Stefan] Graz Univ, Dept Internal Med, Div Endocrinol & Metab, Graz, Austria. [Roussel, Ronan] Hop Xavier Bichat, Publ Hosp Syst City Paris AP HP, Paris, France. [Roussel, Ronan] INSERM U872, Ctr Rech Cordeliers, Paris, France. [Roussel, Ronan] Paris Diderot Univ, Paris, France. [Scharnagl, Hubert; Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Schumacher, Fredrick R.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Schunkert, Heribert; Hengstenberg, Christian] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany. [Shin, Jianxin] NCI, Bethesda, MD 20892 USA. [Silventoinen, Karri] Univ Helsinki, Dept Sociol, Helsinki, Finland. [Smit, Johannes H.] Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Smit, Johannes H.] Vrije Univ Amsterdam, Dept Psychiat, Amsterdam, Netherlands. [Smith, Albert Vernon; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert Vernon; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Stanton, Alice V.] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [Stott, David J.; van Oort, Floor V. A.] Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Tayo, Bamidele O.; Cooper, Richard S.] Loyola Univ, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 60153 USA. [Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur; Thorsteinsdottir, Unnur; Stefansson, Kari] Amgen Inc, deCODE Genet, Reykjavik, Iceland. [Tyrer, Jonathan P.] Univ Cambridge, Dept Oncol, Cambridge, England. [van der Velde, Nathalie] Acad Med Ctr, Dept Internal Med, Sect Geriatr, Amsterdam, Netherlands. [van Oort, Floor V. A.] Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. [Vermeulen, Sita H.; Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, NL-6525 ED Nijmegen, Netherlands. [Vermeulen, Sita H.] Radboud Univ Nijmegen, Med Ctr, Dept Genet, NL-6525 ED Nijmegen, Netherlands. [Wennauer, Roman] Univ Ulm, Med Ctr, Dept Clin Chem, D-89069 Ulm, Germany. [Willenborg, Christina; Erdmann, Jeanette] DZHK Deutsch Forschungszentrum HerzKreislauferkra, German Res Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany. [Willenborg, Christina; Erdmann, Jeanette] Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany. [Wilsgaard, Tom; Njolstad, Inger] UiT Arct Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway. [Wong, Andrew; Kuh, Diana] UCL, MRC Unit Lifelong Hlth & Ageing, London, England. [Arveiler, Dominique] Univ Strasbourg, Fac Med, Dept Epidemiol & Publ Hlth, Strasbourg, France. [Bakker, Stephan J. L.; Gansevoort, Ron T.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands. [Beilby, John; Hui, Jennie] Univ Western Australia, Pathol & Lab Med, Perth, WA 6009, Australia. [Bergman, Richard N.] Cedars Sinai Diabet & Obes Res Inst, Los Angeles, CA USA. [Biffar, Reiner] Univ Med Greifswald, Dept Prosthet Dent Gerostomatol & Dent Mat, Greifswald, Germany. [Boomsma, Dorret I.] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Bovet, Pascal; Bochud, Murielle] CHU Vaudois, Inst Social & Prevent Med IUMSP, CH-1011 Lausanne, Switzerland. [Bovet, Pascal; Bochud, Murielle] Univ Lausanne, Lausanne, Switzerland. [Bovet, Pascal; Bochud, Murielle] Minist Hlth, Victoria, Seychelles. [Brambilla, Paolo] Univ Milan, Hosp Desio, Dept Hlth Sci, Bicocca, Italy. [Brown, Morris J.] Univ Cambridge, Addenbrookes Hosp, Clin Pharmacol Unit, Cambridge CB2 2QQ, England. [Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Caulfield, Mark J.; Munroe, Patricia B.] Queen Mary Univ London, Barts & London Genome Ctr, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Crawford, Dana C.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Crawford, Dana C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Cupples, L. Adrienne] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Danesh, John; Saleheen, Danish] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [de Faire, Ulf] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden. [den Ruijter, Hester M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Erbel, Raimund] Univ Hosp Essen, West German Heart Ctr, Essen, Germany. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Ferrannini, Ele] Univ Pisa, Dept Internal Med, Pisa, Italy. [Ferrannini, Ele] Univ Pisa, Inst Clin Physiol, Natl Res Council CNR, Pisa, Italy. [Ferrieres, Jean] Toulouse Univ, Rangueil Hosp, Sch Med, Dept Cardiol, Toulouse, France. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Gejman, Pablo V.] Univ Chicago, NorthShore Univ HealthSyst, Evanston, IL USA. [Golay, Alain] Univ Hosp Geneva, Serv Therapeut Educ Diabet Obes & Chron Dis, Geneva, Switzerland. [Haas, David W.] Vanderbilt Univ, Sch Med, Dept Med Pharmacol Pathol Microbiol & Immunol, Nashville, TN 37212 USA. [Hall, Alistair S.] Univ Leeds, Leeds MRC Med Bioinformat Ctr, Leeds, W Yorkshire, England. [Hattersley, Andrew T.] Univ Exeter, Inst Biomed & Clin Sci, Exeter, Devon, England. [Heath, Andrew C.; Madden, Pamela A. F.; Rao, D. C.; Rice, Treva K.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Hicks, Andrew A.; Lakka, Timo A.; Pramstaller, Peter P.] European Acad Bozen, Ctr Biomed, Bolzano EURAC, Bolzano, Italy. [Hicks, Andrew A.; Lakka, Timo A.; Pramstaller, Peter P.] Univ Lubeck, Affiliated Inst, Lubeck, Germany. [Hindorff, Lucia A.] US Natl Inst Hlth, Natl Human Genome Res Inst, Div Genom Med, Bethesda, MD USA. [Hingorani, Aroon D.; Asselbergs, Folkert W.] UCL, Inst Cardiovasc Sci, London, England. [Hovingh, G. Kees; Kastelein, John J. P.] Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands. [Humphries, Steve E.] UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England. [Hunt, Steven C.] Univ Utah, Cardiovasc Genet Div, Dept Internal Med, Salt Lake City, UT USA. [Hypponen, Elina; Hui, Jennie] Univ S Australia, Sch Populat Hlth, Adelaide, SA 5001, Australia. [Hypponen, Elina; Hui, Jennie] Univ S Australia, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia. [Hypponen, Elina] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia. [Hypponen, Elina; Power, Chris] UCL, Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England. [Jarvelin, Marjo-Riitta; O'Connell, Jeffrey R.] Natl Inst Hlth & Welf, Oulu, Finland. [Jarvelin, Marjo-Riitta; O'Connell, Jeffrey R.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Ctr Environm & Hlth, MRC Hlth Protect Agcy HPA, London, England. [Jarvelin, Marjo-Riitta] Oulu Univ Hosp, Unit Primary Care, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Jarvelin, Marjo-Riitta; Sebert, Sylvain] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Kaprio, Jaakko] Univ Helsinki, Hjelt Inst, Dept Publ Hlth, Helsinki, Finland. [Kayser, Manfred] Erasmus MC, Dept Forens Mol Biol, Rotterdam, Netherlands. [Kee, Frank] Queens Univ Belfast, Ctr Excellence Publ Hlth Northern Ireland, UK Clin Res Collaborat, Belfast, Antrim, North Ireland. [Keinanen-Kiukaanniemi, Sirkka M.] Univ Oulu, Fac Med, Inst Hlth Sci, Oulu, Finland. [Keinanen-Kiukaanniemi, Sirkka M.] Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland. [Kiemeney, Lambertus A.] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands. [Kooner, Jaspal S.; Chambers, John C.] Imperial Coll Healthcare NHS Trust, London, England. [Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Kumari, Meena; Langenberg, Claudia; Kivimaki, Mika] UCL, Dept Epidemiol & Publ Hlth, London, England. [Kuusisto, Johanna; Laakso, Markku] Kuopio Univ Hosp, Dept Med, SF-70210 Kuopio, Finland. [Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Kuopio, Finland. [Lehtimaki, Terho] Univ Eastern Finland, Inst Biomed, Dept Physiol, Kuopio, Finland. [Lakka, Timo A.; Rauramaa, Rainer] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland. [Lehtimaki, Terho] Univ Tampere, Dept Clin Chem, Fimlab Labs, FIN-33101 Tampere, Finland. [Lehtimaki, Terho] Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. [Lupoli, Sara] Univ Milan, Dept Hlth Sci, Milan, Italy. [Lupoli, Sara] Fdn Filarete, Milan, Italy. [Manunta, Paolo] Ist Sci San Raffaele, Div Nephrol & Dialysis, I-20132 Milan, Italy. [Manunta, Paolo] Univ Vita Salute San Raffaele, Milan, Italy. [Marette, Andre] Univ Laval, Fac Med, Inst Univ Cardiol & Pneumol Quebec, Quebec City, PQ, Canada. [Marette, Andre; Vohl, Marie-Claude; Perusse, Louis] Univ Laval, Inst Nutr & Funct Foods, Quebec City, PQ, Canada. [McKnight, Barbara; Rudan, Igor] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Moll, Frans L.] Univ Med Ctr Utrecht, Dept Surg, Utrecht, Netherlands. [Morris, Andrew P.] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England. [Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Peters, Annette] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Raitakari, Olli T.] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20520 Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Rankinen, Tuomo; Sarzynski, Mark A.; Bouchard, Claude] Pennington Biomed Res Ctr, Human Genom Lab, Baton Rouge, LA 70808 USA. [Ritchie, Marylyn] Penn State Univ, Ctr Syst Genom, University Pk, PA 16802 USA. [Rudan, Igor] Univ Split, Fac Med, Croatian Ctr Global Hlth, Split, Croatia. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. [Samani, Nilesh J.] Glenfield Hosp, Leicester Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, Leicester, Leics, England. [Saramies, Jouko] South Carelia Cent Hosp, Lappeenranta, Finland. [Schwarz, Peter E. H.] German Ctr Diabet Res DZD, Paul Langerhans Inst Dresden, Dresden, Germany. [Sever, Peter] Univ London Imperial Coll Sci Technol & Med, Int Ctr Circulatory Hlth, London, England. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Vetrans Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD USA. [Sinisalo, Juha] Univ Helsinki, Cent Hosp, Heart & Lung Ctr, Dept Med, Helsinki, Finland. [Tardif, Jean-Claude; Lettre, Guillaume] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. [Tremblay, Angelo; Perusse, Louis] Univ Laval, Dept Kinesiol, Quebec City, PQ, Canada. [Tremoli, Elena] Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy. [Tremoli, Elena] IRCCS, Ctr Cardiol Monzmo, Milan, Italy. [Vohl, Marie-Claude] Univ Laval, Dept Food Sci & Nutr, Quebec City, PQ, Canada. [Amouyel, Philippe] Univ Lille 2, INSERM U744, Inst Pasteur Lille, Lille, France. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands. [Asselbergs, Folkert W.; Jukema, J. Wouter; van der Harst, Pim] Interuniv Cardiol Inst Netherlands, Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands. Univ London Imperial Coll Sci Technol & Med, Lee Kong Chian Sch Med, Singapore, Singapore. [Boehm, Bernhard O.] Nanyang Technol Univ, Singapore 639798, Singapore. [Boerwinkle, Eric] Univ Texas Houston, Hlth Sci Ctr Houston, Houston, TX USA. [de Bakker, Paul I. 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[Saaristo, Timo E.] Finnish Diabet Assoc, Tampere, Finland. [Saaristo, Timo E.] Pirkanmaa Hosp Dist, Tampere, Finland. [Saleheen, Danish] Ctr Noncommun Dis, Karatchi, Pakistan. [Saleheen, Danish] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Schlessinger, David] Natl Inst Aging, Genet Lab, Baltimore, MD USA. [Tuomilehto, Jaakko] Hosp Univ La Paz IdiPAZ, Inst Invest Sanit, Madrid, Spain. [Tuomilehto, Jaakko] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia. [Tuomilehto, Jaakko] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria. [Uusitupa, Matti] Univ Eastern Finland, Dept Publ Hlth & Clin Nutr, Kuopio, Finland. [Uusitupa, Matti] Kuopio Univ Hosp, Res Unit, Kuopio, Finland. [Walker, Mark] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Epidemiol, Munich, Germany. [Walker, Mark; Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-80539 Munich, Germany. [Wichmann, H-Erich] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 1, Neuherberg, Germany. [Zanen, Pieter] Univ Med Ctr Utrecht, Dept Pulmonol, Utrecht, Netherlands. [Deloukas, Panos] King Abdulaziz Univ, Jeddah 21413, Saudi Arabia. [Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth K.; Willer, Cristen J.] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Barroso, Ines] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Res Labs, Cambridge CB2 2QQ, England. [Barroso, Ines] NIHR Cambridge, Addenbrookes Hosp, Biomed Res Ctr, Inst Metab Sci, Cambridge, England. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Strachan, David P.] Univ London, Div Populat Hlth Sci & Educ, London, England. [Beckmann, Jacques S.] CHUV Univ Hosp, Serv Med Genet, Lausanne, Switzerland. [McCarthy, Mark I.] Oxford Univ Hosp NHS Trust, Oxford NIHR Biomed Res Ctr, Oxford, England. [Willer, Cristen J.] Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Willer, Cristen J.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Goddard, Michael E.] Dept Primary Ind, Biosci Res Div, Melbourne, Vic, Australia. [Goddard, Michael E.] Univ Melbourne, Dept Food & Agr Syst, Melbourne, Vic, Australia. RP Visscher, PM (reprint author), Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. EM peter.visscher@uq.edu.au; joelh@broadinstitute.org; t.m.frayling@exeter.ac.uk RI Beckmann, Jacques S /A-9772-2008; Yengo, Loic/D-2692-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Hypponen, Elina/B-2596-2014; Kiemeney, Lambertus/D-3357-2009; EHRET, Georg/A-9532-2009; Colaus, PsyColaus/K-6607-2013; Fall, Tove/O-7226-2014; Palmer, Colin/C-7053-2008; Strawbridge, Rona/H-5422-2012; de Bakker, Paul/B-8730-2009; Sarzynski, Mark/A-9798-2014; Lui, Chun Kin Julian/E-2253-2012; Fehrmann, Rudolf/E-2551-2011; Darbar, Dawood/C-9079-2015; Boehm, Bernhard/F-8750-2015; de Jong, Pim/G-7220-2014; Grallert, Harald/B-3424-2013; Bakker, Stephan/J-4023-2015; Gudnason, Vilmundur/K-6885-2015; Wilson, James F/A-5704-2009; Montgomery, Grant/B-7148-2008; Deloukas, Panos/B-2922-2013; Meitinger, Thomas/O-1318-2015; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Erdmann, Jeanette/P-7513-2014; Sundstrom, Johan/A-6286-2009; Peters, Annette/A-6117-2011; Vermeulen, H.H.M./L-4716-2015; Bovet, Pascal/F-4477-2011; Bouchard, Claude/A-7637-2009; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; Nato, Alejandro/J-3880-2016; Yang, Jian/A-5852-2010; kinnunen, leena/B-7059-2012; Study, GoDARTS/K-9448-2016; Bochud, Murielle/A-3981-2010; mangino, massimo/F-5134-2011; Schwarz, Peter/B-5127-2013; Ramos , Rafel/D-9627-2016; Franke, Lude/P-7036-2016; Ormel, Johan/C-6094-2013; Wijmenga, Cisca/D-2173-2009; Karjalainen, Juha/P-8624-2016; Slagboom, P. Eline/R-4790-2016; Wong, Andrew/M-8899-2016; Verweij, Niek/A-4499-2017; Magnusson, Patrik/C-4458-2017 OI Beckmann, Jacques S /0000-0002-9741-1900; Yengo, Loic/0000-0002-4272-9305; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Franks, Paul/0000-0002-0520-7604; Scherag, Andre/0000-0002-9406-4704; Manunta, Paolo/0000-0003-3976-9696; Shungin, Dmitry/0000-0001-7900-5856; Stanton, Alice/0000-0002-4961-165X; Day, Felix/0000-0003-3789-7651; Magi, Reedik/0000-0002-2964-6011; van der Velde, Nathalie/0000-0002-6477-6209; Moayyeri, Alireza/0000-0002-9143-2161; Deelen, Joris/0000-0003-4483-3701; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Cooper, Matthew/0000-0003-1139-3682; Kristiansson, Kati/0000-0003-4688-107X; Asselta, Rosanna/0000-0001-5351-0619; Bush, William/0000-0002-9729-6519; Ramos , Rafel/0000-0001-7970-5537; Menni, Cristina/0000-0001-9790-0571; Goddard, Michael/0000-0001-9917-7946; TREMOLI, ELENA/0000-0002-0929-6106; Sinisalo, Juha/0000-0002-0169-5137; Kleber, Marcus/0000-0003-0663-7275; Martin, Nicholas/0000-0003-4069-8020; Hypponen, Elina/0000-0003-3670-9399; Kiemeney, Lambertus/0000-0002-2368-1326; EHRET, Georg/0000-0002-5730-0675; Palmer, Colin/0000-0002-6415-6560; Strawbridge, Rona/0000-0001-8506-3585; de Bakker, Paul/0000-0001-7735-7858; Fehrmann, Rudolf/0000-0002-7516-315X; Darbar, Dawood/0000-0002-4103-5977; de Jong, Pim/0000-0003-4840-6854; Bakker, Stephan/0000-0003-3356-6791; Gudnason, Vilmundur/0000-0001-5696-0084; Wilson, James F/0000-0001-5751-9178; Montgomery, Grant/0000-0002-4140-8139; Deloukas, Panos/0000-0001-9251-070X; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Medina-Gomez, Carolina/0000-0001-7999-5538; Visscher, Peter/0000-0002-2143-8760; Eriksson, Johan/0000-0002-2516-2060; Assimes, Themistocles/0000-0003-2349-0009; Ouwehand, Willem/0000-0002-7744-1790; Kaprio, Jaakko/0000-0002-3716-2455; Johansson, Asa/0000-0002-2915-4498; Hattersley, Andrew/0000-0001-5620-473X; Bergmann, Sven/0000-0002-6785-9034; Forouhi, Nita/0000-0002-5041-248X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Nothen, Markus/0000-0002-8770-2464; Buyske, Steven/0000-0001-8539-5416; Watkins, Hugh/0000-0002-5287-9016; Vinkhuyzen, Anna/0000-0003-3352-0603; Mannisto, Satu/0000-0002-8668-3046; Lakka, Timo/0000-0002-9199-2871; Folkersen, Lasse/0000-0003-0708-9530; van der Laan, Sander W./0000-0001-6888-1404; Humphries, Stephen E/0000-0002-8221-6547; Gieger, Christian/0000-0001-6986-9554; Kumari, Meena/0000-0001-9716-1035; Verweij, Niek/0000-0002-4303-7685; Wolffenbuttel, Bruce H.R./0000-0001-9262-6921; sanna, serena/0000-0002-3768-1749; Fraser, Ross/0000-0003-0488-2592; Beekman, Marian/0000-0003-0585-6206; Esko, Tonu/0000-0003-1982-6569; Locke, Adam/0000-0001-6227-198X; Erdmann, Jeanette/0000-0002-4486-6231; Sundstrom, Johan/0000-0003-2247-8454; Bovet, Pascal/0000-0002-0242-4259; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Nato, Alejandro/0000-0002-8745-9046; Yang, Jian/0000-0003-2001-2474; kinnunen, leena/0000-0001-8739-4812; Bochud, Murielle/0000-0002-5727-0218; mangino, massimo/0000-0002-2167-7470; Schwarz, Peter/0000-0001-6317-7880; Ramos , Rafel/0000-0001-8146-5288; Franke, Lude/0000-0002-5159-8802; Slagboom, P. Eline/0000-0002-2875-4723; Wong, Andrew/0000-0003-2079-4779; FU British Heart Foundation [FS/11/35/28871, FS/12/33/29561, FS/12/8/29377, FS/14/12/30540, PG/07/085/23349, RG/08/008/25291, RG/08/014/24067, RG/09/012/28096, RG/10/12/28456, SP/08/002/24118]; Chief Scientist Office [CZB/4/672, CZB/4/710]; Department of Health [RP-PG-0310-1002]; European Research Council [323195]; Medical Research Council [MC_UU_12015/2, G0500070, G0601463, G1002084, MC_PC_U127561128, MC_U106179471, MC_U106179472, MC_UP_A100_1003, MC_UU_12015/1, MC_UU_12015/5, MC_UU_12019/1, MR/K006584/1, MR/K013351/1, MR/L003120/1, MR/L01629X/1]; NCATS NIH HHS [UL1 TR000124]; NCI NIH HHS [P30 CA015704, P30 CA071789]; NHGRI NIH HHS [U01 HG007419]; NHLBI NIH HHS [R01 HL109946, R01 HL117626, T32 HL007055]; NICHD NIH HHS [P30 HD018655]; NIDDK NIH HHS [P30 DK063491, P30 DK072488, R01 DK072193, R01 DK075787, R01 DK093757, U01 DK062370]; NIGMS NIH HHS [P01 GM099568, P30 GM103341, R01 GM075091, T32 GM080178]; Wellcome Trust [085301, 090532, 098381, 098395] NR 21 TC 296 Z9 299 U1 28 U2 179 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2014 VL 46 IS 11 BP 1173 EP 1186 DI 10.1038/ng.3097 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA AS2TI UT WOS:000344131900008 PM 25282103 ER PT J AU Xu, P Zhang, XF Wang, XM Li, JT Liu, GM Kuang, YY Xu, J Zheng, XH Ren, LF Wang, GL Zhang, Y Huo, LH Zhao, ZX Cao, DC Lu, CY Li, C Zhou, Y Liu, ZJ Fan, ZH Shan, GL Li, XG Wu, SX Song, LP Hou, GY Jiang, YL Jeney, Z Yu, D Wang, L Shao, CJ Song, L Sun, J Ji, PF Wang, J Li, Q Xu, LM Sun, FY Feng, JX Wang, CH Wang, SL Wang, BS Li, Y Zhu, YP Xue, W Zhao, L Wang, JT Gu, Y Lv, WH Wu, KJ Xiao, JF Wu, JY Zhang, Z Yu, J Sun, XW AF Xu, Peng Zhang, Xiaofeng Wang, Xumin Li, Jiongtang Liu, Guiming Kuang, Youyi Xu, Jian Zheng, Xianhu Ren, Lufeng Wang, Guoliang Zhang, Yan Huo, Linhe Zhao, Zixia Cao, Dingchen Lu, Cuiyun Li, Chao Zhou, Yi Liu, Zhanjiang Fan, Zhonghua Shan, Guangle Li, Xingang Wu, Shuangxiu Song, Lipu Hou, Guangyuan Jiang, Yanliang Jeney, Zsigmond Yu, Dan Wang, Li Shao, Changjun Song, Lai Sun, Jing Ji, Peifeng Wang, Jian Li, Qiang Xu, Liming Sun, Fanyue Feng, Jianxin Wang, Chenghui Wang, Shaolin Wang, Baosen Li, Yan Zhu, Yaping Xue, Wei Zhao, Lan Wang, Jintu Gu, Ying Lv, Weihua Wu, Kejing Xiao, Jingfa Wu, Jiayan Zhang, Zhang Yu, Jun Sun, Xiaowen TI Genome sequence and genetic diversity of the common carp, Cyprinus carpio SO NATURE GENETICS LA English DT Article ID LINKAGE MAP; MICROSATELLITE LOCI; TELEOST FISH; HOX CLUSTERS; EVOLUTION; DUPLICATION; L.; DIVERSIFICATION; PIGMENTATION; ANNOTATION AB The common carp, Cyprinus carpio, is one of the most important cyprinid species and globally accounts for 10% of freshwater aquaculture production. Here we present a draft genome of domesticated C. carpio (strain Songpu), whose current assembly contains 52,610 protein-coding genes and approximately 92.3% coverage of its paleotetraploidized genome (2n = 100). The latest round of whole-genome duplication has been estimated to have occurred approximately 8.2 million years ago. Genome resequencing of 33 representative individuals from worldwide populations demonstrates a single origin for C. carpio in 2 subspecies (C. carpio Haematopterus and C. carpio carpio). Integrative genomic and transcriptomic analyses were used to identify loci potentially associated with traits including scaling patterns and skin color. In combination with the high-resolution genetic map, the draft genome paves the way for better molecular studies and improved genome-assisted breeding of C. carpio and other closely related species. C1 [Xu, Peng; Li, Jiongtang; Xu, Jian; Zhang, Yan; Zhao, Zixia; Liu, Zhanjiang; Hou, Guangyuan; Jiang, Yanliang; Ji, Peifeng; Wang, Jian; Li, Qiang; Xu, Liming; Wang, Baosen; Li, Yan; Zhu, Yaping; Xue, Wei; Zhao, Lan; Wang, Jintu; Sun, Xiaowen] Chinese Acad Fishery Sci, Ctr Appl Aquat Genom, Beijing, Peoples R China. [Zhang, Xiaofeng; Kuang, Youyi; Zheng, Xianhu; Cao, Dingchen; Lu, Cuiyun; Li, Chao; Gu, Ying; Lv, Weihua; Sun, Xiaowen] Chinese Acad Fishery Sci, Heilongjiang River Fisheries Res Inst, Harbin, Peoples R China. [Wang, Xumin; Liu, Guiming; Ren, Lufeng; Wang, Guoliang; Huo, Linhe; Fan, Zhonghua; Shan, Guangle; Li, Xingang; Wu, Shuangxiu; Song, Lipu; Yu, Dan; Wang, Li; Shao, Changjun; Song, Lai; Sun, Jing; Wu, Kejing; Xiao, Jingfa; Wu, Jiayan; Zhang, Zhang; Yu, Jun] Chinese Acad Sci, Key Lab Genome Sci & Informat, Beijing Inst Genom, Beijing, Peoples R China. [Zhou, Yi] Harvard Univ, Sch Med, Stem Cell Program, Div Hematol & Oncol,Boston Childrens Hosp, Boston, MA USA. [Zhou, Yi] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Liu, Zhanjiang; Sun, Fanyue] Auburn Univ, Dept Fisheries & Allied Aquacultures, Fish Mol Genet & Biotechnol Lab, Auburn, AL 36849 USA. [Jeney, Zsigmond] Res Inst Fisheries Aquaculture & Irrigat, Szarvas, Hungary. [Feng, Jianxin] Henan Acad Fishery Sci, Zhengzhou, Peoples R China. [Wang, Chenghui] Shanghai Ocean Univ, Coll Fisheries & Life Sci, Shanghai, Peoples R China. [Wang, Shaolin] Univ Virginia, Dept Psychiat & Neurobiol Sci, Charlottesville, VA USA. RP Sun, XW (reprint author), Chinese Acad Fishery Sci, Ctr Appl Aquat Genom, Beijing, Peoples R China. EM junyu@big.ac.cn; sunxw@cafs.ac.cn RI Xu, Peng/J-4018-2012; Wang, Shaolin/M-2282-2013 OI Wang, Shaolin/0000-0003-0866-4584 FU National High-Technology Research and Development Program of China (863 program) [2011AA100401, 2011AA100402, 2009AA10Z105]; National Department Public Benefit Research Foundation of China [200903045]; National Basic Research Program of China (973 Program) [2010CB126305]; National Natural Science Foundation of China [31302174, 31101893]; Special Scientific Research Funds for Central Non-Profit Institutes of the Chinese Academy of Fishery Sciences [2009B002, 2011C016] FX We acknowledge Z. Zhu, N. Li, J. Gui, Z. Bao, G. Zhang, X.L. Zhang, J. Li, Y. Liu, Q. Liu and S. Chen for their support on the common carp genome project. We thank H. Hu, G.Z. Liu, J.H. Yu and C.J. Li for their assistance in sample collection and Y. Wan, T. Sun, W. Liu, L. Jiang, Shu Wang, Y. Zhu, X. Xing, P. Zhou and R. Cut for genotyping and sequencing. We thank J. Postlethwait, G. Hulata, L. David, L. Orban and F. Zhao for their helpful discussions. We acknowledge grant support from the National High-Technology Research and Development Program of China (863 program; 2011AA100401,2011AA100402 and 2009AA10Z105), the National Department Public Benefit Research Foundation of China (200903045), the National Basic Research Program of China (973 Program; 2010CB126305), the National Natural Science Foundation of China (31302174 and 31101893) and Special Scientific Research Funds for Central Non-Profit Institutes of the Chinese Academy of Fishery Sciences (2009B002 and 2011C016). NR 43 TC 80 Z9 88 U1 16 U2 92 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2014 VL 46 IS 11 BP 1212 EP 1219 DI 10.1038/ng.3098 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA AS2TI UT WOS:000344131900012 PM 25240282 ER PT J AU Cox, AD Fesik, SW Kimmelman, AC Luo, J Der, CJ AF Cox, Adrienne D. Fesik, Stephen W. Kimmelman, Alec C. Luo, Ji Der, Channing J. TI Drugging the undruggable RAS: Mission Possible? SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID PANCREATIC TUMOR-GROWTH; ONCOGENIC K-RAS; INDUCED MYELOPROLIFERATIVE DISEASE; SYNTHETIC LETHAL INTERACTIONS; MEDIATED NUCLEOTIDE EXCHANGE; SMALL-MOLECULE INHIBITION; SQUAMOUS-CELL CARCINOMAS; INDUCED LUNG-CANCER; IN-VIVO; FARNESYLTHIOSALICYLIC ACID AB Despite more than three decades of intensive effort, no effective pharmacological inhibitors of the RAS oncoproteins have reached the clinic, prompting the widely held perception that RAS proteins are 'undruggable'. However, recent data from the laboratory and the clinic have renewed our hope for the development of RAS-inhibitory molecules. In this Review, we summarize the progress and the promise of five key approaches. Firstly, we focus on the prospects of using direct inhibitors of RAS. Secondly, we address the issue of whether blocking RAS membrane association is a viable approach. Thirdly, we assess the status of targeting RAS downstream effector signalling, which is arguably the most favourable current approach. Fourthly, we address whether the search for synthetic lethal interactors of mutant RAS still holds promise. Finally, RAS-mediated changes in cell metabolism have recently been described and we discuss whether these changes could be exploited for new therapeutic directions. We conclude with perspectives on how additional complexities, which are not yet fully understood, may affect each of these approaches. C1 [Cox, Adrienne D.; Der, Channing J.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Fesik, Stephen W.] Vanderbilt Univ, Sch Med, Nashville, TN 37232 USA. [Kimmelman, Alec C.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Luo, Ji] NCI, Bethesda, MD 20892 USA. RP Der, CJ (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. EM cjder@med.unc.edu FU US National Institutes of Health (NIH) [CA042978, CA179193, CA175747]; Lustgarten Foundation for Pancreatic Cancer Research, USA; Pancreatic Cancer Action Network-American Association for Cancer Research; NIH [DPI OD006933/DP1CA174419, P50A095103-12, RC2CA148375, R01 CA157490]; Lustgarten Foundation for Pancreatic Cancer Research; American Cancer Society Research Scholar Grant [RSG-13-298-01-TBG]; Lustgarten Foundation; US National Cancer Institute Intramural Program FX The work of C.J.D. and A.D.C. is supported by US National Institutes of Health (NIH) grants CA042978, CA179193 and CA175747, and by grants from the Lustgarten Foundation for Pancreatic Cancer Research, USA, and the Pancreatic Cancer Action Network-American Association for Cancer Research. The work of S.W.F. is supported by NIH grants DPI OD006933/DP1CA174419 (NIH Director's Pioneer Award; S.W F.), P50A095103-12 (NCI SPORE in GI Cancer; R. J. Coffey), and RC2CA148375 (NIH ARRA Stimulus Grant; L. J. Marnett), and by the Lustgarten Foundation for Pancreatic Cancer Research. The work of A.C.K. is supported by NIH grant R01 CA157490, American Cancer Society Research Scholar Grant RSG-13-298-01-TBG and by the Lustgarten Foundation. A.C.K. is a consultant for Forma Therapeutics. The work of J.L. is supported by the US National Cancer Institute Intramural Program. NR 230 TC 158 Z9 160 U1 13 U2 92 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 EI 1474-1784 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD NOV PY 2014 VL 13 IS 11 BP 828 EP 851 DI 10.1038/nrd4389 PG 24 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA AS4AR UT WOS:000344216500027 PM 25323927 ER PT J AU Meyer, CA Liu, XS AF Meyer, Clifford A. Liu, X. Shirley TI Identifying and mitigating bias in next-generation sequencing methods for chromatin biology SO NATURE REVIEWS GENETICS LA English DT Review ID CHIP-SEQ DATA; DIFFERENTIAL EXPRESSION ANALYSIS; ALLELE-SPECIFIC EXPRESSION; DNA-BINDING PROTEINS; SHORT READ ALIGNMENT; HI-C DATA; TRANSCRIPTION FACTORS; QUALITY-CONTROL; HUMAN GENOME; GENE-EXPRESSION AB Next-generation sequencing (NGS) technologies have been used in diverse ways to investigate various aspects of chromatin biology by identifying genomic loci that are bound by transcription factors, occupied by nucleosomes or accessible to nuclease cleavage, or loci that physically interact with remote genomic loci. However, reaching sound biological conclusions from such NGS enrichment profiles requires many potential biases to be taken into account. In this Review, we discuss common ways in which biases may be introduced into NGS chromatin profiling data, approaches to diagnose these biases and analytical techniques to mitigate their effect. C1 [Meyer, Clifford A.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. RP Meyer, CA (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM cliff@research.dfci.harvard.edu; xsliu@jimmy.harvard.edu FU US National Institutes of Health [R01GM099409] FX The authors thank members of X.S.L and M. Brown's laboratories for their discussions. This work is supported by the US National Institutes of Health grant R01GM099409. NR 117 TC 43 Z9 43 U1 9 U2 57 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD NOV PY 2014 VL 15 IS 11 BP 709 EP 721 DI 10.1038/nrg3788 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA AS1CI UT WOS:000344014300008 PM 25223782 ER PT J AU Kambayashi, T Laufer, TM AF Kambayashi, Taku Laufer, Terri M. TI Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell? SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID CD4(+) T-CELLS; INNATE LYMPHOID-CELLS; INTESTINAL EPITHELIAL-CELLS; ALLERGIC AIRWAY INFLAMMATION; HELPER TYPE-2 RESPONSE; HUMAN MAST-CELLS; FC-EPSILON-RI; IN-VIVO; HUMAN EOSINOPHILS; IL-4 PRODUCTION AB Dendritic cells, macrophages and B cells are regarded as the classical antigen-presenting cells of the immune system. However, in recent years, there has been a rapid increase in the number of cell types that are suggested to present antigens on MHC class II molecules to CD4(+) T cells. In this Review, we describe the key characteristics that define an antigen-presenting cell by examining the functions of dendritic cells. We then examine the functions of the haematopoietic cells and non-haematopoietic cells that can express MHC class II molecules and that have been suggested to represent 'atypical' antigen-presenting cells. We consider whether any of these cell populations can prime naive CD4(+) T cells and, if not, question the effects that they do have on the development of immune responses. C1 [Kambayashi, Taku] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kambayashi, Taku] Univ Penn, Div Rheumatol, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Laufer, Terri M.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Laufer, TM (reprint author), Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. EM tlaufer@mail.med.upenn.edu FU VA Merit Award; US National Institutes of Health; American Asthma Foundation FX Work in the laboratory of T.M.L. is supported by a VA Merit Award. Research in the laboratory of T.K. is supported by funding from the US National Institutes of Health and the American Asthma Foundation. NR 159 TC 49 Z9 49 U1 5 U2 33 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 EI 1474-1741 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD NOV PY 2014 VL 14 IS 11 BP 719 EP 730 DI 10.1038/nri3754 PG 12 WC Immunology SC Immunology GA AS8BQ UT WOS:000344475800008 PM 25324123 ER PT J AU Fishman, JA Grossi, PA AF Fishman, Jay A. Grossi, Paolo A. TI Donor-derived infection-the challenge for transplant safety SO NATURE REVIEWS NEPHROLOGY LA English DT Review ID SOLID-ORGAN TRANSPLANTATION; WEST-NILE-VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C VIRUS; COMMERCIAL RENAL-TRANSPLANTATION; MUSCULOSKELETAL TISSUE DONORS; (KPC)-PRODUCING K. PNEUMONIAE; TRANSMITTED VIRAL-INFECTIONS; GRAM-NEGATIVE BACTERIA; UNITED-STATES AB Organ transplantation, including of the heart, lung, kidney, liver, pancreas, and small bowel, is considered the therapy of choice for end-stage organ failure. Each year, over 70,000 organs are implanted worldwide. One donor may provide multiple organs, as well as corneas and other tissues, for multiple recipients. The degree of risk for transmission of infection carried with grafts, notably of viruses, is largely unknown and, for a specific organ, difficult to assess. The approach to microbiological screening of organ donors varies with national and regional regulations and with the availability and performance of microbiological assays used for potential donors. Transmission of both expected or common, and unexpected infections has been observed in organ transplants, generally recognized after development of clusters of infections among recipients of organs from a common donor. Other than for unusual or catastrophic events, few data exist that define the incidence and manifestations of donor-derived infections or the ideal assays to use in screening to prevent such transmissions. Absolute prevention of the transmission of donor-derived infections in organ transplantation is not possible. However, improvements in screening technologies will enhance the safety of transplantation in the future. C1 [Fishman, Jay A.] Massachusetts Gen Hosp, Div Infect Dis, Transplant Infect Dis Program, Boston, MA 02114 USA. [Fishman, Jay A.] Massachusetts Gen Hosp, MGH Transplantat Ctr, Boston, MA 02114 USA. [Fishman, Jay A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Grossi, Paolo A.] Univ Insubria, Natl Ctr Transplantat, Infect & Trop Dis Dept, I-21100 Varese, Italy. RP Fishman, JA (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Transplant Infect Dis Program, 55 Fruit St, Boston, MA 02114 USA. EM jfishman@partners.org NR 100 TC 4 Z9 5 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5061 EI 1759-507X J9 NAT REV NEPHROL JI Nat. Rev. Nephrol. PD NOV PY 2014 VL 10 IS 11 BP 663 EP 672 DI 10.1038/nrneph.2014.159 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA AS0GH UT WOS:000343955600010 PM 25178971 ER PT J AU Prabhakaran, S Fonarow, GC Smith, EE Liang, L Xian, Y Neely, M Peterson, ED Schwamm, LH AF Prabhakaran, Shyam Fonarow, Gregg C. Smith, Eric E. Liang, Li Xian, Ying Neely, Megan Peterson, Eric D. Schwamm, Lee H. TI Hospital Case Volume Is Associated With Mortality in Patients Hospitalized With Subarachnoid Hemorrhage SO NEUROSURGERY LA English DT Article DE Comprehensive stroke centers; Referral bias; Quality of care ID GUIDELINES-STROKE; UNITED-STATES; OUTCOME RELATIONSHIP; SURGEON VOLUME; CARE; RECOMMENDATIONS; ADMISSIONS; MORBIDITY; ANEURYSMS; REGISTRY AB BACKGROUND: Prior studies have suggested that hospital case volume may be associated with improved outcomes after subarachnoid hemorrhage (SAH), but contemporary national data are limited. OBJECTIVE: To assess the association between hospital case volume for SAH and in-hospital mortality. METHODS: Using the Get With The Guidelines-Stroke registry, we analyzed patients with a discharge diagnosis of SAH between April 2003 and March 2012. We assessed the association of annual SAH case volume with in-hospital mortality by using multivariable logistic regression adjusting for relevant patient, hospital, and geographic characteristics. RESULTS: Among 31,973 patients with SAH from 685 hospitals, the median annual case volume per hospital was 8.5 (25th-75th percentile, 6.7-12.9) patients. Mean in-hospital mortality was 25.7%, but was lower with increasing annual SAH volume: 29.5% in quartile 1 (range, 4-6.6), 27.0% in quartile 2 (range, 6.7-8.5), 24.1% in quartile 3 (range, 8.5-12.7), and 22.1% in quartile 4 (range, 12.9-94.5). Adjusting for patient and hospital characteristics, hospital SAH volume was independently associated with in-hospital mortality (adjusted odds ratio 0.79 for quartile 4 vs 1, 95% confidence interval, 0.67-0.92). The quartile of SAH volume also was associated with length of stay but not with discharge home or independent ambulatory status. CONCLUSION: In a large nationwide registry, we observed that patients treated at hospitals with higher volumes of SAH patients have lower in-hospital mortality, independent of patient and hospital characteristics. Our data suggest that experienced centers may provide more optimized care for SAH patients. C1 [Prabhakaran, Shyam] Northwestern Univ, Dept Neurol, Chicago, IL 60611 USA. [Fonarow, Gregg C.] Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB, Canada. [Liang, Li; Xian, Ying; Neely, Megan; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Div Neurol, Boston, MA 02114 USA. RP Prabhakaran, S (reprint author), Northwestern Univ, Dept Neurol, Feinberg Sch Med, 710 N Lake Shore Dr,Suite 1417, Chicago, IL 60611 USA. EM sprabhak@nmff.org OI Schwamm, Lee/0000-0003-0592-9145; Smith, Eric/0000-0003-3956-1668 NR 34 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X EI 1524-4040 J9 NEUROSURGERY JI Neurosurgery PD NOV PY 2014 VL 75 IS 5 BP 500 EP 508 DI 10.1227/NEU.0000000000000475 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA AS2PD UT WOS:000344121100003 PM 24979097 ER PT J AU Sun, PZ Wang, Y Mandeville, E Chan, ST Lo, EH Ji, XM AF Sun, Phillip Zhe Wang, Yu Mandeville, Emiri Chan, Suk-Tak Lo, Eng H. Ji, Xunming TI Validation of fast diffusion kurtosis MRI for imaging acute ischemia in a rodent model of stroke SO NMR IN BIOMEDICINE LA English DT Article DE acute stroke; diffusion-weighted imaging (DWI); diffusion kurtosis imaging (DKI); mean diffusion (MD); mean kurtosis (MK) ID EXPERIMENTAL CEREBRAL-ISCHEMIA; PERFUSION-WEIGHTED MRI; TISSUE; VISUALIZATION; COEFFICIENT; PARAMETERS; INFARCTION; MISMATCH; LESIONS; HUMANS AB Diffusion-weighted imaging (DWI) captures ischemic tissue that is likely to infarct, and has become one of the most widely used acute stroke imaging techniques. Diffusion kurtosis imaging (DKI) has lately been postulated as a complementary MRI method to stratify the heterogeneously damaged DWI lesion. However, the conventional DKI acquisition time is relatively long, limiting its use in the acute stroke setting. Recently, a fast kurtosis mapping method has been demonstrated in fixed brains and control subjects. The fast DKI approach provides mean diffusion and kurtosis measurements under substantially reduced scan time, making it amenable to acute stroke imaging. Because it is not practical to obtain and compare different means of DKI to test whether the fast DKI method can reliably detect diffusion and kurtosis lesions in acute stroke patients, our study investigated its diagnostic value using an animal model of acute stroke, a critical step before fast DKI acquisition can be routinely applied in the acute stroke setting. We found significant correlation, per voxel, between the diffusion and kurtosis coefficients measured using the fast and conventional DKI protocols. In acute stroke rats, the two DKI methods yielded diffusion and kurtosis lesions that were in good agreement. Importantly, substantial kurtosis-diffusion lesion mismatch was observed using the conventional (26 +/- 13%, P<0.01) and fast DKI methods (23 +/- 8%, P<0.01). In addition, regression analysis showed that the kurtosis-diffusion lesion mismatches obtained using conventional and fast DKI methods were substantially correlated (R-2=0.57, P=0.02). Our results confirmed that the recently proposed fast DKI method is capable of capturing heterogeneous diffusion and kurtosis lesions in acute ischemic stroke, and thus is suitable for translational applications in the acute stroke clinical setting. Copyright (c) 2014 John Wiley & Sons, Ltd. C1 [Sun, Phillip Zhe; Wang, Yu; Chan, Suk-Tak] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. [Sun, Phillip Zhe; Wang, Yu; Mandeville, Emiri; Chan, Suk-Tak; Lo, Eng H.] Harvard Univ, Sch Med, Charlestown, MA USA. [Wang, Yu; Ji, Xunming] Capital Med Univ, Xuanwu Hosp, Cerebrovasc Dis Res Inst, Beijing, Peoples R China. [Mandeville, Emiri; Lo, Eng H.] Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Radiol & Neurol, Charlestown, MA USA. RP Ji, XM (reprint author), Capital Med Univ, Xuanwu Hosp, Cerebrovasc Dis Res Inst, Beijing, Peoples R China. EM jixm@ccmu.edu.cn RI Chan, Suk-tak/G-5846-2015 FU NIH/NIBIB [1K01EB009771]; NIH/NINDS [1R21NS085574]; NBRPC [2011CB-70780420] FX This study was supported in part by grants from NIH/NIBIB 1K01EB009771, NIH/NINDS 1R21NS085574 and NBRPC 2011CB-70780420. NR 37 TC 12 Z9 14 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0952-3480 EI 1099-1492 J9 NMR BIOMED JI NMR Biomed. PD NOV PY 2014 VL 27 IS 11 BP 1413 EP 1418 DI 10.1002/nbm.3188 PG 6 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA AR9WR UT WOS:000343927900017 PM 25208309 ER PT J AU Nieminen, HJ Salmi, A Karppinen, P Haeggstrom, E Hacking, SA AF Nieminen, H. J. Salmi, A. Karppinen, P. Haeggstrom, E. Hacking, S. A. TI The potential utility of high-intensity ultrasound to treat osteoarthritis SO OSTEOARTHRITIS AND CARTILAGE LA English DT Review DE Ultrasound; Osteoarthritis; Cartilage; Bone; Drug delivery; Orthopedic surgery ID GUIDED FOCUSED ULTRASOUND; INTRAARTICULAR DRUG-DELIVERY; ACOUSTIC RADIATION FORCE; TEMPERATURE-SENSITIVE LIPOSOMES; SHOCK-WAVE LITHOTRIPSY; CHONDROCYTES IN-VITRO; ARTICULAR-CARTILAGE; POSTTRAUMATIC OSTEOARTHRITIS; THERAPEUTIC ULTRASOUND; KNEE OSTEOARTHRITIS AB Osteoarthritis (OA) is a widespread musculoskeletal disease that reduces quality of life and for which there is no cure. The treatment of OA is challenging since cartilage impedes the local and systemic delivery of therapeutic compounds (TCs). This review identifies high-intensity ultrasound (HIU) as a non-contact technique to modify articular cartilage and subchondral bone. HIU enables new approaches to overcome challenges associated with drug delivery to cartilage and new non-invasive approaches for the treatment of joint disease. Specifically, HIU has the potential to facilitate targeted drug delivery and release deep within cartilage, to repair soft tissue damage, and to physically alter tissue structures including cartilage and bone. The localized, non-invasive ultrasonic delivery of TCs to articular cartilage and subchondral bone appears to be a promising technique in the immediate future. (C) 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Nieminen, H. J.; Salmi, A.; Karppinen, P.; Haeggstrom, E.] Univ Helsinki, Dept Phys, FIN-00014 Helsinki, Finland. [Hacking, S. A.] Massachusetts Gen Hosp, Dept Orthopaed, Boston, MA 02114 USA. [Hacking, S. A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Hacking, SA (reprint author), Harvard Univ, Sch Med, Dept Orthopaed, Lab Musculoskeletal Res & Innovat, 55 Fruit St,Rm GRJ 1120, Boston, MA 02114 USA. EM heikki.nieminen@helsinki.fi; ari.salmi@helsinki.fi; pasi.karppinen@gmail.com; edward.haeggstrom@helsinki.fi; ahacking@yahoo.com RI Salmi, Ari/B-1317-2009 FU Academy of Finland [253579] FX The authors are grateful for the insight, suggestions and constructive criticisms provided by Prof A.J. Grodzinsky. Thank you. The work of H.J. Nieminen is supported by the Academy of Finland (no. 253579). NR 152 TC 3 Z9 3 U1 3 U2 21 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 EI 1522-9653 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD NOV PY 2014 VL 22 IS 11 BP 1784 EP 1799 DI 10.1016/j.joca.2014.07.025 PG 16 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA AS3NR UT WOS:000344186000004 PM 25106678 ER PT J AU Tan, CO Battaglino, RA Doherty, AL Gupta, R Lazzari, AA Garshick, E Zafonte, R Morse, LR AF Tan, C. O. Battaglino, R. A. Doherty, A. L. Gupta, R. Lazzari, A. A. Garshick, E. Zafonte, R. Morse, L. R. TI Adiponectin is associated with bone strength and fracture history in paralyzed men with spinal cord injury SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Adiponectin; Biomarker; Finite element analysis; Fracture; Rehabilitation medicine; Spinal cord injury ID MAPK SIGNALING PATHWAY; LOWER-EXTREMITY BONE; MINERAL DENSITY; SERUM ADIPONECTIN; POSTMENOPAUSAL WOMEN; CANDIDATE BIOMARKER; PLASMA ADIPONECTIN; HUMAN OSTEOBLASTS; ELDERLY-MEN; FAT MASS AB We explored the association between adiponectin levels and bone strength in paralyzed men with spinal cord injury. We found that bone strength was inversely associated with circulating adiponectin levels. Thus, strength estimates and adiponectin levels may improve fracture risk prediction and detection of response to osteogenic therapies following spinal cord injury. Previous research has demonstrated an inverse relationship between circulating adiponectin and bone mineral density, suggesting that adiponectin may be used as a biomarker for bone health. However, this relationship may reflect indirect effects on bone metabolism via adipose-mediated mechanical pathways rather than the direct effects of adipokines on bone metabolism. Thus, we explored the association between circulating adiponectin levels and bone strength in 27 men with spinal cord injury. Plasma adiponectin levels were quantified by ELISA assay. Axial stiffness and maximal load to fracture of the distal femur were quantified via finite element analysis using reconstructed 3D models of volumetric CT scans. We also collected information on timing, location, and cause of previous fractures. Axial stiffness and maximal load were inversely associated with circulating adiponectin levels (R (2) = 0.44, p = 0.01; R (2) = 0.58, p = 0.05) after adjusting for injury duration and lower extremity lean mass. In individuals with post-SCI osteoporotic fractures, distal femur stiffness (p = 0.01) and maximal load (p = 0.005) were lower, and adiponectin was higher (p = 0.04) than those with no fracture history. Based on these findings, strength estimates may improve fracture risk prediction and detection of response to osteogenic therapies following spinal cord injury. Furthermore, our findings suggest that circulating adiponectin may indeed be a feasible biomarker for bone health and osteoporotic fracture risk in paralyzed individuals with spinal cord injury. C1 [Tan, C. O.; Doherty, A. L.; Zafonte, R.; Morse, L. R.] Spaulding Rehabil Hosp, Spaulding Harvard SCI Model Syst, Boston, MA USA. [Tan, C. O.; Zafonte, R.; Morse, L. R.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Morse, L. R.] Forsyth Inst, Cambridge, MA 02115 USA. [Battaglino, R. A.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Gupta, R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Lazzari, A. A.] Boston Univ Sch Med, Primary Care Sect, VA Boston Healthcare Syst, Boston, MA USA. [Lazzari, A. A.] Boston Univ Sch Med, Rheumatol Sect, VA Boston Healthcare Syst, Boston, MA USA. [Garshick, E.] VA Boston Healthcare Syst, Pulm & Crit Care Med Sect, Med Serv, Boston, MA USA. [Garshick, E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. RP Morse, LR (reprint author), Forsyth Inst, Cambridge, MA 02115 USA. EM Leslie.morse@mgh.harvard.edu RI battaglino, ricardo/D-2892-2015; Morse, Leslie/C-9442-2015; Tan, Can Ozan/E-2598-2016 OI Morse, Leslie/0000-0002-7426-6341; Tan, Can Ozan/0000-0001-9673-9907 FU Department of Defense [W81XWH-10-1-1043]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [1R01AR059270-01]; Department of Education, National Institute on Disability and Rehabilitation Research [H133N110010] FX We thank Sam Davis, clinical research coordinator and technician, Boston VA Healthcare System, for assisting with bone density scans; and Rachael Burns and Kara Loo, research assistants, Boston VA Healthcare System, for collection of anthropometric data. This study received support from the Department of Defense (W81XWH-10-1-1043), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (1R01AR059270-01), and the Department of Education, National Institute on Disability and Rehabilitation Research (H133N110010). NR 43 TC 3 Z9 3 U1 0 U2 10 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD NOV PY 2014 VL 25 IS 11 BP 2599 EP 2607 DI 10.1007/s00198-014-2786-2 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS3HE UT WOS:000344167500010 PM 24980185 ER PT J AU Sethi, RKV Kozin, ED Fagenholz, PJ Lee, DJ Shrime, MG Gray, ST AF Sethi, Rosh K. V. Kozin, Elliott D. Fagenholz, Peter J. Lee, Daniel J. Shrime, Mark G. Gray, Stacey T. TI Epidemiological Survey of Head and Neck Injuries and Trauma in the United States SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE otolaryngology; head and neck; trauma; injury; emergency department ID FACIAL FRACTURES; RISK-FACTORS; MANAGEMENT; OUTCOMES; PATTERNS; SURGERY; COSTS AB Objective. Head and neck trauma results in a range of injuries, spanning minor lacerations to life-threatening airway compromise. Few studies provide in-depth analysis of injuries to the head and neck (HN). We aim to (1) describe HN injury prevalence in the US and (2) investigate patient disposition and the outcome of mortality. Study Design. Case series with chart review. Setting. Nationwide emergency department (ED) sample. Methods. The 2011 database was queried for encounters with a primary diagnosis of HN injury, as categorized by the Barell Injury Matrix. Weighted estimates for demographics, injury category, and mechanism were extracted. Predictors of mortality and admission were determined by multivariable regression. Results. We identified 131 million ED encounters. A weighted total of 5,418,539 visits were related to primary HN injuries. Average age was 30 (SE = 0.4), and 56.8% were male. Sixty-four percent of injuries were attributed to fall or blunt trauma. Open wounds comprised 41.8% of injuries. The most common procedure was laceration repair (70%). The majority of patients (97%) were discharged home. Mortality rate was less than 1%. Predictors of admission and mortality (P < .05) included multiple trauma, vessel trauma, and burns. Other risk factors included foreign-body, older age, and male gender. Conclusions. Primary HN injuries commonly present to emergency rooms in the US. The majority of HN injuries are non-life threatening and do not require admission to the hospital or result in death. These data have implications for HN injury surveillance and may be used to risk-stratify patients who present with injuries in the acute care setting. C1 [Sethi, Rosh K. V.; Kozin, Elliott D.; Lee, Daniel J.; Shrime, Mark G.; Gray, Stacey T.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Sethi, Rosh K. V.; Kozin, Elliott D.; Lee, Daniel J.; Shrime, Mark G.; Gray, Stacey T.] Massachusetts Gen Hosp, Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. [Fagenholz, Peter J.] Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Shrime, Mark G.] Harvard Interfac Initiat Hlth Policy, Cambridge, MA USA. RP Kozin, ED (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. EM Elliott_kozin@meei.harvard.edu RI Kozin, Elliott/J-1225-2014 OI Kozin, Elliott/0000-0002-0305-0682 FU NIDCD NIH HHS [T32 DC000020] NR 27 TC 5 Z9 5 U1 0 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD NOV PY 2014 VL 151 IS 5 BP 776 EP 784 DI 10.1177/0194599814546112 PG 9 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AS6FO UT WOS:000344360100011 PM 25139950 ER PT J AU Steinberg, WM Nauck, MA Zinman, B Daniels, GH Bergenstal, RM Mann, JFE Ravn, LS Moses, AC Stockner, M Baeres, FMM Marso, SP Buse, JB AF Steinberg, William M. Nauck, Michael A. Zinman, Bernard Daniels, Gilbert H. Bergenstal, Richard M. Mann, Johannes F. E. Ravn, Lasse Steen Moses, Alan C. Stockner, Mette Baeres, Florian M. M. Marso, Steven P. Buse, John B. CA LEADER Trial Investigators TI LEADER 3-Lipase and Amylase Activity in Subjects With Type 2 Diabetes Baseline Data From Over 9000 Subjects in the LEADER Trial SO PANCREAS LA English DT Article DE pancreatitis; lipase; amylase; type 2 diabetes ID ACUTE-PANCREATITIS; ALPHA-AMYLASE; LIPASE; EXENATIDE; LIRAGLUTIDE; RISK; OBESITY; CANCER; COHORT; SERUM AB Objectives: This report from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial describes baseline lipase and amylase activity in type 2 diabetic subjects without acute pancreatitis symptoms before randomization to the glucagonlike peptide analog liraglutide or placebo. Methods: The LEADER is an international randomized placebo-controlled trial evaluating the cardiovascular safety of liraglutide in 9340 type 2 diabetic patients at high cardiovascular risk. Fasting lipase and amylase activity was assessed at baseline, before receiving liraglutide or placebo, using a commercial assay (Roche) with upper limit of normal values of 63 U/L for lipase and 100 U/L for amylase. Results: Either or both enzymes were above the upper limit of normal in 22.7% of subjects; 16.6%(n = 1540) had an elevated lipase level (including 1.2% >3-fold elevated), and 11.8% (n = 1094) had an elevated amylase level (including 0.2% >3-fold elevated). In multivariable regression models, severely reduced kidney function was associated with the largest effect on increasing activity of both. However, even among subjects with normal kidney function, 12.2% and 7.7% had elevated lipase and amylase levels. Conclusions: In this large study of type 2 diabetic patients, nearly 25% had elevated lipase or amylase levels without symptoms of acute pancreatitis. The clinician must take these data into account when evaluating abdominal symptoms in type 2 diabetic patients. C1 [Steinberg, William M.] George Washington Univ, Med Ctr, Dept Med, Rockville, MD 20854 USA. [Nauck, Michael A.] Diabet Zentrum Bad Lauterberg, Dept Internal Med Diabetol, Bad Lauterberg Im Harz, Germany. [Zinman, Bernard] Univ Toronto, Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Dept Med, Toronto, ON M5G 1X5, Canada. [Daniels, Gilbert H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Thyroid Unit, Boston, MA USA. [Daniels, Gilbert H.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Bergenstal, Richard M.] Pk Nicollet Inst Res & Educ, Int Diabet Ctr, Minneapolis, MN USA. [Mann, Johannes F. E.] Univ Erlangen Nurnberg, Dept Med, D-91054 Erlangen, Germany. [Ravn, Lasse Steen; Moses, Alan C.; Stockner, Mette; Baeres, Florian M. M.] Novo Nordisk AS, Bagsvaerd, Denmark. [Marso, Steven P.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Cardiol, Dallas, TX 75390 USA. [Buse, John B.] Univ N Carolina, Sch Med, Dept Med, Div Endocrinol, Chapel Hill, NC USA. RP Steinberg, WM (reprint author), George Washington Univ, Rockville Internal Med Grp, Dept Med, 1201 Seven Locks Rd, Rockville, MD 20854 USA. EM wstein6905@aol.com RI Zinman, Bernard/E-7266-2013; BALCI, Mustafa Kemal/C-2979-2016 OI BALCI, Mustafa Kemal/0000-0002-6494-3249 NR 43 TC 17 Z9 17 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1223 EP 1231 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600015 PM 25275271 ER PT J AU Biczo, G Vegh, ET Shalbueva, N French, SW Elperin, J Lotshaw, E Mareninova, OA Hegyi, P Rakonczay, Z Gukovskaya, AS AF Biczo, G. Vegh, E. T. Shalbueva, N. French, S. W. Elperin, J. Lotshaw, E. Mareninova, O. A. Hegyi, P. Rakonczay, Z., Jr. Gukovskaya, A. S. TI Mitochondrial ATP Synthase Dysfunction Mediates L-arginine-Induced Pancreatitis SO PANCREAS LA English DT Meeting Abstract C1 [Biczo, G.; Vegh, E. T.; Shalbueva, N.; Elperin, J.; Lotshaw, E.; Mareninova, O. A.; Gukovskaya, A. S.] VA Greater Los Angeles, Los Angeles, CA USA. [Biczo, G.; Vegh, E. T.; Shalbueva, N.; Elperin, J.; Lotshaw, E.; Mareninova, O. A.; Gukovskaya, A. S.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Biczo, G.; Vegh, E. T.; Hegyi, P.; Rakonczay, Z., Jr.] Univ Szeged, Szeged, Hungary. [French, S. W.] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1344 EP 1345 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600055 ER PT J AU Das, KK Marchegiani, G Geng, X Xiao, H Huynh, T Fernandez-del Castillo, C Pitman, MB Das, KM Mino-Kenudson, M AF Das, K. K. Marchegiani, G. Geng, X. Xiao, H. Huynh, T. Fernandez-del Castillo, C. Pitman, M. B. Das, K. M. Mino-Kenudson, M. TI Comparison of the International Consensus Guidelines for Management of Intraductal Papillary Mucinous Neoplasm (IPMN) With Analysis of Pancreatic Cyst Fluid Aspirates for mAb Das-1 Reactivity in Identifying High-risk and Malignant IPMN SO PANCREAS LA English DT Meeting Abstract C1 [Das, K. K.] Univ Penn, Div Gastroenterol, Philadelphia, PA 19104 USA. [Marchegiani, G.; Fernandez-del Castillo, C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Xiao, H.; Huynh, T.; Pitman, M. B.; Mino-Kenudson, M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Geng, X.; Das, K. M.] Rutgers RWJMS, Div Gastroenterol, New Brunswick, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1352 EP 1352 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600085 ER PT J AU Maertin, S Nitsche, CJ Elperin, JM Sendler, M Grippo, PJ Eibl, G Mayerle, J Lerch, MM Gukovskaya, AS AF Maertin, S. Nitsche, C. J. Elperin, J. M. Sendler, M. Grippo, P. J. Eibl, G. Mayerle, J. Lerch, M. M. Gukovskaya, A. S. TI Prosurvival Effect of Autophagy in Pancreatic Cancer Cells is Determined by Kras and p53 Mutational Status SO PANCREAS LA English DT Meeting Abstract C1 [Maertin, S.; Elperin, J. M.; Gukovskaya, A. S.] VA Greater Los Angeles, Los Angeles, CA USA. [Maertin, S.; Eibl, G.; Gukovskaya, A. S.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Maertin, S.; Nitsche, C. J.; Sendler, M.; Mayerle, J.; Lerch, M. M.] Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany. [Grippo, P. J.] Univ Illinois, Chicago, IL USA. RI Lerch, Markus M./E-2206-2016 OI Lerch, Markus M./0000-0002-9643-8263 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1386 EP 1386 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600228 ER PT J AU Marchegiani, G Paulo, JA Sahora, K Fernandez-del Castillo, C AF Marchegiani, G. Paulo, J. A. Sahora, K. Fernandez-del Castillo, C. TI The Proteome of Surgical Pancreatic Juice SO PANCREAS LA English DT Meeting Abstract C1 [Marchegiani, G.; Sahora, K.; Fernandez-del Castillo, C.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Paulo, J. A.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1388 EP 1388 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600236 ER PT J AU Marchegiani, G Kenudson, MM Ferrone, C Warshaw, AL Lillemoe, K Fernandez-del Castillo, C AF Marchegiani, G. Kenudson, M. Mino Ferrone, C. Warshaw, A. L. Lillemoe, K. Fernandez-del Castillo, C. TI Oncocytic Type IPMN: A Unique Malignant Subset With Good Long-Term Prognosis SO PANCREAS LA English DT Meeting Abstract C1 [Marchegiani, G.; Ferrone, C.; Warshaw, A. L.; Lillemoe, K.; Fernandez-del Castillo, C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Kenudson, M. Mino] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1388 EP 1388 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600235 ER PT J AU Nakagawa, A Mino-Kenudson, M Lillemoe, KD Fernandez-del Castillo, C Warshaw, AL Thayer, SP Liss, AS AF Nakagawa, A. Mino-Kenudson, M. Lillemoe, K. D. Fernandez-del Castillo, C. Warshaw, A. L. Thayer, S. P. Liss, A. S. TI Pancreatic Tuft Cells Principally Reside in the Ampulla and Proximal Intrapancreatic Biliary Duct in Mouse and Exhibit Increased Expression and Altered Localization in Response to Inflammatory Injury SO PANCREAS LA English DT Meeting Abstract C1 [Nakagawa, A.; Lillemoe, K. D.; Fernandez-del Castillo, C.; Warshaw, A. L.; Thayer, S. P.; Liss, A. S.] Massachusetts Gen Hosp, Warshaw Inst Pancreat Canc Res, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Mino-Kenudson, M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1394 EP 1395 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600263 ER PT J AU Pimienta, M Lee, GE Gukovskaya, AS Gukovsky, I Mareninova, OA AF Pimienta, M. Lee, G. E. Gukovskaya, A. S. Gukovsky, I. Mareninova, O. A. TI mTOR Mediates p62/SQSTM1 Synthesis in Pancreatic Acinar Cells SO PANCREAS LA English DT Meeting Abstract C1 Univ Calif Los Angeles, VA Greater Los Angeles, Los Angeles, CA USA. Southern Calif Res Ctr ALPD & Cirrhosis, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1401 EP 1401 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600289 ER PT J AU Soll, AH Keefer, LA Streiner, DL Lee, ML Freedman, SD Mahvi, D Buxbaum, J Pandol, S Lo, S AF Soll, A. H. Keefer, L. A. Streiner, D. L. Lee, M. L. Freedman, S. D. Mahvi, D. Buxbaum, J. Pandol, S. Lo, S. TI A Comprehensive Biopsychosocial (BPS) Assessment of Patients With Pancreatobiliary Disorders (PD) Illuminates Mechanisms Underlying Symptoms and Alters Clinical Decision-Making SO PANCREAS LA English DT Meeting Abstract C1 Univ Calif Los Angeles, Los Angeles, CA USA. Northwestern, Chicago, IL USA. BIDMC, Boston, MA USA. Cedars Sinai, Los Angeles, CA USA. USC, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1409 EP 1409 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600324 ER PT J AU Wu, SV Pham, H Million, M Chen, MC Go, VLW Jiang, M AF Wu, S. V. Pham, H. Million, M. Chen, M. C. Go, V. L. W. Jiang, M. TI Expression and Functional Characterization of Bitter Taste Receptors in Rat Pancreas SO PANCREAS LA English DT Meeting Abstract C1 [Wu, S. V.; Chen, M. C.; Go, V. L. W.] Univ Calif Los Angeles, Ctr Excellence Pancreat Dis, Los Angeles, CA USA. [Pham, H.; Million, M.] Univ Calif Los Angeles, Dept Med, Div Digest Dis, Los Angeles, CA 90024 USA. [Jiang, M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pharmacol, Los Angeles, CA 90095 USA. [Wu, S. V.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1422 EP 1422 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600381 ER PT J AU Wu, SV Chen, MC Tache, Y Go, VLW AF Wu, S. V. Chen, M. C. Tache, Y. Go, V. L. W. TI Characterization of Corticotropin-Releasing Hormone (CRH) Type I System in Human Pancreatic Endocrine Tumors SO PANCREAS LA English DT Meeting Abstract C1 [Wu, S. V.; Chen, M. C.; Go, V. L. W.] Univ Calif Los Angeles, David Geffen Sch Med, Ctr Excellence Pancreat Dis, Los Angeles, CA 90095 USA. [Wu, S. V.; Tache, Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 EI 1536-4828 J9 PANCREAS JI Pancreas PD NOV PY 2014 VL 43 IS 8 BP 1423 EP 1423 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS6GO UT WOS:000344362600384 ER PT J AU Powis, K Lockman, S Smeaton, L Hughes, MD Fawzi, W Ogwu, A Moyo, S van Widenfelt, E von Oettingen, J Makhema, J Essex, M Shapiro, RL AF Powis, Kathleen Lockman, Shahin Smeaton, Laura Hughes, Michael D. Fawzi, Wafaie Ogwu, Anthony Moyo, Sikhulile van Widenfelt, Erik von Oettingen, Julia Makhema, Joseph Essex, Max Shapiro, Roger L. TI Vitamin D Insufficiency in HIV-infected Pregnant Women Receiving Antiretroviral Therapy is Not Associated With Morbidity, Mortality or Growth Impairment in Their Uninfected Infants in Botswana SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE HIV-exposed uninfected infants; maternal vitamin D; morbidity; mortality; growth ID SUB-SAHARAN AFRICA; CHILD-MORTALITY; D DEFICIENCY; OUTCOMES; AGE; UNDERNUTRITION; TRANSMISSION; PNEUMONIA; COUNTRIES; TANZANIA AB Background: Low maternal 25(OH) D (vitamin D) values have been associated with higher mortality and impaired growth among HIV-exposed uninfected (HEU) infants of antiretroviral (ART)-naive women. These associations have not been studied among HEU infants of women receiving ART. Methods: We performed a nested case-control study in the Botswana Mma Bana Study, a study providing ART to women during pregnancy and breast-feeding. Median maternal vitamin D values, and the proportion with maternal vitamin D insufficiency, were compared between women whose HEU infants experienced morbidity/mortality during 24 months of follow-up and women with nonhospitalized HEU infants. Growth faltering was assessed for never hospitalized infants attending the 24-month-of-life visit. Multivariate logistic regression models determined associations between maternal vitamin D insufficiency and infant morbidity/mortality and growth faltering. Results: Delivery plasma was available and vitamin D levels assayable from 119 (86%) of 139 cases and 233 (84%) of 278 controls, and did not differ significantly between cases and controls [median: 36.7 ng/mL, interquartile range (IQR): 29.1-44.7 vs. 37.1 ng/mL, IQR: 30.0-47.2, P = 0.32]. Vitamin D insufficiency (<32 ng/mL) was recorded among 112 (31.8%) of 352 women at delivery and occurred most frequently among women delivering in winter. Multivariate logistic regression models adjusted for maternal HIV disease progression did not show associations between maternal vitamin D insufficiency at delivery and child morbidity/mortality, or 24-month-of-life growth faltering. Conclusions: Vitamin D insufficiency was common among ART-treated pregnant women in Botswana, but was not associated with morbidity, mortality or growth impairment in their HIV-uninfected children. C1 [Powis, Kathleen] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Powis, Kathleen] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Powis, Kathleen; Lockman, Shahin; Essex, Max; Shapiro, Roger L.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Powis, Kathleen; Lockman, Shahin; Ogwu, Anthony; Moyo, Sikhulile; van Widenfelt, Erik; Makhema, Joseph; Essex, Max; Shapiro, Roger L.] Botswana Harvard AIDS Inst Partnership, Gaborone, Botswana. [Lockman, Shahin] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Smeaton, Laura; Hughes, Michael D.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Fawzi, Wafaie] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [von Oettingen, Julia] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA. [Shapiro, Roger L.] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. RP Powis, K (reprint author), 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM kpowis@partners.org RI Moyo, Sikhulile/E-1464-2015; OI Moyo, Sikhulile/0000-0003-3821-4592; von Oettingen, Julia Elisabeth/0000-0003-0631-1435 FU National Institute of Allergy and Infectious Diseases [U01-AI066454]; Brigham and Women's Global Women's Health Fellowship; Harvard University Center for AIDS Research [P30 AI060354]; National Institute of Child Health and Human Development Grant [1K23HD070774-01A1]; Fogarty AITRP [D43 TW000004] FX Mma Bana study was supported by a grant (U01-AI066454) from the National Institute of Allergy and Infectious Diseases. Funding support from Brigham and Women's Global Women's Health Fellowship supported K.P.'s salary during the Mma Bana study. K. P. received salary support from a Harvard University Center for AIDS Research grant (P30 AI060354) and a National Institute of Child Health and Human Development Grant (1K23HD070774-01A1) for this project. The Fogarty AITRP grant (D43 TW000004) provided funding for A.O. and S. M. Mma Bana study drugs were provided by Abbott Pharmaceuticals, GlaxoSmithKline, and the government of Botswana. NR 38 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 EI 1532-0987 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD NOV PY 2014 VL 33 IS 11 BP 1141 EP 1147 DI 10.1097/INF.0000000000000428 PG 7 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA AS6DH UT WOS:000344354400015 PM 25037041 ER PT J AU Tyson, ME Bohl, DD Blickman, JG AF Tyson, Mary E. Bohl, Daniel D. Blickman, Johan G. TI A randomized controlled trial: child life services in pediatric imaging SO PEDIATRIC RADIOLOGY LA English DT Article DE Randomized controlled trial; Child life specialists; Family-centered care; Pediatric imaging sciences; Child distress; Parent satisfaction ID HOSPITALIZED CHILDREN; PREPARING CHILDREN; PSYCHOLOGICAL INTERVENTIONS; EMERGENCY-DEPARTMENT; LACERATION REPAIR; PAIN MANAGEMENT; MRI; DISTRESS; SEDATION; THERAPY AB Children undergoing procedures in pediatric health care facilities and their families have been shown to benefit from psychosocial services and interventions such as those provided by a Certified Child Life Specialist (CCLS). The comprehensive impact of a CCLS in a pediatric imaging department is well recognized anecdotally but has not been examined in a prospective or randomized controlled fashion. We prospectively assessed the impact of a CCLS on parent satisfaction, staff satisfaction, child satisfaction, and parent and staff perceptions of child pain and distress in a pediatric imaging department. Eligible children between 1 and 12 years of age (n = 137) presenting to the pediatric imaging department for an imaging procedure were randomly assigned to an intervention or control arm. Those assigned to the intervention received the comprehensive services of a CCLS. The control group received standard of care, which did not include any child life services. Quantitative measures of satisfaction and perception of child pain and distress were assessed by parents and staff using a written 5-point Likert scale questionnaire after the imaging procedure. Children 4 and older were asked to answer 3 questions on a 3-point scale. Statistically significant differences between the intervention and control groups were found in 19 out of 24 measures. Parents in the intervention group indicated higher satisfaction and a lower perception of their child's pain and distress. Staff in the intervention group indicated greater child cooperation and a lower perception of the child's pain and distress. Children in the intervention group indicated a better overall experience and less fear than those in the control group. Child life specialists have a quantifiably positive impact on the care of children in imaging departments. Measures of parent satisfaction, staff satisfaction, child satisfaction, child pain and child distress are shown to be positively impacted by the services of a CCLS. These results have significant implications for hospitals striving to increase satisfaction, decrease costs and improve quality of care. In a health care landscape that is changing quickly and increasingly focused on the cost of care, future research should assess whether the core tenants of the child life profession support and contribute quantifiably to high-quality, cost-effective practices in health care. C1 [Tyson, Mary E.; Blickman, Johan G.] Univ Rochester, Med Ctr, Golisano Childrens Hosp, Rochester, NY 14642 USA. [Tyson, Mary E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bohl, Daniel D.] Yale Univ, Sch Med, New Haven, CT USA. RP Tyson, ME (reprint author), 601 Elwood Ave,Box 648, Rochester, NY 14642 USA. EM Mary_Tyson@dfci.harvard.edu NR 79 TC 7 Z9 7 U1 3 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 EI 1432-1998 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD NOV PY 2014 VL 44 IS 11 BP 1426 EP 1432 DI 10.1007/s00247-014-3005-1 PG 7 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA AS3HF UT WOS:000344167600015 PM 24801818 ER PT J AU Lemly, DC Lawlor, K Scherer, EA Kelemen, S Weitzman, ER AF Lemly, Diana C. Lawlor, Katherine Scherer, Emily A. Kelemen, Skyler Weitzman, Elissa R. TI College Health Service Capacity to Support Youth With Chronic Medical Conditions SO PEDIATRICS LA English DT Article DE health care transition; young adults; college/university health; chronic medical conditions/special health care needs ID CARE NEEDS; YOUNG-ADULTS; INCREASING INCIDENCE; CHRONIC ILLNESS; UNITED-STATES; ADOLESCENTS; CHILDREN; TYPE-1; TRANSITION; STUDENTS AB BACKGROUND AND OBJECTIVE: Twenty percent of US youth have a chronic medical condition and many attend college. Guidelines for transition from pediatric to adult care do not address college health services, and little is known about their capacity to identify, support, and provide care for these youth. The objective of this study was to describe college health center policies, practices, and resources for youth with chronic medical conditions (YCMC). METHODS: Survey of medical directors from health centers of a representative sample of 200 4-year US colleges with >= 400 enrolled undergraduate students. Patterns of identification, management, and support for youth with a general chronic medical condition and with asthma, diabetes, and depression, were investigated; chi(2) and Fisher exact tests were used to ascertain differences by institutional demographics. RESULTS: Directors at 153 institutions completed the survey (76.5% response rate). Overall, 42% of schools had no system to identify YCMC. However, almost a third (31%) did identify and add to a registry of incoming YCMC on review of medical history, more likely in private (P < .001) and small (<5000 students, P = .002) colleges; 24% of health centers contacted YCMC to check-in/make initial appointments. Most institutions could manage asthma and depression (83% and 69%, respectively); 51% could manage diabetes on campus. CONCLUSIONS: Relatively few US colleges have health systems to identify and contact YCMC, although many centers have capacity to provide primary care and management of some conditions. Guidelines for transition should address policy and practices for pediatricians and colleges to enhance comanagement of affected youth. C1 [Lemly, Diana C.; Lawlor, Katherine; Scherer, Emily A.; Weitzman, Elissa R.] Boston Childrens Hosp, Div Adolescent Young Adult Med, Boston, MA USA. [Kelemen, Skyler; Weitzman, Elissa R.] Boston Childrens Hosp, Dept Emergency Med, Boston, MA USA. [Lemly, Diana C.; Scherer, Emily A.; Weitzman, Elissa R.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Scherer, Emily A.] Geisel Sch Med Dartmouth, Hanover, NH USA. RP Lemly, DC (reprint author), Massachusetts Gen Hosp, Div Adolescent & Young Adult Med, 55 Fruit St, Boston, MA 02114 USA. EM dlemly@partners.org FU Leadership Education in Adolescent Health training grant from the Maternal and Child Health Bureau, Health Resources and Services Administration [T71MC00009]; Gallagher Grant, Adolescent Division Boston Children's Hospital; Boston Children's Hospital Program for Patient Safety and Quality; Center for Integration of Medicine and Innovative Technology [220376]; National Institute on Alcohol Abuse and Alcoholism [1R01AA021913-01]; Harvard Catalyst under parent National Institute of Health [027343.386541.05230, 1U54RR025224-0]; National Institutes of Health (NIH) FX Funded in part by Leadership Education in Adolescent Health training grant T71MC00009 from the Maternal and Child Health Bureau, Health Resources and Services Administration (Dr Lemly, trainee); the Gallagher Grant, Adolescent Division Boston Children's Hospital to Dr Lemly; and to Dr Weitzman, an intramural research grant from the Boston Children's Hospital Program for Patient Safety and Quality, award 220376 from the Center for Integration of Medicine and Innovative Technology, award 1R01AA021913-01 from the National Institute on Alcohol Abuse and Alcoholism and award 027343.386541.05230 from the Harvard Catalyst under parent National Institute of Health award 1U54RR025224-0. Funded by the National Institutes of Health (NIH). NR 41 TC 6 Z9 6 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2014 VL 134 IS 5 BP 885 EP 891 DI 10.1542/peds.2014-1304 PG 7 WC Pediatrics SC Pediatrics GA AS6PU UT WOS:000344385900036 PM 25349315 ER PT J AU Winickoff, JP Nabi-Burza, E Chang, YC Regan, S Drehmer, J Finch, S Wasserman, R Ossip, D Hipple, B Woo, H Klein, J Rigotti, NA AF Winickoff, Jonathan P. Nabi-Burza, Emara Chang, Yuchiao Regan, Susan Drehmer, Jeremy Finch, Stacia Wasserman, Richard Ossip, Deborah Hipple, Bethany Woo, Heide Klein, Jonathan Rigotti, Nancy A. TI Sustainability of a Parental Tobacco Control Intervention in Pediatric Practice SO PEDIATRICS LA English DT Article DE parental smoking; smoking cessation; secondhand smoke ID SMOKING-CESSATION; ADOLESCENT SMOKING; UNITED-STATES; CHILDREN; EXPOSURE; HEALTH; SMOKERS; PROTECT; LEAD; CARE AB OBJECTIVE: To determine whether an evidence-based pediatric outpatient intervention for parents who smoke persisted after initial implementation. METHODS: A cluster randomized controlled trial of 20 pediatric practices in 16 states that received either Clinical and Community Effort Against Second- hand Smoke Exposure (CEASE) intervention or usual care. The intervention provided practices with training to provide evidence-based assistance to parents who smoke. The primary outcome, assessed by the 12-month follow-up telephone survey with parents, was provision of meaningful tobacco control assistance, defined as discussing various strategies to quit smoking, discussing smoking cessation medication, or recommending the use of the state quitline after initial enrollment visit. We also assessed parental quit rates at 12 months, determined by self-report and biochemical verification. RESULTS: Practices' rates of providing any meaningful tobacco control assistance (55% vs 19%), discussing various strategies to quit smoking (25% vs 10%), discussing cessation medication (41% vs 11%), and recommending the use of the quitline (37% vs 9%) were all significantly higher in the intervention than in the control groups, respectively (P<.0001 for each), during the 12-month postintervention implementation. Receiving any assistance was associated with a cotinine-confirmed quitting adjusted odds ratio of 1.89 (95% confidence interval: 1.13-3.19). After controlling for demographic and behavioral factors, the adjusted odds ratio for cotinine-confirmed quitting in intervention versus control practices was 1.07 (95% confidence interval: 0.64-1.78). CONCLUSIONS: Intervention practices had higher rates of delivering tobacco control assistance than usual care practices over the 1-year follow-up period. Parents who received any assistance were more likely to quit smoking; however, parents' likelihood of quitting smoking was not statistically different between the intervention and control groups. Maximizing parental quit rates will require more complete systems-level integration and adjunctive cessation strategies. C1 [Winickoff, Jonathan P.; Nabi-Burza, Emara; Drehmer, Jeremy; Hipple, Bethany] Massachusetts Gen Hosp Children, Div Gen Acad Pediat, Ctr Child & Adolescent Hlth Res & Policy, Boston, MA 02114 USA. [Winickoff, Jonathan P.; Klein, Jonathan] AAP Richmond Ctr Excellence, Elk Grove Village, IL USA. [Finch, Stacia; Wasserman, Richard; Woo, Heide] Amer Acad Pediat, Elk Grove Village, IL USA. [Winickoff, Jonathan P.; Nabi-Burza, Emara; Chang, Yuchiao; Regan, Susan; Drehmer, Jeremy; Hipple, Bethany; Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Chang, Yuchiao; Regan, Susan; Rigotti, Nancy A.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Wasserman, Richard] Univ Vermont, Dept Pediat, Burlington, VT USA. [Ossip, Deborah] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Woo, Heide] Univ Calif Los Angeles, Los Angeles, CA USA. RP Winickoff, JP (reprint author), Massachusetts Gen Hosp Children, Div Gen Acad Pediat, Ctr Child & Adolescent Hlth Res & Policy, 15th Floor,Suite 1542A,100 Cambridge St, Boston, MA 02114 USA. EM jwinickoff@partners.org RI Wasserman , Richard/G-3775-2015; OI Drehmer, Jeremy/0000-0002-5022-5836 FU National Institutes of Health National Cancer Institute [R01-CA127127]; National Institute on Drug Abuse; Agency for Healthcare Research and Quality; Flight Attendant Medical Research Institute; Pediatric Research in Office Settings (PROS) Network; Health Resources and Services Administration Maternal and Child Health Bureau [UA6MC15585]; American Academy of Pediatrics; National Institutes of Health (NIH) FX This study was supported by the National Institutes of Health National Cancer Institute grant R01-CA127127 (to Dr Winickoff), the National Institute on Drug Abuse, and the Agency for Healthcare Research and Quality. This study was also partially supported by a grant from the Flight Attendant Medical Research Institute to the AAP Julius B. Richmond Center and the Pediatric Research in Office Settings (PROS) Network, which receives core funding from the Health Resources and Services Administration Maternal and Child Health Bureau (UA6MC15585) and the American Academy of Pediatrics. Funded by the National Institutes of Health (NIH). NR 36 TC 9 Z9 9 U1 1 U2 7 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2014 VL 134 IS 5 BP 933 EP 941 DI 10.1542/peds.2014-0639 PG 9 WC Pediatrics SC Pediatrics GA AS6PU UT WOS:000344385900042 PM 25332492 ER PT J AU Van Cleave, J AF Van Cleave, Jeanne TI Escalating Violence in PG-13 Movies SO PEDIATRICS LA English DT Editorial Material DE violence; movie ID CHILDREN C1 [Van Cleave, Jeanne] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. [Van Cleave, Jeanne] MassGen Hosp Children, Div Gen Acad Pediat, Boston, MA USA. RP Van Cleave, J (reprint author), 15th Floor C100,100 Cambridge St, Boston, MA 02144 USA. EM jvancleave@partners.org NR 7 TC 0 Z9 0 U1 1 U2 7 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2014 VL 134 IS 5 BP 1024 EP 1025 DI 10.1542/peds.2014-2803 PG 2 WC Pediatrics SC Pediatrics GA AS6PU UT WOS:000344385900052 PM 25332493 ER PT J AU Sullivan, DR Ganzini, L Lopez-Chavez, A Slatore, CG AF Sullivan, Donald R. Ganzini, Linda Lopez-Chavez, Ariel Slatore, Christopher G. TI Association of patient characteristics with chemotherapy receipt among depressed and non-depressed patients with non-small cell lung cancer SO PSYCHO-ONCOLOGY LA English DT Article DE Depression; Lung Cancer; Epidemiology; Treatment Receipt; Race ID RACIAL-DIFFERENCES; DISPARITIES; TRENDS; COMORBIDITY; OUTCOMES; IMPACT; AGE C1 [Sullivan, Donald R.; Ganzini, Linda; Slatore, Christopher G.] Portland VA Med Ctr, Portland, OR USA. [Sullivan, Donald R.; Slatore, Christopher G.] Oregon Hlth & Sci Univ, Dept Med, Div Pulm & Crit Care Med, Portland, OR 97201 USA. [Ganzini, Linda] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Lopez-Chavez, Ariel] Oregon Hlth & Sci Univ, Dept Med, Div Hematol & Med Oncol, Portland, OR 97201 USA. [Slatore, Christopher G.] Portland VA Med Ctr, Sect Pulm & Crit Care Med, Portland, OR USA. RP Sullivan, DR (reprint author), 3710 SW US Vet Hosp Rd,R&D 66, Portland, OR 97239 USA. EM sullivad@ohsu.edu OI Sullivan, Donald/0000-0003-3266-3389; Slatore, Christopher/0000-0003-0958-8122 FU NCATS NIH HHS [UL1 TR000128, UL1TR000128]; NHLBI NIH HHS [5 T32 HL083808-05-32, T32 HL083808] NR 18 TC 1 Z9 1 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 EI 1099-1611 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD NOV PY 2014 VL 23 IS 11 BP 1318 EP 1322 DI 10.1002/pon.3528 PG 5 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA AS4JX UT WOS:000344242500016 PM 24771684 ER PT J AU Grant, P Sakellis, C Jacene, HA AF Grant, Paul Sakellis, Christopher Jacene, Heather A. TI Gynecologic Oncologic Imaging With PET/CT SO SEMINARS IN NUCLEAR MEDICINE LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; RECURRENT OVARIAN-CANCER; ADVANCED CERVICAL-CANCER; PARAAORTIC NODAL METASTASIS; POST-THERAPY SURVEILLANCE; SQUAMOUS-CELL CARCINOMA; SECONDARY CYTOREDUCTIVE SURGERY; GASTROINTESTINAL STROMAL TUMORS; CLINICAL-PRACTICE GUIDELINES; STANDARDIZED UPTAKE VALUE AB FDG-PET/CT has been evaluated in a variety of gynecologic malignancies in a variety of settings and is approved by the Centers for Medicare & Medicaid Services for the initial and subsequent treatment strategies of these malignancies. Cervical cancer is typically very FDG avid, and FDG-PET/CT appears to be most valuable for initial staging, radiation therapy planning, and detection of recurrent disease. For ovarian cancer, the most value of FDG-PET/ CT appears to be for detecting recurrent disease in the setting of rising CA-125 level and negative or equivocal anatomical imaging studies. Initial studies evaluating response to therapy are promising and further work in this area is needed. FDG uptake in both nonmalignant and physiological processes in the pelvis can make interpretation of FDG-PET/CT in this region challenging and knowledge of these entities and patterns can avoid misinterpretation. Some of the most common findings relate to the cyclic changes that occur as part of the menstrual cycle in premenopausal women. Mucinous tumors and low-volume or peritoneal carcinomatosis are causes of false-negative results on FDG-PET/CT studies. As new tracers are developed, comparisons with patient outcomes and standards of care (eg, FDG-PET/CD will be needed. (C) 2014 Elsevier Inc. All rights reserved. C1 [Grant, Paul; Sakellis, Christopher; Jacene, Heather A.] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Grant, Paul; Sakellis, Christopher; Jacene, Heather A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA USA. RP Jacene, HA (reprint author), 450 Brookline Ave,DL203, Boston, MA 02215 USA. EM hjacene@partners.org NR 151 TC 6 Z9 6 U1 3 U2 17 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0001-2998 EI 1558-4623 J9 SEMIN NUCL MED JI Semin. Nucl. Med. PD NOV PY 2014 VL 44 IS 6 BP 461 EP 478 DI 10.1053/j.semnuclmed.2014.06.005 PG 18 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AS3WQ UT WOS:000344206400007 PM 25362236 ER PT J AU Tracy, M Morgenstern, H Zivin, K Aiello, AE Galea, S AF Tracy, Melissa Morgenstern, Hal Zivin, Kara Aiello, Allison E. Galea, Sandro TI Traumatic event exposure and depression severity over time: results from a prospective cohort study in an urban area SO SOCIAL PSYCHIATRY AND PSYCHIATRIC EPIDEMIOLOGY LA English DT Article DE Depression; Traumatic events; Stressful events; Violence; Injuries ID POSTTRAUMATIC-STRESS-DISORDER; NATIONAL COMORBIDITY SURVEY; POPULATION-BASED COHORT; PRIMARY-CARE PATIENTS; LIFE EVENTS; GENERAL-POPULATION; MAJOR DEPRESSION; MENTAL-HEALTH; RISK-FACTORS; SOCIAL SUPPORT AB Purpose A substantial proportion of adults experience traumatic events each year, yet little is known about the effects of different types of traumatic events on depression severity over time. We prospectively assessed the effects of traumatic event exposure during a 1-year period on changes in depression severity during that period among a representative sample of adults living in Detroit, Michigan in the United States. Methods We used data from 1,054 participants in the first two waves of the Detroit Neighborhood Health Study (2008-2010). Depression severity was measured with the Patient Health Questionnaire-9 (PHQ-9). Negative binomial regression was used to estimate the effect of traumatic event exposure on depression severity at Wave 2, adjusting for Wave 1 PHQ-9 score and potential confounders. Results The mean depression severity score at Wave 2 among those exposed to at least one traumatic event during follow-up was 1.71 times higher than among those with no traumatic event exposure [95 % confidence interval (CI) 1.27-2.29]. Also positively associated with depression severity at Wave 2 (vs. no traumatic events) were assaultive violence (mean ratio 2.49, 95 % CI 1.41-4.38), injuries and other directly experienced shocking events (mean ratio 2.59, 95 % CI 1.62-3.82), and three or more traumatic events (mean ratio 2.58, 95 % CI 1.62-4.09). Conclusions Violence, injuries, and other directly experienced traumatic events increase depression severity and may be useful targets for interventions to alleviate the burden of depression in urban areas. C1 [Tracy, Melissa; Galea, Sandro] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Tracy, Melissa; Morgenstern, Hal; Aiello, Allison E.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Morgenstern, Hal] Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI 48109 USA. [Zivin, Kara] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI 48109 USA. [Zivin, Kara] US Dept Vet Affairs, Ann Arbor, MI 48113 USA. RP Tracy, M (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, 722 W 168th St,Room 515, New York, NY 10032 USA. EM mt2682@columbia.edu FU National Institutes of Health [DA022720, DA022720-S1, MH088283, MH078152, MH082729] FX This study was supported by the National Institutes of Health (Grants DA022720, DA022720-S1, MH088283, MH078152, and MH082729). NR 121 TC 3 Z9 3 U1 5 U2 14 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0933-7954 EI 1433-9285 J9 SOC PSYCH PSYCH EPID JI Soc. Psychiatry Psychiatr. Epidemiol. PD NOV PY 2014 VL 49 IS 11 BP 1769 EP 1782 DI 10.1007/s00127-014-0884-2 PG 14 WC Psychiatry SC Psychiatry GA AS1UM UT WOS:000344067300009 PM 24816599 ER PT J AU Foroud, T Lai, DB Koller, D van't Hof, F Kurki, MI Anderson, CS Brown, RD Connolly, ES Eriksson, JG Flaherty, M Fornage, M von und zu Fraunberg, M Gaal, EI Laakso, A Hernesniemi, J Huston, J Jaaskelainen, JE Kiemeney, LA Kivisaari, R Kleindorfer, D Ko, N Lehto, H Mackey, J Meissner, I Moomaw, CJ Mosley, TH Moskala, M Niemela, M Palotie, A Pera, J Rinkel, G Ripke, S Rouleau, G Ruigrok, Y Sauerbeck, L Slowik, A Vermeulen, SH Woo, D Worrall, BB Broderick, J AF Foroud, Tatiana Lai, Dongbing Koller, Daniel van't Hof, Femke Kurki, Mitja I. Anderson, Craig S. Brown, Robert D., Jr. Connolly, Edward Sander Eriksson, Johan G. Flaherty, Matthew Fornage, Myriam von und zu Fraunberg, Mikael Gaal, Emilia I. Laakso, Aki Hernesniemi, Juha Huston, John Jaaskelainen, Juha E. Kiemeney, Lambertus A. Kivisaari, Riku Kleindorfer, Dawn Ko, Nerissa Lehto, Hanna Mackey, Jason Meissner, Irene Moomaw, Charles J. Mosley, Thomas H. Moskala, Marek Niemela, Mika Palotie, Aarno Pera, Joanna Rinkel, Gabriel Ripke, Stephan Rouleau, Guy Ruigrok, Ynte Sauerbeck, Laura Slowik, Agnieszka Vermeulen, Sita H. Woo, Daniel Worrall, Bradford B. Broderick, Joseph CA Familial Intracranial TI Genome-Wide Association Study of Intracranial Aneurysm Identifies a New Association on Chromosome 7 SO STROKE LA English DT Article DE chromosomes; human; pair 7; genome-wide association study; intracranial aneurysm ID GENETIC RISK-FACTORS; SUBARACHNOID HEMORRHAGE; CEREBRAL ANEURYSMS; SEQUENCE VARIANT; ISCHEMIC-STROKE; FAMILY-HISTORY; METAANALYSIS; AGE; REGION; SUSCEPTIBILITY AB Background and Purpose Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. Methods Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. Results Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0x10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14x10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91x10(-10)). Conclusions We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA. C1 [Foroud, Tatiana; Lai, Dongbing; Koller, Daniel; Mackey, Jason] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [van't Hof, Femke; Ruigrok, Ynte] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Kurki, Mitja I.; von und zu Fraunberg, Mikael; Jaaskelainen, Juha E.] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Kurki, Mitja I.; von und zu Fraunberg, Mikael; Jaaskelainen, Juha E.] Univ Eastern Finland, Kuopio, Finland. [Kurki, Mitja I.; Palotie, Aarno; Ripke, Stephan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kurki, Mitja I.; Palotie, Aarno; Ripke, Stephan] Harvard Univ, Sch Med, Boston, MA USA. [Kurki, Mitja I.; Palotie, Aarno; Ripke, Stephan] Broad Inst Harvard & MIT, Cambridge, MA USA. [Anderson, Craig S.] Univ Sydney, Sydney, NSW 2006, Australia. [Anderson, Craig S.] Royal Prince Alfred Hosp, Sydney, NSW, Australia. [Brown, Robert D., Jr.; Huston, John; Meissner, Irene] Mayo Clin, Rochester, MN USA. [Connolly, Edward Sander] Columbia Univ, Sch Med, New York, NY USA. [Eriksson, Johan G.; Gaal, Emilia I.] Univ Helsinki, Helsinki, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Natl Inst Hlth & Welf, Helsinki, Finland. [Eriksson, Johan G.] Vasa Cent Hosp, Vaasa, Finland. [Eriksson, Johan G.; Gaal, Emilia I.; Laakso, Aki; Hernesniemi, Juha; Kivisaari, Riku; Lehto, Hanna; Niemela, Mika] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Flaherty, Matthew; Kleindorfer, Dawn; Moomaw, Charles J.; Sauerbeck, Laura; Woo, Daniel; Broderick, Joseph] Univ Cincinnati, Cincinnati, OH 45221 USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. [Kiemeney, Lambertus A.; Vermeulen, Sita H.] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Ko, Nerissa] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Jackson, MS USA. [Moskala, Marek; Pera, Joanna; Slowik, Agnieszka] Jagiellonian Univ, Coll Med, Krakow, Poland. [Palotie, Aarno] Wellcome Trust Sanger Inst, Cambridge, England. [Rouleau, Guy] Univ Montreal, Montreal, PQ, Canada. [Worrall, Bradford B.] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. RP Foroud, T (reprint author), Indiana Univ Sch Med, 410 W 10th St,HS 4021, Indianapolis, IN 46202 USA. EM tforoud@iu.edu RI Kiemeney, Lambertus/D-3357-2009; Niemela, Mika/F-2539-2015; Vermeulen, H.H.M./L-4716-2015; OI Kiemeney, Lambertus/0000-0002-2368-1326; Niemela, Mika/0000-0003-1526-0684; Eriksson, Johan/0000-0002-2516-2060 FU National Institutes of Health (NIH) [UL1RR025005]; National Health and Medical Research Council (NHMRC) of Australia [R01NS39512, R03NS083468]; Health Research Council of New Zealand; NHMRC Senior Principal Research Fellowship; Veni grant by The Netherlands Organization for Scientific Research (NOW) [91610016]; Dutch Heart Foundation [2008B004]; Jagiellonian University Medical College [K/ZDS/001456]; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100 009C, HHSN268201100010C, HHSN268201100011C, HHSN 268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; NIH [HHSN268200625226C]; [R01-HL70825] FX Infrastructure was partly supported by grant number UL1RR025005, a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research. This study was also supported by R01NS39512 (Dr Broderick), R03NS083468 (Dr Foroud), the National Health and Medical Research Council (NHMRC) of Australia, and the Health Research Council of New Zealand. Additional funding was provided by an NHMRC Senior Principal Research Fellowship (Dr Anderson), a Veni grant by The Netherlands Organization for Scientific Research (NOW; project no. 91610016; Dr Ruigrok), a grant from the Dutch Heart Foundation (project no. 2008B004; Dr van't Hof), and a grant from Jagiellonian University Medical College K/ZDS/001456. Atherosclerosis Risk in Communities is performed as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100 009C, HHSN268201100010C, HHSN268201100011C, and HHSN 268201100012C), 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. NR 29 TC 6 Z9 7 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD NOV PY 2014 VL 45 IS 11 BP 3194 EP 3199 DI 10.1161/STROKEAHA.114.006096 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AS6CD UT WOS:000344351500021 PM 25256182 ER PT J AU Xian, Y Holloway, RG Smith, EE Schwamm, LH Reeves, MJ Bhatt, DL Schulte, PJ Cox, M Olson, DM Hernandez, AF Lytle, BL Anstrom, KJ Fonarow, GC Peterson, ED AF Xian, Ying Holloway, Robert G. Smith, Eric E. Schwamm, Lee H. Reeves, Mathew J. Bhatt, Deepak L. Schulte, Phillip J. Cox, Margueritte Olson, DaiWai M. Hernandez, Adrian F. Lytle, Barbara L. Anstrom, Kevin J. Fonarow, Gregg C. Peterson, Eric D. TI Racial/Ethnic Differences in Process of Care and Outcomes Among Patients Hospitalized With Intracerebral Hemorrhage SO STROKE LA English DT Article DE cerebral hemorrhage; continental population groups; ethnology; outcomes research; quality of health care ID ASSOCIATION/AMERICAN STROKE ASSOCIATION; NOT-RESUSCITATE ORDERS; ACUTE ISCHEMIC-STROKE; QUALITY-OF-CARE; AMERICAN-HEART-ASSOCIATION; GUIDELINES-STROKE; MORTALITY; PROFESSIONALS; BLACKS; MODELS AB Background and Purpose Although racial/ethnic differences in care are pervasive in many areas of medicine, little is known whether intracerebral hemorrhage (ICH) care processes or outcomes differ by race/ethnicity. Methods We analyzed 123 623 patients with ICH (83 216 white, 22 147 black, 10 519 Hispanic, and 7741 Asian) hospitalized at 1199 Get With The Guidelines-Stroke hospitals between 2003 and 2012. Multivariable logistic regression with generalized estimating equation was used to evaluate the association among race, stroke performance measures, and in-hospital outcomes. Results Relative to white patients, black, Hispanic, and Asian patients were significantly younger, but more frequently had more severe stroke (median National Institutes of Health Stroke Scale, 9, 10, 10, and 11, respectively; P<0.001). After adjustment for both patient and hospital-level characteristics, black patients were more likely to receive deep venous thrombosis prophylaxis, rehabilitation assessment, dysphagia screening, and stroke education, but less likely to have door to computed tomographic time 25 minutes and smoking cessation counseling than whites. Both Hispanic and Asian patients had higher odds of dysphagia screening but lower odds of smoking cessation counseling. In-hospital all-cause mortality was lower for blacks (23.0%), Hispanics (22.8%), and Asians (25.3%) than for white patients (27.6%). After risk adjustment, all minority groups had lower odds of death, of receiving comfort measures only or of being discharged to hospice. In contrast, they were more likely to exceed the median length of stay when compared with white patients. Conclusions Although individual quality indicators in ICH varied by race/ethnicity, black, Hispanic, and Asian patients with ICH had lower risk-adjusted in-hospital mortality than white patients with ICH. C1 [Xian, Ying; Schulte, Phillip J.; Cox, Margueritte; Hernandez, Adrian F.; Lytle, Barbara L.; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC 27705 USA. [Holloway, Robert G.] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14627 USA. [Smith, Eric E.] Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB, Canada. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Reeves, Mathew J.] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Olson, DaiWai M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. RP Xian, Y (reprint author), Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM ying.xian@duke.edu RI Hernandez, Adrian F./A-7818-2016; OI Schwamm, Lee/0000-0003-0592-9145; Hernandez, Adrian F./0000-0003-3387-9616; Smith, Eric/0000-0003-3956-1668 FU American Heart Association-Pharmaceutical Roundtable; David and Stevie Spina; Boeringher-Ingelheim; Merck; Bristol-Myers Squib/Sanofi Pharmaceutical Partnership; Janseen Pharmaceutical Companies of Johnson Johnson; AHA Pharmaceutical Roundtable FX This study received an award from the American Heart Association-Pharmaceutical Roundtable and from David and Stevie Spina. The Get With The Guidelines-Stroke (GWTG-Stroke) program is provided by the American Heart Association/American Stroke Association (AHA/ASA). The GWTG-Stroke has been funded in the past through support from Boeringher-Ingelheim, Merck, Bristol-Myers Squib/Sanofi Pharmaceutical Partnership, Janseen Pharmaceutical Companies of Johnson & Johnson and the AHA Pharmaceutical Roundtable. The funding organizations had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation of the article. Representatives from the AHA reviewed and approved a draft of the article. This study used the GWTG-Stroke database. The interpretation and reporting of these data are the sole responsibility of the authors and do not necessarily represent the official views of the AHA. NR 35 TC 5 Z9 5 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD NOV PY 2014 VL 45 IS 11 BP 3243 EP 3250 DI 10.1161/STROKEAHA.114.005620 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AS6CD UT WOS:000344351500029 PM 25213344 ER PT J AU Ciura, VA Brouwers, HB Pizzolato, R Ortiz, CJ Rosand, J Goldstein, JN Greenberg, SM Pomerantz, SR Gonzalez, RG Romero, JM AF Ciura, Viesha A. Brouwers, H. Bart Pizzolato, Raffaella Ortiz, Claudia J. Rosand, Jonathan Goldstein, Joshua N. Greenberg, Steven M. Pomerantz, Stuart R. Gonzalez, R. Gilberto Romero, Javier M. TI Spot Sign on 90-Second Delayed Computed Tomography Angiography Improves Sensitivity for Hematoma Expansion and Mortality Prospective Study SO STROKE LA English DT Article DE cerebral hemorrhage; computed tomography angiography; mortality ID PRIMARY INTRACEREBRAL HEMORRHAGE; CONTRAST EXTRAVASATION; IDENTIFIES PATIENTS; POSTCONTRAST CT; HIGHEST RISK; SCORE; PREDICTOR; GROWTH; VOLUME AB Background and Purpose The computed tomography angiography (CTA) spot sign is a validated biomarker for poor outcome and hematoma expansion in intracerebral hemorrhage. The spot sign has proven to be a dynamic entity, with multimodal imaging proving to be of additional value. We investigated whether the addition of a 90-second delayed CTA acquisition would capture additional intracerebral hemorrhage patients with the spot sign and increase the sensitivity of the spot sign. Methods We prospectively enrolled consecutive intracerebral hemorrhage patients undergoing first pass and 90-second delayed CTA for 18 months at a single academic center. Univariate and multivariate logistic regression were performed to assess clinical and neuroimaging covariates for relationship with hematoma expansion and mortality. Results Sensitivity of the spot sign for hematoma expansion on first pass CTA was 55%, which increased to 64% if the spot sign was present on either CTA acquisition. In multivariate analysis the spot sign presence was associated with significant hematoma expansion: odds ratio, 17.7 (95% confidence interval, 3.7-84.2; P=0.0004), 8.3 (95% confidence interval, 2.0-33.4; P=0.004), and 12.0 (95% confidence interval, 2.9-50.5; P=0.0008) if present on first pass, delayed, or either CTA acquisition, respectively. Spot sign presence on either acquisitions was also significant for mortality. Conclusions We demonstrate improved sensitivity for predicting hematoma expansion and poor outcome by adding a 90-second delayed CTA, which may enhance selection of patients who may benefit from hemostatic therapy. C1 [Ciura, Viesha A.; Pizzolato, Raffaella; Ortiz, Claudia J.; Pomerantz, Stuart R.; Gonzalez, R. Gilberto; Romero, Javier M.] Harvard Univ, Sch Med, Dept Radiol, Div Neuroradiol,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Brouwers, H. Bart; Rosand, Jonathan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02115 USA. [Brouwers, H. Bart; Rosand, Jonathan; Goldstein, Joshua N.] Harvard Univ, Sch Med, Dept Neurol, Div Neurocrit Care & Emergency Neurol,Massachuset, Boston, MA 02115 USA. [Brouwers, H. Bart; Rosand, Jonathan; Goldstein, Joshua N.; Greenberg, Steven M.] Harvard Univ, Sch Med, Dept Neurol, Hemorrhag Stroke Res Grp,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Brouwers, H. Bart; Rosand, Jonathan; Goldstein, Joshua N.] Harvard Univ, Sch Med, Dept Neurol, J Philip Kistler Stroke Res Ctr,Massachusetts Gen, Boston, MA 02115 USA. [Goldstein, Joshua N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA 02115 USA. [Brouwers, H. Bart] Univ Utrecht, Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurosurg, Utrecht, Netherlands. RP Romero, JM (reprint author), Massachusetts Gen Hosp, Div Neuroradiol, 55 Fruit St,Gray 2,Rm 273A, Boston, MA 02114 USA. EM jmromero@mgh.harvard.edu RI Goldstein, Joshua/H-8953-2016 FU National Institutes of Health-National Institute of Neurological Disorders and Stroke Specialized Programs of Translational Research in Acute Stroke (NIH-NINDS SPOTRIAS) [P50NS051343] FX Dr Brouwers was supported by the National Institutes of Health-National Institute of Neurological Disorders and Stroke Specialized Programs of Translational Research in Acute Stroke (NIH-NINDS SPOTRIAS) fellowship grant P50NS051343. NR 31 TC 10 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD NOV PY 2014 VL 45 IS 11 BP 3293 EP 3297 DI 10.1161/STROKEAHA.114.005570 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AS6CD UT WOS:000344351500037 PM 25300974 ER PT J AU Saposnik, G Fonarow, GC Pan, WQ Liang, L Hernandez, AF Schwamm, LH Smith, EE AF Saposnik, Gustavo Fonarow, Gregg C. Pan, Wenquin Liang, Li Hernandez, Adrian F. Schwamm, Lee H. Smith, Eric E. CA AHA Get-With-The-Guidelines Stroke TI Guideline-Directed Low-Density Lipoprotein Management in High-Risk Patients With Ischemic Stroke Findings From Get With The Guidelines-Stroke 2003 to 2012 SO STROKE LA English DT Article DE cardiovascular diseases; cholesterol; diabetes mellitus; dyslipidemias; LDL cholesterol; prevention & control; standards; stroke; therapeutics ID HEALTH-CARE PROFESSIONALS; CARDIOVASCULAR-DISEASE; PERFORMANCE-MEASURES; TASK-FORCE; PREVENTION; CHOLESTEROL; ATTACK; ASSOCIATION; OUTCOMES; PROGRAM AB Background and Purpose Limited information is available on stroke prevention in high-risk patients with preexisting cardiovascular disease. Our aim was to use admission low-density lipoprotein (LDL) values to evaluate differences in the attainment of National Cholesterol Education Program-Adult Treatment Panel III guidelines goals at the time of the index event in high-risk patients with stroke and preexisting cardio- or cerebrovascular disease. Methods Observational study, using data from the Get-With-The-Guidelines-Stroke Registry including 913 436 patients with an acute ischemic stroke or transient ischemic attack from April 2003 to September 2012. Participants were classified as high risk if they had history of transient ischemic attack (TIA), stroke (cardiovascular disease), and coronary artery disease (CAD). Results Of the 913 436 patients admitted with an acute stroke or TIA, 194 557 (21.3%) had previous stroke/TIA, 148 833 (16.3%) had previous CAD, and 88 605 (9.7%) had concomitant CAD and cardiovascular disease. Overall, only 68% of patients with stroke were at their preadmission National Cholesterol Education Program III guideline-recommended LDL target; 51.3% had LDL <100 mg/dL; and only 19.8% had LDL<70 mg/dL. Among those presenting with a recurrent stroke, >45% had LDL>100 mg/dL. When compared with patients with CAD, patients with previous TIA/stroke were less likely to have LDL<100 or <70 mg/dL. In multivariable analysis, older age, men, white race, lack of major vascular risk factors, previous use of cholesterol-lowering therapy, and care provided in larger hospitals were associated with meeting LDL targets on admission testing. Conclusions Management of dyslipidemia in high-risk patients with preexistent CAD or stroke continues to be suboptimal. Only 1 in 5 patients with prior TIA/stroke had LDL levels <70 mg/dL. C1 [Saposnik, Gustavo] Univ Toronto, St Michaels Hosp, Dept Med, Div Neurol,Stroke Outcomes Res Ctr, Toronto, ON M5B 1W8, Canada. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. [Pan, Wenquin; Liang, Li; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Stroke Serv, Boston, MA 02114 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Inst Heart Vasc & Stroke Care, Boston, MA 02114 USA. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Calgary Stroke Program, Calgary, AB, Canada. RP Saposnik, G (reprint author), St Michaels Hosp, Stroke Outcomes Res Ctr, Div Neurol, 55 Queen St E,Room 93, Toronto, ON M5C 1R6, Canada. EM saposnikg@smh.ca RI Smith, Eric/C-5443-2012; Hernandez, Adrian F./A-7818-2016 OI Smith, Eric/0000-0003-3956-1668; Schwamm, Lee/0000-0003-0592-9145; Hernandez, Adrian F./0000-0003-3387-9616 FU American Heart Association; American Stroke Association; Pfizer, Inc, New York, NY; Merck-Schering Plough Partnership (North Wales, PA) FX The Get-with-the-Guidelines is funded by the American Heart Association and the American Stroke Association. The program is also supported in part by unrestricted educational grants to the American Heart Association by Pfizer, Inc, New York, NY, and the Merck-Schering Plough Partnership (North Wales, PA), who did not participate in the design, analysis, article preparation, or approval. NR 33 TC 9 Z9 10 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD NOV PY 2014 VL 45 IS 11 BP 3343 EP 3351 DI 10.1161/STROKEAHA.114.006736 PG 9 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AS6CD UT WOS:000344351500045 PM 25300975 ER PT J AU Hattori, Y Okamoto, Y Maki, T Yamamoto, Y Oishi, N Yamahara, K Nagatsuka, K Takahashi, R Kalaria, RN Fukuyama, H Kinoshita, M Ihara, M AF Hattori, Yorito Okamoto, Yoko Maki, Takakuni Yamamoto, Yumi Oishi, Naoya Yamahara, Kenichi Nagatsuka, Kazuyuki Takahashi, Ryosuke Kalaria, Raj N. Fukuyama, Hidenao Kinoshita, Makoto Ihara, Masafumi TI Silent Information Regulator 2 Homolog 1 Counters Cerebral Hypoperfusion Injury by Deacetylating Endothelial Nitric Oxide Synthase SO STROKE LA English DT Article DE carotid artery stenosis; cerebral ischemia; dementia; endothelial nitric oxide synthase; mouse; SIRT1 ID AMYOTROPHIC-LATERAL-SCLEROSIS; CELLULAR PRION PROTEIN; EXTENDS LIFE-SPAN; ALZHEIMERS-DISEASE; MOUSE MODEL; NEURODEGENERATIVE DISEASE; SACCHAROMYCES-CEREVISIAE; SIRT1 DEACETYLASE; ISCHEMIC DAMAGE; BRAIN AB Background and Purpose Silent information regulator 2 homolog 1 (SIRT1) is a protein deacetylase that has been reported to suppress neurodegenerative and cardiovascular diseases in model organisms. We hypothesized that neurovascular protection is one of the diverse actions of SIRT1. This study was designed to determine whether SIRT1 protects against the consequences of cerebral hypoperfusion in vivo. MethodsSirt1-overexpressing (Sirt1-Tg) mice driven by a prion promoter and their wild-type littermates were subjected to bilateral common carotid artery stenosis using external microcoils. Using Sirt1-Tg mice, we assessed the effect of SIRT1 on cerebral blood flow, cerebral angioarchitecture, histological and ultrastructural changes, and spatial working memory at several time points. We also evaluated the effects of preadministration of SIRT1 inhibitors or endothelial nitric oxide synthase inhibitors on cerebral blood flow after bilateral common carotid artery stenosis in Sirt1-Tg mice. Levels of acetylated and nonacetylated endothelial nitric oxide synthase were measured semiquantitatively with immunoblotting. Results Cerebral hypoperfusion induced by bilateral common carotid artery stenosis caused memory impairment and histological changes in wild-type littermates. However, these phenotypes were rescued in Sirt1-Tg mice, where cerebral blood flow was maintained even poststenosis. Electron microscopic analyses showed irregularities in the vascular endothelia, such as tight junction openings in wild-type mice, which were absent in Sirt1-Tg littermates. Brain endothelial nitric oxide synthase was acetylated after cerebral hypoperfusion in wild-type littermates but remained unacetylated in Sirt1-Tg mice. Moreover, treatment with SIRT1 inhibitors and endothelial nitric oxide synthase inhibitors abolished the vasculoprotective effects of SIRT1. Conclusions Our results indicate that neurovascular endothelial SIRT1 potentiation upregulates the nitric oxide system and counters cerebral hypoperfusion injury. This novel cerebral blood flow-preserving mechanism offers potential molecular targets for future therapeutic intervention. C1 [Hattori, Yorito; Takahashi, Ryosuke] Kyoto Univ, Grad Sch Med, Dept Neurol, Kyoto, Japan. [Oishi, Naoya; Fukuyama, Hidenao] Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Kyoto, Japan. [Hattori, Yorito; Yamamoto, Yumi; Yamahara, Kenichi; Ihara, Masafumi] Natl Cerebral & Cardiovasc Ctr, Dept Regenerat Med & Tissue Engn, Osaka 5658565, Japan. [Okamoto, Yoko] Natl Cerebral & Cardiovasc Ctr, Dept Pathol, Osaka 5658565, Japan. [Nagatsuka, Kazuyuki; Ihara, Masafumi] Natl Cerebral & Cardiovasc Ctr, Dept Stroke & Cerebrovasc Dis, Osaka 5658565, Japan. [Maki, Takakuni] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Maki, Takakuni] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Maki, Takakuni] Harvard Univ, Sch Med, Boston, MA USA. [Takahashi, Ryosuke; Kinoshita, Makoto] Japan Sci Technol Corp, CREST, Saitama, Japan. [Kalaria, Raj N.] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Kinoshita, Makoto] Nagoya Univ, Grad Sch Sci, Div Biol Sci, Nagoya, Aichi 4648601, Japan. RP Ihara, M (reprint author), Natl Cerebral & Cardiovasc Ctr, Dept Stroke & Cerebrovasc Dis, Osaka 5658565, Japan. EM ihara@ncvc.go.jp OI Ihara, Masafumi/0000-0002-7102-4048; Yamamoto, Yumi/0000-0001-7188-9618 FU Ministry of Health, Labour, and Welfare [0605-1]; Ministry of Education, Culture, Sports, Science, and Technology [23390233]; Takeda Science Foundation; Japan Science Technology Corporation; Alzheimer's Research UK; [2311531]; [25116514]; [25893301] FX We gratefully acknowledge grant support from the Ministry of Health, Labour, and Welfare (Dr Ihara, no. 0605-1), the Ministry of Education, Culture, Sports, Science, and Technology (Dr Ihara, Grant-in-Aid for Scientific Research (B), no. 23390233; Dr Hattori, Grant-in-Aid for Research Activity Start-up, no. 25893301; Dr Kinoshita, Grant-in-Aid for Scientific Research on Innovative Areas, no. 2311531 and 25116514), the Takeda Science Foundation (Dr Ihara), Japan Science Technology Corporation (Dr Takahashi), and Alzheimer's Research UK (Dr Kalaria). NR 40 TC 9 Z9 9 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD NOV PY 2014 VL 45 IS 11 BP 3403 EP 3411 DI 10.1161/STROKEAHA.114.006265 PG 9 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA AS6CD UT WOS:000344351500053 PM 25213338 ER PT J AU Chellali, A Schwaitzberg, SD Jones, DB Romanelli, J Miller, A Rattner, D Roberts, KE Cao, CGL AF Chellali, Amine Schwaitzberg, Steven D. Jones, Daniel B. Romanelli, John Miller, Amie Rattner, David Roberts, Kurt E. Cao, Caroline G. L. TI Toward scar-free surgery: an analysis of the increasing complexity from laparoscopic surgery to NOTES SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article DE NOTES continuum; Laparoscopic surgery; Cholecystectomy; Hierarchical task analysis; Timeline analysis; Cognitive task analysis ID TRANSLUMENAL ENDOSCOPIC SURGERY; NOTES TRANSVAGINAL CHOLECYSTECTOMY; HIERARCHICAL DECOMPOSITION; SERIES AB NOTES is an emerging technique for performing surgical procedures, such as cholecystectomy. Debate about its real benefit over the traditional laparoscopic technique is on-going. There have been several clinical studies comparing NOTES to conventional laparoscopic surgery. However, no work has been done to compare these techniques from a Human Factors perspective. This study presents a systematic analysis describing and comparing different existing NOTES methods to laparoscopic cholecystectomy. Videos of endoscopic/laparoscopic views from fifteen live cholecystectomies were analyzed to conduct a detailed task analysis of the NOTES technique. A hierarchical task analysis of laparoscopic cholecystectomy and several hybrid transvaginal NOTES cholecystectomies was performed and validated by expert surgeons. To identify similarities and differences between these techniques, their hierarchical decomposition trees were compared. Finally, a timeline analysis was conducted to compare the steps and substeps. At least three variations of the NOTES technique were used for cholecystectomy. Differences between the observed techniques at the substep level of hierarchy and on the instruments being used were found. The timeline analysis showed an increase in time to perform some surgical steps and substeps in NOTES compared to laparoscopic cholecystectomy. As pure NOTES is extremely difficult given the current state of development in instrumentation design, most surgeons utilize different hybrid methods-combination of endoscopic and laparoscopic instruments/optics. Results of our hierarchical task analysis yielded an identification of three different hybrid methods to perform cholecystectomy with significant variability among them. The varying degrees to which laparoscopic instruments are utilized to assist in NOTES methods appear to introduce different technical issues and additional tasks leading to an increase in the surgical time. The NOTES continuum of invasiveness is proposed here as a classification scheme for these methods, which was used to construct a clear roadmap for training and technology development. C1 [Chellali, Amine; Schwaitzberg, Steven D.] Harvard Univ, Sch Med, Dept Surg, Cambridge Hlth Alliance, Cambridge, MA 02138 USA. [Chellali, Amine] Univ Evry, Dept Comp Engn, Evry, France. [Jones, Daniel B.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Surg, Boston, MA 02215 USA. [Romanelli, John] Tufts Univ, Sch Med, Dept Surg, Baystate Med Ctr, Springfield, MA 01199 USA. [Miller, Amie] Wright State Univ, Dept Surg, Dayton, OH 45435 USA. [Rattner, David] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Roberts, Kurt E.] Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USA. [Cao, Caroline G. L.] Wright State Univ, Dept Biomed Ind & Human Factors Engn, Russ Engn Ctr 207, Dayton, OH 45435 USA. RP Cao, CGL (reprint author), Wright State Univ, Dept Biomed Ind & Human Factors Engn, Russ Engn Ctr 207, 3640 Colonel Glenn Hwy, Dayton, OH 45435 USA. EM amine.chellali@issyl-lab.org; caroline.cao@wright.edu FU NIH/NIBIB [R01EB009362] FX The authors gratefully acknowledge the support of this study by NIH/NIBIB (Grant No. R01EB009362). NR 34 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0930-2794 EI 1432-2218 J9 SURG ENDOSC JI Surg. Endosc. PD NOV PY 2014 VL 28 IS 11 BP 3119 EP 3133 DI 10.1007/s00464-014-3565-z PG 15 WC Surgery SC Surgery GA AS3HL UT WOS:000344168200013 PM 24902811 ER PT J AU Jakobiec, FA Rai, R Rashid, A Kanoff, J Mukai, S AF Jakobiec, Frederick A. Rai, Ruju Rashid, Alia Kanoff, Justin Mukai, Shizuo TI Dystrophic hyaloid artery remnants and other abnormalities in a buphthalmic eye with retinoblastoma SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE hyaloid artery; dystrophic calcification; retinoblastoma; buphthalmos; crystalline lens; cataract; deformation of lens; lens capsule; lens epithelium ID PERSISTENT FETAL VASCULATURE; EXUDATIVE VITREORETINOPATHY; CATARACTS; MUTATION; GENE AB Partial persistence of the hyaloid artery unaccompanied by hyperplastic primary vitreous has not been previously reported in association with retinoblastoma. We describe an 18-month-old child with such a finding who had a retinoblastoma that was undifferentiated, extensively necrotic, heavily calcified, and completely filled the eyeball. The enucleated globe harbored a nonperfused, fossilized remnant of the hyaloid artery due to DNA/calcium deposition in the vascular wall. This structure inserted into a lenticular, extracapsular, fibrous plaque corresponding to a Mittendorf dot. The tumor had induced a placoid cataractous lens, obliterated the anterior and posterior chambers, caused glaucoma leading to buphthalmos, and extended into the optic nerve and extraocularly to involve the orbit. We conclude that the retinoblastoma arose early in ocular morphogenesis, at around 4 months gestation, when the programmed involution of the hyaloid artery begins. This process would typically end at 7-8 months gestation, but was aborted by the tumor. The patient died 6 weeks after surgery without receiving further treatment because of the parents' resistance. (C) 2014 Elsevier Inc. All rights reserved. C1 [Jakobiec, Frederick A.; Rai, Ruju; Rashid, Alia] Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, Dept Ophthalmol, Boston, MA 02114 USA. [Jakobiec, Frederick A.; Rai, Ruju; Rashid, Alia; Kanoff, Justin; Mukai, Shizuo] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Kanoff, Justin; Mukai, Shizuo] Massachusetts Eye & Ear Infirm, Retina Serv, Dept Ophthalmol, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, 243 Charles St Suite 328, Boston, MA 02114 USA. EM Fred_jakobiec@meei.harvard.edu FU Mukai Fund of the Massachusetts Eye and Ear Infirmary FX SM is supported in part by gifts to the Mukai Fund of the Massachusetts Eye and Ear Infirmary. None of the authors reported a proprietary or commercial interest in any product mentioned or concept discussed in this article. NR 26 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6257 EI 1879-3304 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD NOV-DEC PY 2014 VL 59 IS 6 BP 636 EP 642 DI 10.1016/j.survophthal.2014.05.002 PG 7 WC Ophthalmology SC Ophthalmology GA AS0LC UT WOS:000343967600005 PM 25233827 ER PT J AU Pantanowitz, L Dickinson, K Evans, AJ Hassell, LA Henricks, WH Lennerz, JK Lowe, A Parwani, AV Riben, M Smith, CD Tuthill, JM Weinstein, RS Wilbur, DC Krupinski, EA Bernard, J AF Pantanowitz, Liron Dickinson, Kim Evans, Andrew J. Hassell, Lewis A. Henricks, Walter H. Lennerz, Jochen K. Lowe, Amanda Parwani, Anil V. Riben, Michael Smith, Daniel Tuthill, J. Mark Weinstein, Ronald S. Wilbur, David C. Krupinski, Elizabeth A. Bernard, Jordana TI ATA Clinical Guidelines for Telepathology SO TELEMEDICINE AND E-HEALTH LA English DT Article ID DIGITAL PATHOLOGY; FROZEN-SECTION; SURGICAL PATHOLOGY; PRIMARY DIAGNOSIS; PATIENT-CARE; WHOLE; SYSTEM; CYTOPATHOLOGY; PROSPECTS; FUTURE C1 [Pantanowitz, Liron; Parwani, Anil V.] Univ Pittsburgh, Dept Pathol, Med Ctr, Pittsburgh, PA USA. [Dickinson, Kim] Digital Pathol Assoc, LabCorp, Irvine, CA USA. [Evans, Andrew J.] Toronto Gen Hosp, Dept Pathol, Univ Hlth Network, Toronto, ON, Canada. [Hassell, Lewis A.] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Henricks, Walter H.] Cleveland Clin, Dept Pathol, Cleveland, OH 44106 USA. [Henricks, Walter H.] Cleveland Clin, Inst Lab Med, Cleveland, OH 44106 USA. [Lennerz, Jochen K.] Univ Ulm, Inst Pathol, D-89069 Ulm, Germany. [Lowe, Amanda] Visiopharm, Broomfield, CO USA. [Riben, Michael] MD Anderson Hosp, Dept Pathol, Houston, TX USA. [Smith, Daniel] Keesler Air Force Base, Dept Pathol, Biloxi, MS USA. [Tuthill, J. Mark] Henry Ford Hlth Syst, Pathol Informat, Detroit, MI USA. [Weinstein, Ronald S.] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Wilbur, David C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [Krupinski, Elizabeth A.] Univ Arizona, Dept Med Imaging, Tucson, AZ USA. [Bernard, Jordana] Amer Telemed Assoc, Washington, DC USA. RP Pantanowitz, L (reprint author), Univ Pittsburgh, UPMC Shadyside Hosp, Dept Pathol, 5150 Ctr Ave,Suite 201, Pittsburgh, PA 15232 USA. EM pantanowitzl@upmc.edu NR 65 TC 5 Z9 5 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 EI 1556-3669 J9 TELEMED E-HEALTH JI Telemed. e-Health PD NOV 1 PY 2014 VL 20 IS 11 BP 1049 EP 1056 DI 10.1089/tmj.2014.9976 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AS8BZ UT WOS:000344476600012 PM 25384254 ER PT J AU Haugen, B McDermott, M Carrothers, TC Daniels, GH Ross, DS Klibanski, A Crowley, WF Bigos, ST Wartofsky, L Cooper, DS Ladenson, PW Hershman, JM Brent, G Shupnik, P Samuels, MH Nagataki, S Pacini, F Maciel, RMB Singer, P Donelson, CH Ridgway, H AF Haugen, Bryan McDermott, Michael Carrothers, Terri C. Daniels, Gilbert H. Ross, Douglas S. Klibanski, Anne Crowley, William F., Jr. Bigos, S. Thomas Wartofsky, Leonard Cooper, David S. Ladenson, Paul W. Hershman, Jerome M. Brent, Gregory Shupnik, Peggy Samuels, Mary H. Nagataki, Shigenobu Pacini, Furio Maciel, Rui M. B. Singer, Peter Donelson, Carla Hamre Ridgway, Hap CA Colorado Grp Massachusetts Gen Hosp Grp TI E. Chester Ridgway, MD, MACP (1942-2014) IN MEMORIAM SO THYROID LA English DT Biographical-Item C1 [Haugen, Bryan; McDermott, Michael; Carrothers, Terri C.] Univ Colorado, Sch Med, Aurora, CO 80045 USA. [Haugen, Bryan] Univ Colorado, Sch Med, Div Endocrinol Metab & Diabet, Aurora, CO USA. [Daniels, Gilbert H.] Mass Gen Hosp, Boston, MA USA. [Daniels, Gilbert H.; Ross, Douglas S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Daniels, Gilbert H.; Ross, Douglas S.; Klibanski, Anne; Crowley, William F., Jr.] Harvard Univ, Sch Med, Boston, MA USA. [Klibanski, Anne] Massachusetts Gen Hosp, Partners HealthCare, Boston, MA 02114 USA. [Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Crowley, William F., Jr.] Massachusetts Gen Hosp, Harvard Reprod Endocrine Unit, Boston, MA 02114 USA. [Bigos, S. Thomas] Togus Vet Affairs Med Ctr, Endocrine Serv, Augusta, ME USA. [Wartofsky, Leonard] MedStar Washington Hosp Ctr, Washington, DC USA. [Wartofsky, Leonard] Georgetown Univ, Sch Med, Washington, DC USA. [Cooper, David S.; Ladenson, Paul W.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Hershman, Jerome M.] Univ Calif Los Angeles, David Geffen Sch Med, Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. [Brent, Gregory] Univ Calif Los Angeles, David Geffen Sch Med, Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA 90095 USA. [Shupnik, Peggy] Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. [Samuels, Mary H.] Oregon Hlth & Sci Univ, Div Endocrinol Diabet & Clin Nutr, Portland, OR 97201 USA. [Samuels, Mary H.] Oregon Hlth & Sci Univ, Clin & Translat Res Ctr, Portland, OR 97201 USA. [Nagataki, Shigenobu] Nagasaki Univ, Tokyo, Japan. [Nagataki, Shigenobu] AOTA, Tokyo, Japan. [Nagataki, Shigenobu] Radiat Effects Assoc, Tokyo, Japan. [Pacini, Furio] Univ Siena, European Thyroid Assoc, I-53100 Siena, Italy. [Pacini, Furio] Univ Siena, Dept Endocrinol & Metab, I-53100 Siena, Italy. [Maciel, Rui M. B.] Univ Fed Sao Paulo, Lab Mol & Translat Endocrinol, Div Endocrinol, Dept Med,Escola Paulista Med, Sao Paulo, Brazil. [Singer, Peter] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. RP Haugen, B (reprint author), Univ Colorado, Sch Med, Aurora, CO 80045 USA. EM Bryan.haugen@ucdenver.edu; Michael.mcdermott@ucdenver.edu; Terri.carrothers@ucdenver.edu; gdaniels@partners.org; dross@partners.org; aklibanski@partners.org; wcrowley@partners.org; BIGOS_STHOMAS@comcast.net; Leonard.Wartofsky@Medstar.net; DSCooper@jhmi.edu; ladenson@jhmi.edu; jhershmn@g.ucla.edu; gbrent@ucla.edu; mas3x@virginia.edu; samuelsm@ohsu.edu; shigenobu.nagataki@nifty.com; pacini8@unisi.it; Rui.Maciel@grupofleury.com.br; psinger@med.usc.edu; carladonelson@aol.com; rockinrrranch@wildblue.net NR 1 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD NOV 1 PY 2014 VL 24 IS 11 BP 1555 EP 1565 DI 10.1089/thy.2014.2411 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AS9EZ UT WOS:000344547100001 ER PT J AU Mann, JK Chopera, D Omarjee, S Kuang, XMT Le, AQ Anmole, G Danroth, R Mwimanzi, P Reddy, T Carlson, J Radebe, M Goulder, PJR Walker, BD Karim, SA Novitsky, V Williamson, C Brockman, MA Brumme, ZL Ndung'u, T AF Mann, Jaclyn K. Chopera, Denis Omarjee, Saleha Kuang, Xiaomei T. Le, Anh Q. Anmole, Gursev Danroth, Ryan Mwimanzi, Philip Reddy, Tarylee Carlson, Jonathan Radebe, Mopo Goulder, Philip J. R. Walker, Bruce D. Karim, Salim Abdool Novitsky, Vladimir Williamson, Carolyn Brockman, Mark A. Brumme, Zabrina L. Ndung'u, Thumbi TI Nef-mediated down-regulation of CD4 and HLA class I in HIV-1 subtype C infection: Association with disease progression and influence of immune pressure SO VIROLOGY LA English DT Article DE HIV-1 Nef; HIV-1 subtype C; CD4 down-regulation; HLA-I down-regulation; HIV-1 disease progression; HLA-associated polymorphisms; Immune evasion ID T-CELL RESPONSES; SIMIAN IMMUNODEFICIENCY VIRUS; COMPLEX CLASS-I; VIRAL LOAD; TYPE-1 REPLICATION; GAG; TRANSMISSION; ESCAPE; MUTATIONS; EPITOPES AB Nef plays a major role in HIV-1 pathogenicity. We studied HIV-1 subtype C infected individuals in acute/early (n=120) or chronic (n=207) infection to investigate the relationship between Nef-mediated CD4/HLA-I down-regulation activities and disease progression, and the influence of immune-driven sequence variation on these Nef functions. A single Nef sequence per individual was cloned into an expression plasmid, followed by transfection of a T cell line and measurement of CD4 and HLA-I expression. In early infection, a trend of higher CD4 down-regulation ability correlating with higher viral load set point was observed (r=0.19, p=0.05), and higher HLA-I down-regulation activity was significantly associated with faster rate of CD4 decline (p=0.02). HLA-I down-regulation function correlated inversely with the number HLA-associated polymorphisms previously associated with reversion in the absence of the selecting HLA allele (r=-0.21, p=0.0002). These data support consideration of certain Nef regions in HIV-1 vaccine strategies designed to attenuate the infection course. (C) 2014 Elsevier Inc. All rights reserved. C1 [Mann, Jaclyn K.; Chopera, Denis; Omarjee, Saleha; Radebe, Mopo; Ndung'u, Thumbi] Univ KwaZulu Natal, HIV Pathogenesis Programme, ZA-4001 Durban, South Africa. [Mann, Jaclyn K.; Chopera, Denis; Omarjee, Saleha; Radebe, Mopo; Ndung'u, Thumbi] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV, ZA-4001 Durban, South Africa. [Chopera, Denis; Williamson, Carolyn] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Chopera, Denis; Williamson, Carolyn] Univ Cape Town, Div Med Virol, ZA-7925 Cape Town, South Africa. [Chopera, Denis; Williamson, Carolyn] Natl Hlth Lab Serv, ZA-7925 Cape Town, South Africa. [Kuang, Xiaomei T.; Anmole, Gursev; Brockman, Mark A.] Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada. [Le, Anh Q.; Danroth, Ryan; Mwimanzi, Philip; Brockman, Mark A.; Brumme, Zabrina L.] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada. [Reddy, Tarylee] MRC, Biostat Unit, ZA-4001 Durban, South Africa. [Carlson, Jonathan] Microsoft Res, Los Angeles, CA 90024 USA. [Goulder, Philip J. R.] Univ Oxford, Dept Paediat, Oxford OX1 3SY, England. [Goulder, Philip J. R.; Walker, Bruce D.; Ndung'u, Thumbi] Ragon Inst MGH MIT & Harvard Univ, Cambridge, MA 02139 USA. [Walker, Bruce D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Walker, Bruce D.] Harvard Univ, Boston, MA 02114 USA. [Walker, Bruce D.] Howard Hughes Med Res Inst, Chevy Chase, MD 20815 USA. [Karim, Salim Abdool] Univ KwaZulu Natal, Ctr AIDS Programme Res South Africa, ZA-4001 Durban, South Africa. [Novitsky, Vladimir] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Novitsky, Vladimir] Botswana Harvard Sch Publ Hlth, AIDS Initiat Partnership HIV Res & Educ, Gaborone, Botswana. [Brockman, Mark A.; Brumme, Zabrina L.] British Columbia Ctr Excellence HIV AIDS, Vancouver, BC V6Z 1Y6, Canada. [Ndung'u, Thumbi] Max Planck Inst Infect Biol, D-10117 Berlin, Germany. RP Ndung'u, T (reprint author), Univ KwaZulu Natal, HIV Pathogenesis Programme, 719 Umbilo Rd, ZA-4013 Durban, South Africa. EM ndungu@ukzn.ac.za OI , Carolyn/0000-0003-0125-1226; Ndung'u, Thumbi/0000-0003-2962-3992; Abdool Karim, Salim/0000-0002-4986-2133; Brockman, Mark/0000-0001-6432-1426 FU NIH [R37AI067073, RO1-AI057027]; International AIDS Vaccine Initiative [UKZNRSA1001]; Canada-Sub Saharan Africa (CANSSA) HIV/AIDS Network - Global Health Research Initiative; Canadian Institutes of Health Research (CIHR); Canadian International Development Agency; International Development Research Centre [106355-001]; Canadian Institutes for Health Research (CIHR); Sanofi-Aventis; Clinical Infectious Diseases Research Initiative Fellowship; Claude Leon Foundation, South Africa; CAHR/BMS Master's Scholarship in Basic Science; CIHR Frederick Banting and Charles Best Masters Award; Merck-Canada Training of Aboriginal Youth in Biomedical Labs program at Simon Fraser University; Michael Smith Foundation for Health Research (MSFHR; Canada); CIHR; MSFHR; Howard Hughes Medical Institute FX This research was funded by the NIH (R37AI067073, RO1-AI057027) and the International AIDS Vaccine Initiative (UKZNRSA1001). JKM received a pilot grant from the Canada-Sub Saharan Africa (CANSSA) HIV/AIDS Network, funded by the Global Health Research Initiative, a collaborative partnership of the Canadian Institutes of Health Research (CIHR), the Canadian International Development Agency, and the International Development Research Centre (project 106355-001). DRC is a recipient of the Canada-HOPE fellowship from the Canadian Institutes for Health Research (CIHR) and Sanofi-Aventis, and fellowships from the Clinical Infectious Diseases Research Initiative Fellowship and the Claude Leon Foundation, South Africa. XTK is funded by a CAHR/BMS Master's Scholarship in Basic Science. AQL is funded by a CIHR Frederick Banting and Charles Best Masters Award. RD is supported by the Merck-Canada Training of Aboriginal Youth in Biomedical Labs program at Simon Fraser University. PM is the recipient of Postdoctoral fellowships from the Michael Smith Foundation for Health Research (MSFHR; Canada) and the CIHR. MAB holds a Canada Research Chair, Tier 2, in Viral Pathogenesis and Immunity. ZLB is the recipient of a CIHR New Investigator Award and a Scholar Award from the MSFHR. TN holds the South African DST/NRF Research Chair in Systems Biology of HIV/AIDS, the Victor Daitz Chair in HIV/TB Research and an International Early Career Scientist Award from the Howard Hughes Medical Institute. NR 56 TC 5 Z9 5 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD NOV PY 2014 VL 468 BP 214 EP 225 DI 10.1016/j.virol.2014.08.009 PG 12 WC Virology SC Virology GA AS7KF UT WOS:000344434400025 PM 25193656 ER PT J AU Smith, JA Haberstroh, FS White, EA Livingston, DM DeCaprio, JA Howley, PM AF Smith, Jennifer A. Haberstroh, Friederike S. White, Elizabeth A. Livingston, David M. DeCaprio, James A. Howley, Peter M. TI SMCX and components of the TIP60 complex contribute to E2 regulation of the HPV E6/E7 promoter SO VIROLOGY LA English DT Article DE Papillomavirus; E2; LCR; Transcriptional repression; SMCX; Methylation; Chromatin; H3K4; EP400; TIP60 ID PAPILLOMAVIRUS ONCOGENE EXPRESSION; HISTONE ACETYLASE COMPLEX; CERVICAL-CARCINOMA CELLS; E2-MEDIATED REPRESSION; GROWTH-INHIBITION; PROTEIN; DEMETHYLASE; DNA; REGION; BRD4 AB An important step in the malignant progression of HPV-associated lesions is the dysregulation of expression of the viral E6 and E7 oncogenes. This is often achieved through the loss of expression of E2, which represses the HPV LCR promoter and E6/E7 expression. Our previous studies confirmed a role for Brd4 in mediating the E2 transcriptional repression function, and identified JARID1C/SMCX and EP400 as contributors to E2-mediated repression. Here we show that TIP60, a component of the TIP60/TRRAP histone acetyltransferase complex, also contributes to the E2 repression function, and we extend our studies on SMCX. Di- and tri-methyl marks on histone H3K4 are reduced in the presence of E2 and SMCX, suggesting a mechanism by which SMCX contributes to E2-mediated repression of the HPV LCR. Together, these findings lead us to hypothesize that E2 recruits histone-modifying cellular proteins to the HPV LCR, resulting in transcriptional repression of E6 and E7. (C) 2014 Elsevier Inc. All rights reserved. C1 [Smith, Jennifer A.; Haberstroh, Friederike S.; White, Elizabeth A.; Howley, Peter M.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Livingston, David M.; DeCaprio, James A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Livingston, David M.; DeCaprio, James A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [DeCaprio, James A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Howley, PM (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM peter_howley@hms.harvard.edu FU NIH [T32CA009361]; NRSA [F32A1080075, R01CA116720, P01CA050661] FX We thank S. Iwase and Y. Shi (Harvard Medical School) for providing SMCX expression constructs, D. Di Maio (Yale University) for the HeLa/16E6/16E7 cells, B. Price (Dana Farber Cancer Institute) for TIP60 expression construct, and R. Roeder (Rockefeller University) for EP400 fragment expression constructs. We are grateful to members of the Howley lab for helpful discussions and feedback on various aspects on this project, in particular L. Zhao for constructing the mutant BPV1 E2 plasmids. This work was supported by the NIH Grants T32CA009361 to J.A.S., individual NRSA F32A1080075 to E.A.W., R01CA116720 to P.M.H. and P01CA050661 to D.M.L., J.A.D. and P.M.H. NR 46 TC 7 Z9 7 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD NOV PY 2014 VL 468 BP 311 EP 321 DI 10.1016/j.virol.2014.08.022 PG 11 WC Virology SC Virology GA AS7KF UT WOS:000344434400036 PM 25222147 ER PT J AU Dhaliwal, G Sehgal, NL AF Dhaliwal, Gurpreet Sehgal, Niraj L. TI Demystify Leadership in Order to Cultivate It SO ACADEMIC MEDICINE LA English DT Editorial Material C1 [Dhaliwal, Gurpreet; Sehgal, Niraj L.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Dhaliwal, Gurpreet] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Sehgal, Niraj L.] Univ Calif San Francisco, Ctr Hlth Profess, San Francisco, CA USA. RP Dhaliwal, G (reprint author), San Francisco VA Med Ctr, 4150 Clement St 111, San Francisco, CA 94121 USA. EM gurpreet.dhaliwal@ucsf.edu NR 3 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD NOV PY 2014 VL 89 IS 11 BP 1441 EP 1441 DI 10.1097/ACM.0000000000000489 PG 1 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA AR9MC UT WOS:000343897500012 PM 25350336 ER PT J AU McDonald, CC Curry, AE Kandadai, V Sommers, MS Winston, FK AF McDonald, Catherine C. Curry, Allison E. Kandadai, Venk Sommers, Marilyn S. Winston, Flaura K. TI Comparison of teen and adult driver crash scenarios in a nationally representative sample of serious crashes SO ACCIDENT ANALYSIS AND PREVENTION LA English DT Article DE Teen drivers; Adult drivers; Crash-contributing factors; Crash scenarios; Risk factors; Traffic safety ID RISKY DRIVING BEHAVIOR; NOVICE DRIVERS; PASSENGERS AB Motor vehicle crashes are the leading cause of death and acquired disability during the first four decades of life. While teen drivers have the highest crash risk, few studies examine the similarities and differences in teen and adult driver crashes. We aimed to: (1) identify and compare the most frequent crash scenarios integrated information on a vehicle's movement prior to crash, immediate pre-crash event, and crash configuration for teen and adult drivers involved in serious crashes, and (2) for the most frequent scenarios, explore whether the distribution of driver critical errors differed for teens and adult drivers. We analyzed data from the National Motor Vehicle Crash Causation Survey, a nationally representative study of serious crashes conducted by the U.S. National Highway Traffic Safety Administration from 2005 to 2007. Our sample included 642 16- to 19-year-old and 1167 35- to 54-year-old crash-involved drivers (weighted n = 296,482 and 439,356, respectively) who made a critical error that led to their crash's critical pre-crash event (i.e., event that made the crash inevitable). We estimated prevalence ratios (PR) and 95% confidence intervals (CI) to compare the relative frequency of crash scenarios and driver critical errors. The top five crash scenarios among teen drivers, accounting for 37.3% of their crashes, included: (1) going straight, other vehicle stopped, rear end; (2) stopped in traffic lane, turning left at intersection, turn into path of other vehicle; (3) negotiating curve, off right edge of road, right roadside departure; (4) going straight, off right edge of road, right roadside departure; and (5) stopped in lane, turning left at intersection, turn across path of other vehicle. The top five crash scenarios among adult drivers, accounting for 33.9% of their crashes, included the same scenarios as the teen drivers with the exception of scenario (3) and the addition of going straight, crossing over an intersection, and continuing on a straight path. For two scenarios ((1) and (3) above), teens were more likely than adults to make a critical decision error (e.g., traveling too fast for conditions). Our findings indicate that among those who make a driver critical error in a serious crash, there are few differences in the scenarios or critical driver errors for teen and adult drivers. (C) 2014 Elsevier Ltd. All rights reserved. C1 [McDonald, Catherine C.; Sommers, Marilyn S.] Univ Penn, Sch Nursing, Ctr Global Womens Hlth, Ctr Hlth Equ Res, Philadelphia, PA 19104 USA. [McDonald, Catherine C.; Curry, Allison E.; Kandadai, Venk; Winston, Flaura K.] Childrens Hosp Philadelphia, Ctr Injury Res & Prevent, Philadelphia, PA 19104 USA. [Curry, Allison E.] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Winston, Flaura K.] Univ Penn, Perelman Sch Med, Div Gen Pediat, Philadelphia, PA 19104 USA. [Winston, Flaura K.] Childrens Hosp Philadelphia, Natl Sci Fdn Ctr Child Injury Prevent Studies, Philadelphia, PA 19104 USA. RP McDonald, CC (reprint author), Univ Penn, Sch Nursing, Ctr Global Womens Hlth, Ctr Hlth Equ Res, Claire Fagin Hall,418 Curie Blvd, Philadelphia, PA 19104 USA. EM mcdonalc@nursing.upenn.edu; currya@email.chop.edu; kandadaiv@email.chop.edu; ssommer@nursing.upenn.edu; flaura@mail.med.upenn.edu NR 31 TC 7 Z9 7 U1 2 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0001-4575 EI 1879-2057 J9 ACCIDENT ANAL PREV JI Accid. Anal. Prev. PD NOV PY 2014 VL 72 BP 302 EP 308 DI 10.1016/j.aap.2014.07.016 PG 7 WC Ergonomics; Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary; Transportation SC Engineering; Public, Environmental & Occupational Health; Social Sciences - Other Topics; Transportation GA AR8SC UT WOS:000343843700030 PM 25103321 ER PT J AU Beidas, RS Edmunds, J Ditty, M Watkins, J Walsh, L Marcus, S Kendall, P AF Beidas, Rinad S. Edmunds, Julie Ditty, Matthew Watkins, Jessica Walsh, Lucia Marcus, Steven Kendall, Philip TI Are Inner Context Factors Related to Implementation Outcomes in Cognitive-Behavioral Therapy for Youth Anxiety? SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Article DE Evidence-based practice; Inner context; Implementation outcomes ID MENTAL-HEALTH; RANDOMIZED-TRIAL; ORGANIZATIONAL READINESS; DISSEMINATION TRIAL; TREATMENT INTEGRITY; CHILDHOOD ANXIETY; CONSULTATION; CLINICIAN; STRATEGIES; SERVICES AB Among the challenges facing the mental health field are the dissemination and implementation of evidence-based practices. The present study investigated the relationships between inner context variables (i.e., adopter characteristics and individual perceptions of intra-organizational factors) and two implementation outcomes-independently rated therapist fidelity on a performance-based role-play (i.e., adherence and skill) and self-reported penetration of cognitive behavioral therapy for youth anxiety following training. A significant relationship was found between inner context variables and fidelity. Specifically, adopter characteristics were associated with adherence and skill; individual perceptions of intra-organizational factors were associated with adherence. Inner context variables were not associated with penetration. Future directions are discussed. C1 [Beidas, Rinad S.; Walsh, Lucia] Univ Penn, Perelman Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Edmunds, Julie] Judge Baker Childrens Ctr, Ctr Effect Child Therapy, Boston, MA USA. [Ditty, Matthew; Marcus, Steven] Univ Penn, Sch Social Policy & Practice, Philadelphia, PA 19104 USA. [Watkins, Jessica] Bryn Mawr Coll, Bryn Mawr, PA 19010 USA. [Marcus, Steven] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Kendall, Philip] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. RP Beidas, RS (reprint author), Univ Penn, Perelman Sch Med, Dept Psychiat, 3535 Market St,3015, Philadelphia, PA 19104 USA. EM rbeidas@upenn.edu FU NIMH NIH HHS [K23 MH099179, MH063747, MH086436, R01 MH063747, R25 MH080916, U01 MH063747, F31 MH083333, MH083333, MH099179] NR 62 TC 8 Z9 8 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-587X EI 1573-3289 J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD NOV PY 2014 VL 41 IS 6 BP 788 EP 799 DI 10.1007/s10488-013-0529-x PG 12 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AS0UW UT WOS:000343994900009 PM 24202067 ER PT J AU Tsai, AC Weiser, SD AF Tsai, Alexander C. Weiser, Sheri D. TI Population-Based Study of Food Insecurity and HIV Transmission Risk Behaviors and Symptoms of Sexually Transmitted Infections Among Linked Couples in Nepal SO AIDS AND BEHAVIOR LA English DT Article DE Food insecurity; Nepal; HIV ID SUB-SAHARAN AFRICA; FEMALE SEX WORKERS; INTRAHOUSEHOLD ALLOCATION; TRANSACTIONAL SEX; WOMEN; HIV/AIDS; POVERTY; PREVALENCE; HEALTH; ISSUES AB Food insecurity has recently emerged as an important risk factor for HIV acquisition among women worldwide. No previous studies have used linked data that would permit investigation of the extent to which food insecurity may have differential associations with HIV transmission risk behaviors or symptoms of sexually transmitted infections (STIs) among men and women in the same households. We used nationally representative data on linked couples from the Nepal 2011 Demographic and Health Survey. The primary explanatory variable of interest was food insecurity, measured with a modified version of the Household Food Insecurity Access Scale. In multivariable logistic regression models, women in food insecure households were less likely to report recent condom use and more likely to report symptoms consistent with STIs. These patterns were absent among men. Interventions targeting food insecurity may have beneficial implications for both HIV prevention and gender equity in Nepal. C1 [Tsai, Alexander C.] Massachusetts Gen Hosp, Chester M Pierce MD Div Global Psychiat, Boston, MA 02114 USA. [Tsai, Alexander C.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Tsai, Alexander C.] Harvard Univ, Sch Med, Boston, MA USA. [Tsai, Alexander C.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Weiser, Sheri D.] Univ Calif San Francisco, San Francisco Gen Hosp, Div HIV AIDS, San Francisco, CA USA. RP Tsai, AC (reprint author), Massachusetts Gen Hosp, Chester M Pierce MD Div Global Psychiat, Room 1529-E3,100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM actsai@partners.org RI Nguyen, Giang/D-9027-2016; OI Tsai, Alexander/0000-0001-6397-7917 FU NIMH NIH HHS [K23 MH096620, K23MH096620] NR 55 TC 4 Z9 4 U1 1 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 EI 1573-3254 J9 AIDS BEHAV JI AIDS Behav. PD NOV PY 2014 VL 18 IS 11 BP 2187 EP 2197 DI 10.1007/s10461-014-0794-z PG 11 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA AR8BY UT WOS:000343801700014 PM 24833522 ER PT J AU Wang, S Luo, XD Barnes, D Sano, M Yaffe, K AF Wang, Sophia Luo, Xiaodong Barnes, Deborah Sano, Mary Yaffe, Kristine TI Physical Activity and Risk of Cognitive Impairment Among Oldest-Old Women SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Cognitive aging; cohort studies; dementia; physical activity; oldest-old ID ALZHEIMERS-DISEASE; EXECUTIVE FUNCTION; DEMENTIA; PREVALENCE; AGE; ASSOCIATION; EXERCISE; DECLINE; COHORT; ADULTS AB Objectives: Physical activity may reduce the risk of cognitive decline in the elderly, but its effects among the oldest-old (i.e., those aged 85 years and older) are not well known. Our study assessed the association between very late-life physical activity and 5-year risk of mild cognitive impairment (MCI) or dementia and neuropsychological test performance among oldest-old women. Methods: This prospective study was conducted at three sites. Participants included 1,249 women (mean [standard deviation] age: 83.3 [2.8] years). Baseline physical activity was measured by self-reported blocks walked per week and analyzed according to tertile. Five years later, surviving participants who were 85 years and older (oldest-old) completed neuropsychological testing and underwent adjudication of clinical cognitive status (normal, MCI, or dementia). All analyses were adjusted for baseline age, education, cognition, depression, body mass index, hypertension, smoking, and coronary artery disease. Results: Compared with women in the lowest tertile, women in the highest tertile were less likely to develop dementia (13.0% versus 23.2%; multivariate adjusted odds ratio: 0.54 [95% confidence interval: 0.36-0.82]). However, risk of MCI was not associated with physical activity. Physical activity was also associated with higher performance 5 years later on tests of global cognition, category fluency, and executive function but not phonemic fluency, memory, or attention. Conclusions: Higher level of very late-life physical activity was associated with a lower risk of subsequent dementia in oldest-old women. These findings support future studies for late-life physical activity interventions for the prevention of dementia among oldest-old women. C1 [Wang, Sophia; Barnes, Deborah; Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Wang, Sophia; Barnes, Deborah; Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Luo, Xiaodong; Sano, Mary] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Luo, Xiaodong; Sano, Mary] Vet Affairs Med Ctr, Bronx, NY USA. [Barnes, Deborah; Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Wang, S (reprint author), Langley Porter Neuropsychiat Inst, 401 Parnassus Ave,GPP 0984, San Francisco, CA 94103 USA. EM sophia.wang@ucsf.edu FU VA Neurosciences Research fellowship; Mount Sinai Alzheimer's Disease Research Center award from National Institute of Aging (NIA) [P50AG005138-27]; National Center for Research Resources' Clinical and Translational Science Award [UL1RR029887]; NIA [K24 AG 031155]; Alzheimer's Association; APA/Lilly Resident Research Award; [AG05407]; [AR35582]; [AG05394]; [AR3354]; [AR35583]; [R01 AG005407]; [R01 AG027576-22]; [2 R01 AG005394-22A1]; [2R01 AG027574-22A1]; [5R01AG026720-04] FX Data collection and sharing for SOF and SOF-WISE are supported by grants AG05407, AR35582, AG05394, AR3354, AR35583, R01 AG005407, R01 AG027576-22, 2 R01 AG005394-22A1, 2R01 AG027574-22A1, and 5R01AG026720-04. The study was coordinated by the University of California at San Francisco, and the SOF data are disseminated by the University of California at San Francisco. This study was also supported in part by a VA Neurosciences Research fellowship (S. W.), Mount Sinai Alzheimer's Disease Research Center award P50AG005138-27 from the National Institute of Aging (NIA) (X. L., M. S.), UL1RR029887 from the National Center for Research Resources' Clinical and Translational Science Award (M. S.), grant K24 AG 031155 from the NIA and an Independent Investigator Award from the Alzheimer's Association (KY). Dr. Wang also received the APA/Lilly Resident Research Award for this work. NR 40 TC 7 Z9 7 U1 0 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD NOV PY 2014 VL 22 IS 11 BP 1149 EP 1157 DI 10.1016/j.jagp.2013.03.002 PG 9 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AR8YG UT WOS:000343856600011 PM 23831179 ER PT J AU Donovan, NJ Wadsworth, LP Lorius, N Locascio, JJ Rentz, DM Johnson, KA Sperling, RA Marshall, GA AF Donovan, Nancy J. Wadsworth, Lauren P. Lorius, Natacha Locascio, Joseph J. Rentz, Dorene M. Johnson, Keith A. Sperling, Reisa A. Marshall, Gad A. CA Alzheimer Dis Neuroimaging TI Regional Cortical Thinning Predicts Worsening Apathy and Hallucinations Across the Alzheimer Disease Spectrum SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Apathy; hallucinations; MRI; cortical thinning; CSF biomarkers; Alzheimer disease ID POSITRON-EMISSION-TOMOGRAPHY; MILD COGNITIVE IMPAIRMENT; NEUROPSYCHIATRIC SYMPTOMS; CEREBROSPINAL-FLUID; FUNCTIONAL IMPAIRMENT; VISUAL HALLUCINATIONS; PSYCHOSIS; SIGNATURE; PERFUSION; DEMENTIA AB Objectives: To examine regions of cortical thinning and cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers associated with apathy and hallucinations in a continuum of individuals including clinically normal elderly, mild cognitive impairment, and mild AD dementia. Design: Cross-sectional and longitudinal studies. Setting: Fifty-seven research sites across North America. Participants: Eight-hundred twelve community-dwelling volunteers; 413 participants in the CSF substudy. Measurements: Structural magnetic resonance imaging data and CSF concentrations of amyloid-beta 1-42, total tau, and phosphorylated tau derived from the Alzheimer Disease Neuroimaging Initiative database were analyzed. Apathy and hallucinations were measured at baseline and over 3 years using the Neuropsychiatric Inventory-Questionnaire. General linear models and mixed effects models were used to evaluate the relationships among baseline cortical thickness in seven regions, and baseline CSF biomarkers, apathy, and hallucinations at baseline and longitudinally. Covariates included diagnosis, sex, age, apolipoprotein E genotype, premorbid intelligence, memory performance, processing speed, antidepressant use, and AD duration. Results: Reduced baseline inferior temporal cortical thickness was predictive of increasing apathy over time, and reduced supramarginal cortical thickness was predictive of increasing hallucinations over time. There was no association with cortical thickness at baseline. CSF biomarkers were not related to severity of apathy or hallucinations in cross-sectional or longitudinal analyses. Conclusions: These results suggest that greater baseline temporal and parietal atrophy is associated with worsening apathy and hallucinations in a large AD spectrum cohort, while adjusting for multiple disease-related variables. Localized cortical neurodegeneration may contribute to the pathophysiology of apathy and hallucinations and their adverse consequences in AD. C1 [Donovan, Nancy J.; Lorius, Natacha; Rentz, Dorene M.; Johnson, Keith A.; Sperling, Reisa A.; Marshall, Gad A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Alzheimer Res & Treatment, Boston, MA 02115 USA. [Donovan, Nancy J.; Rentz, Dorene M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Donovan, Nancy J.; Rentz, Dorene M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Wadsworth, Lauren P.; Lorius, Natacha; Locascio, Joseph J.; Rentz, Dorene M.; Sperling, Reisa A.; Marshall, Gad A.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Johnson, Keith A.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Donovan, NJ (reprint author), Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, 221 Longwood Ave,BL 104H, Boston, MA 02115 USA. EM njdonovan@partners.org FU National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering [U01 AG024904]; Rosalinde and Arthur Gilbert Foundation/AFAR New Investigator Awards in Alzheimer's disease; Massachusetts Alzheimer's Disease Research Center [P50 AG005134]; Harvard Aging Brain Study [P01 AGO36694]; [R01 AG027435]; [K23 AG033634]; [K24 AG035007]; [D01 HP08794-04-00] FX The Alzheimer's Disease Neuroimaging Initiative (ADNI) (NIH grant U01 AG024904) is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; AstraZeneca AB; Bayer Schering Pharma AG; Bristol-Myers Squibb; Eisai Global Clinical Development; Elan Corporation; Genentech; GE Healthcare; GlaxoSmithKline; Innogenetics; Johnson and Johnson; Eli Lilly and Co.; Medpace, Inc.; Merck and Co., Inc.; Novartis AG; Pfizer, Inc.; F. Hoffman-La Roche; Schering-Plough; Synarc, Inc.; as well as nonprofit partners the Alzheimer's Association and Alzheimer's Drug Discovery Foundation, with participation from the U.S. Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles.; This study was also supported by R01 AG027435, K23 AG033634, K24 AG035007, D01 HP08794-04-00, the Rosalinde and Arthur Gilbert Foundation/AFAR New Investigator Awards in Alzheimer's disease, the Massachusetts Alzheimer's Disease Research Center (P50 AG005134) and the Harvard Aging Brain Study (P01 AGO36694). NR 41 TC 16 Z9 17 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD NOV PY 2014 VL 22 IS 11 BP 1168 EP 1179 DI 10.1016/j.jagp.2013.03.006 PG 12 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AR8YG UT WOS:000343856600013 PM 23890751 ER PT J AU Gurrera, RJ Karel, MJ Azar, AR Moye, J AF Gurrera, Ronald J. Karel, Michele J. Azar, Armin R. Moye, Jennifer TI Neuropsychological Performance Within-Person Variability Is Associated with Reduced Treatment Consent Capacity SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Decisional capacity; executive function; cognitive impairment ID ALZHEIMERS-DISEASE; COGNITIVE IMPAIRMENT; COMPETENCE; DEMENTIA; PREDICTORS; ADULTS; HEALTH; SPAN AB Objective: The capacity of older adults to make healthcare decisions is often impaired in dementia and has been linked to performance on specific neuropsychological tasks. Within-person across-test neuropsychological performance variability has been shown to predict future dementia. This study examined the relationship of within-person across-test neuropsychological performance variability to a current construct of treatment decision (consent) capacity. Methods: Participants completed a neuropsychological test battery and a standardized capacity assessment. Standard scores were used to compute mean neuropsychological performance and within-person across-test variability. Assessments were performed in the participant's preferred location (e.g., outpatient clinic office, senior center, or home). Participants were recruited from the community with fliers and advertisements and consisted of men (N = 79) and women (N = 80) with (N = 83) or without (N = 76) significant cognitive impairment. Participants completed the MacArthur Competence Assessment Tool-Treatment and 11 neuropsychological tests commonly used in the cognitive assessment of older individuals. Results: Neuropsychological performance and within-person variability were independently associated with continuous and dichotomous measures of capacity, and within-person neuropsychological variability was significantly associated with within-person decisional ability variability. Prevalence of incapacity was greater than expected in participants with and without significant cognitive impairment when decisional abilities were considered separately. Conclusion: These findings are consistent with an emerging construct of consent capacity in which discrete decisional abilities are differentially associated with cognitive processes and indicate that the sensitivity and accuracy of consent capacity assessments can be improved by evaluating decisional abilities separately. C1 [Gurrera, Ronald J.; Karel, Michele J.; Azar, Armin R.; Moye, Jennifer] VA Boston Healthcare Syst, Brockton, MA 02301 USA. [Gurrera, Ronald J.; Karel, Michele J.; Azar, Armin R.; Moye, Jennifer] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Gurrera, RJ (reprint author), VA Boston Healthcare Syst, 940 Belmont St 116A, Brockton, MA 02301 USA. EM ronald_gurrera@hms.harvard.edu RI Moye, Jennifer/F-2240-2017 OI Moye, Jennifer/0000-0002-3434-347X FU NIMH [R29 MH57104] FX Supported by a NIMH grant to Jennifer Moye (R29 MH57104) and with resources and the use of facilities at the VA Boston Healthcare System. NR 42 TC 1 Z9 1 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD NOV PY 2014 VL 22 IS 11 BP 1200 EP 1209 DI 10.1016/j.jagp.2013.03.010 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AR8YG UT WOS:000343856600016 PM 23831178 ER PT J AU Bartels, SJ Pratt, SI Mueser, KT Forester, BP Wolfe, R Cather, C Xie, HY McHugo, GJ Bird, B Aschbrenner, KA Naslund, JA Feldman, J AF Bartels, Stephen J. Pratt, Sarah I. Mueser, Kim T. Forester, Brent P. Wolfe, Rosemarie Cather, Corinne Xie, Haiyi McHugo, Gregory J. Bird, Bruce Aschbrenner, Kelly A. Naslund, John A. Feldman, James TI Long-Term Outcomes of a Randomized Trial of Integrated Skills Training and Preventive Healthcare for Older Adults with Serious Mental Illness SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Older adults; serious mental illness; psychosocial skills training; healthcare management; preventive healthcare; integrated care ID PILOT PSYCHOSOCIAL INTERVENTION; CHRONIC PSYCHOTIC DISORDERS; CHRONIC-SCHIZOPHRENIA; PEOPLE; RELIABILITY; INSTRUMENT; DEPRESSION; CLINICIAN; CONSUMERS; OLMSTEAD AB Objective: This report describes 1-, 2-, and 3-year outcomes of a combined psychosocial skills training and preventive healthcare intervention (Helping Older People Experience Success [HOPES]) for older persons with serious mental illness. Methods: A randomized controlled trial compared HOPES with treatment as usual (TAU) for 183 older adults (age >= 50 years [mean age: 60.2]) with serious mental illness (28% schizophrenia, 28% schizoaffective disorder, 20% bipolar disorder, 24% major depression) from two community mental health centers in Boston, Massachusetts, and one in Nashua, New Hampshire. HOPES comprised 12 months of weekly skills training classes, twice-monthly community practice trips, and monthly nurse preventive healthcare visits, followed by a 1-year maintenance phase of monthly sessions. Blinded evaluations of functioning, symptoms, and service use were conducted at baseline and at a 1-year (end of the intensive phase), 2-year (end of the maintenance phase), and 3-year (12 months after the intervention) follow-up. Results: HOPES compared with TAU was associated with improved community living skills and functioning, greater self-efficacy, lower overall psychiatric and negative symptoms, greater acquisition of preventive healthcare (more frequent eye exams, visual acuity, hearing tests, mammograms, and Pap smears), and nearly twice the rate of completed advance directives. No differences were found for medical severity, number of medical conditions, subjective health status, or acute service use at the 3-year follow-up. Conclusion: Skills training and nurse facilitated preventive healthcare for older adults with serious mental illness was associated with sustained long-term improvement in functioning, symptoms, self-efficacy, preventive healthcare screening, and advance care planning. C1 [Bartels, Stephen J.; Pratt, Sarah I.; Mueser, Kim T.; Aschbrenner, Kelly A.] Geisel Sch Med Dartmouth, Dept Psychiat, Hanover, NH USA. [Bartels, Stephen J.] Geisel Sch Med Dartmouth, Dept Community & Family Med, Hanover, NH USA. [Bartels, Stephen J.; Pratt, Sarah I.; Naslund, John A.] Dartmouth Coll, Dartmouth Inst Hlth Policy & Clin Practice, Hanover, NH 03755 USA. [Mueser, Kim T.; Wolfe, Rosemarie; Xie, Haiyi; McHugo, Gregory J.] Dartmouth Psychiat Res Ctr, Lebanon, NH USA. [Mueser, Kim T.] Boston Univ, Ctr Psychiat Rehabil, Boston, MA 02215 USA. [Forester, Brent P.] Harvard Univ, Dept Psychiat, Cambridge, MA 02138 USA. [Forester, Brent P.] McLean Hosp, Geriatr Psychiat Res Program, Belmont, MA 02178 USA. [Cather, Corinne] Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. [Bird, Bruce] Vinfen, Cambridge, MA USA. [Feldman, James] Massachusetts Mental Hlth Ctr, Boston, MA 02115 USA. RP Bartels, SJ (reprint author), Ctr Hlth & Aging, 46 Centerra Pkwy,Ste 200, Lebanon, NH 03766 USA. EM sbartels@dartmouth.edu FU National Institute of Mental Health [R01 MH62324] FX The study was supported by a grant from the National Institute of Mental Health (R01 MH62324). NR 43 TC 8 Z9 8 U1 2 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD NOV PY 2014 VL 22 IS 11 BP 1251 EP 1261 DI 10.1016/j.jagp.2013.04.013 PG 11 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AR8YG UT WOS:000343856600021 PM 23954039 ER PT J AU Sultzer, DL Leskin, LP Melrose, RJ Harwood, DG Narvaez, TA Ando, TK Mandelkern, MA AF Sultzer, David L. Leskin, Lorraine P. Melrose, Rebecca J. Harwood, Dylan G. Narvaez, Theresa A. Ando, Timothy K. Mandelkern, Mark A. TI Neurobiology of Delusions, Memory, and Insight in Alzheimer Disease SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Alzheimer disease; delusions; insight; memory; FDG-PET; cerebral metabolism ID NEUROBEHAVIORAL RATING-SCALE; REGIONAL CORTICAL METABOLISM; CEREBRAL-BLOOD-FLOW; BEHAVIORAL DISTURBANCES; PSYCHIATRIC-SYMPTOMS; COGNITIVE DEFICITS; NATIONAL INSTITUTE; PSYCHOTIC SYMPTOMS; IMPAIRED INSIGHT; WORKING-MEMORY AB Objective: Delusional thoughts are common among patients with Alzheimer disease (AD) and may be conceptually linked to memory deficits (cannot recall accurate information, which leads to inaccurate beliefs) and poor insight (unable to appreciate the illogic of beliefs). This study's goals were to examine the clinical associations among delusions, memory deficits, and poor insight; explore neurobiologic correlates for these symptoms; and identify shared mechanisms. Methods: In a cross-sectional analysis, 88 outpatients with AD (mean Mini-Mental State Exam score: 19.3) were studied. Delusional thoughts were assessed with the Neuropsychiatric Inventory, level of inaccurate insight was assessed with the Neurobehavioral Rating Scale, and memory was assessed with the Mattis Dementia Rating Scale memory subscale. F-18-fluorodeoxyglucose positron emission tomography was used to measure regional cortical metabolism. Relationships between clinical ratings and regional cortical metabolic activity (voxel-based) were assessed using SPM2. Results: Patients with delusions had lower Dementia Rating Scale memory subscale scores. Neurobehavioral Rating Scale inaccurate insight scores were no different in those with and without delusions. Cortical metabolic activity was lower in the right lateral frontal cortex, orbitofrontal cortex, and bilateral temporal cortex in patients with delusions. Low cortical metabolic activity in the right lateral, inferior, and medial temporal cortex was associated with poorer memory. This region partially overlapped the region of hypometabolism associated with delusions. In contrast, low cortical metabolic activity in bilateral medial frontal cortex was associated with poor insight. Conclusion: Delusions in AD are associated with dysfunction in specific frontal and temporal cortical regions. Delusions are partially clinically and neurobiologically linked to memory deficits but not to poor insight. C1 [Sultzer, David L.; Leskin, Lorraine P.; Melrose, Rebecca J.; Harwood, Dylan G.; Narvaez, Theresa A.; Ando, Timothy K.] VA Greater Los Angeles Healthcare Syst, Brain Behav & Aging Res Ctr, Los Angeles, CA 90073 USA. [Mandelkern, Mark A.] VA Greater Los Angeles Healthcare Syst, Nucl Med Serv, Los Angeles, CA 90073 USA. [Sultzer, David L.; Melrose, Rebecca J.; Harwood, Dylan G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Mandelkern, Mark A.] Univ Calif Irvine, Dept Phys, Irvine, CA 92717 USA. RP Sultzer, DL (reprint author), VA Greater Los Angeles Healthcare Syst, Brain Behav & Aging Res Ctr, 11301 Wilshire Blvd,116AE, Los Angeles, CA 90073 USA. EM dsultzer@ucla.edu FU Department of Veterans Affairs; National Institute of Mental Health [R01MH56031]; Eli Lilly FX Supported in part by the Department of Veterans Affairs (Merit Review Award to DLS; Career Development Award to RJM) and the National Institute of Mental Health (R01MH56031).; Dr. Sultzer has received research support from Eli Lilly and has served as a consultant to Otsuka Pharmaceutical and Eli Lilly. NR 59 TC 6 Z9 6 U1 3 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD NOV PY 2014 VL 22 IS 11 BP 1346 EP 1355 DI 10.1016/j.jagp.2013.06.005 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA AR8YG UT WOS:000343856600030 PM 24021220 ER PT J AU Leyva, B Allen, JD Tom, LS Ospino, H Torres, MI Abraido-Lanza, AF AF Leyva, Bryan Allen, Jennifer D. Tom, Laura S. Ospino, Hosffman Torres, Maria Idali Abraido-Lanza, Ana F. TI Religion, Fatalism, and Cancer Control: A Qualitative Study among Hispanic Catholics SO AMERICAN JOURNAL OF HEALTH BEHAVIOR LA English DT Article DE fatalism; cancer fatalism; religion; Catholic; Latinos; Hispanics; cancer; cancer screening ID MEXICAN-AMERICAN WOMEN; BREAST-CANCER; CERVICAL-CANCER; AFRICAN-AMERICAN; HEALTH BEHAVIORS; PROSTATE-CANCER; SCREENING BEHAVIORS; EXPLANATORY MODELS; UNITED-STATES; BELIEFS AB Objectives: To assess cancer perceptions among churchgoers and to examine the potential influence of fatalism and religious beliefs on the use of cancer screening tests. Methods: Eight semi-structured focus groups were conducted among 67 Hispanic Catholics in Massachusetts. Results: In this sample, there were few references to fatalistic beliefs about cancer and nearly universal endorsement of the utility of cancer screening for cancer early detection. Most participants reported that their religious beliefs encouraged them to use health services, including cancer-screening tests. Although participants agreed that God plays an active role in health, they also affirmed the importance of self-agency in determining cancer outcomes. Conclusions: Our findings challenge the assumption that fatalism is an overriding perspective among Hispanics. Catholic religious beliefs may contribute to positive health attitudes and behaviors. C1 [Leyva, Bryan] NCI, NIH, Bethesda, MD 20892 USA. [Allen, Jennifer D.] Tufts Univ, Boston, MA 02111 USA. [Tom, Laura S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ospino, Hosffman] Boston Coll, Sch Theol & Minist, Chestnut Hill, MA 02167 USA. [Torres, Maria Idali] Univ Massachusetts, Dept Anthropol, Boston, MA 02125 USA. [Abraido-Lanza, Ana F.] Columbias Mailman Sch Publ Hlth, New York, NY USA. RP Leyva, B (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM leyvabryan@gmail.com RI Allen, Jennifer/M-2113-2015 FU NCATS NIH HHS [UL1TR000040, UL1 TR000040]; NCCDPHP CDC HHS [U48DP001946, U48 DP001946]; NCI NIH HHS [U54CA156732, U54 CA156732]; NIGMS NIH HHS [R25 GM062454, R25GM062454] NR 85 TC 5 Z9 5 U1 3 U2 13 PU PNG PUBLICATIONS PI OAK RIDGE PA 2205-K OAK RIDGE RD, #115, OAK RIDGE, NC 27310 USA SN 1945-7359 J9 AM J HEALTH BEHAV JI Am. J. Health Behav. PD NOV PY 2014 VL 38 IS 6 BP 839 EP 849 DI 10.5993/AJHB.38.6.6 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AS1JE UT WOS:000344036600006 PM 25207510 ER PT J AU Welsh, MM Federinko, SP Burnett, DG Gackstetter, GD Boyko, EJ Seelig, AD Wells, TS Hooper, TI AF Welsh, Marleen M. Federinko, Susan P. Burnett, Daniel G. Gackstetter, Gary D. Boyko, Edward J. Seelig, Amber D. Wells, Timothy S. Hooper, Tomoko I. TI Deployment-Related Depression Screening, 2001-2008 Comparing Clinical Versus Research Surveys SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; MILITARY SERVICE MEMBERS; HEALTH-CARE UTILIZATION; MILLENNIUM COHORT; US MILITARY; SMALLPOX VACCINATION; COMBAT DEPLOYMENT; ENROLLMENT; IMPACT; AFGHANISTAN AB Background: Potential adverse mental health effects of deployment, including depression, are an ongoing concern. Although a previous study assessed under-reporting of depression on post-deployment health assessments compared to anonymous surveys, those results were not examined at the individual level to identify demographic or military factors that may be associated with unwillingness to report depression symptoms. Purpose: To compare self-reported depression symptoms on post-deployment health assessments with responses to the same depression questions on a research survey. Methods: This cross-sectional study analyzed depression screening responses from 2001 to 2008 from participants of the Millennium Cohort Study, a longitudinal military cohort study, who completed a post-deployment health assessment within 30 days of a research survey. Kappa statistics and percent positive and negative agreement were calculated. Demographic and military characteristics associated with discordant screening results were examined. Initial analyses were performed in 2011, with additional analyses in 2013. Results: Moderate agreement (kappa=0.464) was observed between paired survey responses. A higher proportion of active duty members, the unmarried, and new accessions into military service endorsed depression symptoms on the research survey but not the military-linked survey. In stratified analyses, agreement was higher in Reserve/National Guard members than active duty (kappa=0.561 vs 0.409). New active duty accessions showed lower agreement (kappa=0.388), as did unmarried active duty participants (kappa=0.304). Conclusions: Deployment health surveys are important tools for identifying returning service members experiencing depression symptoms. However, these findings suggest that ongoing stigma and barriers to appropriate follow-up mental health care remain to be addressed in the military setting. (C) 2014 American Journal of Preventive Medicine. All rights reserved. C1 [Welsh, Marleen M.; Federinko, Susan P.; Burnett, Daniel G.; Hooper, Tomoko I.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Gackstetter, Gary D.] Analyt Serv Inc, Falls Church, VA USA. [Boyko, Edward J.] Vet Affairs Puget Sound Hlth Care Syst, Epidemiol Res & Informat Ctr, Seattle, WA USA. [Seelig, Amber D.] Naval Hlth Res Ctr, Deployment Hlth Res Dept, San Diego, CA USA. [Wells, Timothy S.] Optum, Ann Arbor, MI USA. RP Welsh, MM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Room A1040H,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM marleen.welsh.ctr@usuhs.edu FU Management Information Division, U.S. Defense Manpower Data Center (Seaside CA); Military Operational Medicine Research Program; U.S. Army Medical Research and Materiel Command; Military Operational Medicine Research Program, U.S. Army Medical Research and Materiel Command (Fort Detrick MD) FX We would like to thank the entire Millennium Cohort Study Team from the Deployment Health Research Department, Naval Health Research Center, San Diego CA, for their support, as well as the Millennium Cohort Study co-investigators for their leadership. We are also indebted to the Millennium Cohort Study participants, without whom these analyses would not be possible. We appreciate the support from the Management Information Division, U.S. Defense Manpower Data Center (Seaside CA), Military Operational Medicine Research Program, and U.S. Army Medical Research and Materiel Command.; The Millennium Cohort Study is funded through the Military Operational Medicine Research Program, U.S. Army Medical Research and Materiel Command (Fort Detrick MD). Resources from the Veterans Affairs Puget Sound Health Care System supported Dr. Boyko's involvement in this research. NR 26 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 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD NOV PY 2014 VL 47 IS 5 BP 531 EP 540 DI 10.1016/j.amepre.2014.07.036 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AR6DP UT WOS:000343673800001 PM 25241198 ER PT J AU Lehavot, K Browne, KC Simpson, TL AF Lehavot, Keren Browne, Kendall C. Simpson, Tracy L. TI Examining Sexual Orientation Disparities in Alcohol Misuse Among Women Veterans SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; SUBSTANCE USE; MENTAL-HEALTH; PHYSICAL ABUSE; MINORITY VETERANS; TRAUMA EXPOSURE; FEMALE VETERANS; BINGE DRINKING; UNITED-STATES; CHILD-ABUSE AB Background: Alcohol misuse is a significant health concern among women veterans, especially among lesbian and bisexual veterans. Mediators that might explain alcohol disparities between heterosexual and sexual minority veterans have not yet been identified. Purpose: To examine the role of civilian and military traumas and mental health symptoms (i.e., depression, post-traumatic stress disorder) in explaining sexual orientation disparities in alcohol misuse between sexual minority and heterosexual women veterans across the U.S. Methods: Women veterans were recruited using Internet methods to participate in an online, anonymous, national survey (N=699, 37% lesbian or bisexual) from February to May 2013. Path analysis was used to examine a model wherein sexual orientation both directly and indirectly predicted alcohol misuse through trauma exposures and mental health symptoms. Data were analyzed in November 2013. Results: Findings indicated significant disparities in alcohol misuse among women veterans by sexual orientation, with indirect effects via childhood trauma, physical victimization in adulthood both during the military and as a civilian, and depressive and post-traumatic stress disorder symptoms. Conclusions: Lesbian and bisexual women veterans reported higher rates of some trauma exposures and mental health symptoms than their heterosexual counterparts, partly accounting for their higher rates of alcohol misuse. Interventions that attend to both victimization and drinking among this population are needed, as well as future research that addresses other factors influencing alcohol misuse. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Lehavot, Keren; Browne, Kendall C.; Simpson, Tracy L.] Univ Washington, Mental Illness Res Educ & Clin Ctr, Seattle, WA 98195 USA. [Simpson, Tracy L.] Univ Washington, Ctr Excellence Substance Abuse Treatment & Educ, Seattle, WA 98195 USA. [Lehavot, Keren; Browne, Kendall C.; Simpson, Tracy L.] Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Lehavot, Keren; Browne, Kendall C.; Simpson, Tracy L.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Lehavot, K (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 1660 S Columbian Way S-116-POC, Seattle, WA 98108 USA. EM klehavot@uw.edu FU VISN-20 Mental Illness Research, Education, and Clinical Center; VA CSR&D Career Development Award [CX000867]; Advanced Fellowship Program in Mental Illness Research and Treatment FX This research was supported by a research grant to K. Lehavot and T. Simpson from the VISN-20 Mental Illness Research, Education, and Clinical Center. Dr. Lehavot's effort was supported by a VA CSR&D Career Development Award (CX000867). This material is the result of work supported by resources from the U.S. Department of Veterans Affairs Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, and the Veterans Affairs Puget Sound Health Care System, Seattle WA. The views expressed in this article are those of the authors and do not represent the views of the Department of Veterans Affairs or the U.S. government. NR 55 TC 5 Z9 6 U1 3 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD NOV PY 2014 VL 47 IS 5 BP 554 EP 562 DI 10.1016/j.amepre.2014.07.002 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AR6DP UT WOS:000343673800003 PM 25241197 ER PT J AU Mahabee-Gittens, EM Collins, BN Murphy, S Woo, H Chang, Y Dempsey, J Weiley, V Winickoff, JP AF Mahabee-Gittens, E. Melinda Collins, Bradley N. Murphy, Sybil Woo, Heide Chang, Yuchiao Dempsey, Janelle Weiley, Victoria Winickoff, Jonathan P. TI The Parent-Child Dyad and Risk Perceptions Among Parents Who Quit Smoking SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; TOBACCO CONTROL; INTERVENTION; EXPOSURE; SECONDHAND; CESSATION; ASTHMA; METAANALYSIS; BEHAVIOR; DISEASE AB Background: Most parental smokers are deeply invested in their child's health, but it is unknown what factors influence parent risk perceptions of the effects of smoking on their child's health and benefits to the child of cessation. Purpose: To explore differences in former versus current smokers' beliefs about harm of continuing to smoke, benefits of quitting, and how much smoking interferes with their parenting. Methods: As part of a cluster RCT to increase tobacco control in the pediatric setting, we analyzed data collected at the ten control arm practices for 24 months starting in May 2010; a cross-sectional secondary data analysis was conducted in 2013. Parents were asked about smoking status and perceived harm, benefit, and well-being related to smoking behaviors. Results: Of the 981 enrolled smoking parents, 710 (72.4%) were contacted at 12 months. The odds of having successfully quit at 12 months was 4.12 times more likely (95% CI=1.57, 10.8) for parents who believed that quitting will benefit their children; 1.68 times more likely (95% CI=1.13, 2.51) for parents with more than a high school education; and 1.74 times greater (95% CI=1.13, 2.68) for parents with children under age 3 years. Another factor associated with having successfully quit was a prior quit attempt. Conclusions: Providers' smoking-cessation advice and support should begin early and underscore how cessation will benefit the health and well-being of patients' children. Additionally, parents who have recently attempted to quit may be particularly primed for another attempt. (C) 2014 American Journal of Preventive Medicine C1 [Mahabee-Gittens, E. Melinda] Univ Cincinnati, Sch Med, Cincinnati Childrens Hosp Med Ctr, Div Emergency Med, Cincinnati, OH USA. [Collins, Bradley N.] Temple Univ, Hlth Behav Res Clin, Dept Publ Hlth, Philadelphia, PA 19122 USA. [Collins, Bradley N.] Temple Univ, Hlth Behav Res Clin, Dept Pediat, Philadelphia, PA 19122 USA. [Murphy, Sybil; Dempsey, Janelle; Winickoff, Jonathan P.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Ctr Child & Adolescent Hlth Res & Policy, Boston, MA 02114 USA. [Chang, Yuchiao] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Woo, Heide] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Weiley, Victoria] Amer Acad Pediat, Pediat Res Off Settings, Elk Grove Village, IL USA. [Winickoff, Jonathan P.] Amer Acad Pediat, Richmond Ctr Excellence, Elk Grove Village, IL USA. RP Mahabee-Gittens, EM (reprint author), Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA. EM melinda.mahabee-gittens@cchmc.org FU NIH National Cancer Institute [R01-CA127127]; National Institute on Drug Abuse; Agency for Healthcare Research and Quality; Flight Attendant Medical Research Institute; Health Resources and Services Administration Maternal and Child Health Bureau [HRSA 5-UA6-10-001]; AAP FX This study was funded by the NIH National Cancer Institute (grant No. R01-CA127127 to Dr. Winickoff), National Institute on Drug Abuse, and the Agency for Healthcare Research and Quality. This study was also partially supported by a grant from the Flight Attendant Medical Research Institute to the AAP Julius B. Richmond Center, and the PROS Network, which receives core funding from the Health Resources and Services Administration Maternal and Child Health Bureau (No. HRSA 5-UA6-10-001) and the AAP. Clinical trial registration: NCT00664261. NR 26 TC 4 Z9 4 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD NOV PY 2014 VL 47 IS 5 BP 596 EP 603 DI 10.1016/j.amepre.2014.07.010 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AR6DP UT WOS:000343673800007 PM 25201508 ER PT J AU Ushiku, T Arnason, T Fukayama, M Lauwers, GY AF Ushiku, Tetsuo Arnason, Thomas Fukayama, Masashi Lauwers, Gregory Y. TI Extra-ampullary Duodenal Adenocarcinoma SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE adenocarcinoma; Brunner gland hyperplasia; gastric metaplasia; extra-ampullary duodenum; carcinogenesis ID GASTRIC-FOVEOLAR METAPLASIA; SMALL-BOWEL ADENOCARCINOMA; SMALL-INTESTINE; UNITED-STATES; CANCER; CARCINOMA; HYPERPLASIA; EXPRESSION; CETUXIMAB; PATTERNS AB Extra-ampullary duodenal adenocarcinomas are rare, and when studied, frequently have been grouped with jejunoileal adenocarcinomas. Nevertheless, anecdotal experiences suggest that these neoplasms may present 2 or more distinct phenotypes. To better characterize these neoplasms, we performed a retrospective review of 38 cases with a special focus on the morphologic and immunophenotypic characteristics and their clinicopathologic significance. Our cohort of extra-ampullary duodenal adenocarcinomas was classified on the basis of the morphologic features into gastric type (n = 19, 50%), intestinal type (n = 14, 37%), pancreaticobiliary type (n = 2, 5%), and others (n = 3, 8%). Most gastric-type adenocarcinomas (n = 18, 95%) developed in the proximal duodenum, whereas the other types were located equally in the proximal and distal duodenum. Intestinal-type dysplasia was present at the periphery of 8 (57%) intestinal-type adenocarcinomas, and 8 (42%) gastric-type adenocarcinoma were associated with gastric-type dysplasia. Gastric foveolar metaplasia (n = 12) and Brunner gland hyperplasia (n = 10) were exclusively recognized adjacent to gastric-type adenocarcinomas. Notably, intestinal-type histology and the absence of lymph node metastasis were significantly associated with favorable disease-free survival in univariate and multivariate analyses. In summary, this study demonstrated that 2 major subsets of extra-ampullary duodenal adenocarcinoma, intestinal type and gastric type, are associated with distinct histopathologic features and clinical behavior. C1 [Ushiku, Tetsuo; Arnason, Thomas; Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ushiku, Tetsuo; Fukayama, Masashi] Univ Tokyo, Dept Pathol, Tokyo 1130033, Japan. [Arnason, Thomas] Queen Elizabeth 2 Hlth Sci Ctr, Div Anat Pathol, Halifax, NS, Canada. RP Ushiku, T (reprint author), Univ Tokyo, Dept Pathol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan. EM usikut-tky@umin.ac.jp NR 33 TC 7 Z9 7 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD NOV PY 2014 VL 38 IS 11 BP 1484 EP 1493 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA AR9GE UT WOS:000343880200004 PM 25310836 ER PT J AU Wojcik, JB Bellizzi, AM Dal Cin, P Bredella, MA Fletcher, CDM Hornicek, FJ Deshpande, V Hornick, JL Nielsen, GP AF Wojcik, John B. Bellizzi, Andrew M. Dal Cin, Paola Bredella, Miriam A. Fletcher, Christopher D. M. Hornicek, Francis J. Deshpande, Vikram Hornick, Jason L. Nielsen, G. Petur TI Primary Sclerosing Epithelioid Fibrosarcoma of Bone Analysis of a Series SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE primary bone tumor; sarcoma; immunohistochemistry; MUC4; SATB2; sclerosing epithelioid fibrosarcoma ID GRADE-FIBROMYXOID-SARCOMA; MARKER; MUC4; DIFFERENTIATION; REARRANGEMENTS; TUMORS AB Sclerosing epithelioid fibrosarcoma (SEF) is a rare, aggressive malignant neoplasm characterized by small nests and linear arrays of epithelioid cells embedded in a dense collagenous matrix. Very few primary SEFs of bone have been reported. Recognition is critical, as the dense extracellular collagenous matrix can be interpreted as osteoid, leading to misdiagnosis as-osteosarcoma. MUC4 and SATB2 are 2 recently characterized immunohistochemical markers for SEF and osteosarcoma, respectively. In reports to date, osteosarcomas are positive for SATB2 and negative for MUC4, whereas soft tissue SEFs have shown the opposite immunohistochemical profile (SATB2 - /MUC4+). The purpose of this study was to characterize the clinicopathologic and immunohistochemical features of 8 primary SEFs of bone. The patients presented at a wide range of ages (25 to 73 y; median 52 y). Tumors mostly involved long bones of the extremities, with 3 cases involving the femur, 2 involving the ulna, and 1 involving the humerus. Other sites of involvement included the second rib (1) and the C6 vertebra (1). Follow-up information was available for 7 patients, 3 of whom developed metastases within 2 years of diagnosis. The other 4 patients were free of local recurrence or metastases at 1, 5, 12, and > 84 months of follow-up, respectively. Radiographically, the tumors were predominantly lytic and poorly marginated. Histologically, 6 tumors showed pure SEF morphology, and 2 showed hybrid SEF/low-grade fibromyxoid sarcoma morphology. Focal dystrophic mineralization was seen in 1 case but was limited to areas of necrosis. None of the tumors showed the lace-like pattern of mineralization typical of osteosarcoma. The majority (6/8) of the tumors strongly expressed MUC4. SATB2 was negative in all but 1 case, which showed variable weak to moderate staining in similar to 50% of nuclei. In general, the combination of morphology, MUC4 expression, and the absence of SATB2 expression was highly useful in arriving at the correct diagnosis. C1 [Wojcik, John B.; Bredella, Miriam A.; Hornicek, Francis J.; Deshpande, Vikram; Nielsen, G. Petur] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Dal Cin, Paola; Fletcher, Christopher D. M.; Hornick, Jason L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bellizzi, Andrew M.] Univ Iowa, Dept Pathol, Iowa City, IA 52242 USA. RP Wojcik, JB (reprint author), Massachusetts Gen Hosp, Dept Pathol, MGH Pathol Serv, Warren Bldg 225,55 Fruit St, Boston, MA 02114 USA. EM jwojcik@partners.org NR 23 TC 8 Z9 9 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD NOV PY 2014 VL 38 IS 11 BP 1538 EP 1544 PG 7 WC Pathology; Surgery SC Pathology; Surgery GA AR9GE UT WOS:000343880200011 PM 24921641 ER PT J AU Sakurai, U Lauwers, GY Vieth, M Sawabe, M Arai, T Yoshida, T Aida, J Takubo, K AF Sakurai, Urara Lauwers, Gregory Y. Vieth, Michael Sawabe, Motoji Arai, Tomio Yoshida, Tatsuya Aida, Junko Takubo, Kaiyo TI Gastric High-grade Dysplasia Can Be Associated With Submucosal Invasion Evaluation of its Prevalence in a Series of 121 Endoscopically Resected Specimens SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE gastric neoplasm; gastric dysplasia; intramucosal adenocarcinoma; endoscopic resection ID GASTROINTESTINAL EPITHELIAL NEOPLASIA; WESTERN PATHOLOGISTS; DIAGNOSIS; BIOPSIES; JAPANESE AB Gastric neoplasms classified as high-grade dysplasia (HGD) by Western pathologists are frequently diagnosed as tubular adenocarcinoma in Japan. Here, we evaluated the prevalence of submucosal and lymphovascular invasion in a series of 125 endoscopically resected gastric neoplasms. On the basis of Western criteria, the lesions were classified as poorly cohesive carcinomas (n = 4) (excluded from further analysis), low-grade dysplasia (n = 4), pure HGD (n = 78), HGD with tubular adenocarcinoma (n = 4), and pure tubular adenocarcinoma (n = 35). Submucosal invasion was found in 3.8% of the 78 HGDs, 75.0% of the 4 HGDs combined with adenocarcinoma, and 11.4% of the 35 adenocarcinomas. Venous invasion was detected in 1.3% of the 78 HGDs, 75% of the 4 HGDs combined with adenocarcinoma, and none of the 35 tubular adenocarcinomas. Lymphatic invasion was absent in HGD but noted in 25% of the HGDs combined with adenocarcinoma, and 2.9% of the tubular adenocarcinomas. Thus, we demonstrated that lesions characterized as HGD on the basis of Western criteria can be associated with submucosal and lymphovascular invasion. Endoscopic therapy has made it less crucial to differentiate between HGD and intramucosal adenocarcinoma in biopsy samples of small tubular neoplasms. However, it is important to recognize that the criteria for dysplasia currently used in the West may understate the degree of malignant potential. To limit any diagnostic discrepancy between biopsy, endoscopic resection, and surgical specimens, it is suggested that the features of HGD and adenocarcinoma be reevaluated, which may result in some lesions being classified as mucosal adenocarcinoma. C1 [Sakurai, Urara; Vieth, Michael; Sawabe, Motoji] Tokyo Metropolitan Geriatr Hosp, Dept Pathol, Tokyo, Japan. [Yoshida, Tatsuya] Kudanzaka Hosp, Dept Surg, Tokyo, Japan. [Aida, Junko; Takubo, Kaiyo] Metropolitan Inst Gerontol, Res Team Geriatr Pathol, Itabashi Ku, Tokyo 1730015, Japan. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Vieth, Michael] Klinikum Bayreuth, Inst Pathol, Bayreuth, Germany. RP Takubo, K (reprint author), Metropolitan Inst Gerontol, Res Team Geriatr Pathol, Itabashi Ku, Sakae Cho 35-2, Tokyo 1730015, Japan. EM uraras@musa-shino.jrc.or.jp; GLAUWERS@mgh.harvard.edu; vieth.lkpathol@uni-bayreuth.de; takubo@tmig.or.jp NR 14 TC 5 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 EI 1532-0979 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD NOV PY 2014 VL 38 IS 11 BP 1545 EP 1550 PG 6 WC Pathology; Surgery SC Pathology; Surgery GA AR9GE UT WOS:000343880200012 PM 25310837 ER PT J AU Chung, JW Ju, MH Kinnier, CV Haut, ER Baker, DW Bilimoria, KY AF Chung, Jeanette W. Ju, Mila H. Kinnier, Christine V. Haut, Elliott R. Baker, David W. Bilimoria, Karl Y. TI Evaluation of hospital factors associated with hospital postoperative venous thromboembolism imaging utilisation practices SO BMJ QUALITY & SAFETY LA English DT Article ID DEEP-VEIN THROMBOSIS; TRAUMA DATA-BANK; FACTORS-AN ANALYSIS; REPORTED DVT RATES; QUALITY-OF-CARE; SURVEILLANCE BIAS; DEFENSIVE MEDICINE; UNCERTAINTY; PHYSICIANS; OUTCOMES AB Background Recent research suggests that hospital rates of postoperative venous thromboembolism (VTE) are subject to surveillance bias: the more hospitals 'look for' VTE, the more VTE they find. However, little is known about what drives variation in hospital VTE imaging rates. We conducted an observational study to examine hospital and market characteristics that were associated with hospital-level rates of postoperative VTE imaging, focusing on hospitals with particularly high rates. Methods For Medicare beneficiaries undergoing 11 major operations (2009-2010) at 2820 hospitals, hospital-level postoperative VTE imaging use rates were calculated. Hospital characteristics associated with hospital VTE imaging use rates were examined including case severity, size, ownership, VTE process measure adherence, accreditations, staffing, malpractice environment, and county market factors. Associations between explanatory variables and VTE imaging rates were assessed using quantile regressions at the 25th, median, 75th and 90th quantiles. Results Mean postoperative VTE imaging rates ranged from 85.26 (SD=67.38) per 1000 discharges in the lowest quartile of hospitals ranked by VTE imaging rates to 168.86 (SD=76.70) in the highest quartile. Drivers of high imaging rates at the 90th quantile were high resident-to-bed ratio (coefficient=51.35, p<0.01), Joint Commission accreditation (coefficient=19.05, p<0.01), presence of other hospitals in the same market with high imaging rates (coefficient=15.29, p<0.01), average case severity (coefficient=11.97, p<0.01), local malpractice costs (coefficient=11.29, p<0.01), and market competition (coefficient=11.03, p<0.01). Conclusions Hospital teaching status, resident-to-bed ratio, malpractice environment and local market factors drive hospital postoperative VTE imaging use, suggesting that non-clinical forces predominantly drive hospital VTE imaging practices. C1 [Chung, Jeanette W.; Ju, Mila H.; Kinnier, Christine V.; Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Dept Surg, SOQIC, Chicago, IL 60611 USA. [Kinnier, Christine V.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Haut, Elliott R.] Johns Hopkins Univ, Sch Med, Dept Surg Anesthesiol & Crit Care Med, Baltimore, MD USA. [Haut, Elliott R.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Baker, David W.] Northwestern Univ, Div Gen Internal Med & Geriatr, Chicago, IL 60611 USA. RP Bilimoria, KY (reprint author), Northwestern Univ, Feinberg Sch Med, NW Mem Hosp, Surg Outcomes & Qual Improvement Ctr,Dept Surg, 676 St Clair St,Arkes Pavil Suite 6-650, Chicago, IL 60611 USA. EM k-bilimoria@northwestern.edu FU Northwestern Memorial Hospital FX Northwestern Memorial Hospital. NR 42 TC 3 Z9 3 U1 1 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 2044-5415 EI 2044-5423 J9 BMJ QUAL SAF JI BMJ Qual. Saf. PD NOV PY 2014 VL 23 IS 11 BP 947 EP 956 DI 10.1136/bmjqs-2014-003150 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AR9EZ UT WOS:000343876600010 PM 25136140 ER PT J AU Golshan, M Losk, K Kadish, S Lin, NU Hirshfield-Bartek, J Cutone, L Sagara, Y Aydogan, F Camuso, K Weingart, SN Bunnell, C AF Golshan, Mehra Losk, Katya Kadish, Sarah Lin, Nancy U. Hirshfield-Bartek, Judith Cutone, Linda Sagara, Yasuaki Aydogan, Fatih Camuso, Kristen Weingart, Saul N. Bunnell, Craig TI Understanding process-of-care delays in surgical treatment of breast cancer at a comprehensive cancer center SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Breast cancer; Surgery; Waits and delays ID DIAGNOSIS; SURVIVAL; TIME AB Few studies have examined care processes within providers' and institutions' control that expedite or delay care. The authors investigated the timeliness of breast cancer care at a comprehensive cancer center, focusing on factors influencing the time from initial consultation to first definitive surgery (FDS). The care of 1,461 women with breast cancer who underwent surgery at Dana-Farber/Brigham and Women's Cancer Center from 2011 to 2013 was studied. The interval between consultation and FDS was calculated to identify variation in timeliness of care based on procedure, provider, and patients' sociodemographic characteristics. Targets of 14 days for lumpectomy and mastectomy and 28 days from mastectomy with immediate reconstruction were set and used to define delay. Mean days between consultation and FDS was 21.6 (range 1-175, sd 15.8) for lumpectomy, 36.7 (5-230, 29.1) for mastectomy, and 37.5 (7-111, 16) for mastectomy with reconstruction. Patients under 40 were less likely to be delayed (OR = 0.56, 95 % CI = 0.33-0.94, p = 0.03). Patients undergoing mastectomy alone (OR = 2.64, 95 % CI = 1.80-3.89, p < 0.0001) and mastectomy with immediate reconstruction (OR = 1.34 95 % CI = 1.00-1.79, p = 0.05) were more likely to be delayed when compared to lumpectomy. Substantial variation in surgical timeliness was identified. This study provides insight into targets for improvement including better coordination with plastic surgery and streamlining pre-operative testing. Cancer centers may consider investing in efforts to measure and improve the timeliness of cancer care. C1 [Golshan, Mehra] Dana Farber Canc Inst, Dept Surg, Boston, MA 02215 USA. [Golshan, Mehra; Cutone, Linda; Sagara, Yasuaki; Aydogan, Fatih] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Losk, Katya; Kadish, Sarah; Lin, Nancy U.; Hirshfield-Bartek, Judith; Camuso, Kristen; Weingart, Saul N.; Bunnell, Craig] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Golshan, M (reprint author), Dana Farber Canc Inst, Dept Surg, 450 Brookline Ave, Boston, MA 02215 USA. EM mgloshan@partners.org FU National Comprehensive Cancer Network (NCCN) Opportunities for Improvement Grant FX This initiative was supported in part by the National Comprehensive Cancer Network (NCCN) Opportunities for Improvement Grant NR 15 TC 6 Z9 7 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 EI 1573-7217 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD NOV PY 2014 VL 148 IS 1 BP 125 EP 133 DI 10.1007/s10549-014-3124-2 PG 9 WC Oncology SC Oncology GA AR8DT UT WOS:000343806400013 PM 25270121 ER PT J AU Iyer, SP Beck, JT Stewart, AK Shah, J Kelly, KR Isaacs, R Bilic, S Sen, S Munshi, NC AF Iyer, Swaminathan P. Beck, Joseph Taddeus Stewart, A. Keith Shah, Jatin Kelly, Kevin R. Isaacs, Randi Bilic, Sanela Sen, Suman Munshi, Nikhil C. TI A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE BHQ880; multiple myeloma; skeletal-related event; Phase I ID RECEPTOR-RELATED PROTEIN-5; STEM-CELL TRANSPLANTATION; BONE-DISEASE; SERUM CONCENTRATIONS; DOUBLE-BLIND; IN-VITRO; DKK1; DICKKOPF-1; OSTEOBLASTS; GROWTH AB Dickkopf-1 (DKK1), expressed by myeloma cells, suppresses osteoblast function and plays a key role in bone disease in multiple myeloma. BHQ880, a human neutralizing IgG1 anti-DKK1 monoclonal antibody, is being investigated for its impact on multiple myeloma-related bone disease and as an agent with potential anti-myeloma activity. The primary objectives of this Phase IB study were to determine the maximum tolerated dose (MTD) of BHQ880 and to characterize the dose-limiting toxicity (DLT) of escalating doses in combination with anti-myeloma therapy and zoledronic acid. Twenty-eight patients were enrolled and received BHQ880 at doses of 3-40mg/kg. No DLTs were reported, therefore, the MTD was not determined. The recommended Phase II dose was declared as 10mg/kg, based mainly on saturation data. There was a general trend towards increased bone mineral density (BMD) observed over time; specific increases in spine BMD from Cycle 12 onwards irrespective of new skeletal-related events on study were observed, and increases in bone strength at the spine and hip were also demonstrated in some patients. BHQ880 in combination with zoledronic acid and anti-myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma. C1 [Iyer, Swaminathan P.] Weill Cornell Med Coll, Houston Methodist Canc Ctr, Houston, TX 77030 USA. [Beck, Joseph Taddeus] Highlands Oncol Grp PA, Fayetteville, AR USA. [Stewart, A. Keith] Mayo Clin, Coll Med, Div Hematol Oncol, Scottsdale, AZ USA. [Shah, Jatin] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kelly, Kevin R.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Isaacs, Randi; Bilic, Sanela; Sen, Suman] Novartis Pharmaceut, E Hanover, NJ USA. [Munshi, Nikhil C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Munshi, Nikhil C.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Boston, MA USA. RP Iyer, SP (reprint author), Weill Cornell Med Coll, Houston Methodist Canc Ctr, 6445 Main St,Floor 21, Houston, TX 77030 USA. EM spiyer@houstonmethodist.org FU Novartis Pharmaceuticals FX Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Kate Gaffey, PhD for her medical editorial assistance with this manuscript. NR 35 TC 26 Z9 29 U1 2 U2 11 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 NOV PY 2014 VL 167 IS 3 BP 366 EP 375 DI 10.1111/bjh.13056 PG 10 WC Hematology SC Hematology GA AS0MB UT WOS:000343970000009 PM 25139740 ER PT J AU Goldman, S Smith, L Galardy, P Perkins, SL Frazer, JK Sanger, W Anderson, JR Gross, TG Weinstein, H Harrison, L Shiramizu, B Barth, M Cairo, MS AF Goldman, Stanton Smith, Lynette Galardy, Paul Perkins, Sherrie L. Frazer, John Kimble Sanger, Warren Anderson, James R. Gross, Thomas G. Weinstein, Howard Harrison, Lauren Shiramizu, Bruce Barth, Matthew Cairo, Mitchell S. TI Rituximab with chemotherapy in children and adolescents with central nervous system and/or bone marrow-positive Burkitt lymphoma/leukaemia: a Children's Oncology Group Report SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE children; Burkitt lymphoma; Burkitt leukaemia; chemotherapy; rituximab ID NON-HODGKINS-LYMPHOMA; B-CELL LYMPHOMA; ACUTE-LYMPHOBLASTIC-LEUKEMIA; PLUS RITUXIMAB; ADULT BURKITT; CODOX-M/IVAC; PHASE-II; RISK; INTERMEDIATE; THERAPY AB Children and adolescents with Burkitt Lymphoma (BL) and combined central nervous system (CNS) and bone marrow involvement still have a poor prognosis with chemotherapy alone. We therefore investigated in children and adolescents with bone marrow (25% blasts) and/or CNS-positive Burkitt lymphoma the chemoimmunotherapy combination of rituximab (375mg/m(2)) and the standard chemotherapy arm of our previously reported French-American-British (FAB) Lymphome Malins de Burkitt (LMB) 96 trial. Central pathological and cytogenetic characterization was also performed. There were 40 evaluable patients with Burkitt histology (25 with leukaemia and 15 with CNS disease +/- leukaemia). The chemoimmunotherapy regimen was well tolerated. The incidence of grade III/IV mucositis during induction cycles with combined chemotherapy and rituximab was 31% and 26%, respectively. The 3-year event-free survival (EFS)/overall survival (OS) was 90% (95% confidence interval [CI], 76-96%) in the entire cohort and 93% (95% CI, 61-99%) in patients with CNS disease. Based on the results of this trial, an international randomized study of FAB/LMB 96 chemotherapy +/- rituximab for high-risk patients is currently under investigation. C1 [Goldman, Stanton] Med City Childrens Hosp, Div Pediat Hematol Oncol, Dallas, TX USA. [Smith, Lynette; Anderson, James R.] Univ Nebraska, Coll Publ Hlth, Dept Biostat, Omaha, NE 68182 USA. [Galardy, Paul] Mayo Clin, Dept Pediat Hematol Oncol, Rochester, MN USA. [Perkins, Sherrie L.] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Frazer, John Kimble] Univ Oklahoma, Hlth Sci Ctr, Sect Pediat Hematol Oncol, Oklahoma City, OK USA. [Sanger, Warren] Univ Nebraska, Ctr Human Genet, Omaha, NE 68182 USA. [Gross, Thomas G.] NCI, Ctr Global Hlth, NIH, Rockville, MD USA. [Weinstein, Howard] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Pediat Hematol Oncol, Boston, MA USA. [Harrison, Lauren; Cairo, Mitchell S.] New York Med Coll, Dept Pediat, Valhalla, NY 10595 USA. [Shiramizu, Bruce] Univ Hawaii, Div Pediat Hematol Oncol, Honolulu, HI 96822 USA. [Barth, Matthew] Roswell Pk Canc Inst, Dept Pediat, Buffalo, NY 14263 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Med, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Pathol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Microbiol & Immunol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. RP Cairo, MS (reprint author), New York Med Coll, Div Pediat Hematol Oncol & Stem Cell Transplantat, 40 Sunshine Cottage Rd,Skyline IN D12, Valhalla, NY 10595 USA. EM Mitchell_cairo@nymc.edu OI Frazer, John Kimble/0000-0003-2936-2817 FU Division of Cancer Treatment, National Cancer Institute (NCI); National Institutes of Health, Department of Health and Human Services (COG) [CA98413-09]; Pediatric Cancer Research Foundation; National Institutes of Health, Department of Health and Human Services (COG) (jn) FX Supported by the Division of Cancer Treatment, National Cancer Institute (NCI), and National Institutes of Health, Department of Health and Human Services (COG) (jn and CA98413-09) and the Pediatric Cancer Research Foundation. NCI provided support for data collection and analysis but no role in data interpretation, writing of the manuscript or the decision on journal submission. NR 22 TC 19 Z9 19 U1 0 U2 2 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 NOV PY 2014 VL 167 IS 3 BP 394 EP 401 DI 10.1111/bjh.13040 PG 8 WC Hematology SC Hematology GA AS0MB UT WOS:000343970000012 PM 25066629 ER PT J AU De Pascale, G Bittner, EA AF De Pascale, Gennaro Bittner, Edward A. TI Influenza-Associated Critical Illness: Estimating the Burden and the Burden of Estimation SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE burden of disease; critical illness; influenza ID UNITED-STATES C1 [De Pascale, Gennaro; Bittner, Edward A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [De Pascale, Gennaro] Univ Cattolica Sacro Cuore, Agostino Gemelli Hosp, Dept Intens Care & Anesthesiol, I-00168 Rome, Italy. RP De Pascale, G (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. NR 11 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD NOV PY 2014 VL 42 IS 11 BP 2441 EP 2442 DI 10.1097/CCM.0000000000000589 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA AR9JC UT WOS:000343889000028 PM 25319905 ER PT J AU Aizer, J Bolster, MB AF Aizer, Juliet Bolster, Marcy B. TI Fracture Liaison Services: Promoting Enhanced Bone Health Care SO CURRENT RHEUMATOLOGY REPORTS LA English DT Article DE Fracture liaison service; FLS; Osteoporosis management; Osteoporosis treatment; Secondary fracture prevention; Fracture prevention; Quality of care; Bone health ID RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; HIP FRACTURE; COST-EFFECTIVENESS; OSTEOPOROSIS TREATMENT; ZOLEDRONIC ACID; TRAUMA FRACTURE; UNITED-KINGDOM; OLDER WOMEN; MORTALITY AB The high prevalence of osteoporotic fractures and their major effect on morbidity and mortality emphasizes the critical need to optimize bone health care. Patients presenting with fragility fractures are at high risk of subsequent fracture, but treatment rates have remained low for these patients. Recently developed fracture liaison services have successfully increased osteoporosis treatment, with improved patient outcomes. We review factors contributing to the treatment gap in osteoporosis, the function of fracture liaison services in reducing this gap, and lessons learned from the literature on effective formats, key elements, and suggestions for managing challenges in implementation of a fracture liaison service. C1 [Aizer, Juliet] Weill Cornell Med Coll, Hosp Special Surg, Div Rheumatol, New York, NY 10021 USA. [Bolster, Marcy B.] Harvard Univ, Div Rheumatol, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Aizer, J (reprint author), Weill Cornell Med Coll, Hosp Special Surg, Div Rheumatol, 535 E 70th St, New York, NY 10021 USA. EM AizerJ@HSS.edu; Mbolster@MGH.Harvard.edu FU Rheumatology Research Foundation Clinician Scholar Educator Award; Eli Lilly FX Juliet Aizer reports that she has no conflict of interest. Dr. Aizer received funding in part from the Rheumatology Research Foundation Clinician Scholar Educator Award. Marcy B. Bolster reports the receipt of a research grant from Eli Lilly, outside the submitted work. NR 49 TC 6 Z9 6 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3774 EI 1534-6307 J9 CURR RHEUMATOL REP JI Curr. Rheumatol. Rep. PD NOV PY 2014 VL 16 IS 11 AR 455 DI 10.1007/s11926-014-0455-2 PG 8 WC Rheumatology SC Rheumatology GA AR9KZ UT WOS:000343893800003 PM 25240684 ER PT J AU Fisher, MC Pillinger, MH Keenan, RT AF Fisher, Mark C. Pillinger, Michael H. Keenan, Robert T. TI Inpatient Gout: A Review SO CURRENT RHEUMATOLOGY REPORTS LA English DT Review DE Gout, Inpatient; Hospitalization; Healthcare Burden ID HEALTH-CARE UTILIZATION; SERUM URIC-ACID; HOSPITALIZED-PATIENTS; POSTSURGICAL GOUT; ARTHRITIS; MANAGEMENT; ATTACKS; COMORBIDITIES; POPULATION; PREVALENCE C1 [Fisher, Mark C.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Pillinger, Michael H.] NYU, Sch Med, Dept Med, New York, NY USA. [Keenan, Robert T.] Duke Univ, Div Rheumatol & Immunol, Sch Med, Durham, NC 27706 USA. RP Fisher, MC (reprint author), Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, 2100 Yawkey 55 Fruit St, Boston, MA 02114 USA. EM MFISHER6@mgh.harvard.edu OI Pillinger, Michael/0000-0003-3168-1542 FU Takeda; Savient FX Michael H. Pillinger reports that he has served as a consultant for Savient, and for Crealta. He is the recipient of investigator-initiated grants from Takeda and Savient, and currently serves as a site investigator for a clinical study by Takeda, outside the submitted work. NR 31 TC 0 Z9 0 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3774 EI 1534-6307 J9 CURR RHEUMATOL REP JI Curr. Rheumatol. Rep. PD NOV PY 2014 VL 16 IS 11 AR 458 DI 10.1007/s11926-014-0458-z PG 5 WC Rheumatology SC Rheumatology GA AR9KZ UT WOS:000343893800005 PM 25304216 ER PT J AU Beca, F Pinheiro, J Rios, E Pontes, P Amendoeira, I AF Beca, Francisco Pinheiro, Jorge Rios, Elisabete Pontes, Patricia Amendoeira, Isabel TI Genotypes and Prevalence of HPV Single and Multiple Concurrent Infections in Women with HSIL SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Article DE Gynaecological cytology; genotyping; HPV ID NUTRITION EXAMINATION SURVEY; HUMAN-PAPILLOMAVIRUS; UNITED-STATES; NATIONAL-HEALTH; CERVICAL-CANCER; FEMALES; VACCINE AB The contribution of human papillomavirus (HPV) types to the carcinogenesis of cervical cancer has been established for a long time. However, the role of phylogenetically related and rare variants remains uncertain, as well as the influence of concurrent multiple HPV genotypes infection. We aimed at studying the prevalence of several HPV genotypes infecting women with single versus concurrent multiple HPV genotypes infection with a HSIL diagnosis in a cervical cytology. We conducted a cross-sectional study using Thin-Prep((R)) liquid-based cervical cytology specimens with the diagnosis of high-grade squamous intraepithelial lesion (HSIL), in which HPV genotype was sequentially tested. Genotypes were determined with a PapilloCheck((R)) system, a DNA-Chip for the type-specific identification of 18 high-risk and six low-risk types of HPV. Of the total study population, 176 cases had a diagnosis of HSIL and positive HPV genotyping result, being HPV16 the most prevalent genotype (48.86%; 95%CI: 41.58-56.19) followed by HPV31 (14.20%; 95%CI: 9.75-20.18). Concurrent multiple HPV genotypes were detected in 36.93% (95%CI: 30.15-44.27) of the patients. The prevalence of the 10 most common HPV genotypes detected varied significantly according to the presence of single vs. concurrent multiple HPV genotypes (P=0.022). Moreover, women with concurrent multiple HPV genotypes were on average 3.53 (95%CI: 0.43-6.64) years younger than women with single genotype infection. Our results suggest that women with multiple genotype HPV infection differ in terms of age and distribution of the most prevalent HPV genotypes. Additionally, we provide further evidence of the predominance of HPV16 in HSIL lesions of the uterine cervix. Diagn. Cytopathol. 2014;42:919-923. (c) 2014 Wiley Periodicals, Inc. C1 [Beca, Francisco; Rios, Elisabete; Amendoeira, Isabel] Univ Porto, IPATIMUP Inst Mol Pathol & Immunol, P-4100 Oporto, Portugal. [Beca, Francisco; Pinheiro, Jorge; Rios, Elisabete] Univ Porto, Fac Med, Dept Pathol & Oncol, P-4100 Oporto, Portugal. [Beca, Francisco; Pinheiro, Jorge; Rios, Elisabete; Pontes, Patricia; Amendoeira, Isabel] Ctr Hosp Sao Joao, Dept Pathol, Oporto, Portugal. RP Beca, F (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM francisco_debeca@dfci.harvard.edu OI Beca, Francisco/0000-0002-4409-012X FU Fundacao para a Ciencia e Tecnologia (FCT); FCT [HMSP-ICJ/0006/2012] FX Contract grant sponsor: Fundacao para a Ciencia e Tecnologia (FCT).; Contract grant sponsor: FCT (F.F.B.); contract grant number: HMSP-ICJ/0006/2012. NR 17 TC 6 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 8755-1039 EI 1097-0339 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD NOV PY 2014 VL 42 IS 11 BP 919 EP 923 DI 10.1002/dc.23143 PG 5 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA AS0MA UT WOS:000343969900001 PM 24623593 ER PT J AU Michot, C Le Goff, C Mahaut, C Afenjar, A Brooks, AS Campeau, PM Destree, A Di Rocco, M Donnai, D Hennekam, R Heron, D Jacquemont, S Kannu, P Lin, AE Manouvrier-Hanu, S Mansour, S Marlin, S McGowan, R Murphy, H Raas-Rothschild, A Rio, M Simon, M Stolte-Dijkstra, I Stone, JR Sznajer, Y Tolmie, J Touraine, R van den Ende, J Van der Aa, N van Essen, T Verloes, A Munnich, A Cormier-Daire, V AF Michot, Caroline Le Goff, Carine Mahaut, Clementine Afenjar, Alexandra Brooks, Alice S. Campeau, Philippe M. Destree, Anne Di Rocco, Maja Donnai, Dian Hennekam, Raoul Heron, Delphine Jacquemont, Sebastien Kannu, Peter Lin, Angela E. Manouvrier-Hanu, Sylvie Mansour, Sahar Marlin, Sandrine McGowan, Ruth Murphy, Helen Raas-Rothschild, Annick Rio, Marlene Simon, Marleen Stolte-Dijkstra, Irene Stone, James R. Sznajer, Yves Tolmie, John Touraine, Renaud van den Ende, Jenneke Van der Aa, Nathalie van Essen, Ton Verloes, Alain Munnich, Arnold Cormier-Daire, Valerie TI Myhre and LAPS syndromes: clinical and molecular review of 32 patients SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Review DE Myhre syndrome; SMAD4; LAPS; long-term follow-up ID TUMOR-SUPPRESSOR GENE; SHORT STATURE; MUTATIONS; FEMALE; SMAD4; DELINEATION; DPC4 AB Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy, prognathism and short stature syndrome (LAPS). This study aimed to review the features of Myhre and LAPS patients to define the clinical spectrum of SMAD4 mutations. We included 17 females and 15 males ranging in age from 8 to 48 years. Thirty were diagnosed with Myhre syndrome and two with LAPS. SMAD4 coding sequence was analyzed by Sanger sequencing. Clinical and radiological features were collected from a questionnaire completed by the referring physicians. All patients displayed a typical facial gestalt, thickened skin, joint limitation and muscular pseudohypertrophy. Growth retardation was common (68.7%) and was variable in severity (from -5.5 to -2 SD), as was mild-to-moderate intellectual deficiency (87.5%) with additional behavioral problems in 56.2% of the patients. Significant health concerns like obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis, pericarditis and early death occurred in four. Twenty-nine patients had a de novo heterozygous SMAD4 mutation, including both patients with LAPS. In 27 cases mutation affected Ile500 and in two cases Arg496. The three patients without SMAD4 mutations had typical findings of Myhre syndrome. Myhre-LAPS syndrome is a clinically homogenous condition with life threatening complications in the course of the disease. Our identification of SMAD4 mutations in 29/32 cases confirms that SMAD4 is the major gene responsible for Myhre syndrome. C1 [Michot, Caroline; Le Goff, Carine; Mahaut, Clementine; Rio, Marlene; Munnich, Arnold; Cormier-Daire, Valerie] Paris Descartes Univ, Sorbonne Paris Cite, Necker Enfants Malad Hosp, Inst Imagine,Dept Genet,INSERM Unit U781, F-75015 Paris, France. [Afenjar, Alexandra] Armand Trousseau CHU, Ctr Reference Malad Rares Anomalies Dev & Syndrom, Neuropediat Dept, Paris, France. [Brooks, Alice S.; Simon, Marleen] Ersamus MC, Dept Clin Genet, Rotterdam, Netherlands. [Campeau, Philippe M.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Destree, Anne] Inst Pathol & Genet, Dept Human Genet, Gosselies, Belgium. [Di Rocco, Maja] Gaslini Inst, Dept Pediat, Unit Rare Dis, Genoa, Italy. [Donnai, Dian; Murphy, Helen] Univ Manchester, St Marys Hosp, Manchester Acad Hlth Sci Ctr, Manchester M13 0JH, Lancs, England. [Hennekam, Raoul] Univ Amsterdam, Acad Med Ctr, Dept Pediat, NL-1105 AZ Amsterdam, Netherlands. [Heron, Delphine] CHU Pitie Salpetriere, UPMC, GRC, Genet & Cytogenet Dept, Paris, France. [Jacquemont, Sebastien] CHUV, Dept Genet, Vaud, Switzerland. [Kannu, Peter] Hosp Sick Children, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada. [Lin, Angela E.] Massachussets Gen Hosp Children, Boston, MA USA. [Manouvrier-Hanu, Sylvie] Univ Hosp, Dept Clin Genet, Lille, France. [Mansour, Sahar] St Georges Healthcare NHS Trust, Clin Genet, London, England. [Marlin, Sandrine] Armand Trousseau CHU, Ctr Reference Surdites Genet, Genet & Med Embryol Unit, Paris, France. [McGowan, Ruth; Tolmie, John] West Scotland Reg Genet Serv, Glasgow, Lanark, Scotland. [Raas-Rothschild, Annick] Meir Med Ctr, Inst Human Genet, Kefar Sava, Israel. [Stolte-Dijkstra, Irene; van Essen, Ton] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Stone, James R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sznajer, Yves] Clin Univ St Luc, Ctr Human Genet, B-1200 Brussels, Belgium. [Touraine, Renaud] St Etienne CHU, Dept Clin Genet, St Etienne, France. [van den Ende, Jenneke; Van der Aa, Nathalie] Dept Med Genet, Edegem, Belgium. [van den Ende, Jenneke; Van der Aa, Nathalie] Univ Antwerp Hosp, Edegem, Belgium. [Verloes, Alain] Robert Debre Hosp, AP HP, Dept Genet, INSERM U676, Paris, France. RP Cormier-Daire, V (reprint author), Paris Descartes Univ, Sorbonne Paris Cite, Necker Enfants Malad Hosp, Dept Genet,INSERM Unit U781, 149 Rue Sevres, F-75015 Paris, France. EM valerie.cormier-daire@inserm.fr RI Campeau, Philippe/J-8614-2015 OI Campeau, Philippe/0000-0001-9713-7107 NR 28 TC 8 Z9 8 U1 3 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD NOV PY 2014 VL 22 IS 11 BP 1272 EP 1277 DI 10.1038/ejhg.2013.288 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AR8UR UT WOS:000343850200007 PM 24424121 ER PT J AU Deelen, P Menelaou, A van Leeuwen, EM Kanterakis, A van Dijk, F Medina-Gomez, C Francioli, LC Hottenga, JJ Karssen, LC Estrada, K Kreiner-Moller, E Rivadeneira, F van Setten, J Gutierrez-Achury, J Westra, HJ Franke, L van Enckevort, D Dijkstra, M Byelas, H van Duijn, CM de Bakker, PIW Wijmenga, C Swertz, MA AF Deelen, Patrick Menelaou, Androniki van Leeuwen, Elisabeth M. Kanterakis, Alexandros van Dijk, Freerk Medina-Gomez, Carolina Francioli, Laurent C. Hottenga, Jouke Jan Karssen, Lennart C. Estrada, Karol Kreiner-Moller, Eskil Rivadeneira, Fernando van Setten, Jessica Gutierrez-Achury, Javier Westra, Harm-Jan Franke, Lude van Enckevort, David Dijkstra, Martijn Byelas, Heorhiy van Duijn, Cornelia M. de Bakker, Paul I. W. Wijmenga, Cisca Swertz, Morris A. CA Genome Netherlands Consortium TI Improved imputation quality of low-frequency and rare variants in European samples using the 'Genome of The Netherlands' SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE genotype imputation; GWAS; GoNL; rare variants; reference sets; reference panel ID GENOTYPE IMPUTATION; WIDE ASSOCIATION; DISEASE; COMMON; ARRAY; POWER; LOCI AB Although genome-wide association studies (GWAS) have identified many common variants associated with complex traits, low-frequency and rare variants have not been interrogated in a comprehensive manner. Imputation from dense reference panels, such as the 1000 Genomes Project (1000G), enables testing of ungenotyped variants for association. Here we present the results of imputation using a large, new population-specific panel: the Genome of The Netherlands (GoNL). We benchmarked the performance of the 1000G and GoNL reference sets by comparing imputation genotypes with 'true' genotypes typed on ImmunoChip in three European populations (Dutch, British, and Italian). GoNL showed significant improvement in the imputation quality for rare variants (MAF 0.05-0.5%) compared with 1000G. In Dutch samples, the mean observed Pearson correlation, r(2), increased from 0.61 to 0.71. We also saw improved imputation accuracy for other European populations (in the British samples, r(2) improved from 0.58 to 0.65, and in the Italians from 0.43 to 0.47). A combined reference set comprising 1000G and GoNL improved the imputation of rare variants even further. The Italian samples benefitted the most from this combined reference (the mean r(2) increased from 0.47 to 0.50). We conclude that the creation of a large population-specific reference is advantageous for imputing rare variants and that a combined reference panel across multiple populations yields the best imputation results. C1 [Deelen, Patrick; Kanterakis, Alexandros; van Dijk, Freerk; Gutierrez-Achury, Javier; Westra, Harm-Jan; Franke, Lude; Dijkstra, Martijn; Byelas, Heorhiy; Wijmenga, Cisca; Swertz, Morris A.] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Deelen, Patrick; Kanterakis, Alexandros; van Dijk, Freerk; van Enckevort, David; Dijkstra, Martijn; Byelas, Heorhiy; Swertz, Morris A.] Univ Groningen, Univ Med Ctr Groningen, Genom Coordinat Ctr, NL-9700 RB Groningen, Netherlands. [Menelaou, Androniki; Francioli, Laurent C.; van Setten, Jessica; de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, NL-9700 RB Utrecht, Netherlands. [van Leeuwen, Elisabeth M.; Karssen, Lennart C.] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Kreiner-Moller, Eskil; Rivadeneira, Fernando] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Medina-Gomez, Carolina; Estrada, Karol; Kreiner-Moller, Eskil; Rivadeneira, Fernando; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Medina-Gomez, Carolina; Rivadeneira, Fernando] Netherlands Consortium Hlth Aging, Netherlands Genom Initiat, Rotterdam, Netherlands. [Hottenga, Jouke Jan] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Estrada, Karol] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Dept Med, Boston, MA 02114 USA. [Estrada, Karol] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Kreiner-Moller, Eskil] COPSAC, Copenhagen, Denmark. [Kreiner-Moller, Eskil] Copenhagen Prospect Studies Asthma Childhood, Copenhagen, Denmark. [Kreiner-Moller, Eskil] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark. [van Enckevort, David] Netherlands Bioinformat Ctr, NBIC BioAssist, Nijmegen, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Epidemiol, Utrecht, Netherlands. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [de Bakker, Paul I. W.] Broad Inst Harvard & MIT, Cambridge, MA USA. RP Swertz, MA (reprint author), Univ Groningen, Univ Med Ctr Groningen, Genom Coordinat Ctr, NL-9700 RB Groningen, Netherlands. EM m.a.swertz@gmail.com RI Ye, Kai/B-3640-2012; de Bakker, Paul/B-8730-2009; Franke, Lude/P-7036-2016; Wijmenga, Cisca/D-2173-2009; Slagboom, P. Eline/R-4790-2016; Suchiman, H. Eka D./F-5024-2017; OI Wolffenbuttel, Bruce H.R./0000-0001-9262-6921; Deelen, Patrick/0000-0002-5654-3966; Medina-Gomez, Carolina/0000-0001-7999-5538; Karssen, Lennart C./0000-0002-1959-342X; de Bakker, Paul/0000-0001-7735-7858; van Schaik, Barbera/0000-0002-5568-8127; Wijmenga, Cisca/0000-0002-5635-1614; Beekman, Marian/0000-0003-0585-6206; Franke, Lude/0000-0002-5159-8802; Slagboom, P. Eline/0000-0002-2875-4723; Suchiman, H. Eka D./0000-0002-7168-5516; Rivadeneira, Fernando/0000-0001-9435-9441; Kreiner, Eskil/0000-0003-1204-2438 FU BBMRI-NL; Netherlands Organization for Scientific Research (NWO) [184.021.007]; Netherlands Organization for Scientific Research [184021007] FX This study was made possible by rainbow grant 2 from BBMRI-NL to MS, a research infrastructure financed by the Netherlands Organization for Scientific Research (NWO project 184.021.007). We thank the Target project (http://www.rug.nl/target) for providing the compute infrastructure, and the BigGrid/eBioGrid project (http://www.ebiogrid.nl) for sponsoring the pipeline implementation. We thank Jackie Senior for careful reading and editing the manuscript. This study made use of data generated by the 'Genome of the Netherlands' project, which is funded by the Netherlands Organization for Scientific Research (grant no. 184021007). The data were made available as a Rainbow Project of BBMRI-NL. Samples were contributed by LifeLines (http://lifelines.nl/lifelines-research/general), the Leiden Longevity Study (http://www.healthy-ageing.nl; http://www.langleven.net), the Netherlands Twin Registry (NTR: http://www.tweelingenregister.org), the Rotterdam studies, (http://www.erasmus-epidemiology.nl/rotterdamstudy), and the Genetic Research in Isolated Populations program (http://www.epib.nl/research/geneticepi/research.html#gip). The sequencing was carried out in collaboration with BGI (Shenzhen, China). NR 26 TC 27 Z9 27 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 EI 1476-5438 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD NOV PY 2014 VL 22 IS 11 BP 1321 EP 1326 DI 10.1038/ejhg.2014.19 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AR8UR UT WOS:000343850200014 PM 24896149 ER PT J AU Sweeney, EM Thakur, KT Lyons, JL Smith, BR Willey, JZ Cervantes-Arslanian, AM Hickey, MK Uchino, K Haussen, DC Koch, S Schwamm, LH Elkind, MSV Shinohara, RT Mateen, FJ AF Sweeney, E. M. Thakur, K. T. Lyons, J. L. Smith, B. R. Willey, J. Z. Cervantes-Arslanian, A. M. Hickey, M. K. Uchino, K. Haussen, D. C. Koch, S. Schwamm, L. H. Elkind, M. S. V. Shinohara, R. T. Mateen, F. J. TI Outcomes of intravenous tissue plasminogen activator for acute ischaemic stroke in HIV-infected adults SO EUROPEAN JOURNAL OF NEUROLOGY LA English DT Article DE cerebral infarction; cerebrovascular diseases and cerebral circulation; HIV; infections; neurological disorders; stroke; thrombolysis ID UNITED-STATES; RISK; EVENTS AB Background and purposeTo our knowledge there are no studies reporting the use and short-term outcomes of intravenous tissue plasminogen activator (IV-TPA) for the treatment of acute ischaemic stroke (AIS) in people living with HIV. MethodsThe US Nationwide Inpatient Sample (NIS) (2006-2010) was searched for HIV-infected AIS patients treated with IV-TPA. ResultsIn the NIS, 2.2% (62/2877) of HIV-infected AIS cases were thrombolyzed with IV-TPA (median age 52years, range 27-78, 32% female, 22% Caucasian) vs. 2.1% (19335/937896) of HIV-uninfected cases (median age 72years, range 17-102years, 50% female, 74% Caucasian; P=0.77). There were more deaths in HIV-infected versus uninfected patients with stroke (220/2877, 7.6% vs. 49089/937547, 5.2%, P<0.001) but no difference in the proportion of deaths amongst IV-TPA-treated patients. The age- and sex-adjusted odds ratio for death following IV-TPA administration in HIV-infected versus uninfected patients was 2.26 (95% CI 1.12, 4.58), but the interaction on mortality between HIV and IV-TPA use was not statistically significant, indicating no difference in risk of in-hospital death by HIV serostatus with IV-TPA use. A higher number of HIV-infected patients remained in hospital versus died or were discharged at both 10 and 30days (P<0.01 at 10 and 30days). No difference in the proportion of intracerebral hemorrhage in the two groups was found (P=0.362). ConclusionsThe in-hospital mortality is higher amongst HIV-infected AIS patients than HIV-uninfected patients. However, the risk of death amongst HIV-infected patients treated with IV-TPA is similar to HIV-uninfected groups. C1 [Sweeney, E. M.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Thakur, K. T.] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. [Lyons, J. L.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Smith, B. R.] NINDS, Sect Infect Nervous Syst, NIH, Bethesda, MD 20892 USA. [Willey, J. Z.; Elkind, M. S. V.] Columbia Univ, Dept Neurol, Coll Phys & Surg, New York, NY USA. [Cervantes-Arslanian, A. M.] Boston Univ, Dept Neurol, Boston, MA 02215 USA. [Hickey, M. K.; Schwamm, L. H.; Mateen, F. J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Uchino, K.] Cleveland Clin, Cerebrovasc Ctr, Cleveland, OH 44106 USA. [Haussen, D. C.; Koch, S.] Univ Miami, Dept Neurol, Miami, FL USA. [Elkind, M. S. V.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Shinohara, R. T.] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Mateen, FJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St,AC-720, Boston, MA 02114 USA. EM fmateen@partners.org OI Schwamm, Lee/0000-0003-0592-9145 FU HIV/AIDS from Canadian Institute of Health Research (CIHR) FX Dr Mateen received salary support from an HIV/AIDS priority grant from the Canadian Institute of Health Research (CIHR). NR 13 TC 3 Z9 4 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1351-5101 EI 1468-1331 J9 EUR J NEUROL JI Eur. J. Neurol. PD NOV PY 2014 VL 21 IS 11 BP 1394 EP 1399 DI 10.1111/ene.12506 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AR8EH UT WOS:000343808000009 PM 25040336 ER PT J AU Agaku, IT Odukoya, OO Olufajo, O Filippidis, FT Vardavas, CI AF Agaku, Israel T. Odukoya, Oluwakemi O. Olufajo, Olubode Filippidis, Filippos T. Vardavas, Constantine I. TI Support for smoke-free cars when children are present: a secondary analysis of 164,819 US adults in 2010/2011 SO EUROPEAN JOURNAL OF PEDIATRICS LA English DT Article DE Secondhand smoke; Tobacco control; Cars; Children; Exposure ID SECONDHAND SMOKE; UNITED-STATES; EXPOSURE; MIDDLE AB Comprehensive smoke-free legislations prohibiting smoking in indoor areas of workplaces, bars, and restaurants have been adopted in most of the USA; however, limited efforts have focused on regulating secondhand smoke (SHS) exposure in the family car. The objective of this study was to identify the determinants and national/state-specific population support for smoke-free cars, in the presence of any occupant in general, but particularly when children are present. National data of US adults aged a parts per thousand yen18 years (n = 164,819) were obtained from the 2010/2011 Tobacco Use Supplement of the Current Population Survey. Among all US adults, a significantly greater proportion supported smoke-free cars when it was specified that the occupant was a child compared to when not specified (93.4 vs. 73.7 %, p < 0.05). Age, race/ethnicity, gender, current tobacco use, marital status, and the existence of household smoke-free regulations all mediated population support for smoke-free cars. Conclusion: While differences within the US population were noted, this study however showed overwhelming support for smoke-free car policies, particularly when children are present. Policies which prohibit smoking in indoor or confined areas such as cars may benefit public health by protecting nonsmoking children and adults from involuntary SHS exposure. C1 [Agaku, Israel T.; Vardavas, Constantine I.] Harvard Univ, Sch Publ Hlth, Ctr Global Tobacco Control, Dept Social & Behav Sci, Boston, MA 02215 USA. [Odukoya, Oluwakemi O.] Univ Lagos, Coll Med, Dept Community Hlth & Primary Care, Idi Araba, Lagos State, Nigeria. [Olufajo, Olubode] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Filippidis, Filippos T.] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Vardavas, Constantine I.] Univ Crete, Clin Social & Family Med, Iraklion, Greece. RP Agaku, IT (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Global Tobacco Control, Dept Social & Behav Sci, 401 Pk Dr Landmark Ctr 4th Floor West Wing 677, Boston, MA 02215 USA. EM iagaku@post.harvard.edu; drolukemiodukoya@yahoo.com; oao777@mail.harvard.edu; f.filippidis@mail.harvard.edu; vardavas@hsph.harvard.edu RI Vardavas, Constantine/O-4961-2016; OI Filippidis, Filippos/0000-0002-2101-2559 NR 24 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6199 EI 1432-1076 J9 EUR J PEDIATR JI Eur. J. Pediatr. PD NOV PY 2014 VL 173 IS 11 BP 1459 EP 1466 DI 10.1007/s00431-014-2344-0 PG 8 WC Pediatrics SC Pediatrics GA AR8FQ UT WOS:000343811600008 PM 24889334 ER PT J AU Thomadsen, B Nath, R Bateman, FB Farr, J Glisson, C Islam, MK LaFrance, T Moore, ME Xu, XG Yudelev, M AF Thomadsen, Bruce Nath, Ravinder Bateman, Fred B. Farr, Jonathan Glisson, Cal Islam, Mohammad K. LaFrance, Terry Moore, Mary E. Xu, X. George Yudelev, Mark TI POTENTIAL HAZARD DUE TO INDUCED RADIOACTIVITY SECONDARY TO RADIOTHERAPY: THE REPORT OF TASK GROUP 136 OF THE AMERICAN ASSOCIATION OF PHYSICISTS IN MEDICINE SO HEALTH PHYSICS LA English DT Review DE accelerators, medical; exposure, occupational; radiation risk; radiation therapy ID NEUTRON-THERAPY FACILITY; RADIATION PROTECTION ASPECTS; ENERGY LINEAR-ACCELERATOR; ACTIVATION PRODUCTS; PROTON THERAPY; MULTILEAF COLLIMATOR; STAFF PROTECTION; DOSE-EQUIVALENT; LAYER-STACKING; SAFETY SURVEY AB External-beam radiation therapy mostly uses high-energy photons (x-rays) produced by medical accelerators, but many facilities now use proton beams, and a few use fast-neutron beams. High-energy photons offer several advantages over lower-energy photons in terms of better dose distributions for deep-seated tumors, lower skin dose, less sensitivity to tissue heterogeneities, etc. However, for beams operating at or above 10 MV, some of the materials in the accelerator room and the radiotherapy patient become radioactive due primarily to photonuclear reactions and neutron capture, exposing therapy staff and patients to unwanted radiation dose. Some recent advances in radiotherapy technology require treatments using a higher number of monitor units and monitor-unit rates for the same delivered dose, and compared to the conventional treatment techniques and fractionation schemes, the activation dose to personnel can be substantially higher. Radiotherapy treatments with proton and neutron beams all result in activated materials in the treatment room. In this report, the authors review critically the published literature on radiation exposures from induced radioactivity in radiotherapy. They conclude that the additional exposure to the patient due to induced radioactivity is negligible compared to the overall radiation exposure as a part of the treatment. The additional exposure to the staff due to induced activity from photon beams is small at an estimated level of about 1 to 2 mSv y(-1). This is well below the allowed occupational exposure limits. Therefore, the potential hazard to staff from induced radioactivity in the use of high-energy x-rays is considered to be low, and no specific actions are considered necessary or mandatory. However, in the spirit of the "As Low as Reasonably Achievable (ALARA)" program, some reasonable steps are recommended that can be taken to reduce this small exposure to an even lower level. The dose reduction strategies suggested should be followed only if these actions are considered reasonable and practical in the individual clinics. Therapists working with proton beam and neutron beam units handle treatment devices that do become radioactive, and they should wear extremity monitors and make handling apertures and boluses their last task upon entering the room following treatment. Personnel doses from neutron-beam units can approach regulatory limits depending on the number of patients and beams, and strategies to reduce doses should be followed. C1 [Thomadsen, Bruce] Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. [Nath, Ravinder] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA. [Bateman, Fred B.] NIST, Radiat Phys Div, Gaithersburg, MD 20899 USA. [Farr, Jonathan] St Jude Childrens Res Hosp, Dept Radiol Sci, Div Radiat Oncol, Memphis, TN 38105 USA. [Glisson, Cal] Loma Linda Univ, Off Radiat Safety, Loma Linda, CA 92354 USA. [Islam, Mohammad K.] Princess Margaret Hosp, Dept Radiat Phys, Toronto, ON M5G 2M9, Canada. [LaFrance, Terry] Baystate Hlth Syst Inc, Med Phys Radiat Safety Dept, Springfield, MA 01199 USA. [Moore, Mary E.] Philadelphia VA Med Ctr, Radiat Safety Off, Philadelphia, PA 19104 USA. [Xu, X. George] Rensselaer Polytech Inst, Program Nucl Engn & Engn Phys, Troy, NY 12180 USA. [Yudelev, Mark] Ted B Wahby Canc Ctr, Mt Clemens, MI 48043 USA. RP Thomadsen, B (reprint author), Univ Wisconsin, Dept Med Phys, Wisconsin Inst Med Res 1005, 1111 Highland Ave, Madison, WI 53705 USA. EM brthomad@wisc.edu NR 72 TC 3 Z9 3 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD NOV PY 2014 VL 107 IS 5 BP 442 EP 460 DI 10.1097/HP.0000000000000139 PG 19 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA AR7QF UT WOS:000343773700009 PM 25271934 ER PT J AU Augustinack, JC van der Kouwe, AJW Salat, DH Benner, T Stevens, AA Annese, J Fischl, B Frosch, MP Corkin, S AF Augustinack, Jean C. van der Kouwe, Andre J. W. Salat, David H. Benner, Thomas Stevens, Allison A. Annese, Jacopo Fischl, Bruce Frosch, Matthew P. Corkin, Suzanne TI HM's Contributions to Neuroscience: A Review and Autopsy Studies SO HIPPOCAMPUS LA English DT Editorial Material DE hippocampus; entorhinal cortex; perirhinal cortex; parahippocampal cortex; amygdala ID MEDIAL TEMPORAL-LOBE; AMNESIC PATIENT HM; WHITE-MATTER LESIONS; SEMANTIC KNOWLEDGE; ALZHEIMERS-DISEASE; PERCEPTUAL IDENTIFICATION; PATHOLOGICAL MARKERS; PERIRHINAL CORTEX; PROFOUND AMNESIA; CEREBRAL-CORTEX AB H.M., Henry Molaison, was one of the world's most famous amnesic patients. His amnesia was caused by an experimental brain operation, bilateral medial temporal lobe resection, carried out in 1953 to relieve intractable epilepsy. He died on December 2, 2008, and that night we conducted a wide variety of in situ MRI scans in a 3 T scanner at the Massachusetts General Hospital (Mass General) Athinoula A. Martinos Center for Biomedical Imaging. For the in situ experiments, we acquired a full set of standard clinical scans, 1 mm isotropic anatomical scans, and multiple averages of 440 m isotropic anatomical scans. The next morning, H.M.'s body was transported to the Mass General Morgue for autopsy. The photographs taken at that time provided the first documentation of H.M.'s lesions in his physical brain. After tissue fixation, we obtained ex vivo structural data at ultra-high resolution using 3 T and 7 T magnets. For the ex vivo acquisitions, the highest resolution images were 210 m isotropic. Based on the MRI data, the anatomical areas removed during H.M.'s experimental operation were the medial temporopolar cortex, piriform cortex, virtually all of the entorhinal cortex, most of the perirhinal cortex and subiculum, the amygdala (except parts of the dorsal-most nucleicentral and medial), anterior half of the hippocampus, and the dentate gyrus (posterior head and body). The posterior parahippocampal gyrus and medial temporal stem were partially damaged. Spared medial temporal lobe tissue included the dorsal-most amygdala, the hippocampal-amygdalo-transition-area, approximate to 2 cm of the tail of the hippocampus, a small part of perirhinal cortex, a small portion of medial hippocampal tissue, and approximate to 2 cm of posterior parahippocampal gyrus. H.M.'s impact on the field of memory has been remarkable, and his contributions to neuroscience continue with a unique dataset that includes in vivo, in situ, and ex vivo high-resolution MRI. (c) 2014 Wiley Periodicals, Inc. C1 [Augustinack, Jean C.; van der Kouwe, Andre J. W.; Salat, David H.; Benner, Thomas; Stevens, Allison A.; Fischl, Bruce; Corkin, Suzanne] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. [Annese, Jacopo] Brain Observ, San Diego, CA 92101 USA. [Annese, Jacopo] Univ Calif San Diego, Dept Radiol, San Diego, CA 92093 USA. [Fischl, Bruce] MIT, CSAIL, Cambridge, MA 02139 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. [Corkin, Suzanne] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Augustinack, JC (reprint author), 149,13th St,Room 2301, Charlestown, MA 02129 USA. EM jean@nmr.mgh.harvard.edu FU NCRR NIH HHS [P41-RR14075, U24 RR021382]; NIA NIH HHS [5R01AG008122-22, AG022381]; NIBIB NIH HHS [R01EB006758]; NIMH NIH HHS [5U01-MH093765] NR 95 TC 15 Z9 15 U1 6 U2 53 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1050-9631 EI 1098-1063 J9 HIPPOCAMPUS JI Hippocampus PD NOV PY 2014 VL 24 IS 11 BP 1267 EP 1286 DI 10.1002/hipo.22354 PG 20 WC Neurosciences SC Neurosciences & Neurology GA AR8NC UT WOS:000343830700002 PM 25154857 ER PT J AU Rossaint, R Lewandowski, K Zapol, WM AF Rossaint, R. Lewandowski, K. Zapol, W. M. TI Our paper 20 years later: Inhaled nitric oxide for the acute respiratory distress syndrome-discovery, current understanding, and focussed targets of future applications SO INTENSIVE CARE MEDICINE LA English DT Article DE Nitric oxide; Acute respiratory distress syndrome; Pulmonary arterial hypertension; Selective vasodilation; Arterial oxygenation ID RANDOMIZED CONTROLLED-TRIAL; PERSISTENT PULMONARY-HYPERTENSION; CONGENITAL HEART-DISEASE; ACUTE LUNG INJURY; PRETERM INFANTS; PREMATURE-INFANTS; CARDIAC-SURGERY; AEROSOLIZED PROSTACYCLIN; MECHANICAL VENTILATION; CEREBRAL MALARIA AB More than 20 years have passed since we reported our results of treating patients with the acute respiratory distress syndrome (ARDS) with inhaled nitric oxide (iNO). The main finding was that iNO alleviated pulmonary hypertension (PH) by selective vasodilation of pulmonary vessels in ventilated lung areas. This, in turn, improved arterial oxygenation. We now set out to review the time span between the discovery of NO in 1987 and today in order to identify and describe interesting areas of research and clinical practice surrounding the application of iNO. Enhancement of ventilation-perfusion matching and alleviation of PH in ARDS, treatment of PH of the newborn, and treatment of perioperative PH in congenital heart disease serve as just a few exciting examples for the successful use of iNO. Breathing NO prevents PH induced by stored blood transfusions or sickle cell disease. Exploiting the anti-inflammatory properties of NO helps to treat malaria. Regarding the use of iNO in ARDS, there remains the unresolved question of whether important outcome parameters can be positively influenced. At first glance, several randomized controlled trials and meta-analyses seem to send the clear message: "There is none!" Careful analyses, however, leave sufficient room for doubt that the ideal study to produce the unequivocal proof for the inability of iNO to positively impact on important outcome parameters has, as yet, not been conducted. In summary, the discovery of and research on the many positive effects of iNO has improved care of critically ill patients worldwide. It is a noble effort to continue on this path. C1 [Rossaint, R.] Univ Klinikum Aachen, Anasthesiol Klin, D-52074 Aachen, Germany. [Lewandowski, K.] Elisabeth Krankenhaus Essen, Klin Anasthesiol Intens Med & Schmerztherapie, D-45138 Essen, Germany. [Zapol, W. M.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Rossaint, R (reprint author), Univ Klinikum Aachen, Anasthesiol Klin, Pauwelsstr 30, D-52074 Aachen, Germany. EM rrossaint@ukaachen.de; k.lewandowski@contilia.de NR 78 TC 8 Z9 9 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0342-4642 EI 1432-1238 J9 INTENS CARE MED JI Intensive Care Med. PD NOV PY 2014 VL 40 IS 11 BP 1649 EP 1658 DI 10.1007/s00134-014-3458-6 PG 10 WC Critical Care Medicine SC General & Internal Medicine GA AR9GF UT WOS:000343880300004 PM 25201565 ER PT J AU Williams, DL Mazefsky, CA Walker, JD Minshew, NJ Goldstein, G AF Williams, Diane L. Mazefsky, Carla A. Walker, Jon D. Minshew, Nancy J. Goldstein, Gerald TI Associations Between Conceptual Reasoning, Problem Solving, and Adaptive Ability in High-functioning Autism SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Autism; Conceptual reasoning; Problem solving; Adaptive behavior; Cognitive ID DIAGNOSTIC OBSERVATION SCHEDULE; SOCIAL-SKILLS INTERVENTIONS; DEVELOPMENTAL DISORDERS; SPECTRUM DISORDERS; IMPAIRED MEMORY; YOUNG-ADULTS; CHILDREN; INDIVIDUALS; BEHAVIOR; DYSFUNCTION AB The Abstract thinking is generally highly correlated with problem-solving ability which is predictive of better adaptive functioning. Measures of conceptual reasoning, an ecologically-valid laboratory measure of problem-solving, and a report measure of adaptive functioning in the natural environment, were administered to children and adults with and without autism. The individuals with autism had weaker conceptual reasoning ability than individuals with typical development of similar age and cognitive ability. For the autism group, their flexible thinking scores were significantly correlated with laboratory measures of strategy formation and rule shifting and with reported overall adaptive behavior but not socialization scores. Therefore, in autism, flexibility of thought is potentially more important for adaptive functioning in the natural environment than conceptual reasoning or problem-solving. C1 [Williams, Diane L.] Duquesne Univ, Dept Speech Language Pathol, Pittsburgh, PA 15219 USA. [Mazefsky, Carla A.; Minshew, Nancy J.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Walker, Jon D.; Goldstein, Gerald] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. [Minshew, Nancy J.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. RP Goldstein, G (reprint author), VA Pittsburgh Healthcare Syst, Univ Dr, Pittsburgh, PA 15240 USA. EM Ggold@nb.net RI Williams, Diane/B-4128-2017 FU NICHD NIH HHS [HD35469]; NIDCD NIH HHS [K23DC006691] NR 56 TC 3 Z9 3 U1 4 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 EI 1573-3432 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD NOV PY 2014 VL 44 IS 11 SI SI BP 2908 EP 2920 DI 10.1007/s10803-014-2190-y PG 13 WC Psychology, Developmental SC Psychology GA AR6XK UT WOS:000343724000022 PM 25099486 ER PT J AU Proctor, SP Maule, AL Heaton, KJ Adam, GE AF Proctor, Susan P. Maule, Alexis L. Heaton, Kristin J. Adam, Gina E. TI Permethrin exposure from fabric-treated military uniforms under different wear-time scenarios SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Article DE permethrin; urinary biomarkers; absorbed dose; military; biomonitoring; pesticides; epidemiology ID PYRETHROID INSECTICIDES; IXODES-RICINUS; US POPULATION; METABOLITES; IMPREGNATION; HEALTH; TICKS AB The objective of the project was to ascertain whether urinary biomarkers of permethrin exposure are detected after wearing post-tailored, fabric-treated military uniforms under two different wear-time exposure scenarios. Study A occurred over 3.5 days and involved six participants wearing treated uniforms continuously for 30-32 h. Urine collection occurred at scheduled time points before, during, and after wearing the uniform. Study B, conducted over 19 days, included 11 participants wearing treated uniforms for 3 consecutive days, 8 h each day (with urine collection before, during, and after wear). Urinary biomarkers of permethrin (3-phenoxybenzoic acid (3PBA), cis- 2,2-(dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (cDCCA), trans- 2,2(dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (tDCCA)) were detected during and after wear. Biomarker detection generally occurred over the 10- to 12-h period after putting on the uniform and subsided 24 h following uniform removal (in both Study A and B scenarios). Those wearing permethrin-treated uniforms under the longer wear-time scenario (Study A) excreted significantly higher cumulative mean levels compared with those in Study B (3.29 times higher for 3PBA and 2.23 times higher for the sum of c/tDCCA (P <= 0.001)). Findings suggest that wearing permethrin-treated clothing does increase absorbed, internal dose levels of permethrin above population levels and is significantly related to wear-time duration. C1 [Proctor, Susan P.; Maule, Alexis L.; Heaton, Kristin J.; Adam, Gina E.] US Army Res Inst Environm Med, Mil Performance Div, Natick, MA 01760 USA. [Proctor, Susan P.; Maule, Alexis L.; Heaton, Kristin J.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Proctor, Susan P.] VA Boston Healthcare Syst, Boston, MA USA. RP Proctor, SP (reprint author), US Army Res Inst Environm Med, Mil Performance Div, Kansas St Bldg 42, Natick, MA 01760 USA. EM susan.p.proctor.civ@mail.mil NR 20 TC 3 Z9 3 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 EI 1559-064X J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD NOV-DEC PY 2014 VL 24 IS 6 BP 572 EP 578 DI 10.1038/jes.2013.65 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA AS0IJ UT WOS:000343960800004 PM 24104061 ER PT J AU Steele, SR Bleier, J Champagne, B Hassan, I Russ, A Senagore, AJ Sylla, P Pigazzi, A AF Steele, Scott R. Bleier, Joshua Champagne, Brad Hassan, Imran Russ, Andrew Senagore, Anthony J. Sylla, Patricia Pigazzi, Alessio TI Improving Outcomes and Cost-Effectiveness of Colorectal Surgery SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Enhanced recovery; Surgical site infection; Simulation; Outcomes; Anastomotic leak; Ostomy; Colorectal surgery ID RANDOMIZED-CLINICAL-TRIAL; SURGICAL SITE INFECTION; POSTOPERATIVE INSULIN-RESISTANCE; LAPAROSCOPIC SIGMOID RESECTION; THORACIC EPIDURAL ANALGESIA; ENHANCED RECOVERY PATHWAYS; RECTAL-CANCER SURGERY; SPECIMEN EXTRACTION; DIVERTING ILEOSTOMY; ANASTOMOTIC LEAKAGE C1 [Steele, Scott R.] Madigan Army Med Ctr, Ft Lewis, WA 98431 USA. [Bleier, Joshua] Hosp Univ PA, Penn Hosp, Div Colon & Rectal Surg, Philadelphia, PA 19106 USA. [Champagne, Brad; Russ, Andrew] Case Med Ctr, Univ Hosp, Div Colorectal Surg, Cleveland, OH USA. [Hassan, Imran] Univ Iowa, Dept Surg, Iowa City, IA 52242 USA. [Senagore, Anthony J.] Cent Michigan Univ, Coll Med, Saginaw, MI 48601 USA. [Sylla, Patricia] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02142 USA. [Pigazzi, Alessio] Univ Calif Irvine, Sch Med, Dept Surg, Orange, CA 92868 USA. RP Steele, SR (reprint author), Madigan Army Med Ctr, Ft Lewis, WA 98431 USA. EM harkersteele@mac.com; Joshua.bleier@uphs.upenn.edu; brad.champagne@uhhospitals.org; ihassan1995@yahoo.com; Andrew.Russ@UHhospitals.org; anthony.senagore@cmich.edu; psylla@partners.org; apigazzi@uci.edu NR 95 TC 4 Z9 4 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD NOV PY 2014 VL 18 IS 11 BP 1944 EP 1956 DI 10.1007/s11605-014-2643-9 PG 13 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AR9TM UT WOS:000343919700008 PM 25205538 ER PT J AU Fisichella, PM Patti, MG AF Fisichella, P. Marco Patti, Marco G. TI GERD Procedures: When and What? SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Gastroesophageal reflux disease; Esophageal manometry; Ambulatory pH monitoring; Partial fundoplication; Total fundoplication; Morbid obesity; Roux-en-Y gastric bypass ID GASTROESOPHAGEAL-REFLUX DISEASE; LAPAROSCOPIC NISSEN FUNDOPLICATION; ANTIREFLUX SURGERY; ESOPHAGEAL; OBESITY; PATHOPHYSIOLOGY; PERISTALSIS; EXPERIENCE; TRIAL AB Background The topic of "when and what" for gastroesophageal reflux disease (GERD) procedures centers on the correct indications for antireflux surgery gleaned from a thorough preoperative evaluation (the "when") and on the right antireflux operation to perform once the ideal candidate is identified (the "what"). Aims The goals of this evidence-based review are the following: (1) to identify the key indications for surgery and predictors of good outcomes in the initial evaluation of patients with symptoms of GERD; (2) to describe the operations for GERD in the armamentarium of the general surgeon and their indications, as well as the technical elements of the operation; and (3) to describe the optimal surgical treatment of GERD and obesity when the two diseases coexist. C1 [Fisichella, P. Marco] Harvard Univ, Sch Med, Dept Surg, Boston VA Healthcare Syst, Boston, MA 02132 USA. [Patti, Marco G.] Univ Chicago, Pritzker Sch Med, Ctr Esophageal Dis, Dept Surg, Chicago, IL 60637 USA. RP Fisichella, PM (reprint author), Harvard Univ, Sch Med, Dept Surg, Boston VA Healthcare Syst, 1400 VFW Pkwy, Boston, MA 02132 USA. EM piero.fisichella@va.gov NR 28 TC 2 Z9 2 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD NOV PY 2014 VL 18 IS 11 BP 2047 EP 2053 DI 10.1007/s11605-014-2558-5 PG 7 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AR9TM UT WOS:000343919700020 PM 24981658 ER PT J AU Kitchens, WH Liu, C Ryan, ET Fernandez-del Castillo, C AF Kitchens, William H. Liu, Charles Ryan, Edward T. Fernandez-del Castillo, Carlos TI Hepatic Hydatid Cyst: A Rare Cause of Recurrent Pancreatitis SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Pancreatitis; Hydatid cysts; Echinococcus ID INTRABILIARY RUPTURE AB A case of pancreatitis secondary to a hepatic hydatid cyst is illustrated together with its preoperative imaging and intraoperative appearance. Cystobiliary communication is a common complication of large hydatid cysts, and episodes of recurrent pancreatitis resulting from passage of cyst contents down the biliary tract are rarely described. The clinical manifestations, diagnostic workup, and surgical management options of echinococcal-related pancreatitis are discussed, and a review of the literature is provided. C1 [Kitchens, William H.; Fernandez-del Castillo, Carlos] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Kitchens, William H.] Emory Univ Hosp, Emory Transplant Ctr, Atlanta, GA 30322 USA. [Liu, Charles] Harvard Univ, Sch Med, Boston, MA USA. [Ryan, Edward T.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. RP Fernandez-del Castillo, C (reprint author), Massachusetts Gen Hosp, Dept Surg, ACC 366 15 Parkman St, Boston, MA 02114 USA. EM cfernandez@mgh.harvard.edu NR 11 TC 1 Z9 1 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X EI 1873-4626 J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD NOV PY 2014 VL 18 IS 11 BP 2057 EP 2059 DI 10.1007/s11605-014-2630-1 PG 3 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AR9TM UT WOS:000343919700022 PM 25149853 ER PT J AU O'Leary, TJ AF O'Leary, Timothy J. TI Reflecting on My Time as Editor-in-Chief SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Editorial Material C1 US Dept Vet Affairs, Washington, DC 20420 USA. RP O'Leary, TJ (reprint author), US Dept Vet Affairs, Washington, DC 20420 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2014 VL 16 IS 6 BP 593 EP 594 DI 10.1016/j.jmoldx.2014.09.001 PG 2 WC Pathology SC Pathology GA AR7YZ UT WOS:000343794200001 PM 25307753 ER PT J AU O'Leary, TJ AF O'Leary, Timothy J. TI Regulating Laboratory-Developed Tests SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Editorial Material ID LOCALIZED PROSTATE-CANCER; RETRACTED ARTICLE. SEE; RADICAL PROSTATECTOMY; INTERVENTION; PIVOT C1 US Dept Vet Affairs, Washington, DC 20420 USA. RP O'Leary, TJ (reprint author), US Dept Vet Affairs, Washington, DC 20420 USA. NR 19 TC 0 Z9 1 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2014 VL 16 IS 6 BP 595 EP 598 DI 10.1016/j.jmoldx.2014.09.002 PG 4 WC Pathology SC Pathology GA AR7YZ UT WOS:000343794200002 PM 25307754 ER PT J AU Mandelker, D Amr, SS Pugh, T Gowrisankar, S Shakhbatyan, R Duffy, E Bowser, M Harrison, B Lafferty, K Mahanta, L Rehm, HL Funke, BH AF Mandelker, Diana Amr, Sami S. Pugh, Trevor Gowrisankar, Sivakumar Shakhbatyan, Rimma Duffy, Elizabeth Bowser, Mark Harrison, Bryan Lafferty, Katherine Mahanta, Lisa Rehm, Heidi L. Funke, Birgit H. TI Comprehensive Diagnostic Testing for Stereocilin An Approach for Analyzing Medically Important Genes with High Homology SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID POLYCYSTIC KIDNEY-DISEASE; HEARING-LOSS; GENOME; LOCUS; PSEUDOGENES; DFNB16; DUPLICATIONS; MUTATIONS; DEAFNESS AB Next-generation sequencing (NGS) technologies have revolutionized genetic testing by enabling simultaneous analysis of unprecedented numbers of genes. However, genes with high-sequence homology pose challenges to current NGS technologies. Because diagnostic sequencing is moving toward exome analysis, knowledge of these homologous genes is essential to avoid false positive and negative results. An example is the STRC gene, one of >70 genes known to contribute to the genetic basis of hearing loss. STRC is 99.6% identical to a pseudogene (pSTRC) and therefore inaccessible to standard NGS methodologies. The STRC locus is also known to be a common site for large deletions. Comprehensive diagnostic testing for inherited hearing loss therefore necessitates a combination of several approaches to avoid pseudogene interference. We have developed a clinical test that combines standard NGS and NGS-based copy number assessment supplemented with a long-range PCR-based Sanger or MiSeq assay to eliminate pseudogene contamination. By using this combination of assays we could identify biallelic STRC variants in 14% (95% CI, 8%-24%) of individuals with isolated nonsyndromic hearing loss who had previously tested negative on our 70-gene hearing loss panel, corresponding to a detection rate of 11.2% (95% CI, 6%-19%) for previously untested patients. This approach has broad applicability because medically significant genes for many disease areas include genes with high-sequence homology. C1 [Mandelker, Diana] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Amr, Sami S.; Pugh, Trevor; Gowrisankar, Sivakumar; Shakhbatyan, Rimma; Duffy, Elizabeth; Bowser, Mark; Harrison, Bryan; Lafferty, Katherine; Mahanta, Lisa; Rehm, Heidi L.; Funke, Birgit H.] Partners Healthcare Personalized Med, Mol Med Lab, Cambridge, MA USA. [Funke, Birgit H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. RP Funke, BH (reprint author), 65 Landsdowne St, Cambridge, MA 02139 USA. EM bfunke@partners.org OI Amr, Sami/0000-0003-0927-6057 FU Partners HealthCare Center for Personalized Genetic Medicine (PCPGM) FX Supported by the Partners HealthCare Center for Personalized Genetic Medicine (PCPGM). NR 19 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2014 VL 16 IS 6 BP 639 EP 647 DI 10.1016/j.jmoldx.2014.06.003 PG 9 WC Pathology SC Pathology GA AR7YZ UT WOS:000343794200008 PM 25157971 ER PT J AU MacConaill, LE Garcia, E Shivdasani, P Ducar, M Adusumilli, R Breneiser, M Byrne, M Chung, L Conneely, J Crosby, L Garraway, LA Gong, X Hahn, WC Hatton, C Kantoff, PW Kluk, M Kuo, F Jia, YH Joshi, R Longtine, J Manning, A Palescandolo, E Sharaf, N Sholl, L van Hummelen, P Wade, J Wollinson, BM Zepf, D Rollins, BJ Lindeman, NI AF MacConaill, Laura E. Garcia, Elizabeth Shivdasani, Priyanka Ducar, Matthew Adusumilli, Ravali Breneiser, Marc Byrne, Mark Chung, Lawrence Conneely, Jodie Crosby, Lauren Garraway, Levi A. Gong, Xin Hahn, William C. Hatton, Charlie Kantoff, Philip W. Kluk, Michael Kuo, Frank Jia, Yonghui Joshi, Ruchi Longtine, Janina Manning, Allison Palescandolo, Emanuele Sharaf, Nematullah Sholl, Lynette van Hummelen, Paul Wade, Jacqueline Wollinson, Bruce M. Zepf, Dimity Rollins, Barrett J. Lindeman, Neal I. TI Prospective Enterprise-Level Molecular Genotyping of a Cohort of Cancer Patients SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID CELL LUNG-CANCER; METASTATIC COLORECTAL-CANCER; GASTROINTESTINAL STROMAL TUMORS; BRAF MUTATIONS; GENE-MUTATIONS; SOMATIC MUTATIONS; ADENOCARCINOMA; LEUKEMIA; THERAPY; GENOME AB Ongoing cancer genome characterization studies continue to elucidate the spectrum of genomic abnormalities that drive many cancers, and in the clinical arena assessment of the driver genetic alterations in patients is playing an increasingly important diagnostic and/or prognostic rote for many cancer types. However, the landscape of genomic abnormalities is still unknown for less common cancers, and the influence of specific genotypes on clinical behavior is often still unclear. To address some of these deficiencies, we developed Profile, a prospective cohort study to obtain genomic information on all patients at a large tertiary care medical center for cancer-related care. We enrolled patients with any cancer diagnosis, and, for each patient (unselected for cancer site or type) we applied mass spectrometric genotyping (OncoMap) of 471 common recurrent mutations in 41 cancer-related genes. We report the results of the first 5000 patients, of which 26% exhibited potentially actionable somatic mutations. These observations indicate the utility of genotyping in advancing the field of precision oncology. C1 [MacConaill, Laura E.; Garcia, Elizabeth; Shivdasani, Priyanka; Byrne, Mark; Chung, Lawrence; Conneely, Jodie; Crosby, Lauren; Gong, Xin; Kluk, Michael; Kuo, Frank; Jia, Yonghui; Joshi, Ruchi; Longtine, Janina; Manning, Allison; Sharaf, Nematullah; Sholl, Lynette; Wade, Jacqueline; Zepf, Dimity; Lindeman, Neal I.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [MacConaill, Laura E.; Ducar, Matthew; Adusumilli, Ravali; Breneiser, Marc; Garraway, Levi A.; Hahn, William C.; Hatton, Charlie; Palescandolo, Emanuele; van Hummelen, Paul; Wollinson, Bruce M.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Garraway, Levi A.; Hahn, William C.; Kantoff, Philip W.; Rollins, Barrett J.] Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA USA. RP Lindeman, NI (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St,Shapiro 2020, Boston, MA 02115 USA. EM laura_macconaill@dfci.harvard.edu; nlindeman@partners.org FU Dana-Farber Cancer Institute; NITA [R33 CA 155554]; National Heart, Lung, and Blood Institute Grand Opportunity (GO); Lung GO Sequencing Project [HL-102923]; WHI Sequencing Project [HL-102924]; Broad GO Sequencing Project [HL-102925]; Seattle GO Sequencing Project [HL-102926]; Heart GO Sequencing Project [HL-103010] FX Supported by the Dana-Farber Cancer Institute and NITA grant R33 CA 155554.; We thank the National Heart, Lung, and Blood Institute Grand Opportunity (GO) Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). NR 62 TC 28 Z9 28 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2014 VL 16 IS 6 BP 660 EP 672 DI 10.1016/j.jmoldx.2014.06.004 PG 13 WC Pathology SC Pathology GA AR7YZ UT WOS:000343794200010 PM 25157968 ER PT J AU Lincoln, S Kurian, A Desmond, A Gabree, M Powers, M Monzon, F Ellisen, L Ford, J AF Lincoln, S. Kurian, A. Desmond, A. Gabree, M. Powers, M. Monzon, F. Ellisen, L. Ford, J. TI Traditional vs. Next-Generation Testing of Hereditary Breast and Ovarian Cancer Genes in a Large Clinical Population SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 12-15, 2014 CL National Harbor, MD SP Assoc Mol Pathol C1 [Lincoln, S.; Powers, M.; Monzon, F.] Invitae, San Francisco, CA USA. [Kurian, A.; Ford, J.] Stanford Univ, Stanford, CA 94305 USA. [Desmond, A.; Gabree, M.; Ellisen, L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2014 VL 16 IS 6 MA G04 BP 699 EP 700 PG 2 WC Pathology SC Pathology GA AR7YZ UT WOS:000343794200018 ER PT J AU Church, A Grimmett, L Garcia, E Kim, A Glade-Bender, J DuBois, SG MacConaill, LE Stegmaier, K London, WB Crompton, BD Shusterman, S Diller, L Rodriguez-Galindo, C Lindeman, NI Janeway, KA Harris, MH AF Church, A. Grimmett, L. Garcia, E. Kim, A. Glade-Bender, J. DuBois, S. G. MacConaill, L. E. Stegmaier, K. London, W. B. Crompton, B. D. Shusterman, S. Diller, L. Rodriguez-Galindo, C. Lindeman, N. I. Janeway, K. A. Harris, M. H. TI Analysis of Somatic Copy Number Alterations in Pediatric Solid Tumors Using Both Array Comparative Genomic Hybridization and High Throughput Sequencing SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 12-15, 2014 CL National Harbor, MD SP Assoc Mol Pathol C1 [Church, A.; Stegmaier, K.; London, W. B.; Crompton, B. D.; Shusterman, S.; Diller, L.; Rodriguez-Galindo, C.; Janeway, K. A.; Harris, M. H.] Boston Childrens Hosp, Boston, MA USA. [Grimmett, L.] Claritas Genom, Cambridge, MA USA. [Garcia, E.; Lindeman, N. I.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kim, A.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Glade-Bender, J.] Columbia Univ, Med Ctr, New York, NY USA. [DuBois, S. G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [MacConaill, L. E.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2014 VL 16 IS 6 MA ST30 BP 752 EP 752 PG 1 WC Pathology SC Pathology GA AR7YZ UT WOS:000343794200246 ER PT J AU Stachler, MD Carter, S Taylor-Weiner, A Peng, S Getz, G Bass, A AF Stachler, M. D. Carter, S. Taylor-Weiner, A. Peng, S. Getz, G. Bass, A. TI Barrett's Esophagus Has a Mutation Frequency Comparable to Invasive Cancers but Lacks Oncogene Activation SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 12-15, 2014 CL National Harbor, MD SP Assoc Mol Pathol C1 [Stachler, M. D.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Carter, S.; Taylor-Weiner, A.; Getz, G.] Broad Inst, Cambridge, MA USA. [Peng, S.; Bass, A.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2014 VL 16 IS 6 MA ST40 BP 754 EP 754 PG 1 WC Pathology SC Pathology GA AR7YZ UT WOS:000343794200256 ER PT J AU Ducar, M Abo, R Leslin, C Shivdasani, P Chung, L Gong, X Fendler, B Davineni, P Chin, G Van Hummelen, P Garcia, E Rollins, B Lindeman, N Macconaill, L AF Ducar, M. Abo, R. Leslin, C. Shivdasani, P. Chung, L. Gong, X. Fendler, B. Davineni, P. Chin, G. Van Hummelen, P. Garcia, E. Rollins, B. Lindeman, N. Macconaill, L. TI Building a Clinical-Grade Next-Generation Sequence Analysis Pipeline from Research Tools SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 12-15, 2014 CL National Harbor, MD SP Assoc Mol Pathol C1 [Ducar, M.; Abo, R.; Van Hummelen, P.; Rollins, B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Leslin, C.; Shivdasani, P.; Chung, L.; Gong, X.; Fendler, B.; Davineni, P.; Chin, G.; Garcia, E.; Lindeman, N.; Macconaill, L.] Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2014 VL 16 IS 6 MA TT02 BP 772 EP 772 PG 1 WC Pathology SC Pathology GA AR7YZ UT WOS:000343794200332 ER PT J AU Castellanos-Rizaldos, E Paweletz, C Oxnard, GR Mamon, H Janne, PA Makrigiorgos, MG AF Castellanos-Rizaldos, E. Paweletz, C. Oxnard, G. R. Mamon, H. Jaenne, P. A. Makrigiorgos, M. G. TI Digital Mutation Scanning by Using an Enhanced Ratio of Signals SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 12-15, 2014 CL National Harbor, MD SP Assoc Mol Pathol C1 [Castellanos-Rizaldos, E.; Paweletz, C.; Oxnard, G. R.; Mamon, H.; Jaenne, P. A.; Makrigiorgos, M. G.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2014 VL 16 IS 6 MA TT07 BP 773 EP 773 PG 1 WC Pathology SC Pathology GA AR7YZ UT WOS:000343794200337 ER PT J AU Aziz, N Zhao, Q Durtschi, J Bry, L Driscoll, DK Funke, BH Gibson, JS Grody, WW Hedge, MR Leonard, DG Merker, JD Nagarajan, R Palicki, LA Robetorye, RS Santani, AB Schrijver, I Weck, KE Voelkerding, KV AF Aziz, N. Zhao, Q. Durtschi, J. Bry, L. Driscoll, D. K. Funke, B. H. Gibson, J. S. Grody, W. W. Hedge, M. R. Leonard, D. G. Merker, J. D. Nagarajan, R. Palicki, L. A. Robetorye, R. S. Santani, A. B. Schrijver, I. Weck, K. E. Voelkerding, K. V. TI A Pilot Methods-Based Proficiency Test for Next-Generation Sequencing (NGS) SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 12-15, 2014 CL National Harbor, MD SP Assoc Mol Pathol C1 [Aziz, N.] Phoenix Childrens Hosp, Phoenix, AZ USA. [Aziz, N.; Zhao, Q.; Driscoll, D. K.; Palicki, L. A.] Coll Amer Pathologists, Northfield, IL USA. [Durtschi, J.; Voelkerding, K. V.] ARUP Labs, Salt Lake City, UT USA. [Bry, L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Funke, B. H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Gibson, J. S.] Univ Cent Florida, Coll Med, Orlando, FL 32816 USA. [Grody, W. W.] Univ Calif Los Angeles, Ctr Hlth Sci, Los Angeles, CA 90024 USA. [Hedge, M. R.] Emory Univ, Sch Med, Decatur, GA 30033 USA. [Leonard, D. G.] Univ Vermont, Coll Med, Burlington, VT USA. [Merker, J. D.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Nagarajan, R.] Washington Univ, St Louis, MO USA. [Robetorye, R. S.] Mayo Clin, Phoenix, AZ USA. [Santani, A. B.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Schrijver, I.] Stanford Univ, Stanford, CA 94305 USA. [Weck, K. E.] Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2014 VL 16 IS 6 MA TT13 BP 775 EP 775 PG 1 WC Pathology SC Pathology GA AR7YZ UT WOS:000343794200343 ER PT J AU MacConaill, LE Garcia, E Sholl, L Ducar, M Leslin, C Jia, Y Kuo, FC Rollins, BJ Lindeman, N AF MacConaill, L. E. Garcia, E. Sholl, L. Ducar, M. Leslin, C. Jia, Y. Kuo, F. C. Rollins, B. J. Lindeman, N. TI Profile Oncopanel: Clinical-grade Next-Generation Sequencing of 275 Cancer-Related Genes Applied to Specimens from 1800 Consecutive Unselected Cancer Patients SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology (AMP) CY NOV 12-15, 2014 CL National Harbor, MD SP Assoc Mol Pathol C1 [MacConaill, L. E.; Garcia, E.; Sholl, L.; Leslin, C.; Jia, Y.; Kuo, F. C.; Lindeman, N.] Brigham & Womens Hosp, Boston, MA 02115 USA. [MacConaill, L. E.; Garcia, E.; Ducar, M.; Rollins, B. J.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 EI 1943-7811 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2014 VL 16 IS 6 MA TT44 BP 782 EP 782 PG 1 WC Pathology SC Pathology GA AR7YZ UT WOS:000343794200374 ER PT J AU Liu, XH Joshi, SK Ravishankar, B Laron, D Kim, HT Feeley, BT AF Liu, Xuhui Joshi, Sunil K. Ravishankar, Bharat Laron, Dominique Kim, Hubert T. Feeley, Brian T. TI Upregulation of transforming growth factor-beta signaling in a rat model of rotator cuff tears SO JOURNAL OF SHOULDER AND ELBOW SURGERY LA English DT Article DE Massive rotator cuff tear; transforming growth factor-beta; fibrosis ID SUPRASCAPULAR NERVE INJURY; SKELETAL-MUSCLE; FATTY INFILTRATION; MESENCHYMAL TRANSITION; ARTHROSCOPIC REPAIR; INTERVAL SLIDES; SCAR FORMATION; ATROPHY; FIBROSIS; SMAD2 AB Background: Muscle atrophy, fatty infiltration, and fibrosis of the muscle have been described as important factors governing outcome after rotator cuff injury and repair. Muscle fibrosis is also thought to have a role in determining muscle compliance at the time of surgery. The transforming growth factor-beta (TGF-beta) pathways are highly conserved pathways that exert a potent level of control over muscle gene expression and are critical regulators of fibrosis in multiple organ systems. It has been shown that TGF-beta can regulate important pathways of muscle atrophy, including the Akt/mammalian target of rapamycin pathway. The purpose of this study was to evaluate the expression of TGF-beta and its downstream effectors of fibrosis after a massive rotator cuff tear (RCT) in a previously established rat model. Methods: To simulate a massive RCT, infraspinatus and supraspinatus tenotomy and suprascapular nerve transection were performed on Sprague-Dawley rats with use of a validated model. Two and 6 weeks after surgery, supraspinatus muscles were harvested to study alterations in TGF-beta signaling by Western blotting, quantitative polymerase chain reaction, and histologic analysis. Results: There was a significant increase in fibrosis in the rotator cuff muscle after RCT in our animal model. There was a concomitant increase in TGF-beta gene and protein expression at both 2 and 6 weeks after RCT. Evaluation of the TGF-beta signaling pathway revealed an increase in SMAD2 activation but not in SMAD3. There was an increase in profibrotic markers collagen I, collagen III, and alpha-smooth muscle actin. Conclusions: TGF-beta signaling is significantly upregulated in rat supraspinatus muscles after RCTs. (C) 2014 Journal of Shoulder and Elbow Surgery Board of Trustees. C1 [Liu, Xuhui; Joshi, Sunil K.; Ravishankar, Bharat; Kim, Hubert T.] San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA USA. [Liu, Xuhui; Joshi, Sunil K.; Ravishankar, Bharat; Laron, Dominique; Kim, Hubert T.; Feeley, Brian T.] Univ Calif San Francisco, Dept Orthopaed Surg, San Francisco, CA 94158 USA. RP Feeley, BT (reprint author), Univ Calif San Francisco, Dept Orthopaed Surg, 1500 Owens Ave,Box 3004, San Francisco, CA 94158 USA. EM feeleyb@orthosurg.ucsf.edu FU Orthopaedic Research and Education Foundation; National Institutes of Health [NIH R03AR060871] FX Funding was provided by a grant from the Orthopaedic Research and Education Foundation (Young Investigator Grant) and the National Institutes of Health (NIH R03AR060871). NR 34 TC 3 Z9 3 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1058-2746 J9 J SHOULDER ELB SURG JI J. Shoulder Elbow Surg. PD NOV PY 2014 VL 23 IS 11 BP 1709 EP 1716 DI 10.1016/j.jse.2014.02.029 PG 8 WC Orthopedics; Sport Sciences; Surgery SC Orthopedics; Sport Sciences; Surgery GA AR8DF UT WOS:000343805000021 PM 24875732 ER PT J AU Sherman, KL Kinnier, CV Farina, DA Wayne, JD Laskin, WB Agulnik, M Attar, S Hayes, JP Peabody, T Bilimoria, KY AF Sherman, Karen L. Kinnier, Christine V. Farina, Domenico A. Wayne, Jeffrey D. Laskin, William B. Agulnik, Mark Attar, Samer Hayes, John P. Peabody, Terrance Bilimoria, Karl Y. TI Examination of National Lymph Node Evaluation Practices for Adult Extremity Soft Tissue Sarcoma SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE neoplasms; lymph node excision; lymphatic metastasis; retrospective studies ID MM THICK MELANOMAS; PROGNOSTIC-FACTORS; BIOPSY; METASTASIS; LYMPHADENECTOMY; POPULATION; DISSECTION; EFFICACY; YOUNGER; SPREAD AB Background and ObjectivesLymph node evaluation recommendations for extremity soft tissue sarcoma (ESTS) are absent from national guidelines. Our objectives were (1) to assess rates and predictors of nodal evaluation, and (2) to assess rates and predictors of nodal metastases. MethodsESTS patients from the National Cancer Data Base (2000-2009) were assessed, and regression models were used to identify factors associated with nodal evaluation and metastases. ResultsOf 27,536 ESTS patients, 1,924 (7%) underwent nodal evaluation, and of these, 290 (15%) had nodal metastases. Nodal evaluation was most frequently performed for rhabdomyosarcoma (15.6%), angiosarcoma (10.0%), clear cell sarcoma (39.3%), epithelioid sarcoma (28.1%), and synovial sarcoma (9.3%). On multivariable analysis, factors associated with nodal evaluation included histologic subtype, tumor size, and grade. Nodal metastasis rates were highest among patients with rhabdomyosarcoma (32.1%), angiosarcoma (24.1%), clear cell sarcoma (27.7%), and epithelioid sarcoma (31.8%). On multivariable analysis, factors associated with nodal metastases included histologic subtype, tumor size, and grade. ConclusionsNodal evaluation rates are highest among certain expected subtypes but are generally low. However, nodal metastasis rates for many histologic subtypes in patients selected for lymph node evaluation may be higher than previously reported. Multi-institutional studies should address nodal evaluation for ESTS. J. Surg. Oncol. 2014 110:682-688. (c) 2014 Wiley Periodicals, Inc. C1 [Sherman, Karen L.; Kinnier, Christine V.; Farina, Domenico A.; Wayne, Jeffrey D.; Laskin, William B.; Agulnik, Mark; Attar, Samer; Hayes, John P.; Peabody, Terrance; Bilimoria, Karl Y.] Robert H Lurie Comprehens Canc Ctr, Northwestern Inst Comparat Effectiveness Res NICE, Chicago, IL USA. [Sherman, Karen L.; Kinnier, Christine V.; Farina, Domenico A.; Wayne, Jeffrey D.; Bilimoria, Karl Y.] Northwestern Univ, Dept Surg, Feinberg Sch Med, Surg Oncol & Qual Improvement Ctr, Chicago, IL 60611 USA. [Kinnier, Christine V.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Laskin, William B.] NW Mem Hosp, Dept Pathol, Chicago, IL 60611 USA. [Agulnik, Mark] NW Mem Hosp, Dept Med, Div Hematol Oncol, Chicago, IL 60611 USA. [Attar, Samer; Peabody, Terrance] NW Mem Hosp, Dept Orthoped Surg, Chicago, IL 60611 USA. [Hayes, John P.] NW Mem Hosp, Dept Radiat Oncol, Chicago, IL 60611 USA. RP Bilimoria, KY (reprint author), Northwestern Univ, Dept Surg, Surg Outcomes & Qual Improvement Ctr, 676N St Clair St,Suite 6-650, Chicago, IL 60611 USA. EM k-bilimoria@northwestern.edu FU American Cancer Society; De Boer Family Sarcoma Foundation FX Grant sponsor: American Cancer Society; Grant sponsor: De Boer Family Sarcoma Foundation. NR 26 TC 6 Z9 6 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-4790 EI 1096-9098 J9 J SURG ONCOL JI J. Surg. Oncol. PD NOV PY 2014 VL 110 IS 6 BP 682 EP 688 DI 10.1002/jso.23687 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA AR9FN UT WOS:000343878300009 PM 24910401 ER PT J AU Walker, KL Kirillova, O Gillespie, SE Hsiao, D Pishchalenko, V Pai, AK Puro, JE Plumley, R Kudyakov, R Hu, WM Allisany, A McBurnie, M Kurtz, SE Hazlehurst, BL AF Walker, Kari L. Kirillova, Olga Gillespie, Suzanne E. Hsiao, David Pishchalenko, Valentyna Pai, Akshatha Kalsanka Puro, Jon E. Plumley, Robert Kudyakov, Rustam Hu, Weiming Allisany, Art McBurnie, MaryAnn Kurtz, Stephen E. Hazlehurst, Brian L. TI Using the CER Hub to ensure data quality in a multi-institution smoking cessation study SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID CLINICAL-RESEARCH; INFORMATICS; RECORDS AB Comparative effectiveness research (CER) studies involving multiple institutions with diverse electronic health records (EHRs) depend on high quality data. To ensure uniformity of data derived from different EHR systems and implementations, the CER Hub informatics platform developed a quality assurance (QA) process using tools and data formats available through the CER Hub. The QA process, implemented here in a study of smoking cessation services in primary care, used the `emrAdapter' tool programmed with a set of quality checks to query large samples of primary care encounter records extracted in accord with the CER Hub common data framework. The tool, deployed to each study site, generated error reports indicating data problems to be fixed locally and aggregate data sharable with the central site for quality review. Across the CER Hub network of six health systems, data completeness and correctness issues were prevalent in the first iteration and were considerably improved after three iterations of the QA process. A common issue encountered was incomplete mapping of local EHR data values to those defined by the common data framework. A highly automated and distributed QA process helped to ensure the correctness and completeness of patient care data extracted from EHRs for a multi-institution CER study in smoking cessation. C1 [Walker, Kari L.; Kirillova, Olga; Gillespie, Suzanne E.; Hu, Weiming; Allisany, Art; McBurnie, MaryAnn; Hazlehurst, Brian L.] Kaiser Permanente Northwest, Ctr Hlth Res, Portland, OR 97227 USA. [Hsiao, David; Pishchalenko, Valentyna] Kaiser Permanente Hawaii, Ctr Hlth Res, Honolulu, HI USA. [Pai, Akshatha Kalsanka] Emory Univ, Atlanta, GA 30322 USA. [Puro, Jon E.] OCHIN Inc, Portland, OR USA. [Plumley, Robert] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Kudyakov, Rustam] Baylor Hlth Care Syst, Ctr Clin Innovat, Dallas, TX USA. [Kurtz, Stephen E.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Hazlehurst, BL (reprint author), Kaiser Permanente Northwest, Ctr Hlth Res, 3800 N Interstate Ave, Portland, OR 97227 USA. EM Brian.hazlehurst@kpchr.org FU Agency for Health Care Research and Quality (AHRQ), US Department of Health and Human Services [R01HS019828] FX This research, and the CER Hub project (http://www.cerhub.org), is funded by grant R01HS019828 (Hazlehurst, PI) from the Agency for Health Care Research and Quality (AHRQ), US Department of Health and Human Services. NR 21 TC 2 Z9 2 U1 3 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD NOV PY 2014 VL 21 IS 6 BP 1129 EP 1135 DI 10.1136/amiajnl-2013-002629 PG 7 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 AR7RJ UT WOS:000343776700029 PM 24993545 ER PT J AU Groszmann, Y Howitt, BE Bromley, B Feltmate, CM Benacerraf, BR AF Groszmann, Yvette Howitt, Brooke E. Bromley, Bryann Feltmate, Colleen M. Benacerraf, Beryl R. TI Decidualized Endometrioma Masquerading as Ovarian Cancer in Pregnancy SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE decidualized endometrioma; gynecologic ultrasound; pregnancy; sonography ID SONOGRAPHIC FEATURES; MIMICKING MALIGNANCY; ADNEXAL MASSES; MANAGEMENT; DIAGNOSIS; TUMORS AB Objectives To identify the sonographic features of decidualized endometriomas in patients treated at a single institution and to determine whether sonographic findings can distinguish these lesions from malignant ovarian tumors during pregnancy. Methods We conducted a retrospective cohort study that included pregnant women with a histologic diagnosis of decidualized endometrioma between January 1, 2005, and December 1, 2012, and had an ovarian cyst or mass seen preoperatively on obstetrical sonography. Sonographic characteristics of these masses were retrospectively evaluated using the International Ovarian Tumor Analysis Group definitions for adnexal masses. Results Seventeen patients with 22 adnexal masses were included in our study. Nine of 22 lesions (41%) were classified as unilocular solid, and 14 of 22 (64%) had solid components, of which 12 of 14(86%) had substantial blood flow. Septations were present in 8 of 22 masses (36%). Cyst sizes varied from 30 to 120 and 32 to 270 mm at the initial and follow-up scans, respectively. Eight patients had no follow-up scans and underwent surgery within 3 weeks of diagnosis. The other 9 patients (14 masses), had follow-up scans and underwent surgery from 3 to 34 weeks after their initial scans. Eight of these masses showed no notable change in size or appearance, and 1 became smaller. Conclusions There were no characteristic sonographic features identified to distinguish decidualized endometrioma from ovarian malignancy. However, lesions showing no change in size over 4 weeks or lacking solid components and vascularity are more likely to be benign rather than malignant and may justify delaying surgery until delivery or postpartum. C1 [Groszmann, Yvette; Bromley, Bryann; Benacerraf, Beryl R.] Diagnost Ultrasound Associates PC, Boston, MA USA. [Groszmann, Yvette; Bromley, Bryann; Feltmate, Colleen M.; Benacerraf, Beryl R.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Howitt, Brooke E.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bromley, Bryann; Benacerraf, Beryl R.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Bromley, Bryann; Feltmate, Colleen M.; Benacerraf, Beryl R.] Dana Farber Canc Inst, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Bromley, Bryann; Benacerraf, Beryl R.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. RP Groszmann, Y (reprint author), Diagnost Ultrasound Associates PC, 1 Brookline Pl,Suite 506, Brookline, MA 02445 USA. EM bbsono@aol.com NR 15 TC 1 Z9 1 U1 0 U2 1 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 EI 1550-9613 J9 J ULTRAS MED JI J. Ultrasound Med. PD NOV PY 2014 VL 33 IS 11 BP 1909 EP 1915 DI 10.7863/ultra.33.11.1909 PG 7 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA AR7ZB UT WOS:000343794400004 PM 25336477 ER PT J AU Cudkowicz, ME Titus, S Kearney, M Yu, H Sherman, A Schoenfeld, D Hayden, D Shui, A Brooks, B Conwit, R Felsenstein, D Greenblatt, DJ Keroack, M Kissel, JT Miller, R Rosenfeld, J Rothstein, JD Simpson, E Tolkoff-Rubin, N Zinman, L Shefner, JM AF Cudkowicz, Merit E. Titus, Sarah Kearney, Marianne Yu, Hong Sherman, Alexander Schoenfeld, David Hayden, Douglas Shui, Amy Brooks, Benjamin Conwit, Robin Felsenstein, Donna Greenblatt, David J. Keroack, Myles Kissel, John T. Miller, Robert Rosenfeld, Jeffrey Rothstein, Jeffrey D. Simpson, Ericka Tolkoff-Rubin, Nina Zinman, Lorne Shefner, Jeremy M. CA Ceftriaxone Study Investigators TI Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial SO LANCET NEUROLOGY LA English DT Article ID CEREBROSPINAL-FLUID; NERVOUS-SYSTEM; ALS; GLUTAMATE; RILUZOLE; INFECTIONS; EXPRESSION; SURVIVAL; MODELS; STROKE AB Background Glutamate excitotoxicity might contribute to the pathophysiology of amyotrophic lateral sclerosis. In animal models, decreased excitatory aminoacid transporter 2 (EAAT2) overexpression delays disease onset and prolongs survival, and ceftriaxone increases EAAT2 activity We aimed to assess the safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis in a combined phase 1, 2, and 3 clinical trial. Methods This three-stage randomised, double-blind, placebo-controlled study was done at 59 clinical sites in the USA and Canada between Sept 4, 2006, and July 30, 2012. Eligible adult patients had amyotrophic lateral sclerosis, a vital capacity of more than 60% of that predicted for age and height, and symptom duration of less than 3 years. In stages 1 (pharmacokinetics) and 2 (safety), participants were randomly allocated (2:1) to ceftriaxone (2 g or 4 g per day) or placebo. In stage 3 (efficacy), participants assigned to ceftriaxone in stage 2 received 4 g ceftriaxone, participants assigned to placebo in stage 2 received placebo, and new participants were randomly assigned (2:1) to 4 g ceftriaxone or placebo. Participants, family members, and site staff were masked to treatment assignment. Randomisation was done by a computerised randomisation sequence with permuted blocks of 3. Participants received 2 g ceftriaxone or placebo twice daily through a central venous catheter administered at home by a trained caregiver. To minimise biliary side-effects, participants assigned to ceftriaxone also received 300 mg ursodeoxycholic acid twice daily and those assigned to placebo received matched placebo capsules. The coprimary efficacy outcomes were survival and functional decline, measured as the slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00349622. Findings Stage 3 included 66 participants from stages 1 and 2 and 448 new participants. In total, 340 participants were randomly allocated to ceftriaxone and 173 to placebo. During stages 1 and 2, mean ALSFRS-R declined more slowly in participants who received 4 g ceftriaxone than in those on placebo (difference 0.51 units per month, 95% CI 0.02 to 1. 00; P=0.0416), but in stage 3 functional decline between the treatment groups did not differ (0.09, 0-06 to 024; p=0.2370). No significant differences in survival between the groups were recorded in singe 3 (HR 0.90, 95% CI 0-71 to 1-15; p=0.4146). Gastrointestinal adverse events and hepatobiliary adverse events were more common in the ceftriaxone group than in the placebo group (gastrointestinal, 245 of 340 [72%] ceftriaxone vs 97 of 173 [56%] placebo, p=0. 0004; hepatobiliary, 211 [62%] vs 19 [11%], p<0.0001). Significantly more participants who received ceftriaxone had serious hepatobiliary serious adverse events (41 participants [12%]) than did those who received placebo (0 participants). Interpretation Despite promising stage 2 data, stage 3 of this trial of ceftriaxone in amyotrophic lateral sclerosis did not show clinical efficacy. The adaptive design allowed for seamless transition from one phase to another, and central venous catheter use in the home setting was shown to be feasible. C1 [Cudkowicz, Merit E.; Titus, Sarah; Kearney, Marianne; Yu, Hong; Sherman, Alexander; Schoenfeld, David; Hayden, Douglas; Shui, Amy; Felsenstein, Donna; Tolkoff-Rubin, Nina] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Brooks, Benjamin] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Conwit, Robin] NINDS, Bethesda, MD 20892 USA. [Greenblatt, David J.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Keroack, Myles] Eliot Hlth Syst, Manchester, NH USA. [Kissel, John T.] Ohio State Univ, Columbus, OH 43210 USA. [Miller, Robert] Calif Pacific Med Ctr, San Francisco, CA USA. [Rosenfeld, Jeffrey] Univ Calif San Francisco, Fresno, CA USA. [Rothstein, Jeffrey D.] Johns Hopkins Univ, Baltimore, MD USA. [Simpson, Ericka] Methodist Hosp, Houston, TX 77030 USA. [Zinman, Lorne] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Shefner, Jeremy M.] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. RP Cudkowicz, ME (reprint author), Neurol Clin Res Inst, 165 Cambridge St,Floor 6, Boston, MA 02114 USA. EM mcudkowicz@partners.org OI Caress, James/0000-0002-5814-6083 FU National Institute of Neurological Disorders and Stroke FX National Institute of Neurological Disorders and Stroke. NR 42 TC 22 Z9 22 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 EI 1474-4465 J9 LANCET NEUROL JI Lancet Neurol. PD NOV PY 2014 VL 13 IS 11 BP 1083 EP 1091 DI 10.1016/S1474-4422(14)70222-4 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA AR7TZ UT WOS:000343783900015 PM 25297012 ER PT J AU Bilgic, B Fan, AP Polimeni, JR Cauley, SF Bianciardi, M Adalsteinsson, E Wald, LL Setsompop, K AF Bilgic, Berkin Fan, Audrey P. Polimeni, Jonathan R. Cauley, Stephen F. Bianciardi, Marta Adalsteinsson, Elfar Wald, Lawrence L. Setsompop, Kawin TI Fast Quantitative Susceptibility Mapping with L1-Regularization and Automatic Parameter Selection SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE Quantitative susceptibility mapping; Regularization; Total variation; L-curve ID ENABLED DIPOLE INVERSION; MAGNETIC-SUSCEPTIBILITY; BRAIN IRON; HIGH-FIELD; IN-VIVO; MRI; PHASE; MULTIPLE; MAP; COSMOS AB PurposeTo enable fast reconstruction of quantitative susceptibility maps with total variation penalty and automatic regularization parameter selection. Methods(1)-Regularized susceptibility mapping is accelerated by variable splitting, which allows closed-form evaluation of each iteration of the algorithm by soft thresholding and fast Fourier transforms. This fast algorithm also renders automatic regularization parameter estimation practical. A weighting mask derived from the magnitude signal can be incorporated to allow edge-aware regularization. ResultsCompared with the nonlinear conjugate gradient (CG) solver, the proposed method is 20 times faster. A complete pipeline including Laplacian phase unwrapping, background phase removal with SHARP filtering, and (1)-regularized dipole inversion at 0.6 mm isotropic resolution is completed in 1.2 min using MATLAB on a standard workstation compared with 22 min using the CG solver. This fast reconstruction allows estimation of regularization parameters with the L-curve method in 13 min, which would have taken 4 h with the CG algorithm. The proposed method also permits magnitude-weighted regularization, which prevents smoothing across edges identified on the magnitude signal. This more complicated optimization problem is solved 5 times faster than the nonlinear CG approach. Utility of the proposed method is also demonstrated in functional blood oxygen level-dependent susceptibility mapping, where processing of the massive time series dataset would otherwise be prohibitive with the CG solver. ConclusionOnline reconstruction of regularized susceptibility maps may become feasible with the proposed dipole inversion. Magn Reson Med 72:1444-1459, 2014. (c) 2013 Wiley Periodicals, Inc. C1 [Bilgic, Berkin; Fan, Audrey P.; Polimeni, Jonathan R.; Cauley, Stephen F.; Bianciardi, Marta; Adalsteinsson, Elfar; Wald, Lawrence L.; Setsompop, Kawin] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Fan, Audrey P.; Adalsteinsson, Elfar] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Polimeni, Jonathan R.; Bianciardi, Marta; Wald, Lawrence L.; Setsompop, Kawin] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Adalsteinsson, Elfar; Wald, Lawrence L.] Harvard MIT Hlth Sci & Technol, Cambridge, MA USA. RP Bilgic, B (reprint author), Bldg 75,Room 2-102,13th St, Charlestown, MA 02129 USA. EM berkin@nmr.mgh.harvard.edu RI Polimeni, Jonathan/P-1395-2014; Cauley, Stephen/P-1386-2014; Setsompop, Kawin/P-1464-2014; bilgic, berkin/P-1811-2014; Wald, Lawrence/D-4151-2009 OI Polimeni, Jonathan/0000-0002-1348-1179; Setsompop, Kawin/0000-0003-0455-7634; FU NIH [R00EB012107] FX Grant sponsor: NIH; Grant number: R00EB012107. NR 40 TC 30 Z9 30 U1 1 U2 16 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 NOV PY 2014 VL 72 IS 5 BP 1444 EP 1459 DI 10.1002/mrm.25029 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AR9ED UT WOS:000343873900026 PM 24259479 ER PT J AU Guerriero, RM Pier, DB de Gusmao, CM Bernson-Leung, ME Maski, KP Urion, DK Waugh, JL AF Guerriero, Rejean M. Pier, Danielle B. de Gusmao, Claudio M. Bernson-Leung, Miya E. Maski, Kiran P. Urion, David K. Waugh, Jeff L. TI Increased Pediatric Functional Neurological Symptom Disorders After the Boston Marathon Bombings: A Case Series SO PEDIATRIC NEUROLOGY LA English DT Article DE functional neurological disorder; somatoform disorder; conversion disorder; terrorism ID HEALTH-CARE UTILIZATION; TERRORIST ATTACKS; CONVERSION DISORDER; FOLLOW-UP; ADOLESCENTS; COMPLAINTS; DIAGNOSIS; CHILDREN; ILLNESS; TERM AB BACKGROUND: Functional neurological symptom disorders are frequently the basis for acute neurological consultation. In children, they are often precipitated by high-frequency everyday stressors. The extent to which a severe traumatic experience may also precipitate functional neurological abnormalities is unknown. METHODS: For the 2-week period after the Boston Marathon bombings, we prospectively collected data on patients whose presentation suggested a functional neurological symptom disorder. We assessed clinical and demographic variables, duration of symptoms, extent of educational impact, and degree of connection to the Marathon bombing. We contacted all patients at 6 months after presentation to determine the outcome and accuracy of the diagnosis. RESULTS: In a parallel study, we reported a baseline of 2.6 functional neurological presentations per week in our emergency room. In the week after the Marathon bombings, this frequency tripled. Ninety-one percent of presentations were delayed by 1 week, with onset around the first school day after a city-wide lockdown. Seventy-three percent had a history of a prior psychiatric diagnosis. At the 6 months follow-up, no functional neurological symptom disorder diagnoses were overturned and no new organic diagnosis was made. CONCLUSIONS: Pediatric functional neurological symptom disorder may be precipitated by both casual and high-intensity stressors. The 3.4-fold increase in incidence after the Boston Marathon bombings and city-wide lockdown demonstrates the marked effect that a community-wide tragedy can have on the mental health of children. Care providers must be aware of functional neurological symptom disorders after stressful community events in vulnerable patient populations, particularly those with prior psychiatric diagnoses. C1 [Guerriero, Rejean M.; Pier, Danielle B.; de Gusmao, Claudio M.; Bernson-Leung, Miya E.; Maski, Kiran P.; Urion, David K.; Waugh, Jeff L.] Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Waugh, Jeff L.] Massachusetts Gen Hosp, Pediat Movement Disorders Clin, Boston, MA 02114 USA. RP Waugh, JL (reprint author), Boston Childrens Hosp, Dept Neurol, 300 Longwood Ave,Fegan 11, Boston, MA 02115 USA. EM jeff.waugh@childrens.harvard.edu OI Pier, Danielle/0000-0001-8621-9131; Bernson-Leung, Miya/0000-0002-7766-2323 NR 25 TC 2 Z9 3 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 EI 1873-5150 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD NOV PY 2014 VL 51 IS 5 BP 619 EP 623 DI 10.1016/j.pediatrneurol.2014.07.011 PG 5 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA AS0GF UT WOS:000343955400006 PM 25152961 ER PT J AU Lin, LS Jung, M Mgcloud, RF Viswanath, K AF Lin, Leesa Jung, Mins Mgcloud, Rachel F. Viswanath, Kasisomayajula TI Media Use and Communication Inequalities in a Public Health Emergency: A Case Study of 2009-2010 Pandemic Influenza A Virus Subtype H1N1 SO PUBLIC HEALTH REPORTS LA English DT Article ID OF-THE-LITERATURE; NONPHARMACEUTICAL INTERVENTIONS; BEHAVIORAL-RESPONSES; TELEPHONE SURVEYS; HONG-KONG; KNOWLEDGE; TRANSMISSION; PREPAREDNESS; ASSOCIATIONS; PERCEPTIONS AB Objectives. Studies have shown that differences among individuals and social groups in accessing and using information on health and specific threats have an impact on their knowledge and behaviors. These differences, characterized as communication inequalities, may hamper the strength of a society's response to a public health emergency. Such inequalities not only make vulnerable populations subject to a disproportionate burden of adversity, but also compromise the public health system's efforts to prevent and respond to pandemic influenza outbreaks. We investigated the effect of socioeconomic status (SES) and health communication behaviors (including barriers) on people's knowledge and misconceptions about pandemic influenza A(H1N1) (pH1N1) and adoption of prevention behaviors. Methods. The data for this study came from a survey of 1,569 respondents drawn from a nationally representative sample of American adults during pH1N1. We conducted logistic regression analyses when appropriate. Results. We found that (1) SES has a significant association with barriers to information access and processing, levels of pH1N1-related knowledge, and misconceptions; (2) levels of pH1N1-related knowledge are associated positively with the adoption of recommended prevention measures and negatively with the adoption of incorrect protective behaviors; and (3) people with higher SES, higher news exposure, and higher levels of pH1N1-related knowledge, as well as those who actively seek information, are less likely than their counterparts to adopt incorrect prevention behaviors. Conclusion. Strategic public health communication efforts in public health preparedness and during emergencies should take into account potential communication inequalities and develop campaigns that reach across different social groups. C1 [Lin, Leesa; Jung, Mins; Mgcloud, Rachel F.; Viswanath, Kasisomayajula] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA USA. [Lin, Leesa; Mgcloud, Rachel F.; Viswanath, Kasisomayajula] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Lin, Leesa] Harvard Univ, Sch Publ Hlth, Div Policy Translat & Leadership Dev, Boston, MA 02115 USA. [Jung, Mins] Dongduk Womens Univ, Dept Hlth Sci, Seoul, South Korea. RP Lin, LS (reprint author), Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, 677 Huntington Ave,Landmark Ctr,3rd Fl E, Boston, MA 02115 USA. EM llin@hsph.harvard.edu FU Centers for Disease Control and Prevention (CDC) [5PO1TP000307-05] FX Institutional Review Board approval was obtained from the Harvard School of Public Health. The authors acknowledge funding support from the Centers for Disease Control and Prevention (CDC) grant #5PO1TP000307-05. The content of this publication as well as the views expressed in this article are solely those of the authors and do not necessarily represent the views of CDC. NR 55 TC 5 Z9 5 U1 0 U2 8 PU ASSOC SCHOOLS PUBLIC HEALTH PI WASHINGTON PA 1900 M ST NW, STE 710, WASHINGTON, DC 20036 USA SN 0033-3549 J9 PUBLIC HEALTH REP JI Public Health Rep. PD NOV-DEC PY 2014 VL 129 SU 4 BP 49 EP 60 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AS3XD UT WOS:000344207600008 PM 25355975 ER PT J AU Wander, PL Fahrenbruch, CE Rea, TD AF Wander, P. L. Fahrenbruch, C. E. Rea, T. D. TI The dispatcher assisted resuscitation trial: Indirect benefits of emergency research SO RESUSCITATION LA English DT Article DE Cardiac arrest; Waiver of consent; Ethics; Hawthorne effect; Epidemiology ID HOSPITAL CARDIAC-ARREST; ASSOCIATION; SURVIVAL AB Objective: Conduct of emergency research under waiver of consent produces special challenges. Moreover, the act of performing research may have unintended effects, potentially beneficial or detrimental. The Dispatcher-Assisted Randomized Trial (DART) was designed to compare 2 types of dispatcher cardiopulmonary (CPR) instruction, but not intended to affect the proportion of arrest victims that received bystander CPR. We sought to determine whether odds of receiving bystander CPR were higher during DART than during the periods before and after. Methods: We conducted an observational cohort study of 8626 adults who suffered non-traumatic out-of-hospital cardiac arrest prior to emergency medical services (EMS) arrival in greater King County, Washington, between January 1, 1999, and December 31, 2011. Bystander CPR status was assessed through review of dispatch recordings and EMS reports to classify any bystander CPR (any B-CPR), and further categorized as bystander CPR with or without dispatcher assistance (DA-CPR and B-CPR, no DA). We used multivariable logistic regression to evaluate odds of B-CPR before, during, and after DART. Results: The proportions receiving any B- CPR were 52% before DART (1817/3468), 59% during DART (2093/3527), and 54% after DART (885/1631). Compared to the period before DART, odds of receiving any B- CPR were higher during DART (OR = 1.35, 95% CI = 1.23-1.49), but no different after (OR = 1.10, 0.98-1.24). Compared to the before period, odds of DA-CPR were higher during DART (OR = 1.79, 1.59-2.02) but no different after (OR = 0.94, 0.80-1.10). Conclusions: Odds of bystander CPR were higher during the trial, an increase related to higher likelihood of DA-CPR. The finding suggests a possible indirect community-wide benefit due to the interventional trial. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Wander, P. L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Wander, P. L.; Rea, T. D.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Fahrenbruch, C. E.; Rea, T. D.] Publ Hlth Seattle & King Cty, Emergency Med Serv Div, Seattle, WA USA. [Wander, P. L.] VA Puget Sound Hlth Care Syst, Hosp & Specialty Med Serv, Seattle, WA 98108 USA. RP Wander, PL (reprint author), Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. EM lwander@u.washington.edu OI Wander, Pandora/0000-0003-3671-1464 FU NHLBI NIH HHS [T32 HL007902] NR 16 TC 1 Z9 1 U1 2 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-9572 J9 RESUSCITATION JI Resuscitation PD NOV PY 2014 VL 85 IS 11 BP 1594 EP 1598 DI 10.1016/j.resuscitation.2014.08.026 PG 5 WC Critical Care Medicine; Emergency Medicine SC General & Internal Medicine; Emergency Medicine GA AR8LQ UT WOS:000343827100035 PM 25195982 ER PT J AU Lee-Huang, S Huang, PL Huang, PL AF Lee-Huang, Sylvia Huang, Philip Lin Huang, Paul Lee TI Live-Cell Real-Time Imaging of Mitochondria in HIV-1-Infected Cells SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Editorial Material C1 [Lee-Huang, Sylvia; Huang, Philip Lin] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA. [Huang, Paul Lee] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Huang, Paul Lee] Harvard Univ, Sch Med, Boston, MA USA. RP Lee-Huang, S (reprint author), NYU, Sch Med, Dept Biochem & Mol Pharmacol, 550 1st St, New York, NY 10016 USA. EM sylvia.leehuang@nyumc.org OI Lee-Huang, Sylvia/0000-0003-3302-241X FU NIAID NIH HHS [R01 AI031343] NR 4 TC 1 Z9 1 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 EI 1931-8405 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD NOV 1 PY 2014 VL 30 IS 11 BP 1025 EP 1026 DI 10.1089/aid.2014.0161 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA AR7OY UT WOS:000343770300003 PM 25275699 ER PT J AU Torriani, M Gill, CM Daley, S Oliveira, AL Azevedo, DC Bredella, MA AF Torriani, Martin Gill, Corey M. Daley, Scott Oliveira, Adriana L. Azevedo, Debora C. Bredella, Miriam A. TI Compartmental neck fat accumulation and its relation to cardiovascular risk and metabolic syndrome SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID SUBCUTANEOUS ADIPOSE-TISSUE; CARDIOMETABOLIC RISK; ABDOMINAL OBESITY; CIRCUMFERENCE; ASSOCIATION; ADULTS; MEN AB Background: Neck circumference is a predictor of cardiovascular disease (CVD) risk. However, detailed assessment of neck fat has not been explored, and the contribution from individual neck fat compartments to CVD risk is unknown. Objective: The objective was to measure neck adipose tissue (NAT) compartments and examine relations with CVD risk markers, with the hypothesis that neck adipose tissue (NAT) accumulation preferentially involves specific compartments that contribute differently to metabolic risk. Design: We retrospectively studied 303 subjects with successfully treated malignancies or benign etiologies [151 women, 152 men; mean (+/- SD) age: 55 +/- 17 y; mean body mass index (BMI; in kg/m(2)): 28 +/- 6] who underwent whole-body positron emission tomography/computed tomography. NAT was measured at the level of the C5 vertebral body, subdivided into posterior (NATpost), subcutaneous (NATsc), and perivertebral (NATperivert) compartments. Data on CVD risk factors (BMI, abdominal circumference, visceral and abdominal subcutaneous adipose tissue, blood pressure, serum lipids, and fasting plasma glucose) were collected. We compared NAT compartments across lean, overweight, and obese groups and performed multivariate regression models correlating NAT with CVD risk factors. Receiver operating characteristic curve and prevalence ratio analyses were performed to examine the association of NAT compartments with metabolic syndrome. Results: NATpost and NATsc were more consistently associated with cardiometabolic risk, especially in women, correlating with visceral adipose tissue (P < 0.0001) and triglycerides (P < 0.001) and a nearly 1.5-fold increase in the prevalence ratio for metabolic syndrome after adjustment for age and BMI (P < 0.05). NATsc was most abundant in women, whereas intermuscular compartments (NATpost and NATperivert) were higher in men. In both sexes, NATpost and NATperivert showed the largest increment between lean and obese subjects. Conclusions: Neck fat compartments expand differently with increasing adiposity, correlate with CVD risk factors, and are associated with metabolic syndrome, most notably NATpost and NATsc in women. Although neck circumference remains an important method to assess metabolic risk, cross-sectional NAT assessment provides further insight into fat accumulation in the neck. C1 [Torriani, Martin] Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Torriani, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,YAW 6048, Boston, MA 02114 USA. EM mtorriani@mgh.harvard.edu FU NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Pilot and Feasibility Grant, Nutrition and Obesity Research Center at Harvard [P30DK040561] FX Supported in part by NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) P30DK040561 Pilot and Feasibility Grant, Nutrition and Obesity Research Center at Harvard. NR 23 TC 7 Z9 7 U1 0 U2 5 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD NOV PY 2014 VL 100 IS 5 BP 1244 EP 1251 DI 10.3945/ajcn.114.088450 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AR3ZT UT WOS:000343528500005 PM 25332322 ER PT J AU Crocker, JB Lee-Lewandrowski, E Lewandrowski, N Baron, J Gregory, K Lewandrowski, K AF Crocker, J. Benjamin Lee-Lewandrowski, Elizabeth Lewandrowski, Nicole Baron, Jason Gregory, Kimberly Lewandrowski, Kent TI Implementation of Point-of-Care Testing in an Ambulatory Practice of an Academic Medical Center SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Point-of-care testing; Practice efficiency; Cost-effectiveness; Primary care; Hemoglobin A,c; Lipid panel; Comprehensive metabolic panel ID EMERGENCY-DEPARTMENT; CENTER IMPACT; STAY AB Objectives: Point-of-care laboratory testing (POCT) offers reduced turnaround time and may promote improved operational efficiency. Few studies have been reported that document improvements from implementing POCT in primary care. Methods: We measured metrics of practice efficiency in a primary care practice before and after implementation of POCT, including the total number of tests ordered, letters and phone calls to patients, and revisits due to abnormal test results. We performed a cost and revenue analysis. Results: Following implementation of POCT, there was a 21% decrease in tests ordered per patient (P <.0001); a decrease in follow-up phone calls and letters by 89% and 85%, respectively (i) <.0001 and P <.0001); and a 61% decrease in patient revisits (13 =.0002). Estimated testing revenues exceeded expenses by $6.62 per patient, and potential cost savings from improved efficiency were $24.64 per patient. Conclusions: POCT can significantly improve clinical operations with cost reductions through improved practice efficiency. C1 [Crocker, J. Benjamin; Lewandrowski, Nicole] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lee-Lewandrowski, Elizabeth; Baron, Jason; Gregory, Kimberly; Lewandrowski, Kent] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Crocker, J. Benjamin; Lee-Lewandrowski, Elizabeth; Baron, Jason; Lewandrowski, Kent] Harvard Univ, Sch Med, Boston, MA USA. RP Lewandrowski, K (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Gray 5 Chem, Boston, MA 02114 USA. EM klewandrowski@partners.org FU Siemens Point-of-Care; Abaxis FX This study was funded or supported in part by Siemens Point-of-Care and Abaxis. The authors have no other conflicts of interest to declare. All authors had access to the study data and participated in the design and implementation of the study and contributed to the preparation of the manuscript. Siemens and Abaxis had no role in the design of the study or in its implementation and had no role in developing the manuscript. NR 14 TC 8 Z9 8 U1 0 U2 1 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD NOV PY 2014 VL 142 IS 5 BP 640 EP 646 DI 10.1309/AJCPYK1KV2KBCDDL PG 7 WC Pathology SC Pathology GA AR6IJ UT WOS:000343687100011 PM 25319979 ER PT J AU Pace, M Koury, K Gulur, P AF Pace, Meredith Koury, Katharine Gulur, Padma TI Epidurals in Patients Receiving Thromboprophylaxis with Unfractionated Heparin Three Times a Day: The Value of Activated Partial Thromboplastin Time Testing SO ANESTHESIA AND ANALGESIA LA English DT Article ID NEURAXIAL ANESTHESIA; REGIONAL-ANESTHESIA; ANALGESIA; SOCIETY AB BACKGROUND: Dosing subcutaneous (SC) unfractionated heparin (UFH) 3 times a day (TID) for deep venous thrombosis prophylaxis is used for patients in the United States undergoing nonorthopedic surgery. There is a lack of data on the risks of neuraxial techniques in patients receiving TID SC UFH; however, concerns have been raised about higher bleeding risks. In this prospective study, we evaluated the value of activated partial thromboplastin time (aPTT) testing at the time of removal of epidural catheters as a risk-reduction strategy for this population. METHODS: We collected data from our electronic hospital databases for all patients receiving epidural analgesia in conjunction with 5000 units TID or twice daily dosing (BID) SC UFH from December 2011 to December 2013. Our cohort received aPTT testing before removal of the catheter in all patients receiving TID SC UFH. An aPTT was ordered for patients receiving BID SC UFH only if risk factors for abnormal coagulation variables were identified. Chart reviews were performed on all patients with abnormal aPTT values to evaluate contributing risk factors. RESULTS: Over a 2-year period, 3523 epidurals were placed at our institution, including 714 (20.3%) for patients receiving TID SC UFH, and 1594 (45.2%) for patients receiving BID SC UFH. Of those patients receiving BID SC UFH, 186 (11.7%) had aPTT values drawn on the basis of risk factors. Ten (5.4 %, 95% CI: 2.6%-9.7%) of those patients had an aPTT value of greater than 35 seconds on the date of epidural removal. Of those patients receiving TID SC UFH, 20(2.8%, 95% Cl: 1.7%-4.3%) had an initial aPTT value of more than 35 seconds on the date of epidural removal. All patients who had abnormal aPTT values on TID heparin dosing were identified as having obvious concomitant risk factors for coagulation parameter abnormalities. There were no epidural hematomas in patients receiving either BID or TID dosing (95% CI: 0%-0.001%). CONCLUSIONS: The routine use of aPTT testing on patients receiving TID SC UFH at the time of removal of epidural catheters as a risk-reduction strategy is not supported by our results, where only 2.8% (95% Cl: 1.7%-4.3%) of these patients had abnormal aPTT values. Our study adds to the limited data currently available on the safety of epidural analgesia in patients receiving TID SC UFH. Given the rare incidence of neuraxial hematoma (95% CI: 0%-0.001%), definitive conclusions on the risks of TID SC UFH administration in patients receiving epidural analgesia cannot be drawn based on our sample size. C1 [Pace, Meredith; Koury, Katharine; Gulur, Padma] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Gulur, P (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 15 Parkman St,WACC 340, Boston, MA 02114 USA. EM pgulur@partners.org NR 13 TC 3 Z9 3 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 EI 1526-7598 J9 ANESTH ANALG JI Anesth. Analg. PD NOV PY 2014 VL 119 IS 5 BP 1215 EP 1218 DI 10.1213/ANE.0000000000000437 PG 4 WC Anesthesiology SC Anesthesiology GA AR5OK UT WOS:000343633500031 PM 25225890 ER PT J AU Quiroga, MJ Carroll, DW Brown, TM AF Quiroga, Martha J. Carroll, David W. Brown, Thomas M. TI Ascorbate- and Zinc-Responsive Parkinsonism SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE vitamins; psychiatry; Parkinson disease; nutrition; central nervous system ID CENTRAL-NERVOUS-SYSTEM; VITAMIN-C; MATRIX METALLOPROTEINASES; HEMODIALYSIS-PATIENTS; DISEASE; SCURVY; ACID; DEFICIENCY; EXCRETION; REQUIREMENTS AB Objective: To report a case of Parkinsonisnn rapidly responsive to intravenous replacement of vitamin C and zinc. Case Summary: A 66-year-old man with Parkinsonisnn, pleural effusion, and bipolar disorder was found to have low serum vitamin C and zinc levels. Intravenous replacement of these micronutrients led to resolution of the movement disorder in less than 24 hours. Discussion: Parkinsonism has been associated with vitamin C deficiency, and recent cases of scurvy complicated by Parkinsonisnn have responded well to intravenous replacement of vitamin C. In this case, deficiency of zinc may have contributed to the development of a movement disorder. The likely pathophysiology of, and treatment recommendations for, Parkinsonism linked to deficiencies of vitamin C and zinc are reviewed. Conclusions: Whereas vitamin C has a strong link with Parkinsonism, the potential role of zinc has only been suspected. This case report highlights some of the potential links between zinc deficiency and Parkinsonism. C1 [Quiroga, Martha J.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX USA. [Carroll, David W.; Brown, Thomas M.] Audie L Murphy Mem Vet Adm Med Ctr, San Antonio, TX 78229 USA. RP Brown, TM (reprint author), Audie L Murphy Mem Vet Adm Med Ctr, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM thomas.brown5@va.gov NR 43 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1060-0280 EI 1542-6270 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD NOV PY 2014 VL 48 IS 11 BP 1515 EP 1520 DI 10.1177/1060028014545356 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AR1PE UT WOS:000343356300015 PM 25070397 ER PT J AU Baker, JF Ostergaard, M George, M Shults, J Emery, P Baker, DG Conaghan, PG AF Baker, Joshua F. Ostergaard, Mikkel George, Michael Shults, Justine Emery, Paul Baker, Daniel G. Conaghan, Philip G. TI Greater body mass independently predicts less radiographic progression on X-ray and MRI over 1-2 years SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID ACTIVE RHEUMATOID-ARTHRITIS; NECROSIS-FACTOR-ALPHA; METHOTREXATE THERAPY; DISEASE-ACTIVITY; JOINT DAMAGE; GO-FORWARD; DOUBLE-BLIND; PHASE-III; GOLIMUMAB; ASSOCIATION AB Introduction Greater body mass index (BMI) has been associated with less radiographic progression in rheumatoid arthritis (RA). We evaluated the association between BMI and joint damage progression as measured by X-ray and MRI. Methods 1068 subjects with RA from two clinical trials of golimumab (GO-BEFORE and GO-FORWARD) had radiographs performed at weeks 0, 52 and 104 and evaluated using the van der Heijde-Sharp (vdHS) scoring system. Contrast-enhanced MRIs of the dominant wrist and hand were obtained at weeks 0, 12, 24, 52 and 104. Multivariable logistic regression evaluated the risk of radiographic progression for each BMI category (<25, 25-30, >30 kg/m(2)). Within GO-BEFORE, piecewise, robust generalised estimating equations marginal models assessed the probability of MRI erosion progression for each BMI category. Multivariable linear regression models assessed baseline associations between BMI and bone oedema (a precursor of bone erosion). Results Higher BMI category was associated with a lower probability of progression in vdHS score at weeks 52 and 104 independent of potential confounders. Higher BMI was also independently associated with a lower probability of progression in MRI erosion score over 2 years. Subjects with greater BMI demonstrated less bone oedema independent of differences in other disease severity measures, including MRI synovitis in the same joints. Conclusions Greater BMI is associated with a lower risk of progression on X-ray and MRI over 2 years. Subjects with greater BMI also demonstrate less bone oedema at baseline. Greater BMI may indicate a less aggressive RA phenotype and aid in risk stratification. C1 [Baker, Joshua F.] Philadelphia Vet Affairs Med Ctr, Div Rheumatol, Philadelphia, PA USA. [Baker, Joshua F.; George, Michael] Univ Penn, Sch Med, Div Rheumatol, Philadelphia, PA 19104 USA. [Baker, Joshua F.; Shults, Justine] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Ostergaard, Mikkel] Glostrup Cty Hosp, Copenhagen Ctr Arthrit Res, Ctr Rheumatol & Spine Dis, Copenhagen, Denmark. [Ostergaard, Mikkel] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark. [Emery, Paul; Conaghan, Philip G.] Univ Leeds, Leeds Inst Rheumat & Musculoskeletal Med, Leeds, W Yorkshire, England. [Emery, Paul; Conaghan, Philip G.] Chapel Allerton Hosp, NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds, W Yorkshire, England. [Baker, Daniel G.] Janssen Res & Dev LLC, Spring House, PA USA. RP Baker, JF (reprint author), Hosp Univ Penn, Div Rheumatol, Dept Med, 8 Penn Tower Bldg,34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM bakerjo@uphs.upenn.edu FU Veterans Affairs Clinical Science Research and Development Career Development Award; Arthritis Research UK FX JFB is supported by a Veterans Affairs Clinical Science Research and Development Career Development Award. PGC is funded in part by a grant from Arthritis Research UK. This ancillary study did not receive additional funding. NR 23 TC 22 Z9 22 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD NOV PY 2014 VL 73 IS 11 BP 1923 EP 1928 DI 10.1136/annrheumdis-2014-205544 PG 6 WC Rheumatology SC Rheumatology GA AR0ZR UT WOS:000343308200012 PM 25091439 ER PT J AU Baddley, JW Winthrop, KL Chen, L Liu, LY Grijalva, CG Delzell, E Beukelman, T Patkar, NM Xie, FL Saag, KG Herrinton, LJ Solomon, DH Lewis, JD Curtis, JR AF Baddley, John W. Winthrop, Kevin L. Chen, Lang Liu, Liyan Grijalva, Carlos G. Delzell, Elizabeth Beukelman, Timothy Patkar, Nivedita M. Xie, Fenglong Saag, Kenneth G. Herrinton, Lisa J. Solomon, Daniel H. Lewis, James D. Curtis, Jeffrey R. TI Non-viral opportunistic infections in new users of tumour necrosis factor inhibitor therapy: results of the SAfety Assessment of Biologic ThERapy (SABER) Study SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID SERIOUS BACTERIAL-INFECTIONS; FACTOR-ALPHA ANTAGONISTS; RHEUMATOID-ARTHRITIS; GRANULOMATOUS INFECTIONS; PNEUMOCYSTIS PNEUMONIA; MYCOBACTERIAL DISEASES; ANTIBODY THERAPY; BRITISH-SOCIETY; RISK-FACTORS; INFLIXIMAB AB Objectives To determine among patients with autoimmune diseases in the USA whether the risk of non-viral opportunistic infections (OI) was increased among new users of tumour necrosis factor a inhibitors (TNFI), when compared to users of non-biological agents used for active disease. Methods We identified new users of TNFI among cohorts of rheumatoid arthritis (RA), inflammatory bowel disease and psoriasis-psoriatic arthritis-ankylosing spondylitis patients during 1998-2007 using combined data from Kaiser Permanente Northern California, two pharmaceutical assistance programmes for the elderly, Tennessee Medicaid and US Medicaid/Medicare programmes. We compared incidence of non-viral OI among new TNFI users and patients initiating nonbiological disease-modifying antirheumatic drugs (DMARD) overall and within each disease cohort. Cox regression models were used to compare propensity-score and steroid-adjusted OI incidence between new TNFI and non-biological DMARD users. Results Within a cohort of 33 324 new TNFI users we identified 80 non-viral OI, the most common of which was pneumocystosis (n=16). In the combined cohort, crude rates of non-viral OI among new users of TNFI compared to those initiating non-biological DMARD was 2.7 versus 1.7 per 1000-person-years (aHR 1.6, 95% CI 1.0 to 2.6). Baseline corticosteroid use was associated with non-viral OI (aHR 2.5, 95% CI 1.5 to 4.0). In the RA cohort, rates of non-viral OI among new users of infliximab were higher when compared to patients newly starting non-biological DMARD (aHR 2.6, 95% CI 1.2 to 5.6) or new etanercept users (aHR 2.9, 95% CI 1.5 to 5.4). Conclusions In the USA, the rate of non-viral OI was higher among new users of TNFI with autoimmune diseases compared to non-biological DMARD users. C1 [Baddley, John W.; Chen, Lang; Delzell, Elizabeth; Beukelman, Timothy; Patkar, Nivedita M.; Xie, Fenglong; Saag, Kenneth G.; Curtis, Jeffrey R.] Univ Alabama Birmingham, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. [Baddley, John W.] Birmingham VA Med Ctr, Med Serv, Birmingham, AL USA. [Winthrop, Kevin L.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Liu, Liyan; Herrinton, Lisa J.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Grijalva, Carlos G.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Solomon, Daniel H.] Harvard Univ, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Lewis, James D.] Univ Penn, Perlman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Baddley, JW (reprint author), Univ Alabama Birmingham, Dept Med, Div Infect Dis, 1900 Univ Blvd,229 Tinsley Harrison Tower, Birmingham, AL 35294 USA. EM jbaddley@uab.edu FU US Food and Drug Administration (FDA); US Department of Health and Human Services (DHHS); Agency for Healthcare Research and Quality [U18 HS17919]; Agency for Healthcare Research and Quality (AHRQ) [1K08HS017552-01]; National Institutes of Health [AR053351]; AHRQ [R01HS018517]; NIH via the University of Alabama at Birmingham Center for Clinical and Translational Science [5KL2 RR025776-03]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [5P60AR56116] FX This work was supported by the US Food and Drug Administration (FDA), US Department of Health and Human Services (DHHS) and the Agency for Healthcare Research and Quality, grant U18 HS17919. KLW's work on this manuscript was funded by an Agency for Healthcare Research and Quality (AHRQ) grant (1K08HS017552-01). JRC receives support from the National Institutes of Health (AR053351) and AHRQ (R01HS018517). TB was supported by NIH grant 5KL2 RR025776-03 via the University of Alabama at Birmingham Center for Clinical and Translational Science. CGG received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, grant 5P60AR56116. The authors are indebted to the Tennessee Bureau of TennCare of the Department of Finance and Administration, which provided the Tennessee Medicare data. NR 34 TC 24 Z9 24 U1 2 U2 8 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 EI 1468-2060 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD NOV PY 2014 VL 73 IS 11 BP 1942 EP 1948 DI 10.1136/annrheumdis-2013-203407 PG 7 WC Rheumatology SC Rheumatology GA AR0ZR UT WOS:000343308200015 PM 23852763 ER PT J AU Reisner, SL Biello, K Rosenberger, JG Austin, SB Haneuse, S Perez-Brumer, A Novak, DS Mimiaga, MJ AF Reisner, Sari L. Biello, Katie Rosenberger, Joshua G. Austin, S. Bryn Haneuse, Sebastien Perez-Brumer, Amaya Novak, David S. Mimiaga, Matthew J. TI Using a Two-Step Method to Measure Transgender Identity in Latin America/the Caribbean, Portugal, and Spain SO ARCHIVES OF SEXUAL BEHAVIOR LA English DT Article DE Transgender; Gender identity; HIV; Health; Surveillance ID SEXUALLY-TRANSMITTED INFECTIONS; BASE-LINE DATA; RISK BEHAVIORS; HIV-INFECTION; MENTAL-HEALTH; NONTRANSGENDER MEN; GENDER; SEX; DEPRESSION; VULNERABILITY AB Few comparative data are available internationally to examine health differences by transgender identity. A barrier to monitoring the health and well-being of transgender people is the lack of inclusion of measures to assess natal sex/gender identity status in surveys. Data were from a cross-sectional anonymous online survey of members (n > 36,000) of a sexual networking website targeting men who have sex with men in Spanish-and Portuguese-speaking countries/territories in Latin America/the Caribbean, Portugal, and Spain. Natal sex/gender identity status was assessed using a two-step method (Step 1: assigned birth sex, Step 2: current gender identity). Male-to-female (MTF) and female-to-male (FTM) participants were compared to non-transgender males in age-adjusted regression models on socioeconomic status (SES) (education, income, sex work), masculine gender conformity, psychological health and well-being (lifetime suicidality, past-week depressive distress, positive self-worth, general self-rated health, gender related stressors), and sexual health (HIV-infection, past-year STIs, past-3 month unprotected anal orvaginal sex). The two-step method identified 190 transgender participants (0.54 %; 158 MTF, 32 FTM). Of the 12 health-related variables, six showed significant differences between the three groups: SES, masculine gender conformity, lifetime suicidality, depressive distress, positive self-worth, and past-year genital herpes. A two-step approach is recommended for health surveillance efforts to assess natal sex/gender identity status. Cognitive testing to formally validate assigned birth sex and current gender identity survey items in Spanish and Portuguese is encouraged. C1 [Reisner, Sari L.; Austin, S. Bryn; Perez-Brumer, Amaya] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Reisner, Sari L.; Biello, Katie; Perez-Brumer, Amaya; Mimiaga, Matthew J.] Fenway Inst Fenway Hlth, Boston, MA USA. [Biello, Katie; Mimiaga, Matthew J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Rosenberger, Joshua G.] George Mason Univ, Dept Global & Community Hlth, Fairfax, VA 22030 USA. [Austin, S. Bryn] Childrens Hosp, Div Adolescent & Young Adult Med, Boston, MA 02115 USA. [Austin, S. Bryn] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Haneuse, Sebastien] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Novak, David S.] Online Buddies Inc, OLB Res Inst, Cambridge, MA USA. [Mimiaga, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. RP Reisner, SL (reprint author), Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, 677 Huntington Ave,Kresge 7th Floor, Boston, MA 02115 USA. EM sreisner@hsph.harvard.edu OI Perez-Brumer, Amaya/0000-0003-2441-4358 FU NIMH NIH HHS [R25 MH083620, R01 MH094323]; PHS HHS [6T71-MC00009, MC00001] NR 58 TC 15 Z9 17 U1 2 U2 10 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0004-0002 EI 1573-2800 J9 ARCH SEX BEHAV JI Arch. Sex. Behav. PD NOV PY 2014 VL 43 IS 8 BP 1503 EP 1514 DI 10.1007/s10508-014-0314-2 PG 12 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA AR9PW UT WOS:000343907900004 PM 25030120 ER PT J AU Kemmerly, T Kaunitz, JD AF Kemmerly, Thomas Kaunitz, Jonathan D. TI Gastroduodenal mucosal defense SO CURRENT OPINION IN GASTROENTEROLOGY LA English DT Review DE autophagy; gastrointestinal defense; innate immune system; mucins; toll-like receptors ID OXIDATIVE STRESS; EPITHELIAL-CELLS; DENDRITIC CELLS; EXPRESSION; ACID; MICE; HOMEOSTASIS; DYSFUNCTION; INFECTION; P38-ALPHA AB Purpose of review To review recent developments in the field of gastroduodenal mucosal defense. Recent findings Research in the field of gastroduodenal mucosal defense has focused on continued elucidation of molecular mechanisms that protect the mucosa and influence healing at the cellular level. Review of literature over the past year reveals that familiar proteins and mediators, such as nitric oxide, toll-like receptors, nucleotide-binding oligomerization domain-containing proteins (NOD2), beta-defensins, macrophages, dendritic cells, mucins, autophagy, and the influence of aging and diet, are still subjects of study, but also brings into light new processes and mediators, such as dual oxidases, defense against radiation injuries, and novel proteins such as ZBP-89. Summary These new published findings contribute to our overall understanding of gastroduodenal defense and suggest innovative avenues of future research and possible novel therapeutic targets. C1 [Kemmerly, Thomas] Cedars Sinai Med Residency Program, Los Angeles, CA USA. [Kaunitz, Jonathan D.] Greater Los Angeles Vet Affairs Healthcare Syst, WLAVA Med Ctr, Los Angeles, CA USA. [Kaunitz, Jonathan D.] UCLA Sch Med, Dept Med, Los Angeles, CA USA. [Kaunitz, Jonathan D.] UCLA Sch Med, Dept Surg, Los Angeles, CA USA. [Kaunitz, Jonathan D.] CURE Digest Dis Res Ctr, Dept Med, Los Angeles, CA USA. [Kaunitz, Jonathan D.] Brentwood Biomed Res Inst, Los Angeles, CA USA. RP Kaunitz, JD (reprint author), West Los Angeles VAMC, Bldg 114,Room 217E, Los Angeles, CA 90073 USA. EM jake@ucla.edu FU NIH/NIDDK; DVA; Boehringer-Ingelheim Pharmaceuticals GmbH FX Grant Support: NIH/NIDDK, DVA, and Boehringer-Ingelheim Pharmaceuticals GmbH. NR 33 TC 3 Z9 3 U1 0 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0267-1379 EI 1531-7056 J9 CURR OPIN GASTROEN JI Curr. Opin. Gastroenterol. PD NOV PY 2014 VL 30 IS 6 BP 583 EP 588 DI 10.1097/MOG.0000000000000124 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AR5NZ UT WOS:000343632400010 PM 25229259 ER PT J AU Hall, JF Bordeianou, L Hyman, N Read, T Bartus, C Schoetz, D Marcello, PW AF Hall, Jason F. Bordeianou, Liliana Hyman, Neil Read, Thomas Bartus, Christine Schoetz, David Marcello, Peter W. TI Outcomes After Operations for Anal Fistula: Results of a Prospective, Multicenter, Regional Study SO DISEASES OF THE COLON & RECTUM LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-of-Colon-and-Rectal-Surgeons CY MAY 17-21, 2014 CL Hollywood, FL SP Amer Soc Colon & Rectal Surg DE Advancement flap; Anal; Fistula; Fistulotomy; LIFT; Seton ID ADVANCEMENT FLAP; IN-ANO; MANAGEMENT; SURGERY AB BACKGROUND: There are various surgical techniques used treat anal fistulas. The adoption and success rates of newer techniques have not been clearly established. OBJECTIVE: The purpose of this study was to determine the healing rate after operations for anal fistulas in New England colorectal surgery practices. DESIGN: We conducted a retrospective review of a prospectively collected database. SETTINGS: The study was conducted at colorectal surgery practices in New England. PATIENTS: A prospective, multicenter registry was created by the New England Society of Colon and Rectal Surgeons. Surgeons were invited to collect data prospectively regarding patients operated on for anal fistulas between January 1, 2011, and August 1, 2013. Fistula classification, surgical intervention, continence scores, and healing were determined by the treating surgeon. INTERVENTION: Operation for anal fistula was performed. MAIN OUTCOME MEASURES: We measured the proportion of patients with healed fistulas at 3 months. RESULTS: Sixteen surgeons submitted data regarding 240 operations for fistula with curative intent. Mean patient age was 45 +/- 14 years. A total of 158 patients (66%) were men, and 110 (46%) had undergone an anorectal operation. Twenty-nine (12%) had Crohn's disease. The healing rates of fistulotomy, advancement flap, and fistula plugs at 3 months were 94% (95% CI, 89-97), 60% (95% CI, 33-77), and 20% (95% CI, 5-50). The healing rate of the ligation of intersphincteric fistula tract procedure at 3 months was 79% (95% CI, 65-88). Hospital site was the only variable associated with healing (p < 0.05). Hospitals that performed more ligation of intersphincteric fistula tract procedures had higher healing rates at 3 months (p < 0.0001). LIMITATIONS: This study was limited by selection bias and reporting bias. CONCLUSIONS: A wide variety of techniques are used to treat anal fistulas in our region. Fistulotomy continues to have excellent results. There has been enthusiastic early adoption of the ligation of intersphincteric fistula tract technique. Early healing rates after the ligation of intersphincteric fistula tract procedure appear to be excellent. C1 [Hall, Jason F.; Read, Thomas; Schoetz, David; Marcello, Peter W.] Lahey Hosp & Med Ctr, Dept Colon & Rectal Surg, Burlington, MA 01805 USA. [Bordeianou, Liliana] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Hyman, Neil] Univ Vermont, Dept Surg, Coll Med, Burlington, VT 05405 USA. [Bartus, Christine] Hartford Healthcare Med Grp, Dept Surg, Farmington, CT USA. RP Hall, JF (reprint author), Lahey Hosp & Med Ctr, Dept Colon & Rectal Surg, Burlington, MA 01805 USA. EM Jason.F.Hall@Lahey.org NR 11 TC 3 Z9 3 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0012-3706 EI 1530-0358 J9 DIS COLON RECTUM JI Dis. Colon Rectum PD NOV PY 2014 VL 57 IS 11 BP 1304 EP 1308 DI 10.1097/DCR.0000000000000216 PG 5 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA AR6CI UT WOS:000343670100009 PM 25285698 ER PT J AU Villasana, LE Westbrook, GL Schnell, E AF Villasana, L. E. Westbrook, G. L. Schnell, E. TI Neurologic impairment following closed head injury predicts post-traumatic neurogenesis SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Closed head injury; Traumatic brain injury; Adult neurogenesis; Hippocampus; Neurologic severity score ID TRAUMATIC BRAIN-INJURY; ADULT HIPPOCAMPAL NEUROGENESIS; GLASGOW COMA SCALE; DENTATE GYRUS; GRANULE CELLS; NEURONAL DIFFERENTIATION; ABERRANT NEUROGENESIS; COGNITIVE RECOVERY; RATS; PROLIFERATION AB In the mammalian hippocampus, neurogenesis persists into adulthood, and increased generation of newborn neurons could be of clinical benefit following concussive head injuries. Post-traumatic neurogenesis has been well documented using "open" traumatic brain injury (TBI) models in rodents: however, human TBI most commonly involves closed head injury. Here we used a closed head injury (CHI) model to examine post-traumatic hippocampal neurogenesis in mice. All mice were subjected to the same CHI protocol, and a gross-motor based injury severity score was used to characterize neurologic impairment 1 h after the injury. When analyzed 2 weeks later, post-traumatic neurogenesis was significantly increased only in mice with a high degree of transient neurologic impairment immediately after injury. This increase was associated with an early increase in c-fos activity, and subsequent reactive astrocytosis and microglial activation in the dentate gyrus. Our results demonstrate that the initial degree of neurologic impairment after closed head injury predicts the induction of secondary physiologic and pathophysiologic processes, and that animals with severe neurologic impairment early after injury manifest an increase in post-traumatic neurogenesis in the absence of gross anatomic pathology. Published by Elsevier Inc. C1 [Villasana, L. E.; Schnell, E.] OHSU, Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. [Westbrook, G. L.] OHSU, Vollum Inst, Portland, OR 97239 USA. [Schnell, E.] Portland VA Med Ctr, Portland, OR 97239 USA. RP Schnell, E (reprint author), Portland VA Med Ctr, 3710 SW US Vet Hosp Rd,P3ANES, Portland, OR 97239 USA. EM schneler@ohsu.edu FU Department of Veteran's Affairs Career Development Award (CDA-2); National Institute of General Medical Sciences [T32-GM082770]; National Institute of Mental Health [R01-MH046613]; National Institutes of Health for the OHSU Imaging Center [P30-NS061800] FX We would like to thank Nee lay Pandit for constructing the closed-head weight drop device and for assistance generating pilot data for this study, and to Dr. Stefanie Kaech-Petrie for assistance with imaging. Funding for the present work was provided by a Department of Veteran's Affairs Career Development Award (CDA-2) to Dr. Schnell, a National Institute of General Medical Sciences T32-GM082770 to Dr. Villasana, a National Institute of Mental Health R01-MH046613 to Dr. Westbrook, and a National Institutes of Health P30-NS061800 for the OHSU Imaging Center. NR 50 TC 2 Z9 2 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 EI 1090-2430 J9 EXP NEUROL JI Exp. Neurol. PD NOV PY 2014 VL 261 BP 156 EP 162 DI 10.1016/j.expneurol.2014.05.016 PG 7 WC Neurosciences SC Neurosciences & Neurology GA AR4AX UT WOS:000343531500016 PM 24861442 ER PT J AU Lee, JH Fisher, DE AF Lee, Ju Hee Fisher, David E. TI Melanocyte stem cells as potential therapeutics in skin disorders SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE graying hair; melanocyte; melanocyte stem cell; pigmentation; vitiligo ID OUTER-ROOT-SHEATH; HUMAN HAIR-FOLLICLES; NEURAL CREST; TRANSCRIPTION FACTOR; STABLE VITILIGO; BCL-2-DEFICIENT MICE; CELLULAR-ORIGIN; DOMINANT ROLE; KIT-LIGAND; IN-VITRO AB Introduction: Melanocytes produce pigment granules that color both skin and hair. In the hair follicles melanocytes are derived from stem cells (MelSCs) that are present in hair bulges or sub-bulge regions and function as melanocyte reservoirs. Quiescence, maintenance, activation and proliferation of MelSCs are controlled by specific activities in the microenvironment that can influence the differentiation and regeneration of melanocytes. Therefore, understanding MelSCs and their niche may lead to use of MelSCs in new treatments for various pigmentation disorders. Areas covered: We describe here pathophysiological mechanisms by which melanocyte defects lead to skin pigmentation disorders such as vitiligo and hair graying. The development, migration and proliferation of melanocytes and factors involved in the survival, maintenance and regeneration of MelSCs are reviewed with regard to the biological roles and potential therapeutic applications in skin pigmentation diseases. Expert opinion: MelSC biology and niche factors have been studied mainly in murine experimental models. Human MelSC markers or methods to isolate them are much less well understood. Identification, isolation and culturing of human MelSCs would represent a major step toward new biological therapeutic options for patients with recalcitrant pigmentary disorders or hair graying. By modulating the niche factors for MelSCs, it may one day be possible to control skin pigmentary disorders and prevent or reverse hair graying. C1 [Lee, Ju Hee; Fisher, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02129 USA. [Lee, Ju Hee; Fisher, David E.] Cutaneous Biol Res Ctr, Boston, MA 02129 USA. [Lee, Ju Hee] Yonsei Univ, Coll Med, Dept Dermatol, Seoul 120752, South Korea. [Lee, Ju Hee] Cutaneous Biol Res Inst, Seoul 120752, South Korea. RP Fisher, DE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02129 USA. EM dfisher3@partners.org FU NIH; Dr Miriam and Sheldon G. Adelson Medical Research Foundation; Melanoma Research Alliance FX This work was supported by research grants from the NIH, the Dr Miriam and Sheldon G. Adelson Medical Research Foundation, and The Melanoma Research Alliance. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. NR 114 TC 2 Z9 2 U1 8 U2 21 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 EI 1744-7682 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD NOV PY 2014 VL 14 IS 11 BP 1569 EP 1579 DI 10.1517/14712598.2014.935331 PG 11 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA AR6US UT WOS:000343719200004 PM 25104310 ER PT J AU Vaduganathan, M Greene, SJ Ambrosy, AP Gheorghiade, M AF Vaduganathan, Muthiah Greene, Stephen J. Ambrosy, Andrew P. Gheorghiade, Mihai TI Lipids, statins, and clinical outcomes in heart failure: rethinking the data SO HEART FAILURE REVIEWS LA English DT Article DE Statins; Lipids; Heart failure; Outcomes ID LEFT-VENTRICULAR DYSFUNCTION; C-REACTIVE PROTEIN; ROSUVASTATIN MULTINATIONAL TRIAL; REDUCED EJECTION FRACTION; ACUTE CORONARY SYNDROMES; SERUM TOTAL CHOLESTEROL; EVEREST TRIAL; THERAPY; MORTALITY; EVENTS AB Lower serum lipid levels are paradoxically predictive of poor clinical outcomes in hospitalized and ambulatory patients with heart failure (HF). In large randomized controlled trials, statins did not demonstrate an overall mortality benefit in chronic HF patients. We currently lack adequate prospective data that aggressive lipid management in HF truly alters disease course and progression. Despite their traditional use as lipid-lowering agents, hypothesis-generating works have suggested that statins may show benefit in specific enriched HF subgroups. Given that patients hospitalized for HF continue to face a high post-discharge event rate and that statins are increasingly inexpensive, widely available, and generally well tolerated, it is imperative that we identify those HF patients most likely to benefit and reconsider testing these agents in specific subpopulations. C1 [Vaduganathan, Muthiah] Harvard Univ, Massachusetts Gen Hosp, Dept Med, Sch Med, Boston, MA 02114 USA. [Greene, Stephen J.; Gheorghiade, Mihai] Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. [Ambrosy, Andrew P.] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. RP Greene, SJ (reprint author), Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. EM mvaduganathan@partners.org; stephen-greene@md.northwestern.edu NR 38 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1382-4147 EI 1573-7322 J9 HEART FAIL REV JI Heart Fail. Rev. PD NOV PY 2014 VL 19 IS 6 BP 695 EP 698 DI 10.1007/s10741-014-9423-1 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AR6XA UT WOS:000343723000001 PM 24509934 ER PT J AU Zamani, P Jacobs, DR Segers, P Duprez, DA Brumback, L Kronmal, RA Lilly, SM Townsend, RR Budoff, M Lima, JA Hannan, P Chirinos, JA AF Zamani, Payman Jacobs, David R., Jr. Segers, Patrick Duprez, Daniel A. Brumback, Lyndia Kronmal, Richard A. Lilly, Scott M. Townsend, Raymond R. Budoff, Matthew Lima, Joao A. Hannan, Peter Chirinos, Julio A. TI Reflection Magnitude as a Predictor of Mortality The Multi-Ethnic Study of Atherosclerosis SO HYPERTENSION LA English DT Article DE arteries; atherosclerosis; mortality ID INCIDENT CARDIOVASCULAR EVENTS; LEFT-VENTRICULAR MASS; ANKLE-BRACHIAL INDEX; PRESSURE WAVE-FORM; ARTERIAL STIFFNESS; LOADING SEQUENCE; SYSTOLIC PRESSURE; RELAXATION; MESA; DISEASE AB Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [P-b] to that of the forward wave [P-f]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8 +/- 1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11-1.55; P=0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01-1.51; P=0.04), including the coronary calcium score, ankle-brachial index, common carotid intima-media thickness, and ascending thoracic aortic Agatston score. P-b was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in P-b =2.18; 95% CI=1.21-3.92; P=0.009). Reflection magnitude (HR=1.71; 95% CI=1.06-2.77; P=0.03) and P-b (HR=5.02; 95% CI=1.29-19.42; P=0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis. C1 [Zamani, Payman; Chirinos, Julio A.] Hosp Univ Penn, Div Cardiovasc Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Zamani, Payman; Chirinos, Julio A.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Jacobs, David R., Jr.; Hannan, Peter] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Duprez, Daniel A.] Univ Minnesota, Sch Med, Div Cardiol, Minneapolis, MN 55455 USA. [Segers, Patrick] Univ Ghent, IBiTech, iMinds Future Hlth Dept, B-9000 Ghent, Belgium. [Brumback, Lyndia; Kronmal, Richard A.] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA. [Lilly, Scott M.] Ohio State Univ, Div Cardiovasc Med, Heart & Vasc Ctr, Columbus, OH 43210 USA. [Townsend, Raymond R.] Univ Penn, Div Nephrol Hypertens, Perelman Sch Med, Philadelphia, PA 19104 USA. [Budoff, Matthew] Los Angeles Biomed Res Inst, Torrance, CA USA. [Lima, Joao A.] Johns Hopkins Univ Hosp, Div Cardiol, Baltimore, MD 21287 USA. RP Zamani, P (reprint author), Hosp Univ Penn, Div Cardiovasc Med, 3400 Spruce St,8 Gates, Philadelphia, PA 19104 USA. EM pzamani@upenn.edu RI Lilly, Scott/K-3620-2013 OI Lilly, Scott/0000-0002-2597-6806 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95169]; National Institutes of Aging grant [1R21AG0411802-01]; Institute for Translational Medicine and Therapeutics of the University of Pennsylvania from the National Center for Research Resources [UL1RR024134]; [RR-024156]; [5-T32-HL007843-17] FX This research as supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute and RR-024156, as well as National Institutes of Aging grant 1R21AG0411802-01 (J.A.C.). Dr Zamani is supported, in part, by the Institute for Translational Medicine and Therapeutics of the University of Pennsylvania (grant number UL1RR024134 from the National Center for Research Resources) and by 5-T32-HL007843-17. NR 30 TC 17 Z9 17 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD NOV PY 2014 VL 64 IS 5 BP 958 EP + DI 10.1161/HYPERTENSIONAHA.114.03855 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AR4ZB UT WOS:000343593700013 PM 25259746 ER PT J AU Zoccali, C Curatola, G Panuccio, V Tripepi, R Pizzini, P Versace, M Bolignano, D Cutrupi, S Politi, R Tripepi, G Ghiadoni, L Thadhani, R Mallamaci, F AF Zoccali, Carmine Curatola, Giuseppe Panuccio, Vincenzo Tripepi, Rocco Pizzini, Patrizia Versace, Marica Bolignano, Davide Cutrupi, Sebastiano Politi, Raffaele Tripepi, Giovanni Ghiadoni, Lorenzo Thadhani, Ravi Mallamaci, Francesca TI Paricalcitol and Endothelial Function in Chronic Kidney Disease Trial SO HYPERTENSION LA English DT Article DE atherosclerosis; chronic kidney disease; endothelium; hypertension; paricalcitol; vitamin D ID STAGE RENAL-DISEASE; VITAMIN-D-RECEPTOR; RANDOMIZED CONTROLLED-TRIAL; DIASTOLIC DYSFUNCTION; OXIDATIVE STRESS; REDUCTION; MORTALITY; FAILURE; HYPERTENSION; ALBUMINURIA AB Altered vitamin D metabolism and low levels of the active form of this vitamin, 1,25-dihydroxy-vitamin D, is a hallmark of chronic kidney disease (CKD), but there is still no randomized controlled trial testing the effect of active forms of vitamin D on vascular function in patients with CKD. Paricalcitol and ENdothelial fuNction in chronic kidneY disease (PENNY) is a double-blinded randomized controlled trial (ClinicalTrials.gov, NCT01680198) testing the effect of an active form of vitamin D, paricalcitol (2 mu g/dx12 weeks) on endothelium-dependent and endothelium-independent vasodilatation in 88 patients with stage 3 to 4 CKD and parathormone >65 pg/mL (paricalcitol, n=44; placebo, n=44). Paricalcitol treatment reduced parathormone (-75 pg/mL; 95% confidence interval, -90 to -60), whereas parathormone showed a small rise during placebo (21 pg/mL; 95% confidence interval, 5-36). Blood pressure did not change in both study arms. Baseline flow-mediated dilation was identical in patients on paricalcitol (3.6 +/- 2.9%) and placebo (3.6 +/- 2.9%) groups. After 12 weeks of treatment, flow-mediated dilation rose in the paricalcitol but not in the placebo group, and the betweengroup difference in flow-mediated dilation changes (the primary end point, 1.8%; 95% confidence interval, 0.3-3.1%) was significant (P=0.016), and the mean proportional change in flow-mediated dilation was 61% higher in paricalcitol-treated patients than in placebo-treated patients. Such an effect was abolished 2 weeks after stopping the treatment. No effect of paricalcitol on endothelium-independent vasodilatation was registered. Paricalcitol improves endothelium-dependent vasodilatation in patients with stage 3 to 4 CKD. Findings in this study support the hypothesis that vitamin D may exert favorable effects on the cardiovascular system in patients with CKD. C1 [Zoccali, Carmine; Panuccio, Vincenzo; Mallamaci, Francesca] Osped Riuniti Reggio Calabria, Nephrol Hypertens & Renal Transplantat Unit, I-89124 Reggio Di Calabria, Italy. [Zoccali, Carmine; Curatola, Giuseppe; Panuccio, Vincenzo; Tripepi, Rocco; Pizzini, Patrizia; Versace, Marica; Bolignano, Davide; Cutrupi, Sebastiano; Politi, Raffaele; Tripepi, Giovanni; Mallamaci, Francesca] CNR IBIM IFC Clin Epidemiol & Pathophysiol Renal, Reggio Di Calabria, Italy. [Ghiadoni, Lorenzo] Univ Pisa, Dept Clin & Expt Med, Pisa, Italy. [Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. RP Zoccali, C (reprint author), Osped Riuniti Reggio Calabria, CNR IBIM IFC Clin Epidemiol & Pathophysiol Renal, VIA Vallone Petrara 55-57, I-89124 Reggio Di Calabria, Italy. EM carmine.zoccali@tin.it OI Bolignano, Davide/0000-0003-3032-245X; Ghiadoni, Lorenzo/0000-0002-7399-2720 FU Abbott SRL FX This study was supported by a grant of Abbott SRL. The study was designed by the first author (C. Zoccali) and approved by the funding company (Abbot). The sponsor did not participate in data collection and in the statistical analysis and writing of the article. The first author made the final decision to submit for publication. The sponsor had an opportunity to review the article, but all decisions about the final manuscript we,re, made by the study investigators. All authors vouch for the, integrity of the data. NR 35 TC 24 Z9 25 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD NOV PY 2014 VL 64 IS 5 BP 1005 EP + DI 10.1161/HYPERTENSIONAHA.114.03748 PG 10 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AR4ZB UT WOS:000343593700018 PM 25259743 ER PT J AU Chirinos, JA Rietzschel, ER Shiva-Kumar, P De Buyzere, ML Zamani, P Claessens, T Geraci, S Konda, P De Bacquer, D Akers, SR Gillebert, TC Segers, P AF Chirinos, Julio A. Rietzschel, Ernst R. Shiva-Kumar, Prithvi De Buyzere, Marc L. Zamani, Payman Claessens, Tom Geraci, Salvatore Konda, Prasad De Bacquer, Dirk Akers, Scott R. Gillebert, Thierry C. Segers, Patrick TI Effective Arterial Elastance Is Insensitive to Pulsatile Arterial Load SO HYPERTENSION LA English DT Article DE arterial load; characteristic impedance; effective arterial elastance; total arterial compliance; ventricular-arterial coupling; wave reflections ID PRESERVED EJECTION FRACTION; VARYING MYOCARDIAL STRESS; LEFT-VENTRICULAR MASS; PULSE-WAVE VELOCITY; HEART-FAILURE; SYSTOLIC PRESSURE; NONINVASIVE EVALUATION; DIASTOLIC FUNCTION; CONVERTING-ENZYME; AORTIC STIFFNESS AB Effective arterial elastance (E-A) was proposed as a lumped parameter that incorporates pulsatile and resistive afterload and is increasingly being used in clinical studies. Theoretical modeling studies suggest that E-A is minimally affected by pulsatile load, but little human data are available. We assessed the relationship between E-A and arterial load determined noninvasively from central pressure-flow analyses among middle-aged adults in the general population (n=2367) and a diverse clinical population of older adults (n=193). In a separate study, we investigated the sensitivity of E-A to changes in pulsatile load induced by isometric exercise (n=73). The combination of systemic vascular resistance and heart rate predicted 95.6% and 97.8% of the variability in E-A among middle-aged and older adults, respectively. E-A demonstrated a quasi-perfect linear relationship with the ratio of systemic vascular resistance/heart period (middle-aged adults, R=0.972; older adults, R=0.99; P<0.0001). Aortic characteristic impedance, total arterial compliance, reflection magnitude, and timing accounted together for <1% of the variability in E-A in either middle-aged or older adults. Despite pronounced changes in pulsatile load induced by isometric exercise, changes in E-A were not independently associated with changes pulsatile load but were rather a nearly perfect linear function of the ratio of systemic vascular resistance/heart period (R=0.99; P<0.0001). Our findings demonstrate that E-A is simply a function of systemic vascular resistance and heart rate and is negligibly influenced by (and insensitive to) changes in pulsatile afterload in humans. Its current interpretation as a lumped parameter of pulsatile and resistive afterload should thus be reassessed. C1 [Chirinos, Julio A.; Zamani, Payman] Perelman Sch Med, Dept Med, Philadelphia, PA USA. [Chirinos, Julio A.; Zamani, Payman] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Chirinos, Julio A.; Shiva-Kumar, Prithvi; Geraci, Salvatore; Akers, Scott R.] Philadelphia VA Med Ctr, Dept Med, Philadelphia, PA USA. [Rietzschel, Ernst R.; De Buyzere, Marc L.; De Bacquer, Dirk] Ghent Univ Hosp, Dept Cardiovasc Dis, Ghent, Belgium. [Rietzschel, Ernst R.] Univ Ghent, Dept Publ Hlth, B-9000 Ghent, Belgium. [Claessens, Tom] Univ Ghent, Dept Ind Technol & Construct, B-9000 Ghent, Belgium. [Claessens, Tom; Segers, Patrick] Univ Ghent, Inst Biomed Technol, iMinds Future Hlth Dept, B-9000 Ghent, Belgium. RP Chirinos, JA (reprint author), Univ Penn, Philadelphia VA Med Ctr, Dept Med, 3800 Woodland Ave,Rm 8B111, Philadelphia, PA 19104 USA. EM Julio.chirinos@uphs.upenn.edu OI Gillebert, Thierry/0000-0002-3832-919X FU Fonds voor Wetenschappelijk Onderzoek Viaanderen research grants [G.0427.03, FWO G.0838.10]; [1R21AG043802-01] FX This research was funded by Fonds voor Wetenschappelijk Onderzoek Viaanderen research grants G.0427.03 and FWO G.0838.10 (for the Asklepios Study) and 1R21AG043802-01 (J.A. Chirinos) NR 47 TC 9 Z9 10 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0194-911X EI 1524-4563 J9 HYPERTENSION JI Hypertension PD NOV PY 2014 VL 64 IS 5 BP 1022 EP + DI 10.1161/HYPERTENSIONAHA.114.03696 PG 18 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AR4ZB UT WOS:000343593700020 PM 25069668 ER PT J AU Baltajian, K Hecht, JL Wenger, JB Salahuddin, S Verlohren, S Perschel, FH Zsengeller, ZK Thadhani, R Karumanchi, SA Rana, S AF Baltajian, Kedak Hecht, Jonathan L. Wenger, Julia B. Salahuddin, Saira Verlohren, Stefan Perschel, Frank H. Zsengeller, Zsuzsanna K. Thadhani, Ravi Karumanchi, S. Ananth Rana, Sarosh TI Placental lesions of vascular insufficiency are associated with anti-angiogenic state in women with preeclampsia SO HYPERTENSION IN PREGNANCY LA English DT Article DE Angiogenic factors; Placenta; Placental lesions ID MATERNAL PLASMA; SUSPECTED PREECLAMPSIA; SFLT-1/PLGF RATIO; GROWTH-FACTOR; HYPERTENSION; CIRCULATION; PREGNANCIES; CONTRIBUTE; DIAGNOSIS; ECLAMPSIA AB Objective: To evaluate if placental histopathological changes of vascular insufficiency correlate with circulating angiogenic factors in patients with preeclampsia. Materials and methods: Subjects were selected from a previous prospective cohort study of preeclampsia based on the availability of plasma anti-angiogenic factor (sFlt1) and pro-angiogenic factor (PlGF) measurements and placental histology specimens. Preeclamptic patients were divided into two groups based on plasma levels of these factors described as a ratio: anti-angiogenic preeclampsia with sFlt1/PlGF ratio >= 85 and normal angiogenic preeclampsia with sFlt1/PlGF585. The placental lesions of vascular insufficiency that were studied specifically included atherosis, infarcts, syncytial knots, acute and chronic abruption, hematoma, and fetal thrombosis. The data are shown as median (quartile 1 and quartile 3) or n (%) when appropriate. Results: The anti-angiogenic preeclampsia group (N=48) presented at an earlier gestational age (weeks) than the normal angiogenic group (N=28); {32 (28, 34) versus 35 (32, 36), p=0.002}, had higher systolic blood pressure (mmHg) {154 (147, 168) versus 147 (132, 158), p=0.02}, delivered early (weeks) {(32 (29, 34) versus 36 (34, 37), p<0.001} and had lower birth weight (grams) {(1550 (1055, 2060) versus 2655 (2285, 3343), p<0.001}. Several pathologic lesions were found significantly more often in the anti-angiogenic preeclampsia group; atherosis {27.7% versus 3.6%, p<0.05}, infarcts {58.3% versus 3.6%, p=0.002}, and syncytial knots {81.3% versus 39.3%, p<0.001}. Conclusion: Preeclamptic patients with imbalance in circulating angiogenic factors have disproportionally higher rates of placental vascular lesions historically associated with severe disease. C1 [Baltajian, Kedak; Salahuddin, Saira; Karumanchi, S. Ananth; Rana, Sarosh] Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Div Maternal Fetal Med, Boston, MA 02215 USA. [Hecht, Jonathan L.; Zsengeller, Zsuzsanna K.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Hecht, Jonathan L.; Wenger, Julia B.; Zsengeller, Zsuzsanna K.; Thadhani, Ravi; Karumanchi, S. Ananth] Harvard Univ, Sch Med, Boston, MA USA. [Wenger, Julia B.; Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Verlohren, Stefan] Charite, Campus Virchow Clin, Dept Obstet, D-13353 Berlin, Germany. [Perschel, Frank H.] Charite, Dept Lab Med Clin Chem & Pathobiochem, D-13353 Berlin, Germany. [Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA. [Karumanchi, S. Ananth] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Rana, S (reprint author), Beth Israel Deaconess Med Ctr, 330 Brookline Ave,Kirstein 382, Boston, MA 02215 USA. EM srana1@bidmc.harvard.edu OI Verlohren, Stefan/0000-0003-3507-8636 FU NIH KO8 award FX All other authors report no conflict. R. T. and S. A. K have financial interest in Aggamin LLC. S. R. is supported by NIH KO8 award and S. A. K is an investigator of the Howard Hughes Medical Institute. NR 35 TC 7 Z9 7 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1064-1955 EI 1525-6065 J9 HYPERTENS PREGNANCY JI Hypertens. Pregnancy PD NOV PY 2014 VL 33 IS 4 BP 427 EP 439 DI 10.3109/10641955.2014.926914 PG 13 WC Obstetrics & Gynecology; Physiology; Peripheral Vascular Disease SC Obstetrics & Gynecology; Physiology; Cardiovascular System & Cardiology GA AR6DX UT WOS:000343674700006 PM 25062083 ER PT J AU Jin, JO Zhang, W Du, JY Yu, Q AF Jin, Jun-O Zhang, Wei Du, Jiang-yuan Yu, Qing TI BDCA1-Positive Dendritic Cells (DCs) Represent a Unique Human Myeloid DC Subset That Induces Innate and Adaptive Immune Responses to Staphylococcus aureus Infection SO INFECTION AND IMMUNITY LA English DT Article ID ANTIGEN CROSS-PRESENTATION; BLOOD-STREAM INFECTION; METHICILLIN-RESISTANT; MEDIATED PHAGOCYTOSIS; ESCHERICHIA-COLI; IN-VIVO; BACTEREMIA; RECEPTORS; RECOGNITION; ENDOCARDITIS AB Staphylococcus aureus bloodstream infection (bacteremia) is a major cause of morbidity and mortality and places substantial cost burdens on health care systems. The role of peripheral blood dendritic cells (PBDCs) in the immune responses against S. aureus infection has not been well characterized. In this study, we demonstrated that BDCA1(+) myeloid DCs (mDCs) represent a unique PBDC subset that can induce immune responses against S. aureus infection. BDCA1(+) mDCs could engulf S. aureus and strongly upregulated the expression of costimulatory molecules and production of proinflammatory cytokines. Furthermore, BDCA1(+) mDCs expressed high levels of major histocompatibility complex (MHC) class I and II molecules in response to S. aureus and greatly promoted proliferation and gamma interferon (IFN-gamma) production in CD4 and CD8 T cells. Moreover, BDCA1(+) mDCs expressed higher levels of Toll-like receptor 2 (TLR-2) and scavenger receptor A (SR-A) than those on CD16(+) and BDCA3(+) mDCs, and these two receptors were both required for the recognition of S. aureus and the subsequent activation of BDCA1(+) mDCs. Finally, BDCA1(+) mDC-mediated immune responses against S. aureus were dependent on MyD88 signaling pathways. These results demonstrate that human BDCA1(+) mDCs represent a unique subset of mDCs that can respond to S. aureus to undergo maturation and activation and to induce Th1 and Tc1 immune responses. C1 [Jin, Jun-O; Zhang, Wei; Du, Jiang-yuan; Yu, Qing] Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, Shanghai 200433, Peoples R China. [Yu, Qing] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. RP Jin, JO (reprint author), Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, Shanghai 200433, Peoples R China. EM Junojin1@gmail.com FU NIDCR NIH HHS [R01 DE023838] NR 48 TC 8 Z9 9 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD NOV PY 2014 VL 82 IS 11 BP 4466 EP 4476 DI 10.1128/IAI.01851-14 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AR4UQ UT WOS:000343582900004 PM 25114114 ER PT J AU Pope, HG Kanayama, G Hudson, JI DeLuca, J Isaacs, S Baggish, A Weiner, R Bhasin, S AF Pope, Harrison G. Kanayama, Gen Hudson, James I. DeLuca, James Isaacs, Stephanie Baggish, Aaron Weiner, Rory Bhasin, Shalender TI Prolonged impairment of sexual function associated with anabolic-androgenic steroid abuse: An underrecognized problem SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Meeting Abstract CT 17th World Congress of Psychophysiology of the International-Organization-of-Psychophysiology (IOP) CY SEP 23-27, 2014 CL Hiroshima, JAPAN SP Int Org Psychophysiol C1 [Pope, Harrison G.; Kanayama, Gen; Hudson, James I.; Baggish, Aaron; Weiner, Rory; Bhasin, Shalender] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [DeLuca, James; Isaacs, Stephanie] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 EI 1872-7697 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD NOV PY 2014 VL 94 IS 2 BP 237 EP 237 DI 10.1016/j.ijpsycho.2014.08.918 PG 1 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA AR2AJ UT WOS:000343385400335 ER PT J AU Parker-Autry, CY Gleason, JL Griffin, RL Markland, AD Richter, HE AF Parker-Autry, Candace Y. Gleason, Jonathan L. Griffin, Russell L. Markland, Alayne D. Richter, Holly E. TI Vitamin D deficiency is associated with increased fecal incontinence symptoms SO INTERNATIONAL UROGYNECOLOGY JOURNAL LA English DT Article DE Vitamin D; Pelvic floor; Fecal incontinence ID RANDOMIZED CONTROLLED-TRIAL; PELVIC FLOOR DISORDERS; CALCIUM SUPPLEMENTATION; MUSCLE-TISSUE; HEALTH; WOMEN; PREVALENCE; RECEPTOR; OUTCOMES; ADULTS AB Introduction and hypothesis Vitamin D is an important micronutrient in muscle function. We hypothesize that vitamin D deficiency may contribute to fecal incontinence (FI) symptoms by affecting the anal continence mechanism. Our goal was to characterize the association of vitamin D deficiency as a variable affecting FI symptoms and its impact on health-related quality of life (HR-QoL). Methods This case-control study assessed women seen at a tertiary-care referral center. Participants were identified as having had a serum vitamin D level obtained within a year of their visit: cases were women presenting for care for FI symptoms; controls were women without any pelvic floor symptoms presenting to the same clinical site for general gynecologic care. Cases completed the Modified Manchester Health Questionnaire (MMHQ) and the Fecal Incontinence Severity Index to measure symptom severity and burden on QoL. Results Among the 31 cases and 81 controls, no demographic or medical differences existed. Women with FI had lower vitamin D levels (mean 29.2 +/- 12.3 cases vs. 35 +/- 14.1 ng/ml controls p=0.04). The odds of vitamin D deficiency were higher in women with FI compared with controls [odds ratio (OR) 2.77, 95 % confidence interval (CI) 1.08-7.09]. Among cases, women with vitamin D deficiency (35 %) had higher MMHQ scores, indicating greater FI symptom burden [51.3 +/- 29.3 (vitamin D deficient) vs. 30 +/- 19.5 (vitamin D sufficiency), p=0.02]. No differences were noted for FI severity, p=0.07. Conclusions Vitamin D deficiency is prevalent in women with fecal incontinence and may contribute to patient symptom burden. C1 [Parker-Autry, Candace Y.] Wake Forest Univ, Bowman Gray Sch Med, Dept Obstet & Gynecol, Winston Salem, NC 27103 USA. [Gleason, Jonathan L.] Caril Clin, Div Female Pelv Med & Reconstruct Surg, Dept Obstet & Gynecol, Roanoke, VA USA. [Griffin, Russell L.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Markland, Alayne D.] Univ Alabama Birmingham, Dept Vet Affairs, Div Gerontol Geriatr & Palliat Care, Birmingham VA Med Ctr,Dept Med, Birmingham, AL USA. [Richter, Holly E.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Div Urogynecol & Pelv Reconstruct Surg, Birmingham, AL 35294 USA. RP Parker-Autry, CY (reprint author), 4th Floor Watlington Hall,Med Ctr Blvd, Winston Salem, NC 27157 USA. EM cparkera@wakehealth.edu OI Markland, Alayne/0000-0002-6567-6744 FU National Center for Advancing Translational Research of the National Institutes of Health [UL1TR00165]; National Institute of Diabetes and Digestive and Kidney Diseases [2K24-DK068389] FX Research reported in this publication was supported by the National Center for Advancing Translational Research of the National Institutes of Health under award number UL1TR00165 and by National Institute of Diabetes and Digestive and Kidney Diseases 2K24-DK068389 to Holly E. Richter, PhD, MD. NR 26 TC 1 Z9 1 U1 1 U2 5 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-3462 EI 1433-3023 J9 INT UROGYNECOL J JI Int. Urogynecol. J. PD NOV PY 2014 VL 25 IS 11 BP 1483 EP 1489 DI 10.1007/s00192-014-2389-7 PG 7 WC Obstetrics & Gynecology; Urology & Nephrology SC Obstetrics & Gynecology; Urology & Nephrology GA AR5XQ UT WOS:000343655000006 PM 24807423 ER PT J AU Hutchinson, CV Walker, JA Davidson, C AF Hutchinson, Claire V. Walker, James A. Davidson, Colin TI Oestrogen, ocular function and low-level vision: a review SO JOURNAL OF ENDOCRINOLOGY LA English DT Review DE oestrogen; menopause; eye; vision ID HORMONE-REPLACEMENT THERAPY; OPEN-ANGLE GLAUCOMA; WAVELENGTH-SENSITIVE CONES; BREAST-CANCER SURVIVORS; INTRAOCULAR-PRESSURE; BLOOD-FLOW; POSTMENOPAUSAL WOMEN; RECEPTOR-BETA; MACULAR DEGENERATION; DRY EYE AB Over the past 10 years, a literature has emerged concerning the sex steroid hormone oestrogen and its role in human vision. Herein, we review evidence that oestrogen (oestradiol) levels may significantly affect ocular function and low-level vision, particularly in older females. In doing so, we have examined a number of vision-related disorders including dry eye, cataract, increased intraocular pressure, glaucoma, age-related macular degeneration and Leber's hereditary optic neuropathy. In each case, we have found oestrogen, or lack thereof, to have a role. We have also included discussion of how oestrogen-related pharmacological treatments for menopause and breast cancer can impact the pathology of the eye and a number of psychophysical aspects of vision. Finally, we have reviewed oestrogen's pharmacology and suggest potential mechanisms underlying its beneficial effects, with particular emphasis on anti-apoptotic and vascular effects. C1 [Hutchinson, Claire V.] Univ Leicester, Coll Med Biol Sci & Psychol, Leicester LE1 9HN, Leics, England. [Walker, James A.] Harvard Univ, Sch Med, Ctr Human Genet Res, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Davidson, Colin] Univ London, St Georges Med Sch, Div Biomed Sci, London SW17 0RE, England. RP Hutchinson, CV (reprint author), Univ Leicester, Coll Med Biol Sci & Psychol, Leicester LE1 9HN, Leics, England. EM ch190@le.ac.uk OI Davidson, Colin/0000-0002-8180-7943 NR 99 TC 2 Z9 2 U1 0 U2 17 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 EI 1479-6805 J9 J ENDOCRINOL JI J. Endocrinol. PD NOV PY 2014 VL 223 IS 2 BP R9 EP R18 DI 10.1530/JOE-14-0349 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AR5YT UT WOS:000343659000001 PM 25143633 ER PT J AU Flannery, AM Mazzola, CA Klimo, P Duhaime, AC Baird, LC Tamber, MS Limerick, DD Nikas, DC Kemp, J Post, AF Auguste, KI Choudhri, AF Mitchell, LS Buffa, D AF Flannery, Ann Marie Mazzola, Catherine A. Klimo, Paul, Jr. Duhaime, Ann-Christine Baird, Lissa C. Tamber, Mandeep S. Limerick, David D., Jr. Nikas, Dimitrios C. Kemp, Joanna Post, Alexander F. Auguste, Kurtis I. Choudhri, Asim F. Mitchell, Laura S. Buffa, Debby TI Pediatric hydrocephalus: systematic literature review and evidence-based guidelines Foreword SO JOURNAL OF NEUROSURGERY-PEDIATRICS LA English DT Editorial Material C1 [Flannery, Ann Marie; Kemp, Joanna] St Louis Univ, Dept Neurol Surg, St Louis, MO 63103 USA. [Mazzola, Catherine A.] Goryeb Childrens Hosp, Div Pediat Neurol Surg, Morristown, NJ USA. [Klimo, Paul, Jr.; Choudhri, Asim F.] Univ Tennessee, Ctr Hlth Sci, Dept Neurosurg, Memphis, TN 38163 USA. [Klimo, Paul, Jr.] Le Bonheur Childrens Hosp, Memphis, TN USA. [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Dept Pediat Neurosurg, Boston, MA 02114 USA. [Baird, Lissa C.] Oregon Hlth & Sci Univ, Dept Neurol Surg, Portland, OR 97201 USA. [Tamber, Mandeep S.] Univ Pittsburgh, Childrens Hosp Pittsburgh, Dept Pediat Neurol Surg, Pittsburgh, PA 15213 USA. [Limerick, David D., Jr.] Washington Univ, Sch Med, Dept Neurol Surg, Div Pediat Neurosurg, St Louis, MO USA. [Nikas, Dimitrios C.] Univ Illinois, Dept Neurosurg, Chicago, IL USA. [Nikas, Dimitrios C.] Advocate Childrens Hosp, Oak Lawn, IL USA. [Post, Alexander F.] Goryeb Childrens Hosp, Morristown Med Ctr, Dept Neurosci & Pediat, Div Pediat Neurol Surg, Morristown, NJ USA. [Auguste, Kurtis I.] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA. [Choudhri, Asim F.] Univ Tennessee, Ctr Hlth Sci, Dept Radiol, Memphis, TN 38163 USA. [Choudhri, Asim F.] Univ Tennessee, Ctr Hlth Sci, Dept Ophthalmol, Memphis, TN 38163 USA. [Choudhri, Asim F.] Le Bonheur Childrens Hosp, Le Bonheur Neurosci Inst, Memphis, TN USA. [Mitchell, Laura S.] Congress Neurol Surg, Guidelines Dept, Schaumburg, IL USA. [Buffa, Debby] Hydrocephalus Assoc, Bethesda, MD USA. RP Flannery, AM (reprint author), St Louis Univ, Dept Neurol Surg, St Louis, MO 63103 USA. NR 1 TC 0 Z9 0 U1 1 U2 2 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1933-0707 EI 1933-0715 J9 J NEUROSURG-PEDIATR JI J. Neurosurg.-Pediatr. PD NOV PY 2014 VL 14 SU S BP 1 EP 2 DI 10.3171/2014.8.PEDS14426 PG 2 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA AR4AT UT WOS:000343531100001 PM 25988776 ER PT J AU Flannery, AM Duhaime, AC Tamber, MS Kemp, J AF Flannery, Ann Marie Duhaime, Ann-Christine Tamber, Mandeep S. Kemp, Joanna TI Pediatric hydrocephalus: systematic literature review and evidence-based guidelines. Part 3: Endoscopic computer-assisted electromagnetic navigation and ultrasonography as technical adjuvants for shunt placement SO JOURNAL OF NEUROSURGERY-PEDIATRICS LA English DT Review DE cerebrospinal fluid shunt; hydrocephalus; ultrasonography; ventricular catheter; ventricular shunt; computer-assisted navigation; image-guided navigation; electromagnetic guidance; endoscopy; practice guidelines ID SLIT-VENTRICLE SYNDROME; VENTRICULOPERITONEAL SHUNT; CLINICAL ARTICLE; CHILDREN; CATHETERS; NEURONAVIGATION; MULTICENTER; INSERTION; FAILURE; RATES AB Object. This systematic review was undertaken to answer the following question: Do technical adjuvants such as ventricular endoscopic placement, computer-assisted electromagnetic guidance, or ultrasound guidance improve ventricular shunt function and survival? Methods. The US National Library of Medicine PubMed/MEDLINE database and the Cochrane Database of Systematic Reviews were queried using MeSH headings and key words specifically chosen to identify published articles detailing the use of cerebrospinal fluid shunts for the treatment of pediatric hydrocephalus. Articles meeting specific criteria that had been delineated a priori were then examined, and data were abstracted and compiled in evidentiary tables. These data were then analyzed by the Pediatric Hydrocephalus Systematic Review and Evidence-Based Guidelines Task Force to consider evidence-based treatment recommendations. Results. The search yielded 163 abstracts, which were screened for potential relevance to the application of technical adjuvants in shunt placement. Fourteen articles were selected for full-text review. One additional article was selected during a review of literature citations. Eight of these articles were included in the final recommendations concerning the use of endoscopy, ultrasonography, and electromagnetic image guidance during shunt placement, whereas the remaining articles were excluded due to poor evidence or lack of relevance. The evidence included 1 Class I, I Class II, and 6 Class III papers. An evidentiary table of relevant articles was created. Conclusions. RECOMMENDATION: There is insufficient evidence to recommend the use of endoscopic guidance for routine ventricular catheter placement. STRENGTH OF RECOMMENDATION: Level I, high degree of clinical certainty. RECOMMENDATION: The routine use of ultrasound-assisted catheter placement is an option. STRENGTH OF RECOMMENDATION: Level III, unclear clinical certainty. RECOMMENDATION: The routine use of computer-assisted electromagnetic (EM) navigation is an option. STRENGTH OF RECOMMENDATION: Level III, unclear clinical certainty. C1 [Flannery, Ann Marie; Kemp, Joanna] St Louis Univ, Dept Neurol Surg, St Louis, MO 63110 USA. [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Dept Pediat Neurosurg, Boston, MA 02114 USA. [Tamber, Mandeep S.] Univ Pittsburgh, Childrens Hosp Pittsburgh, Dept Pediat Neurol Surg, Pittsburgh, PA 15213 USA. RP Flannery, AM (reprint author), St Louis Univ, Dept Neurol Surg, 3565 Vista Ave, St Louis, MO 63110 USA. EM flanneam@slu.edu FU CNS Pediatric Section; AANS Pediatric Section FX The systematic review and evidence-based guidelines were funded exclusively by the CNS and AANS Pediatric Section, which received no funding from outside commercial sources to support the development of this document. NR 15 TC 3 Z9 3 U1 0 U2 1 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1933-0707 EI 1933-0715 J9 J NEUROSURG-PEDIATR JI J. Neurosurg.-Pediatr. PD NOV PY 2014 VL 14 SU S BP 24 EP 29 DI 10.3171/2014.7.PEDS14323 PG 6 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA AR4AT UT WOS:000343531100004 PM 25988779 ER PT J AU Klimo, P Van Poppel, M Thompson, CJ Baird, LC Duhaime, AC Flannery, AM AF Klimo, Paul, Jr. Van Poppel, Mark Thompson, Clinton J. Baird, Lissa C. Duhaime, Ann-Christine Flannery, Ann Marie TI Pediatric hydrocephalus: systematic literature review and evidence-based guidelines. Part 6: Preoperative antibiotics for shunt surgery in children with hydrocephalus: a systematic review and meta-analysis SO JOURNAL OF NEUROSURGERY-PEDIATRICS LA English DT Review DE preoperative; perioperative; antibiotics; intravenous; shunt; cerebrospinal fluid; infection; meta-analysis; pediatrics; evidence-based guidelines; practice guidelines; hydrocephalus ID CEREBROSPINAL-FLUID SHUNTS; PLACEBO-CONTROLLED TRIAL; PROPHYLACTIC ANTIBIOTICS; DOUBLE-BLIND; ANTIMICROBIAL PROPHYLAXIS; RANDOMIZED TRIAL; UNITED-STATES; INFECTIONS; EFFICACY; TRIMETHOPRIM AB Object. The objective of this systematic review and meta-analysis was twofold: to answer the question "What is the evidence for the effectiveness of prophylactic intravenous antibiotics for infection prevention in shunt surgery?" and to make treatment recommendations based on the available evidence. Methods. The US National Library of Medicine PubMed/MEDLINE database and the Cochrane Database of Systematic Reviews were queried using MeSH headings and key words relevant to prophylactic antibiotic use in children undergoing a shunt operation. Abstracts were reviewed to identify which studies met the inclusion criteria. An evidentiary table was assembled summarizing the studies and the quality of evidence (Classes I-III) A meta-analysis was conducted using a random-effects model to calculate a cumulative estimate of treatment effect using risk ratio (RR). Heterogeneity was assessed using chi-square and I-2 statistics. A sensitivity analysis was also conducted. Based on the quality of the literature and the result of the meta-analysis, a recommendation was rendered (Level I, II, or III). Results. Nine studies (4 Class 1,3 Class II, and 2 Class III) met our inclusion criteria. Of 7 randomized controlled trials (RCTs), 3 were downgraded from Class I to Class II because of significant quality issues, and all RCTs were potentially underpowered. In only 2 Class II retrospective cohort studies were preoperative antibiotic agents found to be protective against shunt infection. When the data from the individual studies were pooled together, the infection rate in the prophylactic antibiotics group was 7.3% compared with 9.4% in the control group. Using a random-effects model, the cumulative RR was 0.73 (95% CI 0.45-1.16), indicating no reduction in the risk of shunt infection with the administration of prophylactic perioperative antibiotic agents. A sensitivity analysis of RCTs only (n = 7) and higher-quality RCTs (n = 4) further strengthened the finding of no benefit. Conclusions. Within the limits of this systematic review and meta-analysis, administration of preoperative antibiotic agents for shunt surgery in children was not found to lower the infection risk (quality of evidence: Class I; strength of recommendation, Level I). RECOMMENDATION: The use of preoperative antibiotic agents cannot be recommended to prevent shunt infection in patients with hydrocephalus. The use of preoperative antibiotics for shunt surgery in children has not been shown to lower the risk of shunt infection. STRENGTH OF RECOMMENDATION: Level I, high clinical certainty. C1 [Klimo, Paul, Jr.] Univ Tennessee, Ctr Hlth Sci, Semmes Murphey Neurol & Spine Inst, Memphis, TN 38163 USA. [Klimo, Paul, Jr.; Van Poppel, Mark] Univ Tennessee, Ctr Hlth Sci, Dept Neurosurg, Memphis, TN 38163 USA. [Klimo, Paul, Jr.; Van Poppel, Mark] Le Bonheur Childrens Hosp, Memphis, TN USA. [Baird, Lissa C.] Oregon Hlth & Sci Univ, Dept Neurol Surg, Portland, OR 97201 USA. [Thompson, Clinton J.] George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC USA. [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Dept Pediat Neurosurg, Boston, MA 02114 USA. [Flannery, Ann Marie] St Louis Univ, Dept Neurol Surg, St Louis, MO 63110 USA. RP Flannery, AM (reprint author), St Louis Univ, Dept Neurol Surg, 3565 Vista Ave, St Louis, MO 63110 USA. EM flanneam@slu.edu FU CNS Pediatric Section; AANS Pediatric Section FX The systematic review and evidence-based guidelines were funded exclusively by the CNS and AANS Pediatric Section, which received no funding from outside commercial sources to support the development of this document. NR 44 TC 7 Z9 7 U1 0 U2 2 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1933-0707 EI 1933-0715 J9 J NEUROSURG-PEDIATR JI J. Neurosurg.-Pediatr. PD NOV PY 2014 VL 14 SU S BP 44 EP 52 DI 10.3171/2014.7.PEDS14326 PG 9 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA AR4AT UT WOS:000343531100007 PM 25988782 ER PT J AU Kemp, J Flannery, AM Tamber, MS Duhaime, AC AF Kemp, Joanna Flannery, Ann Marie Tamber, Mandeep S. Duhaime, Ann-Christine TI Pediatric hydrocephalus: systematic literature review and evidence-based guidelines. Part 9: Effect of ventricular catheter entry point and position SO JOURNAL OF NEUROSURGERY-PEDIATRICS LA English DT Review DE practice guidelines; cerebrospinal fluid shunts; hydrocephalus; ventricular catheter; ventricular catheter placement; ventricular catheter position ID PLACEMENT; SHUNTS AB Object. The objective of this guideline was to answer the following question: Do the entry point and position of the ventricular catheter have an effect on shunt function and survival? Methods. Both the US National Library of Medicine/MEDLINE database and the Cochrane Database of Systematic Reviews were queried using MeSH headings and key words specifically chosen to identify published articles detailing the use of CSF shunts for the treatment of pediatric hydrocephalus. Articles meeting specific criteria that had been delineated a priori were then examined, and data were abstracted and compiled in evidentiary tables. Results. The search yielded 184 abstracts, which were screened for potential relevance to the clinical question of the effect of ventricular catheter entry site on shunt survival. An initial review of the abstracts identified 14 papers that met the inclusion criteria, and these were recalled for full-text review. After review of these articles, only 4 were noted to be relevant for an analysis of the impact of entry point on shunt survival; an additional paper was retrieved during the review of full-text articles and was included as evidence to support the recommendation. The evidence included 1 Class II paper and 4 Class III papers. An evidentiary table was created including the relevant articles. Conclusion. RECOMMENDATION: There is insufficient evidence to recommend the occipital versus frontal point of entry for the ventricular catheter; therefore, both entry points are options for the treatment of pediatric hydrocephalus. STRENGTH OF RECOMMENDATION: Level III, unclear degree of clinical certainty. C1 [Kemp, Joanna; Flannery, Ann Marie] St Louis Univ, Dept Neurol Surg, St Louis, MO 63110 USA. [Tamber, Mandeep S.] Univ Pittsburgh, Childrens Hosp Pittsburgh, Dept Pediat Neurol Surg, Pittsburgh, PA 15213 USA. [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Dept Pediat Neurosurg, Boston, MA 02114 USA. RP Flannery, AM (reprint author), St Louis Univ, Dept Neurol Surg, 3565 Vista Ave, St Louis, MO 63110 USA. EM flanneam@slu.edu FU CNS; AANS Pediatric Section FX The systematic review and evidence-based guidelines were funded exclusively by the CNS and the AANS Pediatric Section, which received no funding from outside commercial sources to support the development of this document. NR 17 TC 3 Z9 3 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1933-0707 EI 1933-0715 J9 J NEUROSURG-PEDIATR JI J. Neurosurg.-Pediatr. PD NOV PY 2014 VL 14 SU S BP 72 EP 76 DI 10.3171/2014.7.PEDS14329 PG 5 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA AR4AT UT WOS:000343531100010 PM 25988785 ER PT J AU Nielson, JL Guandique, CF Liu, AW Burke, DA Lash, AT Moseanko, R Hawbecker, S Strand, SC Zdunowski, S Irvine, KA Brock, JH Nout-Lomas, YS Gensel, JC Anderson, KD Segal, MR Rosenzweig, ES Magnuson, DS Whittemore, SR McTigue, DM Popovich, PG Rabchevsky, AG Scheff, SW Steward, O Courtine, G Edgerton, VR Tuszynski, MH Beattie, MS Bresnahan, JC Ferguson, AR AF Nielson, Jessica L. Guandique, Cristian F. Liu, Aiwen W. Burke, Darlene A. Lash, A. Todd Moseanko, Rod Hawbecker, Stephanie Strand, Sarah C. Zdunowski, Sharon Irvine, Karen-Amanda Brock, John H. Nout-Lomas, Yvette S. Gensel, John C. Anderson, Kim D. Segal, Mark R. Rosenzweig, Ephron S. Magnuson, David S. K. Whittemore, Scott R. McTigue, Dana M. Popovich, Phillip G. Rabchevsky, Alexander G. Scheff, Stephen W. Steward, Oswald Courtine, Gregoire Edgerton, V. Reggie Tuszynski, Mark H. Beattie, Michael S. Bresnahan, Jacqueline C. Ferguson, Adam R. TI Development of a Database for Translational Spinal Cord Injury Research SO JOURNAL OF NEUROTRAUMA LA English DT Article DE monkeys; rodents; bioinformatics; translation; syndromics ID TRAUMATIC BRAIN-INJURY; INDEPENDENCE MEASURE; WALKING INDEX; TIME LIMITS; RECOVERY; SCALE; VALIDITY; MULTICENTER; RELIABILITY; COMPRESSION AB Efforts to understand spinal cord injury (SCI) and other complex neurotrauma disorders at the pre-clinical level have shown progress in recent years. However, successful translation of basic research into clinical practice has been slow, partly because of the large, heterogeneous data sets involved. In this sense, translational neurological research represents a "big data" problem. In an effort to expedite translation of pre-clinical knowledge into standards of patient care for SCI, we describe the development of a novel database for translational neurotrauma research known as Visualized Syndromic Information and Outcomes for Neurotrauma-SCI (VISION-SCI). We present demographics, descriptive statistics, and translational syndromic outcomes derived from our ongoing efforts to build a multi-center, multi-species pre-clinical database for SCI models. We leveraged archived surgical records, postoperative care logs, behavioral outcome measures, and histopathology from approximately 3000 mice, rats, and monkeys from pre-clinical SCI studies published between 1993 and 2013. The majority of animals in the database have measures collected for health monitoring, such as weight loss/gain, heart rate, blood pressure, postoperative monitoring of bladder function and drug/fluid administration, behavioral outcome measures of locomotion, and tissue sparing postmortem. Attempts to align these variables with currently accepted common data elements highlighted the need for more translational outcomes to be identified as clinical endpoints for therapeutic testing. Last, we use syndromic analysis to identify conserved biological mechanisms of recovery after cervical SCI between rats and monkeys that will allow for more-efficient testing of therapeutics that will need to be translated toward future clinical trials. C1 [Nielson, Jessica L.; Guandique, Cristian F.; Liu, Aiwen W.; Beattie, Michael S.; Bresnahan, Jacqueline C.; Ferguson, Adam R.] Univ Calif San Francisco, Brain & Spinal Injury Ctr, Dept Neurol Surg, San Francisco, CA 94110 USA. [Burke, Darlene A.; Magnuson, David S. K.; Whittemore, Scott R.] Univ Louisville, Kentucky Spinal Cord Injury Res Ctr, Dept Neurol Surg, Louisville, KY 40292 USA. [Lash, A. Todd] Ohio State Univ, Off Res Off Responsible Res Practices, Columbus, OH 43210 USA. [Moseanko, Rod; Hawbecker, Stephanie; Strand, Sarah C.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Zdunowski, Sharon; Edgerton, V. Reggie] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA USA. [Irvine, Karen-Amanda] Univ Calif San Francisco, Dept Neurol, San Francisco VA Med Ctr, San Francisco, CA 94110 USA. [Brock, John H.; Rosenzweig, Ephron S.; Tuszynski, Mark H.] Univ Calif San Diego, Dept Neurosci, Ctr Neural Repair, La Jolla, CA 92093 USA. [Nout-Lomas, Yvette S.] Colorado State Univ, Coll Vet Med & Biomed Sci, Dept Clin Sci, Ft Collins, CO 80523 USA. [Gensel, John C.; Rabchevsky, Alexander G.; Scheff, Stephen W.] Univ Kentucky, Chandler Med Ctr, Spinal Cord & Brain Injury Res Ctr, Lexington, KY USA. [Anderson, Kim D.] Univ Miami, Miller Sch Med, Miami Project Cure Paralysis, Dept Neurol Surg, Miami, FL 33136 USA. [Segal, Mark R.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Ctr Bioinformat & Mol Biostat, San Francisco, CA 94110 USA. [McTigue, Dana M.; Popovich, Phillip G.] Ohio State Univ, Dept Neurosci, Ctr Brain & Spinal Cord Repair, Columbus, OH 43210 USA. [Scheff, Stephen W.] Univ Kentucky, Dept Anat & Neurobiol, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. [Steward, Oswald] Univ Calif Irvine, Dept Anat & Neurobiol, Reeve Irvine Res Ctr, Irvine, CA 92717 USA. [Steward, Oswald] Univ Calif Irvine, Dept Neurobiol & Behav, Reeve Irvine Res Ctr, Irvine, CA USA. [Steward, Oswald] Univ Calif Irvine, Dept Neurosurg, Reeve Irvine Res Ctr, Irvine, CA USA. [Courtine, Gregoire] Swiss Fed Inst Technol, Ctr Neuroprosthet, CH-1015 Lausanne, Switzerland. [Courtine, Gregoire] Swiss Fed Inst Technol, Brain Mind Inst, CH-1015 Lausanne, Switzerland. [Tuszynski, Mark H.] Vet Adm Med Ctr, La Jolla, CA USA. RP Ferguson, AR (reprint author), Univ Calif San Francisco, Brain & Spinal Injury Ctr, Dept Neurol Surg, 1001 Potrero Ave,Bldg 1,Room 101, San Francisco, CA 94110 USA. EM adam.ferguson@ucsf.edu OI Steward, Oswald/0000-0001-7069-8756; Nielson, Jessica/0000-0002-3677-3959; courtine, gregoire/0000-0002-5744-4142; Nout-Lomas, Yvette/0000-0001-6583-2308; Magnuson, David/0000-0003-3816-3676; , John/0000-0001-8980-108X FU NIH [R01NS067092, F32NS079030, R01NS038079, R01NS042291, R01NS031193, R01NS032000]; Craig H. Neilsen Foundation [224308]; Wings for Life [WFLUS008/12]; NYS CoRE [CO19772, R21 AG032518, R01 NS052292, P01 RR15576, P30 GM103507, R01 NS073584, R01 NS045734, R01 NS089324, R01 NS059776, P30-NS045758, P01NS010165]; Veterans Administration; Kentucky Spinal Cord and Head Injury Research Trust; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Research for Cure; Roman Reed Spinal Cord Injury Research Fund of the State of California; Craig H. Neilsen Foundation; American Paralysis Association; Paralyzed Veterans of America; Christopher and Dana Reeve Foundation; [NIH-N01-NS-3-2353]; [NIH-NO1-NS-3-2354] FX The authors thank, in alphabetical order, Rochelle Deibert, Crystal Forrider, Jenny Haefeli, J. Russell Huie, Amity Lin, Brandon Miller, Vladimir Muraru, Ellen Stuck, AmyTovar, Montina J. Van Meter, and Sergio Veiga for their technical assistance and fruitful discussions regarding database development. This work was supported by NIH grants R01NS067092 (to A. R. F.) and F32NS079030 (to J. L. N.); Craig H. Neilsen Foundation 224308, and Wings for Life WFLUS008/12. Primary data collection was supported by NIH grants R01NS038079, R01NS042291, R01NS031193, and R01NS032000; NYS CoRE CO19772, R21 AG032518, R01 NS052292, P01 RR15576, P30 GM103507, R01 NS073584, R01 NS045734, R01 NS089324, R01 NS059776, P30-NS045758, P01NS010165, NIH-N01-NS-3-2353, and NIH-NO1-NS-3-2354 contract (Facilities of Research Excellence in Spinal Cord Injury), the Veterans Administration, the Kentucky Spinal Cord and Head Injury Research Trust, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Research for Cure, the Roman Reed Spinal Cord Injury Research Fund of the State of California, the Craig H. Neilsen Foundation, the American Paralysis Association, Paralyzed Veterans of America, and the Christopher and Dana Reeve Foundation. NR 35 TC 11 Z9 11 U1 3 U2 18 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 NOV 1 PY 2014 VL 31 IS 21 BP 1789 EP 1799 DI 10.1089/neu.2014.3399 PG 11 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AR0TW UT WOS:000343285300004 PM 25077610 ER PT J AU Eddy, KT Gray, EK AF Eddy, Kamryn T. Gray, Emily K. TI Is Seeking a Panacea for Anorexia Nervosa a Fool's Errand? Long-Term Outcomes of Family-Based Treatment SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Editorial Material ID THERAPY C1 [Eddy, Kamryn T.; Gray, Emily K.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Eddy, Kamryn T.; Gray, Emily K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Eddy, KT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Eating Disorders Clin & Res Program, 2 Longfellow Pl,Suite 200, Boston, MA 02114 USA. EM keddy@mgh.harvard.edu NR 5 TC 0 Z9 0 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD NOV PY 2014 VL 53 IS 11 BP 1150 EP 1152 DI 10.1016/j.jaac.2014.08.008 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA AR5JG UT WOS:000343620600003 PM 25440304 ER PT J AU Hudziak, JJ Albaugh, MD Ducharme, S Karama, S Spottswood, M Crehan, E Evans, AC Botteron, KN AF Hudziak, James J. Albaugh, Matthew D. Ducharme, Simon Karama, Sherif Spottswood, Margaret Crehan, Eileen Evans, Alan C. Botteron, Kelly N. CA Brain Dev Cooperative Grp TI Cortical Thickness Maturation and Duration of Music Training: Health-Promoting Activities Shape Brain Development SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE music; MRI; cortical thickness ID AUTOMATED 3-D EXTRACTION; MRI DATA; NIH MRI; CHILDREN; REGISTRATION; PERFORMANCE; SURFACES; INNER AB Objective: To assess the extent to which playing a musical instrument is associated with cortical thickness development among healthy youths. Method: Participants were part of the National Institutes of Health (NLH) Magnetic Resonance Imaging (MET) Study of Normal Brain Development. This study followed a longitudinal design such that participants underwent MRI scanning and behavioral testing on up to 3 separate visits, occurring at 2-year intervals. MET, IQ, and music training data were available for 232 youths (334 scans), ranging from 6 to 18 years of age. Cortical thickness was regressed against the number of years that each youth had played a musical instrument. Next, thickness was regressed against an "Age x Years of Playing" interaction term. Age, gender, total brain volume, and scanner were controlled for in analyses. Participant ID was entered as a random effect to account for within-person dependence. False discovery rate correction was applied (p <.05). Results: There was no association between thickness and years playing a musical instrument. The "Age x Years of Playing" interaction was associated with thickness in motor, premotor, and supplementary motor cortices, as well as prefrontal and parietal cortices. Follow-up analysis revealed that music training was associated with an increased rate of thickness maturation. Results were largely unchanged when IQ and handedness were included as covariates. Conclusion: Playing a musical instrument was associated with more rapid cortical thickness maturation within areas implicated in motor planning and coordination, visuospatial ability, and emotion and impulse regulation. However, given the quasi-experimental nature of this study, we cannot rule out the influence of confounding variables. C1 [Hudziak, James J.; Albaugh, Matthew D.; Crehan, Eileen] Univ Vermont, Coll Med, Vermont Ctr Children Youth & Families, Burlington, VT 05401 USA. [Ducharme, Simon] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ducharme, Simon] Harvard Univ, McLean Hosp, Belmont, MA 02178 USA. [Karama, Sherif; Evans, Alan C.] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ, Canada. [Karama, Sherif] McGill Univ, Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada. [Spottswood, Margaret] Harvard Univ, Cambridge Hlth Alliance, Cambridge, MA 02138 USA. [Botteron, Kelly N.] Washington Univ, Mallinckrodt Inst Radiol, Sch Med, St Louis, MO 63130 USA. RP Hudziak, JJ (reprint author), Univ Vermont, Coll Med, Vermont Ctr Children Youth & Families, Univ Hlth Ctr Campus,1 South Prospect St, Burlington, VT 05401 USA. EM james.hudziak@uvm.edu RI Albaugh, Matthew/R-4349-2016 FU National Institute of Child Health and Human Development (NICHD); National Institute on Drug Abuse (NIDA); National Institute of Mental Health (NIMH); National Institute of Neurological Disorders and Stroke (NINDS) [N01-HD02-3343, N01-MH9-0002, N01-NS-9-2314, N01-NS-9-2315, N01-NS-9-2316, N01-NS-9-2317, N01-NS-9-2319, N01-NS-9-2320]; Child and Adolescent Psychology Training and Research Foundation; Canadian Institutes of Health Research; Fonds de Recherche en Sante du Quebec FX This project has been funded in whole or in part with federal funds from the National Institute of Child Health and Human Development (NICHD), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS; contract numbers N01-HD02-3343, N01-MH9-0002, N01-NS-9-2314, N01-NS-9-2315, N01-NS-9-2316, N01-NS-9-2317, N01-NS-9-2319, and N01-NS-9-2320). Dr. Albaugh is funded by a grant from the Child and Adolescent Psychology Training and Research Foundation. Dr Ducharme receives financial support from the Canadian Institutes of Health Research with a Frederick Banting and Charles Best Canada Graduate Scholarships-Master's Award. Dr. Karama is supported by the Fonds de Recherche en Sante du Quebec. NR 36 TC 13 Z9 13 U1 1 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD NOV PY 2014 VL 53 IS 11 BP 1153 EP 1161 DI 10.1016/j.jaac.2014.06.015 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA AR5JG UT WOS:000343620600004 PM 25440305 ER PT J AU Shoag, J Halpern, J Goldfarb, DS Eisner, BH AF Shoag, Jonathan Halpern, Joshua Goldfarb, David S. Eisner, Brian H. TI Risk of Chronic and End Stage Kidney Disease in Patients with Nephrolithiasis SO JOURNAL OF UROLOGY LA English DT Article DE kidney calculi; kidney failure, chronic; dialysis; epidemiology; urolithiasis ID UNITED-STATES; METABOLIC SYNDROME; STONES; PREVALENCE; HISTORY; ADULTS; TRENDS AB Purpose: We examine kidney stone disease as a potential risk factor for chronic kidney disease, end stage kidney disease and treatment with dialysis. Materials and Methods: The NHANES (National Health and Nutrition Examination Survey) 2007-2010 database was interrogated for patients with a history of kidney stones. Demographics and comorbid conditions including age, gender, body mass index, diabetes, hemoglobin A1c, hypertension, gout and smoking were also assessed. Multivariate analysis adjusting for patient demographics and comorbidities was performed to assess differences in the prevalence of chronic kidney disease and treatment with dialysis between the 2 groups. History of nephrolithiasis was assessed with the question, "Have you ever had kidney stones?" Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 ml/minute/1.73 m(2) and/or a urinary albuminto-creatinine ratio greater than 30 mg/gm. Statistical calculations were performed using Stata (R) software with determinations of p values and 95% CI where appropriate. Results: The study included an analysis of 5,971 NHANES participants for whom data on chronic kidney disease and kidney stones were available, of whom 521 reported a history of kidney stones. On multivariate analysis a history of kidney stones was associated with chronic kidney disease and treatment with dialysis (OR 1.50, 1.10-2.04, p - 0.013 and OR 2.37, 1.13-4.96, p - 0.025, respectively). This difference appeared to be driven by women, where a history of kidney stones was associated with a higher prevalence of chronic kidney disease (OR 1.76, 1.13-2.763, p - 0.016) and treatment with dialysis (OR 3.26, 1.48-7.16, p - 0.004). There was not a significant association between kidney stone history and chronic kidney disease or treatment with dialysis in men. Conclusions: Kidney stone history is associated with an increased risk of chronic kidney disease and treatment with dialysis among women even after adjusting for comorbid conditions. Large scale prospective studies are needed to further characterize the relationship between nephrolithiasis and chronic kidney disease. C1 [Shoag, Jonathan; Halpern, Joshua] Weill Cornell Med Coll, Dept Urol, New York, NY USA. [Goldfarb, David S.] New York Harbor VA Healthcare Syst, New York, NY USA. [Goldfarb, David S.] NYU, Sch Med, New York, NY USA. [Eisner, Brian H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. RP Eisner, BH (reprint author), Dept Urol, GRB 1102,55 Fruit St, Boston, MA 02114 USA. EM beisner@partners.org OI Goldfarb, David/0000-0002-9215-1273 NR 22 TC 19 Z9 19 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD NOV PY 2014 VL 192 IS 5 BP 1440 EP 1445 DI 10.1016/j.juro.2014.05.117 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA AR8YJ UT WOS:000343856900038 PM 24929140 ER PT J AU Richard, J Veillette, M Batraville, LA Coutu, M Chapleau, JP Bonsignori, M Bernard, N Tremblay, C Roger, M Kaufmann, DE Finzi, A AF Richard, Jonathan Veillette, Maxime Batraville, Laurie-Anne Coutu, Mathieu Chapleau, Jean-Philippe Bonsignori, Mattia Bernard, Nicole Tremblay, Cecile Roger, Michel Kaufmann, Daniel E. Finzi, Andres TI Flow cytometry-based assay to study HIV-1 gp120 specific antibody-dependent cellular cytotoxicity responses SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE HIV-1; ADCC responses; gp120 Env; FACS-based method; ADCC-mediating antibodies ID HUMAN-IMMUNODEFICIENCY-VIRUS; VACCINE EFFICACY TRIAL; MEDIATED-CYTOTOXICITY; EFFECTOR FUNCTION; NK CELLS; CONFORMATIONAL TRANSITIONS; INFECTED INDIVIDUALS; DISEASE PROGRESSION; INNER DOMAIN; ADCC AB Increased attention on the role of Fc-mediated effector functions against HIV-1 has led to renewed interest into the role that antibody-dependent cellular cytotoxicity (ADCC) could play in controlling viral transmission and/or the rate of disease progression. While (51)Chromium release assays have traditionally been used to study ADCC responses against HIV-1, a number of alternative flow-cytometry-based assays were recently developed. In this study, an alternative flow-cytometry-based assay was established to allow non-radioactive measurement of ADCC-mediated elimination of HIV-1 gp120 envelope glycoprotein (Env)-coated target cells. This assay relies on staining target and effector cells with different dyes, which allows precise gating and permits the calculation of the number of surviving target cells by normalization to flow-cytometry particles. By using small concentrations of recombinant gp120 Env, suitable targets cells that recapitulate the ADCC response mediated against HIV-1-infected cells were generated. Finally, this method was applied successfully to screen human sera for ADCC activity directed against HIV-1 gp120 Env. (C) 2014 Elsevier B.V. All rights reserved. C1 [Richard, Jonathan; Veillette, Maxime; Batraville, Laurie-Anne; Coutu, Mathieu; Chapleau, Jean-Philippe; Tremblay, Cecile; Roger, Michel; Kaufmann, Daniel E.; Finzi, Andres] Univ Montreal, Ctr Rech CHUM, Montreal, PQ, Canada. [Richard, Jonathan; Veillette, Maxime; Batraville, Laurie-Anne; Coutu, Mathieu; Chapleau, Jean-Philippe; Tremblay, Cecile; Roger, Michel; Kaufmann, Daniel E.; Finzi, Andres] Univ Montreal, Dept Microbiol Infectiol & Immunol, Montreal, PQ, Canada. [Bonsignori, Mattia] Duke Univ, Med Ctr, Duke Human Vaccine Inst, Durham, NC 27706 USA. [Bernard, Nicole] McGill Univ, Ctr Hlth, Res Inst, Div Expt Med, Montreal, PQ, Canada. [Tremblay, Cecile] Inst Natl Sante Publ Quebec, Quebec City, PQ, Canada. [Kaufmann, Daniel E.] Massachusetts Gen Hosp, MIT & Harvard, Ragon Inst, Cambridge, MA USA. [Finzi, Andres] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ, Canada. RP Finzi, A (reprint author), CRCHUM, 900 St Denis St,Tour Viger,R09-420, Montreal, PQ H2X 0A9, Canada. EM andres.finzi@umontreal.ca FU Canada Foundation for Innovation Program Leader [29866]; CIHR Operating Grants [119334, 134117]; FRQS Establishment of Young Scientist Grant [26702]; CIHR catalyst Grant [126630]; FRQS AIDS and Infectious Diseases Network; Canada Research Chair on Retroviral Entry; CIHR Fellowship award [135349]; CIHR Doctoral Research Award [291485]; COPSE award FX The authors thank Nathalie Brassard and Stephanie Matte for technical assistance as well as Mario Legault for cohort coordination. We thank Dr Jean-Pierre Routy and Ms Josee Girouard for providing access to leukapheresis samples. We thank Dr David Evans for kindly providing CEM-NKr cells, Dr George Lewis for L9-i1, Dr James Robinson and Dr Guido Ferrari for A32 and its Fab fragment. This work was supported by a Canada Foundation for Innovation Program Leader Grant #29866, by CIHR Operating Grants #119334 and #134117, by a FRQS Establishment of Young Scientist Grant #26702 to A.F, by a CIHR catalyst Grant #126630 to A.F and M.R. and by the FRQS AIDS and Infectious Diseases Network. A.F. is the recipient of a Canada Research Chair on Retroviral Entry. J.R was supported by a CIHR Fellowship award #135349, M.V. was supported by a CIHR Doctoral Research Award #291485 and JPC by a COPSE award. CT is a FRQS scholar and University of Montreal/Pfizer chair on HIV translational research. We are thankful for subject's participation and collaboration. The authors have no conflicts of interest to report. NR 31 TC 18 Z9 18 U1 3 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 EI 1879-0984 J9 J VIROL METHODS JI J. Virol. Methods PD NOV PY 2014 VL 208 BP 107 EP 114 DI 10.1016/j.jviromet.2014.08.003 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA AR1KN UT WOS:000343344200018 PM 25125129 ER PT J AU Streeck, H Lu, R Beckwith, N Milazzo, M Liu, M Routy, JP Little, S Jessen, H Kelleher, AD Hecht, F Sekaly, RP Alter, G Heckerman, D Carrington, M Rosenberg, ES Altfeld, M AF Streeck, Hendrik Lu, Richard Beckwith, Noor Milazzo, Mark Liu, Michelle Routy, Jean-Pierre Little, Susan Jessen, Heiko Kelleher, Anthony D. Hecht, Frederick Sekaly, Rafick-Pierre Alter, Galit Heckerman, David Carrington, Mary Rosenberg, Eric S. Altfeld, Marcus TI Emergence of Individual HIV-Specific CD8 T Cell Responses during Primary HIV-1 Infection Can Determine Long-Term Disease Outcome SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIRAL LOAD; LYMPHOCYTE ESCAPE; TYPE-1 INFECTION; SET-POINT; AIDS; PROGRESSION; VIREMIA; EPITOPE; GAG AB Events during primary HIV-1 infection have been shown to be critical for the subsequent rate of disease progression. Early control of viral replication, resolution of clinical symptoms and development of a viral set point have been associated with the emergence of HIV-specific CD8 T cell responses. Here we assessed which particular HIV-specific CD8 T cell responses contribute to long-term control of HIV-1. A total of 620 individuals with primary HIV-1 infection were screened by gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay for HLA class I-restricted, epitope-specific CD8 T cell responses using optimally defined epitopes approximately 2 months after initial presentation. The cohort was predominantly male (97%) and Caucasian (83%) (Fiebig stages II/III [n = 157], IV [n = 64], V [n = 286], and VI [n = 88] and Fiebig stage not determined [n = 25]). Longitudinal viral loads, CD4 count, and time to ART were collected for all patients. We observed strong associations between viral load at baseline (initial viremia) and the established early viral set points (P < 0.0001). Both were significantly associated with HLA class I genotypes (P = 0.0009). While neither the breadth nor the magnitude of HIV-specific CD8 T cell responses showed an influence on the early viral set point, a broader HIV-specific CD8 T cell response targeting epitopes within HIV-1 Gag during primary HIV-1 infection was associated with slower disease progression. Moreover, the induction of certain HIV-specific CD8 T cell responses-but not others-significantly influenced the time to ART initiation. Individual epitope-specific CD8 T cell responses contribute significantly to HIV-1 disease control, demonstrating that the specificity of the initial HIV-specific CD8 T cell response rather than the restricting HLA class I molecule alone is a critical determinant of antiviral function. IMPORTANCE Understanding which factors are involved in the control of HIV-1 infection is critical for the design of therapeutic strategies for patients living with HIV/AIDS. Here, using a cohort of over 600 individuals with acute and early HIV-1 infection, we assessed in unprecedented detail the individual contribution of epitope-specific CD8 T cell responses directed against HIV-1 to control of viremia and their impact on the overall course of disease progression. C1 [Streeck, Hendrik; Lu, Richard; Milazzo, Mark; Liu, Michelle] Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA. [Streeck, Hendrik; Lu, Richard; Milazzo, Mark; Liu, Michelle] Henry M Jackson Fdn Adv Mil Med, Bethesda, MD USA. [Streeck, Hendrik; Alter, Galit; Carrington, Mary; Altfeld, Marcus] Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. [Beckwith, Noor] Harvard Univ, Sch Med, Boston, MA USA. [Routy, Jean-Pierre] McGill Univ, Div Hematol, Montreal, PQ, Canada. [Routy, Jean-Pierre] McGill Univ, Royal Victoria Hosp, Immunodeficiency Serv, Montreal, PQ H3A 1A1, Canada. [Little, Susan] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Jessen, Heiko] HIV Clin Praxis Jessen, Berlin, Germany. [Kelleher, Anthony D.] UNSW, Kirby Inst, Sydney, NSW, Australia. [Hecht, Frederick] Univ Calif San Francisco, Dept Med, San Francisco Gen Hosp, San Francisco, CA USA. [Sekaly, Rafick-Pierre] Vaccine & Gene Therapy Inst Florida, Div Infect Dis, Port St Lucie, FL USA. [Heckerman, David] Microsoft Res, eSci Grp, Los Angeles, CA USA. [Carrington, Mary] Leidos Biomedical Res Inc, Frederick Natl Lab Canc Res, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD USA. [Rosenberg, Eric S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Altfeld, Marcus] Heinrich Pette Inst, Hamburg, Germany. RP Streeck, H (reprint author), Walter Reed Army Inst Res, US Mil HIV Res Program, Silver Spring, MD 20910 USA. EM hstreeck@hivresearch.org OI Beckwith, Noor/0000-0001-6025-8642 FU NIH [P01 AI074415]; CIHR CTN/HIV trial network [CTN 247]; FRQ-S SIDA/maladies infectieuses; U.S. National Institutes of Health (NIH) [R01 AI091450-01, R01 AI094602-01]; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. [W81XWH-11-2-0174]; U.S. Department of Defense (DOD); Frederick National Laboratory for Cancer Research [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research FX This study was supported in part by NIH P01 AI074415 and in part by CIHR CTN/HIV trial network (CTN 247) and FRQ-S SIDA/maladies infectieuses. H. S. is funded by the U.S. National Institutes of Health (NIH) (R01 AI091450-01 and R01 AI094602-01) and a cooperative agreement (W81XWH-11-2-0174) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DOD). This project was also funded in whole or in part by federal funds from the Frederick National Laboratory for Cancer Research, under contract no. HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. NR 31 TC 7 Z9 7 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD NOV PY 2014 VL 88 IS 21 BP 12793 EP 12801 DI 10.1128/JVI.02016-14 PG 9 WC Virology SC Virology GA AR1BN UT WOS:000343314900051 PM 25165102 ER PT J AU Baeten, JM Donnell, D Mugo, NR Ndase, P Thomas, KK Campbell, JD Wangisi, J Tappero, JW Bukusi, EA Cohen, CR Katabira, E Ronald, A Tumwesigye, E Were, E Fife, KH Kiarie, J Farquhar, C John-Stewart, G Kidoguchi, L Coombs, RW Hendrix, C Marzinke, MA Frenkel, L Haberer, JE Bangsberg, D Celum, C AF Baeten, Jared M. Donnell, Deborah Mugo, Nelly R. Ndase, Patrick Thomas, Katherine K. Campbell, James D. Wangisi, Jonathan Tappero, Jordan W. Bukusi, Elizabeth A. Cohen, Craig R. Katabira, Elly Ronald, Allan Tumwesigye, Elioda Were, Edwin Fife, Kenneth H. Kiarie, James Farquhar, Carey John-Stewart, Grace Kidoguchi, Lara Coombs, Robert W. Hendrix, Craig Marzinke, Mark A. Frenkel, Lisa Haberer, Jessica E. Bangsberg, David Celum, Connie CA Partners PrEP Study Team TI Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial SO LANCET INFECTIOUS DISEASES LA English DT Article ID ANTIRETROVIRAL THERAPY; PREVENTION; INFECTION; TRANSMISSION; INITIATION; MACAQUES; WOMEN; MEN AB Background Antiretroviral pre-exposure prophylaxis (PrEP), with daily oral tenofovir disoproxil fumarate or tenofovir disoproxil fumarate in combination with emtricitabine, has been shown to be efficacious for HIV-1 prevention. Although the use of more than one antiretroviral agent is essential for effective HIV-1 treatment, more than one agent might not be required for effective prophylaxis. We assessed the efficacy of single-agent tenofovir disoproxil fumarate relative to combination emtricitabine plus tenofovir disoproxil fumarate as PrEP. Methods We did a randomised, double-blind, placebo-controlled three-group phase 3 trial of daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate PrEP in HIV-1 uninfected individuals in heterosexual HIV-1 serodiscordant couples from Kenya and Uganda. After an interim review, the trial's placebo group was discontinued and thereafter the active groups were continued, and participants initially randomly assigned to placebo were offered rerandomisation in a 1:1 ratio to tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate as PrEP. The primary endpoints were HIV-1 seroconversion and safety. This trial is registered with ClinicalTrials.gov, number NCT00557245. Findings 4410 (99.6%) of 4427 couples received tenofovir disoproxil fumarate or emtridtabine plus tenofovir disoproxil fumarate and were followed up for HIV-1 acquisition. Of 52 incident HIV-1 infections, 31 occurred in individuals assigned tenofovir disoproxil fumarate (incidence 0.71 cases per 100 person-years) and 21 were in those assigned emtridtabine plus tenofovir disoproxil fumarate (0.48 cases per 100 person-years); HIV-1 incidence in the placebo group until discontinuation was two cases per 100 person-years. HIV-1 prevention efficacy with emtridtabine plus tenofovir disoproxil fumarate was not significantly different from that of tenofovir disoproxil fumarate alone (hazard ratio [HR] 0.67, 95% CI 0.39-1.17; p=0.16). Detection of tenofovir in plasma samples, compared with no detection and as measured in seroconverters and a subset of non-seroconverters, was associated with an 85% relative risk reduction in HIV-1 acquisition for the tenofovir disoproxil fumarate group (HR 0-15, 95% CI 0.06-0.37; p<0.0001) and 93% for the emtridtabine plus tenofovir disoproxil fumarate group (0.07, 0.02-0.23; p<0.0001). No significant differences were noted in the frequency of deaths, serious adverse events, or serum creatinine and phosphorus abnormalities between the two groups. Interpretation These results do not rule out the potential for a slight difference in HIV-1 protection with tenofovir disoproxil fumarate compared with emtricitabine plus tenofovir disoproxil fumarate, but show that once-daily oral tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate regimens both provide high protection against HIV-1 acquisition in heterosexual men and women. C1 [Baeten, Jared M.; Donnell, Deborah; Mugo, Nelly R.; Ndase, Patrick; Thomas, Katherine K.; Bukusi, Elizabeth A.; Kiarie, James; Farquhar, Carey; John-Stewart, Grace; Kidoguchi, Lara; Celum, Connie] Univ Washington, Dept Global Hlth, Seattle, WA 98104 USA. [Baeten, Jared M.; Farquhar, Carey; John-Stewart, Grace; Coombs, Robert W.; Celum, Connie] Univ Washington, Dept Med, Seattle, WA 98104 USA. [Baeten, Jared M.; Farquhar, Carey; John-Stewart, Grace; Celum, Connie] Univ Washington, Dept Epidemiol, Seattle, WA 98104 USA. [Coombs, Robert W.; Frenkel, Lisa] Univ Washington, Dept Lab Med, Seattle, WA 98104 USA. [John-Stewart, Grace; Frenkel, Lisa] Univ Washington, Dept Pediat, Seattle, WA 98104 USA. [Donnell, Deborah] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. [Mugo, Nelly R.] Kenya Govt Med Res Ctr, Clin Res Ctr, Nairobi, Kenya. [Bukusi, Elizabeth A.] Kenya Govt Med Res Ctr, Ctr Microbiol Res, Nairobi, Kenya. [Campbell, James D.] Ctr Dis Control & Prevent, Entebbe, Uganda. [Wangisi, Jonathan] AIDS Support Org, Kampala, Uganda. [Tappero, Jordan W.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Bukusi, Elizabeth A.; Kiarie, James] Univ Nairobi, Dept Obstet & Gynecol, Nairobi, Kenya. [Bukusi, Elizabeth A.; Kiarie, James] Kenyatta Natl Hosp, Nairobi, Kenya. [Bukusi, Elizabeth A.; Cohen, Craig R.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Katabira, Elly; Ronald, Allan] Makerere Univ, Infect Dis Inst, Kampala, Uganda. [Ronald, Allan] Univ Manitoba, Dept Med, Winnipeg, MB, Canada. [Tumwesigye, Elioda] Kabwohe Clin Res Ctr, Kabwohe, Uganda. [Were, Edwin] Moi Univ, Dept Reprod Hlth, Eldoret, Kenya. [Fife, Kenneth H.] Indiana Univ, Dept Med, Indianapolis, IN USA. [Hendrix, Craig; Marzinke, Mark A.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Frenkel, Lisa] Seattle Childrens Hosp, Res Inst, Seattle, WA USA. [Haberer, Jessica E.; Bangsberg, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Haberer, Jessica E.; Bangsberg, David] Harvard Univ, Sch Med, Boston, MA USA. RP Baeten, JM (reprint author), Univ Washington, Int Clin Res Ctr, Dept Global Hlth, Box 359927,325 Ninth Ave, Seattle, WA 98104 USA. EM jbaeten@uw.edu OI Ronald, Allan/0000-0002-5746-3490; Donnell, Deborah/0000-0002-0587-7480 FU Bill & Melinda Gates Foundation; US National Institutes of Health FX Bill & Melinda Gates Foundation and US National Institutes of Health. NR 29 TC 27 Z9 29 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1473-3099 EI 1474-4457 J9 LANCET INFECT DIS JI Lancet Infect. Dis. PD NOV PY 2014 VL 14 IS 11 BP 1055 EP 1064 DI 10.1016/S1473-3099(14)70937-5 PG 10 WC Infectious Diseases SC Infectious Diseases GA AR7EZ UT WOS:000343743700030 PM 25300863 ER PT J AU Moon, HS Batirel, S Mantzoros, CS AF Moon, Hyun-Seuk Batirel, Saime Mantzoros, Christos S. TI Alpha linolenic acid and oleic acid additively down-regulate malignant potential and positively cross-regulate AMPK/S6 axis in OE19 and OE33 esophageal cancer cells SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article DE Alpha Linolenic acid; Oleic acid; Esophageal cancer; Malignant potential; AMPK/S6 axis ID ACTIVATED PROTEIN-KINASE; BREAST-CANCER; FATTY-ACIDS; SIGNALING PATHWAY; CARCINOMA; GROWTH; PROSTATE; DISEASE; LIPIDS; RISK AB Objective. Both oleic acid (OA) and alpha-linolenic acid (ALA) have been proposed to down-regulate cell proliferation of prostate, breast, and bladder cancer cells. However, direct evidence that OA and/or ALA suppresses to the development of esophageal cancer has not been studied. Also, no previous studies have evaluated how OA and/or ALA regulates malignant potential (cell proliferation, migration, colony formation and adhesion) and intracellular signaling pathways, and whether their effects might be synergistic and/or additive in esophageal cancer cells has not yet been elucidated. Materials/Methods. We conducted in vitro studies and evaluated whether OA and ALA alone or in combination may regulate malignant potential in OE19 and OE33 esophageal cancer cell lines. Results. Both OA and ALA significantly down-regulated cell proliferation, adhesion and/or migration. OA and/or ALA did not change the number of colonies but decrease colony sizes when compared to control. Also, we observed that OA and/or ALA positively cross-regulates the expression levels of AMPK/S6 axis. Moreover, OA and ALA up-regulated tumor suppressor genes (p53, p21, and p27) and these effects are abolished by AMPK siRNA administration. Importantly, we observed that these effects are additively regulated by OA and ALA in combination when compared to control in OE19 and OE33 esophageal cancer cell lines. Conclusions. Our novel mechanistic studies provide evidence for an important role for OA and ALA in esophageal cancer, and suggest that OA and/or ALA might be useful agents in the management or chemoprevention of esophageal cancer. (C) 2014 Elsevier Inc. All rights reserved. C1 [Moon, Hyun-Seuk; Batirel, Saime; Mantzoros, Christos S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. [Moon, Hyun-Seuk] Korea Univ, Coll Life Sci & Biotechnol, Div Biotechnol, Lab Metab Engn, Seoul 136713, South Korea. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA 02130 USA. RP Moon, HS (reprint author), Korea Univ, Coll Life Sci & Biotechnol, Div Biotechnol, Lab Metab Engn, 145 Anam Ro, Seoul 136713, South Korea. EM mhs72@korea.ac.kr RI Moon, Hyun-Seuk/G-8576-2015 OI Moon, Hyun-Seuk/0000-0002-5216-2090 FU National Institutes of Health [DK081913]; Clinical Science Research and Development Service of the VA Office of Research and Development [1I01CX000422-01A1]; Korea University Grant; Beth Israel Deaconess Medical Center FX This work was supported by the National Institutes of Health (DK081913) and the Clinical Science Research and Development Service of the VA Office of Research and Development (1I01CX000422-01A1). The Laboratory of Metabolic Engineering is supported by Korea University Grant. The Mantzoros Laboratory is supported by a discretionary grant from Beth Israel Deaconess Medical Center. NR 35 TC 6 Z9 6 U1 1 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD NOV PY 2014 VL 63 IS 11 BP 1447 EP 1454 DI 10.1016/j.metabol.2014.07.009 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AR4AV UT WOS:000343531300010 PM 25129649 ER PT J AU Miller, MW Sadeh, N AF Miller, M. W. Sadeh, N. TI Traumatic stress, oxidative stress and post-traumatic stress disorder: neurodegeneration and the accelerated-aging hypothesis SO MOLECULAR PSYCHIATRY LA English DT Review ID MILD COGNITIVE IMPAIRMENT; DNA-DAMAGE; SLEEP-DEPRIVATION; ALZHEIMER-DISEASE; PSYCHOLOGICAL STRESS; INSULIN-RESISTANCE; PARKINSONS-DISEASE; EXAM STRESS; LIFE STRESS; VITAMIN-E AB Post-traumatic stress disorder (PTSD) is associated with elevated risk for a variety of age-related diseases and neurodegeneration. In this paper, we review evidence relevant to the hypothesis that chronic PTSD constitutes a form of persistent life stress that potentiates oxidative stress (OXS) and accelerates cellular aging. We provide an overview of empirical studies that have examined the effects of psychological stress on OXS, discuss the stress-perpetuating characteristics of PTSD, and then identify mechanisms by which PTSD might promote OXS and accelerated aging. We review studies on OXS-related genes and the role that they may have in moderating the effects of PTSD on neural integrity and conclude with a discussion of directions for future research on antioxidant treatments and biomarkers of accelerated aging in PTSD. C1 VA Boston Healthcare Syst, Natl Ctr PTSD, Dept Psychiat, Boston, MA 02130 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Miller, MW (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, 150 South Huntington Ave, Boston, MA 02130 USA. EM mark.miller5@va.gov OI Sadeh, Naomi/0000-0002-8101-3190 FU National Institute on Mental Health [R21MH102834]; Department of Veterans Affairs [1I01BX002150-01] FX This study was supported by the National Institute on Mental Health award R21MH102834 and a Department of Veterans Affairs Merit Review Grant (1I01BX002150-01) awarded to MWM. NR 131 TC 33 Z9 33 U1 10 U2 34 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD NOV PY 2014 VL 19 IS 11 BP 1156 EP 1162 DI 10.1038/mp.2014.111 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA AR5ZT UT WOS:000343662300002 PM 25245500 ER PT J AU Kim, SH Steele, JW Lee, SW Clemenson, GD Carter, TA Treuner, K Gadient, R Wedel, P Glabe, C Barlow, C Ehrlich, ME Gage, FH Gandy, S AF Kim, S. H. Steele, J. W. Lee, S. W. Clemenson, G. D. Carter, T. A. Treuner, K. Gadient, R. Wedel, P. Glabe, C. Barlow, C. Ehrlich, M. E. Gage, F. H. Gandy, S. TI Proneurogenic Group II mGluR antagonist improves learning and reduces anxiety in Alzheimer A beta oligomer mouse SO MOLECULAR PSYCHIATRY LA English DT Article ID ADULT HIPPOCAMPAL NEUROGENESIS; GLUTAMATE-RECEPTOR ANTAGONIST; AMYLOID-BETA; TRANSGENIC MICE; COGNITIVE IMPAIRMENT; CELL-PROLIFERATION; DENTATE GYRUS; DISEASE; MGS0039; NEURONS AB Proneurogenic compounds have recently shown promise in some mouse models of Alzheimer's pathology. Antagonists at Group II metabotropic glutamate receptors (Group II mGluR: mGlu(2), mGlu(3)) are reported to stimulate neurogenesis. Agonists at those receptors trigger gamma secretase-inhibitor-sensitive biogenesis of A beta 42 peptides from isolated synaptic terminals, which is selectively suppressed by antagonist pretreatment. We have assessed the therapeutic potential of chronic pharmacological inhibition of Group II mGluR in Dutch APP (Alzheimer's amyloid precursor protein E693Q) transgenic mice that accumulate Dutch amyloid-beta (A beta) oligomers but never develop A beta plaques. BCI-838 is a clinically well-tolerated, orally bioavailable, investigational prodrug that delivers to the brain BCI-632, the active Group II mGluR antagonist metabolite. Dutch A beta-oligomer forming APP transgenic mice (APP E693Q) were dosed with BCI-838 for 3 months. Chronic treatment with BCI-838 was associated with reversal of transgene-related amnestic behavior, reduction in anxiety, reduction in levels of brain A beta monomers and oligomers, and stimulation of hippocampal neurogenesis. Group II mGluR inhibition may offer a unique package of relevant properties as an Alzheimer's disease therapeutic or prophylactic by providing both attenuation of neuropathology and stimulation of repair. C1 [Kim, S. H.; Steele, J. W.; Ehrlich, M. E.; Gandy, S.] Icahn Sch Med Mt Sinai, Alzheimers Dis Res Ctr, Dept Neurol, New York, NY 10029 USA. [Lee, S. W.; Clemenson, G. D.; Gage, F. H.] Salk Inst Biol Studies, Genet Lab, La Jolla, CA 92037 USA. [Carter, T. A.; Treuner, K.; Gadient, R.; Wedel, P.; Barlow, C.] BrainCells, San Diego, CA USA. [Glabe, C.] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA. [Ehrlich, M. E.] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA. [Gandy, S.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Gandy, S.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. RP Gandy, S (reprint author), James J Peters VA Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM samuel.gandy@va.gov FU BrightFocus Foundation; Alzheimer's Art Quilt Initiative Award; Cure Alzheimer's Fund Stem Cell Consortium; VA MERIT Review Awards [I01BX000348, I01RX000684]; Gideon and Sarah Gartner Foundation; Louis B Mayer Foundation; National Institute of General Medical Sciences [T32GM062754]; James S McDonnell Foundation; Mathers Foundation; Ellison Foundation; NINDS; NIMH; NIA; JPB Foundation [BCI-838, BCI-632] FX We thank J Bonet and A Morant for assistance with mouse colony management and ML Gage for editorial comments. SHK was supported by BrightFocus Foundation and by an Alzheimer's Art Quilt Initiative Award to MEE. SG was supported by Cure Alzheimer's Fund Stem Cell Consortium, VA MERIT Review Awards I01BX000348 and I01RX000684, the Gideon and Sarah Gartner Foundation and the Louis B Mayer Foundation. JWS was a trainee in the Integrated Pharmacological Sciences Training Program supported by grant T32GM062754 from the National Institute of General Medical Sciences. This work was also supported by the James S McDonnell Foundation, Mathers Foundation, Ellison Foundation, NINDS, NIMH, NIA and JPB Foundation (FHG). BCI-838 and BCI-632 are proprietary compounds that must be obtained through a Material Transfer Agreement with Taisho Pharmaceutical. BCI-838 and BCI- 632 for this research were obtained through a Material Transfer Agreement with BrainCells, Inc. NR 53 TC 11 Z9 11 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD NOV PY 2014 VL 19 IS 11 BP 1235 EP 1242 DI 10.1038/mp.2014.87 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA AR5ZT UT WOS:000343662300013 PM 25113378 ER PT J AU Chen, LJ Na, R Ran, QT AF Chen, Liuji Na, Ren Ran, Qitao TI Enhanced defense against mitochondrial hydrogen peroxide attenuates age-associated cognition decline SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; Brain aging; Mitochondria; Oxidative stress; Beta-amyloid; Peroxiredoxin 3; Mitochondrial H2O2 ID TRANSGENIC MOUSE MODEL; ALZHEIMERS-DISEASE; A-BETA; OXIDATIVE STRESS; ANTIOXIDANT DEFENSE; MEMORY DEFICITS; DNA-DAMAGE; TRANSCRIPTION; DYSFUNCTION; PROTEIN AB Increased mitochondrial hydrogen peroxide (H2O2) is associated with Alzheimer's disease and brain aging. Peroxiredoxin 3 (Prdx3) is the key mitochondrial antioxidant defense enzyme in detoxifying H2O2. To investigate the importance of mitochondrial H2O2 in age-associated cognitive decline, we compared cognition between aged (17-19 months) APP transgenic mice and APP/Prdx3 double transgenic mice (dTG) and between old (24 months) wild-type mice and Prdx3 transgenic mice (TG). Compared with aged APP mice, aged dTG mice showed improved cognition that was correlated with reduced brain amyloid beta levels and decreased amyloid beta production. Old TG mice also showed significantly increased cognitive ability compared with old wild-type mice. Both aged dTG mice and old TG mice had reduced mitochondrial oxidative stress and increased mitochondrial function. Moreover, CREB signaling, a signaling pathway important for cognition was enhanced in both aged dTG mice and old TG mice. Thus, our results indicate that mitochondrial H2O2 is a key culprit of age-associated cognitive impairment, and that a reduction of mitochondrial H2O2 could improve cognition by maintaining mitochondrial health and enhancing CREB signaling. Published by Elsevier Inc. C1 [Chen, Liuji; Na, Ren; Ran, Qitao] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Ran, Qitao] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Res & Dev Serv, San Antonio, TX USA. RP Ran, QT (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM ran@uthscsa.edu FU U.S. Department of Veteran Affairs; Alzheimer's Association FX The study was supported by a Merit Review Award from the U.S. Department of Veteran Affairs and an Investigator Initiated Research Grant from Alzheimer's Association to Qitao Ran. NR 39 TC 8 Z9 8 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD NOV PY 2014 VL 35 IS 11 BP 2552 EP 2561 DI 10.1016/j.neurobiolaging.2014.05.007 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA AR2LX UT WOS:000343419800016 PM 24906890 ER PT J AU Hall, DA Bennett, DA Filley, CM Shah, RC Kluger, B Ouyang, B Berry-Kravis, E AF Hall, Deborah A. Bennett, David A. Filley, Christopher M. Shah, Raj C. Kluger, Benzi Ouyang, Bichun Berry-Kravis, Elizabeth TI Fragile X gene expansions are not associated with dementia SO NEUROBIOLOGY OF AGING LA English DT Article DE FMR1; Fragile X; Alzheimer's disease ID TREMOR/ATAXIA-SYNDROME FXTAS; DISEASE AB The purpose of this study was to determine the frequency of fragile X mental retardation 1 (FMR1) premutation size expansions in individuals with Alzheimer's disease (AD) and other cognitive disorders compared with control subjects. FMR1 genetic screening was completed in patients being seen in a neurobehavioral or AD clinics. Appropriate controls were also collected. A second cohort was a community based, autopsy confirmed, sample of individuals with normal cognitive function, mild cognitive impairment, or AD. There was not an increased frequency of FMR1 expansions in individuals with cognitive disorders, including AD, compared with control subjects. (C) 2014 Elsevier Inc. All rights reserved. C1 [Hall, Deborah A.; Ouyang, Bichun; Berry-Kravis, Elizabeth] Rush Univ, Dept Neurol Sci, Chicago, IL 60611 USA. [Bennett, David A.; Shah, Raj C.] Rush Univ, Rush Alzheimers Dis Ctr, Chicago, IL 60611 USA. [Filley, Christopher M.; Kluger, Benzi] Univ Colorado, Sch Med, Dept Neurol, Aurora, CO USA. [Filley, Christopher M.; Kluger, Benzi] Univ Colorado, Sch Med, Dept Psychiat, Aurora, CO USA. [Filley, Christopher M.] Denver Vet Affairs Med Ctr, Dept Neurol, Denver, CO USA. [Berry-Kravis, Elizabeth] Rush Univ, Dept Pediat, Chicago, IL 60611 USA. [Berry-Kravis, Elizabeth] Rush Univ, Dept Biochem, Chicago, IL 60611 USA. RP Hall, DA (reprint author), Rush Univ, Dept Neurol Sci, 1725 West Harrison St,Suite 755, Chicago, IL 60611 USA. EM Deborah_A_Hall@rush.edu FU National Institute of Neurological Disorders and Stroke [K23NS052487]; National Institute on Aging [P30AG10161, R01AG15819] FX This study was funded by the National Institute of Neurological Disorders and Stroke K23NS052487 (Deborah Hall) and National Institute on Aging P30AG10161 and R01AG15819 (David Bennett). NR 5 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD NOV PY 2014 VL 35 IS 11 BP 2637 EP 2638 DI 10.1016/j.neurobiolaging.2014.04.027 PG 2 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA AR2LX UT WOS:000343419800024 PM 24958193 ER PT J AU Hatano, T Funayama, M Kubo, SI Mata, IF Oji, Y Mori, A Zabetian, CP Waldherr, SM Yoshino, H Oyama, G Shimo, Y Fujimoto, KI Oshima, H Kunii, Y Yabe, H Mizuno, Y Hattori, N AF Hatano, Taku Funayama, Manabu Kubo, Shin-ichiro Mata, Ignacio F. Oji, Yutaka Mori, Akio Zabetian, Cyrus P. Waldherr, Sarah M. Yoshino, Hiroyo Oyama, Genko Shimo, Yasushi Fujimoto, Ken-ichi Oshima, Hirokazu Kunii, Yasuto Yabe, Hirooki Mizuno, Yoshikuni Hattori, Nobutaka TI Identification of a Japanese family with LRRK2 p.R1441G-related Parkinson's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE Parkinson's disease; LRRK2; p.R1441G; Asia; Intrafamilial clinical heterogeneity ID R1441G MUTATION; HAPLOTYPE ANALYSIS; GENETIC-ANALYSIS; G2019S; NEUROPATHOLOGY; PATHOLOGY; CARRIERS; DARDARIN AB Leucine-rich repeat kinase 2 (LRRK2) is a causative gene of autosomal dominant familial Parkinson's disease (PD). We screened for LRRK2 mutations in 3 frequently reported exons (31, 41, and 48) in our cohort of 871 Japanese patients with PD (430 with sporadic PD and 441 probands with familial PD). Direct sequencing analysis of LRRK2 revealed 1 proband (0.11%) with a p.R1441G mutation, identified for the first time in Asian countries, besides frequently reported substitutions including, the p.G2019S mutation (0.11%) and p.G2385R variant (11.37%). Several studies have suggested that the LRRK2 p.R1441G mutation, which is highly prevalent in the Basque country, is extremely rare outside of northern Spain. Further analysis of family members of the proband with the p.R1441G mutation revealed that her mother and first cousin shared the same mutation and parkinsonism. Haplotype analysis revealed a different haplotype from that of the original Spanish families. Our patients demonstrated levodopa-responsive parkinsonism with intrafamilial clinical heterogeneity. This is the first report of familial PD because of the LRRK2 p.R1441G mutation in Asia. (C) 2014 Elsevier Inc. All rights reserved. C1 [Hatano, Taku; Funayama, Manabu; Kubo, Shin-ichiro; Oji, Yutaka; Mori, Akio; Oyama, Genko; Shimo, Yasushi; Mizuno, Yoshikuni; Hattori, Nobutaka] Juntendo Univ, Dept Neurol, Sch Med, Tokyo 1138421, Japan. [Funayama, Manabu; Yoshino, Hiroyo; Hattori, Nobutaka] Juntendo Univ, Grad Sch Med, Res Inst Dis Old Age, Tokyo 1138421, Japan. [Shimo, Yasushi] Juntendo Univ, Dept Res & Therapeut Movement Disorders, Sch Med, Tokyo 1138421, Japan. [Mata, Ignacio F.; Zabetian, Cyrus P.; Waldherr, Sarah M.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Mata, Ignacio F.; Zabetian, Cyrus P.; Waldherr, Sarah M.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Fujimoto, Ken-ichi] Jichi Idai Stn Brain Clin, Fukuoka, Tochigi, Japan. [Oshima, Hirokazu; Kunii, Yasuto; Yabe, Hirooki] Fukushima Med Univ, Dept Neuropsychiat, Fukushima, Japan. RP Hatano, T (reprint author), Juntendo Univ, Dept Neurol, Sch Med, Bunkyo Ku, 2-1-1 Hongo, Tokyo 1138421, Japan. EM thatano@juntendo.ac.jp; nhattori@juntendo.ac.jp RI Funayama, Manabu/E-6485-2013; OI Funayama, Manabu/0000-0002-7412-3631; Zabetian, Cyrus/0000-0002-7739-4306 FU Strategic Research Foundation; KAKENHI [24390224, 25461290]; Japanese Ministry of Education, Culture, Sports, Science and Technology [23111003, 25129707]; Parkinson's Disease Foundation, United States; National Institutes of Health, United States [R01 NS065070, P50 NS062684] FX The authors thank Dr Hideo Mori (Juntendo Koshigaya Hospital) and all the participants in this study. This work was supported by a Strategic Research Foundation Grant-in-Aid Project for Private Universities, Grants-in-Aid for Scientific Research (KAKENHI) (to Nobutaka Hattori, 24390224 and to Taku Hatano, 25461290) and a Grant-in-Aid for Scientific Research on Innovative Areas (to Nobutaka Hattori, 23111003 and to Manabu Funayama, 25129707) from the Japanese Ministry of Education, Culture, Sports, Science and Technology. This work was also supported by grants from the Parkinson's Disease Foundation, United States and the National Institutes of Health, United States (R01 NS065070 and P50 NS062684). Appendix A. Supplementary dataSupplementary Video 1. Supplementary Video 2. NR 31 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 EI 1558-1497 J9 NEUROBIOL AGING JI Neurobiol. Aging PD NOV PY 2014 VL 35 IS 11 AR 2656.e17 DI 10.1016/j.neurobiolaging.2014.05.025 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA AR2LX UT WOS:000343419800029 PM 24973808 ER PT J AU Rao, MN Chau, A Madden, E Inslicht, S Talbot, L Richards, A O'Donovan, A Ruoff, L Grunfeld, C Neylan, TC AF Rao, Madhu N. Chau, Alanna Madden, Erin Inslicht, Sabra Talbot, Lisa Richards, Anne O'Donovan, Aoife Ruoff, Leslie Grunfeld, Carl Neylan, Thomas C. TI Hyperinsulinemic response to oral glucose challenge in individuals with posttraumatic stress disorder SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE Oral glucose; tolerance test; Hyperinsulinemia; Insulin resistance; Glucose metabolism; Sleep; Posttraumatic stress; disorder; Adipocytokines; Diabetes mellitus ID TYPE-2 DIABETES-MELLITUS; ADMINISTERED PTSD SCALE; INSULIN-RESISTANCE; METABOLIC SYNDROME; PHYSICAL ILLNESS; URINARY CORTISOL; SEX-DIFFERENCES; CO-MORBIDITY; PRIMARY-CARE; ADIPONECTIN AB Background: Posttraumatic stress disorder (PTSD) is associated with a 2-4 fold increased risk of developing Type 2 diabetes mellitus. However, detailed assessments of glucose metabolism and insulin secretion in a study designed to minimize confounders are lacking. Furthermore, few studies examine potential mechanisms involved. We analyzed data from a case control study of medically healthy, medication-free adults to determine whether individuals with PTSD had abnormal glucose or insulin response to oral glucose tolerance test (OGTT) compared to controls. Secondarily, we assessed potential mediators such as steep, cortisol and adiponectin. Methods: Data was analyzed from 92 age and gender-matched subjects (44 PTSD, 48 controls). Chronic PTSD was diagnosed using the Structured Clinical Interview for DSM-IV and Clinician Administered PTSD Scale. Subjects underwent 75-g OGTT, actigraphy and sleep diary (to quantify sleep duration), polysomnography (to assess slow wave sleep [SWS] and delta power), and overnight blood sampling (for cortisol and adiponectin). Results: At baseline, individuals with PTSD had mildly increased insulin levels (by 19%, compared to controls, p = 0.048) that was mediated primarily by weight. In response to OGTT, the PTSD group had higher levels of insulin at 120 min (by 44%, p = 0.03) and insulin AUC (by 43%, p = 0.015) compared to controls, after adjusting for confounders. Glucose levels were similar in the two groups. Although self-reported sleep duration, SWS, and delta power differed between PTSD subjects and controls, they did not mediate the effects of PTSD status on insulin response. Conclusion: In this case control study, individuals with PTSD had a hyperinsulinemic response to oral glucose challenge compared to controls, suggestive of insulin resistance. Published by Elsevier Ltd. C1 [Rao, Madhu N.; Madden, Erin; Inslicht, Sabra; Talbot, Lisa; Richards, Anne; O'Donovan, Aoife; Ruoff, Leslie; Grunfeld, Carl; Neylan, Thomas C.] San Francisco VA Med Ctr, San Francisco, CA USA. [Rao, Madhu N.; Grunfeld, Carl] Univ Calif San Francisco, Dept Med, Div Endocrinol & Metab, San Francisco, CA USA. [Chau, Alanna] Albert Einstein Coll Med, New York, NY USA. [Madden, Erin] Northern Calif Inst Res & Educ, San Francisco, CA USA. [Inslicht, Sabra; Talbot, Lisa; Richards, Anne; O'Donovan, Aoife; Neylan, Thomas C.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Rao, MN (reprint author), San Francisco VA Med Ctr, 111F,4150 Clement St, San Francisco, CA 94121 USA. EM Madhu.Rao@usf.edu FU NIH [R01MH073978, K23HL096832, R34MH077667]; NIH GCRC [UL1 RR024131]; Mental Illness Research and Education Clinical Center of the US Veterans Health Administration; Department of Defense; Department of Veterans Affairs FX This research was supported by NIH grants R01MH073978, K23HL096832 and R34MH077667, NIH GCRC grant UL1 RR024131 and grant funding from the Mental Illness Research and Education Clinical Center of the US Veterans Health Administration. Dr. Neylan reported receiving study medication from Actelion for a study funded by the Department of Defense and receiving study medication from Glaxo Smith Kline for a study funded by the Department of Veterans Affairs. The funding agencies had no role in the collection or analysis of the data or in the preparation of this manuscript. NR 59 TC 4 Z9 4 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD NOV PY 2014 VL 49 BP 171 EP 181 DI 10.1016/j.psyneuen.2014.07.006 PG 11 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA AR1KA UT WOS:000343342900019 PM 25108160 ER PT J AU Patel, MS Vagefi, PA AF Patel, Madhukar S. Vagefi, Parsia A. TI Commentary on: Mesohepatectomy for centrally located large hepatocellular carcinoma: Indications, techniques, and outcomes SO SURGERY LA English DT Editorial Material ID LIVER C1 [Patel, Madhukar S.; Vagefi, Parsia A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Transplant Surg, Boston, MA USA. RP Vagefi, PA (reprint author), Massachusetts Gen Hosp, 55 Fruit St,White 521c, Boston, MA 02114 USA. EM pvagefi@mgh.harvard.edu NR 5 TC 1 Z9 1 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD NOV PY 2014 VL 156 IS 5 BP 1188 EP 1189 DI 10.1016/j.surg.2014.06.009 PG 2 WC Surgery SC Surgery GA AR7WG UT WOS:000343787100017 PM 25444317 ER PT J AU Warshaw, AL Ferrone, CR Fernandez-Del Castillo, C AF Warshaw, Andrew L. Ferrone, Cristina R. Fernandez-Del Castillo, Carlos TI In response to Birgir Gudjonsson, MD SO SURGERY LA English DT Letter C1 [Warshaw, Andrew L.; Ferrone, Cristina R.; Fernandez-Del Castillo, Carlos] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Warshaw, AL (reprint author), Massachusetts Gen Hosp, Dept Surg, 55 Fruit St, Boston, MA 02114 USA. EM awarshaw@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD NOV PY 2014 VL 156 IS 5 BP 1286 EP 1286 DI 10.1016/j.surg.2014.06.005 PG 1 WC Surgery SC Surgery GA AR7WG UT WOS:000343787100034 PM 25444320 ER PT J AU Greenberg, CC Habel, LA Hughes, ME Nekhlyudov, L Achacoso, N Acton, L Schrag, D Jiang, W Edge, S Weeks, JC Punglia, RS AF Greenberg, Caprice C. Habel, Laurel A. Hughes, Melissa E. Nekhlyudov, Larissa Achacoso, Ninah Acton, Luana Schrag, Deborah Jiang, Wei Edge, Stephen Weeks, Jane C. Punglia, Rinaa S. TI Characterization and Treatment of Local Recurrence Following Breast Conservation for Ductal Carcinoma In Situ SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID RADIATION-THERAPY; AMERICAN SOCIETY; REGISTRY TRIAL; CANCER; IRRADIATION; BRACHYTHERAPY; RECONSTRUCTION; RADIOTHERAPY; LUMPECTOMY; MANAGEMENT AB The optimal treatment strategy for ductal carcinoma in situ (DCIS) continues to evolve and should consider the consequences of initial treatment on the likelihood, type, and treatment of recurrences. We conducted a retrospective cohort study using two data sources of patients who experienced a recurrence (DCIS or invasive cancer) following breast-conserving surgery (BCS) for index DCIS: patients with an index DCIS diagnosed from 1997 to 2008 at the academic institutions of the National Comprehensive Cancer Network (NCCN; N = 88) and patients with an index DCIS diagnosed from 1990 to 2001 at community-based integrated healthcare delivery sites of the Health Maintenance Organization Cancer Research Network (CRN) (N = 182). Just under half of local recurrences in both cohorts were invasive cancer. While 40 % of patients in both cohorts underwent mastectomy alone at recurrence, treatment of the remaining patients varied. In the earlier CRN cohort, most other patients underwent repeat BCS (39 %) with only 18 % receiving mastectomy with reconstruction, whereas only 16 % had repeat BCS and 44 % had mastectomy with reconstruction in the NCCN cohort. Compared with patients not treated with radiation, those who received radiation for index DCIS were less likely to undergo repeat BCS (NCCN: 6.6 vs. 37 %, p = 0.001; CRN: 20 vs. 48 %, p = 0.0004) and more likely to experience surgical complications after treatment of recurrence (NCCN: 15 vs. 4 %, p = 0.17; CRN: 40 vs. 25 %, p = 0.09). We found that treatment of recurrences after BCS and subsequent complications may be affected by the use of radiotherapy for the index DCIS. Initial treatment of DCIS may have long-term implications that should be considered. C1 [Greenberg, Caprice C.] Univ Wisconsin, Hosp & Clin, Dept Surg, Wisconsin Surg Outcomes Res WiSOR Program, Madison, WI 53792 USA. [Habel, Laurel A.; Achacoso, Ninah; Acton, Luana] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Hughes, Melissa E.; Schrag, Deborah; Weeks, Jane C.] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Dept Med Oncol, Div Populat Sci, Boston, MA 02115 USA. [Nekhlyudov, Larissa] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Nekhlyudov, Larissa] Harvard Vanguard Med Associates, Dept Med, Boston, MA USA. [Jiang, Wei] Brigham & Womens Hosp, Dept Surg, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Edge, Stephen] Baptist Mem Hlth Care Corp, Baptist Canc Ctr, Memphis, TN USA. [Edge, Stephen] Vanderbilt Univ, Sch Med, Dept Surg, Nashville, TN 37212 USA. [Punglia, Rinaa S.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Greenberg, CC (reprint author), Univ Wisconsin, Hosp & Clin, Dept Surg, Wisconsin Surg Outcomes Res WiSOR Program, Madison, WI 53792 USA. EM greenberg@surgery.wisc.edu RI JIANG, WEI /F-3930-2015 FU Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services [HHSA29020050016I]; National Cancer Institute [CA89393, R01 CA 81302, 2U19CA079689] FX This work was supported by Contract No. HHSA29020050016I from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, as part of the Developing Evidence to Inform Decisions About Effectiveness program. The views expressed in this article are those of the authors, and no official endorsement by AHRQ or the US Department of Health and Human Services is intended or should be inferred. This work was also supported by grant no. CA89393 from the National Cancer Institute to the Dana-Farber Cancer Institute, Grant No. R01 CA 81302 to Kaiser Permanente Northern California, and grant no. 2U19CA079689 to Group Health Cooperative (Laurel Habel, Project Leader). NR 33 TC 1 Z9 1 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2014 VL 21 IS 12 BP 3766 EP 3773 DI 10.1245/s10434-014-3802-7 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA AQ8OD UT WOS:000343085600015 PM 24859938 ER PT J AU Zhu, AX Borger, DR Kim, Y Cosgrove, D Ejaz, A Alexandrescu, S Groeschl, RT Deshpande, V Lindberg, JM Ferrone, C Sempoux, C Yau, T Poon, R Popescu, I Bauer, TW Gamblin, TC Gigot, JF Anders, RA Pawlik, TM AF Zhu, Andrew X. Borger, Darrell R. Kim, Yuhree Cosgrove, David Ejaz, Aslam Alexandrescu, Sorin Groeschl, Ryan Thomas Deshpande, Vikram Lindberg, James M. Ferrone, Cristina Sempoux, Christine Yau, Thomas Poon, Ronnie Popescu, Irinel Bauer, Todd W. Gamblin, T. Clark Gigot, Jean Francois Anders, Robert A. Pawlik, Timothy M. TI Genomic Profiling of Intrahepatic Cholangiocarcinoma: Refining Prognosis and Identifying Therapeutic Targets SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID ISOCITRATE DEHYDROGENASE 1; RAS MUTATIONS; BILIARY-TRACT; HEPATOCELLULAR-CARCINOMA; MOLECULAR THERAPIES; LIVER; PATHOGENESIS; CANCERS; KRAS; HYPERMETHYLATION AB The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection. Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined. The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of > 5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis. Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis. C1 [Zhu, Andrew X.; Borger, Darrell R.; Deshpande, Vikram; Ferrone, Cristina] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. [Kim, Yuhree; Cosgrove, David; Ejaz, Aslam; Anders, Robert A.; Pawlik, Timothy M.] Johns Hopkins Univ, Baltimore, MD USA. [Alexandrescu, Sorin; Popescu, Irinel] Fundeni Clin Inst Digest Dis & Liver Transplantat, Bucharest, Romania. [Groeschl, Ryan Thomas; Gamblin, T. Clark] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Lindberg, James M.; Bauer, Todd W.] Univ Virginia, Charlottesville, VA USA. [Sempoux, Christine; Gigot, Jean Francois] Clin Univ St Luc, B-1200 Brussels, Belgium. [Yau, Thomas; Poon, Ronnie] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. RP Zhu, AX (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. EM tpawlik1@jhmi.edu RI POPESCU, IRINEL/B-3048-2008 FU Agios FX We thank Kenneth C. Fan, Hector U. Lopez, and Christina R. Matulis for their technical assistance and Daniel J. Harris for data collection. Supported in part by Agios. NR 34 TC 20 Z9 21 U1 0 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2014 VL 21 IS 12 BP 3827 EP 3834 DI 10.1245/s10434-014-3828-x PG 8 WC Oncology; Surgery SC Oncology; Surgery GA AQ8OD UT WOS:000343085600024 PM 24889489 ER PT J AU Hauch, A Al-Qurayshi, Z Randolph, G Kandil, E AF Hauch, Adam Al-Qurayshi, Zaid Randolph, Gregory Kandil, Emad TI Total Thyroidectomy is Associated with Increased Risk of Complications for Low- and High-Volume Surgeons SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID ICD-10 ADMINISTRATIVE DATA; HOSPITAL VOLUME; UNITED-STATES; OPERATIVE MORTALITY; MULTINODULAR GOITER; SURGICAL VOLUME; CANCER-SURGERY; OUTCOMES; DISEASE; MANAGEMENT AB There has been an increased use of total thyroidectomy (TT), including in the management of benign thyroid diseases. We sought to compare the risk of complications between TT and unilateral thyroidectomy (UT) and to evaluate the effect of surgeon's experience on outcomes. Nationwide Inpatient Sample from 2003 to 2009 was used to perform cross-sectional analysis of all adult patients who underwent TT and UT for benign or malignant conditions. Logistic regression was used to evaluate outcomes and to provide correlation between outcome and surgeon volume. Surgeon volume was categorized as low or high (performing < 10 or > 99 thyroid operations/year, respectively). A total of 62,722 procedures were included. Most cases were TT (57.9 %) performed for benign disease. There was a significantly increased risk of complication after TT compared to UT (20.4 vs. 10.8 %: p < 0.0001). High-volume surgeons performed only 5.0 % of the procedures overall, with 62.6 % of the high-volume surgeon procedures being TTs. Low-volume surgeons were more likely to have postoperative complications after TT compared to high-volume surgeons (odds ratio 1.53, 95 % confidence interval 1.12, 2.11, p = 0.0083). Mean charges were significantly higher for TT compared to lobectomy ($19,365 vs. $15,602, p < 0.0001), and length of stay was longer for TT compared to lobectomy (1.63 vs. 1.29 days, p < 0.0001). TT is associated with a significantly higher risk of complications compared to UT even among high-volume surgeons. Higher surgeon volume is associated with improved patient outcomes. C1 [Hauch, Adam; Al-Qurayshi, Zaid; Kandil, Emad] Tulane Univ, Sch Med, Dept Surg, New Orleans, LA 70112 USA. [Randolph, Gregory] Massachusetts Eye & Ear Infirm, Div Gen Otolaryngol, Boston, MA 02114 USA. RP Hauch, A (reprint author), Tulane Univ, Sch Med, Dept Surg, New Orleans, LA 70112 USA. EM ahauch@tulane.edu OI Al-Qurayshi, Zaid/0000-0002-3534-7253 NR 41 TC 43 Z9 46 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2014 VL 21 IS 12 BP 3844 EP 3852 DI 10.1245/s10434-014-3846-8 PG 9 WC Oncology; Surgery SC Oncology; Surgery GA AQ8OD UT WOS:000343085600026 PM 24943236 ER PT J AU Yamada, S Okumura, N Wei, L Fuchs, BC Fujii, T Sugimoto, H Nomoto, S Takeda, S Tanabe, KK Kodera, Y AF Yamada, Suguru Okumura, Norio Wei, Lan Fuchs, Bryan C. Fujii, Tsutomu Sugimoto, Hiroyuki Nomoto, Shuji Takeda, Shin Tanabe, Kenneth K. Kodera, Yasuhiro TI Epithelial to Mesenchymal Transition is Associated with Shorter Disease-Free Survival in Hepatocellular Carcinoma SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID BREAST-CANCER CELLS; E-CADHERIN; PANCREATIC-CANCER; TUMOR-METASTASIS; TWIST EXPRESSION; GROWTH-FACTOR; LIVER-CANCER; STEM-CELLS; SNAIL; INTERLEUKIN-6 AB Epithelial to mesenchymal transition (EMT) is involved in cancer cell invasion and metastasis as well as chemoresistance. Elucidation of EMT in hepatocellular carcinoma (HCC) might contribute to deeper understanding of its biology. Overall, 100 patients with HCC, who underwent resection, were analyzed. The messenger RNA (mRNA) expression of the epithelial marker E-cadherin and the mesenchymal marker Vimentin were measured, and the EMT status of each patient was determined as follows: Vimentin/E-cadherin < 2 = Epithelial (E), Vimentin/E-cadherin a parts per thousand yen2 = Mesenchymal (M). The correlation between these values and clinicopathological factors and prognosis were analyzed statistically. Moreover, the expression of transcription factors involved in EMT (Twist-1, Snail, Slug, Zeb-1, and Zeb-2) were measured and the role of interleukin (IL)-6 in inducing EMT and chemoresistance was examined. Patients with a mesenchymal tumor were more prone to have an earlier recurrence than those with an epithelial tumor. EMT-inducing transcription factors were more highly expressed in mesenchymal tumors than in epithelial tumors, and Twist-1 and Zeb-2 were significantly overexpressed. alpha-Fetoprotein (AFP) values were significantly higher in patients with epithelial tumors, and AFP-expressing HCC cell lines were more responsive to sorafenib. IL-6 expression was significantly higher in mesenchymal tumors, and knockdown of IL-6 in mesenchymal HCC cell lines increased E-cadherin expression and sensitivity to sorafenib. Analysis of surgically resected tumors suggests that EMT is involved in early disease recurrence in HCC. Twist-1 and Zeb-2 might be important for inducing EMT, and IL-6 might be a potential therapeutic target for alleviating the chemoresistance of mesenchymal HCC tumors. C1 [Yamada, Suguru; Okumura, Norio; Fujii, Tsutomu; Sugimoto, Hiroyuki; Nomoto, Shuji; Takeda, Shin; Kodera, Yasuhiro] Nagoya Univ, Grad Sch Med, Dept Gastroenterol Surg Surg 2, Nagoya, Aichi 4648601, Japan. [Wei, Lan; Fuchs, Bryan C.; Tanabe, Kenneth K.] Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA USA. [Wei, Lan; Fuchs, Bryan C.; Tanabe, Kenneth K.] Harvard Univ, Sch Med, Boston, MA USA. RP Yamada, S (reprint author), Nagoya Univ, Grad Sch Med, Dept Gastroenterol Surg Surg 2, Nagoya, Aichi 4648601, Japan. EM suguru@med.nagoya-u.ac.jp RI Kodera, Yasuhiro/M-4912-2014; Fujii, Tsutomu/M-4838-2014 NR 39 TC 14 Z9 16 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2014 VL 21 IS 12 BP 3882 EP 3890 DI 10.1245/s10434-014-3779-2 PG 9 WC Oncology; Surgery SC Oncology; Surgery GA AQ8OD UT WOS:000343085600032 PM 24833103 ER PT J AU Amri, R Bordeianou, LG Sylla, P Berger, DL AF Amri, Ramzi Bordeianou, Liliana G. Sylla, Patricia Berger, David L. TI Treatment Delay in Surgically-Treated Colon Cancer: Does It Affect Outcomes? SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID COLORECTAL-CANCER; RECTAL-CANCER; THERAPEUTIC DELAY; SURVIVAL; SURGERY; GROWTH AB Treatment delay, or the time lapse between diagnosis and surgery, may have a detrimental effect on cancer outcomes. This study assesses the effect of treatment delay on cancer-related outcomes in a large, continuous series of surgically treated colon cancer patients. All surgical colon cancer cases at our center from 2004 through 2011 were reviewed. Patients who underwent preoperative chemotherapy, emergency admissions, palliative cases, and incidental and postoperative diagnoses were excluded. Treatment delay was correlated with outcomes in univariate and multivariate regression and proportional hazards models. In 769 included patients, for every treatment-delay quartile increase, odds of death decreased by an odds ratio (OR) of 0.78 (p = 0.001), and metastatic recurrence by OR 0.78 (p = 0.013). Shorter survival duration had a hazard ratio (HR) of 0.81 (p = 0.001) and shorter disease-free survival HR 0.72 (p < 0.001). Multivariate regression adjusting for baseline staging greatly reduces these ratios, and makes them non-significant. Similar patterns were shown in high-risk subsets, including stage III disease, ethnic minorities, patients with positive margins, and extramural vascular invasion. The inverse relation between treatment delay and survival and recurrence reflected adequate prioritization of advanced and high-risk cases and concurrently showed that, matched for stage and risk categories, treatment delay was not associated with worse cancer outcomes for patients with colon cancer. A reasonable delay between diagnosis and subsequent surgery is not detrimental to patient outcomes and permits more flexibility in scheduling and justifies allowing time to complete proper preoperative evaluation and staging, improving the quality and safety of resection and treatment. C1 [Amri, Ramzi] Massachusetts Gen Hosp, Div Gen Surg & Gastrointestinal Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Amri, R (reprint author), Massachusetts Gen Hosp, Div Gen Surg & Gastrointestinal Surg, Boston, MA 02114 USA. EM dberger@mgh.harvard.edu OI Amri, Ramzi/0000-0001-7416-6650 NR 18 TC 3 Z9 3 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD NOV PY 2014 VL 21 IS 12 BP 3909 EP 3916 DI 10.1245/s10434-014-3800-9 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA AQ8OD UT WOS:000343085600035 PM 24849522 ER PT J AU Ion, D Stevenson, K Woo, SB Ho, VT Soiffer, R Antin, JH Treister, NS AF Ion, Daniela Stevenson, Kristen Woo, Sook-Bin Ho, Vincent T. Soiffer, Robert Antin, Joseph H. Treister, Nathaniel S. TI Characterization of Oral Involvement in Acute Graft-versus-Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Graft-versus-host disease; Acute; Oral ulcers; Stomatitis ID BONE-MARROW TRANSPLANTATION; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; CLINICAL-TRIALS; MORPHINE; CRITERIA AB Acute graft-versus-host-disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). The purpose of this study was to characterize the oral features associated with aGVHD in patients who underwent HSCT between 1995 and 2010 and developed prominent oral aGVHD. Data was collected from patient medical records and analyzed descriptively. Twenty-one cases were identified, of which 5 (24%) demonstrated only oral features; the remaining 16 had variable involvement of skin (n = 14), liver (n = 7), and gut (n = 5). The median time to onset of any sign of aGVHD was 22 days (range, 8 to 154 days), and that for onset of oral aGVHD was 35 days (range, 11 to 159 days). Sites affected by nonspecific erythema and ulcerations included buccal mucosa (19 of 21; 90%) tongue (18 of 21; 86%; dorsum in 8), labial mucosa (16 of 21; 76%), palatal mucosa (15 of 21; 71%; hard palate in 7), and floor of mouth (7 of 21; 33%). Eight cases (38%) presented with lip ulceration and crusting. In addition to systemic therapies, topical solutions of dexamethasone, tacrolimus, and morphine were used for ancillary support. Oral features of aGVHD may be the initial manifestation and include nonspecific erythema and ulcerations of keratinized and non-keratinized mucosa and lips. Intensive topical therapies may help reduce symptoms and promote healing. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Ion, Daniela] Guys & St Thomas NHS Fdn Trust, Dept Oral Med, London, England. [Stevenson, Kristen] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Woo, Sook-Bin; Treister, Nathaniel S.] Brigham & Womens Hosp, Div Oral Med & Dent, Boston, MA 02115 USA. [Woo, Sook-Bin; Treister, Nathaniel S.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Ho, Vincent T.; Soiffer, Robert; Antin, Joseph H.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Ho, Vincent T.; Soiffer, Robert; Antin, Joseph H.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Treister, NS (reprint author), Brigham & Womens Hosp, Div Oral Med & Dent, 3rd Floor,1620 Tremont St, Boston, MA 02120 USA. EM ntreister@partners.org NR 22 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2014 VL 20 IS 11 BP 1717 EP 1721 DI 10.1016/j.bbmt.2014.06.031 PG 5 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AR1SG UT WOS:000343364300009 PM 24979731 ER PT J AU Hamadani, M Hari, PN Zhang, Y Carreras, J Akpek, G Aljurf, MD Ayala, E Bachanova, V Chen, AI Chen, YB Costa, LJ Fenske, TS Freytes, CO Ganguly, S Hertzberg, MS Holmberg, LA Inwards, DJ Kamble, RT Kanfer, EJ Lazarus, HM Marks, DI Nishihori, T Olsson, R Reddy, NM Rizzieri, DA Savani, BN Solh, M Vose, JM Wirk, B Maloney, DG Smith, SM Montoto, S Saber, W AF Hamadani, Mehdi Hari, Parameswaran N. Zhang, Ying Carreras, Jeanette Akpek, Goerguen Aljurf, Mahmoud D. Ayala, Ernesto Bachanova, Veronika Chen, Andy I. Chen, Yi-Bin Costa, Luciano J. Fenske, Timothy S. Freytes, Cesar O. Ganguly, Siddhartha Hertzberg, Mark S. Holmberg, Leona A. Inwards, David J. Kamble, Rammurti T. Kanfer, Edward J. Lazarus, Hillard M. Marks, David I. Nishihori, Taiga Olsson, Richard Reddy, Nishitha M. Rizzieri, David A. Savani, Bipin N. Solh, Melhem Vose, Julie M. Wirk, Baldeep Maloney, David G. Smith, Sonali M. Montoto, Silvia Saber, Wael TI Early Failure of Frontline Rituximab-Containing Chemo-immunotherapy in Diffuse Large B Cell Lymphoma Does Not Predict Futility of Autologous Hematopoietic Cell Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Autologous transplantation; Rituximab; Early failure; High-dose therapy; Diffuse large B cell lymphoma; Aggressive lymphoma; Non-Hodgkin lymphoma ID NON-HODGKINS-LYMPHOMA; BONE-MARROW TRANSPLANTATION; CHEMOTHERAPY PLUS RITUXIMAB; CHOP-LIKE CHEMOTHERAPY; TRIAL MINT GROUP; CONDITIONING REGIMENS; AGGRESSIVE LYMPHOMA; INTERMEDIATE-GRADE; SALVAGE THERAPY; GERMINAL-CENTER AB The poor prognosis for patients with diffuse large B cell lymphoma (DLBCL) who relapse within 1 year of initial diagnosis after first-line rituximab-based chemo-immunotherapy has created controversy about the role of autologous transplantation (HCT) in this setting. We compared autologous HCT outcomes for chemosensitive DLBCL patients between 2000 and 2011 in 2 cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1 year of initial diagnosis. The ERF cohort was compared with those relapsing >1 year after initial diagnosis (late rituximab failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS) of ERF versus LRF cohorts at 3 years were 9% (95% confidence interval [CI], 6% to 13%) versus 9% (95% CI, 5% to 13%), 47% (95% CI, 41% to 52%) versus 39% (95% CI, 33% to 46%), 44% (95% CI, 38% to 50%) versus 52% (95% CI, 45% to 59%), and 50% (95% CI, 44% to 56%) versus 67% (95% CI, 60% to 74%), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk [RR], 1.31; P = .34). The ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR, 2.08; P < .001) and overall mortality (RR, 3.75; P < .001) within the first 9 months after autologous HCT. Beyond this period, PFS and OS were not significantly different between the ERF and LRF cohorts. Autologous HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS, 44%) and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Hamadani, Mehdi; Hari, Parameswaran N.; Carreras, Jeanette; Saber, Wael] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Zhang, Ying] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Akpek, Goerguen] Banner MD Anderson Canc Ctr, Hematol Oncol Sect, Gilbert, AZ USA. [Hamadani, Mehdi] King Faisal Specialist Hosp Ctr & Res, Dept Oncol, Riyadh, Saudi Arabia. [Ayala, Ernesto; Nishihori, Taiga] H Lee Moffitt Canc Ctr & Res Inst, Blood & Marrow Transplantat Program, Tampa, FL USA. [Bachanova, Veronika; Solh, Melhem] Univ Minnesota, Med Ctr, Blood & Marrow Transplant Program, Minneapolis, MN 55455 USA. [Chen, Andy I.] Oregon Hlth & Sci Univ, Blood & Marrow Transplant Program, Portland, OR 97201 USA. [Chen, Yi-Bin] Massachusetts Gen Hosp, Dept BMT, Boston, MA 02114 USA. [Costa, Luciano J.] Med Univ S Carolina, Blood & Marrow Transplant Program, Charleston, SC 29425 USA. [Fenske, Timothy S.] Froedtert & Med Coll Wisconsin, Div Hematol & Oncol, Milwaukee, WI USA. [Freytes, Cesar O.] South Texas Vet Hlth Care Syst, Blood & Marrow Transplant Program, San Antonio, TX USA. [Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Ganguly, Siddhartha] St Lukes Blood & Marrow Transplant Program, BMT Program, Westwood, KS USA. [Hertzberg, Mark S.] Westmead Hosp, Dept Haematol, Westmead, NSW 2145, Australia. [Holmberg, Leona A.; Maloney, David G.] Fred Hutchinson Canc Res Ctr, Dept Clin Res, Seattle, WA 98104 USA. [Inwards, David J.] Mayo Clin, Dept Hematol, Rochester, MN USA. [Kamble, Rammurti T.] Baylor Coll Med, Dept Hematol Oncol, Houston, TX 77030 USA. [Kamble, Rammurti T.] Ctr Cell & Gene Therapy, Houston, TX USA. [Kanfer, Edward J.] Imperial Coll NHS Trust, Dept Hematol, Hammersmith Hosp, London, England. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Blood & Marrow Transplant Program, Cleveland, OH USA. [Marks, David I.] Univ Hosp Britol NHS Trust, Adult BMT Unit, Bristol, Avon, England. [Olsson, Richard] Karolinska Inst, Div Therapeut Immunol, Dept Lab Med, Stockholm, Sweden. [Olsson, Richard] Uppsala Univ, Ctr Clin Res Sormland, Uppsala, Sweden. [Reddy, Nishitha M.; Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Blood & Marrow Transplant Program, Nashville, TN USA. [Rizzieri, David A.] Duke Univ, Div Hematol Malignancies & Cellular Therapy, Durham, NC USA. [Vose, Julie M.] Nebraska Med Ctr, Dept Internal Med, Omaha, NE USA. [Wirk, Baldeep] SUNY Stony Brook, Med Ctr, BMT Program, Stony Brook, NY 11794 USA. [Smith, Sonali M.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Montoto, Silvia] Barts Hlth NHS Trust, St Bartholomews Hosp, Dept Haematooncol, London, England. 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 OI dandoy, christopher/0000-0002-4001-9203; Olsson, Richard/0000-0001-5970-2128; Hamadani, Mehdi/0000-0001-5372-510X; Hari, Parameswaran/0000-0002-8800-297X FU Public Health Service Grant/Cooperative Agreement from the National Cancer Institute [U24-CA076518]; National Heart, Lung and Blood Institute; National Institute of Allergy and Infectious Diseases; NHLBI and National Cancer Institute [5U10HL069294]; Health Resources and Services Administration [HHSH250201200016C]; Office of Naval Research [N00014-12-1-0142, N00014-13-1-0039]; 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; 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; Leukemia & Lymphoma Society; Medac GmbH; 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; Terumo BCT; Teva Neuroscience, Inc.; Texas Instruments Inc.; University of Minnesota; University of Utah; WellPoint, Inc. FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute, the National Heart, Lung and Blood Institute and the National Institute of Allergy and Infectious Diseases; a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and National Cancer Institute; a contract HHSH250201200016C with Health Resources and Services Administration; 2 Grants N00014-12-1-0142 and N00014-13-1-0039 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; 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; *Terumo BCT; *Teva Neuroscience, Inc.; *Texas Instruments 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 or any other agency of the US Government. NR 35 TC 18 Z9 18 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2014 VL 20 IS 11 BP 1729 EP 1736 DI 10.1016/j.bbmt.2014.06.036 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AR1SG UT WOS:000343364300011 PM 25008330 ER PT J AU Herrera, AF Kim, HT Bindra, B Jones, KT Alyea, EP Armand, P Cutler, CS Ho, VT Nikiforow, S Blazar, BR Ritz, J Antin, JH Soiffer, RJ Koreth, J AF Herrera, Alex F. Kim, Haesook T. Bindra, Bhavjot Jones, Kyle T. Alyea, Edwin P. Armand, Philippe Cutler, Corey S. Ho, Vincent T. Nikiforow, Sarah Blazar, Bruce R. Ritz, Jerome Antin, Joseph H. Soiffer, Robert J. Koreth, John TI A Phase II Study of Bortezomib Plus Prednisone for Initial Therapy of Chronic Graft-versus-Host Disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Chronic graft-versus-host; disease; Hematopoietic stem cell; transplantation; Graft-versus-host disease; Proteasome inhibition ID STEM-CELL TRANSPLANTATION; PROTEASOME INHIBITOR BORTEZOMIB; NF-KAPPA-B; REGULATORY T-CELLS; MINOR HISTOCOMPATIBILITY ANTIGEN; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; MULTIPLE-MYELOMA; CLINICAL-TRIALS; CHRONIC GVHD AB Chronic graft-versus-host disease (GVHD) induces significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Corticosteroids are standard initial therapy, despite limited efficacy and long-term toxicity. Based on our experience using bortezomib as effective acute GVHD prophylaxis, we hypothesized that proteasome-inhibition would complement the immunomodulatory effects of corticosteroids to improve outcomes in chronic GVHD (cGVHD). We undertook a single-arm phase II trial of bortezomib plus prednisone for initial therapy of cGVHD. Bortezomib was administered at 1.3 mg/m(2) i.v. on days 1, 8, 15, and 22 of each 35-day cycle for 3 cycles (15 weeks). Prednisone was dosed at .5 to 1 mg/kg/day, with a suggested taper after cycle 1. All 22 enrolled participants were evaluable for toxicity; 20 were evaluable for response. Bortezomib plus prednisone therapy was well tolerated, with 1 occurrence of grade 3 sensory peripheral neuropathy possibly related to bortezomib. The overall response rate at week 15 in evaluable participants was 80%, including 2 (10%) complete and 14 (70%) partial responses. The organ-specific complete response rate was 73% for skin, 53% for liver, 75% for gastrointestinal tract, and 33% for joint, muscle, or fascia involvement. The median prednisone dose decreased from 50 mg/day to 20 mg/day at week 15 (P < .001). The combination of bortezomib and prednisone for initial treatment of cGVHD is feasible and well tolerated. We observed a high response rate to combined bortezomib and prednisone therapy; however, in this single-arm study, we could not directly measure the impact of bortezomib. Proteasome inhibition may offer benefit in the treatment of cGVHD and should be further evaluated. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Herrera, Alex F.; Bindra, Bhavjot; Jones, Kyle T.; Alyea, Edwin P.; Armand, Philippe; Cutler, Corey S.; Ho, Vincent T.; Nikiforow, Sarah; Ritz, Jerome; Antin, Joseph H.; Soiffer, Robert J.; Koreth, John] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02215 USA. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Blazar, Bruce R.] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN USA. RP Koreth, J (reprint author), Dana Farber Canc Inst, Div Hematol Malignancies, 450 Brookline Ave, Boston, MA 02215 USA. EM john_koreth@dfci.harvard.edu OI Ritz, Jerome/0000-0001-5526-4669 FU Millennium Pharmaceuticals, Inc.; National Institutes of Health/National Cancer Institute [P01 CA142106, R01 CA183559] FX The authors thank the study's registered nurses, Susan Stephenson and Mildred Pasek; the stem-cell transplantation program nurse practitioners, Melissa Cochran, Amy Joyce, Bonnie Dirr, and Katherine Stephans; and all the study participants. This study was supported in part by Millennium Pharmaceuticals, Inc. and by the National Institutes of Health/National Cancer Institute (P01 CA142106, R01 CA183559). J.K. is a Clinical Research Scholar of the Leukemia and Lymphoma Society. NR 45 TC 14 Z9 15 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2014 VL 20 IS 11 BP 1737 EP 1743 DI 10.1016/j.bbmt.2014.06.040 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AR1SG UT WOS:000343364300012 PM 25017765 ER PT J AU Ringden, O Brazauskas, R Wang, ZW Ahmed, I Atsuta, Y Buchbinder, D Burns, LJ Cahn, JY Duncan, C Hale, GA Halter, J Hayashi, RJ Hsu, JW Jacobsohn, DA Kamble, RT Kamani, NR Kasow, KA Khera, N Lazarus, HM Loren, AW Marks, DI Myers, KC Ramanathan, M Saber, W Savani, BN Schouten, HC Socie, G Sorror, ML Steinberg, A Popat, U Wingard, JR Mattsson, J Majhail, NS AF Ringden, Olle Brazauskas, Ruta Wang, Zhiwei Ahmed, Ibrahim Atsuta, Yoshiko Buchbinder, David Burns, Linda J. Cahn, Jean-Yves Duncan, Christine Hale, Gregory A. Halter, Joerg Hayashi, Robert J. Hsu, Jack W. Jacobsohn, David A. Kamble, Rammurti T. Kamani, Naynesh R. Kasow, Kimberly A. Khera, Nandita Lazarus, Hillard M. Loren, Alison W. Marks, David I. Myers, Kasiani C. Ramanathan, Muthalagu Saber, Wael Savani, Bipin N. Schouten, Harry C. Socie, Gerard Sorror, Mohamed L. Steinberg, Amir Popat, Uday Wingard, John R. Mattsson, Jonas Majhail, Navneet S. TI Second Solid Cancers after Allogeneic Hematopoietic Cell Transplantation Using Reduced-Intensity Conditioning SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Hematopoietic cell transplantation; Reduced-intensity conditioning; Nonmyeloablative conditioning; Second cancers; Solid tumors ID BONE-MARROW-TRANSPLANTATION; MALIGNANT NEOPLASMS; SECONDARY CANCERS; MYELOID-LEUKEMIA; APLASTIC-ANEMIA; RISK; CHEMOTHERAPY; CHILDHOOD; SURVIVORS; ADULTS AB We examined risk of second solid cancers after allogeneic hematopoietic cell transplantation (AHCT) using reduced-intensity/nonmyeloablative conditioning (RIC/NMC). RIC/NMC recipients with leukemia/myelodysplastic syndrome (MDS) (n = 2833) and lymphoma (n = 1436) between 1995 and 2006 were included. In addition, RIC/NMC recipients 40 to 60 years of age (n = 2138) were compared with patients of the same age receiving myeloablative conditioning (MAC, n = 6428). The cumulative incidence of solid cancers was 3.35% at 10 years. There was no increase in overall cancer risk compared with the general population (leukemia/MDS: standardized incidence ratio [SIR] .99, P = 1.00; lymphoma: SIR .92, P = .75). However, risks were significantly increased in leukemia/MDS patients for cancers of lip (SIR 14.28), tonsil (SIR 8.66), oropharynx (SIR 46.70), bone (SIR 23.53), soft tissue (SIR 12.92), and vulva (SIR 18.55) and skin melanoma (SIR 3.04). Lymphoma patients had significantly higher risks of oropharyngeal cancer (SIR 67.35) and skin melanoma (SIR 3.52). Among RIC/NMC recipients, age >50 years was the only independent risk factor for solid cancers (hazard ratio [HR] 3.02, P < .001). Among patients ages 40 to 60 years, when adjusted for other factors, there was no difference in cancer risks between RIC/NMC and MAC in leukemia/MDS patients (HR .98, P = .905). In lymphoma patients, risks were lower after RIC/NMC (HR .51, P = .047). In conclusion, the overall risks of second solid cancers in RIC/NMC recipients are similar to the general population, although there is an increased risk of cancer at some sites. Studies with longer follow-up are needed to realize the complete risks of solid cancers after RIC/NMC AHCT. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Ringden, Olle; Mattsson, Jonas] Karolinka Univ Hosp, Ctr Allogene Stem Cell Transplantat, Stockholm, Sweden. [Brazauskas, Ruta] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Wang, Zhiwei; Saber, Wael] Med Coll Wisconsin, Ctr Int Bone & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Ahmed, Ibrahim] Univ New Mexico, Dept Pediat Hematol & Oncol, Albuquerque, NM 87131 USA. [Atsuta, Yoshiko] Nagoya Univ, Grad Sch Med, Japanese Data Ctr Hematopoiet Cell Transplantat, Nagoya, Aichi 4648601, Japan. [Buchbinder, David] Childrens Hosp Orange Cty, Div Pediat Hematol, Orange, CA 92668 USA. [Burns, Linda J.] Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN USA. [Cahn, Jean-Yves] Univ Hosp, Clin Univ Hematol, Grenoble, France. [Duncan, Christine] Dana Farber Canc Inst, Pediat Stem Cell Transplantat Program, Boston, MA 02115 USA. [Hale, Gregory A.] Univ S Florida, All Childrens Hosp, Dept Hematol Oncol, St Petersburg, FL 33701 USA. [Halter, Joerg] Univ Basel Hosp, Dept Hematol, CH-4031 Basel, Switzerland. [Hayashi, Robert J.] Washington Univ, St Louis Childrens Hosp, Div Pediat Hematol Oncol, St Louis, MO 63110 USA. [Hsu, Jack W.; Wingard, John R.] Univ Florida, Shands HealthCare, Div Hematol & Oncol, Gainesville, FL USA. [Jacobsohn, David A.] Childrens Natl Med Ctr, Div Blood & Marrow Transplantat, Washington, DC 20010 USA. [Kamble, Rammurti T.] Baylor Coll Med, Ctr Cell & Gene Therapy, Ctr Gene Therapy, Houston, TX 77030 USA. [Kamani, Naynesh R.] AABB Ctr Cellular Therapies, Bethesda, MD USA. [Kasow, Kimberly A.] Univ North Carolina Hosp, Pediat Bone Marrow Transplantat Program, Chapel Hill, NC USA. [Khera, Nandita] Mayo Clin Arizona, Dept Hematol Oncol, Phoenix, AZ USA. [Lazarus, Hillard M.] Univ Hosp Cleveland, Case Med Ctr, Seidman Canc Ctr, Div Hematol & Oncol, Cleveland, OH 44106 USA. [Loren, Alison W.] Univ Penn, Perelman Sch Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Marks, David I.] Bristol Childrens Hosp, Adult BMT Unit, Bristol, Avon, England. [Myers, Kasiani C.] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USA. [Ramanathan, Muthalagu] UMass Mem Med Ctr, Div Hematol Oncol, Worcester, MA USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Div Hematol Oncol, Nashville, TN USA. [Schouten, Harry C.] Acad Ziekenhuis Maastricht, Dept Med & Hematol, Maastricht, Netherlands. [Socie, Gerard] Hop St Louis, Serv Hematol Greffe de Moelle, Paris, France. [Sorror, Mohamed L.] Univ Washington, Sch Med, Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA USA. [Sorror, Mohamed L.] Univ Washington, Sch Med, Dept Med, Div Med Oncol, Seattle, WA 98195 USA. [Steinberg, Amir] Mt Sinai Med Ctr, Dept Hematol & Med Oncol, Los Angeles, CA USA. [Popat, Uday] Univ Texas Houston, MD Anderson Canc Ctr, Dept Stem Cell Transplantat, Houston, TX 77030 USA. [Majhail, Navneet S.] Cleveland Clin, Blood & Marrow Transplant Program, Cleveland, OH 44195 USA. RP Majhail, NS (reprint author), Cleveland Clin, Taussig Canc Inst, 9500 Euclid Ave,Desk R35, Cleveland, OH 44195 USA. OI Mattsson, Jonas/0000-0002-2163-6644 FU National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases; NHLBI [5U01HL069294]; National Cancer Institute; US Health Resources and Services Administration [HHSH234200637015C]; US Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; Allos, Inc.; Amgen, Inc.; Angioblast; Anonymous donation to the Medical College of Wisconsin; Ariad Pharmaceuticals; Be the Match Foundation; Blue Cross and Blue Shield Association; Bailey Family Foundation; Terumo BCT; Celgene; CellGenix; Children's Leukemia Research Association; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; Leukemia & Lymphoma Society; Medical College of Wisconsin; Merck Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; RemedyMD; Sanofi; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Teva Neuroscience, Inc.; Texas Instruments Inc.; WellPoint, Inc. FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases; Grant/Cooperative Agreement 5U01HL069294 from the NHLBI and National Cancer Institute; a contract (HHSH234200637015C) with the US Health Resources and Services Administration; 2 grants (N00014-06-1-0704 and N00014-08-1-0058) from the US Office of Naval Research; and grants from Allos, Inc.; Amgen, Inc.; Angioblast; Anonymous donation to the Medical College of Wisconsin; Ariad Pharmaceuticals; Be the Match Foundation; Blue Cross and Blue Shield Association; The Bailey Family Foundation; Terumo BCT; Celgene; CellGenix; Children's Leukemia Research Association; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd.; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; RemedyMD; Sanofi; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Teva Neuroscience, Inc.; Texas Instruments Inc.; and WellPoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the US Government. NR 35 TC 10 Z9 10 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2014 VL 20 IS 11 BP 1777 EP 1784 DI 10.1016/j.bbmt.2014.07.009 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AR1SG UT WOS:000343364300018 PM 25042734 ER PT J AU Sharma, M Zhang, MJ Zhong, XB Abidi, MH Akpek, G Bacher, U Callander, NS Dispenzieri, A Freytes, CO Fung, HC Gale, RP Gasparetto, C Gibson, J Holmberg, LA Kindwall-Keller, TL Klumpp, TR Krishnan, AY Landau, HJ Lazarus, HM Lonial, S Maiolino, A Marks, DI Mehta, P Med, JRM Nishihori, T Olsson, R Ramanathan, M Roy, V Savani, BN Schouten, HC Scott, E Tay, J To, LB Vesole, DH Vogl, DT Hari, P AF Sharma, Manish Zhang, Mei-Jie Zhong, Xiaobo Abidi, Muneer H. Akpek, Goerguen Bacher, Ulrike Callander, Natalie S. Dispenzieri, Angela Freytes, Cesar O. Fung, Henry C. Gale, Robert Peter Gasparetto, Cristina Gibson, John Holmberg, Leona A. Kindwall-Keller, Tamila L. Klumpp, Thomas R. Krishnan, Amrita Y. Landau, Heather J. Lazarus, Hillard M. Lonial, Sagar Maiolino, Angelo Marks, David I. Mehta, Paulette Med, Joseph R. Mikhael Nishihori, Taiga Olsson, Richard Ramanathan, Muthalagu Roy, Vivek Savani, Bipin N. Schouten, Harry C. Scott, Emma Tay, Jason To, Luen Bik Vesole, David H. Vogl, Dan T. Hari, Parameswaran TI Older Patients with Myeloma Derive Similar Benefit from Autologous Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Myeloma; Older patients; Autologous transplantation ID STEM-CELL TRANSPLANTATION; PREDNISONE PLUS THALIDOMIDE; RANDOMIZED CONTROLLED-TRIAL; DIAGNOSED MULTIPLE-MYELOMA; SINGLE-CENTER EXPERIENCE; ELDERLY-PATIENTS; HEMATOLOGIC MALIGNANCIES; COMORBIDITY INDEX; INITIAL TREATMENT; ORAL MELPHALAN AB Autologous hematopoietic cell transplantation (AHCT) for plasma cell myeloma is performed less often in people >70 years old than in people <= 70 years old. We analyzed 11,430 AHCT recipients for plasma cell myeloma prospectively reported to the Center for International Blood and Marrow Transplant Research between 2008 and 2011, representing the majority of US AHCT activity during this period. Survival (OS) was compared in 3 cohorts: ages 18 to 59 years (n = 5818), 60 to 69 years (n = 4666), and >70 years (n = 946). Median OS was not reached for any cohort. In multivariate analysis, increasing age was associated with mortality (P = .0006). Myeloma-specific mortality was similar among cohorts at 12%, indicating an age-related effect on nonmyeloma mortality. Analyses were performed in a representative subgroup comparing relapse rate, progression-free survival (PFS), and nonrelapse mortality (NRM). One-year NRM was 0% for age >70 years and 2% for other ages (P = not significant). The three-year relapse rate was 56% in age 18 to 59 years, 61% in age 60 to 69 years, and 63% age >70 (P = not significant). Three-year PFS was similar at 42% in age 18 to 59 years, 38% in age 60 to 69 years, and 33% in age >70 years (P = not significant). Postrelapse survival was significantly worse for the older cohort (P = .03). Older subjects selected for AHCT derived similar antimyeloma benefit without worse NRM, relapse rate, or PFS. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Sharma, Manish] Thomas Jefferson Univ, Dept Med Oncol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Zhang, Mei-Jie; Zhong, Xiaobo; Hari, Parameswaran] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Zhang, Mei-Jie] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Abidi, Muneer H.] Wayne State Univ, Dept Med, Karmanos Canc Inst, Detroit, MI 48202 USA. [Akpek, Goerguen] Banner MD Anderson Canc Ctr, Gilbert, AZ USA. [Bacher, Ulrike] Univ Hamburg, Dept Stem Cell Transplantat, Hamburg, Germany. [Bacher, Ulrike] MLL Munich Leukemia Lab, Munich, Germany. [Callander, Natalie S.] Univ Wisconsin Hosp & Clin, Bone Marrow Transplant Program, Madison, WI 53792 USA. [Dispenzieri, Angela] Mayo Clin, Dept Hematol, Rochester, MN USA. [Freytes, Cesar O.] South Texas Vet Hlth Care Syst, Dept Med, San Antonio, TX USA. [Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Fung, Henry C.] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. [Gale, Robert Peter] Univ London Imperial Coll Sci Technol & Med, Div Expt Med, Dept Med, Hematol Res Ctr, London, England. [Gasparetto, Cristina] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Gibson, John] Royal Prince Alfred Hosp, Inst Haematol, Camperdown, NSW 2050, Australia. [Holmberg, Leona A.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Kindwall-Keller, Tamila L.] Univ Virginia, Dept Med, Charlottesville, VA USA. [Klumpp, Thomas R.] Temple Bone Marrow Transplant Program, Dept Med, Philadelphia, PA USA. [Krishnan, Amrita Y.] City Hope Natl Med Ctr, Dept Hematol Oncol, Duarte, CA 91010 USA. [Landau, Heather J.] Mem Sloan Kettering Canc Ctr, Dept Med, Bone Marrow Transplantat Serv, New York, NY 10021 USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Seidman Canc Ctr, Dept Med, Cleveland, OH USA. [Lonial, Sagar] Emory Univ Hosp, Dept Med, Atlanta, GA 30322 USA. [Maiolino, Angelo] Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Rio De Janeiro, Brazil. [Marks, David I.] Univ Hosp Bristol, NHS Trust, Bristol, Avon, England. [Mehta, Paulette] Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA. [Mehta, Paulette] Univ Arkansas Med Sci, Dept Med, Little Rock, AR 72205 USA. [Med, Joseph R. Mikhael] Mayo Clin Arizona, Dept Hematol Oncol, Phoenix, AZ USA. [Med, Joseph R. Mikhael] Phoenix Childrens Hosp, Phoenix, AZ USA. [Nishihori, Taiga] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Blood & Marrow Transplantat, Tampa, FL 33682 USA. [Nishihori, Taiga] Res Inst, Tampa, FL USA. [Olsson, Richard] Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden. [Olsson, Richard] Uppsala Univ, Ctr Clin Res Sormland, Uppsala, Sweden. [Ramanathan, Muthalagu] UMass Mem Med Ctr, Dept Hematol Malignancies Bone Marrow Transplant, Worcester, MA USA. [Roy, Vivek] Mayo Clin, Dept Med, Blood & Marrow Transplant Program, Jacksonville, FL 32224 USA. [Savani, Bipin N.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Schouten, Harry C.] Acad Ziekenhuis, Maastricht, Netherlands. [Scott, Emma] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Tay, Jason] Univ Ottawa, Ottawa, ON, Canada. [To, Luen Bik] Royal Adelaide Hosp, Adelaide, SA, Australia. [Vesole, David H.] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Vogl, Dan T.] Univ Penn, Med Ctr, Dept Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RP Hari, P (reprint author), Med Coll Wisconsin, Div Hematol & Oncol, Ctr Int Blood & Marrow Transplant Res, 9200 W Wisconsin Ave,Suite C5500, Milwaukee, WI 53226 USA. EM phari@mcw.edu OI Abidi, Muneer/0000-0002-9936-6031; Olsson, Richard/0000-0001-5970-2128; Hari, Parameswaran/0000-0002-8800-297X; Dispenzieri, Angela/0000-0001-8780-9512 FU National Cancer Institute [U24-CA076518]; National Institute of Allergy and Infectious Diseases; NHLBI [5U10HL069294]; NCI [5U10HL069294]; Health Resources and Services Administration [HHSH250201200016C]; Office of Naval Research [N00014-12-1-0142, N00014-13-1-0039]; 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.; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children's Foundation; Kiadis Pharma; Leukemia & Lymphoma Society; Medac GmbH; 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; Terumo BCT; Teva Neuroscience, Inc.; Texas Instruments Inc.; University of Minnesota; University of Utah; WellPoint, Inc; National Heart, Lung and Blood Institute (NHLBI); ROSWELL PARK CANCER INSTITUTE FX The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute, the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases; a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration; two Grants N00014-12-1-0142 and N00014-13-1-0039 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; *Terumo BCT; *Teva Neuroscience, Inc.; *Texas Instruments 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 or any other agency of the US Government. NR 39 TC 14 Z9 14 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2014 VL 20 IS 11 BP 1796 EP 1803 DI 10.1016/j.bbmt.2014.07.013 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AR1SG UT WOS:000343364300021 PM 25046833 ER PT J AU Ballen, KK Joffe, S Brazauskas, R Wang, ZW Aljurf, MD Akpek, G Dandoy, C Frangoul, HA Freytes, CO Khera, N Lazarus, HM LeMaistre, CF Mehta, P Parsons, SK Szwajcer, D Ustun, C Wood, WA Majhail, NS AF Ballen, Karen K. Joffe, Steven Brazauskas, Ruta Wang, Zhiwei Aljurf, Mahmoud D. Akpek, Goergaen Dandoy, Christopher Frangoul, Haydar A. Freytes, Cesar O. Khera, Nandita Lazarus, Hillard M. LeMaistre, Charles F. Mehta, Paulette Parsons, Susan K. Szwajcer, David Ustun, Celalettin Wood, William A. Majhail, Navneet S. TI Hospital Length of Stay in the First 100 Days after Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia in Remission: Comparison among Alternative Graft Sources SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Hematopoietic cell transplantation; Umbilical cord blood; Leukemia; Length of stay; Resource utilization ID UMBILICAL-CORD BLOOD; HIGH-DOSE REGIMENS; BONE-MARROW; REDUCED-INTENSITY; UNRELATED DONOR; UNITED-STATES; CONDITIONING REGIMEN; COST-EFFECTIVENESS; ADULTS; CHILDREN AB Several studies have shown comparable survival outcomes with different graft sources, but the relative resource needs of hematopoietic cell transplantation (HCT) by graft source have not been well studied. We compared total hospital length of stay in the first 100 days after HCT in 1577 patients with acute leukemia in remission who underwent HCT with an umbilical cord blood (UCB), matched unrelated donor (MUD), or mismatched unrelated donor (MMUD) graft between 2008 and 2011. To ensure a relatively homogenous study population, the analysis was limited to patients with acute myelogenous leukemia and acute lymphoblastic leukemia in first or second complete remission who underwent HO' in the United States. To account for early deaths, we compared the number of days alive and out of the hospital in the first 100 days post-transplantation. For children who received myeloablative conditioning, the median time alive and out of the hospital in the first 100 days was 50 days for single UCB recipients, 54 days for double UCB recipients, and 60 days for MUD bone marrow (BM) recipients. In multivariate analysis, use of UCB was significantly associated with fewer days alive and out of the hospital compared with MUD BM. For adults who received myeloablative conditioning, the median time alive and out of the hospital in first 100 days was 52 days for single UCB recipients, 55 days for double UCB recipients, 69 days for MUD BM recipients, 75 days for MUD peripheral blood stem cell (PBSC) recipients, 63 days for MMUD BM recipients, and 67 days for MMUD PBSC recipients. In multivariate analysis, UCB and MMUD BM recipients had fewer days alive and out of the hospital compared with recipients of other graft sources. For adults who received a reduced-intensity preparative regimen, the median time alive and out of the hospital during the first 100 days was 65 days for single UCB recipients, 63 days for double UCB recipients, 79 days for MUD PBSC recipients, and 79 days for MMUD PBSC recipients. Similar to the other 2 groups, receipt of UCB was associated with a fewer days alive and out of the hospital. In conclusion, length of stay in the first 100 days post-transplantation varies by graft source and is longer for UCB HCT recipients. These data provide insight into the resource needs of patients who undergo HCT with these various graft sources. (C) 2014 American Society for Blood and Marrow Transplantation. C1 [Ballen, Karen K.] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Joffe, Steven] Univ Penn, Perelman Sch Med, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. [Brazauskas, Ruta; Wang, Zhiwei] Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Brazauskas, Ruta] Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA. [Aljurf, Mahmoud D.] King Faisal Specialist Hosp & Res Ctr, Dept Oncol, Riyadh 11211, Saudi Arabia. [Akpek, Goergaen] Banner MD Anderson Canc Ctr, Dept Oncol, Gilbert, AZ USA. [Dandoy, Christopher] Cincinnati Childrens Hosp Med Ctr, Dept Hematol Oncol, Cincinnati, OH 45229 USA. [Frangoul, Haydar A.] Vanderbilt Univ, Med Ctr, Dept Pediat Hematol Oncol, Nashville, TN USA. [Freytes, Cesar O.] South Texas Vet Hlth Care Syst, Hematopoiet Stem Cell Transplant Program, San Antonio, TX USA. [Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Khera, Nandita] Mayo Clin Arizona, Dept Hematol Oncol, Phoenix, AZ USA. [Khera, Nandita] Phoenix Childrens Hosp, Phoenix, AZ USA. [Lazarus, Hillard M.] Univ Hosp Cleveland, Case Med Ctr, Seidman Canc Ctr, Dept Med, Cleveland, OH 44106 USA. [LeMaistre, Charles F.] Sarah Cannon, Hematol & Bone Marrow Transplant, Nashville, TN USA. [Mehta, Paulette] Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA. [Mehta, Paulette] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Parsons, Susan K.] Tufts Med Ctr, Dept Med & Pediat, Boston, MA USA. [Szwajcer, David] Univ Manitoba, Dept Hematol, CancerCare Manitoba, Winnipeg, MB, Canada. [Ustun, Celalettin] Univ Minnesota, Med Ctr, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. [Wood, William A.] Univ North Carolina Hosp, Dept Hematol Oncol, Chapel Hill, NC USA. [Majhail, Navneet S.] Cleveland Clin, Blood & Marrow Transplant Program, Cleveland, OH 44195 USA. RP Majhail, NS (reprint author), Cleveland Clin, Blood & Marrow Transplant Program, 9500 Euclid Ave,R35, Cleveland, OH 44195 USA. OI dandoy, christopher/0000-0002-4001-9203 FU National Cancer Institute [U24-CA76518]; National Heart, Lung and Blood Institute (NHLBI); National Institute of Allergy and Infectious Diseases; NHLBI [5U01HL069294]; NCI; Health Resources and Services Administration (HRSA/DHHS) [HHSH234200637015 C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; AABB; Allos, Inc.; Amgen, Inc.; Astellas Pharma US, Inc.; Be the Match Foundation; Biogen Idec BioMarin Pharmaceutical, Inc.; Biovitrum AB; Blood-Center of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Bailey Family Foundation; Terumo BCT Celgene; CellGenix Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Eisai, Inc.; Genentech, Inc.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Kirin Brewery Co., Ltd.; Leukemia & Lymphoma Society; Merck Company; Medical College of Wisconsin; Millennium Pharmaceuticals, Inc.; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Nature Publishing Group; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Pall Life Sciences; Pfizer Inc; Schering Corporation; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex America, Inc.; Texas Instruments Inc.; Vidacare Corporation; ViraCor Laboratories; ViroPharma, Inc.; WellPoint, Inc FX Financial Disclosure: The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute, the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases; a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015 C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Allos, Inc.; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US, Inc.; Be the Match Foundation; Biogen Idec BioMarin Pharmaceutical, Inc.; Biovitrum AB; Blood-Center of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; The Bailey Family Foundation; Terumo BCT Celgene; CellGenix Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Eisai, Inc.; Genentech, Inc.; Genzyme Corporation; Histogenetics, Inc.; HKS Medical Information Systems; Hospira, Inc.; Kirin Brewery Co., Ltd.; The Leukemia & Lymphoma Society; Merck & Company; The Medical College of Wisconsin; Millennium Pharmaceuticals, Inc.; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Nature Publishing Group; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Pall Life Sciences; Pfizer Inc; Schering Corporation; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, Inc.; StemSoft Software, Inc.; Sysmex America, Inc.; Texas Instruments Inc.; Vidacare Corporation; ViraCor Laboratories; ViroPharma, Inc.; and WellPoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the; Navy, the Department of Defense, or any other agency of the U.S. Government. NR 34 TC 4 Z9 4 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD NOV PY 2014 VL 20 IS 11 BP 1819 EP 1827 DI 10.1016/j.bbmt.2014.07.021 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA AR1SG UT WOS:000343364300024 PM 25064747 ER PT J AU Khan, M Simunovic, N Provencher, M AF Khan, Moin Simunovic, Nicole Provencher, Matthew TI Cochrane in CORR (A (R)): Surgery for Rotator Cuff Disease (Review) SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Editorial Material ID CHECKLIST; SHOULDERS; TRIALS; REPAIR C1 [Khan, Moin] McMaster Univ, Div Orthopaed Surg, Hamilton, ON L8S 4L8, Canada. [Simunovic, Nicole] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON L8S 4L8, Canada. [Provencher, Matthew] Harvard Univ, Sch Med, Dept Orthopaed, Boston, MA USA. [Provencher, Matthew] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Khan, M (reprint author), McMaster Univ, Div Orthopaed Surg, 280 Main St W, Hamilton, ON L8S 4L8, Canada. EM Moinkhanmd@gmail.com NR 21 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD NOV PY 2014 VL 472 IS 11 BP 3263 EP 3269 DI 10.1007/s11999-014-3869-2 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AQ9DO UT WOS:000343143900004 PM 25123244 ER PT J AU Bekkers, S Bot, AGJ Makarawung, D Neuhaus, V Ring, D AF Bekkers, Stijn Bot, Arjan G. J. Makarawung, Dennis Neuhaus, Valentin Ring, David TI The National Hospital Discharge Survey and Nationwide Inpatient Sample: The Databases Used Affect Results in THA Research SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID CARDIOVASCULAR DRUGS; MORTALITY; COMPLICATIONS; ARTHROPLASTY; FRACTURE; RISK AB The National Hospital Discharge Survey (NHDS) and the Nationwide Inpatient Sample (NIS) collect sample data and publish annual estimates of inpatient care in the United States, and both are commonly used in orthopaedic research. However, there are important differences between the databases, and because of these differences, asking these two databases the same question may result in different answers. The degree to which this is true for arthroplasty-related research has, to our knowledge, not been characterized. We tested the following null hypotheses: (1) there are no differences between the NHDS and NIS in patient characteristics, comorbidities, and adverse events in patients with hip osteoarthritis treated with THA, and (2) there are no differences between databases in factors associated with inpatient mortality, adverse events, and length of hospital stay after THA. The NHDS and NIS databases use different methods of data collection and weighting to provide data representative of all nonfederal hospital discharges in the United States. In 2006 the NHDS database contained 203,149 patients with hip arthritis treated with hip arthroplasty, and the NIS database included 193,879 patients. Multivariable analyses for factors associated with inpatient mortality, adverse events, and days of care were constructed for each database. We found that 26 of 42 of the factors in demographics, comorbidities, and adverse events after THA in the NIS and NHDS databases differed more than 10%. Age and days of care were associated with inpatient mortality with the NHDS and the NIS although the effect rates differ more than 10%. The NIS identified seven other factors not identified by the NHDS: wound complications, congestive heart failure, new mental disorder, chronic pulmonary disease, dementia, geographic region Northeast, acute postoperative anemia, and sex, that were associated with inpatient mortality even after controlling for potentially confounding variables. For inpatient adverse events, atrial fibrillation, osteoporosis, and female sex were associated with the NHDS and the NIS although the effect rates differ more than 10%. There were different directions for sources of payment, dementia, congestive heart failure, and geographic region. For longer length of stay, common factors differing more than 10% in effect rate included chronic pulmonary disease, atrial fibrillation, complication not elsewhere classified, congestive heart failure, transfusion, discharge nonroutine compared with routine, acute postoperative anemia, hypertension, wound adverse events, and diabetes mellitus, whereas discrepant factors included geographic region, payment method, dementia, sex, and iatrogenic hypotension. Studies that use large databases intended to be representative of the entire United States population can produce different results, likely related to differences in the databases, such as the number of comorbidities and procedures that can be entered in the database. In other words, analyses of large databases can have limited reliability and should be interpreted with caution. Level II, prognostic study. See the Instructions for Authors for a complete description of levels of evidence. C1 [Bekkers, Stijn; Bot, Arjan G. J.; Makarawung, Dennis; Neuhaus, Valentin; Ring, David] Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Yawkey Ctr, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv, Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org OI Bekkers, Stijn/0000-0002-8330-9243; Neuhaus, Valentin/0000-0003-4012-5628 FU VU University Amsterdam; AnnaFonds Travel grant (Dutch Orthopaedic travel grant); VSB-fonds; Prins Bernhard Cultuurfonds; Banning-de Jong fonds; Wright Medical Technologies, Inc (Arlington, TN, USA); Biomet, Inc (Warsaw, IN, USA); Skeletal Dynamics Inc (Miami, FL, USA); AO North America (Paoli, PA, USA); AO International (Davos, Switzerland); Illuminos (East Providence, RI, USA) FX One of the authors (SB) certifies that he or she has received, during the study period, funding from VU University Amsterdam, faculty fund. One of the authors (AGJB) certifies that he or she has received, during the study period, funding from an AnnaFonds Travel grant (Dutch Orthopaedic travel grant) (less than USD 10,000), VSB-fonds, a nonmedical study grant (USD 10,000 to USD 100,000) and Prins Bernhard Cultuurfonds, Banning-de Jong fonds, a nonmedical study grant for excellent Dutch students USD 10,000 to USD 100,000). One of the authors (DR) certifies that he or she, or a member of his or her immediate family, has received or may receive payments or benefits, during the study period, an amount of USD (less than USD 10,000), from Wright Medical Technologies, Inc (Arlington, TN, USA), Biomet, Inc (Warsaw, IN, USA), Skeletal Dynamics Inc (Miami, FL, USA), AO North America (Paoli, PA, USA), AO International (Davos, Switzerland), and Illuminos (East Providence, RI, USA). Each of the remaining authors certifies that he or she, or a member of his or her immediate family, has no funding or commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. NR 23 TC 6 Z9 6 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD NOV PY 2014 VL 472 IS 11 BP 3441 EP 3449 DI 10.1007/s11999-014-3836-y PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AQ9DO UT WOS:000343143900031 PM 25091226 ER PT J AU Menendez, ME Ring, D AF Menendez, Mariano E. Ring, David TI Minorities Are Less Likely to Receive Autologous Blood Transfusion for Major Elective Orthopaedic Surgery SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID TOTAL JOINT ARTHROPLASTY; TOTAL HIP; RACIAL DISPARITIES; KNEE ARTHROPLASTY; UNITED-STATES; HEALTH-CARE; PERIOPERATIVE COMPLICATIONS; ADMINISTRATIVE DATABASES; ALLOGENEIC TRANSFUSION; BARIATRIC SURGERY AB Surgeons commonly arrange for patients to perform autologous blood donation before elective orthopaedic surgery. Understanding sociodemographic patterns of use of autologous blood transfusion can help improve quality of care and cost containment. We sought to determine whether there were (1) racial disparities, (2) insurance-based disparities, or (3) income-based disparities in autologous blood use. Additionally, we evaluated the combined effect of (4) race and insurance and (5) race and income on autologous blood use, and we compared ratios of autologous with allogeneic blood use. Of the more than 3,500,000 patients undergoing major elective orthopaedic surgery identified in the Nationwide Inpatient Sample between 2008 and 2011, 2.4% received autologous blood transfusion and 12% received allogeneic blood transfusion. Multivariable logistic regression was performed to determine the influence of race, insurance status, and income on autologous blood use. Compared with white patients, Hispanic patients had lower odds of autologous blood use for elective hip (odds ratio [OR], 0.75; 95% CI, 0.69-0.82) and knee arthroplasties (OR, 0.71; 95% CI, 0.67-0.75). Black patients had lower odds of receiving autologous blood transfusion for hip arthroplasty (OR, 0.78; 95% CI, 0.74-0.83). Compared with the privately insured, uninsured and publicly insured patients were less likely to receive autologous blood for total joint arthroplasty and spinal fusion. Patients with low and medium income were less likely to have autologous blood transfusion for total joint arthroplasty and spinal fusion compared with high-level income earners. Even at comparable income and insurance levels with whites, Hispanic and black patients tended to be less likely to receive autologous blood transfusion. Ratios of autologous to allogeneic blood use were lower among minority patients. Historically disadvantaged populations receive fewer autologous blood transfusions for elective orthopaedic surgery. Whether the differential use is attributable to patient preference or unequal access to this practice should be investigated further. Level II, prognostic study. See the Instructions for Authors for a complete description of levels of evidence. C1 [Menendez, Mariano E.; Ring, David] Massachusetts Gen Hosp, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Menendez, ME (reprint author), Massachusetts Gen Hosp, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM marianofurrer@gmail.com NR 46 TC 3 Z9 3 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD NOV PY 2014 VL 472 IS 11 BP 3559 EP 3566 DI 10.1007/s11999-014-3793-5 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AQ9DO UT WOS:000343143900050 PM 25028107 ER PT J AU Rassi, AN O'Dea, JA Jia, HB Seto, AH Jang, IK AF Rassi, Andrew N. O'Dea, John A. Jia, Haibo Seto, Arnold H. Jang, Ik-Kyung TI Nonangiographic assessment of coronary artery disease: a practical approach to optical coherence tomography and fractional flow reserve SO CORONARY ARTERY DISEASE LA English DT Review DE fractional flow reserve; optical coherence tomography; percutaneous coronary intervention ID ACUTE MYOCARDIAL-INFARCTION; LEFT MAIN DISEASE; INTRAVASCULAR ULTRASOUND; PRESSURE MEASUREMENT; FOLLOW-UP; ATHEROSCLEROTIC PLAQUES; INTERMEDIATE STENOSIS; BIFURCATION LESIONS; STENT IMPLANTATION; MEDICAL THERAPY AB In an era of increased scrutiny of the appropriateness and safety of revascularization, interventional cardiologists must evolve by adding key tools to their armamentarium. This review highlights the utility of optical coherence tomography and fractional flow reserve in the catheterization lab and provides a practical guide for using these technologies during coronary intervention in various lesion subsets. We propose that fractional flow reserve informs the decision to intervene and optical coherence tomography guides the optimization of the outcome. Coron Artery Dis 25: 608-618 (C) 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Rassi, Andrew N.; O'Dea, John A.; Jia, Haibo; Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div, Boston, MA USA. [Seto, Arnold H.] Univ Calif Irvine, Med Ctr, Div Cardiol, Orange, CA USA. RP Jang, IK (reprint author), Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St,Desk GRB-800, Boston, MA 02114 USA. EM ijang@partners.org NR 53 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0954-6928 EI 1473-5830 J9 CORONARY ARTERY DIS JI Coronary Artery Dis. PD NOV PY 2014 VL 25 IS 7 BP 608 EP 618 DI 10.1097/MCA.0000000000000173 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AQ8XS UT WOS:000343123400012 PM 25203101 ER PT J AU Young, MN Yeh, RW AF Young, Michael N. Yeh, Robert W. TI Public reporting and coronary revascularization: risk and benefit SO CORONARY ARTERY DISEASE LA English DT Review DE coronary artery disease; coronary revascularization; public reporting ID NEW-YORK-STATE; CARDIOVASCULAR DATA REGISTRY; AMERICAN-HEART-ASSOCIATION; ACUTE MYOCARDIAL-INFARCTION; IN-HOSPITAL MORTALITY; INTERVENTIONAL CARDIOLOGY; CARDIOGENIC-SHOCK; CARDIAC-SURGERY; BYPASS-SURGERY; OUTCOMES AB Since the 1980s, the evolution of public reporting of provider-specific and institution-specific clinical outcomes has historically been rooted in the field of cardiology. Although public reporting is not a novel concept, how we collect, analyze, report, and interpret outcome data remains a critical element in quality improvement and in the quest toward providing truly high-value care. In this review, we explore the emergence of public reporting within the scope of cardiovascular medicine, specifically as it relates to surgical and percutaneous coronary revascularization. We highlight both the advantages and the disadvantages of public reporting from the perspective of the patient, the practicing physician, the hospital, and the healthcare system. A discussion on the limitations of public reporting and specific strategies by which it can be improved is presented. Coron Artery Dis 25: 619-626 (C) 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Young, Michael N.] Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, Nashville, TN USA. [Yeh, Robert W.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Yeh, RW (reprint author), Massachusetts Gen Hosp, Div Cardiol, GRB800, Boston, MA 02114 USA. EM ryeh@mgh.harvard.edu FU Hassenfeld Scholars Program; National Heart, Lung, and Blood Institute [1K23HL118138] FX Dr Yeh is supported by the Hassenfeld Scholars Program, as well as the National Heart, Lung, and Blood Institute (1K23HL118138). NR 57 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0954-6928 EI 1473-5830 J9 CORONARY ARTERY DIS JI Coronary Artery Dis. PD NOV PY 2014 VL 25 IS 7 BP 619 EP 626 DI 10.1097/MCA.0000000000000169 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AQ8XS UT WOS:000343123400013 PM 25248138 ER PT J AU Derks, J Reijneveld, JC Douw, L AF Derks, Jolanda Reijneveld, Jacob C. Douw, Linda TI Neural network alterations underlie cognitive deficits in brain tumor patients SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE cognition; connectivity; graph theory; neuro-oncology ID QUALITY-OF-LIFE; RESTING-STATE NETWORKS; LOW-GRADE GLIOMAS; FUNCTIONAL CONNECTIVITY; MAGNETOENCEPHALOGRAPHY; DISEASE; EFFICIENCY; LOCATION; DYNAMICS; EPILEPSY AB Purpose of review Brain tumor patients suffer from cognitive deficits, regardless of tumor grade or location. Deficits have a general character, falling in the domains of attention, working memory, information processing speed, and executive functioning. This review explores a new, brain network-based view of these deficits in brain tumor patients. Recent findings Network theory has evolved within the fields of mathematics and sociology and has resulted in its application to many complex systems, such as social networks, traffic flow networks, and biological protein networks. In the brain, a network can be constructed by assessing either functional or anatomical connections between brain areas, and subsequently extracting their overarching network patterns. Important brain network features are local specialization, operationalized by local clustering, and global integration or path length. Widespread disturbances in network topology are found in brain tumor patients, which relate to their cognitive problems. Furthermore, changes in network topology in response to oncological interventions, particularly tumor resection, go hand in hand with cognitive outcome. Summary Cognitive deficits in brain tumor patients are reflected in whole-brain network disturbances. Possible future clinical use of these findings mostly concerns prognostics and tailoring treatment strategies. C1 [Derks, Jolanda; Douw, Linda] Vrije Univ Amsterdam, Med Ctr, Dept Anat & Neurosci, Amsterdam, Netherlands. [Reijneveld, Jacob C.] Vrije Univ Amsterdam, Med Ctr, Dept Neurol, Amsterdam, Netherlands. [Douw, Linda] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Douw, L (reprint author), Dept Anat & Neurosci, MF G122,Boechorststr 7, NL-1081 BT Amsterdam, Netherlands. EM L.Douw@vumc.nl FU Dutch Epilepsy Foundation [08-08, 09-09, 14-16]; Netherlands Organization for Scientific Research (Veni grant); Society of Science (Branco Weiss Fellowship) FX None were declared for J.D. J.C.R. received grants from the Dutch Epilepsy Foundation (08-08, 09-09 and 14-16). L. D. received a grant from the Netherlands Organization for Scientific Research (Veni grant) and from the Society of Science (Branco Weiss Fellowship). NR 47 TC 3 Z9 3 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 EI 1531-703X J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD NOV PY 2014 VL 26 IS 6 BP 627 EP 633 DI 10.1097/CCO.0000000000000126 PG 7 WC Oncology SC Oncology GA AR0XM UT WOS:000343298200014 PM 25188475 ER PT J AU Spira, AP Chen-Edinboro, LP Wu, MN Yaffe, K AF Spira, Adam P. Chen-Edinboro, Lenis P. Wu, Mark N. Yaffe, Kristine TI Impact of sleep on the risk of cognitive decline and dementia SO CURRENT OPINION IN PSYCHIATRY LA English DT Review DE amyloid; apnea; cognitive decline; dementia; sleep ID ALZHEIMERS-DISEASE PATHOGENESIS; UNITED-STATES; DEPRIVATION; HYPOXIA; QUALITY; MARKERS; INFLAMMATION; DISTURBANCE; POPULATION; EXPRESSION AB Purpose of review Trouble falling or staying asleep, poor sleep quality, and short or long sleep duration are gaining attention as potential risk factors for cognitive decline and dementia, including Alzheimer's disease. Sleep-disordered breathing has also been linked to these outcomes. Here, we review recent observational and experimental studies investigating the effect of poor sleep on cognitive outcomes and Alzheimer's disease, and discuss possible mechanisms. Recent findings Observational studies with self-report and objective sleep measures (e. g. wrist actigraphy, polysomnography) support links between disturbed sleep and cognitive decline. Several recently published studies demonstrate associations between sleep variables and measures of Alzheimer's disease pathology, including cerebrospinal fluid measures of A beta and PET measures of A beta deposition. In addition, experimental studies suggest that sleep loss alters cerebrospinal fluid A beta dynamics, decrements in slow-wave sleep may decrease the clearance of A beta from the brain, and hypoxemia characteristic of sleep-disordered breathing increases A beta production. Summary Findings indicate that poor sleep is a risk factor for cognitive decline and Alzheimer's disease. Although mechanisms underlying these associations are not yet clear, healthy sleep appears to play an important role in maintaining brain health with age, and may play a key role in Alzheimer's disease prevention. C1 [Spira, Adam P.; Chen-Edinboro, Lenis P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Spira, Adam P.] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Wu, Mark N.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA. [Wu, Mark N.] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. RP Spira, AP (reprint author), 624 N Broadway,Hampton House,Rm 794, Baltimore, MD 21205 USA. EM aspira@jhu.edu OI Chen-Edinboro, Lenis/0000-0002-8927-4256 FU National Institute on Aging [1K01AG033195]; National Institute of Mental Health Psychiatric Epidemiology Training Program [T32MH014592]; Burroughs-Wellcome Fund Career Award for Medical Scientists; Alzheimer's Association New Investigator Award; NIH [1R01NS079584, K24AG031155, R01 AG026720] FX Adam Spira is supported in part by a Mentored Research Scientist Development Award (1K01AG033195) from the National Institute on Aging.; Lenis Chen-Edinboro is supported by the National Institute of Mental Health Psychiatric Epidemiology Training Program (T32MH014592).; Mark Wu is supported by NIH 1R01NS079584, a Burroughs-Wellcome Fund Career Award for Medical Scientists, and an Alzheimer's Association New Investigator Award.; Kristine Yaffe is supported in part by NIH K24AG031155 and R01 AG026720. Kristine Yaffe has served on data safety monitoring boards for Takeda and the NIH, and received honoraria from Novartis and Pfizer. NR 50 TC 9 Z9 10 U1 5 U2 42 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7367 EI 1473-6578 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD NOV PY 2014 VL 27 IS 6 BP 478 EP 483 DI 10.1097/YCO.0000000000000106 PG 6 WC Psychiatry SC Psychiatry GA AQ8AM UT WOS:000343042700016 PM 25188896 ER PT J AU Castelino, FV Varga, J AF Castelino, Flavia V. Varga, John TI Emerging cellular and molecular targets in fibrosis: implications for scleroderma pathogenesis and targeted therapy SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE extracellular matrix; fibrosis; myofibroblasts; senescence; stiffness ID SYSTEMIC-SCLEROSIS; EXTRACELLULAR-MATRIX; PULMONARY-FIBROSIS; MYOFIBROBLAST DIFFERENTIATION; SPHINGOSINE 1-PHOSPHATE; LYSOPHOSPHATIDIC ACID; GENE-EXPRESSION; SKIN FIBROSIS; MOUSE MODEL; FIBROBLASTS AB Purpose of review To summarize the recent advances in understanding the novel cytokine pathways, intracellular signaling molecules, cell-fate decisions, cellular aging and senescence, and the cross-talk of effector cells and the extracellular matrix (ECM) in the pathogenesis of systemic sclerosis (SSc) fibrosis. Recent findings Studies from the animal models and human beings implicate novel molecular pathways such as Wnts, the chemokines, chemokine (C-X-C motif) ligand 4 and chemokine (C-C motif) ligand 2, and the lipid mediators lysophosphatidic acid and sphingosine-1-phosphate in the pathogenesis of SSc. These signals, coupled with the mesenchymal cell-fate decisions, contribute to aberrant fibroblast activation and myofibroblast accumulation. The resulting deposition and remodeling of ECM alters the biomechanical environment, and leads to further cross-talk of mechanical signals with biochemical mediators such as focal adhesion kinase, integrin signaling, and Yes-associated protein-transcriptional coactivator with PDZ-binding motif signaling pathways. Summary Progress in understanding the cellular, molecular, and biomechanical regulators of fibrosis has led to the identification of novel targets for interrupting the fibrotic process in SSc. Efforts to antagonize cytokine pathways, affect mesenchymal cell fates, attenuate senescence, and clear activated myofibroblasts, along with modifying the ECM mechanical environment, may ultimately lead to effective therapies in SSc. C1 [Castelino, Flavia V.] Massachusetts Gen Hosp, Div Rheumatol, Boston, MA 02114 USA. [Varga, John] Northwestern Univ, Div Rheumatol, Feinberg Sch Med, Chicago, IL 60611 USA. RP Castelino, FV (reprint author), Massachusetts Gen Hosp, Div Rheumatol, 55 Fruit St,Yawkey 2C-2100, Boston, MA 02114 USA. EM fcastelino@mgh.harvard.edu FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [K08AR062592, R01AR42309]; Scleroderma Foundation; Biogen; Department of Defense FX F.V.C. is supported by the grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08AR062592) and the Scleroderma Foundation. J.V. is supported by the grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR42309), Biogen and the Department of Defense. NR 51 TC 13 Z9 13 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 EI 1531-6963 J9 CURR OPIN RHEUMATOL JI Curr. Opin. Rheumatol. PD NOV PY 2014 VL 26 IS 6 BP 607 EP 614 DI 10.1097/BOR.0000000000000110 PG 8 WC Rheumatology SC Rheumatology GA AQ7KQ UT WOS:000342994000002 PM 25191991 ER PT J AU Middelbeek, RJW Brown, FM AF Middelbeek, Roeland J. W. Brown, Florence M. TI Bariatric Surgery Improves the Metabolic Profile of Morbidly Obese Patients With Type 1 Diabetes. Diabetes Care 2014; 37: e51-e52 SO DIABETES CARE LA English DT Letter C1 [Brown, Florence M.] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Brown, FM (reprint author), Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA. EM florence.brown@joslin.harvard.edu FU NIDDK NIH HHS [T32 DK007260] NR 3 TC 1 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 NOV PY 2014 VL 37 IS 11 BP E250 EP E250 DI 10.2337/dc14-1116 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AR4XD UT WOS:000343588500012 PM 25342845 ER PT J AU Pandit-Taskar, N O'Donoghue, JA Beylergil, V Lyashchenko, S Ruan, ST Solomon, SB Durack, JC Carrasquillo, JA Lefkowitz, RA Gonen, M Lewis, JS Holland, JP Cheal, SM Reuter, VE Osborne, JR Loda, MF Smith-Jones, PM Weber, WA Bander, NH Scher, HI Morris, MJ Larson, SM AF Pandit-Taskar, Neeta O'Donoghue, Joseph A. Beylergil, Volkan Lyashchenko, Serge Ruan, Shutian Solomon, Stephen B. Durack, Jeremy C. Carrasquillo, Jorge A. Lefkowitz, Robert A. Gonen, Mithat Lewis, Jason S. Holland, Jason P. Cheal, Sarah M. Reuter, Victor E. Osborne, Joseph R. Loda, Massimo F. Smith-Jones, Peter M. Weber, Wolfgang A. Bander, Neil H. Scher, Howard I. Morris, Michael J. Larson, Steven M. TI Zr-89-huJ591 immuno-PET imaging in patients with advanced metastatic prostate cancer SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE Zr-89-huJ591; J591 antibody; Prostate cancer; Radioimmunotherapy; Dosimetry ID MEMBRANE ANTIGEN-EXPRESSION; MONOCLONAL-ANTIBODY J591; PEPTIDE RECEPTOR; RADICAL PROSTATECTOMY; C-11-CHOLINE PET/CT; RADIATION-DOSIMETRY; EXTRACELLULAR DOMAIN; BIOCHEMICAL RELAPSE; BOMBESIN HOMODIMER; SMALL MOLECULES AB Purpose Given the bone tropism of prostate cancer, conventional imaging modalities poorly identify or quantify metastatic disease. Zr-89-huJ591 positron emission tomography (PET) imaging was performed in patients with metastatic prostate cancer to analyze and validate this as an imaging biomarker for metastatic disease. The purpose of this initial study was to assess safety, biodistribution, normal organ dosimetry, and optimal imaging time post-injection for lesion detection. Methods Ten patients with metastatic prostate cancer received 5 mCi of Zr-89-huJ591. Four whole-body scans with multiple whole-body count rate measurements and serum activity concentration measurements were obtained in all patients. Biodistribution, clearance, and lesion uptake by Zr-89-huJ591 immuno-PET imaging was analyzed and dosimetry was estimated using MIRD techniques. Initial assessment of lesion targeting of Zr-89-huJ591 was done. Optimal time for imaging post-injection was determined. Results The dose was well tolerated with mild chills and rigors seen in two patients. The clearance of Zr-89-huJ591 from serum was bi-exponential with biological half-lives of 7 +/- 4.5 h (range 1.1-14 h) and 62 +/- 13 h (range 51-89 h) for initial rapid and later slow phase. Whole-body biological clearance was 219 +/- 48 h (range 153-317 h). The mean whole-body and liver residence time was 78.7 and 25.6 h, respectively. Dosimetric estimates to critical organs included liver 7.7 +/- 1.5 cGy/mCi, renal cortex 3.5 +/- 0.4 cGy/mCi, and bone marrow 1.2 +/- 0.2 cGy/mCi. Optimal time for patient imaging after injection was 7 +/- 1 days. Lesion targeting of bone or soft tissue was seen in all patients. Biopsies were performed in 8 patients for a total 12 lesions, all of which were histologically confirmed as metastatic prostate cancer. One biopsy-proven lesion was not positive on Zr-89-huJ591, while the remaining 11 lesions were Zr-89-huJ591 positive. Two biopsy-positive nodal lesions were noted only on Zr-89-huJ591 study, while the conventional imaging modality was negative. Conclusion Zr-89-huJ591 PET imaging of prostate-specific membrane antigen expression is safe and shows good localization of disease in prostate cancer patients. Liver is the critical organ for dosimetry, and 7 +/- 1 days is the optimal imaging time. A larger study is underway to determine lesion detection in an expanded cohort of patients with metastatic prostate cancer. C1 [Pandit-Taskar, Neeta; Beylergil, Volkan; Ruan, Shutian; Solomon, Stephen B.; Durack, Jeremy C.; Carrasquillo, Jorge A.; Lefkowitz, Robert A.; Lewis, Jason S.; Holland, Jason P.; Cheal, Sarah M.; Osborne, Joseph R.; Smith-Jones, Peter M.; Weber, Wolfgang A.; Larson, Steven M.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [O'Donoghue, Joseph A.] Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10021 USA. [Gonen, Mithat] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Reuter, Victor E.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Bander, Neil H.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. [Scher, Howard I.; Morris, Michael J.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Lyashchenko, Serge; Lewis, Jason S.] Mem Sloan Kettering Canc Ctr, Dept Radiochem, New York, NY 10021 USA. [Lyashchenko, Serge; Lewis, Jason S.] Mem Sloan Kettering Canc Ctr, Mol Imaging Probes Core, New York, NY 10021 USA. [Lewis, Jason S.; Weber, Wolfgang A.; Larson, Steven M.] Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol & Chem, New York, NY 10021 USA. [Pandit-Taskar, Neeta; Solomon, Stephen B.; Durack, Jeremy C.; Carrasquillo, Jorge A.; Lefkowitz, Robert A.; Lewis, Jason S.; Osborne, Joseph R.; Weber, Wolfgang A.; Larson, Steven M.] Weill Cornell Med Coll, Dept Radiol, New York, NY USA. [Reuter, Victor E.] Weill Cornell Med Coll, Dept Pathol, New York, NY USA. [Bander, Neil H.] Weill Cornell Med Coll, Dept Urol, New York, NY USA. [Scher, Howard I.; Morris, Michael J.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Loda, Massimo F.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Loda, Massimo F.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Smith-Jones, Peter M.] SUNY Stony Brook, Dept Psychiat & Behav Sci, Stony Brook, NY 11794 USA. RP Pandit-Taskar, N (reprint author), Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave, New York, NY 10021 USA. EM pandit-n@mskcc.org OI O'Donoghue, Joseph A/0000-0002-2761-0015; Holland, Jason/0000-0002-0066-219X; Durack, Jeremy/0000-0002-0672-9586; Carrasquillo, Jorge/0000-0002-8513-5734 FU NIH [P30CA008748]; Landy Research Fund; Hascoe Charitable Foundation FX Starr Cancer Consortium, Prostate cancer program of MSKCC and Center for Targeted Radioimmunotherapy and Diagnosis of the Ludwig Center for Cancer Immunotherapy, David H. Koch Foundation, R21 CA153177-03. RMPIC core is supported in part by NIH P30CA008748, the Landy Research Fund, and Hascoe Charitable Foundation. NR 46 TC 29 Z9 29 U1 3 U2 25 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 EI 1619-7089 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD NOV PY 2014 VL 41 IS 11 BP 2093 EP 2105 DI 10.1007/s00259-014-2830-7 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AQ8CX UT WOS:000343051700013 PM 25143071 ER PT J AU Sinnott, JA Dai, W Liao, KP Shaw, SY Ananthakrishnan, AN Gainer, VS Karlson, EW Churchill, S Szolovits, P Murphy, S Kohane, I Plenge, R Cai, TX AF Sinnott, Jennifer A. Dai, Wei Liao, Katherine P. Shaw, Stanley Y. Ananthakrishnan, Ashwin N. Gainer, Vivian S. Karlson, Elizabeth W. Churchill, Susanne Szolovits, Peter Murphy, Shawn Kohane, Isaac Plenge, Robert Cai, Tianxi TI Improving the power of genetic association tests with imperfect phenotype derived from electronic medical records SO HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; RHEUMATOID-ARTHRITIS RISK; HEALTH RECORDS; PHENOME-WIDE; DISEASE; SEVERITY; SUSCEPTIBILITY; POLYMORPHISMS; UNCERTAINTY; SENSITIVITY AB To reduce costs and improve clinical relevance of genetic studies, there has been increasing interest in performing such studies in hospital-based cohorts by linking phenotypes extracted from electronic medical records (EMRs) to genotypes assessed in routinely collected medical samples. A fundamental difficulty in implementing such studies is extracting accurate information about disease outcomes and important clinical covariates from large numbers of EMRs. Recently, numerous algorithms have been developed to infer phenotypes by combining information from multiple structured and unstructured variables extracted from EMRs. Although these algorithms are quite accurate, they typically do not provide perfect classification due to the difficulty in inferring meaning from the text. Some algorithms can produce for each patient a probability that the patient is a disease case. This probability can be thresholded to define case-control status, and this estimated case-control status has been used to replicate known genetic associations in EMR-based studies. However, using the estimated disease status in place of true disease status results in outcome misclassification, which can diminish test power and bias odds ratio estimates. We propose to instead directly model the algorithm-derived probability of being a case. We demonstrate how our approach improves test power and effect estimation in simulation studies, and we describe its performance in a study of rheumatoid arthritis. Our work provides an easily implemented solution to a major practical challenge that arises in the use of EMR data, which can facilitate the use of EMR infrastructure for more powerful, cost-effective, and diverse genetic studies. C1 [Sinnott, Jennifer A.; Dai, Wei; Cai, Tianxi] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Liao, Katherine P.; Karlson, Elizabeth W.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Shaw, Stanley Y.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Gainer, Vivian S.; Murphy, Shawn] Partners Healthcare, Res Comp, Charlestown, MA 02129 USA. [Churchill, Susanne; Kohane, Isaac] I2b2 Natl Ctr Biomed Comp, Boston, MA 02115 USA. [Szolovits, Peter] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Murphy, Shawn] Massachusetts Gen Hosp, Comp Sci Lab, Boston, MA 02114 USA. [Kohane, Isaac] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Plenge, Robert] Merck Res Labs, Boston, MA 02115 USA. RP Sinnott, JA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM jas953@mail.harvard.edu OI Szolovits, Peter/0000-0001-8411-6403 FU National Institutes of Health (NIH) Grants [T32 GM074897, T32 CA09001]; A. David Mazzone Career Development Award; NIH Grants [R01 GM079330, U01 GM092691, U54 LM008748] FX JAS was supported by the National Institutes of Health (NIH) Grants T32 GM074897 and T32 CA09001 and the A. David Mazzone Career Development Award. TC was supported by NIH Grants R01 GM079330, U01 GM092691 and U54 LM008748. NR 31 TC 3 Z9 3 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 EI 1432-1203 J9 HUM GENET JI Hum. Genet. PD NOV PY 2014 VL 133 IS 11 BP 1369 EP 1382 DI 10.1007/s00439-014-1466-9 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA AR0UU UT WOS:000343287900004 PM 25062868 ER PT J AU Ratnapriya, R Zhan, XW Fariss, RN Branham, KE Zipprer, D Chakarova, CF Sergeev, YV Campos, MM Othman, M Friedman, JS Maminishkis, A Waseem, NH Brooks, M Rajasimha, HK Edwards, AO Lotery, A Klein, BE Truitt, BJ Li, BS Schaumberg, DA Morgan, DJ Morrison, MA Souied, E Tsironi, EE Grassmann, F Fishman, GA Silvestri, G Scholl, HPN Kim, IK Ramke, J Tuo, JS Merriam, JE Merriam, JC Park, KH Olson, LM Farrer, LA Johnson, MP Peachey, NS Lathrop, M Baron, RV Igo, RP Klein, R Hagstrom, SA Kamatani, Y Martin, TM Jiang, YD Conley, Y Sahel, JA Zack, DJ Chan, CC Pericak-Vance, MA Jacobson, SG Gorin, MB Klein, ML Allikmets, R Iyengar, SK Weber, BH Haines, JL Leveillard, T Deangelis, MM Stambolian, D Weeks, DE Bhattacharya, SS Chew, EY Heckenlively, JR Abecasis, GR Swaroop, A AF Ratnapriya, Rinki Zhan, Xiaowei Fariss, Robert N. Branham, Kari E. Zipprer, David Chakarova, Christina F. Sergeev, Yuri V. Campos, Maria M. Othman, Mohammad Friedman, James S. Maminishkis, Arvydas Waseem, Naushin H. Brooks, Matthew Rajasimha, Harsha K. Edwards, Albert O. Lotery, Andrew Klein, Barbara E. Truitt, Barbara J. Li, Bingshan Schaumberg, Debra A. Morgan, Denise J. Morrison, Margaux A. Souied, Eric Tsironi, Evangelia E. Grassmann, Felix Fishman, Gerald A. Silvestri, Giuliana Scholl, Hendrik P. N. Kim, Ivana K. Ramke, Jacqueline Tuo, Jingsheng Merriam, Joanna E. Merriam, John C. Park, Kyu Hyung Olson, Lana M. Farrer, Lindsay A. Johnson, Matthew P. Peachey, Neal S. Lathrop, Mark Baron, Robert V. Igo, Robert P., Jr. Klein, Ronald Hagstrom, Stephanie A. Kamatani, Yoichiro Martin, Tammy M. Jiang, Yingda Conley, Yvette Sahel, Jose-Alan Zack, Donald J. Chan, Chi-Chao Pericak-Vance, Margaret A. Jacobson, Samuel G. Gorin, Michael B. Klein, Michael L. Allikmets, Rando Iyengar, Sudha K. Weber, Bernhard H. Haines, Jonathan L. Leveillard, Thierry Deangelis, Margaret M. Stambolian, Dwight Weeks, Daniel E. Bhattacharya, Shomi S. Chew, Emily Y. Heckenlively, John R. Abecasis, Goncalo R. Swaroop, Anand TI Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration SO HUMAN MOLECULAR GENETICS LA English DT Article ID ONSET RETINAL DEGENERATION; SORSBYS FUNDUS DYSTROPHY; GENOME-WIDE ASSOCIATION; BRUCHS MEMBRANE; TISSUE INHIBITOR; HIGH-RISK; METALLOPROTEINASES-3 TIMP3; MALATTIA LEVENTINESE; RETINITIS-PIGMENTOSA; DRUSEN FORMATION AB Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruch's membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 x 10(-5)). Thus, it appears that rare and common variants in a single gene-FBN2-can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruch's membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes. C1 [Ratnapriya, Rinki; Zipprer, David; Friedman, James S.; Brooks, Matthew; Rajasimha, Harsha K.; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Fariss, Robert N.; Campos, Maria M.] NEI, Biol Imaging Core, NIH, Bethesda, MD 20892 USA. [Sergeev, Yuri V.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Maminishkis, Arvydas] NEI, Sect Epithelial & Retinal Physiol & Dis, NIH, Bethesda, MD 20892 USA. [Tuo, Jingsheng; Chan, Chi-Chao] NEI, Immunopathol Sect, NIH, Bethesda, MD 20892 USA. [Chew, Emily Y.] NEI, Clin Trials Branch, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Zhan, Xiaowei; Abecasis, Goncalo R.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Zhan, Xiaowei; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Branham, Kari E.; Othman, Mohammad; Heckenlively, John R.] Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Chakarova, Christina F.; Waseem, Naushin H.; Bhattacharya, Shomi S.] UCL Inst Ophthalmol, Dept Genet, London EC1V 9EL, England. [Edwards, Albert O.] Univ Oregon, Inst Mol Biol, Eugene, OR 97401 USA. [Edwards, Albert O.] Oregon Retina, Eugene, OR 97401 USA. [Lotery, Andrew] Univ Southampton, Fac Med Clin & Expt Sci, Southampton SO16 6YD, Hants, England. [Klein, Barbara E.; Klein, Ronald] Univ Wisconsin, Sch Med, Dept Ophthalmol & Visual Sci, Madison, WI 53726 USA. [Truitt, Barbara J.; Igo, Robert P., Jr.; Iyengar, Sudha K.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Li, Bingshan; Olson, Lana M.; Haines, Jonathan L.] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37232 USA. [Schaumberg, Debra A.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Schaumberg, Debra A.; Morgan, Denise J.; Morrison, Margaux A.; Deangelis, Margaret M.] Univ Utah, Dept Ophthalmol & Visual Sci, Moran Eye Ctr, Salt Lake City, UT 84132 USA. [Souied, Eric] Univ Paris Est Creteil, Hop Intercommunal Creteil, Hop Henri Mondor, F-94000 Creteil, France. [Tsironi, Evangelia E.] Univ Thessaly, Sch Med, Dept Ophthalmol, Larisa, Greece. [Grassmann, Felix; Weber, Bernhard H.] Univ Regensburg, Inst Human Genet, D-93053 Regensburg, Germany. [Fishman, Gerald A.] Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL 60607 USA. [Silvestri, Giuliana] Queens Univ Belfast, Ctr Vis & Vasc Sci, Belfast, Antrim, North Ireland. [Scholl, Hendrik P. N.; Zack, Donald J.] Johns Hopkins Univ, Wilmer Eye Inst, Baltimore, MD 21287 USA. [Kim, Ivana K.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Ramke, Jacqueline] Fred Hollows Fdn, Auckland, New Zealand. [Ramke, Jacqueline] Univ New S Wales, Sch Social Sci, Sydney, NSW, Australia. [Merriam, Joanna E.; Merriam, John C.; Allikmets, Rando] Columbia Univ, Dept Ophthalmol, New York, NY 10032 USA. [Allikmets, Rando] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Park, Kyu Hyung] Seoul Natl Univ, Dept Ophthalmol, Bundang Hosp, Seoul 463707, South Korea. [Farrer, Lindsay A.] Boston Univ, Dept Med, Sect Biomed Genet, Sch Med, Boston, MA 02215 USA. [Farrer, Lindsay A.] Boston Univ, Dept Ophthalmol, Sect Biomed Genet, Sch Med, Boston, MA 02215 USA. [Farrer, Lindsay A.] Boston Univ, Dept Biostat, Sch Med, Sect Biomed Genet, Boston, MA 02215 USA. [Farrer, Lindsay A.] Boston Univ, Dept Med, Sect Biomed Genet, Sch Publ Hlth, Boston, MA 02215 USA. [Farrer, Lindsay A.] Boston Univ, Dept Ophthalmol, Sect Biomed Genet, Sch Publ Hlth, Boston, MA 02215 USA. [Farrer, Lindsay A.] Boston Univ, Dept Biostat, Sect Biomed Genet, Sch Publ Hlth, Boston, MA 02215 USA. [Johnson, Matthew P.] Texas Biomed Res Inst, San Antonio, TX 78245 USA. [Peachey, Neal S.; Hagstrom, Stephanie A.] Cleveland Clin Fdn, Cole Eye Inst, Cleveland, OH 44195 USA. [Peachey, Neal S.] Louis Stokes Cleveland VA Med Ctr, Cleveland, OH 44195 USA. [Lathrop, Mark; Kamatani, Yoichiro; Sahel, Jose-Alan; Leveillard, Thierry] Univ Paris 06, INSERM, Dept Genet, Inst Vis,UMR S 968, Paris, France. [Baron, Robert V.; Weeks, Daniel E.] Univ Pittsburgh, Dept Human Genet, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Jiang, Yingda; Weeks, Daniel E.] Univ Pittsburgh, Dept Biostat, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Martin, Tammy M.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Conley, Yvette] Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15261 USA. [Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33125 USA. [Pericak-Vance, Margaret A.] Univ Miami, Miller Sch Med, Miami, FL 33125 USA. [Jacobson, Samuel G.] Univ Penn, Dept Ophthalmol, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Gorin, Michael B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Klein, Michael L.] Univ Portland, Macular Degenerat Ctr, Casey Eye Inst, Portland, OR 97201 USA. [Stambolian, Dwight] Univ Penn, Dept Ophthalmol, Philadelphia, PA USA. [Stambolian, Dwight] Univ Penn, Dept Genet, Philadelphia, PA USA. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. EM swaroopa@nei.nih.gov RI DeAngelis, e/J-7863-2015; Kamatani, Yoichiro/N-5513-2015; Sahel, Jose-Alain/F-3172-2017; OI Ramke, Jacqueline/0000-0002-5764-1306; Farrer, Lindsay/0000-0001-5533-4225; Swaroop, Anand/0000-0002-1975-1141; Weeks, Daniel/0000-0001-9410-7228 FU National Eye Institute and National Institutes of Health [EY016862, EY013435, EY09859, EY017362, EY014458, EY019007]; Macula Vision Research Foundation; Foundation Fighting Blindness; Kaplen Foundation; Widgeon Point Charitable Foundation; Harold and Pauline Price Foundation; Elmer and Sylvia Sramek Foundation; Veterans Administration; German Research Foundation [WE 1259/19-2]; NIHR; Welcome Trust [076169/A]; American Health Assistance Foundation [M2007110]; Frost Charitable Trust; Brian Mercer Charitable Trust; Macular Society; Gift of Sight; Research to Prevent Blindness FX This study was supported by Intramural Research Program of the National Eye Institute and National Institutes of Health grants (EY016862, EY013435, EY09859, EY017362, EY014458, EY019007), Macula Vision Research Foundation, Foundation Fighting Blindness, Kaplen Foundation, Widgeon Point Charitable Foundation, Harold and Pauline Price Foundation, Elmer and Sylvia Sramek Foundation, Veterans Administration, Harold and Pauline Price Foundation, German Research Foundation (WE 1259/19-2), NIHR supported BRC at Moorfields Eye Hospital (London), Welcome Trust (076169/A), American Health Assistance Foundation (M2007110), Frost Charitable Trust, Brian Mercer Charitable Trust, Macular Society and the Gift of Sight, and Research to Prevent Blindness. NR 64 TC 13 Z9 13 U1 0 U2 23 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD NOV 1 PY 2014 VL 23 IS 21 BP 5827 EP 5837 DI 10.1093/hmg/ddu276 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AQ9UX UT WOS:000343203600020 PM 24899048 ER PT J AU Jeon, HJ Fava, M Mischoulon, D Baer, L Clain, A Doorley, J DiPierro, M Cardoos, A Papakostas, GI AF Jeon, Hong Jin Fava, Maurizio Mischoulon, David Baer, Lee Clain, Alisabet Doorley, James DiPierro, Moneika Cardoos, Amber Papakostas, George I. TI Psychomotor symptoms and treatment outcomes of ziprasidone monotherapy in patients with major depressive disorder: a 12-week, randomized, double-blind, placebo-controlled, sequential parallel comparison trial SO INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE major depressive disorder; psychomotor symptoms; ziprasidone ID ARIPIPRAZOLE AUGMENTATION; CLINICAL-TRIALS; MOOD DISORDERS; OPEN-LABEL; EFFICACY; NONRESPONSE; OUTPATIENTS; FLUOXETINE; AGITATION; RETARDATION AB The aim of this study was to evaluate efficacy of ziprasidone monotherapy for major depressive disorder (MDD) with and without psychomotor symptoms. In accordance with the sequential parallel comparison design, 106 MDD patients (age 44.0 +/- 10.7 years; female, 43.4%) were recruited and a post-hoc analysis was carried out on 12-week double-blind treatment with either ziprasidone (40-160 mg/day) or placebo, divided into two phases of 6 weeks each to the assigned treatment sequences, drug/drug, placebo/placebo, and placebo/drug. Psychomotor symptoms were evaluated on the basis of the Mini-International Neuropsychiatric Interview at baseline. Efficacy assessments, on the basis of the 17-item Hamilton Depression Rating Scale (HDRS-17) and the Quick Inventory of Depressive Symptomatology Scale, Self-Rated (QIDS-SR), were performed every week throughout the trial. In phase I, ziprasidone monotherapy produced significant improvement in patients with psychomotor symptoms compared with placebo on the basis of HDRS-17 (F = 5.95, P = 0.017) and QIDS-SR (F = 5.26, P=0.025) scores, whereas no significant changes were found in HDRS-17 (F = 2.32, P = 0.15) and QIDS-SR (F = 3.70, P = 0.074) scores in patients without psychomotor symptoms. In phase II, ziprasidone monotherapy produced no significant differences compared with placebo. In the pooled analysis, ziprasidone monotherapy showed significance according to QIDS-SR (Z = 2.00, P = 0.046) and a trend toward statistical significance according to the HDRS-17 (Z=1.66, P = 0.10) in patients with psychomotor symptoms. Ziprasidone monotherapy may produce significant improvement compared with placebo in MDD patients with psychomotor symptoms. (C) 2014 Wolters Kluwer Health broken vertical bar Lippincott Williams & Wilkins. C1 [Jeon, Hong Jin] Sungkyunkwan Univ Sch Med, Dept Psychiat, Depress Ctr, Samsung Med Ctr, Seoul 135710, South Korea. [Jeon, Hong Jin] SAIHST, Seoul, South Korea. [Jeon, Hong Jin; Fava, Maurizio; Mischoulon, David; Baer, Lee; Clain, Alisabet; Doorley, James; DiPierro, Moneika; Cardoos, Amber; Papakostas, George I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. RP Jeon, HJ (reprint author), Sungkyunkwan Univ Sch Med, Dept Psychiat, Depress Ctr, Samsung Med Ctr, 50 Irwon Dong, Seoul 135710, South Korea. EM jeonhj@skku.edu FU Pfizer Inc.; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2011-0013064]; Samsung Medical Center Clinical Research Development Program (CRDP) [SMO1131461] FX This trial was supported by Pfizer Inc. This research was also supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2011-0013064), and the Samsung Medical Center Clinical Research Development Program (CRDP) Grant SMO1131461. Neither sponsor was involved in any extent in the design of the study, analyses of the data, or in commenting on the manuscript. NR 34 TC 3 Z9 3 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0268-1315 EI 1473-5857 J9 INT CLIN PSYCHOPHARM JI Int. Clin. Psychopharmacol. PD NOV PY 2014 VL 29 IS 6 BP 332 EP 338 DI 10.1097/YIC.0000000000000039 PG 7 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA AQ9DP UT WOS:000343144000005 PM 24815673 ER PT J AU Sittig, DF Gonzalez, D Singh, H AF Sittig, Dean F. Gonzalez, Daniel Singh, Hardeep TI Contingency planning for electronic health record-based care continuity: A survey of recommended practices SO INTERNATIONAL JOURNAL OF MEDICAL INFORMATICS LA English DT Article DE Electronic health records ID SAFETY AB Background: Reliable health information technology (HIT) in general, and electronic health record systems (EHRs) in particular are essential to a high-performing healthcare system. When the availability of EHRs are disrupted, alternative methods must be used to maintain the continuity of healthcare. Methods: We developed a survey to assess institutional practices to handle situations when EHRs were unavailable for use (downtime preparedness). We used literature reviews and expert opinion to develop items that assessed the implementation of potentially useful practices. We administered the survey to U.S.-based healthcare institutions that were members of a professional organization that focused on collaboration and sharing of HIT-related best practices among its members. All members were large integrated health systems. Results: We received responses from SO of the 59 (84%) member institutions. Nearly all (96%) institutions reported at least one unplanned downtime (of any length) in the last 3 years and 70% had at least one unplanned downtime greater than 8 h in the last 3 years. Three institutions reported that one or more patients were injured as a result of either a planned or unplanned downtime. The majority of institutions (70-85%) had implemented a portion of the useful practices we identified, but very few practices were followed by all organizations. Conclusions: Unexpected downtimes related to EHRs appear to be fairly common among institutions in our survey. Most institutions had only partially implemented comprehensive contingency plans to maintain safe and effective healthcare during unexpected EHRs downtimes. (C) 2014 Elsevier Ireland Ltd. All rights reserved. C1 [Sittig, Dean F.] Univ Texas Houston, Sch Biomed Informat, Houston, TX 77030 USA. [Sittig, Dean F.] Univ Texas Houston, Mem Hermann Ctr Healthcare Qual & Safety, Houston, TX 77030 USA. [Gonzalez, Daniel] St Lukes Episcopal Hlth Syst, Dept Clin Effectiveness & Performance Measurement, Houston, TX USA. [Singh, Hardeep] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston VA HSR&D Ctr Innovat, Houston, TX 77030 USA. [Singh, Hardeep] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. RP Sittig, DF (reprint author), Univ Texas Houston, Mem Hermann Ctr Healthcare Qual & Safety, 6410 Fannin St,UTPB 1100-43, Houston, TX 77030 USA. EM dean.f.sittig@uth.tmc.edu FU Houston VA Health Services Research 8.7 Development Center of Innovation [GIN 13-413] FX Dr. Singh is partially supported by the Houston VA Health Services Research 8.7 Development Center of Innovation (GIN 13-413). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. NR 30 TC 9 Z9 9 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1386-5056 EI 1872-8243 J9 INT J MED INFORM JI Int. J. Med. Inform. PD NOV PY 2014 VL 83 IS 11 BP 797 EP 804 DI 10.1016/j.ijmedinf.2014.07.007 PG 8 WC Computer Science, Information Systems; Health Care Sciences & Services; Medical Informatics SC Computer Science; Health Care Sciences & Services; Medical Informatics GA AQ8VL UT WOS:000343114700002 PM 25200197 ER PT J AU Haykowsky, MJF Riess, KJ Baggish, AL AF Haykowsky, Mark J. F. Riess, Kenneth J. Baggish, Aaron L. TI Heart transplant recipient finishes the 118th Boston Marathon 27 years post-surgery SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Editorial Material C1 [Haykowsky, Mark J. F.] Univ Alberta, Fac Rehabil Med, Edmonton, AB, Canada. [Riess, Kenneth J.] Northern Alberta Inst Technol, Sch Hlth Sci, Edmonton, AB, Canada. [Baggish, Aaron L.] Massachusetts Gen Hosp, Cardiovasc Performance Program, Boston, MA 02114 USA. RP Haykowsky, MJF (reprint author), Univ Alberta, Fac Rehabil Med, Edmonton, AB, Canada. NR 5 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 EI 1557-3117 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD NOV PY 2014 VL 33 IS 11 BP 1197 EP 1197 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA AR0OS UT WOS:000343271800019 PM 25200379 ER PT J AU Freeman, EE AF Freeman, Esther E. TI A Seat at the Big Table: Expanding the Role of Dermatology at the World Health Organization and Beyond SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material C1 [Freeman, Esther E.] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Freeman, EE (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Bartlett Hall 6R,55 Fruit St, Boston, MA 02114 USA. EM eefreeman@partners.org NR 9 TC 2 Z9 2 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD NOV PY 2014 VL 134 IS 11 BP 2663 EP 2665 DI 10.1038/jid.2014.355 PG 3 WC Dermatology SC Dermatology GA AR0OM UT WOS:000343271200001 PM 25318423 ER PT J AU Reish, RG Kobraei, EM Austen, WG Raskin, KA Liao, EC AF Reish, Richard G. Kobraei, Edward M. Austen, William G., Jr. Raskin, Kevin A. Liao, Eric C. TI The Bone-In-Fillet Flap: A Spare-Parts Approach to Achieving Simultaneous Bony Pelvic Stabilization and Soft Tissue Reconstruction following External Hemipelvectomy SO JOURNAL OF RECONSTRUCTIVE MICROSURGERY LA English DT Letter ID AMPUTATION; RING; DEFECTS C1 [Reish, Richard G.; Kobraei, Edward M.; Austen, William G., Jr.; Raskin, Kevin A.; Liao, Eric C.] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02120 USA. RP Kobraei, EM (reprint author), Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, 1575 Tremont St,Apt 1103, Boston, MA 02120 USA. EM ekobraei@partners.org NR 10 TC 0 Z9 0 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0743-684X EI 1098-8947 J9 J RECONSTR MICROSURG JI J. Reconstr. Microsurg. PD NOV PY 2014 VL 30 IS 9 BP 663 EP 665 DI 10.1055/s-0034-1371511 PG 3 WC Surgery SC Surgery GA AQ9RC UT WOS:000343192000010 PM 24752742 ER PT J AU Rosser, G Tricoci, P Morrow, D Christopoulos, C Niespialowska-Steuden, MN Kozarski, R Wilcox, R Gorog, DA AF Rosser, G. Tricoci, P. Morrow, D. Christopoulos, C. Niespialowska-Steuden, M. N. Kozarski, R. Wilcox, R. Gorog, D. A. TI PAR-1 antagonist vorapaxar favorably improves global thrombotic status in patients with coronary disease SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE Platelets; Thrombolysis; PAR-1 antagonist; Thrombosis ID ENDOGENOUS THROMBOLYSIS; PLATELET REACTIVITY; FIBRINOLYSIS AB To assess the effect of vorapaxar on global thrombotic and thrombolytic status. The propensity for thrombus formation is determined by the balance between prothrombotic factors and endogenous thrombolysis. Impaired thrombolytic status increases cardiovascular risk. Vorapaxar is a novel, oral, protease-activated receptor-1 antagonist that inhibits thrombin-induced platelet activation. In the TRACER and TRA 2A degrees P-TIMI 50 studies, patients with acute coronary syndromes and established atherosclerosis were randomized to vorapaxar 2.5 mg daily or placebo, in addition to standard care. In 57 patients enrolled in a single center, blood was tested with the point-of-care global thrombosis test, on and off treatment. This automated test employs non-anticoagulated blood to assess thrombotic and thrombolytic status, measuring the time required to form a shear-induced thrombus under physiological conditions (occlusion time, OT), and subsequently, the time to achieve endogenous lysis of the thrombus (lysis time, LT). Patients on vorapaxar exhibited longer OT on vs. off treatment [median 561 s (interquartile range 422-654) vs. 372 s(338-454), P = 0.003] and shorter LT on treatment than off [1,158 s(746-1,492) vs. 1,733 s(1,388-2,230), P = 0.016]. Patients on placebo showed no difference in OT [419 s(343-514) vs. 411 s(346-535), P = 0.658] or LT [1,236 s(985-1,594) vs. 1,400 s(1,092-1,686), P = 0.524] on and off treatment. During treatment, OT was longer in patients taking vorapaxar [561 s(422-654) vs. 419 s(343-514), P = 0.009], but LT was similar in vorapaxar and placebo arms [1,158 s(746-1,492) vs. 1,236 s(985-1,594), P = 0.277]. Vorapaxar prolongs OT and shortens LT, with favorable effects on thrombotic and thrombolytic status. In addition to its antiplatelet effect, vorapaxar may enhance endogenous thrombolysis, which is frequently impaired in coronary disease. C1 [Rosser, G.; Niespialowska-Steuden, M. N.; Gorog, D. A.] Univ London Imperial Coll Sci Technol & Med, London, England. [Rosser, G.; Christopoulos, C.; Niespialowska-Steuden, M. N.; Gorog, D. A.] East & North Hertfordshire NHS Trust, Stevenage, Herts, England. [Tricoci, P.] Duke Clin Res Inst, Durham, NC USA. [Morrow, D.] Brigham & Womens Hosp, TIMI Study Grp, Cardiovasc Div, Boston, MA 02115 USA. [Christopoulos, C.; Kozarski, R.; Gorog, D. A.] Univ Hertfordshire, Hatfield AL10 9AB, Herts, England. [Wilcox, R.] Univ Nottingham, Nottingham NG7 2RD, England. RP Gorog, DA (reprint author), Univ London Imperial Coll Sci Technol & Med, London, England. EM d.gorog@imperial.ac.uk NR 20 TC 6 Z9 6 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 EI 1573-742X J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD NOV PY 2014 VL 38 IS 4 BP 423 EP 429 DI 10.1007/s11239-014-1075-4 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA AQ9YN UT WOS:000343216100001 PM 24676931 ER PT J AU Kadir, SN Goodman, DFM Harris, KD AF Kadir, Shabnam N. Goodman, Dan F. M. Harris, Kenneth D. TI High-Dimensional Cluster Analysis with the Masked EM Algorithm SO NEURAL COMPUTATION LA English DT Article ID MODEL; MIXTURES AB Cluster analysis faces two problems in high dimensions: the "curse of dimensionality" that can lead to overfitting and poor generalization performance and the sheer time taken for conventional algorithms to process large amounts of high-dimensional data. We describe a solution to these problems, designed for the application of spike sorting for next-generation, high-channel-count neural probes. In this problem, only a small subset of features provides information about the cluster membership of any one data vector, but this informative feature subset is not the same for all data points, rendering classical feature selection ineffective. We introduce a "masked EM" algorithm that allows accurate and time-efficient clustering of up to millions of points in thousands of dimensions. We demonstrate its applicability to synthetic data and to real-world high-channel-count spike sorting data. C1 [Kadir, Shabnam N.; Harris, Kenneth D.] UCL, UCL Inst Neurol, London WC1E 6DE, England. [Kadir, Shabnam N.; Harris, Kenneth D.] UCL, UCL Dept Neurosci Physiol & Pharmacol, London WC1E 6DE, England. [Goodman, Dan F. M.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Eaton Peabody Labs,Dept Otol & Laryngol, Boston, MA 02114 USA. RP Kadir, SN (reprint author), UCL, UCL Inst Neurol, London WC1E 6DE, England. EM s.kadir@ucl.ac.uk; Dan_Goodman@meei.harvard.edu; kenneth.harris@ucl.ac.uk OI Harris, Kenneth/0000-0002-5930-6456 FU Wellcome Trust [095668] NR 28 TC 40 Z9 41 U1 0 U2 18 PU MIT PRESS PI CAMBRIDGE PA ONE ROGERS ST, CAMBRIDGE, MA 02142-1209 USA SN 0899-7667 EI 1530-888X J9 NEURAL COMPUT JI Neural Comput. PD NOV PY 2014 VL 26 IS 11 BP 2379 EP 2394 DI 10.1162/NECO_a_00661 PG 16 WC Computer Science, Artificial Intelligence; Neurosciences SC Computer Science; Neurosciences & Neurology GA AQ9PB UT WOS:000343186700001 PM 25149694 ER PT J AU Mazurek, MO Keefer, A Shui, A Vasa, RA AF Mazurek, Micah O. Keefer, Amy Shui, Amy Vasa, Roma A. TI One-year course and predictors of abdominal pain in children with autism spectrum disorders: The role of anxiety and sensory over-responsivity SO RESEARCH IN AUTISM SPECTRUM DISORDERS LA English DT Article DE Abdominal pain; Gastrointestinal problems; Anxiety; Sensory problems; Autism; Autism spectrum disorder ID IRRITABLE-BOWEL-SYNDROME; OF-THE-LITERATURE; FUNCTIONAL GASTROINTESTINAL DISORDERS; VISCERAL HYPERSENSITIVITY; SOMATIC COMPLAINTS; SYMPTOMS; METAANALYSIS; PREVALENCE; ADOLESCENTS; MODULATION AB Objectives: To examine the one-year course of parent-reported abdominal pain in children with autism spectrum disorder (ASD), and to determine whether anxiety and sensory over-responsivity (SOR) contribute to the onset or remission of abdominal pain. Methods: Participants included 225 children (ages 2-17) with ASD enrolled in the Autism Speaks Autism Treatment Network. Primary measures included the parent-reported GI Symptom Inventory Questionnaire, Child Behavior Checklist, and Short Sensory Profile. Results: One-fourth (25.8%) experienced chronic abdominal pain (duration >= 3 months) at baseline, persisting at one-year follow-up for 86.7%. New onset pain occurred for 23.8% of those without baseline pain. Anxiety, SOR, and chronic abdominal pain were associated at baseline. SOR significantly predicted new onset pain, but neither anxiety nor SOR were predictors of pain remission. Conclusions: Abdominal pain appears to be common and persistent among children with ASD. The relations among SOR, anxiety and abdominal pain offer information about potential underlying mechanisms. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Mazurek, Micah O.] Univ Missouri, Dept Hlth Psychol, Columbia, MO 65211 USA. [Mazurek, Micah O.] Thompson Ctr Autism & Neurodev Disorders, Columbia, MO 65211 USA. [Keefer, Amy; Vasa, Roma A.] Kennedy Krieger Inst, Ctr Autism & Related Disorders, Baltimore, MD 21211 USA. [Shui, Amy] MassGen Hosp Children, MGH Biostat Ctr, Boston, MA 02114 USA. [Vasa, Roma A.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21287 USA. RP Mazurek, MO (reprint author), Univ Missouri, Dept Hlth Psychol, 205 Portland St, Columbia, MO 65211 USA. EM mazurekm@missouri.edu; keefer@kennedykrieger.org; ashui@mgh.harvard.edu; vasa@kennedykrieger.org OI Mazurek, Micah/0000-0001-7715-6538 NR 57 TC 2 Z9 2 U1 6 U2 31 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1750-9467 EI 1878-0237 J9 RES AUTISM SPECT DIS JI Res. Autism Spectr. Disord. PD NOV PY 2014 VL 8 IS 11 BP 1508 EP 1515 DI 10.1016/j.rasd.2014.07.018 PG 8 WC Education, Special; Psychology, Developmental; Psychiatry; Rehabilitation SC Education & Educational Research; Psychology; Psychiatry; Rehabilitation GA AR1RK UT WOS:000343362100008 ER PT J AU Zhou, ES Recklitis, CJ AF Zhou, Eric S. Recklitis, Christopher J. TI Insomnia in adult survivors of childhood cancer: a report from project REACH SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Insomnia; Sleep disorder; Childhood cancer; Cancer survivorship; Quality of life ID ACUTE LYMPHOBLASTIC-LEUKEMIA; SLEEP QUALITY; BREAST-CANCER; FATIGUE; PREVALENCE; DISTURBANCES; CHILDREN; STRESS; ADOLESCENTS; BEHAVIORS AB Insomnia is a common problem affecting cancer survivors even years after completion of therapy. Childhood cancer survivors may be at particular risk due to vulnerability to the effects of treatment and medical late effects which impact normal sleep development. Using an indicator of clinically significant insomnia (sleep efficiency), we examined a group of adult survivors of childhood cancer to (1) describe clinical insomnia rates, (2) identify physical and psychological correlates of insomnia, and (3) investigate the frequency with which sleep issues were evaluated during a cancer survivorship medical visit. A total of 122 adult survivors of childhood cancer completed standard measures of sleep, psychological distress, and health-related quality of life. Medical records of the 75 survivors with a survivorship medical visit on the day of self-report measure completion were reviewed for documentation of sleep-related issues. Twenty-eight percent of participants endorsed sleep efficiency below 85 %, indicating clinically significant insomnia. Insomnia was associated with poor physical health and anxiety but not with demographic or cancer treatment variables. Medical providers failed to document sleep in visit notes for 67 % of patients with self-reported insomnia. A significant proportion of adult survivors of childhood cancer report insomnia, which is associated with physical and psychological health. Few survivors with insomnia discuss this issue with oncology providers during survivorship care. There is a clear need to screen for insomnia in this population. Patients and providers should take greater responsibility for discussing sleep issues and seeking out proper treatment referrals when it is identified. C1 [Zhou, Eric S.; Recklitis, Christopher J.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Zhou, Eric S.; Recklitis, Christopher J.] Harvard Univ, Sch Med, Boston, MA USA. RP Recklitis, CJ (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM christopher_recklitis@dfci.harvard.edu NR 48 TC 5 Z9 5 U1 3 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD NOV PY 2014 VL 22 IS 11 BP 3061 EP 3069 DI 10.1007/s00520-014-2316-y PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA AQ8DN UT WOS:000343053700022 PM 24935649 ER PT J AU Khan, N Almukhtar, RM AF Khan, N. Almukhtar, R. M. TI Letter: predictors of severe disease in ulcerative colitis - the same or different in Crohn's disease? Authors' reply SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Letter C1 [Khan, N.] Univ Penn, Dept Med, Gastroenterol Sect, Perelman Sch Med, Philadelphia, PA 19104 USA. [Khan, N.] Univ Penn, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Khan, N.] Southeast Louisiana Vet Hlth Care Syst, Gastroenterol Sect, New Orleans, LA USA. [Almukhtar, R. M.] Louisiana State Univ, Hlth Sci Ctr, Dept Epidemiol, New Orleans, LA USA. [Almukhtar, R. M.] Tulane Univ, Hlth Sci Ctr, Dept Internal Med, Sect Gastroenterol & Hepatol, New Orleans, LA 70118 USA. RP Khan, N (reprint author), Univ Penn, Dept Med, Gastroenterol Sect, Perelman Sch Med, Philadelphia, PA 19104 USA. EM nkhan2@tulane.edu NR 5 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 EI 1365-2036 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD NOV PY 2014 VL 40 IS 9 BP 1121 EP 1122 DI 10.1111/apt.12948 PG 2 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA AQ6EU UT WOS:000342903400020 PM 25280262 ER PT J AU Suzuki, J Connery, HS Ellison, TV Renner, JA AF Suzuki, Joji Connery, Hilary S. Ellison, Tatyana V. Renner, John A. TI Preliminary Survey of Office-Based Opioid Treatment Practices and Attitudes Among Psychiatrists Never Receiving Buprenorphine Training to Those Who Received Training During Residency SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID ADDICTION SPECIALISTS; DEPENDENCE; BARRIERS AB Objective: To compare the characteristics, attitudes, and current prescribing practices of recently graduating psychiatrists who completed buprenorphine training during residency to those who never completed any training. Methods: A total of 359 psychiatrists completing residency training between 2008 and 2011 were recruited to complete an on-line survey. Results: Responses from 93 psychiatrists were included for a response rate of 25.9%. Psychiatrists completing any buprenorphine training during residency were more likely to be male and report more favorable views of OBOT with buprenorphine than compared to those who never completed any training. Twenty (38.5%) of those psychiatrists who completed training during residency reported the current prescribing of buprenorphine. Conclusions: Completion of buprenorphine training during residency may be a factor in shaping future attitudes towards OBOT and buprenorphine prescribing practices. Further research is needed to clarify the impact of buprenorphine training during residency. Scientific Significance: Buprenorphine training during residency training may be a contributing factor in shaping future physician attitudes towards office-based opioid treatment and buprenorphine prescribing practices. C1 [Suzuki, Joji; Ellison, Tatyana V.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Suzuki, Joji; Connery, Hilary S.; Ellison, Tatyana V.] Harvard Univ, Sch Med, Boston, MA USA. [Connery, Hilary S.] McLean Hosp, Belmont, MA 02178 USA. [Ellison, Tatyana V.] Harvard Longwood Psychiat Residency Training Prog, Boston, MA USA. [Renner, John A.] VA Boston HealthCare, Boston, MA USA. [Renner, John A.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Suzuki, J (reprint author), Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. EM jsuzuki2@partners.org FU NIDA NIH HHS [U10 DA015831, U10DA15831] NR 11 TC 4 Z9 4 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 EI 1521-0391 J9 AM J ADDICTION JI Am. J. Addict. PD NOV-DEC PY 2014 VL 23 IS 6 BP 618 EP 622 DI 10.1111/j.1521-0391.2014.12143.x PG 5 WC Substance Abuse SC Substance Abuse GA AQ6FF UT WOS:000342904700014 PM 25065457 ER PT J AU Razzaque, MS AF Razzaque, Mohammed Shawkat TI Bone-kidney axis in systemic phosphate turnover SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Review DE Klotho; FGF23; Kidney; Bone; Vitamin-D ID FIBROBLAST-GROWTH-FACTOR; SOFT-TISSUE CALCIFICATION; VITAMIN-D; PARATHYROID-HORMONE; IN-VIVO; PHOSPHORUS HOMEOSTASIS; HEMODIALYSIS-PATIENTS; INORGANIC-PHOSPHATE; TUMORAL CALCINOSIS; MISSENSE MUTATION AB An adequate phosphate balance is essential for the maintenance of skeletal growth, development and function. It is also crucial in basic cellular functions, ranging from cell signaling to energy metabolism. Bone-derived fibroblast growth factor 23 (FGF23), through activating FGF receptor system, plays an important role in the systemic regulation of phosphate metabolism. Under physiological conditions, FGF23 exerts serum phosphate-lowering effects by inducing urinary phosphate excretion. Increased FGF23 activities are associated with hypophosphatemic diseases (i.e., rickets/osteomalacia), while reduced FGF23 activity are linked to hyperphosphatemic diseases (i.e., tumoral calcinosis). Unlike most of the FGF family members, FGF23 needs klotho, as a co-factor to activate its receptor system. In vivo studies have convincingly demonstrated that, in absence of klotho, FGF23 is unable to influence systemic phosphate metabolism. Available information suggests that interactions of FGF23, klotho, and FGFRs regulate renal phosphate metabolism by suppressing sodium-phosphate transporters in the proximal tubular epithelial cells. This article briefly summarizes how bone-kidney communication contributes to physiologic phosphate balance. (C) 2014 Elsevier Inc. All rights reserved. C1 Forsyth Inst, Dept Appl Oral Sci, Cambridge, MA 02142 USA. RP Razzaque, MS (reprint author), Forsyth Inst, Dept Appl Oral Sci, 245 First St, Cambridge, MA 02142 USA. EM mrazzaque@hms.harvard.edu NR 80 TC 4 Z9 4 U1 1 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 EI 1096-0384 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD NOV 1 PY 2014 VL 561 SI SI BP 154 EP 158 DI 10.1016/j.abb.2014.06.031 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA AQ5QI UT WOS:000342863300019 PM 24997362 ER PT J AU Haroutunian, V Katsel, P Roussos, P Davis, KL Altshuler, LL Bartzokis, G AF Haroutunian, V. Katsel, P. Roussos, P. Davis, K. L. Altshuler, L. L. Bartzokis, G. TI Myelination, Oligodendrocytes, and Serious Mental Illness SO GLIA LA English DT Review DE white matter; astrocyte; microglia; GSK-3; metabolic; RAS; apolipoprotein; degeneration; MRI ID CENTRAL-NERVOUS-SYSTEM; 2',3'-CYCLIC NUCLEOTIDE 3'-PHOSPHODIESTERASE; GLYCOGEN-SYNTHASE KINASE-3; WHITE-MATTER; BIPOLAR DISORDER; CHRONIC-SCHIZOPHRENIA; INTRACORTICAL MYELIN; HEALTHY-INDIVIDUALS; SUSCEPTIBILITY GENE; COGNITIVE DECLINE AB Historically, the human brain has been conceptually segregated from the periphery and further dichotomized into gray matter (GM) and white matter (WM) based on the whitish appearance of the exceptionally high lipid content of the myelin sheaths encasing neuronal axons. These simplistic dichotomies were unfortunately extended to conceptually segregate neurons from glia, cognition from behavior, and have been codified in the separation of clinical and scientific fields into medicine, psychiatry, neurology, pathology, etc. The discrete classifications have helped obscure the importance of continual dynamic communication between all brain cell types (neurons, astrocytes, microglia, oligodendrocytes, and precursor (NG2) cells) as well as between brain and periphery through multiple signaling systems. The signaling systems range from neurotransmitters to insulin, angiotensin, and multiple kinases such a glycogen synthase kinase 3 (GSK-3) that together help integrate metabolism, inflammation, and myelination processes and orchestrate the development, plasticity, maintenance, and repair that continually optimize function of neural networks. A more comprehensive, evolution-based, systems biology approach that integrates brain, body, and environmental interactions may ultimately prove more fruitful in elucidating the complexities of human brain function. The historic focus on neurons/GM is rebalanced herein by highlighting the importance of a systems-level understanding of the interdependent age-related shifts in both central and peripheral homeostatic mechanisms that can lead to remarkably prevalent and devastating neuropsychiatric diseases. Herein we highlight the role of glia, especially the most recently evolved oligodendrocytes and the myelin they produce, in achieving and maintaining optimal brain function. The human brain undergoes exceptionally protracted and pervasive myelination (even throughout its GM) and can thus achieve and maintain the rapid conduction and synchronous timing of neural networks on which optimal function depends. The continuum of increasing myelin vulnerability resulting from the human brain's protracted myelination underlies underappreciated communalities between different disease phenotypes ranging from developmental ones such as schizophrenia (SZ) and bipolar disorder (BD) to degenerative ones such as Alzheimer's disease (AD). These shared vulnerabilities also expose significant yet underexplored opportunities for novel treatment and prevention approaches that have the potential to considerably reduce the tremendous burden of neuropsychiatric disease. C1 [Haroutunian, V.; Katsel, P.; Roussos, P.; Davis, K. L.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Haroutunian, V.; Davis, K. L.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Haroutunian, V.; Roussos, P.] MIRECC JJ Peters VA Med Ctr, Bronx, NY USA. [Altshuler, L. L.; Bartzokis, G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Altshuler, L. L.; Bartzokis, G.] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. [Altshuler, L. L.; Bartzokis, G.] Greater Los Angeles VA Healthcare Syst, West Los Angeles, CA USA. RP Bartzokis, G (reprint author), 300 UCLA Med Plaza,Suite 2200, Los Angeles, CA 90095 USA. EM gbar@ucla.edu RI Roussos, Panos/J-7090-2013 OI Roussos, Panos/0000-0002-4640-6239 FU NIH [MH0266029, MH064673, AG027342]; Research and Psychiatry Services of the Department of Veterans Affairs; Litwin Foundation; RCS Foundation FX Grant sponsor: NIH; Grant numbers: MH0266029; MH064673; AG027342; Grant sponsor: Research and Psychiatry Services of the Department of Veterans Affairs, and the Litwin and RCS Foundations. NR 95 TC 41 Z9 43 U1 7 U2 46 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 EI 1098-1136 J9 GLIA JI Glia PD NOV PY 2014 VL 62 IS 11 SI SI BP 1856 EP 1877 DI 10.1002/glia.22716 PG 22 WC Neurosciences SC Neurosciences & Neurology GA AQ4YF UT WOS:000342806800008 PM 25056210 ER PT J AU Bernardino, I Rebola, J Farivar, R Silva, E Castelo-Branco, M AF Bernardino, Ines Rebola, Jose Farivar, Reza Silva, Eduardo Castelo-Branco, Miguel TI Functional Reorganization of the Visual Dorsal Stream as Probed by 3-D Visual Coherence in Williams Syndrome SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID STRUCTURE-FROM-MOTION; FUSIFORM FACE AREA; OBJECT RECOGNITION; CORTEX; PERCEPTION; CHILDREN; MODEL; SHAPE; V6; REPRESENTATIONS AB Object and depth perception from motion cues involves the recruitment of visual dorsal stream brain areas. In 3-D structure-from-motion (SFM) perception, motion and depth information are first extracted in this visual stream to allow object categorization, which is in turn mediated by the ventral visual stream. Such interplay justifies the use of SFM paradigms to understand dorsal-ventral integration of visual information. The nature of such processing is particularly interesting to be investigated in a neurological model of cognitive dissociation between dorsal (impaired) and ventral stream (relatively preserved) processing, Williams syndrome (WS). In the current fMRI study, we assessed dorsal versus ventral stream processing by using a performance-matched 3-D SFM object categorization task. We found evidence for substantial reorganization of the dorsal stream in WS as assessed by whole-brain ANOVA random effects analysis, with subtle differences in ventral activation. Dorsal reorganization was expressed by larger medial recruitment in WS (cuneus, precuneus, and retrosplenial cortex) in contrast with controls, which showed the expected dorsolateral pattern (caudal intraparietal sulcus and lateral occipital cortex). In summary, we found a substantial reorganization of dorsal stream regions in WS in response to simple visual categories and 3-D SFM perception, with less affected ventral stream. Our results corroborate the existence of a medial dorsal pathway that provides the substrate for information rerouting and reorganization in the presence of lateral dorsal stream vulnerability. This interpretation is consistent with recent findings suggesting parallel routing of information in medial and lateral parts of dorsal stream. C1 [Bernardino, Ines; Rebola, Jose; Castelo-Branco, Miguel] Univ Coimbra, P-3000354 Coimbra, Portugal. [Farivar, Reza] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Farivar, Reza] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Farivar, Reza] McGill Univ, Montreal, PQ H3A 2T5, Canada. [Silva, Eduardo] Univ Hosp Coimbra, Coimbra, Portugal. RP Castelo-Branco, M (reprint author), Univ Coimbra, Visual Neurosci Lab, IBILI Fac Med, Azinhaga Santa Comba, P-3000354 Coimbra, Portugal. EM mcbranco@ibili.uc.pt OI Bernardino, Ines/0000-0003-3123-008X; Castelo-Branco, Miguel/0000-0003-4364-6373 FU COMPETE [PEst-C/SAU/UI3282/2013]; [FP7-HEALTH-INNOVATION-1-602186-BRAINTRAIN] FX This work was supported by grants FP7-HEALTH-2013-INNOVATION-1-602186-BRAINTRAIN and COMPETE, PEst-C/SAU/UI3282/2013. NR 52 TC 3 Z9 3 U1 0 U2 11 PU MIT PRESS PI CAMBRIDGE PA ONE ROGERS ST, CAMBRIDGE, MA 02142-1209 USA SN 0898-929X EI 1530-8898 J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD NOV PY 2014 VL 26 IS 11 BP 2624 EP 2636 DI 10.1162/jocn_a_00662 PG 13 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AQ6FB UT WOS:000342904200017 PM 24800629 ER PT J AU Hahn, JW McCormick, MC Silverman, JG Robinson, EB Koenen, KC AF Hahn, Josephine W. McCormick, Marie C. Silverman, Jay G. Robinson, Elise B. Koenen, Karestan C. TI Examining the Impact of Disability Status on Intimate Partner Violence Victimization in a Population Sample SO JOURNAL OF INTERPERSONAL VIOLENCE LA English DT Article DE domestic violence; predicting domestic violence; abuse; victimization; disability ID NATIONAL EPIDEMIOLOGIC SURVEY; PHYSICAL-DISABILITIES; SEXUAL ASSAULT; UNITED-STATES; HEALTH SURVEY; WOMEN; ABUSE; PREVALENCE; RISK; ALCOHOL AB This study examined effects of impairments in physical and mental health on the risk of intimate partner violence (IPV) victimization in a nationally representative sample of U.S. adults (18 years). A total of 34,563 adults completed interviews in two waves of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Physical and mental health impairments, as well as IPV victimization, were assessed using validated surveys in the total sample and by gender. In the total sample, physical health impairments at Wave 1 (odds ratio [OR] = 1.22, 95% confidence interval [CI] = [1.04, 1.42], p < .05) and mental health impairments at Wave 1 (OR = 1.67, 95% CI = [1.45, 1.91], p < .001) were significantly associated with higher risk of IPV victimization at Wave 2, compared with those without reported impairments. Higher risk of later IPV victimization was also seen among females who reported physical health impairments (OR = 1.26, 95% CI [1.04, 1.53], p < .05) and mental health impairments (OR = 1.93, 95% CI = [1.63, 2.28], p < .001) compared with those who did not report similar limitations. Among males, higher risk of IPV victimization was significantly associated with mental health impairments (OR = 1.48, 95% CI = [1.19, 1.82], p < .001), compared with those without mental health impairments. Adults with physical and mental health impairments may benefit from targeted interventions aimed at preventing IPV. C1 [Hahn, Josephine W.] Ctr Court Innovat, New York, NY 10018 USA. [McCormick, Marie C.] Harvard Univ, Sch Publ Hlth, Dept Maternal & Child Hlth, Boston, MA 02115 USA. [McCormick, Marie C.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. [Silverman, Jay G.] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Robinson, Elise B.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Koenen, Karestan C.] Mailman Sch Publ Hlth, New York, NY USA. RP Hahn, JW (reprint author), Ctr Court Innovat, 520 Eighth Ave,18th Floor, New York, NY 10018 USA. EM hahnj@courtinnovation.org RI Koenen, Karestan/K-5402-2014 OI Robinson, Elise/0000-0003-2314-2792; Koenen, Karestan/0000-0003-3293-4281 FU PHS HHS [T03MC07648] NR 51 TC 10 Z9 10 U1 2 U2 16 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0886-2605 EI 1552-6518 J9 J INTERPERS VIOLENCE JI J. Interpers. Violence PD NOV PY 2014 VL 29 IS 17 SI SI BP 3063 EP 3085 DI 10.1177/0886260514534527 PG 23 WC Criminology & Penology; Family Studies; Psychology, Applied SC Criminology & Penology; Family Studies; Psychology GA AQ4XT UT WOS:000342805500002 PM 24860078 ER PT J AU Hall, CA Reynolds, CF Butters, M Zisook, S Simon, N Corey-Bloom, J Lebowitz, BD Begley, A Mauro, C Shear, MK AF Hall, Charles A. Reynolds, Charles F., III Butters, Meryl Zisook, Sidney Simon, Naomi Corey-Bloom, Jody Lebowitz, Barry D. Begley, Amy Mauro, Christine Shear, M. Katherine TI Cognitive functioning in complicated grief SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Complicated grief; Cognition; Persistent Complex Bereavement Disorder (PCBD); Prolonged grief; Montreal Cognitive Assessment (MoCA) ID RATING-SCALE; OLDER-ADULTS; BEREAVEMENT; DEPRESSION; IMPAIRMENT; PREVALENCE; INVENTORY; DISTINCT; ANXIETY AB Complicated grief (CG) is increasingly recognized as a debilitating outcome of bereavement. Given the intensity of the stressor, its chronicity, and its association with depression, it is important to know the impact CG may have on cognitive functioning. This exploratory and descriptive study examined global and domain-specific cognitive functioning in a help-seeking sample of individuals with CG (n = 335) compared to a separately ascertained control sample (n = 250). Cognitive functioning was assessed using the Montreal Cognitive Assessment (MoCA). Controlling for age, sex and education effects, CG participants had lower total MoCA, visuospatial and attention scores relative to control participants. The two groups did not differ significantly in the domains of executive function, language, memory or orientation. Age, sex, and education accounted for much of the variance in MoCA scores, while CG severity and chronicity accounted for a very small percentage of MoCA score variance. Major depression was not a significant predictor of MoCA scores. This study is consistent with previous work demonstrating lower attention and global cognitive performance in individuals with CG compared to control participants. This study newly identifies the visuospatial domain as a target for future studies investigating cognitive functioning in CG. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Hall, Charles A.; Reynolds, Charles F., III; Butters, Meryl; Begley, Amy] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. [Hall, Charles A.] SUNY Downstate Coll Med, Brooklyn, NY USA. [Zisook, Sidney; Lebowitz, Barry D.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Zisook, Sidney] Vet Affairs San Diego Hlthcare Syst, San Diego, CA USA. [Simon, Naomi] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders NMS, Boston, MA 02114 USA. [Corey-Bloom, Jody] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Mauro, Christine] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY 10027 USA. [Shear, M. Katherine] Columbia Univ, Sch Social Work, New York, NY 10027 USA. [Shear, M. Katherine] Columbia Univ, Coll Phys & Surg, New York, NY 10027 USA. RP Reynolds, CF (reprint author), Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. EM reynoldscf@upmc.edu FU National Institute of Mental Health; American Foundation for Suicide Prevention FX The sponsors of the study (the National Institute of Mental Health and the American Foundation for Suicide Prevention) played no role in the conduct of the study, data analyses, or preparation of this manuscript. NR 21 TC 4 Z9 4 U1 5 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD NOV PY 2014 VL 58 BP 20 EP 25 DI 10.1016/j.jpsychires.2014.07.002 PG 6 WC Psychiatry SC Psychiatry GA AQ5RL UT WOS:000342866200004 PM 25088285 ER PT J AU van de Giessen, E Rosell, DR Thompson, JL Xu, XY Girgis, RR Ehrlich, Y Slifstein, M Abi-Dargham, A Siever, LJ AF van de Giessen, Elsmarieke Rosell, Daniel R. Thompson, Judy L. Xu, Xiaoyan Girgis, Ragy R. Ehrlich, Yosefa Slifstein, Mark Abi-Dargham, Anissa Siever, Larry J. TI Serotonin transporter availability in impulsive aggressive personality disordered patients: A PET study with [C-11]DASB SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Impulsive aggression; Intermittent explosive disorder; Serotonin transporter; Positron emission tomography; Anterior cingulate cortex; Callousness ID INTERMITTENT EXPLOSIVE DISORDER; POSITRON-EMISSION-TOMOGRAPHY; MAJOR DEPRESSION; HUMAN BRAIN; PROACTIVE AGGRESSION; GLUCOSE-METABOLISM; AMINE METABOLITES; RECEPTOR-BINDING; VALIDITY; BEHAVIOR AB Serotonin (5-HT) has consistently been implicated in the pathophysiology of impulsive aggression. In the current study, we tested the hypothesis that 5-HT transporter (5-HTT) binding is reduced in the anterior cingulate cortex (ACC) in impulsive aggressive patients. Additionally, we characterized pathological personality dimensions, with a specific focus on callousness (i.e. emotional indifference, a facet of psychopathy). Callousness is putatively positively correlated with presynaptic 5-HT, and thus could potentially confound the hypothesized negative relation between 5-HTT levels and trait aggression. We determined 5-HTT binding with positron emission tomography and [[C-11]DASB in 29 patients with intermittent explosive disorder (IED-IR) and 30 controls. We assessed group differences in 5-HTT binding in the pregenual ACC, amygdala and subcortical regions and examined correlations between 5-HTT binding and clinical measures. There were no significant differences in 5-HTT binding between IED-IR patients and controls. Trait callousness exhibited a significant, positive correlation with ACC 5-HTT availability. Among IED-IR patients, a trend-level negative partial correlation was observed between trait aggression and ACC 5-HTT availability, while covarying for callousness and age. Exploratory analyses revealed a significant negative correlation between state aggression levels and 5-HTT availability in subcortical regions, namely striatum and thalamus. We did not confirm our hypothesis of lower ACC 5-HTT availability in impulsive aggressive patients, however, the positive correlation between callousness and ACC 5-HTT availability likely played a confounding role. Subtypes of aggression (e.g., reactive vs. proactive aggression), which are differentially associated with pathological personality dimensions such as callousness, may contribute to variability between 5-HT functioning and aggression. (C) 2014 Elsevier Ltd. All rights reserved. C1 [van de Giessen, Elsmarieke; Thompson, Judy L.; Xu, Xiaoyan; Girgis, Ragy R.; Slifstein, Mark; Abi-Dargham, Anissa] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [van de Giessen, Elsmarieke; Thompson, Judy L.; Xu, Xiaoyan; Girgis, Ragy R.; Slifstein, Mark; Abi-Dargham, Anissa] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Rosell, Daniel R.; Ehrlich, Yosefa; Siever, Larry J.] Med Ctr, James J Peters Dept Vet Affairs, Bronx, NY 10468 USA. [Rosell, Daniel R.; Ehrlich, Yosefa; Siever, Larry J.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. RP Siever, LJ (reprint author), Med Ctr, James J Peters Dept Vet Affairs, 130 West Kingsbridge Rd,Room 6A-44, Bronx, NY 10468 USA. EM larry.siever@va.gov RI Girgis, Ragy/N-3271-2016 FU National Institute of Mental Health [MH63875]; National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [MO1-RR-00071]; Nederlandse Organisatie voor Wetenschappelijk Onderzoek [825.12.009] FX This research was supported by Grant MH63875 from the National Institute of Mental Health to Larry J. Siever. This publication was made possible by Grant Number MO1-RR-00071 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH. Elsmarieke van de Giessen is supported by a Rubicon grant from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (825.12.009). NR 64 TC 5 Z9 5 U1 4 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD NOV PY 2014 VL 58 BP 147 EP 154 DI 10.1016/j.jpsychires.2014.07.025 PG 8 WC Psychiatry SC Psychiatry GA AQ5RL UT WOS:000342866200021 PM 25145808 ER PT J AU August, DA Sui, JH Cote, CJ AF August, David A. Sui, Jinghu Cote, Charles J. TI Unintentional epidural injection of 88 mu g.kg(-1) of epinephrine SO PEDIATRIC ANESTHESIA LA English DT Article DE sacral epidural; epinephrine; drug overdose; noninvasive monitors; pharmacodynamics; adverse events ID CARDIAC-OUTPUT; CHILDREN; ANESTHESIA; BLOCK AB We report the effects of 88gkg(-1) of epinephrine (1:10000) injected into the caudal epidural space of a 42-week postconceptual age infant. No long-term neurological or cardiovascular sequelae occurred. Noninvasive cardiac output (CO) monitoring revealed increased CO, contractility, and stroke volume for about an hour, accompanied by a reduction in peripheral vascular resistance and a modest increase in pulse and blood pressure. C1 [August, David A.; Cote, Charles J.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Div Pediat Anesthesia, Boston, MA 02114 USA. [Sui, Jinghu] Chinese Acad Med Sci, Dept Anesthesiol, Plast Surg Hosp, Beijing 100730, Peoples R China. RP August, DA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRB 444, Boston, MA 02114 USA. EM daugust@mgh.harvard.edu FU People's Republic of China FX This research was supported in part through the loan of two ICON (R) devices from Cardiotronic/Osypka Medical, Inc., 7463 Draper Ave, La Jolla, CA 92037 and though a study grant for a research fellow supported by the People's Republic of China. Charles J. Cote is a Section Editor of Pediatric Anesthesia. NR 8 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1155-5645 EI 1460-9592 J9 PEDIATR ANESTH JI Pediatr. Anesth. PD NOV PY 2014 VL 24 IS 11 BP 1185 EP 1187 DI 10.1111/pan.12503 PG 3 WC Anesthesiology; Pediatrics SC Anesthesiology; Pediatrics GA AQ6CY UT WOS:000342897000012 PM 25130947 ER PT J AU Meany, HJ London, WB Ambros, PF Matthay, KK Monclair, T Simon, T Garaventa, A Berthold, F Nakagawara, A Cohn, SL Pearson, AD Park, JR AF Meany, Holly J. London, Wendy B. Ambros, Peter F. Matthay, Katherine K. Monclair, Tom Simon, Thorsten Garaventa, Alberto Berthold, Frank Nakagawara, Akira Cohn, Susan L. Pearson, Andrew D. J. Park, Julie R. TI Significance of Clinical and Biologic Features in Stage 3 Neuroblastoma: A Report from the International Neuroblastoma Risk Group Project SO PEDIATRIC BLOOD & CANCER LA English DT Article DE biologic factor; neuroblastoma; treatment outcome ID CHILDRENS ONCOLOGY GROUP; PATHOLOGY CLASSIFICATION; MYCN AMPLIFICATION; N-MYC; 13-CIS-RETINOIC ACID; PROGNOSTIC IMPACT; CHROMOSOME 1P; CANCER GROUP; TUMORS; AGE AB BackgroundInternational Neuroblastoma Staging System (INSS) Stage 3 neuroblastoma is a heterogeneous disease. Data from the International Neuroblastoma Risk Group (INRG) database were analyzed to define patient and tumor characteristics predictive of outcome. ProcedureOf 8,800 patients in the INRG database, 1,483 with INSS Stage 3 neuroblastoma and complete follow-up data were analyzed. Secondary analysis was performed in 1,013 patients (68%) with MYCN-non-amplified (NA) tumors. Significant prognostic factors were identified via log-rank test comparisons of survival curves. Multivariable Cox proportional hazards regression model was used to identify factors independently predictive of event-free survival (EFS). ResultsAge at diagnosis (P<0.0001), tumor MYCN status (P<0.0001), and poorly differentiating/undifferentiated histology (P=0.03) were independent predictors of EFS. Compared to other Stage 3 subgroups, outcome was inferior for patients 547 days with MYCN-NA neuroblastoma (P<0.0001), and within this cohort, serum ferritin 96ng/ml was associated with inferior EFS (P=0.02). For patients <547 days of age with MYCN-NA tumors, serum ferritin levels were prognostic of overall survival (OS) (P=0.04) and chromosome 11q aberration was prognostic of EFS (P=0.03). ConclusionsAmong patients with INSS Stage 3 neuroblastoma patients, age at diagnosis, MYCN status and histology predict outcome. Patients <547 days of age with MYCN-NA tumors that lack chromosome 11q aberrations or those with serum ferritin <96ng/ml have excellent prognosis and should be considered for therapy reduction. Prospective clinical trials are needed to identify optimal therapy for those patients 547 days of age with undifferentiated histology or elevated serum ferritin. Pediatr Blood Cancer 2014;61:1932-1939. (c) 2014 Wiley Periodicals, Inc. C1 [Meany, Holly J.] Childrens Natl Med Ctr, Dept Hematol Oncol, Washington, DC 20010 USA. [London, Wendy B.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston Childrens Hosp, Boston, MA 02115 USA. [Ambros, Peter F.] St Anna Kinderkrebsforsch, Childrens Canc Res Inst, Vienna, Austria. [Matthay, Katherine K.] Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA. [Matthay, Katherine K.] Benioff Childrens Hosp, San Francisco, CA USA. [Monclair, Tom] Univ Oslo, Rikshosp, Univ Hosp, Div Surg,Sect Paediat Surg, N-0027 Oslo, Norway. [Simon, Thorsten; Berthold, Frank] Univ Cologne, Dept Pediat Oncol & Hematol, D-50931 Cologne, Germany. [Garaventa, Alberto] Giannina Gaslini Inst, Dept Paediat Hematol Oncol, Genoa, Italy. [Nakagawara, Akira] Chiba Canc Ctr, Japan Neuroblastoma Study Grp JNBSG, Chiba 2608717, Japan. [Nakagawara, Akira] Chiba Canc Ctr, Div Biochem & Innovat Canc Therapeut, Chiba 2608717, Japan. [Cohn, Susan L.] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. [Pearson, Andrew D. J.] Royal Marsden NHS Fdn Trust, Inst Canc Res, Div Canc Therapeut & Clin Studies, Sutton, Surrey, England. [Pearson, Andrew D. J.] Royal Marsden NHS Fdn Trust, Children & Young Peoples Unit, Sutton, Surrey, England. [Park, Julie R.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle Childrens Hosp, Dept Hematol Oncol, Seattle, WA 98195 USA. RP Meany, HJ (reprint author), Childrens Natl Med Ctr, Dept Hematol Oncol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM hmeany@childrensnational.org OI Cohn, Susan/0000-0001-5749-7650; Ambros, Peter F./0000-0002-5507-7211 FU William Guy Forbeck Research Foundation; Little Heroes Cancer Research Fund; Children's Neuroblastoma Cancer Foundation; Neuroblastoma Children's Cancer Foundation; St. Baldrick's Foundation; Super Jake Foundation; Dougherty; Campini Foundations; Mildred V. Strouss chair; Cancer Research UK Life Chair and Programme Grant; NIHR RM/ICR Biomedical Research Centre; Bushnell Towne Wilkerson Endowed Chair in Pediatric Neuroblastoma FX Grant sponsor: William Guy Forbeck Research Foundation; Grant sponsor: Little Heroes Cancer Research Fund; Grant sponsor: Children's Neuroblastoma Cancer Foundation; Grant sponsor: Neuroblastoma Children's Cancer Foundation; Grant sponsor: St. Baldrick's Foundation; Grant sponsor: Super Jake Foundation; Grant sponsor: Dougherty; Grant sponsor: Campini Foundations; Grant sponsor: Mildred V. Strouss chair; Grant sponsor: Cancer Research UK Life Chair and Programme Grant; Grant sponsor: NIHR RM/ICR Biomedical Research Centre; Grant sponsor: Bushnell Towne Wilkerson Endowed Chair in Pediatric Neuroblastoma NR 40 TC 4 Z9 6 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2014 VL 61 IS 11 BP 1932 EP 1939 DI 10.1002/pbc.25134 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AQ3WD UT WOS:000342723300006 PM 25044743 ER PT J AU Arceci, RJ Allen, C Dunkel, I Jacobsen, E Whitlock, J Vassallo, R Borrell, I Morris, S Reedy, BA Portnoy, A Noble, B Murnane, A Szabo, S Rodriguez-Galindo, C McClain, K Vaiselbuh, S AF Arceci, Robert J. Allen, Carl Dunkel, Ira Jacobsen, Eric Whitlock, James Vassallo, Robert Borrell, Ivan Morris, Shannon Reedy, Beth Ann Portnoy, Alison Noble, Bob Murnane, Amy Szabo, Stephen Rodriguez-Galindo, Carlos McClain, Kenneth Vaiselbuh, Sarah TI AN ORAL PAN-AKT INHIBITOR IN PATIENTS WITH LANGERHANS CELL HISTIOCYTOSIS SHOWS SIGNS OF CLINICAL ACTIVITY SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Arceci, Robert J.] Ronald A Matricaria Inst Mol Med, Phoenix, AZ USA. [Allen, Carl; McClain, Kenneth] Baylor Coll Med, Houston, TX 77030 USA. [Dunkel, Ira] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Jacobsen, Eric; Rodriguez-Galindo, Carlos] Dana Farber Canc Inst, Boston, MA 02115 USA. [Whitlock, James] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Vassallo, Robert] Mayo Clin, Rochester, MN USA. [Borrell, Ivan] Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Morris, Shannon] GlaxoSmithKline, Res Triangle Pk, NC USA. [Reedy, Beth Ann; Portnoy, Alison; Noble, Bob; Murnane, Amy] GlaxoSmithKline, Upper Merion, PA USA. [Szabo, Stephen] GlaxoSmithKline, Collegeville, PA USA. [Vaiselbuh, Sarah] Staten Isl Univ Hosp, Staten Isl, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2014 VL 61 IS 11 BP 2129 EP 2130 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AQ3WD UT WOS:000342723300056 ER PT J AU Arceci, RJ Allen, C Dunkel, I Jacobsen, E Whitlock, J Vassallo, R Borrell, I Morris, S Reedy, BA Portnoy, A Noble, B Murnane, A Szabo, S Rodriguez-Galindo, C McClain, K Vaiselbuh, S AF Arceci, Robert J. Allen, Carl Dunkel, Ira Jacobsen, Eric Whitlock, James Vassallo, Robert Borrell, Ivan Morris, Shannon Reedy, Beth Ann Portnoy, Alison Noble, Bob Murnane, Amy Szabo, Stephen Rodriguez-Galindo, Carlos McClain, Kenneth Vaiselbuh, Sarah TI BONE MARROW NECROSIS, LEUKEMIA AND HEMOPHAGOCYTOSIS; IS THE UNDERLYING CAUSE EBV? SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Arceci, Robert J.] Ronald A Matricaria Inst Mol Med, Phoenix, AZ USA. [Allen, Carl; McClain, Kenneth] Baylor Coll Med, Houston, TX 77030 USA. [Dunkel, Ira] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Jacobsen, Eric; Rodriguez-Galindo, Carlos] Dana Farber Canc Inst, Boston, MA 02115 USA. [Whitlock, James] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Vassallo, Robert] Mayo Clin, Rochester, MN USA. [Borrell, Ivan] Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Morris, Shannon] GlaxoSmithKline, Res Triangle Pk, NC USA. [Reedy, Beth Ann; Portnoy, Alison; Noble, Bob; Murnane, Amy] GlaxoSmithKline, Upper Merion, PA USA. [Szabo, Stephen] GlaxoSmithKline, Collegeville, PA USA. [Vaiselbuh, Sarah] Staten Isl Univ Hosp, Staten Isl, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2014 VL 61 IS 11 BP 2129 EP 2129 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AQ3WD UT WOS:000342723300055 ER PT J AU Badalian-Very, G Vergilio, JA Stevensen, K Bronson, R Fleming, M Rollins, B AF Badalian-Very, Gayane Vergilio, Jo-Anne Stevensen, Kristen Bronson, Roderick Fleming, Mark Rollins, Barrett TI GENETICALLY ENGINEERED MOUSE MODELS OF BRAF V600E EXPRESSION IN LANGERHANS CELLS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Badalian-Very, Gayane; Rollins, Barrett] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Badalian-Very, Gayane; Rollins, Barrett] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Vergilio, Jo-Anne] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Stevensen, Kristen] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Bronson, Roderick] Dana Farber Canc Inst, Dept Microbiol & Immunol, Boston, MA 02115 USA. [Fleming, Mark] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2014 VL 61 IS 11 BP 2130 EP 2130 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AQ3WD UT WOS:000342723300058 ER PT J AU Rodriguez-Galindo, C Degar, B Antonelli, C Rollins, B Ribeiro, K AF Rodriguez-Galindo, Carlos Degar, Barbara Antonelli, Celia Rollins, Barrett Ribeiro, Karina TI DESCRIPTIVE EPIDEMIOLOGY OF LANGERHANS CELL HISTIOCYTOSIS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Boston Childrens Hosp, Sch Med, Boston, MA USA. Fac Ciencias Med Santa Casa Sao Paulo, Dept Social Med, Sao Paulo, Brazil. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2014 VL 61 IS 11 BP 2138 EP 2139 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AQ3WD UT WOS:000342723300091 ER PT J AU Rollins, B Nelson, D Quispel, W Badalian-Very, G van Halteren, A van Hummelen, P Ducar, M MacConnail, L Fleming, M Egeler, M Rollins, B AF Rollins, Barrett Nelson, David Quispel, Willemijn Badalian-Very, Gayane van Halteren, Astrid van Hummelen, Paul Ducar, Matthew MacConnail, Laura Fleming, Mark Egeler, Maarten Rollins, Barrett TI SOMATIC ARAF MUTATIONS IN LANGERHANS CELL HISTIOCYTOSIS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Nelson, David; Badalian-Very, Gayane; Rollins, Barrett] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Nelson, David; Badalian-Very, Gayane; Rollins, Barrett] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Quispel, Willemijn; van Halteren, Astrid] Leiden Univ, Willem Alexander Childrens Hosp, Med Ctr, Immunol Lab, Leiden, Netherlands. [van Hummelen, Paul; Ducar, Matthew; MacConnail, Laura] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [MacConnail, Laura] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Fleming, Mark] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Egeler, Maarten] Hosp Sick Children, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2014 VL 61 IS 11 BP 2139 EP 2139 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA AQ3WD UT WOS:000342723300092 ER PT J AU Wightman, A Young, B Bradford, M Dick, A Healey, P McDonald, R Smith, J AF Wightman, Aaron Young, Bessie Bradford, Miranda Dick, Andre Healey, Patrick McDonald, Ruth Smith, Jodi TI Prevalence and outcomes of renal transplantation in children with intellectual disability SO PEDIATRIC TRANSPLANTATION LA English DT Article DE renal transplant; intellectual disability; ethics; nephrology; outcomes ID KIDNEY-TRANSPLANTATION; MENTAL-RETARDATION; CANDIDATES AB To describe the prevalence and outcomes of renal transplantation in children with ID we performed a retrospective cohort analysis of all children receiving a first kidney-alone transplant in the UNOS dataset from 2008 to 2011. Recipients with definite, probable, and without ID were compared using chi-square tests. Kaplan-Meier curves were constructed for patient and graft survival. Cox proportional hazard models were used to estimate the association between ID and graft failure and patient survival. Over the study period, 332 children with definite (117) or probable (215) ID underwent first renal transplant, accounting for 16% of all first pediatric renal transplants (n=2076). Children with definite ID were not significantly different from children without ID with respect to sex, ethnicity, or prevalence of acute rejection. ID was associated with increased likelihood of deceased donor source. ID was not significantly associated with decreased graft or patient survival. In this first large-scale study, up to 16% of first pediatric renal transplants were performed in children with ID. Short-term graft and patient survival after transplant were equivalent between children with and without ID. Further research is needed to examine long-term outcomes of transplant in this population. C1 [Wightman, Aaron] Univ Wisconsin, Sch Med & Publ Hlth, Div Nephrol, Dept Pediat, Madison, WI 53792 USA. [Young, Bessie] Univ Washington, Sch Med, Dept Med, Div Nephrol,VA Puget Sound Healthcare Syst,Kidney, Seattle, WA 98195 USA. [Bradford, Miranda] Seattle Childrens Res Inst, Ctr Clin & Translat Res, Seattle, WA USA. [Dick, Andre; Healey, Patrick] Univ Washington, Sch Med, Dept Surg, Seattle, WA 98195 USA. [McDonald, Ruth; Smith, Jodi] Univ Washington, Sch Med, Dept Pediat, Div Nephrol, Seattle, WA 98195 USA. RP Wightman, A (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Div Nephrol, Dept Pediat, Mail Code 4108,600 Highland Ave, Madison, WI 53792 USA. EM wightman@pediatrics.wisc.edu OI Wightman, Aaron/0000-0003-0167-0420 FU NIH [5 T32 DK007662]; National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000423] FX Dr. Wightman was supported in part by NIH training grant: 5 T32 DK007662. Dr. Young was supported by resources from the VA Puget Sound Health Care System, Seattle, Washington. Support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR000423). The content is solely the responsibility of the authors and does not necessarily represent the official views of Veterans Affairs or the National Institutes of Health. NR 11 TC 10 Z9 10 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1397-3142 EI 1399-3046 J9 PEDIATR TRANSPLANT JI Pediatr. Transplant. PD NOV PY 2014 VL 18 IS 7 BP 714 EP 719 DI 10.1111/petr.12339 PG 6 WC Pediatrics; Transplantation SC Pediatrics; Transplantation GA AQ5KT UT WOS:000342848100021 PM 25135680 ER PT J AU Boninger, ML Wechsler, LR Stein, J AF Boninger, Michael L. Wechsler, Lawrence R. Stein, Joel TI Robotics, Stem Cells, and Brain-Computer Interfaces in Rehabilitation and Recovery from Stroke Updates and Advances SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Stroke; Stem Cells; Robotics; Rehabilitation; Brain-Computer Interfaces AB Objective: The aim of this study was to describe the current state and latest advances in robotics, stem cells, and brain-computer interfaces in rehabilitation and recovery for stroke. Design: The authors of this summary recently reviewed this work as part of a national presentation. The article represents the information included in each area. Results: Each area has seen great advances and challenges as products move to market and experiments are ongoing. Conclusions: Robotics, stem cells, and brain-computer interfaces all have tremendous potential to reduce disability and lead to better outcomes for patients with stroke. Continued research and investment will be needed as the field moves forward. With this investment, the potential for recovery of function is likely substantial. C1 [Boninger, Michael L.] Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, 3471 5th Ave Suite 201, Pittsburgh, PA 15213 USA. [Boninger, Michael L.] VA Pittsburgh Hlth Care Syst, Human Engn Res Lab, Pittsburgh, PA USA. [Wechsler, Lawrence R.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. [Stein, Joel] Columbia Univ Coll Phys & Surg, Dept Rehabil & Regenerat Med, New York, NY 10032 USA. [Stein, Joel] Weill Cornell Med Coll, Div Rehabil Med, New York, NY USA. RP Boninger, ML (reprint author), Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, 3471 5th Ave Suite 201, Pittsburgh, PA 15213 USA. OI Boninger, Michael/0000-0001-6966-919X FU NIA NIH HHS [P30 AG024827]; NINDS NIH HHS [R01 NS072342] NR 30 TC 2 Z9 2 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0894-9115 EI 1537-7385 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD NOV PY 2014 VL 93 IS 11 SU 3 BP S145 EP S154 DI 10.1097/PHM.0000000000000128 PG 10 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA V44IV UT WOS:000209743600008 PM 25313662 ER PT J AU Maraka, S Jiang, Q Jafari-Khouzani, K Li, L Malik, S Hamidian, H Zhang, T Lu, M Soltanian-Zadeh, H Chopp, M Mitsias, PD AF Maraka, Stefania Jiang, Quan Jafari-Khouzani, Kourosh Li, Lian Malik, Shaneela Hamidian, Hajar Zhang, Talan Lu, Mei Soltanian-Zadeh, Hamid Chopp, Michael Mitsias, Panayiotis D. TI Degree of corticospinal tract damage correlates with motor function after stroke SO ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY LA English DT Article AB Objectives: Direct injury to the corticospinal tract (CST) is a major factor defining motor impairment after stroke. Diffusion tensor imaging (DTI) tractography allows definition of the CST. We sought to determine whether DTI-based assessment of the degree of CST damage correlates with motor impairment at each phase of ischemic stroke. Methods: We evaluated patients at the acute (3-7 days), subacute (30 days), and chronic (90 days) phases of ischemic stroke with DTI and clinical motor scores (upper extremity Fugl-Myer test [UE-FM], motor items of the National Institutes of Health Stroke Scale [mNIHSS]). The CST was identified and virtual fiber numbers (FN) were calculated for the affected and contralateral CST. We used Spearman correlation to study the relationship of FN ratio (FNr) (affected/unaffected CST) with motor scores at each time point, and the regression model to study the association of the acute parameters with chronic motor scores. Results: We studied 23 patients. Mean age was 66.7 (+/- 12) years. FNr correlated with UE-FM score in the acute (r = 0.50, P = 0.032), subacute (r = 0.57, P = 0.007), and chronic (r = 0.67, P = 0.0008) phase, and with mNIHSS in the acute (r = -0.48, P = 0.043), subacute (r = -0.58, P = 0.006), and chronic (r = -0.75, P = 0.0001) phase. The combination of acute NIHSS and FNr significantly predicted chronic UE-FM score (r = 0.74, P = 0.0001). Interpretation: DTIdefined degree of CST injury correlates with motor impairment at each phase of ischemic stroke. The combination of baseline FNr and NIHSS predicts motor outcome. DTI-derived CST assessment could become a surrogate marker of motor impairment in the design of neurorestorative clinical trials. C1 [Maraka, Stefania; Jiang, Quan; Li, Lian; Malik, Shaneela; Chopp, Michael; Mitsias, Panayiotis D.] Henry Ford Hosp, Dept Neurol, K-11,2799 West Grand Blvd, Detroit, MI 48202 USA. [Jafari-Khouzani, Kourosh] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Jafari-Khouzani, Kourosh; Hamidian, Hajar; Soltanian-Zadeh, Hamid] Henry Ford Hosp, Dept Radiol, Detroit, MI 48202 USA. [Malik, Shaneela; Mitsias, Panayiotis D.] Henry Ford Hlth Syst, Inst Neurosci, Stroke & Neurovasc Ctr, Detroit, MI USA. [Hamidian, Hajar] Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. [Zhang, Talan; Lu, Mei] Henry Ford Hlth Syst, Dept Publ Hlth Sci, Detroit, MI USA. RP Mitsias, PD (reprint author), Henry Ford Hosp, Dept Neurol, K-11,2799 West Grand Blvd, Detroit, MI 48202 USA. EM pmitsia1@hfhs.org RI Soltanian-Zadeh, Hamid/K-2903-2016 OI Soltanian-Zadeh, Hamid/0000-0002-7302-6856 FU NINDS NIH HHS [R01 NS070922] NR 36 TC 3 Z9 6 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2328-9503 J9 ANN CLIN TRANSL NEUR JI Ann. Clin. Transl. Neurol. PD NOV PY 2014 VL 1 IS 11 BP 891 EP 899 DI 10.1002/acn3.132 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V45KO UT WOS:000209815700004 PM 25540803 ER PT J AU Cannon, CE Titchenell, PM Groff, DN El Ouaamari, A Kulkarni, RN Birnbaum, MJ Stoffers, DA AF Cannon, Corey E. Titchenell, Paul M. Groff, David N. El Ouaamari, Abdelfattab Kulkarni, Rohit N. Birnbaum, Morris J. Stoffers, Doris A. TI The Polycomb protein, Bmi1 regulates insulin sensitivity SO MOLECULAR METABOLISM LA English DT Article DE Polycomb Reprossive Complex; Hepatic glucose production; Insulin signaling; Muscle glucose uptake AB Objective: The Polycomb Repressive Complexes (PRC) 1 and 2 function to epigenetically repress target genes. The PRC1 component, Bmi1, plays a crucial role in maintenance of glucose homeostasis and beta cell mass through repression of the Ink4a/Arflocus. Here we have explored the role of Bmi1 in regulating glucose homeostasis in the adult animal, which had not been previously reported due to poor postnatal survival of Bmi1(-/-) mice. Methods: The metabolic phenotype of Bmi1(+/-) mice was characterized, both in vivo and ex vivo. Glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps were performed. The insulin signaling pathway was assessed at the protein and transcript level. Results: Here we report a negative correlation between Bmi1 levels and insulin sensitivity in two models of insulin resistance, aging and liver specific insulin receptor deficiency. Further, heterozygous loss of Bmi1 results in increased insulin sensitivity in adult mice, with no impact on body weight or composition. Hyperinsulinemic-euglycemic clamp reveals increased suppression of hepatic glucose production and increased glucose disposal rate, indicating elevated glucose uptake to peripheral tissues, in Bmi1(+/-) mice. Enhancement of insulin signaling, specifically an increase in Akt phosphorylation, in liver and, to a lesser extent, in muscle appears to contribute to this phenotype. Conclusions: Together, these data define a new role for Bmi1 in regulating insulin sensitivity via enhancement of Akt phosphorylation. (C) 2014 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license C1 [Cannon, Corey E.; Titchenell, Paul M.; Groff, David N.; Birnbaum, Morris J.; Stoffers, Doris A.] Univ Penn, Inst Diabet Obes & Metab, Perelman Sch Med, Philadelphia, PA 19104 USA. [Cannon, Corey E.; Titchenell, Paul M.; Groff, David N.; Birnbaum, Morris J.; Stoffers, Doris A.] Univ Penn, Div Endocrinol Diabet & Metab, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [El Ouaamari, Abdelfattab; Kulkarni, Rohit N.] Harvard Univ, Sect Islet Cell & Regenerat Biol, Brigham & Womens Hosp, Joslin Diabet Ctr,Dept Med,Med Sch, Boston, MA 02115 USA. RP Stoffers, DA (reprint author), SCTR 12 126, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM stoffers@mail.med.upenn.edu FU NIDDK NIH HHS [P30 DK019525, F32 DK101175, P01 DK049210, R01 DK068157] NR 21 TC 4 Z9 4 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2212-8778 J9 MOL METAB JI Mol. Metab. PD NOV PY 2014 VL 3 IS 8 BP 794 EP 802 DI 10.1016/j.molmel.2014.08.002 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V42UM UT WOS:000209638700003 PM 25379404 ER PT J AU Lee, E Smith, K Muzikansky, A Gerstner, E Kuhn, J Reardon, D Nayak, L Norden, A Rifenburg, J Pulverenti, J Stokes, D Lam, P Martins, T Hempfling, K McCluskey, C Gaffey, S Batchelor, T Duda, D Jain, R Wen, P AF Lee, Eudocia Smith, Katrina Muzikansky, Alona Gerstner, Elizabeth Kuhn, John Reardon, David Nayak, Lakshmi Norden, Andrew Rifenburg, Jennifer Pulverenti, Julee Stokes, Deirdre Lam, Priscilla Martins, Tiago Hempfling, Kelly McCluskey, Christine Gaffey, Sarah Batchelor, Tracy Duda, Dan Jain, Rakesh Wen, Patrick TI PHASE I STUDYOF PLERIXAFOR AND BEVACIZUMAB IN RECURRENT HIGH-GRADE GLIOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the Society-for-Neuro-Oncology (SNO) CY NOV 13-16, 2014 CL Miami, FL SP Soc Neuro Oncol C1 [Lee, Eudocia; Smith, Katrina; Reardon, David; Nayak, Lakshmi; Norden, Andrew; Rifenburg, Jennifer; Pulverenti, Julee; Stokes, Deirdre; Lam, Priscilla; Martins, Tiago; Hempfling, Kelly; McCluskey, Christine; Gaffey, Sarah; Wen, Patrick] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Lee, Eudocia; Gerstner, Elizabeth; Reardon, David; Nayak, Lakshmi; Norden, Andrew; Batchelor, Tracy; Duda, Dan; Jain, Rakesh; Wen, Patrick] Harvard Univ, Sch Med, Boston, MA USA. [Muzikansky, Alona; Gerstner, Elizabeth; Batchelor, Tracy; Duda, Dan; Jain, Rakesh; Wen, Patrick] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kuhn, John] Univ Texas Austin, Austin, TX 78712 USA. NR 0 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 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA AT-37 DI 10.1093/neuonc/nou237.37 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200067 ER PT J AU Lee, E Reardon, D Schiff, D Drappatz, J Muzikansky, A Grimm, S Norden, A Nayak, L Beroukhim, R Rinne, M Chi, A Batchelor, T Hempfling, K McCluskey, C Smith, K Gaffey, S Wrigley, B Ligon, K Raizer, J Wen, P AF Lee, Eudocia Reardon, David Schiff, David Drappatz, Jan Muzikansky, Alona Grimm, Sean Norden, Andrew Nayak, Lakshmi Beroukhim, Rameen Rinne, Mikael Chi, Andrew Batchelor, Tracy Hempfling, Kelly McCluskey, Christine Smith, Katrina Gaffey, Sarah Wrigley, Brendan Ligon, Keith Raizer, Jeffrey Wen, Patrick TI PANOBINOSTAT IN COMBINATION WITH BEVACIZUMAB FOR RECURRENT GLIOBLASTOMA AND ANAPLASTIC GLIOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the Society-for-Neuro-Oncology (SNO) CY NOV 13-16, 2014 CL Miami, FL SP Soc Neuro Oncol C1 [Lee, Eudocia; Reardon, David; Norden, Andrew; Nayak, Lakshmi; Beroukhim, Rameen; Rinne, Mikael; Hempfling, Kelly; McCluskey, Christine; Smith, Katrina; Gaffey, Sarah; Wrigley, Brendan; Ligon, Keith; Raizer, Jeffrey; Wen, Patrick] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Lee, Eudocia; Reardon, David; Norden, Andrew; Nayak, Lakshmi; Beroukhim, Rameen; Rinne, Mikael; Chi, Andrew; Batchelor, Tracy; Ligon, Keith; Raizer, Jeffrey; Wen, Patrick] Harvard Univ, Sch Med, Boston, MA USA. [Schiff, David] Univ Virginia, Charlottesville, VA USA. [Drappatz, Jan] Univ Pittsburgh, Pittsburgh, PA USA. [Muzikansky, Alona; Chi, Andrew; Batchelor, Tracy] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Grimm, Sean] Cent Dupage Hosp, Warrenville, IL USA. Northwestern Univ, Chicago, IL 60611 USA. NR 0 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 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA AT-36 DI 10.1093/neuonc/nou237.36 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200066 ER PT J AU Reardon, D Schuster, J Tran, D Fink, K Nabors, L Li, G Lukas, R Desjardins, A Ashby, L Duic, JP Aneiro, L Hawthorne, T Green, J Yellin, M Davis, T Sampson, J AF Reardon, David Schuster, James Tran, David Fink, Karen Nabors, Louis Li, Gordon Lukas, Rimas Desjardins, Annick Ashby, Lynn Duic, J. Paul Aneiro, Lynn Hawthorne, Thomas Green, Jennifer Yellin, Michael Davis, Thomas Sampson, John TI ReACT: A PHASE II STUDY OF RINDOPEPIMUT VACCINE (CDX-110) PLUS BEVACIZUMAB IN RELAPSED GLIOBLASTOMA SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the Society-for-Neuro-Oncology (SNO) CY NOV 13-16, 2014 CL Miami, FL SP Soc Neuro Oncol C1 [Reardon, David] Dana Farber Canc Inst, Boston, MA 02115 USA. [Schuster, James] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Tran, David] Washington Univ, St Louis, MO USA. [Fink, Karen] Baylor Res Inst, Dallas, TX USA. [Nabors, Louis] Univ Alabama Birmingham, Birmingham, AL USA. [Li, Gordon] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Lukas, Rimas] Univ Chicago, Chicago, IL 60637 USA. [Desjardins, Annick; Sampson, John] Duke Univ, Med Ctr, Durham, NC USA. [Ashby, Lynn] Barrow Neurol Inst, Phoenix, AZ 85013 USA. [Duic, J. Paul] Long Isl Brain Tumor Ctr Neurol Surg PC, Lake Success, NY USA. [Aneiro, Lynn; Hawthorne, Thomas; Green, Jennifer; Yellin, Michael; Davis, Thomas] Celldex Therapeut Inc, Hampton, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA IT-30 DI 10.1093/neuonc/nou258.28 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200468 ER PT J AU Reardon, D Gokhale, P Ligon, K Liao, XY Rodig, S Zhou, J Qin, L Hodi, S Jones, K Sauer, A Kohl, N Dranoff, G Freeman, G AF Reardon, David Gokhale, Prafulla Ligon, Keith Liao, Xiaoyun Rodig, Scott Zhou, Jun Qin, Lei Hodi, Stephen Jones, Kristen Sauer, Amy Kohl, Nancy Dranoff, Glenn Freeman, Gordon TI IMMUNE CHECKPOINT BLOCKADE FOR GLIOBLASTOMA: PRECLINICAL ACTIVITY OF SINGLE AGENT AND COMBINATORIAL THERAPY SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the Society-for-Neuro-Oncology (SNO) CY NOV 13-16, 2014 CL Miami, FL SP Soc Neuro Oncol C1 [Reardon, David; Gokhale, Prafulla; Ligon, Keith; Liao, Xiaoyun; Rodig, Scott; Zhou, Jun; Qin, Lei; Hodi, Stephen; Jones, Kristen; Sauer, Amy; Kohl, Nancy; Dranoff, Glenn; Freeman, Gordon] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 EI 1523-5866 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD NOV PY 2014 VL 16 SU 5 MA IT-29 DI 10.1093/neuonc/nou258.27 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA CC6CM UT WOS:000350452200467 ER PT J AU Zou, W Yin, LS Shen, JJ Corradetti, MN Kirk, M Munbodh, R Fang, PN Jabbour, SK Simone, CB Yue, NJ Rengan, R Teo, BKK AF Zou, Wei Yin, Lingshu Shen, Jiajian Corradetti, Michael N. Kirk, Maura Munbodh, Reshma Fang, Penny Jabbour, Salma K. Simone, Charles B., II Yue, Ning J. Rengan, Ramesh Teo, Boon-Keng Kevin TI Dynamic simulation of motion effects in IMAT lung SBRT SO RADIATION ONCOLOGY LA English DT Article DE SBRT; Lung motion; Interplay; IMAT AB Background: Intensity modulated arc therapy (IMAT) has been widely adopted for Stereotactic Body Radiotherapy (SBRT) for lung cancer. While treatment dose is optimized and calculated on a static Computed Tomography (CT) image, the effect of the interplay between the target and linac multi-leaf collimator (MLC) motion is not well described and may result in deviations between delivered and planned dose. In this study, we investigated the dosimetric consequences of the inter-play effect on target and organs at risk (OAR) by simulating dynamic dose delivery using dynamic CT datasets. Methods: Fifteen stage I non-small cell lung cancer (NSCLC) patients with greater than 10 mm tumor motion treated with SBRT in 4 fractions to a dose of 50 Gy were retrospectively analyzed for this study. Each IMAT plan was initially optimized using two arcs. Simulated dynamic delivery was performed by associating the MLC leaf position, gantry angle and delivered beam monitor units (MUs) for each control point with different respiratory phases of the 4D-CT using machine delivery log files containing time stamps of the control points. Dose maps associated with each phase of the 4D-CT dose were calculated in the treatment planning system and accumulated using deformable image registration onto the exhale phase of the 4D-CT. The original IMAT plans were recalculated on the exhale phase of the CT for comparison with the dynamic simulation. Results: The dose coverage of the PTV showed negligible variation between the static and dynamic simulation. There was less than 1.5% difference in PTV V95% and V90%. The average inter-fraction and cumulative dosimetric effects among all the patients were less than 0.5% for PTV V95% and V90% coverage and 0.8 Gy for the OARs. However, in patients where target is close to the organs, large variations were observed on great vessels and bronchus for as much as 4.9 Gy and 7.8 Gy. Conclusions: Limited variation in target dose coverage and OAR constraints were seen for each SBRT fraction as well as over all four fractions. Large dose variations were observed on critical organs in patients where these organs were closer to the target. C1 [Zou, Wei; Jabbour, Salma K.; Yue, Ning J.] Rutgers State Univ, Rutgers Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ 08903 USA. [Yin, Lingshu; Kirk, Maura; Munbodh, Reshma; Fang, Penny; Simone, Charles B., II; Teo, Boon-Keng Kevin] Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Shen, Jiajian] Mayo Clin, Dept Radiat Oncol, Phoenix, AZ 85054 USA. [Corradetti, Michael N.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Rengan, Ramesh] Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA. RP Zou, W (reprint author), Rutgers State Univ, Rutgers Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ 08903 USA. EM zouwe@cinj.rutgers.edu NR 23 TC 7 Z9 7 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD NOV 1 PY 2014 VL 9 AR 225 DI 10.1186/s13014-014-0225-3 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA V42LK UT WOS:000209615100001 PM 25365935 ER PT J AU Houston, KE Tomasi, M Yoon, M Paschalis, EI AF Houston, Kevin E. Tomasi, Matteo Yoon, Michael Paschalis, Eleftherios I. TI A Prototype External Magnetic Eyelid Device for Blepharoptosis SO TRANSLATIONAL VISION SCIENCE & TECHNOLOGY LA English DT Article DE Blepharoptosis; Ptosis; Oculomotor Palsy; Cranial Nerve Palsy; Blink; Magnetic; Ptosis Crutch; Reanimation; Paralytic AB Purpose: To test a prototype magnet system (magnetic levator prosthesis) for the ability to comfortably and non-invasively provide eye opening with maintenance of the blink in people with paralytic ptosis and determine preliminary efficacy for short-term clinical application. Methods: The prototype device consisted of a magnet on a spectacle frame and a micro-magnet array mounted externally on the eyelid. Participants with unilateral CN III palsy (n = 3) trialed the predicate (ptosis crutch) and magnet device. Video analysis was used to quantify changes in eyelid opening and subjective responses were documented with a rating scale. A 20-minute and then a 1-week trial were offered. Results: The magnetic levator prosthesis device was effective to provide eye opening while allowing, at minimum, a volitional blink without ill effects on the eyelid skin or ocular surface. Comfort scores ranged from 6 to 9 out of 10 over 3 evaluations. All patients chose an extended trial of the magnet device and reported continued 8-9/10 comfort and efficacy after the extended 1-week trial. Conclusions: Comfortable and effective restoration of eye opening with maintenance of the blink is feasible using external static magnets and warrants further study. Translational Relevance: This is the first careful documentation of the successful use of an externally mounted static magnet system to treat paralytic ptosis. C1 [Houston, Kevin E.; Tomasi, Matteo] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Vis Rehabil Lab,Dept Ophthalmol, Boston, MA 02114 USA. [Houston, Kevin E.] Harvard Med Sch, Spaulding Rehabil Hosp, Vis Serv, Boston, MA USA. [Yoon, Michael] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Oculoplast Serv, Boston, MA USA. [Paschalis, Eleftherios I.] Harvard Med Sch, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston Keratoprosthesis Lab,Dept Ophthalmol, Boston, MA 02114 USA. RP Houston, KE (reprint author), Harvard Med Sch, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Vis Rehabil Lab,Dept Ophthalmol, Boston, MA 02114 USA. EM kevin_houston@meei.harvard.edu; eleftherios_paschalis@meei.harvard.edu NR 15 TC 0 Z9 0 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 2164-2591 J9 TRANSL VIS SCI TECHN JI Transl. Vis. Sci. Technol. PD NOV PY 2014 VL 3 IS 6 AR 9 DI 10.1167/tvst.3.6.9 PG 9 WC Ophthalmology SC Ophthalmology GA V45JW UT WOS:000209813900009 ER PT J AU Lin, Z Feng, RQ Li, JQ Meng, Y Yuan, L Fu, ZZ Guo, J Bringhurst, FR Yang, DH AF Lin, Zhen Feng, Ruiqiang Li, Junqing Meng, Yue Yuan, Liang Fu, Zhaozong Guo, Jun Bringhurst, F. Richard Yang, Dehong TI Nuclear translocation of CBP/p300-interacting protein CITED1 induced by parathyroid hormone requires serine phosphorylation at position 79 in its 63-84 domain SO CELLULAR SIGNALLING LA English DT Article DE Parathyroid hormone; Osteoblastic differentiation; CITED1; Nuclear translocation; Phosphorylation; Osteoblastic mineralization ID BONE; TRANSCRIPTION; OSTEOBLASTS; RECEPTOR; CELLS; MSG1 AB The transcriptional cofactor CITED1 inhibits osteoblastic differentiation and blunts the stimulation of osteoblastic differentiation by parathyroid hormone (PTH). In the MC3T3-E1 osteoblastic cell line, we found that CITED1 was located predominantly in the cytoplasm and that hPTH(1-34) increased translocation of CITED1 from the cytoplasm to the nucleus. This response to hPTH(1-34) was not observed when all 9 serine residues within the 63-84 domain of CITED1 were mutated to alanines (CITED1 9S>A) or when a single serine to alanine mutation was made at position 79 (CITED1 S-79>A). CITED1 containing mutations of these 9 serines to glutamic acid (9S>E) retained the same nuclear translocation response to hPTH(1-34) as the wild type CITED1. ALP activity and formation of mineralized nodules were inhibited in cells transfected with pcDNA3-CFP-CITED1 or with pcDNA3-CFP-CITED1 9S>E with or without hPTH(1-34) treatment (all P < 0.05); these changes were not observed using CITED1 9S>A. Cells exposed to intermittent treatment with hPTH(1-34) expressed more ALP2, Runx2 and osteocalcin than vehicle-treated cells. These effects of hPTH(1-34) were inhibited in cells transfected with pcDNA3-CFP-CITED1 or pcDNA3-CFP-CITED1 9S>E, but were slightly enhanced by the alanine mutants. PKC activator (TPA) increased nuclear translocation of CITED1, whereas a PKC inhibitor (Go6983) blunted the effect of hPTH(1-34) on the nuclear translocation of wildtype CITED1 but not of CITED1 S-79>E. The data indicated that serine phosphorylation at position 79 in the 63-84 domain is associated with PKC activation, and is required for both CITED1 nuclear translocation induced by PTH and the negative effects of CITED1 on osteoblastic differentiation and mineralization. (C) 2014 Elsevier Inc. All rights reserved. C1 [Lin, Zhen; Feng, Ruiqiang; Li, Junqing; Meng, Yue; Yuan, Liang; Fu, Zhaozong; Yang, Dehong] Southern Med Univ, Nanfang Hosp, Dept Spinal Surg, Guangzhou 510515, Guangdong, Peoples R China. [Guo, Jun; Bringhurst, F. Richard] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Yang, DH (reprint author), Southern Med Univ, Nanfang Hosp, Dept Spinal Surg, 1838 Guangzhou North Ave, Guangzhou 510515, Guangdong, Peoples R China. EM drmyang@yahoo.com FU National Natural Science Foundation of China [30973061] FX This work was supported by the National Natural Science Foundation of China (Grant No. 30973061). NR 21 TC 3 Z9 3 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD NOV PY 2014 VL 26 IS 11 BP 2436 EP 2445 DI 10.1016/j.cellsig.2014.06.015 PG 10 WC Cell Biology SC Cell Biology GA AQ3TW UT WOS:000342717400016 PM 25049079 ER PT J AU Miller, C Bauer, MS AF Miller, Christopher Bauer, Mark S. TI Excess Mortality in Bipolar Disorders SO CURRENT PSYCHIATRY REPORTS LA English DT Article DE Bipolar; Mortality; Suicide Cardiovascular ID RANDOMIZED CONTROLLED-TRIAL; CARDIOVASCULAR-DISEASE RISK; WEEKLY SYMPTOMATIC STATUS; SERIOUS MENTAL-ILLNESS; SUICIDAL-BEHAVIOR; ANTIDEPRESSANT USE; LITHIUM TREATMENT; I DISORDER; ELECTROCONVULSIVE-THERAPY; DEPRESSIVE-DISORDERS AB Bipolar disorder is associated with high mortality, and people with this disorder on average may die 10-20 years earlier than the general population. This excess and premature mortality continues to occur despite a large and expanding selection of treatment options dating back to lithium and now including anticonvulsants, antipsychotics, and evidence-based psychotherapies. This review summarizes recent findings on mortality in bipolar disorder, with an emphasis on the role of suicide (accounting for about 15 % of deaths in this population) and cardiovascular disease (accounting for about 3540 % of deaths). Recent care models and treatments incorporating active outreach, integrated mental and physical health care, and an emphasis on patient self-management have shown promise in reducing excess mortality in this population. C1 [Miller, Christopher; Bauer, Mark S.] VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA 02130 USA. [Miller, Christopher; Bauer, Mark S.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Miller, C (reprint author), VA Boston Healthcare Syst, Ctr Healthcare Org & Implementat Res, Boston, MA 02130 USA. EM christopher.miller8@va.gov; mark.bauer@va.gov NR 75 TC 12 Z9 12 U1 0 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 EI 1535-1645 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD NOV PY 2014 VL 16 IS 11 AR 499 DI 10.1007/s11920-014-0499-z PG 7 WC Psychiatry SC Psychiatry GA AQ0AX UT WOS:000342444800006 PM 25194314 ER PT J AU Moran-Santa Maria, MM Flanagan, J Brady, K AF Moran-Santa Maria, Megan M. Flanagan, Julianne Brady, Kathleen TI Ovarian Hormones and Drug Abuse SO CURRENT PSYCHIATRY REPORTS LA English DT Article DE Progesterone; Estrogen; Substance use disorders; Menstrual cycle; Estrous cycle; Addiction ID NICOTINIC ACETYLCHOLINE-RECEPTORS; MENSTRUAL-CYCLE; FEMALE RATS; SEX-DIFFERENCES; GENDER-DIFFERENCES; COCAINE-SEEKING; SMOKED COCAINE; INDUCED REINSTATEMENT; SMOKING-CESSATION; LUTEAL PHASES AB There are significant gender differences in course, symptomology, and treatment of substance use disorders. In general data from clinical and preclinical studies of substance use disorders suggest that women are more vulnerable than men to the deleterious consequences of drug use at every phase of the addiction process. In addition data from epidemiologic studies suggest that the gender gap in the prevalence of substance use is narrowing particularly among adolescence. Therefore, understanding the role of estrogen and progesterone in mediating responses to drugs of abuse is of critical importance to women's health. In this review we will discuss findings from clinical and preclinical studies of 1) reproductive cycle phase; 2) endogenous ovarian hormones; and 3) hormone replacement on responses to stimulants, nicotine, alcohol, opioids, and marijuana. In addition, we discuss data from recent studies that have advanced our understanding of the neurobiologic mechanisms that interact with estrogen and progesterone to mediate drug-seeking behavior. C1 [Moran-Santa Maria, Megan M.; Flanagan, Julianne; Brady, Kathleen] Med Univ S Carolina, Dept Psychiat & Behav Neurosci, Clin Neurosci Div, Charleston, SC 29425 USA. [Brady, Kathleen] Ralph H Johnson VAMC, Charleston, SC 29401 USA. RP Moran-Santa Maria, MM (reprint author), Med Univ S Carolina, Dept Psychiat & Behav Neurosci, Clin Neurosci Div, 125 Doughty St, Charleston, SC 29425 USA. EM moranm@musc.edu FU NIH NIDA/ORWH [P50 DA016511]; NIH/NICHD [K12 HD055885] FX Megan M. Moran-Santa Maria has received grants from NIH NIDA/ORWH (Co-I on P50 DA016511 "Sex and Gender Factors Affecting Women's Health") and NIH/NICHD (K12 HD055885 Recipient "Impact of ovarian hormones on brain activity in cocaine-dependent women during exposure to psychosocial stress"). NR 86 TC 4 Z9 4 U1 2 U2 31 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 EI 1535-1645 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD NOV PY 2014 VL 16 IS 11 AR 511 DI 10.1007/s11920-014-0511-7 PG 8 WC Psychiatry SC Psychiatry GA AQ0AX UT WOS:000342444800018 PM 25224609 ER PT J AU Galland-Girodet, S Pashtan, I MacDonald, SM Ancukiewicz, M Hirsch, AE Kachnic, LA Specht, M Gadd, M Smith, BL Powell, SN Recht, A Taghian, AG AF Galland-Girodet, Sigolene Pashtan, Itai MacDonald, Shannon M. Ancukiewicz, Marek Hirsch, Ariel E. Kachnic, Lisa A. Specht, Michelle Gadd, Michele Smith, Barbara L. Powell, Simon N. Recht, Abram Taghian, Alphonse G. TI Long-term Cosmetic Outcomes and Toxicities of Proton Beam Therapy Compared With Photon-Based 3-Dimensional Conformal Accelerated Partial-Breast Irradiation: A Phase 1 Trial SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID DOSE-VOLUME PARAMETERS; RADIATION-THERAPY; RANDOMIZED-TRIAL; RTOG 0319; RADIOTHERAPY; CANCER; BRACHYTHERAPY; LUMPECTOMY; EXPERIENCE; CARCINOMA AB Purpose: To present long-term outcomes of a prospective feasibility trial using either protons or 3-dimensional conformal photon-based (accelerated partial-breast irradiation [APBI]) techniques. Methods and Materials: From October 2003 to April 2006, 98 evaluable patients with stage I breast cancer were treated with APBI (32 Gy in 8 fractions given twice daily) on a prospective clinical trial: 19 with proton beam therapy (PBT) and 79 with photons or mixed photons/electrons. Median follow-up was 82.5 months (range, 2104 months). Toxicity and patient satisfaction evaluations were performed at each visit. Results: At 7 years, the physician rating of overall cosmesis was good or excellent for 62% of PBT patients, compared with 94% for photon patients (P=.03). Skin toxicities were more common for the PBT group: telangiectasia, 69% and 16% P=.0013); pigmentation changes, 54% and 22% (P=.02); and other late skin toxicities, 62% and 18% (P=.029) for PBT and photons, respectively. There were no significant differences between the groups in the incidences of breast pain, edema, fibrosis, fat necrosis, skin desquamation, and rib pain or fracture. Patient-reported cosmetic outcomes at 7 years were good or excellent for 92% and 96% of PBT and photon patients, respectively (P=.95). Overall patient satisfaction was 93% for the entire cohort. The 7-year local failure rate for all patients was 6%, with 3 local recurrences in the PBT group (7-year rate, 11%) and 2 in photon-treated patients (4%) (P=.22). Conclusions: Local failure rates of 3-dimensional APBI and PBT were similar in this study. However, PBT, as delivered in this study, led to higher rates of long-term telangiectasia, skin color changes, and skin toxicities. We recommend the use of multiple fields and treatment of all fields per treatment session or the use of scanning techniques to minimize skin toxicity. (C) 2014 Elsevier Inc. C1 [Galland-Girodet, Sigolene; Pashtan, Itai; MacDonald, Shannon M.; Ancukiewicz, Marek; Hirsch, Ariel E.; Kachnic, Lisa A.; Powell, Simon N.; Taghian, Alphonse G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Specht, Michelle; Gadd, Michele; Smith, Barbara L.] Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA. [Hirsch, Ariel E.; Kachnic, Lisa A.] Boston Univ, Sch Med, Dept Radiat Oncol, Boston Med Ctr, Boston, MA 02118 USA. [Recht, Abram] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. RP Taghian, AG (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St, Boston, MA 02114 USA. EM ataghian@partners.org NR 24 TC 20 Z9 20 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2014 VL 90 IS 3 BP 493 EP 500 DI 10.1016/j.ijrobp.2014.04.008 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AP8US UT WOS:000342355400005 PM 24880212 ER PT J AU Wattson, DA Tanguturi, SK Spiegel, DY Niemierko, A Biller, BMK Nachtigall, LB Bussiere, MR Swearingen, B Chapman, PH Loeffler, JS Shih, HA AF Wattson, Daniel A. Tanguturi, Shyam K. Spiegel, Daphna Y. Niemierko, Andrzej Biller, Beverly M. K. Nachtigall, Lisa B. Bussiere, Marc R. Swearingen, Brooke Chapman, Paul H. Loeffler, Jay S. Shih, Helen A. TI Outcomes of Proton Therapy for Patients With Functional Pituitary Adenomas SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID GAMMA-KNIFE RADIOSURGERY; LONG-TERM MORTALITY; STEREOTACTIC RADIOSURGERY; TRANSSPHENOIDAL SURGERY; RADIATION-THERAPY; CUSHINGS-DISEASE; GROWTH-HORMONE; FOLLOW-UP; RADIOTHERAPY; MANAGEMENT AB Purpose/Objective(s): This study evaluated the efficacy and toxicity of proton therapy for functional pituitary adenomas (FPAs). Methods and Materials: We analyzed 165 patients with FPAs who were treated at a single institution with proton therapy between 1992 and 2012 and had at least 6 months of follow-up. All but 3 patients underwent prior resection, and 14 received prior photon irradiation. Proton stereotactic radiosurgery was used for 92% of patients, with a median dose of 20 Gy(RBE). The remainder received fractionated stereotactic proton therapy. Time to biochemical complete response (CR, defined as >= 3 months of normal laboratory values with no medical treatment), local control, and adverse effects are reported. Results: With a median follow-up time of 4.3 years (range, 0.5-20.6 years) for 144 evaluable patients, the actuarial 3-year CR rate and the median time to CR were 54% and 32 months among 74 patients with Cushing disease (CD), 63% and 27 months among 8 patients with Nelson syndrome (NS), 26% and 62 months among 50 patients with acromegaly, and 22% and 60 months among 9 patients with prolactinomas, respectively. One of 3 patients with thyroid stimulating hormone-secreting tumors achieved CR. Actuarial time to CR was significantly shorter for corticotroph FPAs (CD/NS) compared with other subtypes (P=.001). At a median imaging follow-up time of 43 months, tumor control was 98% among 140 patients. The actuarial 3-year and 5-year rates of development of new hypopituitarism were 45% and 62%, and the median time to deficiency was 40 months. Larger radiosurgery target volume as a continuous variable was a significant predictor of hypopituitarism (adjusted hazard ratio 1.3, P=.004). Four patients had new-onset postradiosurgery seizures suspected to be related to generously defined target volumes. There were no radiation-induced tumors. Conclusions: Proton irradiation is an effective treatment for FPAs, and hypopituitarism remains the primary adverse effect. (C) 2014 Elsevier Inc. C1 [Wattson, Daniel A.; Tanguturi, Shyam K.] Harvard Univ, Radiat Oncol Program, Boston, MA 02115 USA. [Spiegel, Daphna Y.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Niemierko, Andrzej; Bussiere, Marc R.; Loeffler, Jay S.; Shih, Helen A.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Biller, Beverly M. K.; Nachtigall, Lisa B.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Swearingen, Brooke; Chapman, Paul H.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Shih, HA (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. EM hshih@partners.org FU Novartis FX B.M.K.B. has served as the principal investigator of research grants to the Massachusetts General Hospital from Novartis and as a consultant for HRA Pharma, Novartis, and Pfizer. H.A.S. is an editor for this journal and is a writer for UpToDate. The authors report no other conflict of interest. NR 35 TC 14 Z9 14 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2014 VL 90 IS 3 BP 532 EP 539 DI 10.1016/j.ijrobp.2014.06.068 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AP8US UT WOS:000342355400011 PM 25194666 ER PT J AU Spadea, MF Fassi, A Zaffino, P Riboldi, M Baroni, G Depauw, N Seco, J AF Spadea, Maria Francesca Fassi, Aurora Zaffino, Paolo Riboldi, Marco Baroni, Guido Depauw, Nicolas Seco, Joao TI Contrast-Enhanced Proton Radiography for Patient Set-up by Using X-Ray CT Prior Knowledge SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID PARTICLE THERAPY; BEAM THERAPY; MONTE-CARLO; MOTION; RADIOTHERAPY; TOOL AB Purpose: To obtain a contrasted image of the tumor region during the setup for proton therapy in lung patients, by using proton radiography and x-ray computed tomography (CT) prior knowledge. Methods and Materials: Six lung cancer patients' CT scans were preprocessed by masking out the gross tumor volume (GTV), and digitally reconstructed radiographs along the planned beam's eye view (BEV) were generated, for a total of 27 projections. Proton radiographies (PR) were also computed for the same BEV through Monte Carlo simulations. The digitally reconstructed radiograph was subtracted from the corresponding proton image, resulting in a contrast-enhanced proton radiography (CEPR). Michelson contrast analysis was performed both on PR and CEPR. The tumor region was then automatically segmented on CEPR and compared to the ground truth (GT) provided by physicians in terms of Dice coefficient, accuracy, precision, sensitivity, and specificity. Results: Contrast on CEPR was, on average, 4 times better than on PR. For 10 lateral projections (+/- 45 degrees off of 90 degrees or 270 degrees), although it was not possible to distinguish the tumor region in the PR, CEPR offers excellent GTV visibility. The median +/- quartile values of Dice, precision, and accuracy indexes were 0.86 +/- 0.03, 0.86 +/- 0.06, and 0.88 +/- 0.02, respectively, thus confirming the reliability of the method in highlighting tumor boundaries. Sensitivity and specificity analysis demonstrated that there is no systematic over- or underestimation of the tumor region. Identification of the tumor boundaries using CEPR resulted in a more accurate and precise definition of GTV compared to that obtained from pretreatment CT. Conclusions: In most proton centers, the current clinical protocol is to align the patient using kV imaging with bony anatomy as a reference. We demonstrated that CEPR can significantly improve tumor visualization, allowing better patient set-up and permitting image guided proton therapy (IGPT). (C) 2014 Elsevier Inc. C1 [Spadea, Maria Francesca; Zaffino, Paolo] Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, Catanzaro, Italy. [Fassi, Aurora; Riboldi, Marco; Baroni, Guido] Politecn Milan, Dipartimento Elettron Informaz & Bioingn, Milan, Italy. [Riboldi, Marco; Baroni, Guido] CNAO Fdn, Bioengn Unit, Pavia, Italy. [Depauw, Nicolas; Seco, Joao] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Depauw, Nicolas; Seco, Joao] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Depauw, Nicolas] Univ Wollongong, Ctr Med Radiat Phys, Wollongong, NSW, Australia. RP Spadea, MF (reprint author), Viale Europa, I-88100 Catanzaro, IT, Italy. EM mfspadea@unicz.it RI Riboldi, Marco/I-2980-2014 OI Riboldi, Marco/0000-0002-2431-4966 NR 25 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD NOV 1 PY 2014 VL 90 IS 3 BP 628 EP 636 DI 10.1016/j.ijrobp.2014.06.057 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AP8US UT WOS:000342355400023 PM 25160609 ER PT J AU Donahue, JJ Goranson, AC McClure, KS Van Male, LM AF Donahue, John J. Goranson, Anders C. McClure, Kelly S. Van Male, Lynn M. TI Emotion dysregulation, negative affect, and aggression: A moderated, multiple mediator analysis SO PERSONALITY AND INDIVIDUAL DIFFERENCES LA English DT Article DE Emotion regulation; Physical aggression; Negative affect; Sex differences ID NATIONAL-COMORBIDITY-SURVEY; GENDER-DIFFERENCES; PROACTIVE AGGRESSION; DISORDERS; ANGER; METAANALYSIS; VALIDATION; AVOIDANCE; CHILDHOOD; ANXIETY AB Research on violence has highlighted the role of trait negative affect in reactive aggressive behavior. Emotion dysregulation is a multidimensional construct reflecting maladaptive ways in which a person experiences and responds to emotional states, and has also been empirically linked to aggression. This study sought to test the hypothesis that multiple facets of emotion dysregulation would mediate the relationship between negative affect and physical aggression in a nonclinical sample. An additional aim was to examine the moderating effect of sex in the relationship between negative affect and aggression, and whether mediators differ as a function of sex. Three-hundred and eighteen participants completed measures of physical aggression, difficulties in emotion regulation, and negative affect. Results showed that sex moderated the relationship between negative affect and physical aggression, and emotion dysregulation fully mediated the relationship between these variables in both males and females. While difficulty inhibiting impulsive behavior when distressed was a significant mediator across sexes, difficulties with emotional awareness demonstrated a mediation effect only in males. Findings provide preliminary support for the facets of emotion dysregulation that are important in understanding the negative affect physical aggression association in males and females. Published by Elsevier Ltd. C1 [Donahue, John J.; Goranson, Anders C.] Portland VA Med Ctr, VISN NW MIRECC 20, Portland, OR 97207 USA. [McClure, Kelly S.] La Salle Univ, Dept Psychol, Philadelphia, PA 19141 USA. [Van Male, Lynn M.] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Occupat Hlth Strateg Healthcare Grp 10P3D, VHA CO,Off Publ Hlth,Dept Psychiat, Portland, OR 97207 USA. RP Donahue, JJ (reprint author), Portland VA Med Ctr, VISN NW MIRECC 20, POB 1034, Portland, OR 97207 USA. EM jdonahue81@gmail.com NR 32 TC 6 Z9 6 U1 2 U2 60 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0191-8869 J9 PERS INDIV DIFFER JI Pers. Individ. Differ. PD NOV PY 2014 VL 70 BP 23 EP 28 DI 10.1016/j.paid.2014.06.009 PG 6 WC Psychology, Social SC Psychology GA AO6NO UT WOS:000341469000005 ER PT J AU Winer, LSP Wu, M AF Winer, Lisa S. Pike Wu, Min TI Rapid Analysis of Glycolytic and Oxidative Substrate Flux of Cancer Cells in a Microplate SO PLOS ONE LA English DT Article ID GLUTAMINE-METABOLISM; AEROBIC GLYCOLYSIS; C-MYC; GROWTH; TUMORS; PROLIFERATION; INHIBITION; EXPRESSION; WARBURG; OXYGEN AB Cancer cells exhibit remarkable alterations in cellular metabolism, particularly in their nutrient substrate preference. We have devised several experimental methods that rapidly analyze the metabolic substrate flux in cancer cells: glycolysis and the oxidation of major fuel substrates glucose, glutamine, and fatty acids. Using the XF Extracellular Flux analyzer, these methods measure, in real-time, the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of living cells in a microplate as they respond to substrates and metabolic perturbation agents. In proof-of-principle experiments, we analyzed substrate flux and mitochondrial bioenergetics of two human glioblastoma cell lines, SF188s and SF188f, which were derived from the same parental cell line but proliferate at slow and fast rates, respectively. These analyses led to three interesting observations: 1) both cell lines respired effectively with substantial endogenous substrate respiration; 2) SF188f cells underwent a significant shift from glycolytic to oxidative metabolism, along with a high rate of glutamine oxidation relative to SF188s cells; and 3) the mitochondrial proton leak-linked respiration of SF188f cells increased significantly compared to SF188s cells. It is plausible that the proton leak of SF188f cells may play a role in allowing continuous glutamine-fueled anaplerotic TCA cycle flux by partially uncoupling the TCA cycle from oxidative phosphorylation. Taken together, these rapid, sensitive and high-throughput substrate flux analysis methods introduce highly valuable approaches for developing a greater understanding of genetic and epigenetic pathways that regulate cellular metabolism, and the development of therapies that target cancer metabolism. C1 [Winer, Lisa S. Pike; Wu, Min] Seahorse Biosci Inc, North Billerica, MA USA. RP Wu, M (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM mwu13@mgh.harvard.edu FU Seahorse Bioscience FX This work was conducted in and funded by Seahorse Bioscience. LSPW is an employee and MW was an employee at the time of the work in the company. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 7 Z9 7 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 31 PY 2014 VL 9 IS 10 AR e109916 DI 10.1371/journal.pone.0109916 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS0BN UT WOS:000343943700021 ER PT J AU Schlozman, SC AF Schlozman, Steven C. TI Do Zombies Dream of Undead Sheep? SO SCIENCE LA English DT Book Review C1 [Schlozman, Steven C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. RP Schlozman, SC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. EM sschlozman@mgh.harvard.edu NR 2 TC 0 Z9 0 U1 0 U2 11 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD OCT 31 PY 2014 VL 346 IS 6209 SI SI BP 557 EP 557 DI 10.1126/science.1261500 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR8BE UT WOS:000343799700026 ER PT J AU Gutchess, A AF Gutchess, Angela TI Plasticity of the aging brain: New directions in cognitive neuroscience SO SCIENCE LA English DT Review ID DIRECT-CURRENT STIMULATION; MEDIAL PREFRONTAL CORTEX; AGE-RELATED-CHANGES; EPISODIC MEMORY; SKILL ACQUISITION; OLDER-ADULTS; MOTOR; TASK; ENHANCEMENT; HIPPOCAMPUS AB Cognitive neuroscience has revealed aging of the human brain to be rich in reorganization and change. Neuroimaging results have recast our framework around cognitive aging from one of decline to one emphasizing plasticity. Current methods use neurostimulation approaches to manipulate brain function, providing a direct test of the ways that the brain differently contributes to task performance for younger and older adults. Emerging research into emotional, social, and motivational domains provides some evidence for preservation with age, suggesting potential avenues of plasticity, alongside additional evidence for reorganization. Thus, we begin to see that aging of the brain, amidst interrelated behavioral and biological changes, is as complex and idiosyncratic as the brain itself, qualitatively changing over the life span. C1 [Gutchess, Angela] Brandeis Univ, Dept Psychol, Waltham, MA 02254 USA. [Gutchess, Angela] Brandeis Univ, Volen Natl Ctr Complex Syst, Waltham, MA USA. [Gutchess, Angela] Massachussetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Gutchess, A (reprint author), Brandeis Univ, Dept Psychol, Waltham, MA 02254 USA. EM gutchess@brandeis.edu NR 40 TC 27 Z9 27 U1 9 U2 63 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD OCT 31 PY 2014 VL 346 IS 6209 SI SI BP 579 EP 582 DI 10.1126/science.1254604 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR8BE UT WOS:000343799700036 PM 25359965 ER PT J AU Thibert, RL Duhaime, AC Caruso, PA Stemmer-Rachamimov, A AF Thibert, Ronald L. Duhaime, Ann-Christine Caruso, Paul A. Stemmer-Rachamimov, Anat TI Case 34-2014: A 7-Year-Old Boy with Focal Seizures and Progressive Weakness SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID EPILEPSIA-PARTIALIS-CONTINUA; RASMUSSENS ENCEPHALITIS; FUNCTIONAL HEMISPHERECTOMY; CORTICAL DYSPLASIA; ETIOLOGY; HISTOPATHOLOGY; DIAGNOSIS; PATHOLOGY; FEATURES; CHILDREN C1 [Thibert, Ronald L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Caruso, Paul A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Stemmer-Rachamimov, Anat] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Thibert, Ronald L.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Duhaime, Ann-Christine] Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA USA. [Caruso, Paul A.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Stemmer-Rachamimov, Anat] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Thibert, RL (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NR 24 TC 1 Z9 1 U1 0 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 30 PY 2014 VL 371 IS 18 BP 1737 EP 1746 DI 10.1056/NEJMcpc1305993 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AR7OG UT WOS:000343768500013 PM 25354108 ER PT J AU Barone, A Sengupta, R Warrington, NM Smith, E Wen, PY Brekken, RA Romagnoli, B Douglas, G Chevalier, E Bauer, MP Dembowsky, K Piwnica-Worms, D Rubin, JB AF Barone, Amy Sengupta, Rajarshi Warrington, Nicole M. Smith, Erin Wen, Patrick Y. Brekken, Rolf A. Romagnoli, Barbara Douglas, Garry Chevalier, Eric Bauer, Michael P. Dembowsky, Klaus Piwnica-Worms, David Rubin, Joshua B. TI Combined VEGF and CXCR4 antagonism targets the GBM stem cell population and synergistically improves survival in an intracranial mouse model of glioblastoma SO ONCOTARGET LA English DT Article DE CXCR4; VEGF; perivascular; glioblastoma; stem cells ID CHEMOKINE RECEPTOR CXCR4; ENDOTHELIAL GROWTH-FACTOR; TUMOR-INITIATING CELLS; RECURRENT GLIOBLASTOMA; HEMATOPOIETIC STEM; RAPID MOBILIZATION; PROGENITOR CELLS; SELF-RENEWAL; BRAIN-TUMORS; ANTI-VEGF AB Glioblastoma recurrence involves the persistence of a subpopulation of cells with enhanced tumor-initiating capacity (TIC) that reside within the perivascular space, or niche (PVN). Anti-angiogenic therapies may prevent the formation of new PVN but have not prevented recurrence in clinical trials, suggesting they cannot abrogate TIC activity. We hypothesized that combining anti-angiogenic therapy with blockade of PVN function would have superior anti-tumor activity. We tested this hypothesis in an established intracranial xenograft model of GBM using a monoclonal antibody specific for murine and human VEGF (mcr84) and a Protein Epitope Mimetic (PEM) CXCR4 antagonist, POL5551. When doses of POL5551 were increased to overcome an mcr84-induced improvement in vascular barrier function, combinatorial therapy significantly inhibited intracranial tumor growth and improved survival. Anti-tumor activity was associated with significant changes in tumor cell proliferation and apoptosis, and a reduction in the numbers of perivascular cells expressing the TIC marker nestin. A direct effect on TICs was demonstrated for POL5551, but not mcr84, in three primary patient-derived GBM isolates. These findings indicate that targeting the structure and function of the PVN has superior anti-tumor effect and provide a strong rationale for clinical evaluation of POL5551 and Avastin in patients with GBM. C1 [Barone, Amy; Sengupta, Rajarshi; Warrington, Nicole M.; Rubin, Joshua B.] Washington Univ Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Smith, Erin; Piwnica-Worms, David] Washington Univ Sch Med, BRIGHT Inst, St Louis, MO USA. [Smith, Erin; Piwnica-Worms, David] Washington Univ Sch Med, Mallinckrodt Inst Radiol, Mol Imaging Ctr, St Louis, MO USA. [Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Wen, Patrick Y.] Brigham & Womens Hosp, Dept Neurol, Div Neurooncol, Boston, MA 02115 USA. [Brekken, Rolf A.] UT Southwestern Med Ctr, Hamon Ctr Therapeut Oncol Res, Dallas, TX USA. [Romagnoli, Barbara; Douglas, Garry; Chevalier, Eric; Bauer, Michael P.; Dembowsky, Klaus] PolyPhor Ltd, CH-4123 Allschwil, Switzerland. [Piwnica-Worms, David] Washington Univ Sch Med, Dept Cell Biol & Physiol, St Louis, MO USA. [Piwnica-Worms, David] Univ Texas MD Anderson Canc Ctr, Dept Canc Syst Imaging, Houston, TX 77030 USA. [Rubin, Joshua B.] Washington Univ Sch Med, Dept Anat & Neurobiol, St Louis, MO USA. RP Rubin, JB (reprint author), Washington Univ Sch Med, Dept Pediat, 660 South Euclid Ave, St Louis, MO 63110 USA. EM rubin_j@kids.wustl.edu FU Taylor Rozier Hope for a Cure Foundation; Josie Foundation and Matt's Hats; St Baldrick's Foundation; Effie Marie Cain Scholarship; Washington University Institute of Clinical and Translational Sciences Grant from the National Center for Advancing Translational Sciences [UL1TR000448]; Molecular Imaging Center at Washington University School of Medicine; NIH [P50 CA94056]; NCI Cancer Center Support Grant [P30 CA91842] FX The authors are grateful to Achim Wach and Michel Schmitt of Polyphor Ltd for bioanalytical support. This work was supported by The Taylor Rozier Hope for a Cure Foundation, The Josie Foundation and Matt's Hats (JBR), St Baldrick's Foundation (AB) and the Effie Marie Cain Scholarship (RAB). The publication of this manuscript was also supported by the Washington University Institute of Clinical and Translational Sciences Grant (UL1TR000448) from the National Center for Advancing Translational Sciences. Bioluminescence imaging studies were supported by The Molecular Imaging Center at Washington University School of Medicine and NIH P50 CA94056. Cell sorting service was provided by the Alvin J Siteman Cancer Center at Washington University School of Medicine Flow Cytometry Core. The Siteman Cancer Center is supported in part by NCI Cancer Center Support Grant P30 CA91842. NR 50 TC 12 Z9 12 U1 2 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 30 PY 2014 VL 5 IS 20 BP 9811 EP 9822 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ2AH UT WOS:000348036500023 PM 25238146 ER PT J AU Kfoury, Y Scadden, DT AF Kfoury, Youmna Scadden, David T. TI Cellular thrust and parry in the leukemic niche SO BLOOD LA English DT Editorial Material AB In this issue of Blood, Krevvata et al show that osteoblasts duel with acute leukemia cells, each having adverse effects on the other. C1 [Kfoury, Youmna] Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Cambridge, MA 02138 USA. RP Kfoury, Y (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 9 TC 1 Z9 1 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 30 PY 2014 VL 124 IS 18 BP 2760 EP 2761 DI 10.1182/blood-2014-09-597716 PG 4 WC Hematology SC Hematology GA AY3BC UT WOS:000347458500004 PM 25359983 ER PT J AU Bejar, R Steensma, DP AF Bejar, Rafael Steensma, David P. TI Recent developments in myelodysplastic syndromes SO BLOOD LA English DT Review ID ACUTE MYELOID-LEUKEMIA; PROGNOSTIC SCORING SYSTEM; THERAPY-RELATED MYELODYSPLASIA; METHYLTRANSFERASE GENE EZH2; DETECTABLE CLONAL MOSAICISM; WORLD-HEALTH-ORGANIZATION; STEM-CELL TRANSPLANTATION; COLONY-STIMULATING FACTOR; QUALITY-OF-LIFE; LOW-RISK AB Once thought to be rare disorders, the myelodysplastic syndromes (MDS) are now recognized as among the most common hematological neoplasms, probably affecting >30 000 patients per year in the United States. US regulatory approval of azacitidine, decitabine, and lenalidomide between 2004 and 2006 seemed to herald a new era in the development of disease modifying therapies for MDS, but there have been no further drug approvals for MDS-indications in the United States in the last 8 years. The available drugs are not curative, and few of the compounds that are currently in development are likely to be approved in the near future. As a result, MDS diagnoses continue to place a heavy burden on both patients and health care systems. Incomplete understanding of disease pathology, the inherent biological complexity of MDS, and the presence of comorbid conditions and poor performance status in the typical older patient with MDS have been major impediments to development of effective novel therapies. Here we discuss new insights from genomic discoveries that are illuminating MDS pathogenesis, increasing diagnostic accuracy, and refining prognostic assessment, and which will one day contribute to more effective treatments and improved patient outcomes. C1 [Bejar, Rafael] Univ Calif San Diego, Div Hematol & Oncol, Moores Canc Ctr, La Jolla, CA 92093 USA. [Steensma, David P.] Dana Farber Canc Inst, Div Hematol Malignancies, Dept Med Oncol, Boston, MA 02215 USA. RP Steensma, DP (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM david_steensma@dfci.harvard.edu NR 129 TC 50 Z9 53 U1 3 U2 9 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 OCT 30 PY 2014 VL 124 IS 18 BP 2793 EP 2803 DI 10.1182/blood-2014-04-522136 PG 11 WC Hematology SC Hematology GA AY3BC UT WOS:000347458500011 PM 25237199 ER PT J AU Mostaghel, EA Morgan, A Zhang, XT Marck, BT Xia, J Hunter-Merrill, R Gulati, R Plymate, S Vessella, RL Corey, E Higano, CS Matsumoto, AM Montgomery, RB Nelson, PS AF Mostaghel, Elahe A. Morgan, Andrew Zhang, Xiaotun Marck, Brett T. Xia, Jing Hunter-Merrill, Rachel Gulati, Roman Plymate, Stephen Vessella, Robert L. Corey, Eva Higano, Celestia S. Matsumoto, Alvin M. Montgomery, R. Bruce Nelson, Peter S. TI Prostate Cancer Characteristics Associated with Response to Pre-Receptor Targeting of the Androgen Axis SO PLOS ONE LA English DT Article ID INCREASED SURVIVAL; HORMONAL-THERAPY; CARCINOMA; DIHYDROTESTOSTERONE; TESTOSTERONE; PROGRESSION; ABIRATERONE; RESISTANCE; ENZALUTAMIDE; INDEPENDENCE AB Background: Factors influencing differential responses of prostate tumors to androgen receptor (AR) axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth. Methods: We characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy. Results: In LuCaP35 tumors (intra-tumoral T: DHT ratio 2: 1) dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs. 152 days, HR 2.8, p = 0.0015). In LuCaP96 tumors (T: DHT 10: 1), survival was not improved despite similar DHT reduction (0.02 ng/gm). LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both), reconstitution of intra-tumoral DHT (to similar to 30% of untreated tumors), and similar to 2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively), persistent suppression of intra-tumoral DHT, and 6-8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts. Conclusions: Intrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and should be validated in additional models. C1 [Mostaghel, Elahe A.; Morgan, Andrew; Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Mostaghel, Elahe A.; Marck, Brett T.; Plymate, Stephen; Higano, Celestia S.; Matsumoto, Alvin M.; Montgomery, R. Bruce; Nelson, Peter S.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Zhang, Xiaotun; Vessella, Robert L.; Corey, Eva] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Marck, Brett T.; Plymate, Stephen; Matsumoto, Alvin M.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Xia, Jing; Hunter-Merrill, Rachel; Gulati, Roman] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP Mostaghel, EA (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA. EM emostagh@fhcrc.org FU Prostate Cancer Foundation Career Development Award; Challenge Award; Damon Runyon Genentech-Clinical Investigator Award [C-40-08]; NIH grant [1K23 CA122820-01]; DOD New Investigator Award [W81XWH-10-1-0228]; GlaxoSmithKline; NIH/NCI Pacific Northwest Prostate Cancer SPORE [P50CA97186]; Department of Veterans Affairs; [1RC1 CA146849]; [PC093509]; [PO1 CA 85859] FX Prostate Cancer Foundation Career Development Award (E. A. M.) and Challenge Award (E. A. M., S. P., R. L. V., A. M. M., R. B. M., P.S.N.), Damon Runyon Genentech-Clinical Investigator Award C-40-08 (E. A. M.), NIH grant 1K23 CA122820-01 (E. A. M.), DOD New Investigator Award W81XWH-10-1-0228 (E. A. M.); GlaxoSmithKline (A. M. and P.S.N.); 1RC1 CA146849 (P.S.N.); PC093509 (P.S.N.); PO1 CA 85859 (J.X., R. G., R. V., P.S.N.); the NIH/NCI Pacific Northwest Prostate Cancer SPORE P50CA97186 (J.X., R. H., R. G., P.S.N., R. V.); and the Department of Veterans Affairs (B. T. M., S. P. and A. M. M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 2 Z9 3 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 OCT 30 PY 2014 VL 9 IS 10 AR e111545 DI 10.1371/journal.pone.0111545 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AX2HU UT WOS:000346765000069 PM 25356728 ER PT J AU Suva, ML AF Suva, Mario L. TI Genetics and epigenetics of gliomas SO SWISS MEDICAL WEEKLY LA English DT Review DE adult gliomas; paediatric gliomas; genetics; epigenetics; novel fusion genes; intra-tumoural heterogeneity ID NEWLY-DIAGNOSED GLIOBLASTOMA; GRADE DIFFUSE GLIOMAS; BRAF V600E MUTATION; CELL LUNG-CANCER; IDH MUTATIONS; PEDIATRIC GLIOBLASTOMA; TYROSINE KINASE; FREQUENT ATRX; HISTONE H3.3; 1P/19Q LOSS AB Gliomas are the most common primary intrinsic brain tumours. Their classification is based on phenotypic resemblance to normal glial cells (astrocytomas, oligodendrogliomas, mixed oligoastrocytomas) and pathological grading. Whereas this system is clinically relevant and has been the basis for our understanding of gliomas, systematic use of next-generation sequencing has transformed our knowledge of their pathogenesis and has uncovered genetic changes in an unanticipated number of genes and regulatory elements. In the past few years, in-depth analysis of low-grade astrocytomas and glioblastomas in both paediatric and adult populations has clarified our molecular understanding of these diseases, with distinct molecular events occurring in different age groups. In oligodendrogliomas, recent studies have highlighted mutations in candidate tumour suppressor genes located on 1p/19q, chromosome arms frequently deleted in this tumour. In this review, we discuss recent discoveries in the genetics of adult and paediatric gliomas, and highlight how some of the founding genetic mutations reshape the cancer epigenome. These studies provide an in-depth view of the molecular routes leading to brain tumour development and will be key for refining classification systems and improving clinical care. C1 [Suva, Mario L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Suva, Mario L.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Suva, Mario L.] Harvard Univ, Sch Med, Boston, MA USA. [Suva, Mario L.] Broad Inst Harvard & MIT, Cambridge, MA USA. RP Suva, ML (reprint author), Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Mol Pathol Unit, 149 13th St 6133, Us Charlestown, MA 02129 USA. EM Suva.Mario@mgh.harvard.edu NR 55 TC 0 Z9 0 U1 4 U2 12 PU E M H SWISS MEDICAL PUBLISHERS LTD PI MUTTENZ PA FARNSBURGERSTR 8, CH-4132 MUTTENZ, SWITZERLAND SN 1424-7860 EI 1424-3997 J9 SWISS MED WKLY JI Swiss Med. Wkly. PD OCT 30 PY 2014 VL 144 AR w14018 DI 10.4414/smw.2014.14018 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AT5UJ UT WOS:000345007400003 PM 25356909 ER PT J AU Nehil, M Paquette, J Tokuyasu, T McCormick, F AF Nehil, M. Paquette, J. Tokuyasu, T. McCormick, F. TI High mobility group box 1 promotes tumor cell migration through epigenetic silencing of semaphorin 3A SO ONCOGENE LA English DT Article DE HMGB1; SEMA3A; migration; chromatin; metastasis ID END-PRODUCTS RAGE; INCREASED EXPRESSION; MURINE COLITIS; HMGB1; CANCER; BINDING; PROTEIN; CARCINOMA; RECEPTOR; GROWTH AB High mobility group box 1 (HMGB1) is a 25-kDa chromatin-associated protein that aids in transcription and DNA repair by directly binding to DNA and altering its conformation. Additionally, HMGB1 can act as an extracellular ligand. When released from dying or stressed cells, HMGB1 binds to the RAGE receptor and activates the p42/44 MAP kinase (MAPK) cascade. HMGB1 is overexpressed in many types of cancer and frequently associated with tumor stage and metastasis. This has predominantly been attributed to an autocrine function that drives MAPK pathway activity. However, by using tumor cells with activating MAPK pathway mutations, we have identified a role for HMGB1 in promoting metastasis and tumor growth that is independent of this pathway. In the absence of HMGB1, these tumor cells show defective in vitro migration as well as reduced metastasis and tumor growth in vivo despite high p42/44 phosphorylation. We found that semaphorin 3A (SEMA3A), previously shown to act as a suppressor of angiogenesis and migration, was highly increased during expression in the absence of HMGB1. SEMA3A/HMGB1 double knockdown rescued the migration defect in HMGB1 single knockdown cells. HMGB1 bound at the semaphorin 3A genomic locus, promoted hetrochromatin formation, and decreased occupancy of acetylated histones. Based on human tumor gene expression databases, HMGB1 was significantly inversely correlated with SEMA3A, suggesting that this mechanism may be more widely relevant in different cancer types. C1 [Nehil, M.] Harvard Univ, Med Scool, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Paquette, J.; Tokuyasu, T.; McCormick, F.] Univ Calif San Francisco, Helen Diller Comprehens Canc Ctr, Program Biomed Sci, San Francisco, CA 94158 USA. [Paquette, J.; Tokuyasu, T.; McCormick, F.] Univ Calif San Francisco, Helen Diller Comprehens Canc Ctr, Bioinformat Program, San Francisco, CA 94158 USA. RP McCormick, F (reprint author), Univ Calif San Francisco, Helen Diller Comprehens Canc Ctr, 1450 3rd St,Rm HD-371 UCSF Box 0128, San Francisco, CA 94158 USA. EM mccormick@cc.ucsf.edu OI Tokuyasu, Taku/0000-0003-3401-3195 FU UCSF Tetrad program FX We thank the UCSF Tetrad program for providing funding. We thank Dr Lewis Lanier for all of his advice. We thank Dr Byron Hann, Dr Paul Phojanakong and the UCSF Clinical Therapeutics core for all of their help with mouse xenograft experiments and the UCSF Genome core for their help with gene expression studies. NR 34 TC 5 Z9 5 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD OCT 30 PY 2014 VL 33 IS 44 BP 5151 EP 5162 DI 10.1038/onc.2013.459 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AR9RZ UT WOS:000343914900002 PM 24213571 ER PT J AU Masse, NY Jarosiewicz, B Simeral, JD Bacher, D Stavisky, SD Cash, SS Oakley, EM Berhanu, E Eskandar, E Friehs, G Hochberg, LR Donoghue, JP AF Masse, Nicolas Y. Jarosiewicz, Beata Simeral, John D. Bacher, Daniel Stavisky, Sergey D. Cash, Sydney S. Oakley, Erin M. Berhanu, Etsub Eskandar, Emad Friehs, Gerhard Hochberg, Leigh R. Donoghue, John P. TI Non-causal spike filtering improves decoding of movement intention for intracortical BCIs SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Spike sorting; Neural decoding; Threshold crossing; Non-causal filter; Brain-computer interface; Microelectrode array ID LOCAL-FIELD POTENTIALS; MULTIUNIT ACTIVITY; PREMOTOR CORTICES; GRASP; MOTOR; REACH; TETRAPLEGIA; SIGNAL AB Background: Multiple types of neural signals are available for controlling assistive devices through brain computer interfaces (BCIs). Intracortically recorded spiking neural signals are attractive for BCIs because they can in principle provide greater fidelity of encoded information compared to electrocorticographic (ECoG) signals and electroencephalograms (EEGs). Recent reports show that the information content of these spiking neural signals can be reliably extracted simply by causally band-pass filtering the recorded extracellular voltage signals and then applying a spike detection threshold, without relying on "sorting" action potentials. New method: We show that replacing the causal filter with an equivalent non-causal filter increases the information content extracted from the extracellular spiking signal and improves decoding of intended movement direction. This method can be used for real-time BCI applications by using a 4 ms lag between recording and filtering neural signals. Results: Across 18 sessions from two people with tetraplegia enrolled in the BrainGate2 pilot clinical trial, we found that threshold crossing events extracted using this non-causal filtering method were significantly more informative of each participant's intended cursor kinematics compared to threshold crossing events derived from causally filtered signals. This new method decreased the mean angular error between the intended and decoded cursor direction by 9.7 degrees for participant S3, who was implanted 5.4 years prior to this study, and by 3.5 degrees for participant T2, who was implanted 3 months prior to this study. Conclusions: Non-causally filtering neural signals prior to extracting threshold crossing events may be a simple yet effective way to condition intracortically recorded neural activity for direct control of external devices through BCIs. (C) 2014 Elsevier B.V. All rights reserved. C1 [Masse, Nicolas Y.; Jarosiewicz, Beata; Donoghue, John P.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Masse, Nicolas Y.; Jarosiewicz, Beata; Simeral, John D.; Bacher, Daniel; Hochberg, Leigh R.; Donoghue, John P.] Brown Univ, Brown Inst Brain Sci, Providence, RI 02912 USA. [Jarosiewicz, Beata; Simeral, John D.; Hochberg, Leigh R.; Donoghue, John P.] Rehabil R&D Serv, Dept Vet Affairs, Med Ctr, Ctr Neurorestorat & Neurotechnol, Providence, RI USA. [Simeral, John D.; Bacher, Daniel; Stavisky, Sergey D.; Hochberg, Leigh R.] Brown Univ, Sch Engn, Providence, RI 02912 USA. [Cash, Sydney S.; Oakley, Erin M.; Berhanu, Etsub; Eskandar, Emad; Friehs, Gerhard; Hochberg, Leigh R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cash, Sydney S.; Eskandar, Emad; Hochberg, Leigh R.] Harvard Univ, Sch Med, Boston, MA USA. RP Masse, NY (reprint author), Univ Chicago, Dept Neurobiol, Chicago, IL 60637 USA. EM masse@uchicago.edu OI Hochberg, Leigh/0000-0003-0261-2273; Masse, Nicolas/0000-0002-9094-1298 FU NIH: NIDCD [R01DC009899]; NICHD-NCMRR [N01HD53403, N01HD10018]; Rehabilitation Research and Development Service, Office of Research and Development, Department of Veterans Affairs (Merit Review Awards) [B6453R, A6779I]; Doris Duke Charitable Foundation; Craig H. Neilsen Foundation; MGH-Deane Institute for Integrated Research on Atrial Fibrillation and Stroke; Katie Samson Foundation; Cyberkinetics Neurotechnology Systems (CKI) FX We thank participants S3 and T2 for their dedication to this research. We thank David Rosier, Laurie Barefoot, Katherine Centrella, and the caregiver staff at the Boston Home for their contributions to this research. The contents do not necessarily represent the views of the Department of Veterans Affairs or the United States Government. This work was supported by NIH: NIDCD (R01DC009899) and NICHD-NCMRR (N01HD53403, N01HD10018); Rehabilitation Research and Development Service, Office of Research and Development, Department of Veterans Affairs (Merit Review Awards B6453R and A6779I); Doris Duke Charitable Foundation, Craig H. Neilsen Foundation, MGH-Deane Institute for Integrated Research on Atrial Fibrillation and Stroke, and the Katie Samson Foundation. The pilot clinical trial into which participant S3 was recruited was sponsored in part by Cyberkinetics Neurotechnology Systems (CKI). The BrainGate clinical trial is directed by Massachusetts General Hospital. NR 28 TC 4 Z9 4 U1 2 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD OCT 30 PY 2014 VL 236 BP 58 EP 67 DI 10.1016/j.jneumeth.2014.08.004 PG 10 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AR2CH UT WOS:000343390700008 PM 25128256 ER PT J AU Viale, A Pettazzoni, P Lyssiotis, CA Ying, HQ Sanchez, N Marchesini, M Carugo, A Green, T Seth, S Giuliani, V Kost-Alimova, M Muller, F Colla, S Nezi, L Genovese, G Deem, AK Kapoor, A Yao, WT Brunetto, E Kang, Y Yuan, M Asara, JM Wang, YA Heffernan, TP Kimmelman, AC Wang, HM Fleming, JB Cantley, LC DePinho, RA Draetta, GF AF Viale, Andrea Pettazzoni, Piergiorgio Lyssiotis, Costas A. Ying, Haoqiang Sanchez, Nora Marchesini, Matteo Carugo, Alessandro Green, Tessa Seth, Sahil Giuliani, Virginia Kost-Alimova, Maria Muller, Florian Colla, Simona Nezi, Luigi Genovese, Giannicola Deem, Angela K. Kapoor, Avnish Yao, Wantong Brunetto, Emanuela Kang, Ya'an Yuan, Min Asara, John M. Wang, Y. Alan Heffernan, Timothy P. Kimmelman, Alec C. Wang, Huamin Fleming, Jason B. Cantley, Lewis C. DePinho, Ronald A. Draetta, Giulio F. TI Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function SO NATURE LA English DT Article ID STEM-CELLS; TUMOR-GROWTH; METABOLISM; INHIBITION; LEUKEMIA; AUTOPHAGY; GLUCOSE; INDUCTION; MELANOMA; IMATINIB AB Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in western countries, with a median survival of 6 months and an extremely low percentage of long-term surviving patients. KRAS mutations are known to be a driver event of PDAC(1), but targeting mutant KRAS has proved challenging(2). Targeting oncogene-driven signalling pathways is a clinically validated approach for several devastating diseases(3,4). Still, despite marked tumour shrinkage, the frequency of relapse indicates that a fraction of tumour cells survives shut down of oncogenic signalling(5,6). Here we explore the role of mutant KRAS in PDAC maintenance using a recently developed inducible mouse model of mutated Kras(1) (Kras(G12D), herein KRas) in a p53(LoxP/WT) background. We demonstrate that a subpopulation of dormant tumour cells surviving oncogene ablation (surviving cells) and responsible for tumour relapse has features of cancer stem cells and relies on oxidative phosphorylation for survival. Transcriptomic and metabolic analyses of surviving cells reveal prominent expression of genes governing mitochondrial function, autophagy and lysosome activity, as well as a strong reliance on mitochondrial respiration and a decreased dependence on glycolysis for cellular energetics. Accordingly, surviving cells show high sensitivity to oxidative phosphorylation inhibitors, which can inhibit tumour recurrence. Our integrated analyses illuminate a therapeutic strategy of combined targeting of the KRAS pathway and mitochondrial respiration to manage pancreatic cancer. C1 [Viale, Andrea; Pettazzoni, Piergiorgio; Ying, Haoqiang; Sanchez, Nora; Marchesini, Matteo; Carugo, Alessandro; Green, Tessa; Muller, Florian; Colla, Simona; Nezi, Luigi; Genovese, Giannicola; Deem, Angela K.; Kapoor, Avnish; Yao, Wantong; Wang, Y. Alan; Draetta, Giulio F.] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Viale, Andrea; Pettazzoni, Piergiorgio; Sanchez, Nora; Marchesini, Matteo; Carugo, Alessandro; Green, Tessa; Nezi, Luigi; Yao, Wantong; Draetta, Giulio F.] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Lyssiotis, Costas A.; Cantley, Lewis C.] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Carugo, Alessandro] European Inst Oncol, Dept Expt Oncol, I-20139 Milan, Italy. [Seth, Sahil; Giuliani, Virginia; Kost-Alimova, Maria; Heffernan, Timothy P.] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA. [Brunetto, Emanuela] Ist Sci San Raffaele, Pathol Unit, I-20132 Milan, Italy. [Kang, Ya'an; Fleming, Jason B.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Yuan, Min; Asara, John M.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Dept Med, Boston, MA 02115 USA. [Kimmelman, Alec C.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02215 USA. [Wang, Huamin] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [DePinho, Ronald A.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. RP Viale, A (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. EM aviale@mdanderson.org; gdraetta@mdanderson.org RI Cantley, Lewis/D-1800-2014; OI Cantley, Lewis/0000-0002-1298-7653; Colla, Simona/0000-0001-6583-8910; Seth, Sahil/0000-0003-4579-3959 FU Cancer Center Core Grant [CA16672]; National Cancer Institute (NCI) [CA016672]; MDACC Flow Cytometry and Cellular Imaging Core Facility - NCI [P30CA16672]; FACS; Hirshberg Foundation for Pancreatic Cancer Research; Harvard Stem Cell Institute; Sheikh Ahmed Center for Pancreatic Cancer Research; American Italian Cancer Foundation; National Institutes of Health (NIH) [P01CA117969]; NIH/NCI [P01CA120964]; Viragh Family Foundation FX We thank A. Divakaruni, J. Dunn, C. Smith, K. McGirr and D. Ferrick for their support with the Seahorse Bioscience XF96 Analyser; T. Tieu for vector cloning and J. Kovacs for support with the YSI analyser; J. D. Lechleiter for the protocol to measure mitochondrial potential in vivo; H. Sandoval, C. Tacchetti, M. E. Di Francesco, J. Marszalek and P. Jones for discussions and suggestions; K. Dunner Jr and the High Resolution Electron Microscopy Facility at the MD Anderson Cancer Center (MDACC) for TEM (Cancer Center Core Grant CA16672); W. N. Hittelman and the Center for Targeted Therapy for confocal microscopy; the Dana-Farber Cancer Institute Microarray Core Facility for Affymetrix expression profiling and the MDACC Sequencing and Microarray Facility (SMF) funded by National Cancer Institute (NCI) grant CA016672 (SMF) for exome sequencing; the MDACC Flow Cytometry and Cellular Imaging Core Facility supported by grant NCI#P30CA16672 for flow cytometers and FACS; D. Jayanta for providing GFP-LC3 constructs; B. Perrazzona, U. Varadarajan and R. Dewan for lab management; and S. Jiang for assistance in maintenance of mouse colonies. A. V. is thankful to A. Fantino, S. Rapi, V. Giuliani and P. Viale for their continuous support. This study was supported by grants from the Hirshberg Foundation for Pancreatic Cancer Research to A. V., Harvard Stem Cell Institute to R. A. D. and A. V., Sheikh Ahmed Center for Pancreatic Cancer Research to G. F. D., T. P. H. and A. V., American Italian Cancer Foundation to G. F. D., National Institutes of Health (NIH) P01CA117969 to R. A. D., NIH/NCI P01CA120964 to J. M. A., The Viragh Family Foundation to J. B. F.; C. A. L. is a Pancreatic Cancer Action Network-AACR Pathway to Leadership Fellow. NR 29 TC 174 Z9 178 U1 5 U2 80 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD OCT 30 PY 2014 VL 514 IS 7524 BP 628 EP + DI 10.1038/nature13611 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR8BW UT WOS:000343801500049 PM 25119024 ER PT J AU Song, ZR Rose, S Safran, DG Landon, BE Day, MP Chernew, ME AF Song, Zirui Rose, Sherri Safran, Dana G. Landon, Bruce E. Day, Matthew P. Chernew, Michael E. TI Changes in Health Care Spending and Quality 4 Years into Global Payment SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DELIVERY-SYSTEM REFORM; ALTERNATIVE QUALITY; ACCOUNTABLE CARE; RISK ADJUSTMENT; MEDICAL HOME; CONTRACT; ORGANIZATIONS; PAYER; MASSACHUSETTS; PATIENT AB BACKGROUND Spending and quality under global budgets remain unknown beyond 2 years. We evaluated spending and quality measures during the first 4 years of the Blue Cross Blue Shield of Massachusetts Alternative Quality Contract (AQC). METHODS We compared spending and quality among enrollees whose physician organizations entered the AQC from 2009 through 2012 with those among persons in control states. We studied spending changes according to year, category of service, site of care, experience managing risk contracts, and price versus utilization. We evaluated process and outcome quality. RESULTS In the 2009 AQC cohort, medical spending on claims grew an average of $62.21 per enrollee per quarter less than it did in the control cohort over the 4-year period (P<0.001). This amount is equivalent to a 6.8% savings when calculated as a proportion of the average post-AQC spending level in the 2009 AQC cohort. Analogously, the 2010, 2011, and 2012 cohorts had average savings of 8.8% (P<0.001), 9.1% (P<0.001), and 5.8% (P = 0.04), respectively, by the end of 2012. Claims savings were concentrated in the outpatient-facility setting and in procedures, imaging, and tests, explained by both reduced prices and reduced utilization. Claims savings were exceeded by incentive payments to providers during the period from 2009 through 2011 but exceeded incentive payments in 2012, generating net savings. Improvements in quality among AQC cohorts generally exceeded those seen elsewhere in New England and nationally. CONCLUSIONS As compared with similar populations in other states, Massachusetts AQC enrollees had lower spending growth and generally greater quality improvements after 4 years. Although other factors in Massachusetts may have contributed, particularly in the later part of the study period, global budget contracts with quality incentives may encourage changes in practice patterns that help reduce spending and improve quality. C1 [Song, Zirui] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Song, Zirui; Rose, Sherri; Landon, Bruce E.; Chernew, Michael E.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Safran, Dana G.; Day, Matthew P.] Tufts Univ, Sch Med, Blue Cross Blue Shield Massachusetts, Boston, MA 02111 USA. [Safran, Dana G.] Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. [Landon, Bruce E.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Song, Zirui; Chernew, Michael E.] Natl Bur Econ Res, Cambridge, MA 02138 USA. RP Song, ZR (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM zirui_song@post.harvard.edu FU Commonwealth Fund; National Institute on Aging [F30-AG039175]; National Bureau of Economic Research Fellowship in Aging and Health Economics [T32-AG000186]; Charles H. Hood Foundation FX Supported by a grant from the Commonwealth Fund (to Dr. Chernew), a predoctoral M.D./Ph.D. National Research Service Award from the National Institute on Aging (F30-AG039175, to Dr. Song), a grant from the National Bureau of Economic Research Fellowship in Aging and Health Economics (T32-AG000186, to Dr. Song), and a grant from the Charles H. Hood Foundation (to Dr. Chernew). NR 36 TC 59 Z9 59 U1 2 U2 13 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 OCT 30 PY 2014 VL 371 IS 18 BP 1704 EP 1714 DI 10.1056/NEJMsa1404026 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AR7OG UT WOS:000343768500008 PM 25354104 ER PT J AU Ascierto, PA Grimaldi, AM Anderson, AC Bifulco, C Cochran, A Garbe, C Eggermont, AM Faries, M Ferrone, S Gershenwald, JE Gajewski, TF Halaban, R Hodi, FS Kefford, R Kirkwood, JM Larkin, J Leachman, S Maio, M Marais, R Masucci, G Melero, I Palmieri, G Puzanov, I Ribas, A Saenger, Y Schilling, B Seliger, B Stroncek, D Sullivan, R Testori, A Wang, E Ciliberto, G Mozzillo, N Marincola, FM Thurin, M AF Ascierto, Paolo A. Grimaldi, Antonio M. Anderson, Ana Carrizosa Bifulco, Carlo Cochran, Alistair Garbe, Claus Eggermont, Alexander M. Faries, Mark Ferrone, Soldano Gershenwald, Jeffrey E. Gajewski, Thomas F. Halaban, Ruth Hodi, F. Stephen Kefford, Richard Kirkwood, John M. Larkin, James Leachman, Sancy Maio, Michele Marais, Richard Masucci, Giuseppe Melero, Ignacio Palmieri, Giuseppe Puzanov, Igor Ribas, Antoni Saenger, Yvonne Schilling, Bastian Seliger, Barbara Stroncek, David Sullivan, Ryan Testori, Alessandro Wang, Ena Ciliberto, Gennaro Mozzillo, Nicola Marincola, Francesco M. Thurin, Magdalena TI Future perspectives in melanoma research: meeting report from the "Melanoma Bridge", Napoli, December 5th-8th 2013 SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID STAGE-IV MELANOMA; PRIMARY CUTANEOUS MELANOMA; IMPROVES EARLY-DETECTION; ADOPTIVE CELL TRANSFER; METASTATIC MELANOMA; TUMOR MICROENVIRONMENT; ACQUIRED-RESISTANCE; MEK INHIBITION; BRAF INHIBITOR; MONOCLONAL-ANTIBODIES AB The fourth "Melanoma Bridge Meeting" took place in Naples, December 5 to 8th, 2013. The four topics discussed at this meeting were: Diagnosis and New Procedures, Molecular Advances and Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent research in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors, like BRAF and MEK inhibitors, as well as other signaling pathways inhibitors, are being tested in metastatic melanoma either as monotherapy or in combination, and have yielded promising results. Improved survival rates have also been observed with immune therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e. g., Tim-3) or immune stimulating (e. g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in melanoma as well. This meeting's specific focus was on advances in targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. Significant consideration was given to issues surrounding the development of novel therapeutic targets as further study of patterns of resistance to both immunologic and targeted drugs are paramount to future drug development to guide existing and future therapies. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma. C1 [Ascierto, Paolo A.; Grimaldi, Antonio M.; Ciliberto, Gennaro; Mozzillo, Nicola] Fdn G Pascale, Ist Nazl Tumori, Naples, Italy. [Anderson, Ana Carrizosa] Harvard Univ, Sch Med, Ctr Neurol Dis, Boston, MA USA. [Bifulco, Carlo] Providence Canc Ctr, Earle A Chiles Res Inst, Portland, OR USA. [Cochran, Alistair] Univ Calif Los Angeles, John Wayne Canc Inst, David Geffen Sch Med, Dept Pathol & Lab Med, Santa Monica, CA USA. [Cochran, Alistair] Univ Calif Los Angeles, John Wayne Canc Inst, David Geffen Sch Med, Dept Surg, Santa Monica, CA USA. [Garbe, Claus] Univ Tubingen, Dept Dermatol, Ctr Dermato Oncol, Tubingen, Germany. [Eggermont, Alexander M.] Canc Inst Gustave Roussy, Villejuif, France. [Faries, Mark] John Wayne Canc Inst, Donald L Morton Melanoma Res Program, Santa Monica, CA USA. [Ferrone, Soldano] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA USA. [Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Gajewski, Thomas F.] Univ Chicago Med, Immunol & Canc Program, Dept Med, Chicago, IL USA. [Gajewski, Thomas F.] Univ Chicago Med, Immunol & Canc Program, Dept Pathol, Chicago, IL USA. [Halaban, Ruth] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06510 USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kefford, Richard] Univ Sydney, Westmead Millennium Inst, Westmead Inst Canc Res, Sydney, NSW 2006, Australia. [Kefford, Richard] Univ Sydney, Melanoma Inst Australia, Sydney, NSW 2006, Australia. [Kirkwood, John M.] Univ Pittsburgh, Sch Med, Div Hematol Oncol, Dept Med, Pittsburgh, PA USA. [Kirkwood, John M.] Univ Pittsburgh, Sch Med, Div Hematol Oncol, Dept Dermatol, Pittsburgh, PA USA. [Kirkwood, John M.] Univ Pittsburgh, Sch Med, Div Hematol Oncol, Dept Translat Sci, Pittsburgh, PA USA. [Kirkwood, John M.] Pittsburgh Canc Inst, Melanoma Program, Pittsburgh, PA 15213 USA. [Larkin, James] Royal Marsden NHS Fdn Trust, London, England. [Leachman, Sancy] Oregon Hlth & Sci Univ, Dept Dermatol, Portland, OR USA. [Maio, Michele] Ist Toscano Tumori, Univ Hosp Siena, Dept Oncol, Siena, Italy. [Marais, Richard] Paterson Inst Canc Res, Mol Oncol Grp, Manchester M20 4BX, Lancs, England. [Masucci, Giuseppe] Karolinska Hosp, Dept Oncol Pathol, S-10401 Stockholm, Sweden. [Melero, Ignacio] Univ Navarra Clin, Ctr Invest Med Aplicada, Navarra, Spain. [Palmieri, Giuseppe] CNR, Inst Biomol Chem, Unit Canc Genet, Sassari, Italy. [Puzanov, Igor] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Ribas, Antoni] Univ Calif Los Angeles, David Geffen Sch Med, JCCC, Tumor Immunol Program, Los Angeles, CA 90095 USA. [Saenger, Yvonne] Icahn Sch Med Mt Sinai, Dept Dermatol, Tisch Canc Inst, Div Hematol & Oncol, New York, NY 10029 USA. [Schilling, Bastian] Univ Duisburg Essen, West German Canc Ctr, Univ Hosp, Dept Dermatol, Essen, Germany. [Seliger, Barbara] Univ Halle Wittenberg, Inst Med Immunol, D-06108 Halle, Germany. [Stroncek, David] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Sullivan, Ryan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Melanoma,Canc Ctr, Boston, MA USA. [Testori, Alessandro] Ist Europeo Oncol, Milan, Italy. [Wang, Ena] Sidra Med & Res Ctr, Div Chief Translat Med, Doha, Qatar. [Marincola, Francesco M.] Sidra Med & Res Ctr, Doha, Qatar. [Thurin, Magdalena] NCI, Canc Diag Program, NIH, Bethesda, MD 20892 USA. [Schilling, Bastian] German Canc Consortium DKTK, Heidelberg, Germany. RP Ascierto, PA (reprint author), Fdn G Pascale, Ist Nazl Tumori, Naples, Italy. EM paolo.ascierto@gmail.com; thurinm@mail.nih.gov OI Masucci, Giuseppe/0000-0002-9583-2306; Ciliberto, Gennaro/0000-0003-2851-8605; Palmieri, Giuseppe/0000-0002-4350-2276; MELERO BERMEJO, IGNACIO/0000-0002-1360-348X FU Fondazione Melanoma Onlus; Society of ImmunoTherapy of Cancer (SITC) FX The meeting was supported by Fondazione Melanoma Onlus and the Society of ImmunoTherapy of Cancer (SITC). A special thanks to 3P Solution of Napoli for their support and cooperation in organizing the meeting and to Michael Hoetzel for providing us with the group picture from the meeting. NR 124 TC 6 Z9 6 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD OCT 28 PY 2014 VL 12 AR 277 DI 10.1186/s12967-014-0277-z PG 29 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AT8FX UT WOS:000345170400001 PM 25348889 ER PT J AU McArdle, PF Kittner, SJ Ay, H Brown, RD Meschia, JF Rundek, T Wassertheil-Smoller, S Woo, D Andsberg, G Biffi, A Brenner, DA Cole, JW Corriveau, R de Bakker, PIW Delavaran, H Dichgans, M Grewal, RP Gwinn, K Huq, M Jern, C Jimenez-Conde, J Jood, K Kaplan, RC Katschnig, P Katsnelson, M Labovitz, DL Lemmens, R Li, LX Lindgren, A Markus, HS Peddareddygari, LR Pedersen, A Pera, J Redfors, P Roquer, J Rosand, J Rost, NS Rothwell, PM Sacco, RL Sharma, P Slowik, A Sudlow, C Thijs, V Tiedt, S Valenti, R Worrall, BB AF McArdle, Patrick F. Kittner, Steven J. Ay, Hakan Brown, Robert D., Jr. Meschia, James F. Rundek, Tatjana Wassertheil-Smoller, Sylvia Woo, Daniel Andsberg, Gunnar Biffi, Alessandro Brenner, David A. Cole, John W. Corriveau, Roderick de Bakker, Paul I. W. Delavaran, Hossein Dichgans, Martin Grewal, Raji P. Gwinn, Katrina Huq, Mohammed Jern, Christina Jimenez-Conde, Jordi Jood, Katarina Kaplan, Robert C. Katschnig, Petra Katsnelson, Michael Labovitz, Daniel L. Lemmens, Robin Li, Linxin Lindgren, Arne Markus, Hugh S. Peddareddygari, Leema R. Pedersen, Annie Pera, Joanna Redfors, Petra Roquer, Jaume Rosand, Jonathan Rost, Natalia S. Rothwell, Peter M. Sacco, Ralph L. Sharma, Pankaj Slowik, Agnieszka Sudlow, Cathie Thijs, Vincent Tiedt, Steffen Valenti, Raffaella Worrall, Bradford B. CA NINDS SiGN Study TI Agreement between TOAST and CCS ischemic stroke classification The NINDS SiGN Study SO NEUROLOGY LA English DT Article ID CAUSATIVE CLASSIFICATION; SYSTEM; RELIABILITY; SUBTYPES; TRIAL AB Objective: The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems. Methods: Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems. Results: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; kappa = 0.59, 95% confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (kappa = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (kappa = 0.56, 95% CI 0.54-0.58). Conclusion: Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner. C1 [McArdle, Patrick F.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, College Pk, MD USA. [Kittner, Steven J.; Cole, John W.; Huq, Mohammed] Univ Maryland, College Pk, MD USA. [Ay, Hakan] Harvard Univ, Massachusetts Gen Hosp, Dept Neurol, Med Sch, Cambridge, MA 02138 USA. [Ay, Hakan] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Med Sch, Cambridge, MA 02138 USA. [Brown, Robert D., Jr.] Mayo Clin, Rochester, MN USA. [Meschia, James F.] Mayo Clin Florida, Jacksonville, FL USA. [Rundek, Tatjana; Katsnelson, Michael; Sacco, Ralph L.] Univ Miami, Coral Gables, FL 33124 USA. [Wassertheil-Smoller, Sylvia; Kaplan, Robert C.; Labovitz, Daniel L.] Albert Einstein Coll Med, Bronx, NY USA. [Woo, Daniel] Univ Cincinnati, Cincinnati, OH 45221 USA. [Andsberg, Gunnar; Delavaran, Hossein; Lindgren, Arne] Skane Univ Hosp, Lund, Sweden. [Biffi, Alessandro; Rosand, Jonathan; Rost, Natalia S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Biffi, Alessandro; Rosand, Jonathan; Rost, Natalia S.] Broad Inst, Cambridge, MA USA. [Brenner, David A.] Univ Alabama Birmingham, Birmingham, AL USA. [Corriveau, Roderick; Gwinn, Katrina] NINDS, NIH, Bethesda, MD 20892 USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Dichgans, Martin; Tiedt, Steffen] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany. [Dichgans, Martin] Munich Cluster Syst Neurol SyNergy, Munich, Germany. [Grewal, Raji P.; Peddareddygari, Leema R.] St Francis Med Ctr, Neurosci Inst, Lynwood, CA USA. [Jern, Christina; Jood, Katarina; Pedersen, Annie; Redfors, Petra] Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden. [Jimenez-Conde, Jordi; Roquer, Jaume] IMIM Hosp Univ del Mar, Barcelona, Spain. [Katschnig, Petra] Med Univ Graz, Graz, Austria. [Lemmens, Robin; Thijs, Vincent] VIB, Neurobiol Lab, Vesalius Res Ctr, Leuven, Belgium. [Lemmens, Robin; Thijs, Vincent] Univ Leuven KU Leuven, Expt Neurol Dept Neurosci, Louvain, Belgium. [Lemmens, Robin; Thijs, Vincent] Univ Leuven KU Leuven, Leuven Res Inst Neurosci & Dis LIND, Louvain, Belgium. [Lemmens, Robin; Thijs, Vincent] Univ Hosp Leuven, Dept Neurol, Louvain, Belgium. [Li, Linxin] Univ Oxford, Oxford OX1 2JD, England. [Lindgren, Arne] Lund Univ, S-22100 Lund, Sweden. [Markus, Hugh S.; Valenti, Raffaella] St Georges Univ London, London, England. [Pera, Joanna; Slowik, Agnieszka] Jagiellonian Univ, Coll Med, PL-31007 Krakow, Poland. [Rothwell, Peter M.] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England. [Rothwell, Peter M.] John Radcliffe Hosp, Oxford OX3 9DU, England. [Sharma, Pankaj] Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. [Sudlow, Cathie] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. [Worrall, Bradford B.] Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA 22908 USA. [Worrall, Bradford B.] Univ Virginia Hlth Syst, Dept Hlth Evaluat Sci, Charlottesville, VA USA. RP Worrall, BB (reprint author), Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA 22908 USA. EM bbw9r@virginia.edu RI de Bakker, Paul/B-8730-2009; Thijs, Vincent/C-3647-2009; JIMENEZ-CONDE, JORDI/C-1941-2012 OI de Bakker, Paul/0000-0001-7735-7858; Thijs, Vincent/0000-0002-6614-8417; FU National Institute of Neurological Disorders and Stroke (NINDS) [U01 NS069208] FX The SiGN Network was funded by a cooperative agreement grant from the National Institute of Neurological Disorders and Stroke (NINDS): U01 NS069208. Funding for network members is presented in appendix e-1 on the Neurology (R) Web site at Neurology.org. NR 15 TC 8 Z9 8 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 28 PY 2014 VL 83 IS 18 BP 1653 EP 1660 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AT3RU UT WOS:000344852200015 PM 25261504 ER PT J AU Tan, CO Meehan, WP Iverson, GL Taylor, JA AF Tan, Can Ozan Meehan, William P., III Iverson, Grant L. Taylor, J. Andrew TI Cerebrovascular regulation, exercise, and mild traumatic brain injury SO NEUROLOGY LA English DT Review ID CEREBRAL-BLOOD-FLOW; CORTICAL IMPACT INJURY; HEAD-INJURY; TRANSCRANIAL DOPPLER; MYOGENIC MECHANISMS; DYNAMIC EXERCISE; CO2 REACTIVITY; CARBON-DIOXIDE; NITRIC-OXIDE; AUTOREGULATION AB A substantial number of people who sustain a mild traumatic brain injury report persistent symptoms. Most common among these symptoms are headache, dizziness, and cognitive difficulties. One possible contributor to sustained symptoms may be compromised cerebrovascular regulation. In addition to injury-related cerebrovascular dysfunction, it is possible that prolonged rest after mild traumatic brain injury leads to deconditioning that may induce physiologic changes in cerebral blood flow control that contributes to persistent symptoms in some people. There is some evidence that exercise training may reduce symptoms perhaps because it engages an array of cerebrovascular regulatory mechanisms. Unfortunately, there is very little work on the degree of impairment in cerebrovascular control that may exist in patients with mild traumatic brain injury, and there are no published studies on the subacute phase of recovery from this injury. This review aims to integrate the current knowledge of cerebrovascular mechanisms that might underlie persistent symptoms and seeks to synthesize these data in the context of exploring aerobic exercise as a feasible intervention to treat the underlying pathophysiology. C1 [Tan, Can Ozan; Taylor, J. Andrew] Harvard Univ, Cardiovasc Res Lab, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil,Med Sch, Cambridge, MA 02138 USA. [Meehan, William P., III] Harvard Univ, Micheli Ctr Sports Injury Prevent, Boston Childrens Hosp, Div Sports Med,Dept Pediat & Orthoped,Med Sch, Cambridge, MA 02138 USA. [Iverson, Grant L.] Harvard Univ, Dept Phys Med & Rehabil, Massachusetts Gen Hosp Sport Concuss Clin, Med Sch,Spaulding Rehabil Hosp,Red Sox Fdn, Cambridge, MA 02138 USA. [Iverson, Grant L.] Massachusetts Gen Hosp, Home Base Program, Boston, MA 02114 USA. RP Tan, CO (reprint author), Harvard Univ, Cardiovasc Res Lab, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil,Med Sch, Cambridge, MA 02138 USA. EM cotan@partners.org RI Tan, Can Ozan/E-2598-2016 OI Tan, Can Ozan/0000-0001-9673-9907 FU NFL Players Association FX Dr. Meehan is supported by a grant from the NFL Players Association. NR 60 TC 11 Z9 12 U1 2 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 28 PY 2014 VL 83 IS 18 BP 1665 EP 1672 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA AT3RU UT WOS:000344852200017 PM 25274845 ER PT J AU Miranda, M Walker, RH Bustamante, ML AF Miranda, Marcelo Walker, Ruth H. Bustamante, M. L. TI Electronic message ataxia in multiple system atrophy SO NEUROLOGY LA English DT Editorial Material C1 [Miranda, Marcelo] Clin Las Condes, Dept Neurol, Santiago, Chile. [Walker, Ruth H.] James J Peters Vet Affairs Med Ctr, Dept Neurol, Bronx, NY USA. [Bustamante, M. L.] Univ Chile, Fac Med, Santiago, Chile. RP Miranda, M (reprint author), Clin Las Condes, Dept Neurol, Santiago, Chile. EM marcelomirandac@gmail.com RI Bustamante, Maria Leonor/H-3728-2014 OI Bustamante, Maria Leonor/0000-0001-9071-2463 NR 2 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 28 PY 2014 VL 83 IS 18 BP 1677 EP 1677 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA AT3RU UT WOS:000344852200020 PM 25349273 ER PT J AU Berkowitz, AL Baker, JM Miller, JJ Greenberg, SM AF Berkowitz, Aaron L. Baker, Jessica M. Miller, Julie J. Greenberg, Steven M. TI Mystery Case: Cerebral amyloid angiopathy-related inflammation SO NEUROLOGY LA English DT Editorial Material C1 [Berkowitz, Aaron L.; Baker, Jessica M.; Miller, Julie J.] Harvard Univ, Brigham & Womens Hosp, Dept Neurol, Sch Med, Boston, MA 02115 USA. [Baker, Jessica M.; Miller, Julie J.; Greenberg, Steven M.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Berkowitz, AL (reprint author), Harvard Univ, Brigham & Womens Hosp, Dept Neurol, Sch Med, Boston, MA 02115 USA. EM aberkowitz3@partners.org NR 2 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 28 PY 2014 VL 83 IS 18 BP 1678 EP 1679 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AT3RU UT WOS:000344852200021 PM 25349274 ER PT J AU Roy, R Zurakowski, D Wischhusen, J Frauenhoffer, C Hooshmand, S Kulke, M Moses, MA AF Roy, R. Zurakowski, D. Wischhusen, J. Frauenhoffer, C. Hooshmand, S. Kulke, M. Moses, M. A. TI Urinary TIMP-1 and MMP-2 levels detect the presence of pancreatic malignancies SO BRITISH JOURNAL OF CANCER LA English DT Article DE MMP-2; TIMP-1; urinary biomarker; pancreatic cancer ID TISSUE INHIBITOR; CHROMOGRANIN-A; NEUROENDOCRINE TUMORS; HIGH-RISK; MATRIX METALLOPROTEINASES; CLINICAL-SIGNIFICANCE; PROGNOSTIC-FACTORS; MOLECULAR MARKERS; CANCER; EXPRESSION AB Background: A majority of patients with pancreatic malignancies, including both pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumours (pNETs), present with advanced disease due to a lack of specific symptoms and current diagnostic limitations, making this disease extremely difficult to detect. Our goal was to determine whether urinary matrix metalloproteases (uMMPs) and/or their endogenous inhibitors, urinary tissue inhibitor of metalloproteases (uTIMPs), could be detected in the urine of patients with pancreatic malignancies and whether they may serve as independent predictors of disease status. Methods: Retrospective analyses of urine samples (n = 139) from PDAC and pNET patients as well as age-and sex-matched controls were conducted. Urinary MMP-2 and uTIMP-1 levels were determined using ELISA and zymography. Biomarker expression in tumour and normal pancreatic tissues was analysed via immunohistochemistry (IHC). Results: Multivariable logistic regression analyses indicated that, when controlling for age and sex, uMMP-2 (P<0.0001) and uTIMP-1 (P<0.0001) but not uMMP-9, were significant independent predictors for distinguishing between PDAC patients and healthy controls. Our data also indicated that uMMP-2 was an independent predictor of the presence of pNET. In addition, uTIMP1 levels could differentiate the two cancer groups, PDAC and pNET, respectively. Immunohistochemistry analysis confirmed that MMP-2 and TIMP-1 protein expression is significantly upregulated in PDAC tissue compared with the normal pancreas. Conclusions: Taken together, our results suggest that the detection of uMMP-2 and uTIMP-1 may have diagnostic value in the detection of pancreatic malignancies and that uTIMP-1 m ay be useful in distinguishing between pancreatic adenocarcinoma and neuroendocrine tumours. C1 [Roy, R.; Wischhusen, J.; Moses, M. A.] Boston Childrens Hosp, Program Vasc Biol, Boston, MA USA. [Roy, R.; Wischhusen, J.; Moses, M. A.] Boston Childrens Hosp, Dept Surg, Boston, MA USA. [Zurakowski, D.] Boston Childrens Hosp, Dept Anesthesia, Boston, MA USA. [Frauenhoffer, C.; Hooshmand, S.; Kulke, M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Moses, MA (reprint author), Boston Childrens Hosp, Program Vasc Biol, Boston, MA USA. EM marsha.moses@childrens.harvard.edu FU Advanced Medical Research Foundation; NIH [PO1 CA45548, NIH R01 CA118764, R01 CA 151532-01A1, 5P50CA 127003-5] FX This work is dedicated to the memory of our beloved mentor, the late M Judah Folkman, MD. The authors remain extremely grateful for his enthusiastic interest in this work and for many helpful discussions and suggestions. This work was supported by the Advanced Medical Research Foundation, NIH PO1 CA45548, NIH R01 CA118764, NIH grants R01 CA 151532-01A1 and 5P50CA 127003-5 ( Gastrointestinal Cancer SPORE). We thank Kristin Johnson, Medical Graphics Core Director of the Vascular Biology Program for assistance with the figures. NR 56 TC 12 Z9 13 U1 0 U2 11 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 OCT 28 PY 2014 VL 111 IS 9 BP 1772 EP 1779 DI 10.1038/bjc.2014.462 PG 8 WC Oncology SC Oncology GA AS9NF UT WOS:000344568600014 PM 25137018 ER PT J AU Scirica, BM Braunwald, E Raz, I Cavender, MA Morrow, DA Jarolim, P Udell, JA Mosenzon, O Im, K Umez-Eronini, AA Pollack, PS Hirshberg, B Frederich, R Lewis, BS McGuire, DK Davidson, J Steg, G Bhatt, DL AF Scirica, Benjamin M. Braunwald, Eugene Raz, Itamar Cavender, Matthew A. Morrow, David A. Jarolim, Petr Udell, Jacob A. Mosenzon, Ofri Im, KyungAh Umez-Eronini, Amarachi A. Pollack, Pia S. Hirshberg, Boaz Frederich, Robert Lewis, Basil S. McGuire, Darren K. Davidson, Jaime Steg, Ph. Gabriel Bhatt, Deepak L. CA SAVOR-TIMI 53 Steering Comm TI Heart Failure, Saxagliptin, and Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial SO CIRCULATION LA English DT Article DE diabetes mellitus; heart failure; saxagliptin ID BLOOD-GLUCOSE CONTROL; ACUTE CORONARY SYNDROME; CARDIOVASCULAR OUTCOMES; MYOCARDIAL-INFARCTION; VASCULAR OUTCOMES; CLINICAL-TRIALS; TYPE-2; METFORMIN; EVENTS; DEATH AB Background-Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point. Methods and Results-A total of 16 492 patients with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07-1.51; P=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15-1.88; P=0.002), with no significant difference thereafter (time-varying interaction, P=0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate <= 60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin (P for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups. Conclusions-In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease. C1 [Scirica, Benjamin M.; Braunwald, Eugene; Cavender, Matthew A.; Morrow, David A.; Im, KyungAh; Umez-Eronini, Amarachi A.; Bhatt, Deepak L.] Brigham & Womens Hosp, Cardiovasc Div, Thrombolysis Myocardial Infarct TIMI Study Grp, Boston, MA 02115 USA. [Jarolim, Petr] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Raz, Itamar; Mosenzon, Ofri] Hadassah Hebrew Univ Hosp, Div Internal Med, Diabet Unit, Jerusalem, Israel. [Udell, Jacob A.] Univ Toronto, Womens Coll Hosp, Cardiovasc Div, Toronto, ON, Canada. Univ Toronto, Toronto Gen Hosp, Toronto, ON M5G 1L7, Canada. [Pollack, Pia S.; Hirshberg, Boaz] AstraZeneca Res & Dev, Gaithersburg, MD USA. [Frederich, Robert] Bristol Myers Squibb Co, Princeton, NJ USA. [Lewis, Basil S.] Technion Israel Inst Technol, Cardiovasc Res Inst, Lady Davis Carmel Med Ctr, Haifa, Israel. Technion Israel Inst Technol, Ruth & Bruce Rappaport Sch Med, Haifa, Israel. [McGuire, Darren K.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Davidson, Jaime] Univ Texas SW Med Ctr Dallas, Div Endocrinol, Dept Internal Med, Dallas, TX 75390 USA. [Steg, Ph. Gabriel] Univ Paris Diderot, Dept Hosp Univ FIRE Fibrosis Inflamat Remodelling, Univ Hosp Dept, Inst Natl Sante Rech Med INSERM Unit 1148, Paris, France. Hop Bichat Claude Bernard, AP HP, F-75877 Paris, France. [Steg, Ph. Gabriel] Univ London Imperial Coll Sci Technol & Med, Royal Brompton Hosp, Inst Cardiovasc Med & Sci, London, England. RP Scirica, BM (reprint author), Brigham & Womens Hosp, Cardiovasc Div, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM bscirica@partners.org FU AstraZeneca; Bristol-Myers Squibb; Roche Diagnostics FX SAVOR-TIMI 53 was funded by AstraZeneca and Bristol-Myers Squibb. Biomarker reagents supported by Roche Diagnostics. NR 42 TC 141 Z9 143 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 28 PY 2014 VL 130 IS 18 BP 1579 EP + DI 10.1161/CIRCULATIONAHA.114.010389 PG 35 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AS1TY UT WOS:000344065700011 PM 25189213 ER PT J AU Montazeri, K Unitt, C Foody, JM Harris, JR Partridge, AH Moslehi, J AF Montazeri, Kamaneh Unitt, Christine Foody, JoAnne M. Harris, Jay R. Partridge, Ann H. Moslehi, Javid TI ABCDE Steps to Prevent Heart Disease in Breast Cancer Survivors SO CIRCULATION LA English DT Editorial Material C1 [Montazeri, Kamaneh; Unitt, Christine; Foody, JoAnne M.; Moslehi, Javid] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Harris, Jay R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiat Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. [Partridge, Ann H.; Moslehi, Javid] Harvard Univ, Brigham & Womens Hosp, Sch Med, Adult Survivorship Program,Dana Farber Canc Inst, Boston, MA 02115 USA. [Moslehi, Javid] Vanderbilt Univ Sch Med, Cardiooncol Program, Nashville, TN USA. RP Partridge, AH (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Adult Survivorship Program, 450 Brookline Ave, Boston, MA 02215 USA. EM ahpartridge@partners.org; javid.moslehi@vanderbilt.edu NR 0 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 28 PY 2014 VL 130 IS 18 BP E157 EP E159 DI 10.1161/CIRCULATIONAHA.114.008820 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AS1TY UT WOS:000344065700002 PM 25462826 ER PT J AU Hong, YS Kim, J Pectasides, E Fox, C Hong, SW Ma, QP Wong, GS Peng, S Stachler, MD Thorner, AR Van Hummelen, P Bass, AJ AF Hong, Yong Sang Kim, Jihun Pectasides, Eirini Fox, Cameron Hong, Seung-Woo Ma, Qiuping Wong, Gabrielle S. Peng, Shouyong Stachler, Matthew D. Thorner, Aaron R. Van Hummelen, Paul Bass, Adam J. TI Src Mutation Induces Acquired Lapatinib Resistance in ERBB2-Amplified Human Gastroesophageal Adenocarcinoma Models SO PLOS ONE LA English DT Article ID ADVANCED GASTRIC-CANCER; INHIBITOR SARACATINIB AZD0530; RANDOMIZED PHASE-III; TRASTUZUMAB RESISTANCE; BREAST-CANCER; KINASE INHIBITOR; IN-VIVO; ANTITUMOR-ACTIVITY; COLORECTAL-CANCER; 1ST-LINE THERAPY AB ERBB2-directed therapy is now a routine component of therapy for ERBB2-amplified metastatic gastroesophageal adenocarcinomas. However, there is little knowledge of the mechanisms by which these tumors develop acquired resistance to ERBB2 inhibition. To investigate this question we sought to characterize cell line models of ERBB2-amplified gastroesophageal adenocarcinoma with acquired resistance to ERBB2 inhibition. We generated lapatinib-resistant (LR) subclones from an initially lapatinib-sensitive ERBB2-amplified esophageal adenocarcinoma cell line, OE19. We subsequently performed genomic characterization and functional analyses of resistant subclones with acquired lapatinib resistance. We identified a novel, acquired Src(E527K) mutation in a subset of LR OE19 subclones. Cells with this mutant allele harbour increased Src phosphorylation. Genetic and pharmacologic inhibition of Src resensitized these subclones to lapatinib. Biochemically, Src mutations could activate both the phosphatidylinositol 3-kinase and mitogen activated protein kinase pathways in the lapatinib-treated LR OE19 cells. Ectopic expression of Src (E527K) mutation also was sufficient to induce lapatinib resistance in drug-naive cells. These results indicate that pathologic activation of Src is a potential mechanism of acquired resistance to ERBB2 inhibition in ERBB2-amplified gastroesophageal cancer. Although Src mutation has not been described in primary tumor samples, we propose that the Src hyperactivation should be investigated in the settings of acquired resistance to ERBB2 inhibition in esophageal and gastric adenocarcinoma. C1 [Hong, Yong Sang; Kim, Jihun; Pectasides, Eirini; Fox, Cameron; Ma, Qiuping; Wong, Gabrielle S.; Peng, Shouyong; Stachler, Matthew D.; Bass, Adam J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hong, Yong Sang] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul, South Korea. [Kim, Jihun] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul, South Korea. [Pectasides, Eirini] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Hong, Seung-Woo] Univ Ulsan, Coll Med, Asan Med Ctr, Asan Inst Life Sci, Seoul, South Korea. [Peng, Shouyong; Bass, Adam J.] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA USA. [Stachler, Matthew D.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Thorner, Aaron R.; Van Hummelen, Paul] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Bass, Adam J.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Bass, Adam J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Bass, AJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM adam_bass@dfci.harvard.edu FU American Gastroenterological Association; Anna Fuller Fund; Phi Beta Psi; American Cancer Society; National Institute of Health [P01 CA098101] FX This work was supported by The Funderburg Research Award in Gastric Biology Related to Cancer from the American Gastroenterological Association, The Anna Fuller Fund, Phi Beta Psi, a Research Scholar Grant from the American Cancer Society and P01 CA098101 from the National Institute of Health, all to A.J.B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 3 Z9 3 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 28 PY 2014 VL 9 IS 10 AR e109440 DI 10.1371/journal.pone.0109440 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS0BH UT WOS:000343943100011 PM 25350844 ER PT J AU Pryor, WM Biagioli, M Shahani, N Swarnkar, S Huang, WC Page, DT MacDonald, ME Subramaniam, S AF Pryor, William M. Biagioli, Marta Shahani, Neelam Swarnkar, Supriya Huang, Wen-Chin Page, Damon T. MacDonald, Marcy E. Subramaniam, Srinivasa TI Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington's disease SO SCIENCE SIGNALING LA English DT Article ID AMINO-ACID SUFFICIENCY; SMALL GTPASE RHEB; TSC2 GAP ACTIVITY; R6/2 MOUSE MODEL; P70 S6 KINASE; MUTANT-HUNTINGTIN; MAMMALIAN TARGET; GENE HOMOLOG; RAG GTPASES; STEM-CELLS AB In patients with Huntington's disease (HD), the protein huntingtin (Htt) has an expanded polyglutamine (poly-Q) tract. HD results in early loss of medium spiny neurons in the striatum, which impairs motor and cognitive functions. Identifying the physiological role and molecular functions of Htt may yield insight into HD pathogenesis. We found that Htt promotes signaling by mTORC1 [mechanistic target of rapamycin (mTOR) complex 1] and that this signaling is potentiated by poly-Q-expanded Htt. Knocking out Htt in mouse embryonic stem cells or human embryonic kidney cells attenuated amino acid-induced mTORC1 activity, whereas overexpressing wild-type or poly-Q-expanded Htt in striatal neuronal cells increased basal mTOR activity. Striatal cells expressing endogenous poly-Q-expanded Htt showed an increase in the number and size of mTOR puncta on the perinuclear regions compared to cells expressing wild-type Htt. Pull-down experiments indicated that amino acids stimulated the interaction of Htt and the guanosine triphosphatase (GTPase) Rheb (a protein that stimulates mTOR activity), and that Htt forms a ternary complex with Rheb and mTOR. Pharmacologically inhibiting PI3K (phosphatidylinositol 3-kinase) or knocking down Rheb abrogated mTORC1 activity induced by expression of a poly-Q-expanded amino-terminal Htt fragment. Moreover, striatum-specific deletion of TSC1, encoding tuberous sclerosis 1, a negative regulator of mTORC1, accelerated the onset of motor coordination abnormalities and caused premature death in an HD mouse model. Together, our findings demonstrate that mutant Htt contributes to the pathogenesis of HD by enhancing mTORC1 activity. C1 [Pryor, William M.; Shahani, Neelam; Swarnkar, Supriya; Huang, Wen-Chin; Page, Damon T.; Subramaniam, Srinivasa] Scripps Res Inst Florida, Dept Neurosci, Jupiter, FL 33458 USA. [Biagioli, Marta; MacDonald, Marcy E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Subramaniam, S (reprint author), Scripps Res Inst Florida, Dept Neurosci, Jupiter, FL 33458 USA. EM ssubrama@scripps.edu RI Swarnkar, Supriya/H-8054-2016 OI Swarnkar, Supriya/0000-0001-7596-0215 FU Scripps startup funds; O'Keeffe Neuroscience Scholar Award FX This work was supported by Scripps startup funds (to S. Subramaniam) and O'Keeffe Neuroscience Scholar Award (to W.M.P.). NR 79 TC 14 Z9 14 U1 0 U2 13 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD OCT 28 PY 2014 VL 7 IS 349 AR ra103 DI 10.1126/scisignal.2005633 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AS2ZW UT WOS:000344145900004 PM 25351248 ER PT J AU Umapathy, G El Wakil, A Witek, B Chesler, L Danielson, L Deng, XM Gray, NS Johansson, M Kvarnbrink, S Ruuth, K Schonherr, C Palmer, RH Hallberg, B AF Umapathy, Ganesh El Wakil, Abeer Witek, Barbara Chesler, Louis Danielson, Laura Deng, Xianming Gray, Nathanael S. Johansson, Mikael Kvarnbrink, Samuel Ruuth, Kristina Schonherr, Christina Palmer, Ruth H. Hallberg, Bengt TI The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma SO SCIENCE SIGNALING LA English DT Article ID ACTIVATED PROTEIN-KINASE; SIGNAL-REGULATED KINASE-5; EPIDERMAL-GROWTH-FACTOR; LARGE-CELL LYMPHOMA; ANAPLASTIC LYMPHOMA; LUNG-CANCER; TYROSINE KINASE; N-MYC; GENE; MUTATIONS AB Anaplastic lymphoma kinase (ALK) is an important molecular target in neuroblastoma. Although tyrosine kinase inhibitors abrogating ALK activity are currently in clinical use for the treatment of ALK-positive (ALK(+)) disease, monotherapy with ALK tyrosine kinase inhibitors may not be an adequate solution for ALK(+) neuroblastoma patients. Increased expression of the gene encoding the transcription factor MYCN is common in neuroblastomas and correlates with poor prognosis. We found that the kinase ERK5 [also known as big mitogen-activated protein kinase (MAPK) 1 (BMK1)] is activated by ALK through a pathway mediated by phosphoinositide 3-kinase (PI3K), AKT, MAPK kinase kinase 3 (MEKK3), and MAPK kinase 5 (MEK5). ALK-induced transcription of MYCN and stimulation of cell proliferation required ERK5. Pharmacological or RNA interference-mediated inhibition of ERK5 suppressed the proliferation of neuroblastoma cells in culture and enhanced the antitumor efficacy of the ALK inhibitor crizotinib in both cells and xenograft models. Together, our results indicate that ERK5 mediates ALK-induced transcription of MYCN and proliferation of neuroblastoma, suggesting that targeting both ERK5 and ALK may be beneficial in neuroblastoma patients. C1 [Umapathy, Ganesh; Palmer, Ruth H.; Hallberg, Bengt] Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Med Biochem & Cell Biol, SE-40530 Gothenburg, Sweden. [El Wakil, Abeer; Witek, Barbara; Ruuth, Kristina; Schonherr, Christina; Palmer, Ruth H.] Umea Univ, Dept Mol Biol, S-90187 Umea, Sweden. [Chesler, Louis; Danielson, Laura] Royal Marsden NHS Fdn Trust, Inst Canc Res, Sutton SM2 5NG, Surrey, England. [Deng, Xianming] Xiamen Univ, Sch Life Sci, Xiamen 361005, Fujian, Peoples R China. [Deng, Xianming; Gray, Nathanael S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Johansson, Mikael; Kvarnbrink, Samuel] Umea Univ, Dept Radiat Sci, S-90187 Umea, Sweden. RP Hallberg, B (reprint author), Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Med Biochem & Cell Biol, SE-40530 Gothenburg, Sweden. EM bengt.hallberg@gu.se OI Umapathy, Ganesh/0000-0003-2324-8300; El Wakil, Abeer/0000-0003-2117-0677 FU Swedish Cancer Society [12-0722, 12-0796]; Children's Cancer Foundation [11/020, 13/049]; Swedish Research Council [621-2011-5181, 521-2012-2831]; Lions Cancer Society, Umea [LP13-2012, LP12-1946, AMP13-720]; JC Kempe Foundation FX This study was supported by grants from the Swedish Cancer Society (grant nos. 12-0722 to B.H. and 12-0796 to R.H.P.), the Children's Cancer Foundation (grant nos. 11/020 to B.H. and 13/049 to R.H.P.), the Swedish Research Council (grant nos. 621-2011-5181 to R.H.P. and 521-2012-2831 to B.H.), the Lions Cancer Society, Umea (grant nos. LP13-2012 to B.H., LP12-1946 to R.H.P., and AMP13-720 to A.E.W.), and the JC Kempe Foundation to B.H. and R.H.P. NR 63 TC 17 Z9 17 U1 0 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD OCT 28 PY 2014 VL 7 IS 349 AR ra102 DI 10.1126/scisignal.2005470 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AS2ZW UT WOS:000344145900003 PM 25351247 ER PT J AU Parfenov, M Pedamallu, CS Gehlenborg, N Freeman, SS Danilova, L Bristow, CA Lee, S Hadjipanayis, AG Ivanova, EV Wilkerson, MD Protopopov, A Yang, LX Seth, S Song, XZ Tang, JB Ren, XJ Zhang, JH Pantazi, A Santoso, N Xu, AW Mahadeshwar, H Wheeler, DA Haddad, RI Jung, J Ojesina, AI Issaeva, N Yarbrough, WG Hayes, DN Grandis, JR El-Naggar, AK Meyerson, M Park, PJ Chin, L Seidman, JG Hammerman, PS Kucherlapati, R AF Parfenov, Michael a Pedamallu, Chandra Sekhar bc Gehlenborg, Nils cd Freeman, Samuel S. c Danilova, Ludmila e Bristow, Christopher A. f Lee, Semin d Hadjipanayis, Angela G. a Ivanova, Elena V. bg Wilkerson, Matthew D. h Protopopov, Alexei f Yang, Lixing d Seth, Sahil d Song, Xingzhi d Tang, Jiabin d Ren, Xiaojia a Zhang, Jianhua f Pantazi, Angeliki a Santoso, Netty a Xu, Andrew W. d Mahadeshwar, Harshad f Wheeler, David A. i Haddad, Robert I. j Jung, Joonil c Ojesina, Akinyemi I. bc Issaeva, Natalia k Yarbrough, Wendell G. k Hayes, D. Neil i Grandis, Jennifer R. mn El-Naggar, Adel K. op Meyerson, Matthew bcq Park, Peter J. d Chin, Lynda cf Seidman, J. G. a Hammerman, Peter S. bc Kucherlapati, Raju r CA Canc Genome Atlas Network TI Characterization of HPV and host genome interactions in primary head and neck cancers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer; head and neck; papilloma virus; genome rearrangement; integration sites ID SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS TYPE-16; CERVICAL CARCINOGENESIS; OROPHARYNGEAL CANCER; PROSTATE-CANCER; INTEGRATION; TRANSFORMATION; DNA; KERATINOCYTES; TUMORIGENESIS AB Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis. C1 [Parfenov, Michael a; Hadjipanayis, Angela G. a; Ren, Xiaojia a; Pantazi, Angeliki a; Santoso, Netty a; Seidman, J. G. a] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Meyerson, Matthew bcq] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Gehlenborg, Nils cd; Lee, Semin d; Yang, Lixing d; Seth, Sahil d; Song, Xingzhi d; Tang, Jiabin d; Xu, Andrew W. d] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Pedamallu, Chandra Sekhar bc; Ojesina, Akinyemi I. bc; Meyerson, Matthew bcq; Hammerman, Peter S. bc] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Haddad, Robert I. j] Dana Farber Canc Inst, Dept Med Oncol, Head & Neck Oncol Program, Boston, MA 02215 USA. [Pedamallu, Chandra Sekhar bc; Gehlenborg, Nils cd; Freeman, Samuel S. c; Jung, Joonil c; Ojesina, Akinyemi I. bc; Meyerson, Matthew bcq; Chin, Lynda cf; Hammerman, Peter S. bc] MIT, Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA. [Pedamallu, Chandra Sekhar bc; Gehlenborg, Nils cd; Freeman, Samuel S. c; Jung, Joonil c; Ojesina, Akinyemi I. bc; Meyerson, Matthew bcq; Chin, Lynda cf; Hammerman, Peter S. bc] Harvard Univ, Boston, MA 02115 USA. [Danilova, Ludmila e] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [Bristow, Christopher A. f; Protopopov, Alexei f; Zhang, Jianhua f; Mahadeshwar, Harshad f; Chin, Lynda cf] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Dept Genom Med, Houston, TX 77030 USA. [El-Naggar, Adel K. op] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [El-Naggar, Adel K. op] Univ Texas MD Anderson Canc Ctr, Dept Head & Neck Surg, Houston, TX 77030 USA. [Ivanova, Elena V. bg] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Wilkerson, Matthew D. h] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Hayes, D. Neil i] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Hayes, D. Neil i] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Hayes, D. Neil i] Univ N Carolina, Dept Internal Med, Div Med Oncol, Chapel Hill, NC 27599 USA. [Wheeler, David A. i] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Issaeva, Natalia k; Yarbrough, Wendell G. k] Yale Univ, Sch Med, Dept Surg, Div Otolaryngol, New Haven, CT 06520 USA. [Grandis, Jennifer R. mn] Univ Pittsburgh, Sch Med, Dept Otolaryngol, Pittsburgh, PA 15213 USA. [Grandis, Jennifer R. mn] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA. [Kucherlapati, Raju r] Harvard Univ, Sch Med, Partners HealthCare Ctr Genet & Gen, Boston, MA 02115 USA. RP Seidman, JG (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM seidman@genetics.med.harvard.edu; peterh@broadinstitute.org; rkucherlapati@partners.org RI Holt, Robert/C-3303-2009; Zhao, Ni/P-9086-2014; Weinberger, Paul/B-7007-2008; Jones, Steven/C-3621-2009; Lee, Semin/S-2629-2016; Marra, Marco/B-5987-2008; OI Perou, Charles/0000-0001-9827-2247; Gehlenborg, Nils/0000-0003-0327-8297; Pot, David/0000-0002-1480-9826; Jacobsen, Anders/0000-0001-6847-4980; Sinha, Rileen/0000-0001-5497-5055; Zhao, Ni/0000-0002-7762-3949; Weinberger, Paul/0000-0002-5885-2631; Lee, Semin/0000-0002-9015-6046; Ojesina, Akinyemi/0000-0003-0755-3639; Benz, Stephen/0000-0002-4067-0602; Seth, Sahil/0000-0003-4579-3959 FU National Cancer Institute [U24 CA143867, K08 CA163677, U24 CA144025] FX This study was funded, in part, by National Cancer Institute Grants U24 CA143867 (to M.M.), K08 CA163677 (to P.S.H.), and U24 CA144025 (to R.K.). L.C. is a Cancer Prevention and Research Institute of Texas Scholar in Cancer Research. NR 53 TC 54 Z9 54 U1 4 U2 23 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 OCT 28 PY 2014 VL 111 IS 43 BP 15544 EP 15549 DI 10.1073/pnas.1416074111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6ZL UT WOS:000343729500069 PM 25313082 ER PT J AU Singh, K Connors, SL Macklin, EA Smith, KD Fahey, JW Talalay, P Zimmerman, AW AF Singh, Kanwaljit Connors, Susan L. Macklin, Eric A. Smith, Kirby D. Fahey, Jed W. Talalay, Paul Zimmerman, Andrew W. TI Sulforaphane treatment of autism spectrum disorder (ASD) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CLINICAL-TRIAL; CHILDREN; BROCCOLI; CHEMOPREVENTION; ACTIVATION; ENZYMES; STRESS; CANCER; CHINA AB Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13-27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)-derived from broccoli sprout extracts-or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50-150 mu mol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015-0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation. C1 [Singh, Kanwaljit; Connors, Susan L.; Zimmerman, Andrew W.] Harvard Univ, Sch Med, Massachusetts Gen Hosp Children, Lurie Ctr Autism,Dept Pediat, Lexington, MA 02421 USA. [Singh, Kanwaljit; Zimmerman, Andrew W.] Univ Massachusetts, Sch Med, Dept Pediat Neurol, Worcester, MA 01655 USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Biostat Ctr, Dept Med, Boston, MA 02114 USA. [Smith, Kirby D.] Johns Hopkins Univ, Sch Med, Lewis B & Dorothy Cullman Chemoprotect Ctr, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Fahey, Jed W.; Talalay, Paul] Johns Hopkins Univ, Sch Med, Lewis B & Dorothy Cullman Chemoprotect Ctr, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. RP Talalay, P (reprint author), Johns Hopkins Univ, Sch Med, Lewis B & Dorothy Cullman Chemoprotect Ctr, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. EM ptalalay@jhmi.edu; Andrew.Zimmerman@umassmemorial.org RI Singh, Kanwaljit/B-2210-2016; OI Macklin, Eric/0000-0003-1618-3502 FU Nancy Lurie Marks Family Foundation; Hussman Foundation; Lewis B. and Dorothy Cullman Foundation; Agnes Gund Foundation; N of One Foundation; Brassica Foundation for Chemoprotection Research FX We thank the participants and their families who were consistently interested and gave generously of their time; Scott Zeger for discussions on biostatistics; Jessica Helt and Karmen Koesterer for patient testing and Luisa Masclans for data collection; Ann Neumeyer, who chaired the Data Safety Monitoring Board and was consulted regarding safety and side effects; Jennifer Mullett for assisting with study procedures; and Christine Ferrone and Lisa Nowinski for advising us on regulatory matters and outcome measures. The quality of data collection, retrieval, and analysis were certified by Quality Associates Incorporated. The study was supported by gifts from the Nancy Lurie Marks Family Foundation, the Hussman Foundation, the Lewis B. and Dorothy Cullman Foundation, the Agnes Gund Foundation, the N of One Foundation, and the Brassica Foundation for Chemoprotection Research. NR 39 TC 50 Z9 52 U1 3 U2 28 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 OCT 28 PY 2014 VL 111 IS 43 BP 15550 EP 15555 DI 10.1073/pnas.1416940111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6ZL UT WOS:000343729500070 PM 25313065 ER PT J AU Chen, XY Kositratna, G Zhou, C Manstein, D Wu, MX AF Chen, Xinyuan Kositratna, Garuna Zhou, Chang Manstein, Dieter Wu, Mei X. TI Micro-fractional epidermal powder delivery for improved skin vaccination SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Skin vaccination; Powder delivery; Laser; Microneedle; Local reactogenicity; Vaccine adjuvant ID TRANSCUTANEOUS IMMUNIZATION; LASER TECHNOLOGY; STRATUM-CORNEUM; DRUG-DELIVERY; INFLUENZA; VACCINES; SAFETY; IMMUNOGENICITY; MICRONEEDLES; CHALLENGES AB Skin vaccination has gained increasing attention in the last two decades due to its improved potency compared to intramuscular vaccination. Yet, the technical difficulty and frequent local reactions hamper its broad application in the clinic. In the current study, micro-fractional epidermal powder delivery (EPD) is developed to facilitate skin vaccination and minimize local adverse effects. EPD is based on ablative fractional laser or microneedle treatment of the skin to generate microchannel (MC) arrays in the epidermis followed by topical application of powder drug/vaccine-coated array patches to deliver drug/vaccine into the skin. The novel EPD delivered more than 80% sulforhodamine b (SRB) and model antigen ovalbumin (OVA) into murine, swine, and human skin within 1 h. EPD of OVA induced anti-OVA antibody titer at a level comparable to intradermal (ID) injection and was much more efficient than tape stripping in both delivery efficiency and immune responses. Strikingly, the micro-fractional delivery significantly reduced local side effects of LPS/CpG adjuvant and BCG vaccine, leading to complete skin recovery. In contrast, ID injection induced severe local reactions that persisted for weeks. While reducing local reactogenicity, EPD of OVA/LPS/CpG and BCG vaccine generated a comparable humoral immune response to ID injection. EPD of vaccinia virus encoding OVA induced significantly higher and long-lasting interferon gamma-secreting CD8+ T cells than ID injection. In conclusion, EPD represents a promising technology for needle-free, painless skin vaccination with reduced local reactogenicity and at least sustained immunogenicity. (C) 2014 Elsevier B.V. All rights reserved. C1 [Chen, Xinyuan; Zhou, Chang; Wu, Mei X.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol,Wellman Ctr Photomed, Boston, MA 02114 USA. [Kositratna, Garuna; Manstein, Dieter] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cutaneous Biol Res Ctr,Dept Dermatol, Boston, MA 02114 USA. [Wu, Mei X.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. RP Chen, XY (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 55 Fruit St,Thier 320, Boston, MA 02114 USA. EM xchen14@partners.org; mwu2@partners.org FU National Institutes of Health [AI070785, AI089779, RC1 DA028378]; Bullock-Wellman Fellowship, National Institutes of Health [DA033371, AI107678] FX We thank the Photopathology Core in our Department for tissue sectioning and flow cytometry services. This work is supported in part by the National Institutes of Health grants AI070785, AI089779, and RC1 DA028378 (to M.X.W.), and the Bullock-Wellman Fellowship, National Institutes of Health grants DA033371 and AI107678 (to X.Y.C.). NR 38 TC 11 Z9 11 U1 0 U2 22 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 OCT 28 PY 2014 VL 192 BP 310 EP 316 DI 10.1016/j.jconrel.2014.08.006 PG 7 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA AQ0GF UT WOS:000342460400035 PM 25135790 ER PT J AU Israeli, M Roelen, DL Carrington, M Petersdor, EW Claas, FHJ Haasnoot, GW Oudshoorn, M AF Israeli, Moshe Roelen, Dave L. Carrington, Mary Petersdor, Effie Wang Claas, Frans H. J. Haasnoot, Geert W. Oudshoorn, Machteld TI Association between CTL precursor frequency to HLA-C mismatches and HLA-C antigen cell surface expression SO FRONTIERS IN IMMUNOLOGY LA English DT Article DE cytotoxicT-cell precursor frequency; HLA-C; cell surface expression; allo-reactiyity; CTLp assay ID BONE-MARROW-TRANSPLANTATION; KIR LIGAND INCOMPATIBILITY; CLASS-I MISMATCHES; HIV CONTROL; ALLOREACTIVITY; POLYMORPHISM; NEF; IDENTIFICATION; SUBSTITUTIONS; INFECTION AB Previous studies showed the relevance of the cytotoxic T-cell precursor (CTLp) frequency assay for prediction of the outcome of HLA mismatched hematopoietic cell transplantation (HCT). Recently, it has been shown that HLA-C cell surface expression is correlated with virus specific cytotoxicT-cell responses and viremia control in HIV patients. The aim of the current study was to investigate the association between HLA-C antigen expression and the CTLp frequency to the mismatched HLA-C antigen. In total 115 recipient donor pairs, for whom a successful CTLp assay was performed, were evaluated for this pilot study. All donor recipient pairs were matched at 9/10 alleles with a single mismatch at the HLA-C locus. Antigen expression level of the mismatched HLA-C allele for each recipient and donor was based on the mean fluorescence intensity (MFI) values as described by Apps et al. (1). The cell surface expression of recipient's mismatched HLA-C antigen was significantly lower among CTLp negative (n = 59) compared to CTLp positive (n = 56) pairs (154 and 193 MFI units, respectively, p = 0.0031). This difference was more pronounced in donor recipient pairs that were mismatched for amino-acid residue-116 located in the groove of the HLA-C antigen, suggesting that the importance of peptide binding in the allo-recognition. Furthermore, in the particular case of low expression of the recipient mismatched HLA-C antigen (MFI < 115), CTLp reactivity depended on HLA-C expression level in the donor, the median MFI of donor's mismatched HLA-C antigen was 114 in CTLp negative cases (n = 26), while in CTLp positive cases (n = 15) the median MFI of donor's HLA-C antigen was 193 (p = 0.0093). We conclude that the expression level of the donor and recipient mismatched HLA-C antigens affect CTLp outcome. HLA-C antigen expression levels in combination with the CTLp assay may prove useful for the prediction of the clinical outcome of HLA-C mismatched HCT. C1 [Israeli, Moshe; Roelen, Dave L.; Claas, Frans H. J.; Haasnoot, Geert W.; Oudshoorn, Machteld] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands. [Israeli, Moshe] Rabin Med Ctr, Tissue Typing Lab, Petah Tiqwa, Israel. [Carrington, Mary] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD USA. [Carrington, Mary] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Carrington, Mary] Harvard Univ, Boston, MA 02115 USA. [Petersdor, Effie Wang] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Oudshoorn, Machteld] Europdonor Fdn, Leiden, Netherlands. RP Israeli, M (reprint author), Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, Albinusdreef 2, NL-2300 RC Leiden, Netherlands. EM m.israeli@lumc.nl FU Frederick National Laboratory for Cancer Research [HHSN261200800001E]; Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research FX The authors thank Hanneke Kapsenberg for her valuable technical performance of CTLp tests and the cellular lab of the section of Immunogenetics and Transplantation Immunology for processing the blood samples. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, or does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. NR 32 TC 3 Z9 3 U1 0 U2 2 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-3224 J9 FRONT IMMUNOL JI Front. Immunol. PD OCT 27 PY 2014 VL 5 AR 547 DI 10.3389/fimmu.2014.00547 PG 7 WC Immunology SC Immunology GA CI1NS UT WOS:000354511500001 PM 25386183 ER PT J AU Li, SY Zhai, X Rong, PJ McCabe, MF Zhao, JJ Ben, H Wang, X Wang, SX AF Li, Shaoyuan Zhai, Xu Rong, Peijing McCabe, Michael F. Zhao, Jingjun Ben, Hui Wang, Xing Wang, Shuxing TI Transcutaneous Auricular Vagus Nerve Stimulation Triggers Melatonin Secretion and Is Antidepressive in Zucker Diabetic Fatty Rats SO PLOS ONE LA English DT Article ID MAJOR DEPRESSIVE DISORDER; NMDA RECEPTORS; ACUPUNCTURE; HYPNOSIS; INSOMNIA; BEHAVIOR; SYSTEM; MOUSE; TRIAL AB Decreased circulating melatonin is implicated in depression. We recently found that Zucker diabetic fatty rats (ZDF, fa/fa) develop depression-like behaviors and that transcutaneous auricular vagus nerve stimulation (taVNS) is antidepressive in ZDF rats. Here we studied whether the ZDF rats could be used as a depression rodent model and whether the antidepressive effect of taVNS is mediated through modulation of melatonin secretion. Adult male ZDF and Zucker lean (ZL, fa/+) littermates were used. 30 min-taVNS procedures (2/15 Hz, 2 mA) were administered once daily under anesthesia for 34 consecutive days in pineal intact ZDF (n = 8) and ZL (n = 6) rats, as well as in pinealectomized ZDF rats (n = 8). Forced swimming test (FST) was used to determine depression-like behavior and ELISA to detect plasma melatonin concentration on day 35. We found that naive ZDF rats had a longer immobility time in FST and that long-term (34 days) taVNS treatment ameliorated the depression-like behavior. In both pineal intact and pinealectomized ZDF rats, taVNS induced acute melatonin secretion, both during and after the taVNS session. A low melatonin level is related to the poor FST performance in ZDF rats (R = -0.544) in contrast to ZL rats (R = 0.247). In conclusion, our results show that ZDF rats are ideal candidates of innate depression and that taVNS is antidepressive through triggering melatonin secretion and increasing its production. C1 [Li, Shaoyuan; Zhai, Xu; Rong, Peijing; Zhao, Jingjun; Ben, Hui; Wang, Shuxing] China Acad Chinese Med Sci, Inst Acupuncture & Moxibust, Dept Physiol, Beijing, Peoples R China. [Li, Shaoyuan; Wang, Xing; Wang, Shuxing] Xinxiang Med Univ, Dept Anat, Xinxiang, Henan Province, Peoples R China. [McCabe, Michael F.; Wang, Shuxing] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. RP Rong, PJ (reprint author), China Acad Chinese Med Sci, Inst Acupuncture & Moxibust, Dept Physiol, Beijing, Peoples R China. EM rongpj@hotmail.com; wshuxing@mgh.harvard.edu FU National Natural Science Foundation of China [81271243, 81473780]; Natural Science Foundation of Beijing [7111007]; National Basic Research Program of China (973 Program) [2012CB518503]; Project Supported National Science and Technology Ministry [2012BAF14B10] FX This work was supported by National Natural Science Foundation of China-81271243, 81473780; Natural Science Foundation of Beijing, 7111007; National Basic Research Program of China (973 Program)-2012CB518503; and Project Supported National Science and Technology Ministry-2012BAF14B10. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 3 Z9 3 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2014 VL 9 IS 10 AR e111100 DI 10.1371/journal.pone.0111100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AZ1JF UT WOS:000347994900046 PM 25347185 ER PT J AU Stewart, DS Pierce, DW Hotta, M Stern, AT Forman, SA AF Stewart, Deirdre S. Pierce, David W. Hotta, Mayo Stern, Alex T. Forman, Stuart A. TI Mutations at Beta N265 in gamma-Aminobutyric Acid Type A Receptors Alter Both Binding Affinity and Efficacy of Potent Anesthetics SO PLOS ONE LA English DT Article ID GATED ION CHANNELS; GABA(A) RECEPTOR; GENERAL-ANESTHETICS; ETOMIDATE BINDING; GLYCINE RECEPTORS; SUBUNIT INTERFACE; CROSS-LINKING; AMINO-ACID; SITES; MODULATION AB Etomidate and propofol are potent general anesthetics that act via GABAA receptor allosteric co-agonist sites located at transmembrane beta+/alpha- inter-subunit interfaces. Early experiments in heteromeric receptors identified beta N265 (M2-15') on beta 2 and beta 3 subunits as an important determinant of sensitivity to these drugs. Mechanistic analyses suggest that substitution with serine, the beta 1 residue at this position, primarily reduces etomidate efficacy, while mutation to methionine eliminates etomidate sensitivity and might prevent drug binding. However, the beta N265 residue has not been photolabeled with analogs of either etomidate or propofol. Furthermore, substituted cysteine modification studies find no propofol protection at this locus, while etomidate protection has not been tested. Thus, evidence of contact between beta N265 and potent anesthetics is lacking and it remains uncertain how mutations alter drug sensitivity. In the current study, we first applied heterologous alpha 1 beta 2N265C gamma 2L receptor expression in Xenopus oocytes, thiol-specific aqueous probe modification, and voltage-clamp electrophysiology to test whether etomidate inhibits probe reactions at the beta-265 sidechain. Using up to 300 mu M etomidate, we found both an absence of etomidate effects on alpha 1 beta 2N265C gamma 2L receptor activity and no inhibition of thiol modification. To gain further insight into anesthetic insensitive beta N265M mutants, we applied indirect structurefunction strategies, exploiting second mutations in alpha 1 beta 2/3 gamma 2L GABAA receptors. Using alpha 1M236C as a modifiable and anesthetic-protectable site occupancy reporter in beta+/alpha- interfaces, we found that beta N265M reduced apparent anesthetic affinity for receptors in both resting and GABA-activated states. beta N265M also impaired the transduction of gating effects associated with alpha 1M236W, a mutation that mimics beta+/alpha- anesthetic site occupancy. Our results show that beta N265M mutations dramatically reduce the efficacy/transduction of anesthetics bound in beta+/alpha- sites, and also significantly reduce anesthetic affinity for resting state receptors. These findings are consistent with a role for beta N265 in anesthetic binding within the beta+/alpha- transmembrane sites. C1 [Stewart, Deirdre S.; Pierce, David W.; Hotta, Mayo; Stern, Alex T.; Forman, Stuart A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Forman, SA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM saforman@partners.org FU National Institutes of General Medical Sciences Grant [R01GM089745] FX This work was supported by National Institutes of General Medical Sciences Grant R01GM089745 to SAF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 12 Z9 13 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2014 VL 9 IS 10 AR e111470 DI 10.1371/journal.pone.0111470 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AZ1JF UT WOS:000347994900078 PM 25347186 ER PT J AU Zhang, RC Zhang, YH Zhang, J An, T Huang, Y Guo, X Januzzi, JL Cappola, TP Yin, SJ Wang, YH Zhou, Q Zou, CH Ji, SM Lv, R AF Zhang, Rongcheng Zhang, Yuhui Zhang, Jian An, Tao Huang, Yan Guo, Xiao Januzzi, James L. Cappola, Thomas P. Yin, Shijie Wang, Yunhong Zhou, Qiong Zou, Changhong Ji, Shiming Lv, Rong TI The Prognostic Value of Plasma Soluble ST2 in Hospitalized Chinese Patients with Heart Failure SO PLOS ONE LA English DT Article ID FAMILY-MEMBER ST2; NATIONAL REGISTRY ADHERE; MYOCARDIAL-INFARCTION; NATRIURETIC PEPTIDE; RISK STRATIFICATION; EJECTION FRACTION; ACUTE DYSPNEA; MORTALITY; EPIDEMIC; OUTCOMES AB Background: sST2 has been shown to be a risk predictor in heart failure (HF). Our aim was to explore the characteristics and prognostic value of soluble ST2 (sST2) in hospitalized Chinese patients with HF. Methods and Results: We consecutively enrolled 1528 hospitalized patients with HF. Receiver operating characteristic (ROC) and multivariable Cox proportional hazards analysis were used to assess the prognostic values of sST2. Adverse events were defined as all-cause death and cardiac transplantation. During a median follow-up of 19.1 months, 325 patients experienced adverse events. Compared with patients free of events, sST2 concentrations were significantly higher in patients with events (P<0.001). Univariable and multivariable Cox regression analyses showed sST2 concentrations were significantly associated with adverse events (per 1 log unit, adjusted hazard ratio 1.52, 95% confidence interval: 1.30 to 1.78, P<0.001). An sST2 concentration in the highest quartiles (>55.6 ng/mL) independently predicted events in comparison to the lowest quartile (>= 25.2 ng/mL) when adjusted by multivariable model. In ROC analysis, the area under the curve for sST2 was not different from that for NT-proBNP in short and longer term. Over time, sST2 also improved discrimination and reclassification of risk beyond NT-proBNP. Conclusions: sST2 is a strong independent risk predictor in Chinese patients hospitalized with HF and can significantly provide additional prognostic value to NT-proBNP in risk prediction. C1 [Zhang, Rongcheng; Zhang, Yuhui; Zhang, Jian; An, Tao; Huang, Yan; Guo, Xiao; Yin, Shijie; Wang, Yunhong; Zhou, Qiong; Zou, Changhong; Ji, Shiming; Lv, Rong] Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Heart Failure Ctr Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China. [Zhang, Rongcheng; Zhang, Yuhui; Zhang, Jian; An, Tao; Huang, Yan; Guo, Xiao; Yin, Shijie; Wang, Yunhong; Zhou, Qiong; Zou, Changhong; Ji, Shiming; Lv, Rong] Peking Union Med Coll, Beijing 100021, Peoples R China. [Januzzi, James L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Cappola, Thomas P.] Univ Penn, Sch Med, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA. RP Zhang, YH (reprint author), Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Heart Failure Ctr Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China. EM yuhuizhangjoy@163.com; fwzhangjian62@126.com FU Key Projects in the National Science & Technology Pillar Program of the 12th Five-year Plan Period, Beijing, China [2011BAI11B02] FX This study was supported by grants from the Key Projects in the National Science & Technology Pillar Program of the 12th Five-year Plan Period (No. 2011BAI11B02, project for heart failure), Beijing, China. ST2 assays were provided by Critical Diagnostics, and NT-proBNP assays were provided by Alere Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the NR 28 TC 2 Z9 2 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2014 VL 9 IS 10 AR e110976 DI 10.1371/journal.pone.0110976 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AZ1JF UT WOS:000347994900036 PM 25347817 ER PT J AU Yu, GQ Dye, BA Gail, MH Shi, J Klepac-Ceraj, V Paster, BJ Wang, GQ Wei, WQ Fan, JH Qiao, YL Dawsey, SM Freedman, ND Abnet, CC AF Yu, Guoqin Dye, Bruce A. Gail, Mitchell H. Shi, Jianxin Klepac-Ceraj, Vanja Paster, Bruce J. Wang, Guo-Qing Wei, Wen-Qiang Fan, Jin-Hu Qiao, You-Lin Dawsey, Sanford M. Freedman, Neal D. Abnet, Christian C. TI The association between the upper digestive tract microbiota by HOMIM and oral health in a population-based study in Linxian, China SO BMC PUBLIC HEALTH LA English DT Article DE Microbiota; Oral health; Dental caries; Periodontitis; Bleeding on probe; Attachment loss ID HUMAN SUBGINGIVAL PLAQUE; BACTERIAL DIVERSITY; PERIODONTAL-DISEASE; MOLECULAR ANALYSIS; CHILDHOOD CARIES; RISK INDICATORS; PERMANENT TEETH; ATTACHMENT LOSS; DENTAL-CARIES; COMMUNITY AB Background: Bacteria affect oral health, but few studies have systematically examined the role of bacterial communities in oral diseases. We examined this relationship in a large population-based Chinese cancer screening cohort. Methods: Human Oral Microbe Identification Microarrays were used to test for the presence of 272 human oral bacterial species (97 genera) in upper digestive tract (UDT) samples collected from 659 participants. Oral health was assessed using US NHANES (National Health and Nutrition Examination Survey) protocols. We assessed both dental health (total teeth missing; tooth decay; and the decayed, missing, and filled teeth (DMFT) score) and periodontal health (bleeding on probing (BoP) extent score, loss of attachment extent score, and a periodontitis summary estimate). Results: Microbial richness, estimated by number of genera per sample, was positively correlated with BoP score (P = 0.015), but negatively correlated with tooth decay and DMFT score (P = 0.008 and 0.022 respectively). Regarding beta-diversity, as estimated by the UniFrac distance matrix for pairwise differences among samples, at least one of the first three principal components of the UniFrac distance matrix was correlated with the number of missing teeth, tooth decay, DMFT, BoP, or periodontitis. Of the examined genera, Parvimonas was positively associated with BoP and periodontitis. Veillonellacease [G-1] was associated with a high DMFT score, and Filifactor and Peptostreptococcus were associated with a low DMFT score. Conclusions: Our results suggest distinct relationships between UDT microbiota and dental and periodontal health. Poor dental health was associated with a less microbial diversity, whereas poor periodontal health was associated with more diversity and the presence of potentially pathogenic species. C1 [Yu, Guoqin; Gail, Mitchell H.; Shi, Jianxin; Dawsey, Sanford M.; Freedman, Neal D.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Dye, Bruce A.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Klepac-Ceraj, Vanja; Paster, Bruce J.] Forsyth Inst, Cambridge, MA USA. [Klepac-Ceraj, Vanja] Wellesley Coll, Wellesley, MA 02181 USA. [Paster, Bruce J.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Wang, Guo-Qing; Wei, Wen-Qiang; Fan, Jin-Hu; Qiao, You-Lin] Chinese Acad Med Sci, Inst Canc, Beijing 100021, Peoples R China. [Yu, Guoqin] NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Bethesda, MD 20892 USA. RP Yu, GQ (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. EM yug3@mail.nih.gov RI Freedman, Neal/B-9741-2015; Abnet, Christian/C-4111-2015; Qiao, You-Lin/B-4139-2012 OI Freedman, Neal/0000-0003-0074-1098; Abnet, Christian/0000-0002-3008-7843; Qiao, You-Lin/0000-0001-6380-0871 FU Intramural Research Program of the NIH, National Cancer Institute FX This study was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 43 TC 0 Z9 0 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD OCT 27 PY 2014 VL 14 AR 1110 DI 10.1186/1471-2458-14-1110 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AU1AN UT WOS:000345353500001 PM 25348940 ER PT J AU Zhu, J Gale, EM Atanasova, I Rietz, TA Caravan, P AF Zhu, Jiang Gale, Eric M. Atanasova, Iliyana Rietz, Tyson A. Caravan, Peter TI Hexameric Mn-II Dendrimer as MRI Contrast Agent SO CHEMISTRY-A EUROPEAN JOURNAL LA English DT Article DE dendrimers; imaging agents; manganese; magnetic resonance imaging; NMR spectroscopy ID NEPHROGENIC SYSTEMIC FIBROSIS; METAL-COMPLEXES; WATER-EXCHANGE; MAGNETIC-FIELD; RESONANCE; RELAXATION; RELAXIVITY; GADOLINIUM; DISEASE; LIVER AB A Mn-II chelating dendrimer was prepared as a contrast agent for MRI applications. The dendrimer comprises six tyrosine-derived [Mn(EDTA)(H2O)](2-) moieties coupled to a cyclotriphosphazene core. Variable temperature (ONMR)-O-17 spectroscopy revealed a single water co-ligand per Mn-II that undergoes fast water exchange (k(ex)=(3.0 +/- 0.1)x10(8)s(-1) at 37 degrees C). The 37 degrees C per Mn-II relaxivity ranged from 8.2 to 3.8mM(-1)s(-1) from 0.47 to 11.7T, and is sixfold higher on a per molecule basis. From this field dependence a rotational correlation time was estimated as 0.45(+/- 0.02)ns. The imaging and pharmacokinetic properties of the dendrimer were compared to clinically used [Gd(DTPA)(H2O)](2-) in mice at 4.7T. On first pass, the higher per ion relaxivity of the dendrimer resulted in twofold greater blood signal than for [Gd(DTPA)(H2O)](2-). Blood clearance was fast and elimination occurred through both the renal and hepatobiliary routes. This Mn-II containing dendrimer represents a potential alternative to Gd-based contrast agents, especially in patients with chronic kidney disease where the use of current Gd-based agents may be contraindicated. C1 [Zhu, Jiang; Gale, Eric M.; Rietz, Tyson A.; Caravan, Peter] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA 02141 USA. [Zhu, Jiang] North Sichuan Med Coll, Sichuan Key Lab Med Imaging, Nanchong, Peoples R China. [Atanasova, Iliyana] MIT, Cambridge, MA 02141 USA. RP Caravan, P (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, 149 Thirteenth St,Suite 2301, Charlestown, MA 02141 USA. EM caravan@nmr.mgh.harvard.edu FU National Cancer Institute [CA161221, CA009502]; National Center for Research Resources [RR023385]; China Scholarship Council [201208510160] FX This work was supported by grants from the National Cancer Institute (CA161221 to P.C. and a T32 postdoctoral fellowship to E. M. G., CA009502), and an instrument grant from the National Center for Research Resources (RR023385). J.Z. is supported by the China Scholarship Council (File No. 201208510160). I. A. is a Madrid-MIT M+ Vision fellow. We would like to thank Prof. Jack Szostak for access to a 9.4 T NMR spectrometer. NR 39 TC 11 Z9 11 U1 5 U2 41 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 0947-6539 EI 1521-3765 J9 CHEM-EUR J JI Chem.-Eur. J. PD OCT 27 PY 2014 VL 20 IS 44 BP 14507 EP 14513 DI 10.1002/chem.201403883 PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA AS4EA UT WOS:000344224800041 PM 25224391 ER PT J AU He, LL Sok, D Azadnia, P Hsueh, J Landais, E Simek, M Koff, WC Poignard, P Burton, DR Zhu, J AF He, Linling Sok, Devin Azadnia, Parisa Hsueh, Jessica Landais, Elise Simek, Melissa Koff, Wayne C. Poignard, Pascal Burton, Dennis R. Zhu, Jiang TI Toward a more accurate view of human B-cell repertoire by next-generation sequencing, unbiased repertoire capture and single-molecule barcoding SO SCIENTIFIC REPORTS LA English DT Article ID NEUTRALIZING ANTIBODIES; HIV-1-NEUTRALIZING ANTIBODIES; ADAPTIVE IMMUNITY; HIV-1 VACCINE; MONOCLONAL-ANTIBODIES; POTENT NEUTRALIZATION; IMMUNOGEN DESIGN; BROAD; VIRUS; RECEPTORS AB B-cell repertoire analysis using next-generation sequencing has become a valuable tool for interrogating the genetic record of humoral response to infection. However, key obstacles such as low throughput, short read length, high error rate, and undetermined bias of multiplex PCR method have hindered broader application of this technology. In this study, we report several technical advances in antibody repertoire sequencing. We first demonstrated the ability to sequence antibody variable domains using the Ion Torrent PGM platform. As a test case, we analyzed the PGT121 class of antibodies from IAVI donor 17, an HIV-1-infected individual. We then obtained "unbiased'' antibody repertoires by sequencing the 5'-RACE PCR products of B-cell transcripts from IAVI donor 17 and two HIV-1-uninfected individuals. We also quantified the bias of previously published gene-specific primers by comparing the repertoires generated by 5'-RACE PCR and multiplex PCR. We further developed a single-molecule barcoding strategy to reduce PCR-based amplification noise. Lastly, we evaluated several new PGM technologies in the context of antibody sequencing. We expect that, based upon long-read and high-fidelity next-generation sequencing technologies, the unbiased analysis will provide a more accurate view of the overall antibody repertoire while the barcoding strategy will facilitate high-resolution analysis of individual antibody families. C1 [He, Linling; Sok, Devin; Azadnia, Parisa; Hsueh, Jessica; Poignard, Pascal; Burton, Dennis R.; Zhu, Jiang] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Sok, Devin; Hsueh, Jessica; Landais, Elise; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Sok, Devin; Simek, Melissa; Koff, Wayne C.; Poignard, Pascal; Burton, Dennis R.] Int AIDS Vaccine Initiat IAVI, New York, NY 10004 USA. [Sok, Devin; Hsueh, Jessica; Burton, Dennis R.; Zhu, Jiang] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA. [Burton, Dennis R.] Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Zhu, Jiang] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA. RP Zhu, J (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM jiang@scripps.edu RI poignard, pascal/N-6678-2013; OI Hsueh, Jessica/0000-0002-4070-5270 FU Bill and Melinda Gates Foundation; Ministry of Foreign Affairs of Denmark; Irish Aid; Ministry of Finance of Japan; Ministry of Foreign Affairs of the Netherlands; Norwegian Agency for Development Cooperation (NORAD); United Kingdom Department for International Development (DFID); United States Agency for International Development (USAID); American people through USAID; Scripps Center for HIV/AIDS Immunology & Immunogen Discovery [CHAVI-ID UM1 AI 100663] FX We would like to thank the members of IAVI who participated or provided donor samples in this project. IAVI's work is made possible by generous support from many donors including: the Bill and Melinda Gates Foundation; the Ministry of Foreign Affairs of Denmark; Irish Aid; the Ministry of Finance of Japan; the Ministry of Foreign Affairs of the Netherlands; the Norwegian Agency for Development Cooperation (NORAD); the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID). The full list of IAVI donors is available at www.iavi.org. This work is made possible by the generous support of the American people through USAID. The contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the United States Government. Support for this work was provided by the grants from the Scripps Center for HIV/AIDS Immunology & Immunogen Discovery (CHAVI-ID UM1 AI 100663). NR 46 TC 22 Z9 23 U1 2 U2 19 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 OCT 27 PY 2014 VL 4 AR 6778 DI 10.1038/srep06778 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS0PA UT WOS:000343978700010 PM 25345460 ER PT J AU Hirohashi, T Chase, CM DellaPelle, P Sebastian, D Farkesh, E Colvin, RB Russell, PS Alessandrini, A Madsen, JC AF Hirohashi, Tsutomu Chase, Catharine M. DellaPelle, Patricia Sebastian, Divya Farkesh, Evan Colvin, Robert B. Russell, Paul S. Alessandrini, Alessandro Madsen, Joren C. TI Depletion of T Regulatory Cells Promotes Natural Killer Cell-Mediated Cardiac Allograft Vasculopathy SO TRANSPLANTATION LA English DT Article DE Cardiac allograft vasculopathy; Heart transplantation; NK cells; Tregs; Mice ID TRANSPLANTED MOUSE HEARTS; NK CELLS; CORONARY ATHEROSCLEROSIS; MONOCLONAL-ANTIBODY; INTERFERON-GAMMA; REJECTION; MICE; ACTIVATION; PATHWAY; LESION AB Background. A role for natural killer (NK) cells in cardiac allograft vasculopathy (CAV) was suggested by our earlier observation that CAV arises even in the absence of detectable antidonor T-cell or B-cell reactivity in parental to F1 mouse heart grafts. However, prevention of CAV in this setting required the depletion of both NK and CD4(+) T cells. Methods. To clarify the interrelationship between NK and CD4(+) cells, we analyzed early events and selective depletion of T regulatory cells (Tregs). Hearts from C57BL/6 (B6) donors were transplanted heterotopically into BALB/c x C57BL/6 (CB6F1) recipients and NK cells, CD4(+) T cells, and Tregs were depleted with anti-NK1.1 (PK136), anti-CD4 (GK1.5), or anti-CD25 (PC61), respectively. Results. In contrast to prior studies in which the prevention of CAV at 8 weeks required the codepletion of NK and CD4(+) T cells, NK cells depletion alone eliminated CAV at 3 weeks. Furthermore, depletion of CD25(+) cells accelerated the onset and maturation of CAV at both 2 and 3 weeks (P<0.02 and P<0.001, respectively). However, anti-NK1.1 treatment prevented lesions in CD25-depleted recipients. Finally, CD4(+) T cell depletion alone did not prevent or accelerate development of CAV but inhibited the effect of CD25(+) T cell depletion. Conclusion. These data suggest that NK cells can play an important role in the early pathogenesis of CAV but that their ability to mediate early CAV can be modulated by Tregs. C1 [Hirohashi, Tsutomu; Chase, Catharine M.; Russell, Paul S.; Alessandrini, Alessandro; Madsen, Joren C.] Massachusetts Gen Hosp, Transplantat Ctr, Boston, MA 02114 USA. [Hirohashi, Tsutomu; Chase, Catharine M.; Russell, Paul S.; Alessandrini, Alessandro; Madsen, Joren C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [DellaPelle, Patricia; Sebastian, Divya; Farkesh, Evan; Colvin, Robert B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Madsen, Joren C.] Massachusetts Gen Hosp, Dept Surg, Div Cardiac Surg, Boston, MA 02114 USA. RP Madsen, JC (reprint author), Massachusetts Gen Hosp, White 510a,55 Fruit St, Boston, MA 02114 USA. EM jcmadsen@partners.org FU Roche Organ Transplant Research Foundation; American Society of Transplantation; [R01 HL071932]; [R01 AI081734] FX This work was funded in part by grants from R01 HL071932 (JCM), R01 AI081734 (RBC), a grant from the Roche Organ Transplant Research Foundation, and by a research grant from the American Society of Transplantation (T.H.). NR 25 TC 4 Z9 4 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD OCT 27 PY 2014 VL 98 IS 8 BP 828 EP 834 DI 10.1097/TP.0000000000000329 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA AR9WF UT WOS:000343926300008 PM 25321164 ER PT J AU Tsiachristas, A Waters, BH Adams, SA Bal, R Rutten-van Molken, MPMM AF Tsiachristas, Apostolos Waters, Bethany Hipple Adams, Samantha A. Bal, Roland Rutten-van Molken, Maureen P. M. M. TI Identifying and explaining the variability in development and implementation costs of disease management programs in the Netherlands SO BMC HEALTH SERVICES RESEARCH LA English DT Article DE Chronic disease; Cardiovascular risk; COPD; Disease management; Integrated care; Costs; The Netherlands; ICT ID INTEGRATED CARE; TECHNOLOGY; PAYMENT AB Background: In the Netherlands, disease management programs (DMPs) are used to treat chronic diseases. Their aim is to improve care and to control the rising expenditures related to chronic diseases. A bundled payment was introduced to facilitate the implementation of DMPs. This payment is an all-inclusive price per patient per year for a pre-specified care package. However, it is unclear to which extent the costs of developing and implementing DMPs are included in this price. Consequently, the organizations providing DMPs bear financial risk because the development and implementation (D&I) costs may be substantial. The aim of this paper is to investigate the variability in and drivers of D&I costs among 22 DMPs and highlight characteristics that impact these. Methods: The data was analyzed using a mixed methods approach. Descriptive statistical analysis explored the variability in D&I costs as measured by a self-developed costing instrument and investigated the drivers. In addition, qualitative research, including document analysis and interviews, was conducted to explain the possible underlying reasons of cost variability. Results: The development costs varied from (sic)5,891 to (sic)274,783 and the implementation costs varied from (sic)7,278 to (sic)387,879 across DMPs. Personnel costs were the main component of development. Development costs were strongly correlated with the implementation costs (rho = 0.55), development duration (rho = 0.74), and number of FTEs dedicated DMP development. Organizations with large size and high level of care prior to the implementation of a DMP had relatively low development costs. These findings were in line with the cross-case qualitative comparison where programs with a longer history, more experienced project leadership, previously established ICT systems, and less complex patient populations had lower D&I costs. Conclusions: There is wide variation in D&I costs of DMPs, which is driven primarily by the duration of the development phase and the staff needed to develop and implement a DMP. These drivers are influenced by the attributes of the DMP, characteristics of the target population, project leadership, and ICT involved. There are indications of economies of scale and economies of scope, which may reduce D&I costs. C1 [Tsiachristas, Apostolos; Rutten-van Molken, Maureen P. M. M.] Erasmus Univ, Inst Med Technol Assessment, NL-3000 DR Rotterdam, Netherlands. [Tsiachristas, Apostolos; Waters, Bethany Hipple; Adams, Samantha A.; Bal, Roland; Rutten-van Molken, Maureen P. M. M.] Erasmus Univ, Dept Hlth Policy & Management, NL-3000 DR Rotterdam, Netherlands. [Waters, Bethany Hipple] Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, Boston, MA 02114 USA. RP Tsiachristas, A (reprint author), Erasmus Univ, Inst Med Technol Assessment, POB 1738, NL-3000 DR Rotterdam, Netherlands. EM tsiachristas@bmg.eur.nl RI Rutten-van Molken, Maureen/G-8481-2014 OI Rutten-van Molken, Maureen/0000-0001-8706-3159 FU ZonMw FX The authors would like to thank ZonMw for the financial support as well as the managers and financial controllers in the 22 DMPs for providing data and information. Our special acknowledgments to the interviewees from DMP10 and DMP17. NR 18 TC 2 Z9 2 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD OCT 26 PY 2014 VL 14 AR 518 DI 10.1186/s12913-014-0518-0 PG 14 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AR7BS UT WOS:000343735600001 PM 25343967 ER PT J AU Underhill, ML Hong, FX Berry, DL AF Underhill, Meghan L. Hong, Fangxin Berry, Donna L. TI When study site contributes to outcomes in a multi-center randomized trial: a secondary analysis of decisional conflict in men with localized prostate cancer SO HEALTH AND QUALITY OF LIFE OUTCOMES LA English DT Article DE Localized prostate cancer; Decisional conflict; Decision-making ID PREFERENCES; VALIDATION AB Purpose: Evaluate baseline factors that may explain the influence of study site on decisional conflict (DC) in men from the Personal Patient Profile: Prostate (P3P) randomized trial. Materials and methods: 476 cases from 5 P3P sites were included. Participants completed baseline demographic assessments, 4 subscales of the DC scale at baseline (uncertainty, informed, values clarity, and support), the Expanded Prostate Cancer Index Composite (short form) and the State-Trait Anxiety Inventory. Site data regarding typical practices were collected. Linear regressions were used to model the relation between baseline DC scores and study site adjusting for the list of variables. Results: Baseline decisional uncertainly (p = 0.001) and informed (p = 0.03) subscales were significantly different across sites. Participant demographic and baseline measures were significantly different (p < 0.05) between sites except for trait anxiety. We identified participant level factors that explained study site differences at baseline for the decisional uncertainty and values clarity subscales: a preferred treatment choice at study entry, whether the study program was accessed at home vs. in clinic, number of doctors consulted pre-study, working status, state anxiety, information from the media or a health care provider, and perceived knowledge level. State anxiety was associated with higher DC across all subscales. Conclusions: Individual characteristics of men seeking consultation for LPC were associated with DC at baseline, not the site alone; anxiety contributed to higher conflict. These findings will inform future development and implementation of the P3P and other decision support interventions. C1 [Underhill, Meghan L.; Berry, Donna L.] Dana Farber Canc Inst, Phyllis Cantor Ctr Res Nursing & Patient Care Ser, Boston, MA 02115 USA. [Hong, Fangxin] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Hong, Fangxin] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. RP Underhill, ML (reprint author), Dana Farber Canc Inst, Phyllis Cantor Ctr Res Nursing & Patient Care Ser, 450 Brookline Ave, Boston, MA 02115 USA. EM meghanl_underhill@dfci.harvard.edu NR 16 TC 1 Z9 1 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7525 J9 HEALTH QUAL LIFE OUT JI Health Qual. Life Outcomes PD OCT 25 PY 2014 VL 12 AR 159 DI 10.1186/s12955-014-0159-3 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA AU1BO UT WOS:000345356200002 PM 25344101 ER PT J AU Matreyek, KA Wang, WF Serrao, E Singh, PK Levin, HL Engelman, A AF Matreyek, Kenneth A. Wang, Weifeng Serrao, Erik Singh, Parmit Kumar Levin, Henry L. Engelman, Alan TI Host and viral determinants for MxB restriction of HIV-1 infection SO RETROVIROLOGY LA English DT Article DE Innate immunity; MxB; Mx2; HIV-1; Restriction factor ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 INTEGRASE MUTANTS; DYNAMIN-LIKE MXA; DNA INTEGRATION; ANTIVIRAL SPECIFICITY; REVERSE TRANSCRIPTION; QUANTITATIVE-ANALYSIS; NUCLEAR-ENVELOPE; EARLY STEPS; PROTEIN AB Background: Interferon-induced cellular proteins play important roles in the host response against viral infection. The Mx family of dynamin-like GTPases, which include MxA and MxB, target a wide variety of viruses. Despite considerable evidence demonstrating the breadth of antiviral activity of MxA, human MxB was only recently discovered to specifically inhibit lentiviruses. Here we assess both host and viral determinants that underlie MxB restriction of HIV-1 infection. Results: Heterologous expression of MxB in human osteosarcoma cells potently inhibited HIV-1 infection (similar to 12-fold), yet had little to no effect on divergent retroviruses. The anti-HIV effect manifested as a partial block in the formation of 2-long terminal repeat circle DNA and hence nuclear import, and we accordingly found evidence for an additional post-nuclear entry block. A large number of previously characterized capsid mutations, as well as mutations that abrogated integrase activity, counteracted MxB restriction. MxB expression suppressed integration into gene-enriched regions of chromosomes, similar to affects observed previously when cells were depleted for nuclear transport factors such as transportin 3. MxB activity did not require predicted GTPase active site residues or a series of unstructured loops within the stalk domain that confer functional oligomerization to related dynamin family proteins. In contrast, we observed an N-terminal stretch of residues in MxB to harbor key determinants. Protein localization conferred by a nuclear localization signal (NLS) within the N-terminal 25 residues, which was critical, was fully rescuable by a heterologous NLS. Consistent with this observation, a heterologous nuclear export sequence (NES) abolished full-length MxB activity. We additionally mapped sub-regions within amino acids 26-90 that contribute to MxB activity, finding sequences present within residues 27-50 particularly important. Conclusions: MxB inhibits HIV-1 by interfering with minimally two steps of infection, nuclear entry and post-nuclear trafficking and/or integration, without destabilizing the inherent catalytic activity of viral preintegration complexes. Putative MxB GTPase active site residues and stalk domain Loop 4 -both previously shown to be necessary for MxA function - were dispensable for MxB antiviral activity. Instead, we highlight subcellular localization and a yet-determined function(s) present in the unique MxB N-terminal region to be required for HIV-1 restriction. C1 [Matreyek, Kenneth A.; Wang, Weifeng; Serrao, Erik; Engelman, Alan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Matreyek, Kenneth A.; Wang, Weifeng; Serrao, Erik; Engelman, Alan] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Singh, Parmit Kumar; Levin, Henry L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Eukaryot Transposable Elements, Program Cellular Regulat & Metab, NIH, Bethesda, MD 20892 USA. RP Engelman, A (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. EM alan_engelman@dfci.harvard.edu OI Matreyek, Kenneth/0000-0001-9149-551X FU US National Institute of Health (Harvard University Center for AIDS Research) [AI052014, AI060354]; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank Tamaria Dewdney for comments on the manuscript, Frederic Bushman and Nirav Malani for sharing integration sites obtained from control and transportin 3 and RANBP2 knockdown cells, and Peter Cherepanov for advice on bioinformatics analyses and critical reading of the revised manuscript. This work was supported by US National Institute of Health grants AI052014 (A.E.) and AI060354 (Harvard University Center for AIDS Research) and by the Intramural Research Program of the NIH from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P.K.S. and H.L.L.). NR 65 TC 25 Z9 25 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD OCT 25 PY 2014 VL 11 AR 90 DI 10.1186/s12977-014-0090-z PG 20 WC Virology SC Virology GA AS9OC UT WOS:000344570800001 PM 25348155 ER PT J AU Luengo, A Sullivan, LB Vander Heiden, MG AF Luengo, Alba Sullivan, Lucas B. Vander Heiden, Matthew G. TI Understanding the complex-I-ty of metformin action: limiting mitochondrial respiration to improve cancer therapy SO BMC BIOLOGY LA English DT Editorial Material ID METABOLISM; GLUCONEOGENESIS; PATHWAY; GROWTH; LKB1; AMPK; MICE AB Metformin has been a first-line treatment for type II diabetes mellitus for decades and is the most widely prescribed antidiabetic drug. Retrospective studies have found that metformin treatment is associated with both reduced cancer diagnoses and cancer-related deaths. Despite the prevalence of metformin use in the clinic, its molecular mechanism of action remains controversial. In a recent issue of Cancer & Metabolism, Andrzejewski et al. present evidence that metformin acts directly on mitochondria to inhibit complex I and limits the ability of cancer cells to cope with energetic stress. Here, we discuss evidence that supports the role of metformin as a cancer therapeutic. C1 [Luengo, Alba; Sullivan, Lucas B.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Luengo, Alba; Sullivan, Lucas B.; Vander Heiden, Matthew G.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Vander Heiden, MG (reprint author), MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. EM mvh@mit.edu FU NIGMS NIH HHS [T32 GM007287] NR 13 TC 13 Z9 14 U1 0 U2 9 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 OCT 24 PY 2014 VL 12 AR 82 DI 10.1186/s12915-014-0082-4 PG 4 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AU8WM UT WOS:000345874300001 PM 25347702 ER PT J AU Singh, JA Lu, X Ibrahim, S Cram, P AF Singh, Jasvinder A. Lu, Xin Ibrahim, Said Cram, Peter TI Trends in and disparities for acute myocardial infarction: an analysis of Medicare claims data from 1992 to 2010 SO BMC MEDICINE LA English DT Article DE Myocardial infarction; MI; Disparity; Outcomes; Race; Sex; Mortality; PCI; Hospitalization rates ID AMERICAN-HEART-ASSOCIATION; QUALITY-OF-CARE; FEE-FOR-SERVICE; ETHNIC-DIFFERENCES; UNITED-STATES; MORTALITY; SEX; BENEFICIARIES; DISEASE; REVASCULARIZATION AB Background: It is unknown whether previously reported disparities for acute myocardial infarction (AMI) by race and sex have declined over time. Methods: We used Medicare Part A administrative data files for 1992 to 2010 to evaluate changes in per-capita hospitalization rates for AMI, rates of revascularization (percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG)), and 30-day mortality for four distinct patient subcohorts: black women; black men; white women; and white men, adjusted for age, comorbidities and year using logistic regression. Results: The study sample consisted of 4,045,267 AMI admissions between the years 1992 and 2010 (166,660 black women; 116,201 black men; 1,870,816 white women; 1,891,590 white men). AMI hospitalization rates differed significantly in 1992 to 1993 among black women (61.6 hospitalizations per 10,000 Medicare enrollees), black men (73.2 hospitalizations), white women (72.0 hospitalizations) and white men (113.2 hospitalizations) (P < 0.0001). By 2009 to 2010 AMI hospitalization rates had declined substantially in all cohorts but disparities remained with significantly lower hospitalization rates among women and blacks compared to men and whites, respectively (P < 0.0001). In multivariable-adjusted analyses, despite narrowing of the differences between cohorts over time, disparities in AMI hospitalization rates by race and sex remained statistically significant in 2009 to 2010 (P < 0.001). In 1992 to 1993 and 2009 to 2010, rates of PCI within 30-days of AMI differed significantly among black women (8.6% in 1992 to 1993; 24.2% in 2009 to 2010), black men (10.4% and 32.6%), white women (12.8% and 30.5%), and white men (16.1% and 40.7%) (P < 0.0001). In multivariable-adjusted analyses, racial disparities in procedure utilization appeared somewhat larger and sex-based disparities remained significant. Unadjusted 30-day mortality after AMI in 1992 to 1993 for black women, black men, white women and white men was 20.4%, 17.9%, 23.1% and 19.5%, respectively (P < 0.0001); in 2009 to 2010 mortality was 17.1%, 15.3%, 18.2% and 16.2%, respectively (P < 0.0001). In adjusted analyses, racial differences in mortality declined over time but differences by sex (higher mortality for women) persisted. Conclusions: Disparities in AMI have declined modestly, but remain a problem, particularly with respect to patient sex. C1 [Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham Vet Affairs Med Ctr, Med Serv, Birmingham, AL 35294 USA. [Lu, Xin] Univ Iowa, Carver Coll Med, Dept Internal Med, Div Gen Internal Med, Iowa City, IA 52242 USA. [Lu, Xin] City Vet Adm Med Ctr, CADRE, Iowa City, IA 52242 USA. [Ibrahim, Said] Perelman Univ Penn, Sch Med, Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA 19104 USA. [Cram, Peter] Univ Hlth Network, Div Gen Internal Med & Geriatr, Toronto, ON M5G 2C4, Canada. [Cram, Peter] Mt Sinai Hosp, Toronto, ON M5G 2C4, Canada. [Cram, Peter] Univ Toronto, Fac Med, Toronto, ON, Canada. RP Singh, JA (reprint author), Univ Alabama Birmingham, Birmingham Vet Affairs Med Ctr, Med Serv, 510 S 20th St,Fac Off Tower 805B, Birmingham, AL 35294 USA. EM jasvinder.md@gmail.com FU NHLBI [R01 HL085347]; NIA at the NIH [R01 AG033035]; National Institute of Aging, National Cancer Institute, Agency for Health Quality and Research Center for Education and Research on Therapeutics (CERTs); NIAMS [AR062133]; Department of Veterans Affairs; National Institute of Arthritis and Musculoskeletal and Skin Diseases [K24AR055259] FX This work is also funded in part by R01 HL085347 from NHLBI and R01 AG033035 from NIA at the NIH. JAS is supported by research grants from National Institute of Aging, National Cancer Institute, Agency for Health Quality and Research Center for Education and Research on Therapeutics (CERTs), and the resources and the use of facilities at the Birmingham VA Medical Center, Alabama, USA. PC is supported by a K24 award from NIAMS (AR062133) and by the Department of Veterans Affairs. Dr. Ibrahim is supported by Grant Number K24AR055259 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. NR 35 TC 12 Z9 12 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD OCT 24 PY 2014 VL 12 AR 190 DI 10.1186/s12916-014-0190-6 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA AT4FE UT WOS:000344894400001 PM 25341547 ER PT J AU Yi, CR Allen, JE Russo, B Lee, SY Heindl, JE Baxt, LA Herrera, BB Kahoud, E MacBeath, G Goldberg, MB AF Yi, Chae-ryun Allen, John E. Russo, Brian Lee, Soo Young Heindl, Jason E. Baxt, Leigh A. Herrera, Bobby Brooke Kahoud, Emily MacBeath, Gavin Goldberg, Marcia B. TI Systematic Analysis of Bacterial Effector-Postsynaptic Density 95/Disc Large/Zonula Occludens-1 (PDZ) Domain Interactions Demonstrates Shigella OspE Protein Promotes Protein Kinase C Activation via PDLIM Proteins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article DE Bacterial Pathogenesis; PDZ Domain; Protein Kinase C (PKC); Protein-Protein Interaction; Secretion; Type III Secretion System (T3SS); OspE; PDLIM Proteins; Shigella ID III SECRETION SYSTEM; ENTEROPATHOGENIC ESCHERICHIA-COLI; VIRULENCE FACTOR NLEA; LIM DOMAINS; HOST-CELLS; BINDING; EXPRESSION; TARGETS; PHOSPHORYLATION; JUNCTIONS AB Background: PDZ domains provide specificity in protein-protein interactions in eukaryotic systems. Results:Shigella OspE, which is delivered into human cells during infection, binds PDLIM7 via a PDZ interaction and contributes to activation of PKC. Conclusion: During infection, OspE contributes to activation of PKC through PDZ-mediated binding to PDLIM7. Significance: PDZ interactions likely contribute to pathogenesis of several bacterial pathogens. Diseases caused by many Gram-negative bacterial pathogens depend on the activities of bacterial effector proteins that are delivered into eukaryotic cells via specialized secretion systems. Effector protein function largely depends on specific subcellular targeting and specific interactions with cellular ligands. PDZ domains are common domains that serve to provide specificity in protein-protein interactions in eukaryotic systems. We show that putative PDZ-binding motifs are significantly enriched among effector proteins delivered into mammalian cells by certain bacterial pathogens. We use PDZ domain microarrays to identify candidate interaction partners of the Shigella flexneri effector proteins OspE1 and OspE2, which contain putative PDZ-binding motifs. We demonstrate in vitro and in cells that OspE proteins interact with PDLIM7, a member of the PDLIM family of proteins, which contain a PDZ domain and one or more LIM domains, protein interaction domains that participate in a wide variety of functions, including activation of isoforms of protein kinase C (PKC). We demonstrate that activation of PKC during S. flexneri infection is attenuated in the absence of PDLIM7 or OspE proteins and that the OspE PDZ-binding motif is required for wild-type levels of PKC activation. These results are consistent with a model in which binding of OspE to PDLIM7 during infection regulates the activity of PKC isoforms that bind to the PDLIM7 LIM domain. C1 [Yi, Chae-ryun; Russo, Brian; Baxt, Leigh A.; Herrera, Bobby Brooke; Kahoud, Emily; Goldberg, Marcia B.] Massachusetts Gen Hosp, Div Infect Dis, Cambridge, MA 02139 USA. [Allen, John E.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Lee, Soo Young] Harvard Univ, Sch Med, Program Immunol, Boston, MA 02115 USA. [Russo, Brian; Heindl, Jason E.; Goldberg, Marcia B.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [MacBeath, Gavin] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Goldberg, MB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Cambridge, MA 02139 USA. EM marcia.goldberg@mgh.harvard.edu OI Lee, Soo Young/0000-0003-1524-836X; Heindl, Jason/0000-0003-3919-8045; Allen, John/0000-0001-5005-5139 FU National Institutes of Health [F32 AI092967, R01 AI081724]; American Heart Association [09POST2260574] FX This work was supported, in whole or in part, by National Institutes of Health Grants F32 AI092967 (to L. A. B.) and R01 AI081724 (to M. B. G.). G. M. and J. E. A. are employees and stockholders of Merrimack Pharmaceuticals, Inc.; Supported by American Heart Association Postdoctoral Fellowship 09POST2260574. NR 42 TC 1 Z9 1 U1 1 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 OCT 24 PY 2014 VL 289 IS 43 BP 30101 EP 30113 DI 10.1074/jbc.M114.595868 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AS6JU UT WOS:000344370800050 PM 25124035 ER PT J AU Huang, S Rossi, S Hamalainen, M Ahveninen, J AF Huang, Samantha Rossi, Stephanie Haemaelaeinen, Matti Ahveninen, Jyrki TI Auditory Conflict Resolution Correlates with Medial-Lateral Frontal Theta/Alpha Phase Synchrony SO PLOS ONE LA English DT Article ID ANTERIOR CINGULATE CORTEX; HUMAN CEREBRAL-CORTEX; EVENT-RELATED FMRI; WORKING-MEMORY; COGNITIVE CONTROL; SELECTIVE ATTENTION; PREFRONTAL CORTEX; RESPONSE CONFLICT; CORTICAL SURFACE; VISUAL-ATTENTION AB When multiple persons speak simultaneously, it may be difficult for the listener to direct attention to correct sound objects among conflicting ones. This could occur, for example, in an emergency situation in which one hears conflicting instructions and the loudest, instead of the wisest, voice prevails. Here, we used cortically-constrained oscillatory MEG/EEG estimates to examine how different brain regions, including caudal anterior cingulate (cACC) and dorsolateral prefrontal cortices (DLPFC), work together to resolve these kinds of auditory conflicts. During an auditory flanker interference task, subjects were presented with sound patterns consisting of three different voices, from three different directions (45 degrees left, straight ahead, 45 degrees right), sounding out either the letters "A'' or "O''. They were asked to discriminate which sound was presented centrally and ignore the flanking distracters that were phonetically either congruent (50%) or incongruent (50%) with the target. Our cortical MEG/EEG oscillatory estimates demonstrated a direct relationship between performance and brain activity, showing that efficient conflict resolution, as measured with reduced conflict-induced RT lags, is predicted by theta/alpha phase coupling between cACC and right lateral frontal cortex regions intersecting the right frontal eye fields (FEF) and DLPFC, as well as by increased pre-stimulus gamma (60-110 Hz) power in the left inferior fontal cortex. Notably, cACC connectivity patterns that correlated with behavioral conflict-resolution measures were found during both the pre-stimulus and the pre-response periods. Our data provide evidence that, instead of being only transiently activated upon conflict detection, cACC is involved in sustained engagement of attentional resources required for effective sound object selection performance. C1 [Huang, Samantha; Rossi, Stephanie; Haemaelaeinen, Matti; Ahveninen, Jyrki] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA 02129 USA. [Haemaelaeinen, Matti] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Huang, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA 02129 USA. EM samhuang@nmr.mgh.harvard.edu RI Hamalainen, Matti/C-8507-2013 FU National Institutes of Health [R01MH083744, R21DC010060, R21DC014134, R01HD040712, R01NS037462, 5R01EB009048]; National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health; National Center for Research Resources Shared Instrumentation Grants [S10RR014978, S10RR021110, S10RR019307, S10RR014798, S10RR023401] FX This work was supported by National Institutes of Health Awards R01MH083744, R21DC010060, R21DC014134, R01HD040712, R01NS037462, and 5R01EB009048. This research was carried out at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, and a P41 Biotechnology Resource Grant supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. The research environment was additionally supported by National Center for Research Resources Shared Instrumentation Grants S10RR014978, S10RR021110, S10RR019307, S10RR014798, and S10RR023401. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 109 TC 2 Z9 2 U1 2 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 24 PY 2014 VL 9 IS 10 AR e110989 DI 10.1371/journal.pone.0110989 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS0BL UT WOS:000343943500071 PM 25343503 ER PT J AU Mehan, WA Gonzalez, RG Buchbinder, BR Chen, JW Copen, WA Gupta, R Hirsch, JA Hunter, GJ Hunter, S Johnson, JM Kelly, HR Larvie, M Lev, MH Pomerantz, SR Rapalino, O Rincon, S Romero, JM Schaefer, PW Shah, V AF Mehan, William A., Jr. Gonzalez, R. Gilberto Buchbinder, Bradley R. Chen, John W. Copen, William A. Gupta, Rajiv Hirsch, Joshua A. Hunter, George J. Hunter, Scott Johnson, Jason M. Kelly, Hillary R. Larvie, Mykol Lev, Michael H. Pomerantz, Stuart R. Rapalino, Otto Rincon, Sandra Romero, Javier M. Schaefer, Pamela W. Shah, Vinil TI Optimal Brain MRI Protocol for New Neurological Complaint SO PLOS ONE LA English DT Article ID ATTENUATED INVERSION-RECOVERY; GRADIENT-ECHO MR; SPIN-ECHO; INTRACRANIAL HEMORRHAGE; MULTIPLE-SCLEROSIS; PLANAR SEQUENCES; THIN-SECTION; FLAIR; LESIONS; IMAGES AB Background/Purpose: Patients with neurologic complaints are imaged with MRI protocols that may include many pulse sequences. It has not been documented which sequences are essential. We assessed the diagnostic accuracy of a limited number of sequences in patients with new neurologic complaints. Methods: 996 consecutive brain MRI studies from patients with new neurological complaints were divided into 2 groups. In group 1, reviewers used a 3-sequence set that included sagittal T1-weighted, axial T2-weighted fluid-attenuated inversion recovery, and axial diffusion-weighted images. Subsequently, another group of studies were reviewed using axial susceptibility-weighted images in addition to the 3 sequences. The reference standard was the study's official report. Discrepancies between the limited sequence review and the reference standard including Level I findings (that may require immediate change in patient management) were identified. Results: There were 84 major findings in 497 studies in group 1 with 21 not identified in the limited sequence evaluations: 12 enhancing lesions and 3 vascular abnormalities identified on MR angiography. The 3-sequence set did not reveal microhemorrhagic foci in 15 of 19 studies. There were 117 major findings in 499 studies in group 2 with 19 not identified on the 4-sequence set: 17 enhancing lesions and 2 vascular lesions identified on angiography. All 87 Level I findings were identified using limited sequence (56 acute infarcts, 16 hemorrhages, and 15 mass lesions). Conclusion: A 4-pulse sequence brain MRI study is sufficient to evaluate patients with a new neurological complaint except when contrast or angiography is indicated. C1 [Mehan, William A., Jr.; Gonzalez, R. Gilberto; Buchbinder, Bradley R.; Chen, John W.; Copen, William A.; Gupta, Rajiv; Hirsch, Joshua A.; Hunter, George J.; Hunter, Scott; Johnson, Jason M.; Kelly, Hillary R.; Larvie, Mykol; Lev, Michael H.; Pomerantz, Stuart R.; Rapalino, Otto; Rincon, Sandra; Romero, Javier M.; Schaefer, Pamela W.; Shah, Vinil] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroradiol Div, Boston, MA 02115 USA. RP Gonzalez, RG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroradiol Div, Boston, MA 02115 USA. EM rggonzalez@mgh.harvard.edu NR 23 TC 0 Z9 0 U1 0 U2 0 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 OCT 24 PY 2014 VL 9 IS 10 AR e110803 DI 10.1371/journal.pone.0110803 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS0BL UT WOS:000343943500057 PM 25343371 ER PT J AU Castro, VM McCoy, TH Cagan, A Rosenfield, HR Murphy, SN Churchill, SE Kohane, IS Perlis, RH AF Castro, Victor M. McCoy, Thomas H. Cagan, Andrew Rosenfield, Hannah R. Murphy, Shawn N. Churchill, Susanne E. Kohane, Isaac S. Perlis, Roy H. TI Stratification of risk for hospital admissions for injury related to fall: cohort study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID OLDER-ADULTS; COSTS; CARE; RECLASSIFICATION; PREDICTION; BALANCE; ABILITY; PEOPLE; SCALE; DISCRIMINATION AB Objective To determine whether the ability to stratify an individual patient's hazard for falling could facilitate development of focused interventions aimed at reducing these adverse outcomes. Design Clinical and sociodemographic data from electronic health records were utilized to derive multiple logistic regression models of hospital readmissions for injuries related to falls. Drugs used at admission were summarized based on reported adverse effect frequencies in published drug labeling. Setting Two large academic medical centers in New England, United States. Participants The model was developed with 25 924 individuals age >= 40 with an initial hospital discharge. The resulting model was then tested in an independent set of 13 032 inpatients drawn from the same hospital and 36 588 individuals discharged from a second large hospital during the same period. Main outcome measure Hospital readmissions for injury related to falls. Results Among 25 924 discharged individuals, 680 (2.6%) were evaluated in the emergency department or admitted to hospital for a fall within 30 days of discharge, 1635 (6.3%) within 180 days of discharge, 2360 (9.1%) within one year, and 3465 (13.4%) within two years. Older age, female sex, white or African-American race, public insurance, greater number of drugs taken on discharge, and score for burden of adverse effects were each independently associated with hazard for fall. For drug burden, presence of a drug with a frequency of adverse effects related to fall of 10% was associated with 3.5% increase in odds of falling over the next two years (odds ratio 1.04, 95% confidence interval 1.02 to 1.05). In an independent testing set, the area under the receiver operating characteristics curve was 0.65 for a fall within two years based on cross sectional data and 0.72 with the addition of prior utilization data including age adjusted Charlson comorbidity index. Portability was promising, with area under the curve of 0.71 for the longitudinal model in a second hospital system. Conclusions It is potentially useful to stratify risk of falls based on clinical features available as artifacts of routine clinical care. A web based tool can be used to calculate and visualize risk associated with drug treatment to facilitate further investigation and application. C1 [Castro, Victor M.; McCoy, Thomas H.; Cagan, Andrew; Rosenfield, Hannah R.; Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. [Castro, Victor M.; Cagan, Andrew; Murphy, Shawn N.] Partners HealthCare Syst, Partners Res Comp, Boston, MA 02129 USA. [Castro, Victor M.; Cagan, Andrew; Murphy, Shawn N.] Massachusetts Gen Hosp, Lab Comp Sci, Boston, MA 02114 USA. [Castro, Victor M.; Cagan, Andrew; Murphy, Shawn N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McCoy, Thomas H.; Rosenfield, Hannah R.; Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. [Churchill, Susanne E.] Partners HealthCare Syst, Informat Syst, Natl Ctr Biomed Comp I2b2, Boston, MA 02115 USA. [Kohane, Isaac S.] Brigham & Womens Hosp, Dept Med, Natl Ctr Biomed Comp I2b2, Boston, MA 02115 USA. RP Perlis, RH (reprint author), Simches Res Bldg MGH,185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM rperlis@partners.org OI McCoy, Thomas/0000-0002-5624-0439 NR 34 TC 7 Z9 7 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD OCT 24 PY 2014 VL 349 AR g5863 DI 10.1136/bmj.g5863 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AR7OI UT WOS:000343768700001 PM 25954985 ER PT J AU Glessner, JT Bick, AG Ito, K Homsy, JG Rodriguez-Murillo, L Fromer, M Mazaika, E Vardarajan, B Italia, M Leipzig, J DePalma, SR Golhar, R Sanders, SJ Yamrom, B Ronemus, M Iossifov, I Willsey, AJ State, MW Kaltman, JR White, PS Shen, YF Warburton, D Brueckner, M Seidman, C Goldmuntz, E Gelb, BD Lifton, R Seidman, J Hakonarson, H Chung, WK AF Glessner, Joseph T. Bick, Alexander G. Ito, Kaoru Homsy, Jason G. Rodriguez-Murillo, Laura Fromer, Menachem Mazaika, Erica Vardarajan, Badri Italia, Michael Leipzig, Jeremy DePalma, Steven R. Golhar, Ryan Sanders, Stephan J. Yamrom, Boris Ronemus, Michael Iossifov, Ivan Willsey, A. Jeremy State, Matthew W. Kaltman, Jonathan R. White, Peter S. Shen, Yufeng Warburton, Dorothy Brueckner, Martina Seidman, Christine Goldmuntz, Elizabeth Gelb, Bruce D. Lifton, Richard Seidman, Jonathan Hakonarson, Hakon Chung, Wendy K. TI Increased Frequency of De Novo Copy Number Variants in Congenital Heart Disease by Integrative Analysis of Single Nucleotide Polymorphism Array and Exome Sequence Data SO CIRCULATION RESEARCH LA English DT Article DE DNA copy number variations; genomics; microarray analysis; polymorphism, single nucleotide ID HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; TGF-BETA RECEPTOR; LARGE GENE LISTS; TRANSCRIPTION FACTORS; CONOTRUNCAL DEFECTS; CHROMOSOME 1Q21.1; SEPTAL-DEFECTS; DELETION; MUTATIONS AB Rationale: Congenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis. Objective: To determine the contribution of de novo copy number variants (CNVs) in the pathogenesis of sporadic CHD. Methods and Results: We studied 538 CHD trios using genome-wide dense single nucleotide polymorphism arrays and whole exome sequencing. Results were experimentally validated using digital droplet polymerase chain reaction. We compared validated CNVs in CHD cases with CNVs in 1301 healthy control trios. The 2 complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either single nucleotide polymorphism array (P=7x10(-5); odds ratio, 4.6) or whole exome sequencing data (P=6x10(-4); odds ratio, 3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic (P=0.02; odds ratio, 2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in whole exome sequencing and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions. Conclusions: We demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD. C1 [Glessner, Joseph T.; Golhar, Ryan; Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Italia, Michael; Leipzig, Jeremy; White, Peter S.] Childrens Hosp Philadelphia, Ctr Biomed Informat, Philadelphia, PA 19104 USA. [Goldmuntz, Elizabeth] Childrens Hosp Philadelphia, Div Cardiol, Philadelphia, PA 19104 USA. [Glessner, Joseph T.; Hakonarson, Hakon] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Bick, Alexander G.; Ito, Kaoru; Homsy, Jason G.; Mazaika, Erica; DePalma, Steven R.; Seidman, Christine; Seidman, Jonathan] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Homsy, Jason G.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Rodriguez-Murillo, Laura; Gelb, Bruce D.] Icahn Sch Med Mt Sinai, Dept Pediat, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. [Rodriguez-Murillo, Laura; Fromer, Menachem; Gelb, Bruce D.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Fromer, Menachem] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Fromer, Menachem] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Vardarajan, Badri; Shen, Yufeng] Columbia Univ, Med Ctr, Dept Syst Biol, New York, NY 10032 USA. [Warburton, Dorothy] Columbia Univ, Med Ctr, Dept Genet & Dev Med, New York, NY 10032 USA. [Chung, Wendy K.] Columbia Univ, Med Ctr, Dept Pediat & Med, New York, NY 10032 USA. [Sanders, Stephan J.; Willsey, A. Jeremy; State, Matthew W.; Lifton, Richard] Yale Univ, Dept Genet, New Haven, CT USA. [Brueckner, Martina] Yale Univ, Dept Pediat, New Haven, CT 06520 USA. [Lifton, Richard] Yale Univ, Dept Med, New Haven, CT 06520 USA. [Sanders, Stephan J.; Willsey, A. Jeremy; State, Matthew W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Yamrom, Boris; Ronemus, Michael; Iossifov, Ivan] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Kaltman, Jonathan R.] NHLBI, Dept Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP Hakonarson, H (reprint author), Univ Penn, Dept Pediat, Ctr Appl Genom, Philadelphia, PA 19104 USA. EM hakonarson@email.chop.edu; Wkc15@Cumc.Columbia.Edu OI Leipzig, Jeremy/0000-0001-7224-9620; Sanders, Stephan/0000-0001-9112-5148 FU National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) Pediatric Cardiac Genomics Consortium [U01-HL098188, U01-HL098147, U01-HL098153, U01-HL098163, U01-HL098123, U01-HL098162]; Simons Foundation for Autism Research; NIH Centers for Mendelian Genomics [5U54HG006504]; John S. LaDue Fellowship of Harvard Medical School FX This work was supported by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) Pediatric Cardiac Genomics Consortium (U01-HL098188, U01-HL098147, U01-HL098153, U01-HL098163, U01-HL098123, and U01-HL098162) and in part by the Simons Foundation for Autism Research and the NIH Centers for Mendelian Genomics (5U54HG006504). J.G. Homsy is supported by the John S. LaDue Fellowship of Harvard Medical School. NR 71 TC 40 Z9 43 U1 1 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD OCT 24 PY 2014 VL 115 IS 10 BP 884 EP U209 DI 10.1161/CIRCRESAHA.115.304458 PG 46 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AR7MB UT WOS:000343762700014 PM 25205790 ER PT J AU Wilhelm, CJ Hashimoto, JG Roberts, ML Sonmez, MK Wiren, KM AF Wilhelm, C. J. Hashimoto, J. G. Roberts, M. L. Sonmez, M. K. Wiren, K. M. TI UNDERSTANDING THE ADDICTION CYCLE: A COMPLEX BIOLOGY WITH DISTINCT CONTRIBUTIONS OF GENOTYPE VS. SEX AT EACH STAGE SO NEUROSCIENCE LA English DT Article DE prefrontal cortex; ethanol; sexual dimorphism; inflammation; astrocytes; low level response to alcohol ID GENE COEXPRESSION NETWORKS; HIPPOCAMPAL SLICE CULTURES; ALCOHOL-USE DISORDERS; GENDER-DIFFERENCES; ETHANOL WITHDRAWAL; BRAIN-DAMAGE; MICROGLIAL ACTIVATION; ALVEOLAR MACROPHAGE; RETINOIC ACID; MOUSE-BRAIN AB Ethanol abuse can lead to addiction, brain damage and premature death. The cycle of alcohol addiction has been described as a composite consisting of three stages: intoxication, withdrawal and craving/abstinence. There is evidence for contributions of both genotype and sex to alcoholism, but an understanding of the biological underpinnings is limited. Utilizing both sexes of genetic animal models with highly divergent alcohol withdrawal severity, Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) mice, the distinct contributions of genotype/phenotype and of sex during addiction stages on neuroadaptation were characterized. Transcriptional profiling was performed to identify expression changes as a consequence of chronic intoxication in the medial prefrontal cortex. Significant expression differences were identified on a single platform and tracked over a behaviorally relevant time course that covered each stage of alcohol addiction; i.e., after chronic intoxication, during peak withdrawal, and after a defined period of abstinence. Females were more sensitive to ethanol with higher fold expression differences. Bioinformatics showed a strong effect of sex on the data structure of expression profiles during chronic intoxication and at peak withdrawal irrespective of genetic background. However, during abstinence, differences were observed instead between the lines/phenotypes irrespective of sex. Confirmation of identified pathways showed distinct inflammatory signaling following intoxication at peak withdrawal, with a pro-inflammatory phenotype in females but overall suppression of immune signaling in males. Combined, these results suggest that each stage of the addiction cycle is influenced differentially by sex vs. genetic background and support the development of stage- and sex-specific therapies for alcohol withdrawal and the maintenance of sobriety. Published by Elsevier Ltd. on behalf of IBRO. C1 [Wilhelm, C. J.; Hashimoto, J. G.; Roberts, M. L.; Wiren, K. M.] Dept Vet Affairs Med Ctr, Portland, OR 97239 USA. [Wilhelm, C. J.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97239 USA. [Hashimoto, J. G.; Wiren, K. M.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. [Sonmez, M. K.] Oregon Hlth & Sci Univ, Ctr Spoken Language Understanding, Portland, OR 97239 USA. RP Wilhelm, CJ (reprint author), Portland VA Med Ctr, Res Serv, 3710 SW Vet Hosp Rd, Portland, OR 97239 USA. EM wilhelmc@ohsu.edu FU Department of Veterans Affairs [BX001172, BX001294]; NIH/NIAAA [R01AA021468]; National Institute on Alcohol Abuse and Alcoholism [P60AA010760, R24AA020245] FX This research was supported by grants from the Department of Veterans Affairs (BX001172 (KMW) and BX001294 (CJW)) and from the NIH/NIAAA (R01AA021468 (KMW)). Additionally, this material is the result of work supported with resources and the use of facilities at the Portland VA Medical Center (KMW). We also acknowledge support from National Institute on Alcohol Abuse and Alcoholism for the Portland Alcohol Research Center (P60AA010760) and for the maintenance of colonies of WSR and WSP mice (R24AA020245) used in the present studies and thank Melissa Andrew for assistance with the vapor exposure procedure and Casia Wardzala for comments provided after careful reading of the manuscript. NR 107 TC 7 Z9 7 U1 4 U2 23 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD OCT 24 PY 2014 VL 279 BP 168 EP 186 DI 10.1016/j.neuroscience.2014.08.041 PG 19 WC Neurosciences SC Neurosciences & Neurology GA AR5ON UT WOS:000343633800015 PM 25194791 ER PT J AU Lucia, U Ponzetto, A Deisboeck, TS AF Lucia, Umberto Ponzetto, Antonio Deisboeck, Thomas S. TI A thermo-physical analysis of the proton pump vacuolar-ATPase: the constructal approach SO SCIENTIFIC REPORTS LA English DT Article ID ENERGY TRANSDUCTION; ENTROPY GENERATION; CELL-MEMBRANE; SARCOMA CELLS; FLOW SYSTEMS; TUMOR-CELLS; V-ATPASES; H+-ATPASE; THERMODYNAMICS; IRREVERSIBILITY AB Pumping protons across a membrane was a critical step at the origin of life on earth, and it is still performed in all living organisms, including in human cells. Proton pumping is paramount to keep normal cells alive, e. g. for lysosomal digestion and for preparing peptides for immune recognition, but it goes awry in cancer cells. They acidify their microenvironment hence membrane voltage is lowered, which in turn induces cell proliferation, a hallmark of cancer. Proton pumping is achieved by means of rotary motors, namely vacuolar ATPases (V-ATPase), which are present at many of the multiple cellular interfaces. Therefore, we undertook an examination of the thermodynamic properties of V-ATPases. The principal result is that the V-ATPase-mediated control of the cell membrane potential and the related and consequent environmental pH can potentially represent a valuable support strategy for anticancer therapies. A constructal theory approach is used as a new viewpoint to study how V-ATPase can be modulated for therapeutic purposes. In particular, V-ATPase can be regulated by using external fields, such as electromagnetic fields, and a theoretical approach has been introduced to quantify the appropriate field strength and frequency for this new adjuvant therapeutic strategy. C1 [Lucia, Umberto] Politecn Torino, Dipartimento Energia, I-10129 Turin, Italy. [Ponzetto, Antonio] Univ Turin, Dept Med Sci, I-10126 Turin, Italy. [Deisboeck, Thomas S.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Deisboeck, Thomas S.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Lucia, U (reprint author), Politecn Torino, Dipartimento Energia, Corso Duca Abruzzi 24, I-10129 Turin, Italy. EM umberto.lucia@polito.it OI Lucia, Umberto/0000-0002-3123-2133; ponzetto, antonio/0000-0002-1551-3664 NR 60 TC 12 Z9 12 U1 4 U2 10 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 OCT 24 PY 2014 VL 4 AR 6763 DI 10.1038/srep06763 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR5BA UT WOS:000343598800015 PM 25342534 ER PT J AU Zhang, Y Moschetta, M Huynh, D Tai, YT Zhang, Y Zhang, WJ Mishima, Y Ring, JE Tam, WF Xu, QL Maiso, P Reagan, M Sahin, I Sacco, A Manier, S Aljawai, Y Glavey, S Munshi, NC Anderson, KC Pachter, J Roccaro, AM Ghobrial, IM AF Zhang, Yu Moschetta, Michele Daisy Huynh Tai, Yu-Tzu Zhang, Yong Zhang, Wenjing Mishima, Yuji Ring, Jennifer E. Tam, Winnie F. Xu, Qunli Maiso, Patricia Reagan, Michaela Sahin, Ilyas Sacco, Antonio Manier, Salomon Aljawai, Yosra Glavey, Siobhan Munshi, Nikhil C. Anderson, Kenneth C. Pachter, Jonathan Roccaro, Aldo M. Ghobrial, Irene M. TI Pyk2 promotes tumor progression in multiple myeloma SO BLOOD LA English DT Article ID FOCAL ADHESION KINASE; TYROSINE KINASE; MONOCLONAL GAMMOPATHY; B-CELLS; CANCER; PROTEIN; FAK; ACTIVATION; GROWTH; PROLIFERATION AB Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family that has been recently linked to tumor development. However, its role in modulating multiple myeloma (MM) biology and disease progression remains unexplored. We first demonstrated that patients with MM present with higher expression of Pyk2 compared with healthy individuals. By using loss-of-function approaches, we found that Pyk2 inhibition led to reduction of MM tumor growth in vivo as well as decreased cell proliferation, cellcycle progression, and adhesion ability in vitro. In turn, overexpression of Pyk2 promoted the malignant phenotype, substantiated by enhanced tumor growth and reduced survival. Mechanistically, inhibition of Pyk2 reduced activation of Wnt/beta-catenin signaling by destabilizing beta-catenin, leading to downregulation of c-Myc and Cyclin D1. Furthermore, treatment of MM cells with the FAK/Pyk2 inhibitor VS-4718 effectively inhibited MM cell growth both in vitro and in vivo. Collectively, our findings describe the tumor-promoting role of Pyk2 in MM, thus providing molecular evidence for a novel tyrosine kinase inhibitor as a new therapeutic option in MM. C1 [Zhang, Yu; Moschetta, Michele; Daisy Huynh; Tai, Yu-Tzu; Zhang, Yong; Zhang, Wenjing; Mishima, Yuji; Maiso, Patricia; Reagan, Michaela; Sahin, Ilyas; Sacco, Antonio; Manier, Salomon; Aljawai, Yosra; Glavey, Siobhan; Munshi, Nikhil C.; Anderson, Kenneth C.; Roccaro, Aldo M.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Zhang, Yu] First Peoples Hosp Yunnan Prov, Dept Gastroenterol, Kunming, Peoples R China. [Zhang, Wenjing] Southern Med Univ, Nanfang Hosp, Guangzhou, Guangdong, Peoples R China. [Ring, Jennifer E.; Tam, Winnie F.; Xu, Qunli; Pachter, Jonathan] Verastem Inc, Cambridge, MA USA. RP Ghobrial, IM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM aldo_roccaro@dfci.harvard.edu; irene_ghobrial@dfci.harvard.edu RI Sacco, Antonio/K-4681-2016; Reagan, Michaela/E-3549-2017; OI Sacco, Antonio/0000-0003-2945-9416; Roccaro, Aldo/0000-0002-1872-5128; Maiso, Patricia/0000-0003-3745-1924; Reagan, Michaela/0000-0003-2884-6481 FU Multiple Myeloma Research Foundation; National Institutes of Health, National Cancer Institute [R01CA125690, 1R01CA152607] FX This study was supported in part by the Multiple Myeloma Research Foundation and by the National Institutes of Health, National Cancer Institute (grants R01CA125690 and 1R01CA152607). NR 47 TC 17 Z9 17 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 OCT 23 PY 2014 VL 124 IS 17 BP 2675 EP 2686 DI 10.1182/blood-2014-03-563981 PG 12 WC Hematology SC Hematology GA AY3AR UT WOS:000347457500013 PM 25217697 ER PT J AU Bejar, R Lord, A Stevenson, K Bar-Natan, M Perez-Ladaga, A Zaneveld, J Wang, H Caughey, B Stojanov, P Getz, G Garcia-Manero, G Kantarjian, H Chen, R Stone, RM Neuberg, D Steensma, DP Ebert, BL AF Bejar, Rafael Lord, Allegra Stevenson, Kristen Bar-Natan, Michal Perez-Ladaga, Albert Zaneveld, Jacques Wang, Hui Caughey, Bennett Stojanov, Petar Getz, Gad Garcia-Manero, Guillermo Kantarjian, Hagop Chen, Rui Stone, Richard M. Neuberg, Donna Steensma, David P. Ebert, Benjamin L. TI TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients SO BLOOD LA English DT Article ID PROGNOSTIC SCORING SYSTEM; HEMATOPOIETIC STEM-CELLS; ACUTE MYELOID-LEUKEMIA; DNA METHYLATION; POINT MUTATIONS; SELF-RENEWAL; AZACITIDINE; DECITABINE; LEADS; TRANSFORMATION AB Only a minority of myelodysplastic syndrome (MDS) patients respond to hypomethylating agents (HMAs), but strong predictors of response are unknown. We sequenced 40 recurrently mutated myeloid malignancy genes in tumor DNA from 213 MDS patients collected before treatment with azacitidine (AZA) or decitabine (DEC). Mutations were examined for association with response and overall survival. The overall response rate of 47% was not different between agents. Clonal TET2 mutations predicted response (odds ratio [OR] 1.99, P = .036) when subclones unlikely to be detected by Sanger sequencing (allele fraction <10%) were treated as wild-type (WT). Response rates were highest in the subset of TET2 mutant patients without clonal ASXL1 mutations (OR 3.65, P = .009). Mutations of TP53 (hazard ratio [HR] 2.01, P = .002) and PTPN11 (HR 3.26, P = .006) were associated with shorter overall survival but not drug response. Murine-competitive bone marrow transplantation followed by treatment with AZA demonstrated that Tet2-null cells have an engraftment advantage over Tet2-WT cells. AZA significantly decreased this advantage for Tet2-null cells (P = .002) but not Tet2-WT cells (P = .212). Overall, Tet2 loss appears to sensitize cells to treatment with AZA in vivo, and TET2 mutations can identify patients more likely to respond to HMAs. C1 [Bejar, Rafael; Perez-Ladaga, Albert; Caughey, Bennett] Univ Calif San Diego, Moores Canc Ctr, Div Hematol & Oncol, La Jolla, CA 92093 USA. [Lord, Allegra; Ebert, Benjamin L.] Harvard Univ, Brigham & Womens Hosp, Div Hematol, Sch Med, Boston, MA 02115 USA. [Stevenson, Kristen; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Bar-Natan, Michal; Stone, Richard M.; Steensma, David P.] Dana Farber Canc Inst, Dept Med Oncol, Div Hematol Malignancies, Boston, MA 02115 USA. [Zaneveld, Jacques; Wang, Hui; Chen, Rui] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Stojanov, Petar; Getz, Gad; Ebert, Benjamin L.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Garcia-Manero, Guillermo; Kantarjian, Hagop] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. RP Ebert, BL (reprint author), Brigham & Womens Hosp, 1 Blackfan Circle Karp CHRB 5-211, Boston, MA 02115 USA. EM rabejar@ucsd.edu; bebert@partners.org FU National Institutes of Health, National Heart, Lung and Blood Institute [R01HL082945]; Department of Defense bone marrow failure research program grant; Leukemia and Lymphoma Society Scholar Award; National Institute of Diabetes and Digestive and Kidney Diseases [K08DK091360]; ASH Scholar Award; MD Anderson Cancer Center Leukemia Support Grant (CCSG) [CA016672, MDS P01 CA108631]; Fundacion Ramon Areces FX This work was funded by the National Institutes of Health, National Heart, Lung and Blood Institute (R01HL082945), a Department of Defense bone marrow failure research program grant, a Leukemia and Lymphoma Society Scholar Award (B.L.E.), the National Institute of Diabetes and Digestive and Kidney Diseases (K08DK091360), and an ASH Scholar Award (R.B.). In addition, this research was supported in part by the MD Anderson Cancer Center Leukemia Support Grant (CCSG) CA016672, grant MDS P01 CA108631, and the Fundacion Ramon Areces. NR 36 TC 110 Z9 116 U1 4 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 23 PY 2014 VL 124 IS 17 BP 2705 EP 2712 DI 10.1182/blood-2014-06-582809 PG 8 WC Hematology SC Hematology GA AY3AR UT WOS:000347457500016 PM 25224413 ER PT J AU Yi, P Park, JS Melton, DA AF Yi, Peng Park, Ji-Sun Melton, Douglas A. TI Perspectives on the Activities of ANGPTL8/Betatrophin SO CELL LA English DT Letter ID IDENTIFICATION; BETATROPHIN; LIVER C1 [Yi, Peng] Harvard Univ, Joslin Diabet Ctr, Sch Med, Boston, MA 02215 USA. [Park, Ji-Sun; Melton, Douglas A.] Howard Hughes Med Inst, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Yi, P (reprint author), Harvard Univ, Joslin Diabet Ctr, Sch Med, 1 Joslin Pl, Boston, MA 02215 USA. EM peng.yi@joslin.harvard.edu; dmelton@harvard.edu FU Howard Hughes Medical Institute NR 9 TC 18 Z9 20 U1 2 U2 17 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 OCT 23 PY 2014 VL 159 IS 3 BP 467 EP 468 DI 10.1016/j.cell.2014.09.028 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AS8TU UT WOS:000344521700001 PM 25417096 ER PT J AU Gusarova, V Alexa, CA Na, EQ Stevis, PE Xin, YR Bonner-Weir, S Cohen, JC Hobbs, HH Murphy, AJ Yancopoulos, GD Gromada, J AF Gusarova, Viktoria Alexa, Corey A. Na, Erqian Stevis, Panayiotis E. Xin, Yurong Bonner-Weir, Susan Cohen, Jonathan C. Hobbs, Helen H. Murphy, Andrew J. Yancopoulos, George D. Gromada, Jesper TI ANGPTL8/Betatrophin Does Not Control Pancreatic Beta Cell Expansion SO CELL LA English DT Article ID GLUCOSE-INFUSION; INSULIN-RESISTANCE; BETATROPHIN; MICE; REGENERATION; INDIVIDUALS; REPLICATION; HYPERPLASIA; METABOLISM; DISEASE AB Recently, it was reported that angiopoietin-like protein 8 (ANGPTL8) was the long-sought "betatrophin" that could control pancreatic beta cell proliferation. However, studies of Angptl8(-/-) mice revealed profound reduction of triglyceride levels, but no abnormalities in glucose homeostasis. We now report that Angptl8(-/-) mice undergo entirely normal beta cell expansion in response to insulin resistance resulting from either a high-fat diet or from the administration of the insulin receptor antagonist S961. Furthermore, overexpression of ANGPTL8 in livers of mice doubles plasma triglyceride levels, but does not alter beta cell expansion nor glucose metabolism. These data indicate that ANGPTL8 does not play a role in controlling beta cell growth, nor can it be given to induce such expansion. The findings that plasma triglyceride levels are reduced by Angptl8 deletion and increased following ANGPTL8 overexpression support the possibility that inhibition of ANGPTL8 represents a therapeutic strategy for hypertriglyceridemia. C1 [Gusarova, Viktoria; Alexa, Corey A.; Na, Erqian; Stevis, Panayiotis E.; Xin, Yurong; Murphy, Andrew J.; Yancopoulos, George D.; Gromada, Jesper] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. [Bonner-Weir, Susan] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Cohen, Jonathan C.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Hobbs, Helen H.] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. [Hobbs, Helen H.] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA. RP Gusarova, V (reprint author), Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 USA. EM viktoria.gusarova@regeneron.com OI Murphy, Andrew/0000-0003-4152-4081 FU NIH [PO1 HL20948] FX We wish to thank Lisa Shihanian, Kristen Tramaglini, and Lawrence Miloscio for excellent technical assistance. We would also like to acknowledge support from the NIH (PO1 HL20948). Viktoria Gusarova, Corey A. Alexa, Erqian Na, Panayiotis E. Stevis, Yurong Xin, Andrew J. Murphy, George D. Yancopoulos, and Jesper Gromada are employees and shareholders of Regeneron Pharmaceuticals. NR 22 TC 74 Z9 80 U1 1 U2 8 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 OCT 23 PY 2014 VL 159 IS 3 BP 691 EP 696 DI 10.1016/j.cell.2014.09.027 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AS8TU UT WOS:000344521700022 PM 25417115 ER PT J AU Deran, M Yang, JY Shen, CH Peters, EC Fitamant, J Chan, P Hsieh, M Zhu, SY Asara, JM Zheng, B Bardeesy, N Liu, J Wu, X AF DeRan, Michael Yang, Jiayi Shen, Che-Hung Peters, Eric C. Fitamant, Julien Chan, Puiyee Hsieh, Mindy Zhu, Shunying Asara, John M. Zheng, Bin Bardeesy, Nabeel Liu, Jun Wu, Xu TI Energy Stress Regulates Hippo-YAP Signaling Involving AMPK-Mediated Regulation of Angiomotin-like 1 Protein SO CELL REPORTS LA English DT Article ID CELL-GROWTH; TUMOR-SUPPRESSOR; PROMOTES APOPTOSIS; SIZE-CONTROL; PATHWAY; PROLIFERATION; KINASE; PHOSPHORYLATION; INACTIVATION; ONCOPROTEIN AB Hippo signaling is a tumor-suppressor pathway involved in organ size control and tumorigenesis through the inhibition of YAP and TAZ. Here, we show that energy stress induces YAP cytoplasmic retention and S127 phosphorylation and inhibits YAP transcriptional activity and YAP-dependent transformation. These effects require the central metabolic sensor AMP-activated protein kinase (AMPK) and the upstream Hippo pathway components Lats1/Lats2 and angiomotin-like 1 (AMOTL1). Furthermore, we show that AMPK directly phosphorylates S793 of AMOTL1. AMPK activation stabilizes and increases AMOTL1 steady-state protein levels, contributing to YAP inhibition. The phosphorylation-deficient S793Ala mutant of AMOTL1 showed a shorter half-life and conferred resistance to energy-stress-induced YAP inhibition. Our findings link energy sensing to the Hippo-YAP pathway and suggest that YAP may integrate spatial (contact inhibition), mechanical, and metabolic signals to control cellular proliferation and survival. C1 [DeRan, Michael; Shen, Che-Hung; Chan, Puiyee; Zhu, Shunying; Zheng, Bin; Wu, Xu] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Yang, Jiayi; Peters, Eric C.; Hsieh, Mindy; Liu, Jun] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. [Fitamant, Julien; Bardeesy, Nabeel] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Asara, John M.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA. RP Wu, X (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. EM xwu@cbrc2.mgh.harvard.edu FU MGH; HSCI Seed Grant; Children's Tumor Foundation; American Cancer Society [124929-RSG-13-291-01-TBE]; NIH/NCI [R01CA181537, R01CA166717] FX This work is supported by MGH, HSCI Seed Grant, Children's Tumor Foundation, American Cancer Society (124929-RSG-13-291-01-TBE), NIH/NCI R01CA181537 (X. W.), and NIH/NCI R01CA166717 (B.Z.). We thank Drs. K.-L. Guan, A. Schmitt, J. Brugge, M. Sudol, D. McCollum, J. Avruch, K. Laderoute, and L. Cantley for constructs, antibodies, cell lines, or discussions. E. C. P., M. H., and J. L. are employees of Novartis. NR 34 TC 45 Z9 45 U1 2 U2 13 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 OCT 23 PY 2014 VL 9 IS 2 BP 495 EP 503 DI 10.1016/j.celrep.2014.09.036 PG 9 WC Cell Biology SC Cell Biology GA AS7YZ UT WOS:000344469100010 PM 25373897 ER PT J AU Zhu, J Davoli, T Perriera, JM Chin, CR Gaiha, GD John, SP Sigiollot, FD Gao, G Xu, QK Qu, HJ Pertel, T Sims, JS Smith, JA Baker, RE Maranda, L Ng, A Elledge, SJ Brass, AL AF Zhu, Jian Davoli, Teresa Perriera, Jill M. Chin, Christopher R. Gaiha, Gaurav D. John, Sinu P. Sigiollot, Frederic D. Gao, Geng Xu, Qikai Qu, Hongjing Pertel, Thomas Sims, Jennifer S. Smith, Jennifer A. Baker, Richard E. Maranda, Louise Ng, Aylwin Elledge, Stephen J. Brass, Abraham L. TI Comprehensive Identification of Host Modulators of HIV-1 Replication using Multiple Orthologous RNAi Reagents SO CELL REPORTS LA English DT Article ID DNA-DAMAGE; SCREENS; TRANSCRIPTION; COMPLEX; BINDING; INTEGRATION; EXPRESSION; EXPORT; GOLGI; CELLS AB RNAi screens have implicated hundreds of host proteins as HIV-1 dependency factors (HDFs). While informative, these early studies overlap poorly due to false positives and false negatives. To ameliorate these issues, we combined information from the existing HDF screens together with new screens performed with multiple orthologous RNAi reagents (MORR). In addition to being traditionally validated, the MORR screens and the historical HDF screens were quantitatively integrated by the adaptation of an established analysis program, RIGER, for the collective interpretation of each gene's phenotypic significance. False positives were addressed by the removal of poorly expressed candidates through gene expression filtering, as well as with GESS, which identifies off-target effects. This workflow produced a quantitatively integrated network of genes that modulate HIV-1 replication. We further investigated the roles of GOLGI49, SEC13, and COG in HIV-1 replication. Collectively, the MORR-RIGER method minimized the caveats of RNAi screening and improved our understanding of HIV-1-host cell interactions. C1 [Zhu, Jian; Davoli, Teresa; Gao, Geng; Xu, Qikai; Qu, Hongjing; Elledge, Stephen J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Genet, Boston, MA 02127 USA. [Perriera, Jill M.; Chin, Christopher R.; Baker, Richard E.; Brass, Abraham L.] Univ Massachusetts, Sch Med, Microbiol & Physiol Syst MaPS Dept, Worcester, MA 01655 USA. [Gaiha, Gaurav D.; John, Sinu P.; Pertel, Thomas; Sims, Jennifer S.; Brass, Abraham L.] MIT, Massachusetts Gen Hosp, Ragon Inst, Charlestown, MA 02129 USA. [Gaiha, Gaurav D.; John, Sinu P.; Pertel, Thomas; Sims, Jennifer S.; Brass, Abraham L.] Harvard Univ, Charlestown, MA 02129 USA. [Sigiollot, Frederic D.] Novartis Inst BioMed Res, Cambridge, MA 02115 USA. [Smith, Jennifer A.] Harvard Univ, Sch Med, ICCB Longwood Screening Facil, Boston, MA 02115 USA. [Maranda, Louise] Univ Massachusetts, Dept Quantitat Hlth Sci, Sch Med, North Worcester, MA 01655 USA. [Ng, Aylwin] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Elledge, Stephen J.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Elledge, SJ (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Genet, Boston, MA 02127 USA. EM selledge@genetics.med.harvard.edu; abraham.brass@umassmed.edu FU Bill and Melinda Gates Foundation; Burroughs Wellcome Fund; UMass CFAR; NIH [1R01AI091786] FX We thank S. Chanda (Burnham Institute) and A. Espeseth (Merck & Co.) for generously sharing their primary screen data, the ICCB-L (C. Shamu, S. Rudnicki, S. Johnston, K. Rudnicki, and D. Wrobel), UMass Medical School (P. Spatrick), the UMMS Genomics Core Facility (R. Fish, B. Hobbs, L. Benson, T. Brailey, and J. Barrett), and the Ragon Institute (M. Boyarina, K. Donnelly, and P. Richtmeyer). This research was funded by a grant from the Bill and Melinda Gates Foundation to A.L.B and S.J.E. A.L.B. is grateful to the Bill and Melinda Gates Foundation, the Burroughs Wellcome Fund, the UMass CFAR, and the NIH (1R01AI091786) for their generous support; S.J.E. is an Investigator with the Howard Hughes Medical Institute. NR 30 TC 17 Z9 18 U1 1 U2 6 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 OCT 23 PY 2014 VL 9 IS 2 BP 752 EP 766 DI 10.1016/j.celrep.2014.09.031 PG 15 WC Cell Biology SC Cell Biology GA AS7YZ UT WOS:000344469100031 PM 25373910 ER PT J AU Brown, JD Lin, CY Duan, Q Griffin, G Federation, AJ Paranal, RM Bair, S Newton, G Lichtman, AH Kung, AL Yang, TL Wang, H Luscinskas, FW Croce, KJ Bradner, JE Plutzky, J AF Brown, Jonathan D. Lin, Charles Y. Duan, Qiong Griffin, Gabriel Federation, Alexander J. Paranal, Ronald M. Bair, Steven Newton, Gail Lichtman, Andrew H. Kung, Andrew L. Yang, Tianlun Wang, Hong Luscinskas, Francis W. Croce, Kevin J. Bradner, James E. Plutzky, Jorge TI NF-kappa B Directs Dynamic Super Enhancer Formation in Inflammation and Atherogenesis SO MOLECULAR CELL LA English DT Article ID BROMODOMAIN PROTEIN BRD4; RNA-POLYMERASE-II; P-TEFB; TRANSCRIPTIONAL ELONGATION; SELECTIVE-INHIBITION; BET BROMODOMAINS; GENE-EXPRESSION; CELL IDENTITY; DISEASE; ATHEROSCLEROSIS AB Proinflammatory stimuli elicit rapid transcriptional responses via transduced signals to master regulatory transcription factors. To explore the role of chromatin-dependent signal transduction in the atherogenic inflammatory response, we characterized the dynamics, structure, and function of regulatory elements in the activated endothelial cell epigenome. Stimulation with tumor necrosis factor alpha prompted a dramatic and rapid global redistribution of chromatin activators to massive de novo clustered enhancer domains. Inflammatory super enhancers formed by nuclear factor-kappa B accumulate at the expense of immediately decommissioned, basal endothelial super enhancers, despite persistent histone hyperacetylation. Mass action of enhancer factor redistribution causes momentous swings in transcriptional initiation and elongation. A chemical genetic approach reveals a requirement for BET bromodomains in communicating enhancer remodeling to RNA Polymerase II and orchestrating the transition to the inflammatory cell state, demonstrated in activated endothelium and macrophages. BET bromodomain inhibition abrogates super enhancer-mediated inflammatory transcription, atherogenic endothelial responses, and atherosclerosis in vivo. C1 [Brown, Jonathan D.; Duan, Qiong; Wang, Hong; Croce, Kevin J.; Plutzky, Jorge] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA. [Lin, Charles Y.; Federation, Alexander J.; Paranal, Ronald M.; Bair, Steven; Kung, Andrew L.; Bradner, James E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Duan, Qiong; Yang, Tianlun] Cent S Univ, Xiangya Hosp, Div Cardiovasc, Changsha 410078, Hunan, Peoples R China. [Griffin, Gabriel; Newton, Gail; Lichtman, Andrew H.; Luscinskas, Francis W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Excellence Vasc Biol,Dept Pathol, Boston, MA 02115 USA. [Kung, Andrew L.] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA. RP Bradner, JE (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM james_bradner@dfci.harvard.edu; jplutzky@rics.bwh.harvard.edu FU NIH [K08 HL105678, PO1 HL36028, K08 HL086672-3, K08 CA128972]; Watkins Discovery Research Award; Harris Family Award; US Department of Defense CDMRP [CA120184]; Sarnoff Cardiovascular Research Foundation; Watkins Family Foundation; Burroughs-Wellcome Fund; Damon-Runyon Cancer Research Foundation; Richard and Susan Smith Family Foundation; Next Generation Award; Neissa Foundation; NHLBI [P01 HL048743] FX We are grateful to R. Young, P. Rahl, T. Graf, and C. Van Oevelen for stimulating discussions; M. Berkeley, Z. Herbert, and the late E. Fox (DFCI Microarray Core) for assistance with microarray experiments; and T. Volkert, J. Love, and S. Gupta at the Whitehead Genome Core for assistance with genome sequencing. This research was supported by NIH-K08 HL105678, The Watkins Discovery Research Award and The Harris Family Award (to J.D.B.); US Department of Defense CDMRP CA120184 (to C.Y.L.); Sarnoff Cardiovascular Research Foundation (to G.G. and S.B.); NIH PO1 HL36028 (to F.W.L. and A.H.L.); NIH-K08 HL086672-3 and Watkins Family Foundation (to K. C.); NIH-K08 CA128972, the Burroughs-Wellcome Fund, the Damon-Runyon Cancer Research Foundation, the Richard and Susan Smith Family Foundation, and the Next Generation Award (to J.E.B.); and the Neissa Foundation and NHLBI P01 HL048743 (to J.P.). J.E.B. is the scientific founder of Tensha Therapeutics, which is clinically translating drug-like derivatives of the JQ1 chemical probe of BET bromodomains used in this study as cancer therapeutics. As such, the Dana-Farber Cancer Institute and J.E.B. have been granted minority equity in Tensha. NR 42 TC 82 Z9 83 U1 1 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD OCT 23 PY 2014 VL 56 IS 2 BP 219 EP 231 DI 10.1016/j.molcel.2014.08.024 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AS8FE UT WOS:000344484600005 PM 25263595 ER PT J AU Acton, SE Farrugia, AJ Astarita, JL Mourao-Sa, D Jenkins, RP Nye, E Hooper, S van Blijswijk, J Rogers, NC Snelgrove, KJ Rosewell, I Moita, LF Stamp, G Turley, SJ Sahai, E Sousa, CRE AF Acton, Sophie E. Farrugia, Aaron J. Astarita, Jillian L. Mourao-Sa, Diego Jenkins, Robert P. Nye, Emma Hooper, Steven van Blijswijk, Janneke Rogers, Neil C. Snelgrove, Kathryn J. Rosewell, Ian Moita, Luis F. Stamp, Gordon Turley, Shannon J. Sahai, Erik Reis e Sousa, Caetano TI Dendritic cells control fibroblastic reticular network tension and lymph node expansion SO NATURE LA English DT Article ID T-CELLS; IN-VIVO; B-CELLS; ACTIVATION; INVASION; RHO; MIGRATION; PROTEINS; MOTILITY; CLEC-2 AB After immunogenic challenge, infiltrating and dividing lymphocytes markedly increase lymph node cellularity, leading to organ expansion(1,2). Here we report that the physical elasticity of lymph nodes is maintained in part by podoplanin (PDPN) signalling in stromal fibroblastic reticular cells (FRCs) and its modulation by CLEC-2 expressed on dendritic cells. We show in mouse cells that PDPN induces actomyosin contractility in FRCs via activation of RhoA/C and downstream Rho-associated protein kinase (ROCK). Engagement by CLEC-2 causes PDPN clustering and rapidly uncouples PDPN from RhoA/C activation, relaxing the actomyosin cytoskeleton and permitting FRC stretching. Notably, administration of CLEC-2 protein to immunized mice augments lymph node expansion. In contrast, lymph node expansion is significantly constrained in mice selectively lacking CLEC-2 expression in dendritic cells. Thus, the same dendritic cells that initiate immunity by presenting antigens to T lymphocytes(3) also initiate remodelling of lymph nodes by delivering CLEC-2 to FRCs. CLEC-2 modulation of PDPN signalling permits FRC network stretching and allows for the rapid lymph node expansion-driven by lymphocyte influx and proliferation-that is the critical hallmark of adaptive immunity. C1 [Acton, Sophie E.; Farrugia, Aaron J.; Mourao-Sa, Diego; van Blijswijk, Janneke; Rogers, Neil C.; Snelgrove, Kathryn J.; Reis e Sousa, Caetano] Canc Res UK London Res Inst, Immunobiol Lab, London WC2A 3LY, England. [Acton, Sophie E.] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England. [Farrugia, Aaron J.; Jenkins, Robert P.; Hooper, Steven; Sahai, Erik] Canc Res UK London Res Inst, Tumour Cell Biol Lab, London WC2A 3LY, England. [Astarita, Jillian L.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Nye, Emma; Stamp, Gordon] Canc Res UK London Res Inst, Expt Histopathol Lab, London WC2A 3LY, England. [Rosewell, Ian] Imperial Canc Res Fund, Clare Hall Labs, Canc Res UK London Res Inst, Transgen Lab, Potters Bar EN6 3LD, Herts, England. [Moita, Luis F.] Inst Gulbenkian Ciencias, P-2780156 Oeiras, Portugal. [Moita, Luis F.] Univ Lisbon, Fac Med, Inst Med Mol, P-1649028 Lisbon, Portugal. [Turley, Shannon J.] Genentech Inc, Dept Canc Immunol, San Francisco, CA 94080 USA. RP Acton, SE (reprint author), Canc Res UK London Res Inst, Immunobiol Lab, 44 Lincolns Inn Fields, London WC2A 3LY, England. EM sophie.acton@cancer.org.uk; caetano@cancer.org.uk RI Acton, Sophie/G-9784-2012; OI Acton, Sophie/0000-0003-2704-716X; Sahai, Erik/0000-0002-3932-5086; Moita, Luis/0000-0003-0707-315X; Reis e Sousa, Caetano/0000-0001-7392-2119 FU Henry Wellcome Postdoctoral fellowship; Cancer Research UK FX We thank B. Reizis for CD11c-Cre mice, the LRI Biological Resources staff for animal care and assistance with experiments and R. Horton-Harpin for production of CLEC-2-Fc. We are grateful to M. Y. Gerner and R. N. Germain for critical reading of the manuscript and to all the members of the Immunobiology Laboratory and Tumour Cell Biology Laboratory for helpful discussions and comments. This work was supported by a Henry Wellcome Postdoctoral fellowship (S.E.A.) and core funding from Cancer Research UK (I.R., G.S., E.S. and C.R.S.). NR 28 TC 43 Z9 50 U1 2 U2 30 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 OCT 23 PY 2014 VL 514 IS 7523 BP 498 EP + DI 10.1038/nature13814 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR7RC UT WOS:000343775900042 PM 25341788 ER PT J AU Cockerham, LR Siliciano, JD Sinclair, E O'Doherty, U Palmer, S Yukl, SA Strain, MC Chomont, N Hecht, FM Siliciano, RF Richman, DD Deeks, SG AF Cockerham, Leslie R. Siliciano, Janet D. Sinclair, Elizabeth O'Doherty, Una Palmer, Sarah Yukl, Steven A. Strain, Matt C. Chomont, Nicolas Hecht, Frederick M. Siliciano, Robert F. Richman, Douglas D. Deeks, Steven G. TI CD4(+) and CD8(+) T Cell Activation Are Associated with HIV DNA in Resting CD4(+) T Cells SO PLOS ONE LA English DT Article ID SUPPRESSIVE ANTIRETROVIRAL THERAPY; IMMUNE ACTIVATION; VIRAL PERSISTENCE; INFECTED PATIENTS; RESERVOIR; SIZE; REPLICATION; INTEGRATION; LYMPHOCYTES; EXPRESSION AB The association between the host immune environment and the size of the HIV reservoir during effective antiretroviral therapy is not clear. Progress has also been limited by the lack of a well-accepted assay for quantifying HIV during therapy. We examined the association between multiple measurements of HIV and T cell activation (as defined by markers including CD38, HLA-DR, CCR5 and PD-1) in 30 antiretroviral-treated HIV-infected adults. We found a consistent association between the frequency of CD4(+) and CD8(+) T cells expressing HLA-DR and the frequency of resting CD4(+) T cells containing HIV DNA. This study highlights the need to further examine this relationship and to better characterize the biology of markers commonly used in HIV studies. These results may also have implications for reactivation strategies. C1 [Cockerham, Leslie R.; Hecht, Frederick M.; Deeks, Steven G.] Univ Calif San Francisco, San Francisco Gen Hosp, Div HIV AIDS, San Francisco, CA 94143 USA. [Siliciano, Janet D.; Siliciano, Robert F.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Sinclair, Elizabeth] Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94143 USA. [O'Doherty, Una] Univ Penn, Philadelphia, PA 19104 USA. [Palmer, Sarah] Westmead Millennium Inst Med Res, Westmead, NSW, Australia. [Palmer, Sarah] Univ Sydney, Sydney, NSW 2006, Australia. [Palmer, Sarah] Karolinska Inst, Stockholm, Sweden. [Yukl, Steven A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Strain, Matt C.; Richman, Douglas D.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Richman, Douglas D.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Chomont, Nicolas] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL USA. [Siliciano, Robert F.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. RP Cockerham, LR (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Div HIV AIDS, San Francisco, CA 94143 USA. EM leslie.cockerham@ucsf.edu FU ARCHE Collaborative Research Grant from the Foundation for AIDS Research [amFAR 108165-50-RGRL]; Martin Delaney CARE and DARE Collaboratories (NIH) [AI096113, 1U19AI096109]; NIH [43222]; Howard Hughes Medical Institute; Department of Veterans Affairs; James Pendleton Charitable Trust; National Institutes of Health [AI080193, AI74621, AI69432-S]; CFAR [AI306214]; Department of Veterans Affairs (VA Career Development Award) [1 IK2 CX000520-01]; NIAID [RO1AIO87145, K24AIO69994]; UCSF/Gladstone CFAR [P30 AIO27763]; UCSF Clinical and Translational Research Institute Clinical Research Center [UL 1 RR024131]; Center for AIDS Prevention Studies [P30 MH62246] FX This work was supported by an ARCHE Collaborative Research Grant from the Foundation for AIDS Research (amFAR 108165-50-RGRL), by the Martin Delaney CARE and DARE Collaboratories (NIH grants AI096113 and 1U19AI096109), and by NIH grant 43222 (RFS), and by the Howard Hughes Medical Institute (RFS). For MCS and DDR, this work was supported by the Department of Veterans Affairs, the James Pendleton Charitable Trust, National Institutes of Health (AI080193, AI74621, AI69432-S), and CFAR grant AI306214. For SAY, this work was supported by the Department of Veterans Affairs (VA Career Development Award 1 IK2 CX000520-01). The UCSF SCOPE cohort was supported in part by the NIAID (RO1AIO87145, K24AIO69994), the UCSF/Gladstone CFAR (P30 AIO27763), the UCSF Clinical and Translational Research Institute Clinical Research Center (UL 1 RR024131) and the Center for AIDS Prevention Studies (P30 MH62246). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 16 Z9 16 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 23 PY 2014 VL 9 IS 10 AR e110731 DI 10.1371/journal.pone.0110731 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR5ZY UT WOS:000343662800051 PM 25340755 ER PT J AU Sadaka, A Palmer, K Suzuki, T Gilmore, MS AF Sadaka, Ama Palmer, Kelli Suzuki, Takashi Gilmore, Michael S. TI In Vitro and In Vivo Models of Staphylococcus aureus Endophthalmitis Implicate Specific Nutrients in Ocular Infection SO PLOS ONE LA English DT Article ID VIRULENCE GENE-EXPRESSION; GRAM-POSITIVE BACTERIA; LACTOCOCCUS-LACTIS; ESCHERICHIA-COLI; STATIONARY-PHASE; VITREOUS FLUID; SIALIC ACIDS; RABBIT MODEL; AMINO-ACIDS; CODY AB Purpose: To define global transcriptional responses of Staphylococcus aureus and its codY mutant (CodY is a transcription regulator of virulence and metabolic genes in response to branched-chain amino acids) when growing in bovine aqueous (AH) and vitreous humor (VH) in vitro, and to investigate the impact of codY deletion on S. aureus virulence in a novel murine anterior chamber (AC) infection model. Methods: For the in vitro model, differential transcriptomic gene expression of S. aureus and its codY mutant grown in chemically defined medium (CDM), AH, and VH was analyzed. Furthermore, the strains were inoculated into the AC of mice. Changes in bacterial growth, electroretinography and inflammation scores were monitored. Results: Bovine AH and VH provide sufficient nutrition for S. aureus growth in vitro. Transcriptome analysis identified 72 unique open reading frames differentially regulated >= 10-fold between CDM, AH, and VH. In the AC model, we found comparable growth of the codY mutant and wild type strains in vivo. Average inflammation scores and retinal function were significantly worse for codY mutant-infected eyes at 24 h post-infection. Conclusion: Our in vitro bovine AH and VH models identified likely nutrient sources for S. aureus in the ocular milieu. The in vivo model suggests that control of branched-chain amino acid availability has therapeutic potential in limiting S. aureus endophthalmitis severity. C1 [Sadaka, Ama; Palmer, Kelli; Suzuki, Takashi; Gilmore, Michael S.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02215 USA. [Sadaka, Ama; Palmer, Kelli; Suzuki, Takashi; Gilmore, Michael S.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. [Sadaka, Ama; Palmer, Kelli; Suzuki, Takashi; Gilmore, Michael S.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Sadaka, Ama; Palmer, Kelli; Suzuki, Takashi; Gilmore, Michael S.] Harvard Microbial Sci Initiat, Cambridge, MA USA. RP Gilmore, MS (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02215 USA. EM michael_gilmore@meei.harvard.edu FU NIH/NEI [EY008289]; NIH fellowship [EY020734] FX This project has been funded in part by NIH/NEI grant EY008289. KP was supported by NIH fellowship EY020734. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 1 Z9 1 U1 2 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 OCT 23 PY 2014 VL 9 IS 10 AR e0110872 DI 10.1371/journal.pone.0110872 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR5ZY UT WOS:000343662800065 PM 25340474 ER PT J AU Choy, E Attar, EC Oh, KS Huang, AJ Kerr, DA AF Choy, Edwin Attar, Eyal C. Oh, Kevin S. Huang, Ambrose J. Kerr, Darcy A. TI Case 33-2014: A 60-Year-Old Man with Bone Pain SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HEPATIC EPITHELIOID HEMANGIOENDOTHELIOMA; RANDOMIZED-TRIAL; LIPOSOMAL DOXORUBICIN; FRACTION RADIOTHERAPY; INTERFERON-ALPHA; FOLLOW-UP; 8 GY; BEVACIZUMAB; METASTASES; MASTOCYTOSIS C1 [Choy, Edwin; Attar, Eyal C.] Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. [Oh, Kevin S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Huang, Ambrose J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kerr, Darcy A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Choy, Edwin; Attar, Eyal C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Oh, Kevin S.] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Huang, Ambrose J.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Kerr, Darcy A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Choy, E (reprint author), Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. FU Amgen; Pfizer; Bayer; NPS Pharmaceuticals; Celgene; Janssen Pharmaceuticals FX Dr. Choy reports receiving consulting fees from Amgen, Pfizer, Bayer, and NPS Pharmaceuticals; and Dr. Attar, receiving consulting fees from Celgene and Janssen Pharmaceuticals. No other potential conflict of interest relevant to this article was reported. NR 42 TC 0 Z9 0 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 OCT 23 PY 2014 VL 371 IS 17 BP 1630 EP 1640 DI 10.1056/NEJMcpc1310000 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AR5UF UT WOS:000343648500012 PM 25337753 ER PT J AU Hyle, EP Shepard, JAO AF Hyle, Emily P. Shepard, Jo-Anne O. TI Case 23-2014: Fevers, Rash, Pancytopenia, and Abnormal Liver Function Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Hyle, Emily P.; Shepard, Jo-Anne O.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hyle, EP (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 2 TC 0 Z9 0 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 OCT 23 PY 2014 VL 371 IS 17 BP 1654 EP 1654 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AR5UF UT WOS:000343648500022 PM 25337762 ER PT J AU Cowansage, KK Shuman, T Dillingham, BC Chang, A Golshani, P Mayford, M AF Cowansage, Kiriana K. Shuman, Tristan Dillingham, Blythe C. Chang, Allene Golshani, Peyman Mayford, Mark TI Direct Reactivation of a Coherent Neocortical Memory of Context SO NEURON LA English DT Article ID MULTIPLE TRACE THEORY; RETROSPLENIAL CORTEX; FEAR MEMORY; SPATIAL MEMORY; DORSAL HIPPOCAMPUS; CONJUNCTIVE REPRESENTATIONS; TEMPORARY INACTIVATION; CONDITIONED-STIMULUS; RETROGRADE-AMNESIA; ASSOCIATIVE MEMORY AB Declarative memories are thought to be stored within anatomically distributed neuronal networks requiring the hippocampus; however, it is unclear how neocortical areas participate in memory at the time of encoding. Here, we use a c-fos-based genetic tagging system to selectively express the channelrhodopsin variant, ChEF, and optogenetically reactivate a specific neural ensemble in retrosplenial cortex (RSC) engaged by context fear conditioning. Artificial stimulation of RSC was sufficient to produce both context-specific behavior and downstream cellular activity commensurate with natural experience. Moreover, optogenetically but not contextually elicited responses were insensitive to hippocampal inactivation, suggesting that although the hippocampus is needed to coordinate activation by sensory cues, a higher-order cortical framework can independently subserve learned behavior, even shortly after learning. C1 [Cowansage, Kiriana K.; Dillingham, Blythe C.; Chang, Allene; Mayford, Mark] Scripps Res Inst, Dorris Neurosci Ctr, Dept Mol & Cellular Neurosci, La Jolla, CA 92037 USA. [Dillingham, Blythe C.] Univ Calif Los Angeles, Kellogg Sch Sci & Technol, Los Angeles, CA 90095 USA. [Shuman, Tristan; Golshani, Peyman] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Golshani, Peyman] UCLA Integrat Ctr Learning & Memory, Los Angeles, CA 90073 USA. [Golshani, Peyman] W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. RP Mayford, M (reprint author), Scripps Res Inst, Dorris Neurosci Ctr, Dept Mol & Cellular Neurosci, 10550 North Torrey Pines Rd,DNC 202, La Jolla, CA 92037 USA. EM mmayford@scripps.edu FU NIH [R01MH057368-15, R01DA028300-03, 5T32NS007101-35] FX This work was supported by NIH funding awards R01MH057368-15 and R01DA028300-03 (to M.M.) and 5T32NS007101-35 (to T.S.). We are grateful to Roger Tsien for providing the ChEF construct used to generate this mouse and to Peter Cameron for contributing the mRNA probes used in fos-CatFISH experiments. We also thank Anton Maximov and Denise Cai for providing helpful discussion and comments on the manuscript. NR 67 TC 38 Z9 39 U1 4 U2 18 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 OCT 22 PY 2014 VL 84 IS 2 BP 432 EP 441 DI 10.1016/j.neuron.2014.09.022 PG 10 WC Neurosciences SC Neurosciences & Neurology GA AS3HI UT WOS:000344167900021 PM 25308330 ER PT J AU Velez, JCQ Janech, MG Hicks, MP Morinelli, TA Rodgers, J Self, SE Arthur, JM Fitzgibbon, WR AF Velez, Juan Carlos Q. Janech, Michael G. Hicks, Megan P. Morinelli, Thomas A. Rodgers, Jessalyn Self, Sally E. Arthur, John M. Fitzgibbon, Wayne R. TI Lack of Renoprotective Effect of Chronic Intravenous Angiotensin-(1-7) or Angiotensin-(2-10) in a Rat Model of Focal Segmental Glomerulosclerosis SO PLOS ONE LA English DT Article ID FAWN-HOODED RAT; HYPERTENSIVE-RATS; KIDNEY-DISEASE; FLUID CONCENTRATIONS; ENDOTHELIAL-CELLS; MASS-SPECTROMETRY; ANESTHETIZED RATS; AT(2) RECEPTORS; RENAL-DISEASE; RENIN AB Unopposed angiotensin (Ang) II-mediated cellular effects may lead to progressive glomerulosclerosis. While Ang-II can be locally generated in the kidneys, we previously showed that glomerular podocytes primarily convert Ang-I, the precursor of Ang-II, to Ang-(1-7) and Ang-(2-10), peptides that have been independently implicated in biological actions opposing those of Ang-II. Therefore, we hypothesized that Ang-(1-7) and Ang-(2-10) could be renoprotective in the fawn-hooded hypertensive rat, a model of focal segmental glomerulosclerosis. We evaluated the ability of 8-12 week-long intravenous administration of either Ang-(1-7) or Ang-(2-10) (100-400 ng/kg/min) to reduce glomerular injury in uni-nephrectomized fawn-hooded hypertensive rats, early or late in the disease. Vehicle-treated rats developed hypertension and lesions of focal segmental glomerulosclerosis. No reduction in glomerular damage was observed, as measured by either 24-hour urinary protein excretion or histological examination of glomerulosclerosis, upon Ang-(1-7) or Ang-(2-10) administration, regardless of peptide dose or disease stage. On the contrary, when given at 400 ng/kg/min, both peptides induced a further increase in systolic blood pressure. Content of Ang peptides was measured by parallel reaction monitoring in kidneys harvested at sacrifice. Exogenous administration of Ang-(1-7) and Ang-(2-10) did not lead to a significant increase in their corresponding intrarenal levels. However, the relative abundance of Ang-(1-7) with respect to Ang-II was increased in kidney homogenates of Ang-(1-7)-treated rats. We conclude that chronic intravenous administration of Ang-(1-7) or Ang-(2-10) does not ameliorate glomerular damage in a rat model of focal segmental glomerulosclerosis and may induce a further rise in blood pressure, potentially aggravating glomerular injury. C1 [Velez, Juan Carlos Q.; Janech, Michael G.; Hicks, Megan P.; Morinelli, Thomas A.; Rodgers, Jessalyn; Arthur, John M.; Fitzgibbon, Wayne R.] Med Univ S Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. [Velez, Juan Carlos Q.; Arthur, John M.] Ralph H Johnson Vet Affairs Med Ctr, Med Serv, Charleston, SC USA. [Self, Sally E.] Med Univ S Carolina, Dept Pathol, Charleston, SC 29425 USA. RP Velez, JCQ (reprint author), Med Univ S Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. EM velezj@musc.edu RI Velez, Juan Carlos/N-3782-2016; OI Janech, Michael/0000-0002-3202-4811 FU National Institute of Diabetes and Digestive and Kidney Diseases of the National Institute of Health [DK080944]; American Recovery and Reinvestment Act [DK080944]; Nephcure Foundation; Dialysis Clinics Incorporated FX This work was partially funded by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institute of Health (DK080944) (JCV), American Recovery and Reinvestment Act supplement to DK080944 (MPH and WRF), and The Nephcure Foundation (MGJ), and Dialysis Clinics Incorporated (JCV and TAM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 2 Z9 2 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 22 PY 2014 VL 9 IS 10 AR e110083 DI 10.1371/journal.pone.0110083 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR6DY UT WOS:000343674800024 PM 25337950 ER PT J AU Friedewald, SM Rafferty, EA Conant, EF AF Friedewald, Sarah M. Rafferty, Elizabeth A. Conant, Emily F. TI Breast Cancer Screening With Tomosynthesis and Digital Mammography Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Friedewald, Sarah M.] Advocate Lutheran Gen Hosp, Caldwell Breast Ctr, Park Ridge, IL 60068 USA. [Rafferty, Elizabeth A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Conant, Emily F.] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Friedewald, SM (reprint author), Advocate Lutheran Gen Hosp, Ctr Adv Care, Caldwell Breast Ctr, 1700 Luther Ln, Park Ridge, IL 60068 USA. EM sarah.friedewald@advocatehealth.com NR 6 TC 8 Z9 8 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 22 PY 2014 VL 312 IS 16 BP 1695 EP 1696 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AR0YF UT WOS:000343301400034 PM 25335157 ER PT J AU Armstrong-Javors, A Chu, CJ AF Armstrong-Javors, Amy Chu, Catherine J. TI Child Neurology: Exaggerated dermal melanocytosis in a hypotonic infant A harbinger of GM1 gangliosidosis SO NEUROLOGY LA English DT Editorial Material ID GM1-GANGLIOSIDOSIS; DISEASE C1 [Armstrong-Javors, Amy] Massachusetts Gen Hosp, Dept Neurol, Div Child Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Armstrong-Javors, A (reprint author), Massachusetts Gen Hosp, Dept Neurol, Div Child Neurol, Boston, MA 02114 USA. EM aarmstrong-javors@partners.org NR 11 TC 1 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD OCT 21 PY 2014 VL 83 IS 17 BP E166 EP E168 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA AT3RJ UT WOS:000344851100003 PM 25332452 ER PT J AU Wu, GZ Cai, J Han, Y Chen, JH Huang, ZP Chen, CY Cai, Y Huang, HF Yang, YJ Liu, YK Xu, ZC He, DF Zhang, XQ Hu, XY Pinello, L Zhong, D He, FT Yuan, GC Wang, DZ Zeng, CY AF Wu, Gengze Cai, Jin Han, Yu Chen, Jinghai Huang, Zhan-Peng Chen, Caiyu Cai, Yue Huang, Hefei Yang, Yujia Liu, Yukai Xu, Zaicheng He, Duofen Zhang, Xiaoqun Hu, Xiaoyun Pinello, Luca Zhong, Dan He, Fengtian Yuan, Guo-Cheng Wang, Da-Zhi Zeng, Chunyu TI LincRNA-p21 Regulates Neointima Formation, Vascular Smooth Muscle Cell Proliferation, Apoptosis, and Atherosclerosis by Enhancing p53 Activity SO CIRCULATION LA English DT Article DE apoptosis; atherosclerosis; cell proliferation; MDM2 protein; RNA, long noncoding; tumor suppressor protein p53 ID LONG NONCODING RNAS; DNA-DAMAGE; IN-VIVO; MDM2; GENE; ACETYLATION; DISEASE; PROTEIN; TRANSCRIPTION; DEGRADATION AB Background-Long noncoding RNAs (lncRNAs) have recently been implicated in many biological processes and diseases. Atherosclerosis is a major risk factor for cardiovascular disease. However, the functional role of lncRNAs in atherosclerosis is largely unknown. Methods and Results-We identified lincRNA-p21 as a key regulator of cell proliferation and apoptosis during atherosclerosis. The expression of lincRNA-p21 was dramatically downregulated in atherosclerotic plaques of ApoE(-/-) mice, an animal model for atherosclerosis. Through loss-and gain-of-function approaches, we showed that lincRNA-p21 represses cell proliferation and induces apoptosis in vascular smooth muscle cells and mouse mononuclear macrophage cells in vitro. Moreover, we found that inhibition of lincRNA-p21 results in neointimal hyperplasia in vivo in a carotid artery injury model. Genome-wide analysis revealed that lincRNA-p21 inhibition dysregulated many p53 targets. Furthermore, lincRNA-p21, a transcriptional target of p53, feeds back to enhance p53 transcriptional activity, at least in part, via binding to mouse double minute 2 (MDM2), an E3 ubiquitin-protein ligase. The association of lincRNA-p21 and MDM2 releases MDM2 repression of p53, enabling p53 to interact with p300 and to bind to the promoters/enhancers of its target genes. Finally, we show that lincRNA-p21 expression is decreased in patients with coronary artery disease. Conclusions-Our studies identify lincRNA-p21 as a novel regulator of cell proliferation and apoptosis and suggest that this lncRNA could serve as a therapeutic target to treat atherosclerosis and related cardiovascular disorders. C1 [Wu, Gengze; Cai, Jin; Han, Yu; Chen, Caiyu; Cai, Yue; Huang, Hefei; Yang, Yujia; Liu, Yukai; Xu, Zaicheng; He, Duofen; Zhang, Xiaoqun; Zeng, Chunyu] Third Mil Med Univ, Daping Hosp, Chongqing Inst Cardiol, Dept Cardiol, Chongqing, Peoples R China. [Zhong, Dan; He, Fengtian] Third Mil Med Univ, Coll Basic Med Sci, Dept Biochem & Mol Biol, Chongqing, Peoples R China. [Wu, Gengze; Chen, Jinghai; Huang, Zhan-Peng; Hu, Xiaoyun; Wang, Da-Zhi] Harvard Univ, Sch Med, Dept Cardiol, Boston Childrens Hosp, Boston, MA 02115 USA. [Pinello, Luca] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Pinello, Luca] Harvard Univ, Sch Publ Heath, Boston, MA 02115 USA. [Wang, Da-Zhi] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Wang, DZ (reprint author), Harvard Univ, Sch Med, Dept Cardiol, Boston Childrens Hosp, Boston, MA 02115 USA. EM dwang@enders.tch.harvard.edu; chunyuzeng01@163.com FU National Natural Science Foundation of China [30925018, 31130029]; National Basic Research Program of China [2013CB531104, 2012CB517801]; March of Dimes Foundation; National Institutes of Health [HL085635, HL116919, T32 HL007572]; China Scholarship Council [201207610007] FX This work is supported by grants from National Natural Science Foundation of China (30925018 and 31130029) and National Basic Research Program of China (2013CB531104 and 2012CB517801). Dr Wang is supported by the March of Dimes Foundation and the National Institutes of Health (HL085635 and HL116919). Dr Z.P. Huang is supported by the National Institutes of Health training grant T32 HL007572. Dr Wu is supported by China Scholarship Council N. 201207610007. Dr Wang was an Established Investigator of the American Heart Association. NR 52 TC 64 Z9 79 U1 11 U2 48 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 OCT 21 PY 2014 VL 130 IS 17 BP 1452 EP U64 DI 10.1161/CIRCULATIONAHA.114.011675 PG 30 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AS1TO UT WOS:000344064500007 PM 25156994 ER PT J AU Lauriol, J Keith, K Jaffre, F Couvillon, A Saci, A Goonasekera, SA McCarthy, JR Kessinger, CW Wang, JX Ke, QG Kang, PM Molkentin, JD Carpenter, C Kontaridis, MI AF Lauriol, Jessica Keith, Kimberly Jaffre, Fabrice Couvillon, Anthony Saci, Abdel Goonasekera, Sanjeewa A. McCarthy, Jason R. Kessinger, Chase W. Wang, Jianxun Ke, Qingen Kang, Peter M. Molkentin, Jeffery D. Carpenter, Christopher Kontaridis, Maria I. TI RhoA signaling in cardiomyocytes protects against stress-induced heart failure but facilitates cardiac fibrosis SO SCIENCE SIGNALING LA English DT Article ID SERUM RESPONSE FACTOR; FOCAL ADHESION KINASE; RAT VENTRICULAR MYOCYTES; VASCULAR SMOOTH-MUSCLE; LONG-TERM INHIBITION; IN-VIVO; ISCHEMIA/REPERFUSION INJURY; MYOCARDIAL-INFARCTION; MYOSIN PHOSPHATASE; PRESSURE-OVERLOAD AB The Ras-related guanosine triphosphatase RhoA mediates pathological cardiac hypertrophy, but also promotes cell survival and is cardioprotective after ischemia/reperfusion injury. To understand how RhoA mediates these opposing roles in the myocardium, we generated mice with a cardiomyocyte-specific deletion of RhoA. Under normal conditions, the hearts from these mice showed functional, structural, and growth parameters similar to control mice. Additionally, the hearts of the cardiomyocyte-specific, RhoA-deficient mice subjected to transverse aortic constriction (TAC)-a procedure that induces pressure overload and, if prolonged, heart failure-exhibited a similar amount of hypertrophy as those of the wild-type mice subjected to TAC. Thus, neither normal cardiac homeostasis nor the initiation of compensatory hypertrophy required RhoA in cardiomyocytes. However, in response to chronic TAC, hearts from mice with cardiomyocyte-specific deletion of RhoA showed greater dilation, with thinner ventricular walls and larger chamber dimensions, and more impaired contractile function than those from control mice subjected to chronic TAC. These effects were associated with aberrant calcium signaling, as well as decreased activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and AKT. In addition, hearts from mice with cardiomyocyte-specific RhoA deficiency also showed less fibrosis in response to chronic TAC, with decreased transcriptional activation of genes involved in fibrosis, including myocardin response transcription factor (MRTF) and serum response factor (SRF), suggesting that the fibrotic response to stress in the heart depends on cardiomyocyte-specific RhoA signaling. Our data indicated that RhoA regulates multiple pathways in cardiomyocytes, mediating both cardioprotective (hypertrophy without dilation) and cardio-deleterious effects (fibrosis). C1 [Lauriol, Jessica; Keith, Kimberly; Jaffre, Fabrice; Couvillon, Anthony; Saci, Abdel; Wang, Jianxun; Ke, Qingen; Kang, Peter M.; Carpenter, Christopher; Kontaridis, Maria I.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA. [Goonasekera, Sanjeewa A.; Molkentin, Jeffery D.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Howard Hughes Med Inst, Dept Pediat, Cincinnati, OH 45229 USA. [McCarthy, Jason R.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [McCarthy, Jason R.; Kessinger, Chase W.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kessinger, Chase W.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kontaridis, Maria I.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Kontaridis, MI (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA. EM mkontari@bidmc.harvard.edu FU NIH [R01-HL102368, R01-HL114775]; American Heart Association Postdoctoral fellowship; Beth Israel Deaconess Medical Center Division of Cardiology; Harvard Catalyst, Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH Award) [UL1 TR001102]; Harvard University FX This work was supported by NIH grants R01-HL102368 and R01-HL114775 to M. I. K. and by an American Heart Association Postdoctoral fellowship to J.L. This work was also supported in part by the Beth Israel Deaconess Medical Center Division of Cardiology. Statistical analysis conducted in the manuscript was validated through support by Harvard Catalyst, the Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH Award UL1 TR001102), and financial contributions from Harvard University and its affiliated academic healthcare centers. 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 healthcare centers, or the NIH. NR 80 TC 12 Z9 12 U1 1 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD OCT 21 PY 2014 VL 7 IS 348 AR ra100 DI 10.1126/scisignal.2005262 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AS2ZN UT WOS:000344145100002 PM 25336613 ER PT J AU Seco, J Clasie, B Partridge, M AF Seco, Joao Clasie, Ben Partridge, Mike TI Review on the characteristics of radiation detectors for dosimetry and imaging SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Review DE radiation detectors; radiotherapy; medical imaging; dosimetry; radiation protection ID RADIOCHROMIC FILM DOSIMETRY; IN-VIVO DOSIMETRY; PROTON COMPUTED-TOMOGRAPHY; ELECTRON-BEAM DOSIMETRY; HEAVY-ION RADIOTHERAPY; HIGH-ENERGY PHOTON; OUT BRAGG PEAK; FLAT-PANEL; MONTE-CARLO; DIGITAL RADIOGRAPHY AB The enormous advances in the understanding of human anatomy, physiology and pathology in recent decades have led to ever-improving methods of disease prevention, diagnosis and treatment. Many of these achievements have been enabled, at least in part, by advances in ionizing radiation detectors. Radiology has been transformed by the implementation of multi-slice CT and digital x-ray imaging systems, with silver halide films now largely obsolete for many applications. Nuclear medicine has benefited from more sensitive, faster and higher-resolution detectors delivering ever-higher SPECT and PET image quality. PET/MR systems have been enabled by the development of gamma ray detectors that can operate in high magnetic fields. These huge advances in imaging have enabled equally impressive steps forward in radiotherapy delivery accuracy, with 4DCT, PET and MRI routinely used in treatment planning and online image guidance provided by cone-beam CT. The challenge of ensuring safe, accurate and precise delivery of highly complex radiation fields has also both driven and benefited from advances in radiation detectors. Detector systems have been developed for the measurement of electron, intensity-modulated and modulated arc x-ray, proton and ion beams, and around brachytherapy sources based on a very wide range of technologies. The types of measurement performed are equally wide, encompassing commissioning and quality assurance, reference dosimetry, in vivo dosimetry and personal and environmental monitoring. In this article, we briefly introduce the general physical characteristics and properties that are commonly used to describe the behaviour and performance of both discrete and imaging detectors. The physical principles of operation of calorimeters; ionization and charge detectors; semiconductor, luminescent, scintillating and chemical detectors; and radiochromic and radiographic films are then reviewed and their principle applications discussed. Finally, a general discussion of the application of detectors for x-ray nuclear medicine and ion beam imaging and dosimetry is presented. C1 [Seco, Joao; Clasie, Ben] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. [Seco, Joao; Clasie, Ben] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Partridge, Mike] Univ Oxford, CRUK, MRC Oxford Inst Radiat Oncol, Gray Labs, Oxford OX3 7DQ, England. RP Seco, J (reprint author), Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. EM jseco@partners.org FU Cancer Research UK [C5255/A15935] FX MP gratefully acknowledges funding from Cancer Research UK, grant reference C5255/A15935. NR 169 TC 9 Z9 9 U1 8 U2 65 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 OCT 21 PY 2014 VL 59 IS 20 BP R303 EP R347 DI 10.1088/0031-9155/59/20/R303 PG 45 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AQ8QA UT WOS:000343092300001 PM 25229250 ER PT J AU Koh, DI Han, DY Ryu, H Choi, WI Jeon, BN Kim, MK Kim, Y Kim, JY Parry, L Clarke, AR Reynolds, AB Hur, MW AF Koh, Dong-In Han, Dohyun Ryu, Hoon Choi, Won-Il Jeon, Bu-Nam Kim, Min-Kyeong Kim, Youngsoo Kim, Jin Young Parry, Lee Clarke, Alan R. Reynolds, Albert B. Hur, Man-Wook TI KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE KAISO; p53; cell cycle arrest; apoptosis; p300 ID POSTTRANSLATIONAL MODIFICATION; BINDING-PROTEIN; PARTNER KAISO; DNA-BINDING; P53; CANCER; ACETYLATION; ACTIVATION; REPRESSION; DOMAIN AB An unresolved issue in genotoxic stress response is identification of induced regulatory proteins and how these activate tumor suppressor p53 to determine appropriate cell responses. Transcription factor KAISO was previously described to repress transcription following binding to methylated DNA. In this study, we show that KAISO is induced by DNA damage in p53-expressing cells and then interacts with the p53-p300 complex to increase acetylation of p53 K320 and K382 residues, although decreasing K381 acetylation. Moreover, the p53 with this particular acetylation pattern shows increased DNA binding and potently induces cell cycle arrest and apoptosis by activating transcription of CDKN1A (cyclin-dependent kinase inhibitor 1) and various apoptotic genes. Analogously, in Kaiso KO mouse embryonic fibroblast cells, p53-to-promoter binding and up-regulation of p21 and apoptosis gene expression is significantly compromised. KAISO may therefore be a critical regulator of p53-mediated cell cycle arrest and apoptosis in response to various genotoxic stresses in mammalian cells. C1 [Koh, Dong-In; Choi, Won-Il; Jeon, Bu-Nam; Kim, Min-Kyeong; Hur, Man-Wook] Yonsei Univ, Sch Med, Dept Biochem & Mol Biol, Severance Biomed Res Inst,Brain Korea Plus Projec, Seoul 120752, South Korea. [Han, Dohyun; Kim, Youngsoo] Seoul Natl Univ, Coll Med, Dept Biomed Sci & Biomed Engn, Seoul 110799, South Korea. [Ryu, Hoon] Boston Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA 02130 USA. [Ryu, Hoon] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02130 USA. [Kim, Jin Young] Korea Basic Sci Inst, Mass Spectrometry Res Ctr, Chungbuk 363883, South Korea. [Parry, Lee; Clarke, Alan R.] Cardiff Univ, Cardiff Sch Biosci, Cardiff CF10 3XQ, S Glam, Wales. [Reynolds, Albert B.] Vanderbilt Univ, Dept Cell Biol, Nashville, TN 37232 USA. RP Hur, MW (reprint author), Yonsei Univ, Sch Med, Dept Biochem & Mol Biol, Severance Biomed Res Inst,Brain Korea Plus Projec, Seoul 120752, South Korea. EM mwhur2@yuhs.ac RI clarke, alan/P-2820-2014; Kim, Youngsoo/D-6046-2012; OI Clarke, Alan/0000-0002-4281-426X FU Do-Yak Research Grant from the National Research Foundation of Korea (NRF) of the Korean Government (MSIP) [2011-0028817]; Medical Research Center Grant from the National Research Foundation of Korea (NRF) of the Korean Government (MSIP) [2011-0030086] FX This work was supported by Do-Yak Research Grant 2011-0028817 (to M.-W.H.) and Medical Research Center Grant 2011-0030086 (to M.-W.H.) from the National Research Foundation of Korea (NRF) of the Korean Government (MSIP). NR 36 TC 7 Z9 7 U1 2 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 OCT 21 PY 2014 VL 111 IS 42 BP 15078 EP 15083 DI 10.1073/pnas.1318780111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR0YN UT WOS:000343302600042 PM 25288747 ER PT J AU Robinson, EB Samocha, KE Kosmicki, JA McGrath, L Neale, BM Perlis, RH Daly, MJ AF Robinson, Elise B. Samocha, Kaitlin E. Kosmicki, Jack A. McGrath, Lauren Neale, Benjamin M. Perlis, Roy H. Daly, Mark J. TI Autism spectrum disorder severity reflects the average contribution of de novo and familial influences SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neuropsychiatric genetics; epidemiology; heterogeneity; phenotype ID INTELLECTUAL DISABILITY; PSYCHIATRIC-DISORDERS; GENETIC RISK; MUTATIONS; INTELLIGENCE; IDENTIFICATION; SCHIZOPHRENIA; EPIDEMIOLOGY; RECURRENCE; STABILITY AB Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions-phenotypically and genetically-although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases. C1 [Robinson, Elise B.; Samocha, Kaitlin E.; Kosmicki, Jack A.; Neale, Benjamin M.; Daly, Mark J.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Robinson, Elise B.; Samocha, Kaitlin E.; Kosmicki, Jack A.; McGrath, Lauren; Neale, Benjamin M.; Perlis, Roy H.; Daly, Mark J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Robinson, Elise B.; Samocha, Kaitlin E.; Kosmicki, Jack A.; Neale, Benjamin M.; Perlis, Roy H.; Daly, Mark J.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Robinson, Elise B.; Samocha, Kaitlin E.; Kosmicki, Jack A.; Neale, Benjamin M.; Perlis, Roy H.; Daly, Mark J.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Samocha, Kaitlin E.] Harvard Univ, Sch Med, Program Genet & Genom, Boston, MA 02114 USA. [Kosmicki, Jack A.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [McGrath, Lauren] Amer Univ, Sch Educ Teaching & Hlth, Washington, DC 20016 USA. [McGrath, Lauren; Perlis, Roy H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [McGrath, Lauren; Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Robinson, EB (reprint author), Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. EM erobinson@atgu.mgh.harvard.edu OI Robinson, Elise/0000-0003-2314-2792 FU National Institutes of Mental Health [1K01MH099286-01A1] FX We thank the families who took part in the Simons Simplex Collection study and the clinicians who collected data at each of the study sites. E. B. R. was funded by National Institutes of Mental Health Grant 1K01MH099286-01A1. NR 47 TC 23 Z9 23 U1 4 U2 26 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 OCT 21 PY 2014 VL 111 IS 42 BP 15161 EP 15165 DI 10.1073/pnas.1409204111 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR0YN UT WOS:000343302600056 PM 25288738 ER PT J AU Luo, YC Cai, XN Liu, SC Wang, S Nold-Petry, CA Nold, MF Bufler, P Norris, D Dinarello, CA Fujita, M AF Luo, Yuchun Cai, Xiangna Liu, Sucai Wang, Sen Nold-Petry, Claudia A. Nold, Marcel F. Bufler, Philip Norris, David Dinarello, Charles A. Fujita, Mayumi TI Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tolerance; skin inflammation; allergic contact dermatitis ID REGULATORY T-CELLS; CONTACT HYPERSENSITIVITY; LANGERHANS CELLS; IN-VIVO; MICE; INNATE; TOLERANCE; MEMBERS; DIFFERENTIATION; ACTIVATION AB IL-1 family member IL-37 limits innate inflammation in models of colitis and LPS-induced shock, but a role in adaptive immunity remains unknown. Here, we studied mice expressing human IL-37b isoform (IL-37tg) subjected to skin contact hypersensitivity (CHS) to dinitrofluorobenzene. CHS challenge to the hapten was significantly decreased in IL-37tg mice compared with wild-type (WT) mice (-61%; P < 0.001 at 48 h). Skin dendritic cells (DCs) were present and migrated to lymph nodes after antigen uptake in IL-37tg mice. When hapten-sensitized DCs were adoptively transferred to WT mice, antigen challenge was greatly impaired in mice receiving DCs from IL-37tg mice compared with those receiving DCs from WT mice (-60%; P < 0.01 at 48 h). In DCs isolated from IL-37tg mice, LPS-induced increase of MHC II and costimulatory molecule CD40 was reduced by 51 and 31%, respectively. In these DCs, release of IL-1 beta, IL-6, and IL-12 was reduced whereas IL-10 secretion increased (37%). Consistent with these findings, DCs from IL-37tg mice exhibited a lower ability to stimulate syngeneic and allogeneic naive T cells as well as antigen-specific T cells and displayed enhanced induction of T regulatory (Treg) cells (86%; P < 0.001) in vitro. Histological analysis of CHS skin in mice receiving hapten-sensitized DCs from IL-37tg mice revealed a marked reduction in CD8(+) T cells (-74%) but an increase in Treg cells (2.6-fold). Together, these findings reveal that DCs expressing IL-37 are tolerogenic, thereby impairing activation of effector T-cell responses and inducing Treg cells. IL-37 thus emerges as an inhibitor of adaptive immunity. C1 [Luo, Yuchun; Cai, Xiangna; Liu, Sucai; Wang, Sen; Norris, David; Fujita, Mayumi] Univ Colorado Denver, Dept Dermatol, Aurora, CO 80045 USA. [Dinarello, Charles A.] Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA. [Cai, Xiangna; Wang, Sen] Shantou Univ, Coll Med, Affiliated Hosp 1, Dept Plast & Reconstruct Surg, Shantou City 515041, Peoples R China. [Nold-Petry, Claudia A.; Nold, Marcel F.] Monash Univ, Monash Inst Med Res, Ritchie Ctr, Melbourne, Vic 3800, Australia. [Bufler, Philip] Univ Munich, Childrens Hosp, D-80539 Munich, Germany. [Norris, David; Fujita, Mayumi] Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. RP Dinarello, CA (reprint author), Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA. EM cdinarello@mac.com; mayumi.fujita@ucdenver.edu OI Nold, Marcel/0000-0001-9682-4618; Nold, Claudia/0000-0002-7439-3834 FU National Institutes of Health (NIH) [P30CA046934, P30AR057212]; NIH [P30AR057212, AI-15614]; Veterans Affairs Merit Review Award; Interleukin Foundation; Cancer League of Colorado; Tadamitsu Research Fund FX We thank Alistaire S. Acosta and Karen Helm [supported by National Institutes of Health (NIH) Grants P30CA046934 and P30AR057212], Laura Hoaglin (supported by NIH Grant P30AR057212), and Tania Azam for assisting with experiments, and Kasey Couts, PhD, and Zili Zhai, PhD, for critically reviewing the manuscript. This study was supported in part by research grants from the Veterans Affairs Merit Review Award (to M. F.), Interleukin Foundation (to M. F.), Cancer League of Colorado (to M. F.), Tadamitsu Research Fund (to M. F.), and NIH Pilot Grants P30AR057212 (to M. F.) and AI-15614 (to C.A.D.). NR 38 TC 32 Z9 38 U1 0 U2 8 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 OCT 21 PY 2014 VL 111 IS 42 BP 15178 EP 15183 DI 10.1073/pnas.1416714111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR0YN UT WOS:000343302600059 PM 25294929 ER PT J AU Calligaris, D Caragacianu, D Liu, XH Norton, I Thompson, CJ Richardson, AL Golshan, M Easterling, ML Santagata, S Dillon, DA Jolesz, FA Agar, NYR AF Calligaris, David Caragacianu, Diana Liu, Xiaohui Norton, Isaiah Thompson, Christopher J. Richardson, Andrea L. Golshan, Mehra Easterling, Michael L. Santagata, Sandro Dillon, Deborah A. Jolesz, Ferenc A. Agar, Nathalie Y. R. TI Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE metabolites; FT-ICR MS; molecular pathology; intrasurgical diagnosis ID RECURRENT LARYNGEAL NERVE; INTRAOPERATIVE NEUROMONITORING IONM; FOCUSED ULTRASOUND SURGERY; CONTRAST-ENHANCED MRI; SENTINEL LYMPH-NODE; HUMAN BRAIN-TUMORS; 20-YEAR FOLLOW-UP; THYROID-SURGERY; CONSERVING SURGERY; PREOPERATIVE ASSESSMENT AB Distinguishing tumor from normal glandular breast tissue is an important step in breast-conserving surgery. Because this distinction can be challenging in the operative setting, up to 40% of patients require an additional operation when traditional approaches are used. Here, we present a proof-of-concept study to determine the feasibility of using desorption electrospray ionization mass spectrometry imaging (DESI-MSI) for identifying and differentiating tumor from normal breast tissue. We show that tumor margins can be identified using the spatial distributions and varying intensities of different lipids. Several fatty acids, including oleic acid, were more abundant in the cancerous tissue than in normal tissues. The cancer margins delineated by the molecular images from DESI-MSI were consistent with thosemargins obtained fromhistological staining. Our findings prove the feasibility of classifying cancerous and normal breast tissues using ambient ionization MSI. The results suggest that an MS-based method could be developed for the rapid intraoperative detection of residual cancer tissue during breast-conserving surgery. C1 [Calligaris, David; Caragacianu, Diana; Liu, Xiaohui; Norton, Isaiah; Agar, Nathalie Y. R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Caragacianu, Diana; Jolesz, Ferenc A.; Agar, Nathalie Y. R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Caragacianu, Diana; Golshan, Mehra] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Richardson, Andrea L.; Santagata, Sandro; Dillon, Deborah A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Thompson, Christopher J.; Easterling, Michael L.] Bruker Daltonics Inc, Billerica, MA 01821 USA. [Richardson, Andrea L.; Santagata, Sandro; Agar, Nathalie Y. R.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. RP Agar, NYR (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. EM nathalie_agar@dfci.harvard.edu FU US National Institutes of Health [1DP2OD007383-01]; US Army Medical Research/Center for Integration of Medicine & Innovative Technology Grant [2010A052245]; National Center for Image-Guided Therapy Grant [P41RR019703]; Pediatric Low-Grade Astrocytoma Program at Dana-Farber Cancer Institute; Brain Science Foundation; Daniel E. Ponton Fund for the Neurosciences at Brigham and Women's Hospital FX This work was funded, in part, by US National Institutes of Health Director's New Innovator Award 1DP2OD007383-01 (to N.Y.R.A.), US Army Medical Research/Center for Integration of Medicine & Innovative Technology Grant 2010A052245, and National Center for Image-Guided Therapy Grant P41RR019703. The work received support from the Pediatric Low-Grade Astrocytoma Program at Dana-Farber Cancer Institute, the Brain Science Foundation, and the Daniel E. Ponton Fund for the Neurosciences at Brigham and Women's Hospital. NR 78 TC 37 Z9 38 U1 9 U2 64 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 OCT 21 PY 2014 VL 111 IS 42 BP 15184 EP 15189 DI 10.1073/pnas.1408129111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR0YN UT WOS:000343302600060 PM 25246570 ER PT J AU Sinha, P Kjelgaard, MM Gandhi, TK Tsourides, K Cardinaux, AL Pantazis, D Diamond, SP Held, RM AF Sinha, Pawan Kjelgaard, Margaret M. Gandhi, Tapan K. Tsourides, Kleovoulos Cardinaux, Annie L. Pantazis, Dimitrios Diamond, Sidney P. Held, Richard M. TI Autism as a disorder of prediction SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE probabilistic processing; endophenotype; Markov models; theory; heterogeneity ID EYED VISUAL-ACUITY; SPECTRUM DISORDERS; BASAL GANGLIA; FUNCTIONING AUTISM; ASPERGER-SYNDROME; MOTOR CONTROL; ANIMAL-MODEL; MUTANT MICE; CHILDREN; BEHAVIOR AB A rich collection of empirical findings accumulated over the past three decades attests to the diversity of traits that constitute the autism phenotypes. It is unclear whether subsets of these traits share any underlying causality. This lack of a cohesive conceptualization of the disorder has complicated the search for broadly effective therapies, diagnostic markers, and neural/genetic correlates. In this paper, we describe how theoretical considerations and a review of empirical data lead to the hypothesis that some salient aspects of the autism phenotype may be manifestations of an underlying impairment in predictive abilities. With compromised prediction skills, an individual with autism inhabits a seemingly "magical" world wherein events occur unexpectedly and without cause. Immersion in such a capricious environment can prove overwhelming and compromise one's ability to effectively interact with it. If validated, this hypothesis has the potential of providing unifying insights into multiple aspects of autism, with attendant benefits for improving diagnosis and therapy. C1 [Sinha, Pawan; Kjelgaard, Margaret M.; Gandhi, Tapan K.; Tsourides, Kleovoulos; Cardinaux, Annie L.; Pantazis, Dimitrios; Diamond, Sidney P.; Held, Richard M.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Kjelgaard, Margaret M.] Massachusetts Gen Hosp, Inst Hlth Profess, Dept Commun Sci & Disorders, Boston, MA 02129 USA. [Gandhi, Tapan K.] Def Inst Physiol & Allied Sci, Dept Biomed Engn, New Delhi 110054, India. RP Held, RM (reprint author), MIT, Dept Brain & Cognit Sci, E25-618, Cambridge, MA 02139 USA. EM heldd@neco.edu FU Simons Center for the Social Brain at Massachusetts Institute of Technology; Simons Foundation for Autism Research FX We thank Drs. Helen Tager-Flusberg, Charles Nelson, and Geraldine Dawson for discussions and several parents of children with autism for comments. This work was supported by the Simons Center for the Social Brain at Massachusetts Institute of Technology and by the Simons Foundation for Autism Research. NR 110 TC 46 Z9 46 U1 5 U2 26 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 OCT 21 PY 2014 VL 111 IS 42 BP 15220 EP 15225 DI 10.1073/pnas.1416797111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR0YN UT WOS:000343302600066 PM 25288765 ER PT J AU Sugathan, A Biagioli, M Golzio, C Erdin, S Blumenthal, I Manavalan, P Ragavendran, A Brand, H Lucente, D Miles, J Sheridan, SD Stortchevoi, A Kellis, M Haggarty, SJ Katsanis, N Gusella, JF Talkowski, ME AF Sugathan, Aarathi Biagioli, Marta Golzio, Christelle Erdin, Serkan Blumenthal, Ian Manavalan, Poornima Ragavendran, Ashok Brand, Harrison Lucente, Diane Miles, Judith Sheridan, Steven D. Stortchevoi, Alexei Kellis, Manolis Haggarty, Stephen J. Katsanis, Nicholas Gusella, James F. Talkowski, Michael E. TI CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE CHD8; NPCs; RNA-seq; ChIP-seq; autism ID DE-NOVO MUTATIONS; CANCER GENES; NETWORK; SCHIZOPHRENIA; CHROMATIN; CHILDREN; KNOWLEDGEBASE; PREDICTION; GENETICS; REGIONS AB Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10(-8)) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10(-10)). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis. C1 [Sugathan, Aarathi; Biagioli, Marta; Erdin, Serkan; Blumenthal, Ian; Manavalan, Poornima; Ragavendran, Ashok; Brand, Harrison; Lucente, Diane; Sheridan, Steven D.; Stortchevoi, Alexei; Haggarty, Stephen J.; Gusella, James F.; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. [Sugathan, Aarathi; Erdin, Serkan; Blumenthal, Ian; Ragavendran, Ashok; Brand, Harrison; Sheridan, Steven D.; Stortchevoi, Alexei; Haggarty, Stephen J.; Talkowski, Michael E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Sugathan, Aarathi; Biagioli, Marta; Brand, Harrison; Sheridan, Steven D.; Haggarty, Stephen J.; Talkowski, Michael E.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Gusella, James F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Golzio, Christelle; Katsanis, Nicholas] Duke Univ, Ctr Human Dis Modeling, Durham, NC 27710 USA. [Katsanis, Nicholas] Duke Univ, Dept Cell Biol, Durham, NC 27710 USA. [Miles, Judith] Univ Missouri Hosp & Clin, Thompson Ctr Autism & Neurodev Disorders, Dept Pediat, Columbia, MO 65201 USA. [Miles, Judith] Univ Missouri Hosp & Clin, Thompson Ctr Autism & Neurodev Disorders, Dept Med Genet, Columbia, MO 65201 USA. [Miles, Judith] Univ Missouri Hosp & Clin, Thompson Ctr Autism & Neurodev Disorders, Dept Pathol, Columbia, MO 65201 USA. [Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Kellis, Manolis; Haggarty, Stephen J.; Gusella, James F.; Talkowski, Michael E.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. RP Talkowski, ME (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. EM talkowski@chgr.mgh.harvard.edu RI Erdin, Serkan/B-4988-2008; OI Erdin, Serkan/0000-0001-6587-2625; Katsanis, Nicholas/0000-0002-2480-0171 FU Simons Foundation for Autism Research; Nancy Lurie Marks Family Foundation; NIH [MH095867, MH095088, GM061354]; March of Dimes; Charles Hood Foundation; Brain and Behavioral Research Foundation; Autism Genetic Resource Exchange; Autism Speaks; Pitt-Hopkins Research Foundation FX We thank Dr. Anshul Kundaje of Stanford University and the NIH Roadmap Epigenomics Consortium (nihroadmap.nih.gov/epigenomics/) for providing chromatin state data. This research was supported by the Simons Foundation for Autism Research, the Nancy Lurie Marks Family Foundation, NIH Grants MH095867, MH095088, and GM061354, the March of Dimes, Charles Hood Foundation, the Brain and Behavioral Research Foundation, the Autism Genetic Resource Exchange, Autism Speaks, and Pitt-Hopkins Research Foundation. N.K. is a Distinguished Bromley Professor. NR 55 TC 42 Z9 43 U1 3 U2 34 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 21 PY 2014 VL 111 IS 42 BP E4468 EP E4477 DI 10.1073/pnas.1405266111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AR0YN UT WOS:000343302600012 PM 25294932 ER PT J AU Awqatty, B Samaddar, S Cash, KJ Clark, HA Dubach, JM AF Awqatty, Becker Samaddar, Shayak Cash, Kevin J. Clark, Heather A. Dubach, J. Matthew TI Fluorescent sensors for the basic metabolic panel enable measurement with a smart phone device over the physiological range SO ANALYST LA English DT Article ID SENSITIVE OPTODE MEMBRANE; ION-SELECTIVE ELECTRODES; CELL-PHONE; GLUCOSE BIOSENSOR; EGGSHELL MEMBRANE; MOBILE PHONE; BULK OPTODES; BLOOD; UREA; MICROSPHERES AB The advanced functionality of portable devices such as smart phones provides the necessary hardware to potentially perform complex diagnostic measurements in any setting. Recent research and development have utilized cameras and data acquisition properties of smart phones to create diagnostic approaches for a variety of diseases or pollutants. However, in concentration measurements, such as blood glucose, the performance of handheld diagnostic devices depends largely on the sensing mechanism. To expand measurements to multiple components, often necessary in medical tests, with a single diagnostic device, robust platform based sensors are needed. Here, we developed a suite of dual wavelength fluorescent sensors with response characteristics necessary to measure each component of a basic metabolic panel, a common clinical measurement. Furthermore, the response of these sensors could be measured with a simple optical setup to convert a smart phone into a fluorescence measurement instrument. This approach could be used as a mobile basic metabolic panel measurement system for point of care diagnostics. C1 [Awqatty, Becker; Samaddar, Shayak; Cash, Kevin J.; Clark, Heather A.; Dubach, J. Matthew] Northeastern Univ, Dept Pharmaceut Sci, Boston, MA 02115 USA. [Dubach, J. Matthew] Northeastern Univ, Boston, MA 02115 USA. RP Dubach, JM (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM dubach.matt@mgh.harvard.edu RI Cash, Kevin/A-5233-2013 OI Cash, Kevin/0000-0002-9748-2530 FU NASA SBIR [NNX12CD34P] FX This research was supported by NASA SBIR NNX12CD34P to Ionu Biosystems. NR 46 TC 11 Z9 11 U1 5 U2 43 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 0003-2654 EI 1364-5528 J9 ANALYST JI Analyst PD OCT 21 PY 2014 VL 139 IS 20 BP 5230 EP 5238 DI 10.1039/c4an00999a PG 9 WC Chemistry, Analytical SC Chemistry GA AP9IQ UT WOS:000342393900026 PM 25126649 ER PT J AU Faggen, M Gilchrist, H Donohue, CC Burke, R AF Faggen, Meredith Gilchrist, Heather Donohue, Caitlin C. Burke, Reanne TI Implementation of code status discussion early in the course of treatment for oncology patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT American-Society-of-Clinical-Oncology (ASCO) Quality Care Symposium CY OCT 17-18, 2014 CL Boston, MA SP Amer Soc Clin Oncol C1 [Faggen, Meredith; Gilchrist, Heather; Donohue, Caitlin C.; Burke, Reanne] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2014 VL 32 IS 30 SU S MA 88 PG 1 WC Oncology SC Oncology GA CN2JU UT WOS:000358247800014 ER PT J AU Flaherty, S Morse, D Spinks, T Berger, S Kidin, LM Ross, TW AF Flaherty, Stephen Morse, Denise Spinks, Tracy Berger, Sara Kidin, Lisa M. Ross, Thomas W. TI Lessons learned from a cancer center-specific federal quality reporting program SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT American-Society-of-Clinical-Oncology (ASCO) Quality Care Symposium CY OCT 17-18, 2014 CL Boston, MA SP Amer Soc Clin Oncol C1 Dana Farber Canc Inst, Boston, MA 02115 USA. City Hope Natl Med Ctr, Duarte, CA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Texas MD Anderson Canc Ctr, Off Performance Improvement, Houston, TX 77030 USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2014 VL 32 IS 30 SU S MA 42 PG 1 WC Oncology SC Oncology GA CN2JU UT WOS:000358247800011 ER PT J AU Lane, S Ng, K Sommers, R Dalby, CK Conley, S Rizzo, P Bagley, J Harris, C Fuller, F Nguyen, P Szabatura, A AF Lane, Sharon Ng, Kimmie Sommers, Robin Dalby, Carole Kathleen Conley, Susanne Rizzo, Patricia Bagley, Janet Harris, Christy Fuller, Frances Phuong Nguyen Szabatura, Audrea TI Designing a multidisciplinary oral chemotherapy education and monitoring program SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT American-Society-of-Clinical-Oncology (ASCO) Quality Care Symposium CY OCT 17-18, 2014 CL Boston, MA SP Amer Soc Clin Oncol C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Milford Reg Med Ctr, Dana Farber Canc Inst, Brigham & Womens Canc Ctr, Milford, MA USA. NR 0 TC 0 Z9 0 U1 2 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 OCT 20 PY 2014 VL 32 IS 30 SU S MA 146 PG 1 WC Oncology SC Oncology GA CN2JU UT WOS:000358247800020 ER PT J AU Martins, Y Gonzalez-Suarez, E de Zengotita, L Contreras, M Levine, AL AF Martins, Yolanda Gonzalez-Suarez, Elizabeth de Zengotita, Luis Contreras, Magnolia Levine, Anne L. TI Development and implementation of a longitudinal quality assessment for community outreach programs SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT American-Society-of-Clinical-Oncology (ASCO) Quality Care Symposium CY OCT 17-18, 2014 CL Boston, MA SP Amer Soc Clin Oncol C1 [Martins, Yolanda; Gonzalez-Suarez, Elizabeth; de Zengotita, Luis; Contreras, Magnolia; Levine, Anne L.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2014 VL 32 IS 30 SU S MA 235 PG 1 WC Oncology SC Oncology GA CN2JU UT WOS:000358247800030 ER PT J AU Nipp, RD Powell, E Finkelstein, D Winkfield, KM Percac-Lima, S Chabner, BA Moy, B AF Nipp, Ryan David Powell, Elizabeth Finkelstein, Daniel Winkfield, Karen Marie Percac-Lima, Sanja Chabner, Bruce Allan Moy, Beverly TI Alleviating financial burden for cancer patients in clinical trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT American-Society-of-Clinical-Oncology (ASCO) Quality Care Symposium CY OCT 17-18, 2014 CL Boston, MA SP Amer Soc Clin Oncol C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2014 VL 32 IS 30 SU S MA 10 PG 1 WC Oncology SC Oncology GA CN2JU UT WOS:000358247800004 ER PT J AU Stuver, SO Fraile, B Donohue, CC Odejide, OO Abel, GA Dodek, A Fallon, JA Jacobson, JO AF Stuver, Sherri Oliver Fraile, Belen Donohue, Caitlin C. Odejide, Oreofe Olukemi Abel, Gregory Alan Dodek, Anton Fallon, John A. Jacobson, Joseph O. TI Novel data sharing between a comprehensive cancer center and a private payer to better understand care at the end of life SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT American-Society-of-Clinical-Oncology (ASCO) Quality Care Symposium CY OCT 17-18, 2014 CL Boston, MA SP Amer Soc Clin Oncol C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Blue Cross & Blue Shield Massachusetts, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2014 VL 32 IS 30 SU S MA 1 PG 1 WC Oncology SC Oncology GA CN2JU UT WOS:000358247800002 ER PT J AU Lundberg, P Takizawa, H Kubovcakova, L Guo, GJ Hui, HS Dirnhofer, S Orkin, SH Manz, MG Skoda, RC AF Lundberg, Pontus Takizawa, Hitoshi Kubovcakova, Lucia Guo, Guoji Hui Hao-Shen Dirnhofer, Stephan Orkin, Stuart H. Manz, Markus G. Skoda, Radek C. TI Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TYROSINE KINASE JAK2; GAIN-OF-FUNCTION; POLYCYTHEMIA-VERA; ESSENTIAL THROMBOCYTHEMIA; PROGENITOR CELLS; CLONAL ANALYSIS; ACTIVATING MUTATION; MYELOID METAPLASIA; SOMATIC MUTATIONS; V617F MUTATION AB The majority of patients with myeloproliferative neoplasms (MPNs) carry a somatic JAK2-V617F mutation. Because additional mutations can precede JAK2-V617F, it is questioned whether JAK2-V617F alone can initiate MPN. Several mouse models have demonstrated that JAK2-V617F can cause MPN; however, in all these models disease was polyclonal. Conversely, cancer initiates at the single cell level, but attempts to recapitulate single-cell disease initiation in mice have thus far failed. We demonstrate by limiting dilution and single-cell transplantations that MPN disease, manifesting either as erythrocytosis or thrombocytosis, can be initiated clonally from a single cell carrying JAK2-V617F. However, only a subset of mice reconstituted from single hematopoietic stem cells (HSCs) displayed MPN phenotype. Expression of JAK2-V617F in HSCs promoted cell division and increased DNA damage. Higher JAK2-V617F expression correlated with a short-term HSC signature and increased myeloid bias in single-cell gene expression analyses. Lower JAK2-V617F expression in progenitor and stem cells was associated with the capacity to stably engraft in secondary recipients. Furthermore, long-term repopulating capacity was also present in a compartment with intermediate expression levels of lineage markers. Our studies demonstrate that MPN can be initiated from a single HSC and illustrate that JAK2-V617F has complex effects on HSC biology. C1 [Lundberg, Pontus; Kubovcakova, Lucia; Hui Hao-Shen; Skoda, Radek C.] Univ Basel Hosp, Dept Biomed Expt Hematol, CH-4031 Basel, Switzerland. [Lundberg, Pontus; Kubovcakova, Lucia; Hui Hao-Shen; Skoda, Radek C.] Univ Basel, CH-4031 Basel, Switzerland. [Takizawa, Hitoshi; Manz, Markus G.] Univ Zurich Hosp, Div Hematol, CH-8091 Zurich, Switzerland. [Takizawa, Hitoshi; Manz, Markus G.] Univ Zurich, CH-8091 Zurich, Switzerland. [Guo, Guoji; Orkin, Stuart H.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02215 USA. [Guo, Guoji; Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Dirnhofer, Stephan] Univ Basel Hosp, Inst Pathol, CH-4031 Basel, Switzerland. RP Skoda, RC (reprint author), Univ Basel Hosp, Dept Biomed Expt Hematol, CH-4031 Basel, Switzerland. EM radek.skoda@unibas.ch RI Takizawa, Hitoshi/C-9895-2014 OI Takizawa, Hitoshi/0000-0002-5276-5430 FU Swiss National Science Foundation [310000-120724/1, 32003BB_135712/1, 310030_146528/1]; Swiss Cancer League [KLS-2950-02-2012] FX S.H. Orkin is an Investigator of the Howard Hughes Medical Institute. This work was supported by grants 310000-120724/1 and 32003BB_135712/1 from the Swiss National Science Foundation and the Swiss Cancer League (KLS-2950-02-2012) to R.C. Skoda and by Swiss National Science Foundation grant 310030_146528/1 to M.G. Manz. NR 63 TC 19 Z9 20 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 EI 1540-9538 J9 J EXP MED JI J. Exp. Med. PD OCT 20 PY 2014 VL 211 IS 11 BP 2213 EP 2230 DI 10.1084/jem.20131371 PG 18 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA AT9TK UT WOS:000345268700008 PM 25288396 ER PT J AU Jun, C Villiger, M Oh, WY Bouma, BE AF Jun, Changsu Villiger, Martin Oh, Wang-Yuhl Bouma, Brett E. TI All-fiber wavelength swept ring laser based on Fabry-Perot filter for optical frequency domain imaging SO OPTICS EXPRESS LA English DT Article ID COHERENCE TOMOGRAPHY; SEMICONDUCTOR-LASER; MODE-LOCKING; OCT; DISPERSION AB Innovations in laser engineering have yielded several novel configurations for high repetition rate, broad sweep range, and long coherence length wavelength swept lasers. Although these lasers have enabled high performance frequency-domain optical coherence tomography, they are typically complicated and costly and many require access to proprietary materials or devices. Here, we demonstrate a simplified ring resonator configuration that is straightforward to construct from readily available materials at a low total cost. It was enabled by an insight regarding the significance of isolation against bidirectional operation and by configuring the sweep range of the intracavity filter to exceed its free spectral range. The design can easily be optimized to meet a range of operating specifications while yielding robust and stable performance. As an example, we demonstrate 240 kHz operation with 125 nm sweep range and > 70 mW of average output power and demonstrate high quality frequency domain OCT imaging. The complete component list and directions for assembly of the laser are posted on-line at www.octresearch.org. (C) 2014 Optical Society of America C1 [Jun, Changsu; Villiger, Martin; Bouma, Brett E.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Jun, Changsu; Villiger, Martin; Bouma, Brett E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Oh, Wang-Yuhl] Korea Adv Inst Sci & Technol, Dept Mech Engn, Taejon 305701, South Korea. [Bouma, Brett E.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Jun, C (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM jun.changsu@mgh.harvard.edu FU National Institutes of Health [P41 EB015903]; NRF of Korea [2010-0017465]; MSIP of Korea [GFP/(CISS-2012M3A6A6054200)]; Terumo Corporation FX This work was supported in part by the National Institutes of Health, grant P41 EB015903, by the NRF of Korea, grants 2010-0017465, by the MSIP of Korea, grant GFP/(CISS-2012M3A6A6054200) and by Terumo Corporation. In order to facilitate dissemination of this laser design, we have posted a complete list of required materials and instructions for assembly at www.octresearch.org. NR 29 TC 8 Z9 8 U1 0 U2 7 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD OCT 20 PY 2014 VL 22 IS 21 BP 25805 EP 25816 DI 10.1364/OE.22.025805 PG 12 WC Optics SC Optics GA AS0ZF UT WOS:000344004600118 PM 25401614 ER PT J AU Lim, S Stember, KG He, W Bianca, PC Yelibi, C Marquis, A Sturmer, T Buse, JB Meigs, JB AF Lim, Soo Stember, Katherine G. He, Wei Bianca, Porneala C. Yelibi, Carine Marquis, Alison Stuermer, Til Buse, John B. Meigs, James B. TI Electronic Medical Record Cancer Incidence over Six Years Comparing New Users of Glargine with New Users of NPH Insulin SO PLOS ONE LA English DT Article ID MALIGNANCIES; COHORT; RISK; ANALOGS AB Background: Recent studies suggested that insulin glargine use could be associated with increased risk of cancer. We compared the incidence of cancer in new users of glargine versus new users of NPH in a longitudinal clinical cohort with diabetes for up to 6 years. Methods and Findings: From all patients who had been regularly followed at Massachusetts General Hospital from 1/01/2005 to 12/31/2010, 3,680 patients who had a medication record for glargine or NPH usage were obtained from the electronic medical record (EMR). From those we selected 539 new glargine users (age: 60.1 +/- 13.6 years, BMI: 32.7 +/- 7.5 kg/m(2)) and 343 new NPH users (61.5 +/- 14.1 years, 32.7 +/- 8.3 kg/m(2)) who had no prevalent cancer during 19 months prior to glargine or NPH initiation. All incident cancer cases were ascertained from the EMR requiring at least 2 ICD-9 codes within a 2 month period. Insulin exposure time and cumulative dose were validated. The statistical analysis compared the rates of cancer in new glargine vs. new NPH users while on treatment, adjusted for the propensity to receive one or the other insulin. There were 26 and 28 new cancer cases in new glargine and new NPH users for 1559 and 1126 person-years follow-up, respectively. There were no differences in the propensity-adjusted clinical characteristics between groups. The adjusted hazard ratio for the cancer incidence comparing glargine vs. NPH use was 0.65 (95% CI: 0.36-1.19). Conclusions: Insulin glargine is not associated with development of cancers when compared with NPH in this longitudinal and carefully retrieved EMR data. C1 [Lim, Soo; Stember, Katherine G.; He, Wei; Bianca, Porneala C.; Yelibi, Carine; Meigs, James B.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Lim, Soo; Stember, Katherine G.; He, Wei; Bianca, Porneala C.; Yelibi, Carine; Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Lim, Soo] Seoul Natl Univ, Coll Med, Dept Internal Med, Songnam, South Korea. [Lim, Soo] Seoul Natl Univ, Bundang Hosp, Songnam, South Korea. [Stember, Katherine G.] Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Stember, Katherine G.] Harvard Univ, Sch Med, Boston, MA USA. [Marquis, Alison; Buse, John B.] Univ N Carolina, Sch Med, Div Endocrinol, Chapel Hill, NC USA. [Stuermer, Til] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. EM jmeigs@partners.org FU Sanofi through University of North Carolina at Chapel Hill; [K24 DK080140]; [R01 AG023178] FX This research was funded by Sanofi through a subcontract with the University of North Carolina at Chapel Hill. JBM is supported by K24 DK080140; TS is supported by R01 AG023178. The funders played no role in the study design; collection, analysis, or interpretation of data; the writing of the report; or the decision to submit the article for publication. NR 21 TC 3 Z9 3 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 20 PY 2014 VL 9 IS 10 AR e109433 DI 10.1371/journal.pone.0109433 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AS0AY UT WOS:000343942100025 PM 25329887 ER PT J AU Liang, SH Vasdev, N AF Liang, Steven H. Vasdev, Neil TI C(sp(3))-F-18 Bond Formation by Transition-Metal-Based [F-18]Fluorination SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE Fluorine-18; imaging agents; positron emission tomography; radiochemistry; transition metals ID POSITRON-EMISSION-TOMOGRAPHY; DIARYLIODONIUM-SALTS; OXIDATIVE FLUORINATION; F-18 FLUORIDE; PET; ARENES; STEP C1 [Liang, Steven H.; Vasdev, Neil] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nucl Med & Mol Imaging,Dept Radiol, Boston, MA 02114 USA. RP Liang, SH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nucl Med & Mol Imaging,Dept Radiol, 55 Fruit St,White 427, Boston, MA 02114 USA. EM Liang.Steven@mgh.harvard.edu; Vasdev.Neil@mgh.harvard.edu NR 24 TC 11 Z9 11 U1 2 U2 32 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1433-7851 EI 1521-3773 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PD OCT 20 PY 2014 VL 53 IS 43 BP 11416 EP 11418 DI 10.1002/anie.201407065 PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA AR9CY UT WOS:000343870400003 PM 25243361 ER PT J AU Dias, JO Rocha, MOD de Souza, AC Kreuser, LJ Dias, LAD Tan, TC Teixeira, AL Nunes, MCP AF Dias Junior, Jose Olmpio da Costa Rocha, Manoel Otavio de Souza, Aline Cristina Kreuser, Lucas Jordan de Souza Dias, Laura Alves Tan, Timothy C. Teixeira, Antonio Lucio Nunes, Maria Carmo P. TI Assessment of the source of ischemic cerebrovascular events in patients with Chagas disease SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter DE Chagas disease; Stroke; Ischemic cerebrovascular events; Echocardiography; Carotid intima-media thickness ID TRYPANOSOMA-CRUZI INFECTION; INTIMA-MEDIA THICKNESS; CARDIOMYOPATHY; STROKE C1 [Dias Junior, Jose Olmpio; da Costa Rocha, Manoel Otavio; de Souza, Aline Cristina; de Souza Dias, Laura Alves; Teixeira, Antonio Lucio; Nunes, Maria Carmo P.] Univ Fed Minas Gerais, Sch Med, Postgrad Program Infect Dis & Trop Med, BR-30130100 Belo Horizonte, MG, Brazil. [Kreuser, Lucas Jordan] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Tan, Timothy C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Nunes, MCP (reprint author), Univ Fed Minas Gerais, Sch Med, Dept Internal Med, Av Prof Alfredo Balena 190, BR-30130100 Belo Horizonte, MG, Brazil. EM mcarmo@waymail.com.br NR 13 TC 0 Z9 0 U1 0 U2 3 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 OCT 20 PY 2014 VL 176 IS 3 BP 1352 EP 1354 DI 10.1016/j.ijcard.2014.07.266 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AR9KT UT WOS:000343893300225 PM 25131915 ER PT J AU Tian, JW Vergallo, R Jia, HB Soeda, T Lee, H Yu, B Jang, IK AF Tian, Jinwei Vergallo, Rocco Jia, Haibo Soeda, Tsunenari Lee, Hang Yu, Bo Jang, Ik-Kyung TI Morphologic characteristics of eroded coronary plaques: a combined angiographic, optical coherence tomography, and intravascular ultrasound study SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter DE Acute coronary syndrome; Plaque erosion; Optical coherence tomography ID EROSION C1 [Tian, Jinwei; Jia, Haibo; Yu, Bo] Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, Harbin, Peoples R China. [Tian, Jinwei; Jia, Haibo; Yu, Bo] Chinese Minist Educ, Key Lab Myocardial Ischemia, Harbin, Peoples R China. [Tian, Jinwei; Vergallo, Rocco; Jia, Haibo; Soeda, Tsunenari; Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Div Cardiol, Sch Med, Boston, MA USA. [Lee, Hang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Yu, B (reprint author), Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, 246 Xuefu Rd, Harbin, Peoples R China. EM yubodr@163.com; ijang@partners.org NR 5 TC 2 Z9 4 U1 0 U2 0 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 OCT 20 PY 2014 VL 176 IS 3 BP E137 EP E139 DI 10.1016/j.ijcard.2014.07.204 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AR9KT UT WOS:000343893300025 PM 25127333 ER PT J AU Smith, MR Sweeney, CJ Corn, PG Rathkopf, DE Smith, DC Hussain, M George, DJ Higano, CS Harzstark, AL Sartor, AO Vogelzang, NJ Gordon, MS de Bono, JS Haas, NB Logothetis, CJ Elfiky, A Scheffold, C Laird, AD Schimmoller, F Basch, EM Scher, HI AF Smith, Matthew R. Sweeney, Christopher J. Corn, Paul G. Rathkopf, Dana E. Smith, David C. Hussain, Maha George, Daniel J. Higano, Celestia S. Harzstark, Andrea L. Sartor, A. Oliver Vogelzang, Nicholas J. Gordon, Michael S. de Bono, Johann S. Haas, Naomi B. Logothetis, Christopher J. Elfiky, Aymen Scheffold, Christian Laird, A. Douglas Schimmoller, Frauke Basch, Ethan M. Scher, Howard I. TI Cabozantinib in Chemotherapy-Pretreated Metastatic Castration-Resistant Prostate Cancer: Results of a Phase II Nonrandomized Expansion Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 37th Congress of the European-Society-of-Medical-Oncology (ESMO) CY SEP 28-OCT 02, 2012 CL Vienna, AUSTRIA SP European Soc Med Oncol AB Purpose Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). Patients and Methods Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as >= 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. Results One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. Conclusion The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer. C1 [Smith, Matthew R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sweeney, Christopher J.; Elfiky, Aymen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sweeney, Christopher J.; Corn, Paul G.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Rathkopf, Dana E.; Scher, Howard I.] Mem Sloan Kettering Canc Ctr, Sidney Kimmel Ctr Prostate & Urol Canc, New York, NY 10021 USA. [Rathkopf, Dana E.; Scher, Howard I.] Weill Cornell Med Coll, New York, NY USA. [Smith, David C.; Hussain, Maha] Univ Michigan, Ann Arbor, MI 48109 USA. [George, Daniel J.] Duke Univ, Med Ctr, Durham, NC USA. [Basch, Ethan M.] Univ N Carolina, Chapel Hill, NC USA. [Higano, Celestia S.] Univ Washington, Seattle, WA 98195 USA. [Harzstark, Andrea L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Scheffold, Christian; Laird, A. Douglas; Schimmoller, Frauke] Exelixis, San Francisco, CA USA. [Sartor, A. Oliver] Tulane Univ, Tulane Canc Ctr, New Orleans, LA 70118 USA. [Vogelzang, Nicholas J.] Ctr Comprehens Canc, Las Vegas, NV USA. [Gordon, Michael S.] Pinnacle Oncol Hematol, Scottsdale, AZ USA. [Haas, Naomi B.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [de Bono, Johann S.] Royal Marsden Hosp, Sutton, Surrey, England. RP Smith, MR (reprint author), Massachusetts Gen Hosp, Genitourinary Oncol Program, 55 Fruit St, Boston, MA 02114 USA. EM smith.matthew@mgh.harvard.edu OI Rathkopf, Dana/0000-0002-4503-7582 FU NCI NIH HHS [P30 CA008748, K24 CA121990] NR 11 TC 35 Z9 37 U1 1 U2 7 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 OCT 20 PY 2014 VL 32 IS 30 BP 3391 EP U224 DI 10.1200/JCO.2013.54.5954 PG 10 WC Oncology SC Oncology GA AR9GJ UT WOS:000343880800009 PM 25225437 ER PT J AU Backhus, LM Farjah, F Varghese, TK Cheng, AM Zhou, XH Wood, DE Kessler, L Zeliadt, SB AF Backhus, Leah M. Farjah, Farhood Varghese, Thomas K. Cheng, Aaron M. Zhou, Xiao-Hua Wood, Douglas E. Kessler, Larry Zeliadt, Steven B. TI Appropriateness of Imaging for Lung Cancer Staging in a National Cohort SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; MEDICARE BENEFICIARIES; BREAST-CANCER; BRONCHOGENIC-CARCINOMA; BONE METASTASES; UNITED-STATES; PET-CT; COST; CRITERIA(R); PROSTATE AB Purpose Optimizing evidence-based care to improve quality is a critical priority in the United States. We sought to examine adherence to imaging guideline recommendations for staging in patients with locally advanced lung cancer in a national cohort. Methods We identified 3,808 patients with stage IIB, IIIA, or IIIB lung cancer by using the national Department of Veterans Affairs (VA) Central Cancer Registry (2004-2007) and linked these patients to VA and Medicare databases to examine receipt of guideline-recommended imaging based on National Comprehensive Cancer Network and American College of Radiology Appropriateness Criteria. Our primary outcomes were receipt of guideline-recommended brain imaging and positron emission tomography (PET) imaging. We also examined rates of overuse defined as combined use of bone scintigraphy (BS) and PET, which current guidelines recommend against. All imaging was assessed during the period 180 days before and 180 days after diagnosis. Results Nearly 75% of patients received recommended brain imaging, and 60% received recommended PET imaging. Overuse of BS and PET occurred in 25% of patients. More advanced clinical stage and later year of diagnosis were the only clinical or demographic factors associated with higher rates of guideline-recommended imaging after adjusting for covariates. We observed considerable regional variation in recommended PET imaging and overuse of combined BS and PET. Conclusion Receipt of guideline-recommended imaging is not universal. PET appears to be underused overall, whereas BS demonstrates continued overuse. Wide regional variation suggests that these findings could be the result of local practice patterns, which may be amenable to provider education efforts such as Choosing Wisely. (C) 2014 by American Society of Clinical Oncology C1 [Backhus, Leah M.; Zhou, Xiao-Hua; Zeliadt, Steven B.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Backhus, Leah M.; Farjah, Farhood; Varghese, Thomas K.; Cheng, Aaron M.; Wood, Douglas E.; Kessler, Larry; Zeliadt, Steven B.] Univ Washington, Seattle, WA 98195 USA. RP Backhus, LM (reprint author), Univ Washington, Dept Surg, Div Cardiothorac Surg, 1959 NE Pacific St, Seattle, WA 98195 USA. EM lbackhus@u.washington.edu FU Department of Veterans Affairs [IIR 07-235-2]; National Cancer Institute [NCI 1RC2CA148433] FX Supported by Grants No. IIR 07-235-2 from the Department of Veterans Affairs and No. NCI 1RC2CA148433 from the National Cancer Institute. NR 40 TC 4 Z9 4 U1 0 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 OCT 20 PY 2014 VL 32 IS 30 BP 3428 EP U266 DI 10.1200/JCO.2014.55.6589 PG 9 WC Oncology SC Oncology GA AR9GJ UT WOS:000343880800014 PM 25245440 ER PT J AU Basch, E Loblaw, DA Oliver, TK Carducci, M Chen, RC Frame, JN Garrels, K Hotte, S Kattan, MW Raghavan, D Saad, F Taplin, ME Walker-Dilks, C Williams, J Winquist, E Bennett, CL Wootton, T Rumble, RB Dusetzina, SB Virgo, KS AF Basch, Ethan Loblaw, D. Andrew Oliver, Thomas K. Carducci, Michael Chen, Ronald C. Frame, James N. Garrels, Kristina Hotte, Sebastien Kattan, Michael W. Raghavan, Derek Saad, Fred Taplin, Mary-Ellen Walker-Dilks, Cindy Williams, James Winquist, Eric Bennett, Charles L. Wootton, Ted Rumble, R. Bryan Dusetzina, Stacie B. Virgo, Katherine S. TI Systemic Therapy in Men With Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED PHASE-II; MITOXANTRONE PLUS PREDNISONE; HIGH-DOSE CALCITRIOL; DOUBLE-BLIND; ABIRATERONE ACETATE; DOCETAXEL CHEMOTHERAPY; COMPARING DOCETAXEL; INCREASED SURVIVAL; MEGESTROL-ACETATE; ZIBOTENTAN ZD4054 AB Purpose To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC). Methods The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature. Results When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 (Ra-223; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib. Recommendations Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or Ra-223 should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or combinations of therapies. Palliative care should be offered to all patients. (C) 2014 by American Society of Clinical Oncology C1 [Basch, Ethan; Chen, Ronald C.; Dusetzina, Stacie B.] Univ N Carolina, Chapel Hill, NC USA. [Raghavan, Derek] Carolinas Hlth Care, Levine Canc Inst, Charlotte, NC USA. [Loblaw, D. Andrew] Sunnybrook Hlth Sci Ctr, Odette Canc Ctr, Toronto, ON M4N 3M5, Canada. [Wootton, Ted] Patient Representat, Toronto, ON, Canada. [Hotte, Sebastien; Walker-Dilks, Cindy] McMaster Univ, Hamilton, ON, Canada. [Walker-Dilks, Cindy] Canc Care Ontario, Hamilton, ON, Canada. [Winquist, Eric] London Hlth Sci Ctr, London, ON, Canada. [Saad, Fred] Univ Montreal, Montreal, PQ, Canada. [Oliver, Thomas K.; Rumble, R. Bryan] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. [Carducci, Michael] Johns Hopkins Univ, Baltimore, MD USA. [Frame, James N.] Charleston Area Med Ctr Hlth Syst, Charleston, WV USA. [Kattan, Michael W.] Cleveland Clin, Cleveland, OH 44106 USA. [Taplin, Mary-Ellen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Williams, James] Pennsylvania Prostate Canc Coalit, Camp Hill, PA USA. [Bennett, Charles L.] South Carolina Coll Pharm, Columbia, SC USA. [Virgo, Katherine S.] Emory Univ, Atlanta, GA 30322 USA. RP Basch, E (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org NR 63 TC 63 Z9 64 U1 0 U2 7 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 OCT 20 PY 2014 VL 32 IS 30 BP 3436 EP U133 DI 10.1200/JCO.2013.54.8404 PG 17 WC Oncology SC Oncology GA AR9GJ UT WOS:000343880800015 PM 25199761 ER PT J AU D'Amico, AV AF D'Amico, Anthony V. TI Stereotactic Body Radiation Therapy for Prostate Cancer: The Need to Assess Patient-Reported Outcomes Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID TOXICITY C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, Boston, MA 02115 USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2014 VL 32 IS 30 BP 3457 EP 3457 DI 10.1200/JCO.2014.57.6116 PG 1 WC Oncology SC Oncology GA AR9GJ UT WOS:000343880800024 PM 25185103 ER PT J AU Otto, MW Hearon, BA McHugh, RK Calkins, AW Pratt, E Murray, HW Safren, SA Pollack, MH AF Otto, Michael W. Hearon, Bridget A. McHugh, R. Kathryn Calkins, Amanda W. Pratt, Elizabeth Murray, Heather W. Safren, Steven A. Pollack, Mark H. TI A Randomized, Controlled Trial of the Efficacy of an Interoceptive Exposure-Based CBT for Treatment-Refractory Outpatients with Opioid Dependence SO JOURNAL OF PSYCHOACTIVE DRUGS LA English DT Article DE treatment outcome; cognitive behavioral therapy; opioid dependence; interoceptive exposure; anxiety sensitivity; coping motives ID SUBSTANCE USE DISORDERS; METHADONE-MAINTENANCE TREATMENT; DISTRESS TOLERANCE TREATMENT; ANXIETY SENSITIVITY; HEROIN USERS; COCAINE DEPENDENCE; GENDER-DIFFERENCES; FOLLOW-UP; DRUG-USE; CONTINGENCY MANAGEMENT AB Many patients diagnosed with opioid dependence do not adequately respond to pharmacologic, psychosocial, or combination treatment, highlighting the importance of novel treatment strategies for this population. The current study examined the efficacy of a novel behavioral treatment focusing on internal cues for drug use (Cognitive Behavioral Therapy for Interoceptive Cues; CBT-IC) relative to an active comparison condition, Individual Drug Counseling (IDC), when added to methadone maintenance treatment (MMT) among those who had not responded to MMT. Participants (N=78) were randomly assigned to receive 15 sessions of CBT-IC or IDC as an adjunct to ongoing MMT and counseling. Oral toxicology screens were the primary outcome. Results indicated no treatment differences between CBT-IC and IDC and a small, significant reduction of self-reported drug use, but no change on toxicology screens. Tests of potential moderators, including sex, anxiety sensitivity, and coping motives for drug use, did not yield significant interactions. Among opioid-dependent outpatients who have not responded to MMT and counseling, the addition of IDC or CBT-IC did not result in additive outcome benefits. These results highlight the need for more potent treatment strategies for opioid dependence, particularly among those who do not fully respond to frontline treatment. C1 [Otto, Michael W.; Hearon, Bridget A.; Pratt, Elizabeth; Murray, Heather W.] Boston Univ, Boston, MA 02215 USA. [McHugh, R. Kathryn] McLean Hosp, Belmont, MA 02178 USA. [Calkins, Amanda W.; Safren, Steven A.; Pollack, Mark H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Otto, MW (reprint author), 648 Beacon St,5th Floor, Boston, MA 02215 USA. EM mwotto@bu.edu OI Baker, Amanda/0000-0002-0103-5411 NR 65 TC 1 Z9 1 U1 4 U2 13 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0279-1072 EI 2159-9777 J9 J PSYCHOACTIVE DRUGS JI J. Psychoact. Drugs PD OCT 20 PY 2014 VL 46 IS 5 BP 402 EP 411 DI 10.1080/02791072.2014.960110 PG 10 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA AS0SE UT WOS:000343987500009 PM 25364993 ER PT J AU Fling, BW Dutta, GG Schlueter, H Cameron, MH Horak, FB AF Fling, Brett W. Dutta, Geetanjali Gera Schlueter, Heather Cameron, Michelle H. Horak, Fay B. TI Associations between proprioceptive neural pathway structural connectivity and balance in people with multiple sclerosis SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE somatosensory cortex; somatosensory disorders; white matter pathways; diffusion tensor imaging; diffusion tensor tractography; proprioception ID SUBJECT DIFFUSION DATA; WHITE-MATTER; POSTURAL CONTROL; SOMATOSENSORY INFORMATION; SPATIAL STATISTICS; VOXELWISE ANALYSIS; BRAIN; POSTUROGRAPHY; GAIT; REHABILITATION AB Mobility and balance impairments are a hallmark of multiple sclerosis (MS), affecting nearly half of patients at presentation and resulting in decreased activity and participation, falls, injuries, and reduced quality of life. A growing body of work suggests that balance impairments in people with mild MS are primarily the result of deficits in proprioception, the ability to determine body position in space in the absence of vision. A better understanding of the pathophysiology of balance disturbances in MS is needed to develop evidence-based rehabilitation approaches. The purpose of the current study was to (1) map the cortical proprioceptive pathway in vivo using diffusion-weighted imaging and (2) assess associations between proprioceptive pathway white matter microstructural integrity and performance on clinical and behavioral balance tasks. We hypothesized that people with MS (PwMS) would have reduced integrity of cerebral proprioceptive pathways, and that reduced white matter microstructure within these tracts would be strongly related to proprioceptive-based balance deficits. We found poorer balance control on proprioceptive-based tasks and reduced white matter microstructural integrity of the cortical proprioceptive tracts in PwMS compared with age-matched healthy controls (HC). Microstructural integrity of this pathway in the right hemisphere was also strongly associated with proprioceptive-based balance control in PwMS and controls. Conversely, while white matter integrity of the right hemisphere's proprioceptive pathway was significantly correlated with overall balance performance in HC, there was no such relationship in PwMS. These results augment existing literature suggesting that balance control in PwMS may become more dependent upon (1) cerebellar-regulated proprioceptive control, (2) the vestibular system, and/or (3) the visual system. C1 [Fling, Brett W.; Dutta, Geetanjali Gera; Schlueter, Heather; Cameron, Michelle H.; Horak, Fay B.] Oregon Hlth & Sci Univ, Sch Med, Dept Neurol, Portland, OR 97239 USA. [Fling, Brett W.; Cameron, Michelle H.; Horak, Fay B.] Portland VA Med Ctr, Portland, OR USA. RP Fling, BW (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM fling@ohsu.edu FU National Multiple Sclerosis Society [PI: FG 2018-A-1, RG 5273A1/T, PI: MB 0011, PI: FG 2058-A-1]; Medical Research Foundation of Oregon; N.L. Tartar Research Fund FX We thank the volunteers for participating in this study and the Multiple Sclerosis Center of Oregon for referring patients. We are also grateful to Catherine Tallman for assistance in data analysis. This work was supported by grants from the National Multiple Sclerosis Society (Brett W. Fling, PI: FG 2018-A-1; RG 5273A1/T) and (Fay B. Horak, PI: MB 0011). Additional support was provided by the Medical Research Foundation of Oregon (Brett W. Fling, PI) and the N.L. Tartar Research Fund (Brett W. Fling, PI). Grant awarded by the National Multiple Sclerosis Society (Geetanjali Gera Dutta, PI: FG 2058-A-1). Additional support by the Medical Research Foundation of Oregon (Geetanjali Gera Dutta, PI). NR 79 TC 7 Z9 7 U1 2 U2 18 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD OCT 20 PY 2014 VL 8 AR UNSP 814 DI 10.3389/fnhum.2014.00814 PG 11 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AR2GU UT WOS:000343402600001 PM 25368564 ER PT J AU Lewis, GC Platts-Mills, TF Liberzon, I Bair, E Swor, R Peak, D Jones, J Rathlev, N Lee, D Domeier, R Hendry, P McLean, SA AF Lewis, Gemma C. Platts-Mills, Timothy F. Liberzon, Israel Bair, Eric Swor, Robert Peak, David Jones, Jeffrey Rathlev, Niels Lee, David Domeier, Robert Hendry, Phyllis McLean, Samuel A. TI Incidence and Predictors of Acute Psychological Distress and Dissociation After Motor Vehicle Collision: A Cross-Sectional Study SO JOURNAL OF TRAUMA & DISSOCIATION LA English DT Article DE distress; dissociation; posttraumatic stress disorder; trauma; motor vehicle collision ID POSTTRAUMATIC-STRESS-DISORDER; VIETNAM COMBAT VETERANS; PERITRAUMATIC DISTRESS; SYMPTOMS; TRAUMA; PTSD; ACCIDENTS; DEPRESSION; INVENTORY; ADULTS AB Objective: We examined the incidence and predictors of peritraumatic distress and dissociation after one of the most common forms of civilian trauma exposure: motor vehicle collision (MVC). Method: In this study, patients presenting to the emergency department after MVCs who were without serious injury and discharged to home after evaluation (n = 935) completed an emergency department interview evaluating sociodemographic, collision-related, and psychological characteristics. Results: The incidence and predictors of distress (Peritraumatic Distress Inventory score 23) and dissociation (Michigan Critical Events Perception Scale score >3) were assessed. Distress was present in 355 of 935 patients (38%), and dissociation was present in 260 of 942 patients (28%). These outcomes showed only moderate correlation (r = .45) and had both shared and distinct predictors. Female gender, anxiety symptoms prior to the MVC, and vehicle damage severity predicted both distress and dissociation. Higher socioeconomic status (higher education, higher income, full-time employment) had a protective effect against distress but not dissociative symptoms. Better physical health and worse overall mental health were associated with increased risk of dissociation but not distress. Distress but not dissociation was associated with lower patient confidence in recovery and a longer expected duration of recovery. Conclusion: There are unique predictors of peritraumatic distress and dissociation. Further work is needed to better understand the neurobiology of peritraumatic distress and dissociation and the influence of these peritraumatic outcomes on persistent psychological sequelae. C1 [Lewis, Gemma C.; Platts-Mills, Timothy F.; McLean, Samuel A.] Univ N Carolina, TRYUMPH Res Program, Chapel Hill, NC 27599 USA. [Lewis, Gemma C.; Platts-Mills, Timothy F.; McLean, Samuel A.] Univ N Carolina, Dept Anesthesiol, Chapel Hill, NC 27599 USA. [Lewis, Gemma C.; Platts-Mills, Timothy F.; McLean, Samuel A.] Univ N Carolina, Dept Emergency Med, Chapel Hill, NC 27599 USA. [Liberzon, Israel] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Bair, Eric] Univ N Carolina, Sch Dent, Chapel Hill, NC 27599 USA. [Swor, Robert] William Beaumont Hosp, Dept Emergency Med, Royal Oak, MI 48072 USA. [Peak, David] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Jones, Jeffrey] Spectrum Hlth, Dept Emergency Med, Grand Rapids, MI USA. [Rathlev, Niels] Baystate Med Ctr, Dept Emergency Med, Springfield, MA USA. [Lee, David] N Shore Univ Hosp, Dept Emergency Med, Manhasset, NY USA. [Domeier, Robert] St Joseph Mercy Hosp, Dept Emergency Med, Ann Arbor, MI 48104 USA. [Hendry, Phyllis] Univ Florida, Dept Emergency Med & Pediat, Jacksonville, FL USA. RP McLean, SA (reprint author), Univ N Carolina, Sch Med, Wing C CB 7010, Chapel Hill, NC 27599 USA. EM smclean@aims.unc.edu OI Bair, Eric/0000-0001-8733-7869; McLean, Samuel/0000-0001-9482-3582; Liberzon, Israel/0000-0002-4990-556X FU NIA NIH HHS [K23 AG038548]; NIAMS NIH HHS [R01 AR056328, R01AR056328] NR 90 TC 3 Z9 3 U1 2 U2 20 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1529-9732 EI 1529-9740 J9 J TRAUMA DISSOCIATIO JI J. Trauma Dissociation PD OCT 20 PY 2014 VL 15 IS 5 BP 527 EP 547 DI 10.1080/15299732.2014.908805 PG 21 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AQ1CV UT WOS:000342519900002 PM 24983475 ER PT J AU Wan, GQ Gomez-Casati, ME Gigliello, AR Liberman, MC Corfas, G AF Wan, Guoqiang Gomez-Casati, Maria E. Gigliello, Angelica R. Liberman, M. Charles Corfas, Gabriel TI Neurotrophin-3 regulates ribbon synapse density in the cochlea and induces synapse regeneration after acoustic trauma SO ELIFE LA English DT Article ID DEVELOPING INNER-EAR; SITE-SPECIFIC RECOMBINATION; MAMMALIAN COCHLEA; FACTOR EXPRESSION; GANGLION NEURONS; BDNF EXPRESSION; MESSENGER-RNA; MUTANT MICE; HAIR-CELLS; IN-VIVO AB Neurotrophin-3 (Ntf3) and brain derived neurotrophic factor (Bdnf) are critical for sensory neuron survival and the establishment of neuronal projections to sensory epithelia in the embryonic inner ear, but their postnatal functions remain poorly understood. Using cell-specific inducible gene recombination in mice we found that, in the postnatal inner ear, Bbnf and Ntf3 are required for the formation and maintenance of hair cell ribbon synapses in the vestibular and cochlear epithelia, respectively. We also show that supporting cells in these epithelia are the key endogenous source of the neurotrophins. Using a new hair cell CreER(T) line with mosaic expression, we also found that Ntf3's effect on cochlear synaptogenesis is highly localized. Moreover, supporting cell-derived Ntf3, but not Bbnf, promoted recovery of cochlear function and ribbon synapse regeneration after acoustic trauma. These results indicate that glial-derived neurotrophins play critical roles in inner ear synapse density and synaptic regeneration after injury. C1 [Wan, Guoqiang; Gomez-Casati, Maria E.; Gigliello, Angelica R.; Corfas, Gabriel] Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Wan, Guoqiang; Gomez-Casati, Maria E.; Corfas, Gabriel] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Wan, Guoqiang; Corfas, Gabriel] Univ Michigan, Kresge Hearing Res Inst, Dept Otolaryngol Head & Neck Surg, Ann Arbor, MI 48109 USA. [Liberman, M. Charles; Corfas, Gabriel] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Liberman, M. Charles] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. RP Corfas, G (reprint author), Univ Michigan, Kresge Hearing Res Inst, Med Sci 1 Bldg,Rm 5424A,1150 West Med Ctr Dr, Ann Arbor, MI 48109 USA. EM corfas@med.umich.edu OI Wan, Guoqiang/0000-0003-3841-9301 FU National Institute on Deafness and Other Communication Disorders [R01 DC 004820, P30 DC 005209]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [P30-HD 18655]; Department of Otolaryngology at Boston Children's Hospital; Hearing Health Foundation FX This research was supported in part by National Institute on Deafness and Other Communication Disorders Grants R01 DC 004820 (to G.C.) and P30 DC 005209 (to M.C.L.), Eunice Kennedy Shriver National Institute of Child Health and Human Development Grant P30-HD 18655 (Mental Retardation Research Center) (to G.C.), the Department of Otolaryngology at Boston Children's Hospital and the Hearing Health Foundation (to G.W.). NR 48 TC 28 Z9 28 U1 2 U2 3 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD OCT 20 PY 2014 VL 3 AR e03564 DI 10.7554/eLife.03564 PG 43 WC Biology SC Life Sciences & Biomedicine - Other Topics GA AR2JW UT WOS:000343411600001 ER PT J AU Atukunda, EC Siedner, MJ Obua, C Mugyenyi, GR Twagirumukiza, M Agaba, AG AF Atukunda, Esther C. Siedner, Mark J. Obua, Celestino Mugyenyi, Godfrey R. Twagirumukiza, Marc Agaba, Amon G. TI Sublingual misoprostol versus intramuscular oxytocin for prevention of post-partum haemorrhage in Uganda: a randomised, controlled, non-inferiority trial SO LANCET LA English DT Meeting Abstract CT 2nd Regional Meeting of the World-Health-Summit CY APR, 2014 CL Sao Paulo, BRAZIL SP World Hlth Summit C1 [Atukunda, Esther C.; Mugyenyi, Godfrey R.; Agaba, Amon G.] Mbarara Univ Sci & Technol, Kampala, Uganda. [Siedner, Mark J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Obua, Celestino] Makerere Univ, Coll Hlth Sci, Sch Biomed Sci, Dept Pharmacol & Therapeut, Kampala, Uganda. [Twagirumukiza, Marc] Univ Ghent, Fac Med & Hlth Sci, Dept Pharmacol, B-9000 Ghent, Belgium. EM estheratukunda@gmail.com NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD OCT 19 PY 2014 VL 384 SU 1 BP S3 EP S3 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CQ4GT UT WOS:000360563400003 ER PT J AU Shah, MM Steele, EA White, KP Wilson, DJ AF Shah, Manjool M. Steele, Eric A. White, Kevin P. Wilson, David J. TI Syringoid eccrine carcinoma of the eyelid presenting as cicatricial entropion SO INTERNATIONAL JOURNAL OF OPHTHALMOLOGY LA English DT Letter ID MICROCYSTIC ADNEXAL CARCINOMA; SYRINGOMATOUS CARCINOMA; ORBIT C1 [Shah, Manjool M.; Steele, Eric A.; Wilson, David J.] Oregon Hlth & Sci Univ, Casey Eye Inst, Dept Ophthalmol, Portland, OR 97239 USA. [Steele, Eric A.] Portland VA Med Ctr, Portland, OR 97201 USA. [White, Kevin P.] Oregon Hlth & Sci Univ, Dept Dermatol, Portland, OR 97203 USA. RP Steele, EA (reprint author), Casey Eye Inst, Dept Ophthalmol, 3375 SW Terwilliger Blvd, Portland, OR 97239 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU IJO PRESS PI XI AN PA NO 269 YOUYI EAST RD, XI AN, 710054, PEOPLES R CHINA SN 2222-3959 EI 2227-4898 J9 INT J OPHTHALMOL-CHI JI Int. J. Ophthalmol. PD OCT 18 PY 2014 VL 7 IS 5 BP 912 EP 913 DI 10.3980/j.issn.2222-3959.2014.05.31 PG 2 WC Ophthalmology SC Ophthalmology GA AR0PD UT WOS:000343272900031 PM 25349816 ER PT J AU Huber, RJ Myre, MA Cotman, SL AF Huber, Robert J. Myre, Michael A. Cotman, Susan L. TI Loss of Cln3 Function in the Social Amoeba Dictyostelium discoideum Causes Pleiotropic Effects That Are Rescued by Human CLN3 SO PLOS ONE LA English DT Article ID NEURONAL CEROID-LIPOFUSCINOSIS; JUVENILE BATTEN-DISEASE; CONTRACTILE VACUOLE; ENDOCYTIC PATHWAY; CELL MOTILITY; SCHIZOSACCHAROMYCES-POMBE; MATRICELLULAR PROTEIN; BINDING PROTEINS; COUNTING FACTOR; MEMBRANE AB The neuronal ceroid lipofuscinoses (NCL) are a group of inherited, severe neurodegenerative disorders also known as Batten disease. Juvenile NCL (JNCL) is caused by recessive loss-of-function mutations in CLN3, which encodes a transmembrane protein that regulates endocytic pathway trafficking, though its primary function is not yet known. The social amoeba Dictyostelium discoideum is increasingly utilized for neurological disease research and is particularly suited for investigation of protein function in trafficking. Therefore, here we establish new overexpression and knockout Dictyostelium cell lines for JNCL research. Dictyostelium Cln3 fused to GFP localized to the contractile vacuole system and to compartments of the endocytic pathway. cln3(-) cells displayed increased rates of proliferation and an associated reduction in the extracellular levels and cleavage of the autocrine proliferation repressor, AprA. Mid-and late development of cln3(-) cells was precocious and cln3(-) slugs displayed increased migration. Expression of either Dictyostelium Cln3 or human CLN3 in cln3(-) cells suppressed the precocious development and aberrant slug migration, which were also suppressed by calcium chelation. Taken together, our results show that Cln3 is a pleiotropic protein that negatively regulates proliferation and development in Dictyostelium. This new model system, which allows for the study of Cln3 function in both single cells and a multicellular organism, together with the observation that expression of human CLN3 restores abnormalities in Dictyostelium cln3(-) cells, strongly supports the use of this new model for JNCL research. C1 [Huber, Robert J.; Myre, Michael A.; Cotman, Susan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02163 USA. RP Huber, RJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02163 USA. EM rhuber@mgh.harvard.edu FU Canadian Institutes of Health Research [289813]; National Institutes of Health: National Institute of Neurological Disorders Stroke [R01NS073813] FX This work was supported by a Postdoctoral Fellowship from the Canadian Institutes of Health Research (289813 to R.J.H.) and the National Institutes of Health: National Institute of Neurological Disorders & Stroke (R01NS073813 to S.L.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 87 TC 6 Z9 6 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 17 PY 2014 VL 9 IS 10 AR e110544 DI 10.1371/journal.pone.0110544 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT8TF UT WOS:000345204100091 PM 25330233 ER PT J AU Zhang, WJ Wang, YYE Zhang, Y Leleu, X Reagan, M Zhang, Y Mishima, Y Glavey, S Manier, S Sacco, A Jiang, B Roccaro, AM Ghobrial, IM AF Zhang, Wenjing Wang, Yaoyu E. Zhang, Yu Leleu, Xavier Reagan, Michaela Zhang, Yong Mishima, Yuji Glavey, Siobhan Manier, Salomon Sacco, Antonio Jiang, Bo Roccaro, Aldo M. Ghobrial, Irene M. TI Global Epigenetic Regulation of MicroRNAs in Multiple Myeloma SO PLOS ONE LA English DT Article ID TUMOR-SUPPRESSOR MICRORNAS; DNA METHYLATION; MOLECULAR CLASSIFICATION; EXPRESSION PROFILES; GENE-EXPRESSION; DOWN-REGULATION; CPG ISLAND; CANCER; PROLIFERATION; CELLS AB Epigenetic changes frequently occur during tumorigenesis and DNA hypermethylation may account for the inactivation of tumor suppressor genes in cancer cells. Studies in Multiple Myeloma (MM) have shown variable DNA methylation patterns with focal hypermethylation changes in clinically aggressive subtypes. We studied global methylation patterns in patients with relapsed/ refractory MM and found that the majority of methylation peaks were located in the intronic and intragenic regions in MM samples. Therefore, we investigated the effect of methylation on miRNA regulation in MM. To date, the mechanism by which global miRNA suppression occurs in MM has not been fully described. In this study, we report hypermethylation of miRNAs in MM and perform confirmation in MM cell lines using bisulfite sequencing and methylationspecific PCR (MSP) in the presence or absence of the DNA demethylating agent 5-aza-2'-deoxycytidine. We further characterized the hypermethylation-dependent inhibition of miR-152, -10b-5p and -34c-3p which was shown to exert a putative tumor suppressive role in MM. These findings were corroborated by the demonstration that the same miRNAs were down-regulated in MM patients compared to healthy individuals, alongside enrichment of miR-152-, -10b-5p, and miR-34c-3p-predicted targets, as shown at the mRNA level in primary MM cells. Demethylation or gain of function studies of these specific miRNAs led to induction of apoptosis and inhibition of proliferation as well as down-regulation of putative oncogene targets of these miRNAs such as DNMT1, E2F3, BTRC and MYCBP. These findings provide the rationale for epigenetic therapeutic approaches in subgroups of MM. C1 [Zhang, Wenjing; Zhang, Yu; Leleu, Xavier; Reagan, Michaela; Zhang, Yong; Mishima, Yuji; Glavey, Siobhan; Manier, Salomon; Sacco, Antonio; Roccaro, Aldo M.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Zhang, Wenjing; Jiang, Bo] Southern Med Univ, Nanfang Hosp, Guangzhou, Guangdong, Peoples R China. [Wang, Yaoyu E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02115 USA. [Zhang, Yu] Kunming Univ Sci & Technol, Peoples Hosp Yunnan Prov 1, Kunming, Peoples R China. [Leleu, Xavier] Hosp Lille CHRU, Dept Hematol, Hop Claude Huriez, Lille, France. RP Roccaro, AM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM aldo_roccaro@dfci.harvard.edu; irene_ghobrial@dfci.harvard.edu RI Sacco, Antonio/K-4681-2016; Reagan, Michaela/E-3549-2017; OI Sacco, Antonio/0000-0003-2945-9416; Roccaro, Aldo/0000-0002-1872-5128; Reagan, Michaela/0000-0003-2884-6481 FU Research Project Grant (National Institutes of Health) [RO1CA154648] FX This study was supported by the Research Project Grant (National Institutes of Health/RO1CA154648), and by the Multiple Myeloma Research Foundation (MMRF; www.themmrf.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 8 Z9 9 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 OCT 17 PY 2014 VL 9 IS 10 AR e110973 DI 10.1371/journal.pone.0110973 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AT8TF UT WOS:000345204100112 PM 25330074 ER PT J AU Dowling, P Hayes, C Ting, KR Hameed, A Meiller, J Mitsiades, C Anderson, KC Clynes, M Clarke, C Richardson, P O'Gorman, P AF Dowling, Paul Hayes, Catriona Ting, Kay Reen Hameed, Abdul Meiller, Justine Mitsiades, Constantine Anderson, Kenneth C. Clynes, Martin Clarke, Colin Richardson, Paul O'Gorman, Peter TI Identification of proteins found to be significantly altered when comparing the serum proteome from Multiple Myeloma patients with varying degrees of bone disease SO BMC GENOMICS LA English DT Article DE Biomarkers; Bone disease; C4; Mass spectrometry; PON1; Proteomics ID BIOCHEMICAL MARKERS; OSTEOBLAST FUNCTION; PARAOXONASE; MATRIX; POLYMORPHISMS; LENALIDOMIDE; ASSOCIATION; VITRONECTIN; RESORPTION; DIAGNOSIS AB Background: Bone destruction is a feature of multiple myeloma, characterised by osteolytic bone destruction due to increased osteoclast activity and suppressed or absent osteoblast activity. Almost all multiple myeloma patients develop osteolytic bone lesions associated with severe and debilitating bone pain, pathologic fractures, hypercalcemia, and spinal cord compression, as well as increased mortality. Biomarkers of bone remodelling are used to identify disease characteristics that can help select the optimal management of patients. However, more accurate biomarkers are needed to effectively mirror the dynamics of bone disease activity. Results: A label-free mass spectrometry-based strategy was employed for discovery phase analysis of fractionated patient serum samples associated with no or high bone disease. A number of proteins were identified which were statistically significantly correlated with bone disease, including enzymes, extracellular matrix glycoproteins, and components of the complement system. Conclusions: Enzyme-linked immunosorbent assay of complement C4 and serum paraoxonase/arylesterase 1 indicated that these proteins were associated with high bone disease in a larger independent cohort of patient samples. These biomolecules may therefore be clinically useful in assessing the extent of bone disease. C1 [Dowling, Paul] Natl Univ Ireland, Dept Biol, Maynooth, Kildare, Ireland. [Dowling, Paul; Hayes, Catriona; Ting, Kay Reen; Hameed, Abdul; Meiller, Justine; Clynes, Martin; Clarke, Colin; O'Gorman, Peter] Dublin City Univ, Natl Inst Cellular Biotechnol, Glasnevin, Dublin 9, Ireland. [Hayes, Catriona; Ting, Kay Reen; Hameed, Abdul; O'Gorman, Peter] Mater Misericordiae Univ Hosp, Dublin 7, Ireland. [Mitsiades, Constantine; Anderson, Kenneth C.; Richardson, Paul] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mitsiades, Constantine; Anderson, Kenneth C.; Richardson, Paul] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [O'Gorman, Peter] Univ Coll Dublin, Sch Med & Med Sci, Dublin 4, Ireland. RP Dowling, P (reprint author), Natl Univ Ireland, Dept Biol, Maynooth, Kildare, Ireland. EM paul.dowling@nuim.ie OI Clarke, Colin/0000-0003-2817-9527 FU Science Foundation Ireland Short Term Travel Fellowship FX This work was supported in part by a Science Foundation Ireland Short Term Travel Fellowship. NR 35 TC 5 Z9 5 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 17 PY 2014 VL 15 AR 904 DI 10.1186/1471-2164-15-904 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AS9OM UT WOS:000344571800001 PM 25322877 ER PT J AU Jennelle, L Hunegnaw, R Dubrovsky, L Pushkarsky, T Fitzgerald, ML Sviridov, D Popratiloff, A Brichacek, B Bukrinsky, M AF Jennelle, Lucas Hunegnaw, Ruth Dubrovsky, Larisa Pushkarsky, Tatiana Fitzgerald, Michael L. Sviridov, Dmitri Popratiloff, Anastas Brichacek, Beda Bukrinsky, Michael TI HIV-1 Protein Nef Inhibits Activity of ATP-binding Cassette Transporter A1 by Targeting Endoplasmic Reticulum Chaperone Calnexin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ABCA1-DEPENDENT CHOLESTEROL EFFLUX; TYPE-1 ENVELOPE GLYCOPROTEIN; QUALITY-CONTROL; CLASS-I; INTRACELLULAR TRAFFICKING; EXTRACELLULAR DOMAIN; P-GLYCOPROTEIN; ABCA1; CALRETICULIN; MACROPHAGES AB HIV-infected patients are at increased risk of developing atherosclerosis, in part due to an altered high density lipoprotein profile exacerbated by down-modulation and impairment of ATP-binding cassette transporter A1 (ABCA1) activity by the HIV-1 protein Nef. However, the mechanisms of this Nef effect remain unknown. Here, we show that Nef interacts with an endoplasmic reticulum chaperone calnexin, which regulates folding and maturation of glycosylated proteins. Nef disrupted interaction between calnexin and ABCA1 but increased affinity and enhanced interaction of calnexin with HIV-1 gp160. The Nef mutant that did not bind to calnexin did not affect the calnexin- ABCA1 interaction. Interaction with calnexin was essential for functionality of ABCA1, as knockdown of calnexin blocked the ABCA1 exit from the endoplasmic reticulum, reduced ABCA1 abundance, and inhibited cholesterol efflux; the same effects were observed after Nef overexpression. However, the effects of calnexin knockdown and Nef on cholesterol efflux were not additive; in fact, the combined effect of these two factors together did not differ significantly from the effect of calnexin knockdown alone. Interestingly, gp160 and ABCA1 interacted with calnexin differently; although gp160 binding to calnexin was dependent on glycosylation, glycosylation was of little importance for the interaction between ABCA1 and calnexin. Thus, Nef regulates the activity of calnexin to stimulate its interaction with gp160 at the expense of ABCA1. This study identifies a mechanism for Nef-dependent inactivation of ABCA1 and dysregulation of cholesterol metabolism. C1 [Jennelle, Lucas; Hunegnaw, Ruth; Dubrovsky, Larisa; Pushkarsky, Tatiana; Brichacek, Beda; Bukrinsky, Michael] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20037 USA. [Fitzgerald, Michael L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sviridov, Dmitri] Baker IDI Heart & Diabet Inst, Melbourne, Vic 3004, Australia. [Popratiloff, Anastas] George Washington Ctr Microscopy & Image Anal, Off VP Res, Washington, DC 20037 USA. RP Bukrinsky, M (reprint author), George Washington Univ, Dept Microbiol Immunol & Trop Med, Ross Hall Rm 624,2300 Eye St NW, Washington, DC 20037 USA. EM mbukrins@gwu.edu RI Sviridov, Dmitri/E-7943-2010 FU National Institutes of Health [HL093818, HL101274, AI108533]; [5P30AI087714] FX This work was supported, in whole or in part, by National Institutes of Health Grants HL093818, HL101274, and AI108533 and by Program Grant 5P30AI087714 (to District of Columbia Developmental Center for AIDS Research). This work is part of a dissertation to be presented by R. H. to the Institute for Biomedical Sciences, George Washington University, in partial fulfillment of the requirements for the Ph.D. degree. NR 46 TC 10 Z9 10 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 17 PY 2014 VL 289 IS 42 BP 28870 EP 28884 DI 10.1074/jbc.M114.583591 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AS2XZ UT WOS:000344141000011 PM 25170080 ER PT J AU Zhang, QX Ren, H Baker, GL AF Zhang, Quanxuan Ren, Hong Baker, Gregory L. TI Synthesis of a Library of Propargylated and PEGylated alpha-Hydroxy Acids Toward "Clickable" Polylactides via Hydrolysis of Cyanohydrin Derivatives SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID RING-OPENING POLYMERIZATION; THIOL-YNE CHEMISTRY; DRUG-DELIVERY; GENE DELIVERY; POLY(ALPHA-HYDROXY ACID); BIOLOGICAL-ACTIVITIES; COPOLYMERS; NANOPARTICLES; POLYMERS; NETWORKS AB A new simple and practical protocol for scalable synthesis of a novel library of propargylated and,PEGylated alpha-hydroxy acids toward the preparation of "clickable" polylactides was described. The overall synthesis = readily available propargyl alcohol, bromoacetaldehyde diethyl acetal, and OEGs or PEGs vitas developed as on Venienf procedure with low cost and no' need,of colunni.i, chromatographic purification. The terminal alkyne functionaliti survie` from hydrolysis of the corresponding easily',accessible cyanohydrin derivatives in methanolic sulfuric kcil. Fa'cile desymmetrization, monoffinctionalization, and efficient chain, elongation coupling of OEGs further'enable the incorPoration of OEGs to alpha-hydroxy acids in a simple and efficient' manner.At the end, synthesis of 'allyloxy lactic acid indicates that an alkene group is also compatible with the developed method. C1 [Zhang, Quanxuan; Baker, Gregory L.] Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA. [Ren, Hong] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Ren, Hong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA 02129 USA. RP Zhang, QX (reprint author), Michigan State Univ, Dept Chem, E Lansing, MI 48824 USA. EM zhangqua@msu.edu RI Ren, Hong/J-5191-2015 OI Ren, Hong/0000-0003-0375-0360 FU NIH [5RC2ES018756-02] FX This manuscript is dedicated in memory of my advisor, Prof. Gregory L. Baker, who passed away unexpectedly while this paper was under preparation. The authors gratefully acknowledge the invaluable discussions, assistance, and guidance from Prof. William D. Wulff at Michigan State University during the preparation of this manuscript. This work was funded by NIH 5RC2ES018756-02. NR 57 TC 3 Z9 3 U1 5 U2 38 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD OCT 17 PY 2014 VL 79 IS 20 BP 9546 EP 9555 DI 10.1021/jo5016135 PG 10 WC Chemistry, Organic SC Chemistry GA AR3ZG UT WOS:000343527200012 PM 25255205 ER PT J AU Durand, ML Lin, DT Juliano, AF Sadow, PM AF Durand, Marlene L. Lin, Derrick T. Juliano, Amy F. Sadow, Peter M. TI Case 32-2014: A 78-Year-Old Woman with Chronic Sore Throat and a Tonsillar Mass SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VARICELLA-ZOSTER-VIRUS; NECROSIS-FACTOR; RHEUMATOID-ARTHRITIS; UNITED-STATES; HISTOPLASMOSIS; TUBERCULOSIS; INFECTION; HERPES; DISEASES; NECK C1 [Durand, Marlene L.] Massachusetts Gen Hosp, Dept Infect Dis, Boston, MA 02114 USA. [Juliano, Amy F.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sadow, Peter M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Durand, Marlene L.] Harvard Univ, Sch Med, Dept Infect Dis, Boston, MA USA. [Lin, Derrick T.] Harvard Univ, Sch Med, Dept Head & Neck Oncol, Boston, MA USA. [Juliano, Amy F.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Sadow, Peter M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Lin, Derrick T.; Sadow, Peter M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Juliano, Amy F.] Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. RP Durand, ML (reprint author), Massachusetts Gen Hosp, Dept Infect Dis, Boston, MA 02114 USA. NR 27 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 OCT 16 PY 2014 VL 371 IS 16 BP 1535 EP 1543 DI 10.1056/NEJMcpc1406191 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AQ7KV UT WOS:000342994700012 PM 25317874 ER PT J AU Guckenberger, M Mantel, F Gerszten, PC Flickinger, JC Sahgal, A Letourneau, D Grills, IS Jawad, M Fahim, DK Shin, JH Winey, B Sheehan, J Kersh, R AF Guckenberger, Matthias Mantel, Frederick Gerszten, Peter C. Flickinger, John C. Sahgal, Arjun Letourneau, Daniel Grills, Inga S. Jawad, Maha Fahim, Daniel K. Shin, John H. Winey, Brian Sheehan, Jason Kersh, Ron TI Safety and efficacy of stereotactic body radiotherapy as primary treatment for vertebral metastases: a multi-institutional analysis SO RADIATION ONCOLOGY LA English DT Article ID SPINAL-CORD COMPRESSION; BONE METASTASES; RADIATION-THERAPY; CLINICAL ARTICLE; RANDOMIZED-TRIAL; SURGICAL RESECTION; SINGLE-SESSION; RADIOSURGERY; MYELOPATHY; SURVIVAL AB Purpose: To evaluate patient selection criteria, methodology, safety and clinical outcomes of stereotactic body radiotherapy (SBRT) for treatment of vertebral metastases. Materials and methods: Eight centers from the United States (n = 5), Canada (n = 2) and Germany (n = 1) participated in the retrospective study and analyzed 301 patients with 387 vertebral metastases. No patient had been exposed to prior radiation at the treatment site. All patients were treated with linac-based SBRT using cone-beam CT image-guidance and online correction of set-up errors in six degrees of freedom. Results: 387 spinal metastases were treated and the median follow-up was 11.8 months. The median number of consecutive vertebrae treated in a single volume was one (range, 1-6), and the median total dose was 24 Gy (range 8-60 Gy) in 3 fractions (range 1-20). The median EQD2(10) was 38 Gy (range 12-81 Gy). Median overall survival (OS) was 19.5 months and local tumor control (LC) at two years was 83.9%. On multivariate analysis for OS, male sex (p < 0.001; HR = 0.44), performance status < 90 (p < 0.001; HR = 0.46), presence of visceral metastases (p = 0.007; HR = 0.50), uncontrolled systemic disease (p = 0.007; HR = 0.45), > 1 vertebra treated with SBRT (p = 0.04; HR = 0.62) were correlated with worse outcomes. For LC, an interval between primary diagnosis of cancer and SBRT of = 30 months (p = 0.01; HR = 0.27) and histology of primary disease (NSCLC, renal cell cancer, melanoma, other) (p = 0.01; HR = 0.21) were correlated with worse LC. Vertebral compression fractures progressed and developed de novo in 4.1% and 3.6%, respectively. Other adverse events were rare and no radiation induced myelopathy reported. Conclusions: This multi-institutional cohort study reports high rates of efficacy with spine SBRT. At this time the optimal fractionation within high dose practice is unknown. C1 [Guckenberger, Matthias; Mantel, Frederick] Univ Wurzburg, Dept Radiat Oncol, Wurzburg, Germany. [Gerszten, Peter C.; Flickinger, John C.] Univ Pittsburgh, Med Ctr, Dept Radiat Oncol, Pittsburgh, PA USA. [Gerszten, Peter C.; Flickinger, John C.] Univ Pittsburgh, Med Ctr, Dept Neurol Surg, Pittsburgh, PA USA. [Sahgal, Arjun] Sunnybrook Odette Canc Ctr, Dept Radiat Oncol, Toronto, ON, Canada. [Letourneau, Daniel] Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M4X 1K9, Canada. [Grills, Inga S.; Jawad, Maha] Oakland Univ William Beaumont, Sch Med, Dept Radiat Oncol, Royal Oak, MI USA. [Fahim, Daniel K.] Oakland Univ William Beaumont, Sch Med, Dept Neurosurg, Royal Oak, MI USA. [Shin, John H.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Winey, Brian] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Sheehan, Jason] Univ Virginia, Sch Med, Dept Neurol Surg, Charlottesville, VA 22908 USA. [Kersh, Ron] Riverside Med Ctr, Newport News, VA USA. [Guckenberger, Matthias] Univ Zurich, Dept Radiat Oncol, Zurich, Switzerland. RP Guckenberger, M (reprint author), Univ Wurzburg, Dept Radiat Oncol, Wurzburg, Germany. EM Matthias.Guckenberger@usz.ch OI Guckenberger, Matthias/0000-0002-7146-9071 FU Elekta research grant with all institutions being members of the "Elekta Spine SBRT Research Consortium"; Elekta FX This research was partially supported through an Elekta research grant with all institutions being members of the "Elekta Spine SBRT Research Consortium". This work and these data, however, are the intellectual property of the individual group members and their sponsoring institutions. Dr. Sahgal has received prior honorarium for educational seminars from Elekta and holds research grants from Elekta. NR 39 TC 20 Z9 20 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD OCT 16 PY 2014 VL 9 AR 226 DI 10.1186/s13014-014-0226-2 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AW5FW UT WOS:000346302300001 PM 25319530 ER PT J AU Kim, J Kim, JH Winau, F AF Kim, Jessica Kim, Ji Hyung Winau, Florian TI Thinking Inside the Box: Endogenous alpha-Anomeric Lipid Antigens SO IMMUNITY LA English DT Editorial Material ID NKT CELLS AB The most powerful iNKT cell antigen is alpha-galactosylceramide (a-GalCer), derived from the marine sponge. However, alpha-anomeric glycolipids are thought to be absent in mammals. In this issue of Immunity, Kain et al., (2014) demonstrate the presence of mammalian alpha-linked glycosylceramides, such as alpha-GalCer. C1 [Kim, Jessica; Kim, Ji Hyung; Winau, Florian] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Kim, Jessica; Kim, Ji Hyung; Winau, Florian] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. RP Winau, F (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. EM florian.winau@childrens.harvard.edu NR 9 TC 4 Z9 4 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD OCT 16 PY 2014 VL 41 IS 4 BP 505 EP 506 DI 10.1016/j.immuni.2014.09.020 PG 2 WC Immunology SC Immunology GA AU3HY UT WOS:000345504300001 PM 25367563 ER PT J AU Meltzer, EB Barry, WT Yang, IV Brown, KK Schwarz, MI Patel, H Ashley, A Noble, PW Schwartz, DA Steele, MP AF Meltzer, Eric B. Barry, William T. Yang, Ivana V. Brown, Kevin K. Schwarz, Marvin I. Patel, Hamish Ashley, Allison Noble, Paul W. Schwartz, David A. Steele, Mark P. TI Familial and sporadic idiopathic pulmonary fibrosis: making the diagnosis from peripheral blood SO BMC GENOMICS LA English DT Article DE IPF; FIP; gene signature; Bayesian probit regression ID INTERSTITIAL LUNG-DISEASE; PNEUMONIA; BIOPSIES AB Background: Peripheral blood biomarkers might improve diagnostic accuracy for idiopathic pulmonary fibrosis (IPF). Results: Gene expression profiles were obtained from 89 patients with IPF and 26 normal controls. Samples were stratified according to severity of disease based on pulmonary function. The stratified dataset was split into subsets; two-thirds of the samples were selected to comprise the training set, while one-third was reserved for the validation set. Bayesian probit regression was used on the training set to develop a gene expression model for IPF versus normal. The gene expression model was tested by using it on the validation set to perform class prediction. Unsupervised clustering failed to discriminate between samples of different severity. Therefore, samples of all severities were included in the training and validation sets, in equal proportions. A gene signature model was developed from the training set. The model was built in an iterative fashion with the number of gene features selected to minimize the misclassification error in cross validation. The final model was based on the top 108 discriminating genes in the training set. The signature was successfully applied to the validation set, ROC area under the curve = 0.893, p < 0.0001. Using the optimal threshold (0.74) accurate class predictions were made for 77% of the test cases with sensitivity = 0.70, specificity = 1.00. Conclusions: By using Bayesian probit regression to develop a model, we show that it is entirely possible to make a diagnosis of IPF from the peripheral blood with gene signatures. C1 [Barry, William T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Yang, Ivana V.; Schwarz, Marvin I.; Schwartz, David A.] Univ Colorado, Dept Med, Aurora, CO USA. [Brown, Kevin K.] Natl Jewish Hlth, Denver, CO USA. [Patel, Hamish] Edward Via Coll Osteopath Med, Spartanburg, SC USA. [Noble, Paul W.] Cedars Sinai, Dept Med, Los Angeles, CA USA. [Steele, Mark P.] Vanderbilt Univ, Med Ctr, Div Allergy Pulm & Crit Care, Nashville, TN 37235 USA. RP Steele, MP (reprint author), Vanderbilt Univ, Med Ctr, Div Allergy Pulm & Crit Care, 1313 21st Ave South,1105 Oxford House, Nashville, TN 37235 USA. EM mark.p.steele@vanderbilt.edu FU National Institutes of Health, National Heart Lung Blood Institute, NHLBI [RC1HL067467]; Vanderbilt University School of Medicine FX The authors would like to thank Raven Kidd for assistance in preparation of materials. This work was funded by the National Institutes of Health, National Heart Lung Blood Institute, NHLBI RC1HL067467, Principal Investigator Mark P. Steele, Professor of Medicine, Vanderbilt University School of Medicine. NR 23 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 16 PY 2014 VL 15 AR 902 DI 10.1186/1471-2164-15-902 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AT4CB UT WOS:000344885600001 PM 25318837 ER PT J AU Kalaitzidis, D Scadden, DT AF Kalaitzidis, Demetrios Scadden, David T. TI Deep diving in the blood stem cell-ome SO EMBO JOURNAL LA English DT Editorial Material ID HEMATOPOIETIC STEM; SELF-RENEWAL AB Defining the functional distinctions between cells comprising the bone marrow has yielded fundamental insights into lineage ordering and drivers of blood cell production. A novel, highly granular and multi-dimensional molecular characterization of functional subsets of hematopoietic stem- and progenitor cells recently published in Cell Stem Cell (Cabezas-Wallscheid etal, ) will serve as a landmark and treasure trove for unanticipated insights into basic biology and the development of future targeted medicine. C1 [Kalaitzidis, Demetrios; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Kalaitzidis, Demetrios; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Kalaitzidis, D (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. EM david_scadden@harvard.edu FU NIDDK NIH HHS [K01 DK092300] NR 9 TC 0 Z9 0 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD OCT 16 PY 2014 VL 33 IS 20 BP 2281 EP 2282 DI 10.15252/embj.201489778 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AR9UE UT WOS:000343922500003 PM 25190519 ER PT J AU Wade, BSC Joshi, SH Reuter, M Blumenthal, JD Toga, AW Thompson, PM Giedd, JN AF Wade, Benjamin S. C. Joshi, Shantanu H. Reuter, Martin Blumenthal, Jonathan D. Toga, Arthur W. Thompson, Paul M. Giedd, Jay N. TI Effects of sex chromosome dosage on corpus callosum morphology in supernumerary sex chromosome aneuploidies SO BIOLOGY OF SEX DIFFERENCES LA English DT Article DE Corpus callosum; Sex chromosomes; Aneuploidies; Statistical shape analysis; Sexual differentiation ID DISTANCE MATRIX ANALYSIS; KLINEFELTER-SYNDROME; MOTOR DEVELOPMENT; X-CHROMOSOME; BRAIN; XXY; DEFICITS; MALES; XXXXY; SCHIZOPHRENIA AB Background: Supernumerary sex chromosome aneuploidies (sSCA) are characterized by the presence of one or more additional sex chromosomes in an individual's karyotype; they affect around 1 in 400 individuals. Although there is high variability, each sSCA subtype has a characteristic set of cognitive and physical phenotypes. Here, we investigated the differences in the morphometry of the human corpus callosum (CC) between sex-matched controls 46, XY (N = 99), 46, XX (N = 93), and six unique sSCA karyotypes: 47,XYY (N = 29), 47,XXY (N = 58), 48,XXYY (N = 20), 47,XXX (N = 30), 48,XXXY (N = 5), and 49,XXXXY (N = 6). Methods: We investigated CC morphometry using local and global area, local curvature of the CC boundary, and between-landmark distance analysis (BLDA). We hypothesized that CC morphometry would vary differentially along a proposed spectrum of Y:X chromosome ratio with supernumerary Y karyotypes having the largest CC areas and supernumerary X karyotypes having significantly smaller CC areas. To investigate this, we defined an sSCA spectrum based on a descending Y:X karyotype ratio: 47,XYY, 46,XY, 48,XXYY, 47,XXY, 48,XXXY, 49,XXXXY, 46,XX, 47,XXX. We similarly explored the effects of both X and Y chromosome numbers within sex. Results of shape-based metrics were analyzed using permutation tests consisting of 5,000 iterations. Results: Several subregional areas, local curvature, and BLDs differed between groups. Moderate associations were found between area and curvature in relation to the spectrum and X and Y chromosome counts. BLD was strongly associated with X chromosome count in both male and female groups. Conclusions: Our results suggest that X-and Y-linked genes have differential effects on CC morphometry. To our knowledge, this is the first study to compare CC morphometry across these extremely rare groups. C1 [Wade, Benjamin S. C.; Thompson, Paul M.] Univ So Calif, Inst Neuro Imaging & Informat, Imaging Genet Ctr, Marina Del Rey, CA 90292 USA. [Joshi, Shantanu H.] Univ Calif Los Angeles, Ahmanson Lovelace Brain Mapping Ctr, Dept Neurol, Los Angeles, CA 90095 USA. [Reuter, Martin] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Toga, Arthur W.] Univ So Calif, Keck Sch Med, Inst Neuro Imaging & Informat, Los Angeles, CA 90032 USA. [Blumenthal, Jonathan D.; Giedd, Jay N.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Wade, BSC (reprint author), Univ So Calif, Inst Neuro Imaging & Informat, Imaging Genet Ctr, 4676 Admiralty Way, Marina Del Rey, CA 90292 USA. EM Benjamin.SC.Wade@gmail.com RI Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-2002-8978 FU National Science Foundation [DGE-0707424] FX This material is based upon work supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-0707424. Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. Linda Wade contributed significantly to the editing of this manuscript. NR 58 TC 2 Z9 2 U1 2 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2042-6410 J9 BIOL SEX DIFFER JI Biol. Sex Differ. PD OCT 16 PY 2014 VL 5 AR 16 DI 10.1186/s13293-014-0016-4 PG 18 WC Endocrinology & Metabolism; Genetics & Heredity SC Endocrinology & Metabolism; Genetics & Heredity GA AR7QJ UT WOS:000343774100001 PM 25780557 ER PT J AU Saha, SK Parachoniak, CA Bardeesy, N AF Saha, Supriya K. Parachoniak, Christine A. Bardeesy, Nabeel TI IDH mutations in liver cell plasticity and biliary cancer SO CELL CYCLE LA English DT Article DE cholangiocarcinoma; IDH1; IDH2; Isocitrate Dehydrogenase; mouse models ID ISOCITRATE DEHYDROGENASE 1; COMBINED HEPATOCELLULAR-CHOLANGIOCARCINOMA; INTRAHEPATIC CHOLANGIOCARCINOMA; MUTANT IDH2; DIFFERENTIATION; PROGENITORS; METABOLISM; INHIBITOR; LEUKEMIA; (R)-2-HYDROXYGLUTARATE AB Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer associated with the bile ducts within the liver. These tumors are characterized by frequent gain-of-function mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes-that are also common in subsets of neural, haematopoietic and bone tumors, but rare or absent in the other types of gastrointestinal malignancy. Mutant IDH acts through a novel mechanism of oncogenesis, producing high levels of the metabolite 2-hydroxyglutarate, which interferes with the function of a-ketoglutarate-dependent enzymes that regulate diverse cellular processes including histone demethylation and DNA modification. Recently, we used in vitro stem cell systems and genetically engineered mousemodels (GEMMs) to demonstrate that mutant IDH promotes ICC formation by blocking hepatocyte differentiation and increasing pools of hepatic progenitors that are susceptible to additional oncogenic hits leading to ICC. We found that silencing of HNF4A-encodingamaster transcriptional regulator of hepatocyte identity and quiescence-was critical to mutant IDH-mediated inhibition of liver differentiation. In line with these findings, human ICC with IDH mutations are characterized by a hepatic progenitor cell transcriptional signature suggesting that they are a distinct ICC subtype as compared to IDH wild type tumors. The role of mutant IDH in controlling hepatic differentiation state suggests the potential of newly developed inhibitors of the mutant enzyme as a form of differentiation therapy in a solid tumor. C1 [Bardeesy, Nabeel] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Dept Med,Med Sch, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med,Dept Med, Boston, MA USA. RP Bardeesy, N (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Dept Med,Med Sch, Boston, MA 02114 USA. EM bardeesy.nabeel@mgh.harvard.edu FU NIH [R01CA136567-02, P50CA1270003]; TargetCancer Foundation; V Foundation Translational Award; NCI; American Cancer Society Postdoctoral Fellowship [PF-13-294-01-TBG]; CIHR postdoctoral fellowship FX This work was supported by grants from the NIH (R01CA136567-02 and P50CA1270003) and TargetCancer Foundation to N.B. N.B. holds the Gallagher Endowed Chair in Gastrointestinal Cancer Research at Massachusetts General Hospital and is supported by a V Foundation Translational Award, TargetCancer Foundation, and grants from the NCI. S. K.S. is the recipient of an American Cancer Society Postdoctoral Fellowship (PF-13-294-01-TBG). C.A.P is the recipient of a CIHR postdoctoral fellowship. NR 46 TC 5 Z9 5 U1 2 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD OCT 15 PY 2014 VL 13 IS 20 BP 3176 EP 3182 DI 10.4161/15384101.2014.965054 PG 7 WC Cell Biology SC Cell Biology GA AZ6JU UT WOS:000348327100010 PM 25485496 ER PT J AU Kharbanda, A Rajabi, H Jin, C Alam, M Wong, KK Kufe, D AF Kharbanda, Akriti Rajabi, Hasan Jin, Caining Alam, Maroof Wong, Kwok-Kin Kufe, Donald TI MUC1-C confers EMT and KRAS independence in mutant KRAS lung cancer cells SO ONCOTARGET LA English DT Article DE KRAS; NSCLC; MUC1-C; AKT; ZEB1; EMT; self-renewal ID EPITHELIAL-MESENCHYMAL TRANSITION; STEM-CELLS; ONCOGENIC KRAS; RAS ONCOGENES; ONCOPROTEIN; CARCINOMA; BREAST; INHIBITION; RECEPTOR; PATHWAYS AB Non-small cell lung cancers (NSCLCs) that harbor an oncogenic KRAS mutation are often associated with resistance to targeted therapies. The MUC1-C transmembrane protein is aberrantly overexpressed in NSCLCs and confers a poor outcome; however, the functional role for MUC1-C in mutant KRAS NSCLC cells has remained unclear. The present studies demonstrate that silencing MUC1-C in A549/KRAS(G12S) and H460/KRAS(Q61H) NSCLC cells is associated with downregulation of AKT signaling and inhibition of growth. Overexpression of a MUC1-C(CQC boxed times AQA) mutant, which inhibits MUC1-C homodimerization and function, suppressed both AKT and MEK activation. Moreover, treatment with GO-203, an inhibitor of MUC1-C homodimerization, blocked AKT and MEK signaling and decreased cell survival. The results further demonstrate that targeting MUC1-C suppresses expression of the ZEB1 transcriptional repressor by an AKT-mediated mechanism, and in turn induces miR-200c. In concert with these effects on the ZEB1/miR-200c regulatory loop, targeting MUC1-C was associated with reversal of the epithelial-mesenchymal transition (EMT) and inhibition of self-renewal capacity. Loss of MUC1-C function also attenuated KRAS independence and inhibited growth of KRAS mutant NSCLC cells as tumors in mice. These findings support a model in which targeting MUC1-C inhibits mutant KRAS signaling in NSCLC cells and thereby reverses the EMT phenotype and decreases self-renewal. C1 [Kharbanda, Akriti; Rajabi, Hasan; Jin, Caining; Alam, Maroof; Wong, Kwok-Kin; Kufe, Donald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. EM donald_kufe@dfci.harvard.edu FU National Cancer Institute of the National Institutes of Health [CA166480, CA97098] FX Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers CA166480 and CA97098. NR 43 TC 12 Z9 12 U1 1 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD OCT 15 PY 2014 VL 5 IS 19 BP 8893 EP 8905 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ1ZL UT WOS:000348033800006 PM 25245423 ER PT J AU Das, F Bera, A Ghosh-Choudhury, N Abboud, HE Kasinath, BS Choudhury, GG AF Das, Falguni Bera, Amit Ghosh-Choudhury, Nandini Abboud, Hanna E. Kasinath, Balakuntalam S. Choudhury, Goutam Ghosh TI TGF beta-Induced Deptor Suppression Recruits mTORC1 and Not mTORC2 to Enhance Collagen I (alpha 2) Gene Expression SO PLOS ONE LA English DT Article ID MESANGIAL CELL HYPERTROPHY; PLASMINOGEN-ACTIVATOR INHIBITOR-1; SMOOTH-MUSCLE-CELLS; DIABETIC-NEPHROPATHY; MAMMALIAN TARGET; HIGH GLUCOSE; CALCINEURIN INHIBITORS; MESENCHYMAL TRANSITION; RAPAMYCIN COMPLEXES; SIGNAL-TRANSDUCTION AB Enhanced TGF beta activity contributes to the accumulation of matrix proteins including collagen I (alpha 2) by proximal tubular epithelial cells in progressive kidney disease. Although TGF beta rapidly activates its canonical Smad signaling pathway, it also recruits noncanonical pathway involving mTOR kinase to regulate renal matrix expansion. The mechanism by which chronic TGF beta treatment maintains increased mTOR activity to induce the matrix protein collagen I (alpha 2) expression is not known. Deptor is an mTOR interacting protein that suppresses mTOR activity in both mTORC1 and mTORC2. In proximal tubular epithelial cells, TGF beta reduced deptor levels in a time-dependent manner with concomitant increase in both mTORC1 and mTORC2 activities. Expression of deptor abrogated activity of mTORC1 and mTORC2, resulting in inhibition of collagen I (alpha 2) mRNA and protein expression via transcriptional mechanism. In contrast, neutralization of endogenous deptor by shRNAs increased activity of both mTOR complexes and expression of collagen I (alpha 2) similar to TGF beta treatment. Importantly, downregulation of deptor by TGF beta increased the expression of Hif1 alpha by increasing translation of its mRNA. TGF beta-induced deptor downregulation promotes Hif1 alpha binding to its cognate hypoxia responsive element in the collagen I (alpha 2) gene to control its protein expression via direct transcriptional mechanism. Interestingly, knockdown of raptor to specifically block mTORC1 activity significantly inhibited expression of collagen I (alpha 2) and Hif1 alpha while inhibition of rictor to prevent selectively mTORC2 activation did not have any effect. Critically, our data provide evidence for the requirement of TGF beta-activated mTORC1 only by deptor downregulation, which dominates upon the bystander mTORC2 activity for enhanced expression of collagen I (alpha 2). Our results also suggest the presence of a safeguard mechanism involving deptor-mediated suppression of mTORC1 activity against developing TGF beta-induced renal fibrosis. C1 [Das, Falguni; Bera, Amit; Abboud, Hanna E.; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Ghosh-Choudhury, Nandini] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. [Ghosh-Choudhury, Nandini; Abboud, Hanna E.; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, VA Res, San Antonio, TX USA. RP Choudhury, GG (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. EM choudhuryg@uthscsa.edu FU National Institutes of Health [RO1 DK50190]; Veterans Administration Research Service Merit Review [5I01BX000926]; Veterans Administration Senior Research Career Scientist Award; National Institutes of Health; VA Merit Review grants FX This work was supported by National Institutes of Health RO1 DK50190 and Veterans Administration Research Service Merit Review 5I01BX000926 grants to GGC. GGC is a recipient of Veterans Administration Senior Research Career Scientist Award. HEA is supported by National Institutes of Health. NGC and BSK are supported by VA Merit Review grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 83 TC 4 Z9 4 U1 3 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 15 PY 2014 VL 9 IS 10 AR e109608 DI 10.1371/journal.pone.0109608 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AX2IH UT WOS:000346766200044 PM 25333702 ER PT J AU Liu, YY Nacher, JC Ochiai, T Martino, M Altshuler, Y AF Liu, Yang-Yu Nacher, Jose C. Ochiai, Tomoshiro Martino, Mauro Altshuler, Yaniv TI Prospect Theory for Online Financial Trading SO PLOS ONE LA English DT Article ID LOSS AVERSION; STOCK-MARKET; DISPOSITION; INVESTORS; BEHAVIOR; RISK; LONG AB Prospect theory is widely viewed as the best available descriptive model of how people evaluate risk in experimental settings. According to prospect theory, people are typically risk-averse with respect to gains and risk-seeking with respect to losses, known as the "reflection effect". People are much more sensitive to losses than to gains of the same magnitude, a phenomenon called "loss aversion". Despite of the fact that prospect theory has been well developed in behavioral economics at the theoretical level, there exist very few large-scale empirical studies and most of the previous studies have been undertaken with micro-panel data. Here we analyze over 28.5 million trades made by 81.3 thousand traders of an online financial trading community over 28 months, aiming to explore the large-scale empirical aspect of prospect theory. By analyzing and comparing the behavior of winning and losing trades and traders, we find clear evidence of the reflection effect and the loss aversion phenomenon, which are essential in prospect theory. This work hence demonstrates an unprecedented large-scale empirical evidence of prospect theory, which has immediate implication in financial trading, e.g., developing new trading strategies by minimizing the impact of the reflection effect and the loss aversion phenomenon. Moreover, we introduce three novel behavioral metrics to differentiate winning and losing traders based on their historical trading behavior. This offers us potential opportunities to augment online social trading where traders are allowed to watch and follow the trading activities of others, by predicting potential winners based on their historical trading behavior. C1 [Liu, Yang-Yu] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Liu, Yang-Yu] Harvard Univ, Sch Med, Boston, MA USA. [Liu, Yang-Yu] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Liu, Yang-Yu] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Liu, Yang-Yu] Northeastern Univ, Dept Comp Sci, Boston, MA 02115 USA. [Liu, Yang-Yu] Northeastern Univ, Dept Biol, Boston, MA 02115 USA. [Liu, Yang-Yu] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Nacher, Jose C.] Toho Univ, Fac Sci, Dept Informat Sci, Funabashi, Chiba 274, Japan. [Ochiai, Tomoshiro] Otsuma Womens Univ, Dept Social Informat Studies, Tama, Tokyo, Japan. [Martino, Mauro] IBM Corp, Ctr Innovat Visual Analyt, Watson Res Ctr, Cambridge, MA USA. [Altshuler, Yaniv] MIT, Media Lab, Cambridge, MA 02139 USA. RP Liu, YY (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA. EM yyl@channing.harvard.edu FU NS-CTA - US Army Research Laboratory [W911NF-09-2-0053]; DARPA [11645021]; DTRA [HDTRA1-10-1-0100/BRBAA08-Per4-C-2-0033] FX This work was partially supported by NS-CTA sponsored by US Army Research Laboratory under Agreement No. W911NF-09-2-0053; DARPA under Agreement No. 11645021; DTRA under Agreement No. HDTRA1-10-1-0100/BRBAA08-Per4-C-2-0033. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 0 Z9 0 U1 2 U2 22 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 OCT 15 PY 2014 VL 9 IS 10 AR e109458 DI 10.1371/journal.pone.0109458 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AX2IH UT WOS:000346766200031 PM 25330203 ER PT J AU Ruan, YC Wang, Y Da Silva, N Kim, B Diao, RY Hill, E Brown, D Chan, HC Breton, S AF Ruan, Ye Chun Wang, Yan Da Silva, Nicolas Kim, Bongki Diao, Rui Ying Hill, Eric Brown, Dennis Chan, Hsiao Chang Breton, Sylvie TI CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation through the ZONAB pathway SO JOURNAL OF CELL SCIENCE LA English DT Article DE CFTR; ZO-1; ZONAB; Embryonic development; Epithelial remodeling; Male fertility; Morphogenesis; Proliferation ID TRANSMEMBRANE CONDUCTANCE REGULATOR; MALE REPRODUCTIVE-TRACT; CONGENITAL BILATERAL ABSENCE; CYSTIC-FIBROSIS LUNG; VAS-DEFERENS; RAT EPIDIDYMIS; MALE-INFERTILITY; MALE-FERTILITY; PROTEIN ZO-1; V-ATPASE AB Mutations in CFTR lead to dysfunction of tubular organs, which is currently attributed to impairment of its conductive properties. We now show that CFTR regulates tight junction assembly and epithelial cell differentiation through modulation of the ZO-1-ZONAB pathway. CFTR colocalizes with ZO-1 at the tight junctions of trachea and epididymis, and is expressed before ZO-1 in Wolffian ducts. CFTR interacts with ZO-1 through the CTFR PDZ- binding domain. In a three-dimensional (3D) epithelial cell culture model, CFTR regulates tight junction assembly and is required for tubulogenesis. CFTR inhibition or knockdown reduces ZO-1 expression and induces the translocation of the transcription factor ZONAB (also known as YBX3) from tight junctions to the nucleus, followed by upregulation of the transcription of CCND1 and downregulation of ErbB2 transcription. The epididymal tubules of cftr(-/-) and cftr(Delta F508) mice have reduced ZO-1 levels, increased ZONAB nuclear expression, and decreased epithelial cell differentiation, illustrated by the reduced expression of apical AQP9 and V-ATPase. This study provides a new paradigm for the etiology of diseases associated with CFTR mutations, including cystic fibrosis. C1 [Ruan, Ye Chun; Da Silva, Nicolas; Kim, Bongki; Hill, Eric; Brown, Dennis; Breton, Sylvie] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol,Nephrol Div,Program Membrane Biol, Boston, MA 02114 USA. [Ruan, Ye Chun; Wang, Yan; Diao, Rui Ying; Chan, Hsiao Chang] Chinese Univ Hong Kong, Fac Med, Epithelial Cell Biol Res Ctr, Sch Biomed Sci, Hong Kong, Peoples R China. RP Breton, S (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol,Nephrol Div,Program Membrane Biol, Boston, MA 02114 USA. EM Breton.sylvie@mgh.harvard.edu RI Chan, Hsiao Chang/E-1507-2016 FU National Institutes of Health [HD040793, DK097124]; National 973 project [2012CV944903]; Lalor postdoctoral fellowship [2010-2012]; Boston Area Diabetes and Endocrinology Research Center [DK57521]; Center for the Study of Inflammatory Bowel Disease [DK43341] FX This work was supported by the National Institutes of Health [grant numbers HD040793 and DK097124 (to S.B.)]; and by the National 973 project [grant number 2012CV944903 to H.C.C.]. Y.C.R. was supported by a Lalor postdoctoral fellowship [grant number 2010-2012]. The Microscopy Core facility of the Massachusetts General Hospital (MGH) Program in Membrane Biology receives support from the Boston Area Diabetes and Endocrinology Research Center [grant number DK57521]; and the Center for the Study of Inflammatory Bowel Disease [grant number DK43341]. S.B. is a recipient of the Charles and Ann Sanders Research Scholar Award at MGH. Deposited in PMC for release after 12 months. NR 68 TC 13 Z9 13 U1 1 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD OCT 15 PY 2014 VL 127 IS 20 BP 4396 EP 4408 DI 10.1242/jcs.148098 PG 13 WC Cell Biology SC Cell Biology GA AT3QB UT WOS:000344847800007 PM 25107366 ER PT J AU Pikor, N Astarita, J Kay, R Turley, S Gommerman, J AF Pikor, Natalia Astarita, Jillian Kay, Robert Turley, Shannon Gommerman, Jennifer TI A Th17/Lymphotoxin axis enables cytokine production by brain meningeal stromal cells and propagates de novo CNS-intrinsic T cell responses during inflammation SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 12th International Congress of Neuroimmunology (ISNI) CY NOV 09-13, 2014 CL Mainz, GERMANY C1 [Pikor, Natalia; Kay, Robert; Gommerman, Jennifer] Univ Toronto, Dept Immunol, Toronto, ON, Canada. [Astarita, Jillian; Turley, Shannon] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Astarita, Jillian; Turley, Shannon] Genentech Inc, San Francisco, CA 94080 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 EI 1872-8421 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT 15 PY 2014 VL 275 IS 1-2 SI SI MA 480 BP 69 EP 69 DI 10.1016/j.jneuroim.2014.08.182 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA AT8OK UT WOS:000345192100174 ER PT J AU Souza, ALS Rudin, S Mitchell, K Chang, R Graham, D Huang, SN Choi, JK Yu, DZ Jenkins, B Mandeville, J Dai, GP Webb, M Tomkinson, B Dellovade, T AF Souza, Adriano L. S. Rudin, Stefan Mitchell, Keith Chang, Rui Graham, Danielle Huang, Shuning Choi, Ji-kyung Yu, Dongzi Jenkins, Bruce Mandeville, Joseph Dai, Guangping Webb, Mike Tomkinson, Blake Dellovade, Tammy TI Treatment with ATX-MS-1467 ameliorates pathological changes and inhibits cytokine production in mouse model of multiple sclerosis SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 12th International Congress of Neuroimmunology (ISNI) CY NOV 09-13, 2014 CL Mainz, GERMANY C1 [Souza, Adriano L. S.; Rudin, Stefan; Mitchell, Keith; Chang, Rui; Graham, Danielle; Huang, Shuning; Yu, Dongzi; Tomkinson, Blake; Dellovade, Tammy] EMD Serono Res & Dev Inst Inc, Translat & Biomarker Res Grp, Neurol ETIP, Billerica, MA USA. [Choi, Ji-kyung; Jenkins, Bruce; Mandeville, Joseph; Dai, Guangping] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Webb, Mike] EMD Serono Res & Dev Inst Inc, Neuroimmunol Grp, Neurol ETIP, Billerica, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 EI 1872-8421 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD OCT 15 PY 2014 VL 275 IS 1-2 SI SI MA 461 BP 226 EP 227 DI 10.1016/j.jneuroim.2014.08.607 PG 2 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA AT8OK UT WOS:000345192100596 ER PT J AU Villien, M Wey, HY Mandeville, JB Catana, C Polimeni, JR Sander, CY Zurcher, NR Chonde, DB Fowler, JS Rosen, BR Hooker, JM AF Villien, Marjorie Wey, Hsiao-Ying Mandeville, Joseph B. Catana, Ciprian Polimeni, Jonathan R. Sander, Christin Y. Zuercher, Nicole R. Chonde, Daniel B. Fowler, Joanna S. Rosen, Bruce R. Hooker, Jacob M. TI Dynamic functional imaging of brain glucose utilization using fPET-FDG SO NEUROIMAGE LA English DT Article DE 2-[F-18]-fluorodeoxyglucose (FDG); Glucose utilization; Visual stimulus; MR/PET; PET ID POSITRON-EMISSION-TOMOGRAPHY; HUMAN VISUAL-CORTEX; LUMPED CONSTANT; METABOLIC-RATE; F-18 FLUORODEOXYGLUCOSE; PHOTODYNAMIC THERAPY; SENSORY STIMULATION; PET; ACTIVATION; MODEL AB Glucose is the principal source of energy for the brain and yet the dynamic response of glucose utilization to changes in brain activity is still not fully understood. Positron emission tomography (PET) allows quantitative measurement of glucose metabolism using 2-[F-18]-fluorodeoxyglucose (FDG). However, FDG PET in its current form provides an integral (or average) of glucose consumption over tens of minutes and lacks the temporal information to capture physiological alterations associated with changes in brain activity induced by tasks or drug challenges. Traditionally, changes in glucose utilization are inferred by comparing two separate scans, which significantly limits the utility of the method. We report a novel method to track changes in FDG metabolism dynamically, with higher temporal resolution than exists to date and within a single session. Using a constant infusion of FDG, we demonstrate that our technique (termed fPET-FDG) can be used in an analysis pipeline similar to fMRI to define within-session differential metabolic responses. We use visual stimulation to demonstrate the feasibility of this method. This new method has a great potential to be used in research protocols and clinical settings since fPET-FDG imaging can be performed with most PET scanners and data acquisition and analysis are straightforward. fPET-FDG is a highly complementary technique to MRI and provides a rich new way to observe functional changes in brain metabolism. (C) 2014 Elsevier Inc. All rights reserved. C1 [Villien, Marjorie; Wey, Hsiao-Ying; Mandeville, Joseph B.; Catana, Ciprian; Polimeni, Jonathan R.; Sander, Christin Y.; Zuercher, Nicole R.; Chonde, Daniel B.; Rosen, Bruce R.; Hooker, Jacob M.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Sander, Christin Y.] Massachusetts Gen Hosp, Dept Elect Engn & Comp Sci, Charlestown, MA 02129 USA. [Fowler, Joanna S.; Hooker, Jacob M.] Brookhaven Natl Lab, Dept Biosci, Upton, NY 11973 USA. [Rosen, Bruce R.] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hooker, JM (reprint author), Bldg 149,Room 2301,13th St, Charlestown, MA 02129 USA. EM hooker@nmr.mgh.harvard.edu RI Polimeni, Jonathan/P-1395-2014 OI Polimeni, Jonathan/0000-0002-1348-1179 FU National Institutes of Health [P41EB015896, S10RR019933, R01EB014894]; Harvard/MGH Nuclear Medicine Training Program from the Department of Energy [DE-SC0008430] FX This work was performed at the Athinoula A. Martinos Center and was supported by grants from the National Institutes of Health (P41EB015896, S10RR019933, and R01EB014894). H.Y.W. is supported by the Harvard/MGH Nuclear Medicine Training Program from the Department of Energy (DE-SC0008430). The authors are grateful to Dr. David Izquierdo for providing PET data processing tools; Grae Arabasz and Shirley Hsu for assistance performing MR-PET imaging; and Dr. Louis Sokoloff for helpful correspondence. NR 35 TC 12 Z9 12 U1 2 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 15 PY 2014 VL 100 BP 192 EP 199 DI 10.1016/j.neuroimage.2014.06.025 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AS4HU UT WOS:000344235800016 PM 24936683 ER PT J AU Wang, H Zhu, JF Reuter, M Vinke, LN Yendiki, A Boas, DA Fischl, B Akkin, T AF Wang, Hui Zhu, Junfeng Reuter, Martin Vinke, Louis N. Yendiki, Anastasia Boas, David A. Fischl, Bruce Akkin, Taner TI Cross-validation of serial optical coherence scanning and diffusion tensor imaging: A study on neural fiber maps in human medulla oblongata SO NEUROIMAGE LA English DT Article DE Validation; Diffusion magnetic resonance imaging; Optical coherence tomography; Polarization; Fiber orientation; Anisotropy; Human brain; Connectome ID WHITE-MATTER; FUNCTIONAL CONNECTIVITY; HISTOLOGICAL VALIDATION; TRACTOGRAPHY; BRAIN; TOMOGRAPHY; TISSUE; MICROSCOPY; MRI; SCHIZOPHRENIA AB We established a strategy to perform cross-validation of serial optical coherence scanner imaging (SOCS) and diffusion tensor imaging (DTI) on a postmortem human medulla. Following DTI, the sample was serially scanned by SOCS, which integrates a vibratome slicer and a multi-contrast optical coherence tomography rig for large-scale three-dimensional imaging at microscopic resolution. The DTI dataset was registered to the SOCS space. An average correlation coefficient of 0.9 was found between the co-registered fiber maps constructed by fractional anisotropy and retardance contrasts. Pixelwise comparison of fiber orientations demonstrated good agreement between the DTI and SOCS measures. Details of the comparison were studied in regions exhibiting a variety of fiber organizations. DTI estimated the preferential orientation of small fiber tracts; however, it didn't capture their complex patterns as SOCS did. In terms of resolution and imaging depth, SOCS and DTI complement each other, and open new avenues for cross-modality investigations of the brain. (C) 2014 Elsevier Inc. All rights reserved. C1 [Wang, Hui; Akkin, Taner] Univ Minnesota, Dept Biomed Engn, Minneapolis, MN 55455 USA. [Zhu, Junfeng] Univ Minnesota, Dept Ind & Syst Engn, Minneapolis, MN 55455 USA. [Reuter, Martin; Vinke, Louis N.; Yendiki, Anastasia; Boas, David A.; Fischl, Bruce] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA 02129 USA. [Reuter, Martin; Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. RP Akkin, T (reprint author), 7-105 Hasselmo Hall,312 Church St SE, Minneapolis, MN 55455 USA. EM akkin@umn.edu RI Reuter, Martin/B-3456-2010 OI Reuter, Martin/0000-0002-2665-9693 FU Institute for Engineering in Medicine Seed Grant program; Doctoral Dissertation Fellowship at the University of Minnesota; US National Institute of Health (NIH): the National Institute for Biomedical Imaging and Bioengineering [5R01EB012538, 5P41EB015896-15, R01EB006758]; US National Institute of Health (NIH): the National Center for Research Resources [U24RR021382]; US National Institute of Health (NIH): the National Institute on Aging [AG022381, 5R01AG008122-22]; US National Institute of Health (NIH): the National Institute for Neurological Disorders and Stroke [R01NS052585-01, 1R21NS072652-01, 1R01NS070963]; Shared Instrumentation Grants [1S10RR023401, 1S10RR019307, 1S10RR023043]; NIH Blueprint for Neuroscience Research, multi-institutional Human Connectome Project [5U01MH093765] FX This work was supported in part by the Institute for Engineering in Medicine Seed Grant program and a Doctoral Dissertation Fellowship at the University of Minnesota, and research grants from the US National Institute of Health (NIH): the National Institute for Biomedical Imaging and Bioengineering (5R01EB012538, 5P41EB015896-15, R01EB006758), the National Center for Research Resources (U24RR021382), the National Institute on Aging (AG022381, 5R01AG008122-22), the National Institute for Neurological Disorders and Stroke (R01NS052585-01, 1R21NS072652-01, 1R01NS070963), and was made possible by the resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043. Additional support was provided by the NIH Blueprint for Neuroscience Research (5U01MH093765), part of the multi-institutional Human Connectome Project. In addition, BF has a financial interest in Corticometrics, a company whose medical pursuits focus on brain imaging and measurement technologies. BF's interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. NR 48 TC 10 Z9 10 U1 2 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 15 PY 2014 VL 100 BP 395 EP 404 DI 10.1016/j.neuroimage.2014.06.032 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AS4HU UT WOS:000344235800035 PM 24954840 ER PT J AU McLaren, DG Sperling, RA Atri, A AF McLaren, Donald G. Sperling, Reisa A. Atri, Alireza TI Flexible modulation of network connectivity related to cognition in Alzheimer's disease SO NEUROIMAGE LA English DT Article DE Functional MRI; Functional connectivity; gPPI; Episodic memory; Biomarker; Dementia ID INDEPENDENT COMPONENT ANALYSIS; BRAINS DEFAULT NETWORK; FUNCTIONAL CONNECTIVITY; RESTING-STATE; PSYCHOPHYSIOLOGICAL INTERACTIONS; WORKING-MEMORY; TEMPORAL-LOBE; HIPPOCAMPAL CONNECTIVITY; MODE NETWORK; FMRI AB Functional neuroimaging tools, such as fMRI methods, may elucidate the neural correlates of clinical, behavioral, and cognitive performance. Most functional imaging studies focus on regional task-related activity or resting state connectivity rather than how changes in functional connectivity across conditions and tasks are related to cognitive and behavioral performance. To investigate the promise of characterizing context-dependent connectivity-behavior relationships, this study applies the method of generalized psychophysiological interactions (gPPI) to assess the patterns of associative-memory-related fMRI hippocampal functional connectivity in Alzheimer's disease (AD) associated with performance on memory and other cognitively demanding neuropsychological tests and clinical measures. Twenty-four subjects with mild AD dementia (ages 54-82, nine females) participated in a face-name paired-associate encoding memory study. Generalized PPI analysis was used to estimate the connectivity between the hippocampus and the whole brain during encoding. The difference in hippocampal-whole brain connectivity between encoding novel and encoding repeated face-name pairs was used in multiple-regression analyses as an independent predictor for 10 behavioral, neuropsychological and clinical tests. The analysis revealed connectivity-behavior relationships that were distributed, dynamically overlapping, and task-specific within and across intrinsic networks; hippocampal-whole brain connectivity-behavior relationships were not isolated to single networks, but spanned multiple brain networks. Importantly, these spatially distributed performance patterns were unique for each measure. In general, out-of-network behavioral associations with encoding novel greater than repeated face-name pairs hippocampal-connectivity were observed in the default-mode network, while correlations with encoding repeated greater than novel face-name pairs hippocampal-connectivity were observed in the executive control network (p < 0.05, cluster corrected). Psychophysiological interactions revealed significantly more extensive and robust associations between paired-associate encoding task-dependent hippocampal-whole brain connectivity and performance on memory and behavioral/clinical measures than previously revealed by standard activity-behavior analysis. Compared to resting state and task-activation methods, gPPI analyses may be more sensitive to reveal additional complementary information regarding subtle within-and between-network relations. The patterns of robust correlations between hippocampal-whole brain connectivity and behavioral measures identified here suggest that there are 'coordinated states' in the brain; that the dynamic range of these states is related to behavior and cognition; and that these states can be observed and quantified, even in individuals with mild AD. (C) 2014 Elsevier Inc. All rights reserved. C1 [McLaren, Donald G.; Sperling, Reisa A.; Atri, Alireza] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McLaren, Donald G.; Sperling, Reisa A.; Atri, Alireza] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [McLaren, Donald G.; Atri, Alireza] ENRM VA Med Ctr, Geriatr Res Educ & Clin Ctr, Bedford, MA 01730 USA. [McLaren, Donald G.; Sperling, Reisa A.; Atri, Alireza] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Sperling, Reisa A.] Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, Boston, MA 02115 USA. RP McLaren, DG (reprint author), Dept Neurol, 15 Parkman St, Boston, MA 02114 USA. EM dmclaren2@partners.org; rsperling@rics.bwh.harvard.edu; atri@nmr.mgh.harvard.edu OI McLaren, Donald/0000-0002-0566-4610 FU National Institute on Aging (NIA) [K23 AG027171, F32 AG042228, RO1 AG027435, P01 AG036694]; Harvard-Massachusetts Institute of Technology Health Sciences & Technology Pfizer-Merck Clinical Investigator Training Program; National Institutes of Health (NIH); Forest Pharmaceuticals; Harvard Center for Neurodegeneration Repair; Clinical, Neuroimaging, and Statistics Cores of the Massachusetts AD Research Center (National Institute on Aging (NIA)) [P50 AG05134]; Geriatric Research, Education and Clinical Center (GRECC) at the Edith Nourse Rogers Memorial (ENRM) Veterans Administration Bedford Medical Center; Forest Research Institute FX The study was supported by: National Institute on Aging (NIA) grants: K23 AG027171 (Dr. Atri), F32 AG042228 (Dr. McLaren), RO1 AG027435 (Dr. Sperling), and P01 AG036694 (Dr. Sperling); The Harvard-Massachusetts Institute of Technology Health Sciences & Technology Pfizer-Merck Clinical Investigator Training Program (Dr. Atri); the National Institutes of Health (NIH) loan repayment program (Dr. Atri); Investigator-Initiated Research Grants from Forest Pharmaceuticals and The Harvard Center for Neurodegeneration & Repair; the Clinical, Neuroimaging, and Statistics Cores of the Massachusetts AD Research Center (National Institute on Aging (NIA) grant P50 AG05134 to Drs. Growdon and Hyman); and the Geriatric Research, Education and Clinical Center (GRECC) at the Edith Nourse Rogers Memorial (ENRM) Veterans Administration Bedford Medical Center. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs, the National Institutes of Health or the United States government. Less than 30% of the funds for data collectionwere froman Investigator-Initiated Research Grant from Forest Research Institute. NR 84 TC 7 Z9 9 U1 5 U2 26 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 OCT 15 PY 2014 VL 100 BP 544 EP 557 DI 10.1016/j.neuroimage.2014.05.032 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AS4HU UT WOS:000344235800049 PM 24852459 ER PT J AU Grabner, G Poser, BA Fujimoto, K Polimeni, JR Wald, LL Trattnig, S Toni, I Barth, M AF Grabner, Gunther Poser, Benedikt A. Fujimoto, Kyoko Polimeni, Jonathan R. Wald, Lawrence L. Trattnig, Siegfried Toni, Ivan Barth, Markus TI A study-specific fMRI normalization approach that operates directly on high resolution functional EPI data at 7 Tesla SO NEUROIMAGE LA English DT Article ID PRIMARY SOMATOSENSORY CORTEX; HUMAN CEREBRAL-CORTEX; HUMAN MOTOR CORTEX; HUMAN BRAIN; PROBABILISTIC ATLAS; FINGER SOMATOTOPY; BOLD ACTIVATION; IMAGE-ANALYSIS; OLDER-ADULTS; MRI AB Due to the availability of ultra-high field scanners and novel imaging methods, high resolution, whole brain functional MR imaging (fMRI) has become increasingly feasible. However, it is common to use extensive spatial smoothing to account for inter-subject anatomical variation when pooling over subjects. This reduces the spatial details of group level functional activation considerably, even when the original data was acquired with high resolution. In our study we used an accelerated 3D EPI sequence at 7 Tesla to acquire whole brain fMRI data with an isotropic spatial resolution of 1.1 mm which shows clear gray/white matter contrast due to the stronger T1 weighting of 3D EPI. To benefit from the high spatial resolution on the group level, we develop a study specific, high resolution anatomical template which is facilitated by the good anatomical contrast that is present in the average functional EPI images. Different template generations with increasing accuracy were created by using a hierarchical linear and stepwise non-linear registration approach. As the template is based on the functional data themselves no additional co-registration step with the usual T1-weighted anatomical data is necessary which eliminates a potential source of misalignment. To test the improvement of functional localization and spatial details we performed a group level analysis of a finger tapping experiment in eight subjects. The most accurate template shows better spatial localization - such as a separation of somatosensory and motor areas and of single digit activation - compared to the simple linear registration. The number of activated voxels is increased by a factor of 1.2, 2.5, and 3.1 for somatosensory, supplementary motor area, and dentate nucleus, respectively, for the functional contrast between left versus right hand. Similarly, the number of activated voxels is increased 1.4- and 2.4-fold for right little versus right index finger and left little versus left index finger, respectively. The Euclidian distance between the activation (center of gravity) of the respective fingers was found to be 13.90 mm using the most accurate template. (C) 2014 Elsevier Inc. All rights reserved. C1 [Grabner, Gunther; Poser, Benedikt A.; Toni, Ivan; Barth, Markus] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Ctr Cognit Neuroimaging, NL-6525 ED Nijmegen, Netherlands. [Poser, Benedikt A.; Barth, Markus] Univ Duisburg Essen, Erwin L Hahn Inst Magnet Resonance Imaging, Essen, Germany. [Fujimoto, Kyoko; Polimeni, Jonathan R.; Wald, Lawrence L.] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr, Charlestown, MA USA. [Polimeni, Jonathan R.; Wald, Lawrence L.] Harvard MIT Div Hlth Sci Technol, Cambridge, MA USA. [Grabner, Gunther; Trattnig, Siegfried] Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, MR Ctr Excellence, Vienna, Austria. [Barth, Markus] Univ Queensland, Ctr Adv Imaging, St Lucia, Qld 4072, Australia. [Poser, Benedikt A.] Maastricht Univ, Fac Psychol & Neurosci, Dept Cognit Neurosci, Maastricht Brain Imaging Ctr, Maastricht, Netherlands. RP Barth, M (reprint author), Univ Queensland, Ctr Adv Imaging, 57 Res Rd, St Lucia, Qld 4072, Australia. EM m.barth@uq.edu.au RI Polimeni, Jonathan/P-1395-2014; Toni, Ivan/D-1980-2009; Barth, Markus/B-8446-2008; Poser, Benedikt A/F-4992-2010; Wald, Lawrence/D-4151-2009; OI Polimeni, Jonathan/0000-0002-1348-1179; Toni, Ivan/0000-0003-0936-3601; Barth, Markus/0000-0002-0520-1843; Poser, Benedikt A/0000-0001-8190-4367; Fujimoto, Kyoko/0000-0002-0087-1397 FU NIH [P41EB015896]; NIH-NIBIB [K01-EB011498] FX L.L.W. acknowledges support from NIH, grant number: P41EB015896. J.R.P. acknowledges support from NIH-NIBIB, grant number: K01-EB011498. NR 48 TC 3 Z9 3 U1 1 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD OCT 15 PY 2014 VL 100 BP 710 EP 714 DI 10.1016/j.neuroimage.2014.06.045 PG 5 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AS4HU UT WOS:000344235800065 PM 24973602 ER PT J AU Jackson, JW VanderWeele, TJ Viswanathan, A Blacker, D Schneeweiss, S AF Jackson, John W. VanderWeele, Tyler J. Viswanathan, Anand Blacker, Deborah Schneeweiss, Sebastian TI The Explanatory Role of Stroke as a Mediator of the Mortality Risk Difference Between Older Adults Who Initiate First-Versus Second-Generation Antipsychotic Drugs SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE aged; antipsychotic drugs; cerebrovascular disease; death; mediation analysis; mortality risk; pharmacoepidemiology; stroke ID CEREBROVASCULAR EVENTS; ATYPICAL ANTIPSYCHOTICS; RETROSPECTIVE COHORT; ELDERLY-PATIENTS; DEMENTIA TRIALS; DEATH; MEDICATIONS; METAANALYSIS; ASSOCIATION; RESIDENTS AB Antipsychotic drugs are used to treat dementia-related symptoms in older adults, and observational studies show higher risks of death and stroke associated with the use of first-generation antipsychotic drugs (FGAs) compared with second-generation antipsychotic drugs (SGAs). However, the extent to which stroke explains the differential mortality risk between FGA use and SGA use in older adults is unclear. We followed those who initiated use of antipsychotic drugs (9,777 FGA users and 21,164 SGA users) aged 65 years or older, and who were enrolled in Medicare and either the New Jersey or Pennsylvania pharmacy assistance program during 1994 to 2005, over 180 days for the outcomes of stroke and death. We estimated direct and indirect effects by comparing 180-day mortality risks associated with the use of FGAs versus SGAs as mediated by stroke on the risk ratio scale, as well as the proportion mediated on the risk difference scale. FGA use was associated with marginally higher risks of stroke (risk ratio = 1.24, 95% confidence interval (CI): 1.01, 1.53) and death (risk ratio = 1.15, 95% CI: 1.08, 1.22) compared with SGA use, but stroke explained little (2.7%) of the observed difference in mortality risk. The indirect effect was null (risk ratio = 1.004, 95% CI: 1.000, 1.008), and the direct effect was equal to the total effect of antipsychotic drug type (FGA vs. SGA) on mortality risk (risk ratio = 1.15, 95% CI: 1.08, 1.22). These results suggest that the difference in mortality risk between users of FGAs and SGAs may develop mostly through pathways that do not involve stroke. C1 [Jackson, John W.; Schneeweiss, Sebastian] Brigham & Womens Hosp, Div Pharmacoepidemiol, Boston, MA 02115 USA. [Jackson, John W.; VanderWeele, Tyler J.; Blacker, Deborah; Schneeweiss, Sebastian] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Jackson, John W.; Schneeweiss, Sebastian] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol, Boston, MA 02115 USA. [Jackson, John W.; Blacker, Deborah; Schneeweiss, Sebastian] Harvard Univ, Sch Med, Boston, MA 02115 USA. [VanderWeele, Tyler J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Viswanathan, Anand] Massachusetts Gen Hosp, Dept Neurol, Partners TeleStroke Program, Boston, MA 02114 USA. [Blacker, Deborah] Massachusetts Gen Hosp, Dept Psychiat, Gerontol Res Unit, Boston, MA 02114 USA. [Jackson, John W.] Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. RP Jackson, JW (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM john.jackson@mail.harvard.edu RI Schneeweiss, Sebastian/C-2125-2013 FU National Institute of Mental Health [T32MH017119]; Horace W. Goldsmith Fellowship at Harvard University; National Institutes of Health [R01 ES 017876]; Alzheimer's Association FX J.W.J. was supported by the National Institute of Mental Health (grant T32MH017119) and the Horace W. Goldsmith Fellowship at Harvard University; T.J.V. was supported by the National Institutes of Health (grant R01 ES 017876); D.B. was supported by a grant from the Alzheimer's Association. NR 36 TC 5 Z9 5 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2014 VL 180 IS 8 BP 847 EP 852 DI 10.1093/aje/kwu210 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AR7KX UT WOS:000343759500011 PM 25234432 ER PT J AU Nakayama, S Sng, N Carretero, J Welner, R Hayashi, Y Yamamoto, M Tan, AJ Yamaguchi, N Yasuda, H Li, DN Soejima, K Soo, RA Costa, DB Wong, KK Kobayashi, SS AF Nakayama, Sohei Sng, Natasha Carretero, Julian Welner, Robert Hayashi, Yuichiro Yamamoto, Mihoko Tan, Alistair J. Yamaguchi, Norihiro Yasuda, Hiroyuki Li, Danan Soejima, Kenzo Soo, Ross A. Costa, Daniel B. Wong, Kwok-Kin Kobayashi, Susumu S. TI beta-Catenin Contributes to Lung Tumor Development Induced by EGFR Mutations SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; WNT SIGNALING PATHWAY; TYROSINE PHOSPHORYLATION; EPITHELIAL-CELLS; GENE-EXPRESSION; BREAST-CANCER; CYCLIN D1; DIFFERENTIATION; ADENOCARCINOMA; TUMORIGENESIS AB The discovery of somatic mutations in EGFR and development of EGFR tyrosine kinase inhibitors (TKI) have revolutionized treatment for lung cancer. However, resistance to TKIs emerges in almost all patients and currently no effective treatment is available. Here, we show that beta-catenin is essential for development of EGFR-mutated lung cancers. beta-Catenin was upregulated and activated in EGFR-mutated cells. Mutant EGFR preferentially bound to and tyrosine phosphorylated beta-catenin, leading to an increase in beta-catenin-mediated transactivation, particularly in cells harboring the gefitinib/erlotinib-resistant gatekeeper EGFR-T790M mutation. Pharmacologic inhibition of beta-catenin suppressed EGFR-L858R-T790M mutated lung tumor growth, and genetic deletion of the beta-catenin gene dramatically reduced lung tumor formation in EGFR-L858R-T790M transgenic mice. These data suggest that beta-catenin plays an essential role in lung tumorigenesis and that targeting the beta-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs. (C) 2014 AACR. C1 [Nakayama, Sohei; Sng, Natasha; Welner, Robert; Yamamoto, Mihoko; Tan, Alistair J.; Yamaguchi, Norihiro; Yasuda, Hiroyuki; Costa, Daniel B.; Kobayashi, Susumu S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA USA. [Carretero, Julian] Univ Valencia, Dept Physiol, E-46100 Burjassot, Spain. [Hayashi, Yuichiro] Keio Univ, Sch Med, Dept Pathol, Shinjuku Ku, Tokyo 160, Japan. [Yasuda, Hiroyuki; Soejima, Kenzo] Keio Univ, Sch Med, Dept Pulm Med, Shinjuku Ku, Tokyo, Japan. [Li, Danan; Wong, Kwok-Kin] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Soo, Ross A.] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore. [Soo, Ross A.] Natl Univ Hlth Syst, Dept Haematol Oncol, Singapore, Singapore. [Kobayashi, Susumu S.] Harvard Stem Cell Inst, Cambridge, MA USA. RP Kobayashi, SS (reprint author), Beth Israel Deaconess Med Ctr, Div Hematol Oncol, E CLS-407 330 Brookline Ave, Boston, MA 02215 USA. EM skobayas@bidmc.harvard.edu RI Carretero, Julian/N-5214-2014; OI Carretero, Julian/0000-0001-7269-8506; Costa, Daniel/0000-0002-0689-395X FU NIH [R00CA126026, R01CA169259, P50CA090578, R01CA122794, CA140594, CA163896, CA166480, CA154303, CA120964]; Lung Cancer Foundation of America-International Association to Study Lung Cancer grant; American Cancer Society grant [RSG 11-186]; Bonnie J. Addario Lung Cancer Foundation grant; Singapore National Research Foundation; Ministry of Education under the Research Center of Excellence Programme FX This work was supported by NIH grants (R00CA126026 and R01CA169259 to S.S. Kobayashi, P50CA090578 to D.B. Costa and K.-K. Wong, and R01CA122794, CA140594, CA163896, CA166480, CA154303, and CA120964 to K.-K. Wong), a Lung Cancer Foundation of America-International Association to Study Lung Cancer grant (D.B. Costa), an American Cancer Society grant RSG 11-186 (D.B. Costa), Bonnie J. Addario Lung Cancer Foundation grant (S. Nakayama), and the Singapore National Research Foundation and the Ministry of Education under the Research Center of Excellence Programme (R.A. Soo). NR 50 TC 12 Z9 12 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2014 VL 74 IS 20 BP 5891 EP 5902 DI 10.1158/0008-5472.CAN-14-0184 PG 12 WC Oncology SC Oncology GA AR9CK UT WOS:000343868800019 PM 25164010 ER EF